Note: Descriptions are shown in the official language in which they were submitted.
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- TITLE
ARYLOXY- AND ARYLTHIO- FUSED PYRIDINES AND
S PYRIMIDINES AND DERIVATIVES
FI~T~n OF T~ INV~TTON
This invention relates to novel compounds and
pharmaceutical compositions, and to methods of using
same in the treatment of psychiatric disorders and
neurological diseases including major depression,
anxiety-related disorders, post-traumatic stress
disorder, supranuclear palsy and feeding disorders.
BACKGROUND OF T~ INV~TION
Corticotropin releasing factor (herein referred
to as CRF), a 41 amino acid peptide, is the primary
physiological regulator of proopiomelanocortin(POMC)
-derived peptide secretion from the anterior
pituitary gland [J. Rivier et al., Proc. Nat. Acad.
Sci. (USA) 80:4851 (1983); W. Vale et al., Science
213:1394 (1981)]. In addition to its endocrine role
at the pituitary gland, i~munohistochemical
localization of CRF has demonstrated that the hormone
has a broad extrahypothalamic distribution in the
central nervous system and produces a wide spectrum
of autonomic, electrophysiological and behavioral
effects consistent with a neurotransmitter or
neuromodulator role in brain [W. Vale et al., Rec.
Prog. Horm. Res. 39:245 (1983); G.F. Koob, Persp.
Behav. Med. 2:39 (1985); E.B. De Souza et al., J.
~eurosci. 5:3189 (1985)]. There is also evidence
that CRF plays a significant role in integrating the
response of the immune system to physiological,
psychological, and immunological stressors [J.E.
Blaloc~, Physi ol ogi cal Revi ews 6 9: 1 ( 19 89); J.E.
Morley, Life Sci. 41:527 (1987)].
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Clinical data provide evidence that CRF has a
role in psychiatr-ic disorders and neurological
diseases including depression, anxiety-related
disorders and feeding disorders. A role for CRF has
also been postulated in the etiology and
pathophysiology of Alzheimer's disease, Parkinson's
disease, Huntington's disease, progressive
supranuclear palsy and amyotrophic lateral sclerosis
as they relate to the dysfunction of CRF neurons in
the central nervous system [for review see E.B. De
Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the
concentration of CRF is slgnificantly increased in
the cerebral spinal fluid (CSF) of drug-free
individuals [C.B. Nemeroff et al., Science 226:1342
(1984); C.M. Banki et al., Am. J. Psychiatry 144:873
(1987); R.D. France et al., Biol. Psychiatry 28:86
(1988); M. Arato et al., Biol Psychiatry 25:355
(1989)]. Furthermore, the density of CRF receptors
is significantly decreased in the frontal cortex of
suicide victims, consistent with a hypersecretion of
CRF [C.B. Nemeroff et al., Arch. Gen. Psychiatry
45:577 (1988)]. In addition, there is a blunted
adrenocorticotropin (ACTH) response to CRF (i.v.
administered) observed in depressed patients [P.W.
Gold et al., Am J. Psychiatry 141:619 (1984~; F.
Holsboer et al., Psychoneuroendocrinology 9:147
(1984); P.W. Gold et al., New Eng. J. Med. 314:1129
(1986)]. Preclinical studies in rats and non-human
primates provide additional support for the
hypothesis that hypersecretion of CRF may be involved
in the symptoms seen in human depression [R.M.
Sapolsky, Arch. Gen . Psychiatry 46:1047 (1989)].
There is prell ml n~ry evidence that tricyclic
antidepressants can alter CRF levels and thus
modulate the numbers of CRF receptors in brain
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[Grigoriadis et al., Neuropsychopharmacolo~y 2:53
(1989)].
There has also been a role postulated for CRF in
the etiology of anxiety-related disorders. CRF
~ 5 produces anxiogenic e~fects in ~ni m~l S and
interactions between benzodiazepine / non-
benzodiazepine anxiolytics and CRF have been
demonstrated in a variety of behavioral anxiety
models [D.R. Britton et al., Life Sci. 31:363 (1982);
C.W. Berridge and A.J. Dunn Regul. Peptides 16:83
(1986)]. Preliminary studies using the putative CRF
receptor antagonist a-helical ovine CRF (9-41) in a
variety of behavioral paradigms demonstrate that the
antagonist produces Uanxiolytic-like'' effects that
are qualitatively similar to the benzodiazepines
[C.W. Berridge and A.J. Dunn ~orm. Behav. 21:393
(1987), Brain Research Reviews 15:71 (1990)].
Neurochemical, endocrine and receptor binding studies
have all demonstrated interactions between CRF and
benzodiazepine anxiolytics providing further evidence
for the involvement of CRF in these disorders.
Chlordiazepoxide attenuates the "anxiogenicn effects
of CRF in both the conflict test [K.T. Britton et
al., Psychopharmacology 86:170 (1985); K.T. Britton
et al., Psychopharmacology 94:306 (1988)] and in the
acoustic startle test [N.R. Swerdlow et al.,
Psychopharmacology 88:147 (1986)] in rats. The
benzodiazepine receptor antagonist (Rol5-1788), which
was without behavioral activity alone in the operant
conflict test, reversed the effects of CRF in a dose-
dependent manner while the benzodiazepine inverse
agonist (FG7142) enhanced the actions of CRF [K.T.
Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which
the standard anxiolytics and antidepressants produce
their therapeutic effects remain to be elucidated.
It has been hypothesized however, that they are
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W097/3~46 PCT~S97/0~28
involved in the suppression of the CRF hypersecretion
that is observed_in these disorders. Of particular
interest is that prel; mi n~ry studies e~m- nl ng the
effects of a CRF receptor antagonist (a- helical
CRFg-41) in a variety of behavioral paradigms have
demonstrated that the CRF antagonist produces
~'anxiolytic-like~ effects qualitatively similar to
the benzodiazepines [for review see G.F. Koob and
K.T. Britton, In: Corticotropin-Releasing Factor:
0 Basic and Clinical Studies of a Neuropeptide, E.B. De
Souza and C.B. Nemeroff eds., CRC Press p221 (1990)].
DuPont Merck PCT application US94/11050
describes corticotropin releasing factor antagonist
compounds of the formula:
~5
R1 V17,
J/~X
Il I
M~
and their use to treat psychiatric disorders and
neurological diseases. Included in the description are
fused pyridines and pyrimidines of the formula:
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Fl~3 F 1
R3/~N~<-
X A~D X
M ~
where: Z is CR2 or N; A is CR30 or N; D is CR28 or N;
and R3 can be aryloxy or arylthio.
Pfizer W0 95/33750 describes corticotropin
S releasing factor antagonist compounds useful in the
treatment of CNS and stress disorders. The description
includes compounds of the formulae:
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B R3
R5 R4- ~
Rl,
F~6 R
J
~ 3 ~ ~ ~ ~ Rs
where A is CR7 or N; B is OCHRlR2 or SCHRlR2; Rl iS
substituted or unsubstituted alkyl; R2 is substituted
or unsubstituted alkyl, aryl or heteroaryl; R3 is
methyl, halo, cyano, methoxy, etc.; R4 iS H ,
substituted or unsubstituted alkyl, halo, amino, nitro,
etc.; Rs is substituted or unsubstituted aryl or
heteroaryl; R6 is H or substituted or unsubstituted
alkyl; R7 is H, methyl, halo, cyano, etc.; R16 and R17
taken together form an oxo (=O) group; and G is =O, =S,
=NH, =NCH3, hydrogen, methyl, methoxy, etc.
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Pfizer WO 95/34563 describes corticotropin
releasing factor antagonist compounds, including
compounds of the formula:
B R3
R7~ R,~,
R!; A
S R4
where A, B and the R groups have definitions similar to
those in WO 95/33750.
Pfizer WO 95/33727 describes corticotropin
lO releasing factor antagonist compounds of the formula:
z_~ ~ X1 R3
R, N/N
where A is CH2 and Z can be a heteroaryl moiety.
15Ganguly et al., U.S. Patent 4,076,711
describes triazolo[4,5-d]pyrimidines of the formula:
X Q
~ Q~ X~N--Y
N = N
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where X is halo, -NRlR or alkoxy, with Rl and R each
being H or alkyl;- Y is alkyl, cycloalkyl,
hydroxycycloalkyl, phenyl, bicycloalkyl or phenylalkyl
or bicycloalkylalkyli and Q is H or Y. The patent
states that the compounds are useful in the treatment of
psoriasis.
Tanji et al., Chem. Pharm. Bull. 39(11)3037-
3040(1991), describes triazolo[4,5-d]pyrimidines of the
formula:
~Me halo
/~3 / Ph~ ~X~
Ph Me N --N
where halo is I, Br or Cl, Ph is phenyl and Me is
methyl. No utility for the compounds is described.
Settimo et al., Il Farmaco, Ed. Sc., 35 (4),
308-323 (1980) describes 8-azaadenines (triazolo[4,5-d]
pyrimidines) of the formula:
~N~
I~ /~ N
R1
where Rl is H or benzyl and R2 is p-methylphenyl.
Biagi et al., Il Farmaco, 49 (3), 183-186
(1994), describes N(6)-substituted 2-n-butyl-9-benzyl-8-
azaadenines of the formula:
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N C4Hg
H9C41N~ N~\/
where R2 can be alkyl, phenyl, or benzyl. The paper
states that the compounds have affinity for adenosine
receptors.
Thompson et al., J. Med. Chem., 1991, 34, 2877-
2882, describes N6,9-disubstituted adenines of the
formula:
Ph~ ~H H or Cl
H or Cl/~ Ph_N~,N--CH3
where Ph is phenyl or (when C-2 is unsubstituted~ 2-
fluorophenyl. The paper states that the compounds have
lS selective affinity for the Al adenosine receptor.
Kelley et al., J. Med. Chem. 1990, 31, 606-612,
describes the compound
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- - ~7N Nl~ N
~N~ I R /~N R9
R9 N
where R6 is NHc6Hs and R9 is CH2c6Hs~ and reports that
the compound was inactive when tested for anticonvulsant
S activity. The paper reports that various 6-
(alkylamino)-9-benzyl-9H-purine analogs of the above
compound exhibited anticonvulsant activity.
Kelley et al., J. Med. Chem. 1990, 33, 1360-1363,
describes 6-anilino-9-benzyl-2-choro-9H-purines of the
formula:
R4 Cl
~J~ N~ R4 ,~
Cl~
where Bz is benzyl or (when R4 is H) p-methylbenzyl and
R4 is H or alkyl, alkoxy, halo, cyano, nitro, etc.
Tests of the compounds for antirhinoviral activity are
reported.
Kelley et al., J. Heterocyclic Chem., 28, 1099
(1991), describes 6-substituted-9-(3-formamidobenzyl)-
9H-purines of the formula:
-10--
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NHC6H5
~3~9~ C6H5HN~NCH2C5H~ R
CH2C6H4-o-R1 N
where Rl is NH2 or NHCH0. The compound where Rl is
NHCH0 was tested for benzodiazepine receptor binding and
was inactive, although various analogs were active.
Khairy et al., J. Heterocyclic Chem., 22, 853
(1985), describes synthesis of certain 9-aryl-9H-purin-
6-amines of the formula:
HN~ ~
N~N R5 R4 Rl N J~J\NH
0 H CH3 CH3
where the R groups are H, methyl, ethyl, isopropyl,
chloro or fluoro.
Hoechst EP 298467 (1989~ describes azapurine
derivatives, including compounds of the structure:
R3
NH2
~Q ~NJ OR 2
N--N
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where Q is O, S, SO, SO2 or NH2; X is O, S, SO or SO2; Z
is H, halogen, CF3, 1-3C alkoxy or alkylthio; R2 is
alkyl or alkoxy; R3 is oR2- These compounds are claimed
to be useful for treating virus diseases, autoimmune
diseases and cancers.
SS Pharmaceutical Co. Jp 59062595 (1984) and Jp
56131587 (1981) describe triazolopyrimidine derivatives,
including compounds of the structure:
where Q is O, S, SO2; R is amino or substituted amino,
alkoxy, benzyloxy, halogen, or phenylhydrazino. These
compounds are claimed to be useful as anticancer agents.
~N
N - N
Fuji Jp 60194443 (1985) describe aza-indenes,
including compounds of the structure:
QQ ~ N ~ R
N ~ R3
where Q is O, S; R1, R2 and R3 are H, alkyl, aryl,
aralkyl, amino, hydroxyl, alkoxy, carbamoyl, aryloxy,
alkoxy carbonyl, cyano, halogen, alkylthio, arylthio,
carboxyl, or mercapto, provided that at least one of the
substituents is mercapto. These compounds are claimed to
be useful as light-sensitizing agents, providing high
photographic speed and contrast to silver halide
emulsions.
-12-
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SU~ARY OF THE INVENrION
This invention is a class of novel compounds
~ 5 which are CRF receptor antagonists and which can be
represented by formula I or formula II:
l\~X I~X
- ~U ~ Q ~ z Ar ~ Q ~ z
~J-~y/
R13 G
II
or a pharmaceutically acceptable salt or pro-drug
form thereof, wherein:
X is N or CRl;
Y is N or CR2;
Z is NR3, O, or S(O)ni
G is O or S;
Q is O or S(O)n
Ar is phenyl, naphthyl, pyridyl, pyrimidinyl,
triazinyl, furanyl, quinolinyl, isoquinolinyl,
thienyl, imidazolyl, thiazolyl, indolyl,
pyrrolyl, oxazolyl, benzofuranyl, benzothienyl,
benzthiazolyl, isoxazolyl or pyrazolyl, each
optionally substituted with 1 to 4 R5 groups;
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Rl is independently at each occurrence H, Cl-
C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo,
CN, Cl-C4 haloalkyl, -NR9R10, NR9coR10, _oRll
SH or -S(O)nR12;
R2 is H, Cl-C4 alkyl, Cl-C6 cycloalkyl, halo, CN,
-NR6R7, NR9CoR10, Cl-C4 haloalkyl, -oR7, SH or
-S (O)nR12;
R3 is H, Cl-Clo alkyl, C2-Clo alkenyl, C2-
Clo alkynyl, C3-Cg cycloalkyl or C4-
C12 cycloalkylalkyl each optionally substituted
with 1 to 3 substituents independently selected
at each occurrence from Cl-C6 alkyl,
C3-C6 cycloalkyl, halo, Cl-C4 haloalkyl, cyano,
-oR7, SH, -S(o)nRl3~ -CoR7, -Co2R7~ -oC(o)Rl3,
-NR8CoR7, -N(CoR7)2, -NR8CoNR6R7, -NR8Co2Rl3
-NR6R7, -CoNR6R7, aryl, heteroaryl and
heterocyclyl, where the aryl, heteroaryl or
heterocyclyl is optionally substituted with 1 to
3 substituents independently selected at each
occurrence from Cl-C6 alkyl, C3-C6 cycloalkyl,
halo, Cl-C4 haloalkyl, cyano, -oR7, SH,
-S(o)nRl3~ -CoR7, -Co2R7, -oC(o)Rl3, -NR8CoR7,
-N(CoR7)2, -NR8CoNR6R7, -NR3Co2Rl3~ -NR6R7, and
-CoNR6R7;
R5 is independently at each occurrence Cl-Clo alkyl,
C2-Clo alkenyl, C2-Clo alkynyl, C3-C6
cycloalkyl, C4-C12 cycloalkylalkyl, -NO2, halo,
-CN, Cl-C4 haloalkyl, -NR6R7, NR8CoR7, NR8Co2R7,
-CoR7 -oR7, -CoNR6R7, -Co(NoR9)R7, C02R7, or
-S(o)nR7~ where Cl-Clo alkyl, C2-Clo alkenyl,
C2-Clo alkynyl, C3-C6 cycloalkyl and C4-
C12 ~ycloalkylalkyl are optionally substituted
with 1 to 3 substituents independently selected
-14-
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W097/35~6 PCT~S97/04828
at each occurrence from Cl-C4 alkyl, -NO2, halo,
-CN, -NR6R7~_-NR6R7~ NR8CoR7, NR8C02R7, -CoR7
-oR7, -CoNR6R7, Co2R7/ -Co(NoR9)R7, or -S(o)nR7;
- 5 R6 and R7 are independently at each occurrence H,
Cl-C4 alkyl, Cl-C4 haloalkyl, C2-Cg alkoxyalkyl,
C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl,
aryl(Cl-C4 alkyl)-, heteroaryl or
heteroaryl(Cl-C4 alkyl)-; or NR6R7 is
piperidine, pyrrolidine, piperazine, N-
methylpiperazine, morpholine or thiomorpholine;
R8 is independently at each occurrence H or Cl-C4
alkyl;
R9 and R10 are independently at each occurrence
selected from H, Cl-C4 alkyl, or C3-C6
cycloalkyl;
Rll is H, Cl-C4 alkyl, Cl-C4 haloalkyl, or
C3-C6 cycloalkyl;
R12 is Cl-C4 alkyl or Cl-C4 haloalkyl;
R13 is Cl-C4 alkyl, Cl-C4 haloalkyl, C2-Cg
alkoxyalkyl, C3-C6 cycloalkyl, C4-
C12 cycloalkylalkyl, aryl, aryl(Cl-C4 alkyl)-,
heteroaryl or heteroaryl(Cl-C4 alkyl)-;
aryl is phenyl or naphthyl, each optionally
substituted with 1 to 3 substituents
independently selected at each occurrence from
Cl-C6 alkyl, C3-C6 cycloalkyl, halo, Cl-
C4 haloalkyl, cyano, -oR7, SH, ~S(o)nRl3~ -CoR7,
-Co2R7, -oC(o)Rl3, -NR8CoR7, -N(CoR7)2,
-NR8CoNR6R7, -NR8Co2Rl3~ -NR6R7, and -CoNR6R7;
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heteroaryl is pyridyl, pyrimidinyl, triazinyl,
furanyl, quinolinyl, isoquinolinyl, thienyl,
imidazolyl, thiazolyl, indolyl, pyrrolyl,
oxazolyl, benzofuranyl, benzothienyl,
benzthiazolyl, isoxazolyl or pyrazolyl
optionally substituted with 1 to 3 substituents
independently selected at each occurrence from
Cl-C6 alkyl, C3-C6 cycloalkyl, halo, Cl-
C4 haloalkyl, cyano, -oR7, SH, -S(o)nRl3~ -CoR7,
-C02R7, -oc(o)Rl3, -NR8CoR7, -N(CoR7)2,
-NR8CoNR6R7, -NR8Co2Rl3~ -NR6R7, and -CoNR6R7;
heterocyclyl is saturated or partially saturated
heteroaryl, optionally substituted with 1 to 3
substituents independently selected at each
occurrence from Cl-C6 alkyl, C3-C6 cycloalkyl,
halo, Cl-C4 haloalkyl, cyano, -oR7, SH,
~S (O) nR13 ~ -CoR7, -Co2R7, -OC (O) R13, -NR8CoR7,
-N(CoR7)2, -NR8CoNR6R7, -NR8Co2Rl3~ -NR6R7, and
-coNR6R7i
n is independently at each occurrence 0, 1 or 2;
provided that in formula I, when X and Z are each N and
Y is CR2, then Rl and R2 cannot be mercapto groups.
Included in this invention is the method of
treating affective disorder, anxiety, depression,
irritable bowel syndrome, post-traumatic stress
disorder, supranuclear palsy, immune suppression,
Alzheimer's disease, gastrointestinal disease,
anorexia nervosa or other feeding disorder, drug or
alcohol withdrawal symptoms, drug addiction,
inflammatory disorder, or fertility problem in a
35 m~mm~ 1 comprising administering to the m~mm~ 1 a
therapeutically effective amount of a compound of
formula I or II.
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Also included in this invention are
pharmaceutical compositions comprising a
pharmaceutically acceptable carrier and a
S therapeutically effective amount of any one of the
above-described compounds.
The compounds provided by this invention (and
especially labelled compounds of this invention) are
also useful as standards and reagents in determining
the ability of a potential pharmaceutical to bind to
the CRF receptor.
D~TATT,F~n D~.~CRTPTION OF INVF~l'ITTON
Many compounds of this invention have one or more
asymmetric centers or planes. Unless otherwise
indicated, all chiral (enantiomeric and diastereomeric)
and racemic forms are included in the present invention.
Many geometric isomers of olefins, C=N double bonds, and
the like can also be present in the compounds, and all
such stable isomers are contemplated in the present
invention. The compounds may be isolated in optically
active or racemic forms. It is well known in the art
how to prepare optically active forms, such as by
resolution of racemic forms or by synthesis from
optically active starting materials. All chiral,
(enantiomeric and diastereomeric) and racemic forms and
all geometric isomeric forms of a structure are
intended, unless the specific stereochemistry or isomer
form is specifically indicated.
The term "alkyl~ includes both branched and
straight-chain alkyl having the specified number of
carbon atoms. ~Alkenyl" includes hydrocarbon chains
of either a straight or branched configuration and
one or more unsaturated carbon-carbon bonds which may
occur in any stable point along the chain, such as
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ethenyl, propenyl, and the like. ''AlkynylU includes
hydrocarbon chains of either a straight or branched
configuration and one or more triple carbon-carbon
bonds which may occur in any stable point along the
S chain, such as ethynyl, propynyl and the like.
"Haloalkyl" is intended to include both branched and
straight-chain alkyl having the specified number of
carbon atoms, substituted with l or more halogen;
~alkoxy" represents an alkyl group of indicated
number of carbon atoms attached through an oxygen
bridge; "cycloalkyl" is intended to include saturated
ring groups, including mono-,bi- or poly-cyclic ring
systems, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and so forth. "Halo~ or
''halogenU includes fluoro, chloro, bromo, and iodo.
The term Usubstituted'', as used herein, means
that one or more hydrogen on the designated atom is
replaced with a selection from the indicated group,
provided that the designated atom's normal valency is
not exceeded, and that the substitution results in a
stable compound. When a substitent is keto (i.e.,
=O), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables
are permissible only if such combinations result in
stable compounds. By "stable compoundU or "stable
structure" is meant a compound that is sufficiently
robust to survive isolation to a useful degree of
purity from a reaction mixture, and formulation into
an efficacious therapeutic agent.
The term "pharmaceutically acceptable salts"
includes acid or base salts of the compounds of
formulas (I) and (II). Examples of pharmaceutically
acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such
as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like.
-18-
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wos7/3ss46 rcr/uss7/04s2s
.
Pharmaceutically acceptable salts of the
compounds of the-invention can be prepared by
reacting the free acid or base forms of these
compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic
solvent, or in a mixture of the two; generally,
nonaqueous media like ether, ethyl acetate, ethanol,
isopropanol, or acetonitrile are preferred. Lists of
suitable salts are found in R~min~ton~
Ph~r~celltic~l Scienc~s, 17th ed., Mack Publishing
Company, Easton, PA, 1985, p. 1418, the disclosure of
which is hereby incorporated by reference.
UProdrugs'' are considered to be any covalently
bonded carriers which release the active parent drug
of formula (I) or (II) in vivo when such prodrug is
administered to a m~m~l ian subject. Prodrugs of the
compounds of formula (I) and (II) are prepared by
modifying functional groups present in the compounds
in such a way that the modifications are cleaved,
either in routine manipulation or in vivo, to the
parent compounds. Prodrugs include compounds wherein
hydroxy, amine, or sulfhydryl groups are bonded to
any group that, when ~mini stered to a m~mmAlian
subject, cleaves to form a free hydroxyl, amino, or
sulfhydryl group, respectively. Examples of prodrugs
include, but are not limited to, acetate, formate and
benzoate derivatives of alcohol and amine functional
groups in the compounds of formulas (I) and (II); and
the like.
The term "therapeutically effective amount" of a
compound of this invention means an amount effective
to antagonize abnormal level of CRF or treat the
symptoms of affective disorder, anxiety or depression
in a host.
Synthesis
-19--
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w097/3~46 PCT~S97/0~28
The novel substituted fused pyrimidines of the
present invention-are prepared by one of the general
schemes outlined below wherein Ar, Q, G, X, Y, Z, Rl,
R2, R3 and R13 are as above and L represents a suitable
leaving group such as halo, methanesulfonate, p-
toluenesulfonate, or triflate.
Schemel
Rl ~ N ~ L
A~2H + N ~ NO Ar'Q
L ~I
A 'Q Ar'Q Ar
Vl V
~/ ~
R3 R3
N ~N ~
A~ Q A~'Q Rl3
VIIl VII
Compounds of the type III (Scheme 1) are prepared
by condensing the alkali metal salts of compounds of the
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W O 97/35846 PCT~US97/04828
type I, where Q = O or S, with compounds of the type II
made according to literature procedures [Ashley and
Harris, J Chem Soc., 677(1944~; Albert et al., J Chem
Soc., 3832(1954)] in solvents such as acetonitrile at
S temperatures between 0 and 50~C.
Compounds of the type IV are obtained from
compounds of the type III by treatment with primary
amines such as 4-aminoheptane in solvents such as
dioxane at temperatures between 25 and 100~C. These
amino adducts are converted into compounds of the type V
by reduction with hydrogen in the presence of catalysts
such as platinum on carbon at atmospheric or elevated
pressure or by reducing agents such as sodium
dithionite, or iron in acetic acid.
Compounds of the type VI are prepared from
compounds of the type V through diazotization and
cyclization with an alkali metal nitrite in the presence
of an acid in water with or without an organic cosolvent
such as cyclic ethers or aromatic hydrocarbons.
Compounds of type VII are prepared by the con-
densation of compounds of the type V with phosgene,
thiophosgene, carbonyldiimidazole, thiocarbonyl-
diimidazole, urea, thiourea, guanidine and the like, in
the presence or absence of solvents such as high-boilng
ethers or aromatic hydrocarbons and at temperatures
between 100-200~C.
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Scheme 2
R~ CI R~ IH R~ N
Cl Cl Cl
IX X XI
R3 R3
R~ N R~ N
Cl Cl R13
XIII ~aI
Compounds of the type VIII are prepared by
condensation of the compounds of the type V with
reagents such as acids, acid chlorides, anhydrides,
amides or ortho esters in the presence or absence of
solvents such as ethers or aromatic hydrocarbons at
temperatures between 0 to 200~C.
Compounds of the type VII, where R13 = H, are
alkylated with reagents such as alkyl halides and the
like, in the presence or absence of bases such as sodium
hydroxide, in solvents such as tetrahydrofuran or DMF
and at temperatures between 0 to 100~C to yield
compounds of the type VIII.
Alternatively, compounds of the type VII are
prepared from compounds of the type X (Scheme 2). These
diamino pyrimidines, X, are made from the dichloro-
aminopyrimidines of type IX which are synthesized from
compounds of type II by treatment with reducing agents
such as, but not limited to sodium dithionite, iron or
zinc in the presence of acid, or catalytic hydrogenation
(see: LaRock, Comprehensive Organic Transformations, VCH
Publishers, NY, 1989, 411). The diamino compounds, X,
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are converted into compounds of the type XII using the
same procedure as described for the preparation of
compounds of the type VII from compounds of the type V,
and then condensing compounds of the type XII with salts
of the compounds of the type I in solvents such as DMF
or 2-ethoxyethanol at temperatures between 25 and 200
~C ~
Alternatively, compounds of the type VIII are
prepared from compounds of the type X by first
converting them into compounds of the type XIII using
the same method as described for the preparation of
compounds of the type VIII from compounds of the type V
and then condensing compounds of the type XIII thus
obtained with salts of the compounds of the type I under
the conditions described for the conversion of
compounds of the type I into compounds of the type II.
Alternatively, compounds of type VI are prepared
from compounds of type X by diazotization and
cyclization, as previously described for compounds of
compound type V to compounds of type VI, to give
compounds of type XI. Subse~uent treatment with the
salts of the compounds of the type I with compounds of
type XI, as previously described, provides these tiazolo
adducts of type VI.
The compounds of the present invention and their
synthesis are further illustrated by the following
examples and preparations.
~x~m~le 1
3-Rr~m~-4-ky~roxy-5-~thoxy~cetoDh~none
Bromine (9.62g) in 30mL of chloroform was added dropwise
to a solution of acetovanillone (10.0g) in 150mL of
chloroform maintained at 0-5 ~C, such that the
temperature did not rise above 5 ~C. After the addition
was complete, the mixture was stirred at 0-5~C for 4
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hours. The residue was treated with water. The organic
layer was dried Qver MgSO4 and stripped of the solvent
under reduced pressure to yield a pinkish powder which
was tritrated with ether and filtered to yield the title
compopund, mp 148-152 ~C.
~x~m~le ~
3-Rrom~-4-~y~roxy-5-~thox~y-~-~im~thyl h~n ~en~m~th~nol
Methyl magnesium bromide (3M in diethyl ether, 11.42mL)
was added dropwise to a solution of 5-Bromo-4-hydroxy-
3-methoxyacetophenone (3.0g) in anhydrous
tetrahydrofuran (60mL) maintained at 0-5 ~C under N2 gas,
such that the temperature did not rise above 5 ~C.
After the addition was complete, the solution was
stirred at room temperature for 2 hours. Saturated
ammonium chloride was added dropwise until effervescence
ceased. The mixture was treated with an excess of
saturated ammonium chloride. The organic layer was
dried over MgSO4 and stripped of the solvent under
reduced pressure to yield the title compound as a
viscous oil which solidified over a period of time, mp
107-112 ~C.
~x~m~le 3
3-Rrom~-5-~th~xy-~ ~-~im~th~yl-4-~r6-chloro-2-m~t~yl-5-
~itro-4-Dvrimi~i~ylloxvlh~n~en~m~th~no
3-Bromo-4-hydroxy-5-methoxy-a~a-dimethylbenzenemethan
(1.16g) was dissolved in 10% NaOH (1.78g) and 5mL of
water. The solvent was stripped under reduced pressure.
The salt was taken up in 50mL acetonitrile and added
dropwise by pipette to an already cooled solution (0 -5
~C) of 4,6-dichloro-2-methyl-5-nitro-1,3-pyrimidine
(0.92g) in 80mL of acetonltrile. The mixture was
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WO97/3~K PCT~S97/0~28
stirred at 0~-5~C for 3 hours. The solvent was removed
under reduced pressure and the residue was extracted
with methylene chloride. The extracts were combined and
evaporated under reduced pressure to yield the title
compound.
~x~m,pl e 4
3-Rromo-5-m~th~xV-~ ~-~im~t~yl-4-~r2-m~thvl-5-nitro-6-
o r ( l-nronvlhl~tyl)~minol-4-Dyrimi~invlloxvlhenzenem~th~nol
To a solution of 3-bromo-5-methoxy-a,a-dimethyl-4-[[6-
chloro-2-methyl-5-nitro-4-
pyrimidinyl]oxy]benzenemethanol (1.88g) in anhydrous
1,4-dioxane (50mL) with 0.50g of potassium carbonate,
4-heptylamine (l.OOmL) was added and the solution was
stirred at room temperature for 2 hours. The solvent
was removed under reduced pressure and the residue was
taken up in water and extracted with methylene chloride.
The extracts were combined and dried over MgS04. The
solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel
using a 1:1 mixture of ethyl acetate and hexane to yield
the title compound, mp 138 ~C.
3-Bromo-5-methoxy-a,a-dimethyl-4-[(6-(1-methoxy-
propyl)amino-2-methyl-5-nitro)-4-pyrimidinyl]-
oxybenzenemethanol, m.p. 119-120 ~C, was prepared by the
same procedure.
~x~mnle S
3-Rrom~-5-m~thO~y-~ ~-~imetkyl-4-~5-~mino-~ thvl-6-
~(l-DroDylhl]tvl)~minol-4-~yrimi~invlloxvlhen~n~m~th~n
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Platinum black,(5%,0.25g) was added to a solution of 3-
bromo-S-methoxy-a,a-dimethyl-4-E[2-methyl-5-nitro-6-[(1-
propyl-butyl)amino]-4-pyrimidinyl]oxy]benzenemethanol
(0.80g) in 50mL of ethanol. The mixture was
S hydrogenated at a pressure of 41 psi for 18 hours. The
mixture was filtered through celite and the filtrate was
stripped under reduced pressure. The residue was taken
up in lN NaOH and extracted with methylene chloride.
The combined methylene chloride extracts were dried over
MgSO4 and the filtrate was stripped under reduced
pressure to yield the title compound, mp 114-116 ~C.
~x~le 6
lS 3-Rrom~-5-~th~xy~ im~thvl-4-r(5-~thyl-3-(1-
proDvlhl~tyl)-3H-1.~.3-tri~olo~4.5-~l~vrimi~in-7-vl)-
oxvl h~n~en~m~th~nol
To a solution of 3-bromo-5-methoxy-a,a-dimethyl-4-[[5-
amino-2-methyl-6-[(1-propylbutyl)amino]-4-
pyrimidinyl]oxy]benzene- methanol (0.70g) in 35mL of
glacial acetic acid, 0.10g of sodium nitrite in lmL of
water was added dropwise. The mixture was stirred at
room temperature for 20 minutes and then diluted with
water, basified with lN NaOH and extracted three times
with ethyl acetate. The combined extracts were dried
over MgSO4 and stripped of the solvent under reduced
pressure to yield the title compound as viscous liquid.
~x~le 7
7-r2-Rr~m~-6-~th~xv-4-(1-~thvlethenvl)Dhenoxvl-5-
~thvl-3-(1-Dropylhlltyl)-3H-1 2.3-tri~olor4 5-
~lpvrimi~ine
To a solution of 3-bromo-5-methoxy-a,a-dimethyl-4-[(5-
methyl-3-(1-propylbutyl)-3H-1,2,3-triazolo[4,5-
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d]pyrimidin-7-yl)-oxy]benzenemethanol (O.59g) in 35mL of
benzene, a small ~uantity of p-toluene sulfonic acid was
added. The solution was refluxed under azeotropic
conditions for 1.5 hours. Once cooled to room
S temperature, the solution was washed with saturated
NaHCO3 followed by water. The organic phase was dried
over MgSO4 and the solvent was removed under reduced
pressure. The residue was chromatographed silica gel
using a mixture of 1:1 ethyl acetate and hexane to yield
the title compound as a colorless solid, mp 110-115 ~C.
~x~mnl e 8
7-r2-Rrom~-6-m~thoxv-4-(1-m~thvlethvl~Dh~noxv1-S-m~t
3-(1-Dronvlhl]tvl~-3H-1.~.3-tri~ 7010 r4~5-~l~vri mi ~li ne
Platinum black, 5~ (0.19g) was added to a solution of 7-
[2-bromo-6-methoxy-4-(1-methylethenyl~phenoxy]-5-methyl-
3-(l-propylbutyl)-3H-l~2~3-triazolo[4~5-d]pyrimidine
(0.17g) in 50mL of ethanol. The mixture was
hydrogenated at a pressure of 40 psi for 18 hours and
filtered through celite. The filtrate was stripped of
the solvent under reduced pressure and the residue
recrystallized from hexane to yield the title compound
as a colorless crystalline solid, mp 129-131 ~C.
~x~m~le 9
3-(1-~t~yl~roDvl~-5-m~t~yl-7-(2~4.6-trim~thvlDh~noxy)-
3H-1.~.3-tri~olor4.5-~lDyriml~ine
2,4,6-Trimethylphenol (0.114) was added to a solution of
sodium methoxide (0.334 g) methanol (10 mL) and the
resulting solution was evaporated to dryness under
reduced pressure. The salt thus obtained was taken up
in 10mL of acetonitrile and added dropwise by to a cold
solution (0-5 ~C) of 7-chloro-3-(1-ethylpropyl)-5-
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methyl-3H-1,2,3-triazolo[4,5-d]pyrimidine in 35mL of
acetonitrile, such that the temperature did not rise
above 5~C. The mixture was stirred at 0-5~C for 3 hours.
The solvent was then removed from the mixture under
reduced pressure and the residue treated with water and
extracted three times with methylene chloride. The
combined extracts were dried over MgSO4 and stripped of
the solvent under reduced pressure. The material was
purified on silica gel using a solution of 1% methanol
in methylene chloride to yield the title compound as a
colorless powder, mp 92 ~C.
~x~mnle l0
6-~l-M~tho~ypropyl)~mino-~-m~thvl-5-nitro-4- r (2-hrom~-
6-m~th~xv-4-(1-m~thvleth~nyl)~h~noxylpYrimi~ine.
A few crystals of 4-toluenesulfonic acid were added to a
solution of 3-bromo-5-methoxy-a,a-dimethyl-4-[[6-(1-
methoxypropyl)amino-2-methyl-5-nitro]-pyrimidinyl3]oxy-
benzenemethanol (1.70 g) in benzene (30 ml) and the
resulting mixture was heated overnight under reflux
using Dean-Stark trap. It was then cooled diluted with
benzene (70 mL), washed sucessively with lN aq. NaOH and
water, dried over magnesium sulfate and evaporated to
dryness underreduced pressure to yield a semi solid
which upon trituration with ether and filtration yielded
a yellow solid. Recrystallization from ethanol furnished
the title compound as a light yellow crystalline solid,
m.p. 136-137 ~C.
~x~m~l e ll
~-A~ino-6-(l-m~thoxvDro~yl)~mino-2-mPt~yl-4-~(2-hrom~-6-
m~th~xy-4-(l-m~t~ylethvl)phenoxylDyri m; ~i ne
-28-
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W097/3s&~ PCT~S97/0~28
Platinum black (5%, 250 mg) was added carefully to a
solution of 6-(1-~ethoxypropyl)amino-2-methyl-5-nitro-4-
[(2-bromo-6-methoxy-4(1-methylethenyl)phenoxy]pyrimidine
(550 mg) in ethyl acetate (100 mL) and the resulting
mixture was hydrogenated at 30 p.s.i. overnight. The
mixture was then filtered through a pad of celite and
the filtrate evaporated to dry ness under reduced
pressure to yield the title com-pound as a highly
viscous liquid.
Example 12
7-~2-Rrom~-6-m~thoxv-3-(1-mPth~ypro~yl~-5-m~t~yl-4-(1-
~t~ylethvl)Dh~noxyl-3~-1 2,3-tri~olo~4,5-~lDyrim;~ine
A solution of of sodium nitrite (42 mg) in water ~1 mL)
was added dropwise to a solution of 2-amino-6-(1-
methoxypropyl)- amino-2-methyl-4-[t2-bromo-6-methoxy-4-
(l-methylethyl)- phenoxy]pyrimidine (270 mg) in acetic
acid (10 mL) with stirring at room temperature. After
the addititon was complete, the mixture was stirred
overnight at room temperature over night and stripped of
most of the acetic acid under reduced pressure. The
residue was treated with lN aq. NaOH and extracted with
ethyl acetate (2X). The ethyl acetate extract was was
washed with water, dried over magnesium sulfate and
evaporated to dryness under reduced pressure to yield a
semi-solid which was chromatographed over
silica using 1:1 ethyl acetate:hexane as the eluent to
furnish the title compound, m.p. 149-150 ~C.
IJtility
CRF-R1 Receptor Binding Assay for the Evaluation of
Biological Activity
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W O 97~846 PCTAUS97/04828
The following is a description of the
isolation of cel~ membranes containing cloned human CRF-
R1 receptors for use in the standard binding assay as
well as a description of the assay itself.
Messenger RNA was isolated from human hippocampus.
The mRNA was reverse transcribed using oligo (dt) 12-18
and the coding region was amplified by PCR from start to
stop codons The resulting PCR fragment was cloned into
the EcoRV site of pGEMV, from whence the insert was
reclaimed using XhoI + XbaI and cloned into the XhoI +
XbaI sites of vector pm3ar ( which contains a CMV
promoter, the SV40 't' splice and early poly A signals,
an Epstein-Barr viral origin of replication, and a
hygromycin selectable marker). The resulting expression
vector, called phchCRFR was transfected in 293EBNA cells
and cells retaining the episome were selected in the
presence of 400 ~M hygromycin. Cells surviving 4 weeks
of selection in hygromycin were pooled, adapted to
growth in suspension and used to generate membranes for
the binding assay described below. Individual aliquots
containing approximately 1 x 108 of the suspended cells
were then centrifuged to form a pellet and frozen.
For the binding assay a frozen pellet described
above containing 293EBNA cells transfected with hCRFR1
receptors is homogenized in 10 ml of ice cold tissue
buffer ( 50 mM HEPES buffer pH 7.0, containing 10 mM
MgCl2, 2 mM EGTA, 1 ~g/l aprotinin, 1 ~g/ml leupeptin
and 1 ~g/ml pepstatin). The homogenate is centrifuged
at 40,000 x g for 12 min and the resulting pellet
rehomogenized in 10 ml of tissue buffer. After another
centrifugation at 40,000 x g for 12 min, the pellet is
resuspended to a protein concentration of 360 ~g/ml to
be used in the assay.
Binding assays are performed in 96 well plates;
each well having a 300 ~l capacity. To each well is
added 50 ~l of test drug dilutions (final concentration
of drugs range from 10-1~ - 10-5 M), 100 ~l of 125I-
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W O 97/35846 PCT~US97/04828
ovine-CRF (125I-o-CRF) (final concentration 150 pM) and
150 ~1 of the cell homogenate described above. Plates
are then allowed to incubate at room temperature for 2
hours before filtering the incubate over GF/F filters
(presoaked with 0.3% polyethyleneimine) using an
appropriate cell harvester. Filters are rinsed 2 times
with ice cold assay buffer before removing individual
filters and assessing them for radioactivity on a gamma
counter.
Curves of the inhibition of 125I-o-CRF binding to
cell membranes at various dilutions of test drug are
analyzed by the iterative curve fitting program LIGAND
[P.J. Munson and D. Rodbard, Anal. Biochem. 107:220
(1980), which provides Ki values for inhibition which
are then used to assess biological activity.
A compound is considered to be active if it has
a Ki value of less than about 10000 nM for the
inhibition of CRF to its receptor.
Inhibition of CRF-Stimul~ted Adenvl~te Cvclase
Activity
Inhibition of CRF-stimulated adenylate cyclase
activity was performed as described by G. Battaglia
et al. Synapse 1:572 (1987). Briefly, assays were
carried out at 37~ C for 10 min in 200 ml of buffer
containing 100 mM Tris-HCl (pH 7.4 at 37~ C), 10 mM
MgC12, O.4 mM EGTA, 0.1% BSA, 1 mM
isobutylmethylxanthine (IBMX), 250 units/ml
phosphocreatine kinase, 5 mM creatine phosphate, 100
mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist
peptides (concentration range 10-9 to 10-6m) and 0.8
mg original wet weight tissue (approximately 40-60 mg
protein). Reactions were initiated by the addition
of 1 mM ATP/32P]ATP (approximately 2-4 mCi/tube) and
terminated by the addition of 100 ml of 50 mM Tris-
HCL, 45 mM ATP and 2% sodlum dodecyl sulfate. In
order to monitor the recovery of cAMP, 1 ~l of
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W 0 97135846 PCTrUS97/04828
[3H]cAMP (approximately 40,000 dpm) was added to each
tube prior to separation. The separation of
[32P]cAMP from [32P]ATP was performed by sequential
elution over Dowex and alumina colum~ns. Recovery was
consistently greater than 80%.
Some compounds of this invention were tested in
this assay and found to be active.
In vi vo Biological ~say
The in vivo activity of the compounds of the
present invention can be assessed using any one of
the biological assays available and accepted within
the art. Illustrative of these tests include the
Acoustic Startle Assay, the Stair Clim.bing Test, and
the Chronic Administration Assay. These and other
models useful for the testing of compounds of the
present invention have been outlined in C.W. Berridge
and A.J. Dunn Brain Research Reviews 15:71 (1990)
Compounds may be tested in any species of rodent
or small mammal. Disclosure of the assays herein is
not intended to limit the enablement of the
invention.
The compounds of this invention have utility in
the treatment of inbalances associated with abnormal
levels of corticotropin releasing factor in patients
suffering from depression, affective disorders,
and/or anxiety.
Compounds of this invention can be administered
to treat these abnormalities by means that produce
contact of the active agent with the agent's site of
action in the body of a m~mmA~. The compounds can be
~mi ni stered by any conventional means available for
use in conjunction with pharmaceuticals either as
individual therapeutic agent or in combination of
therapeutic agents. They can be administered alone,
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but will generally be administered with a
pharmaceutical carrier selected on the basis of the
chosen route of administration and standard
pharmaceutical practice.
The dosage administered will vary depending on
the use and known factors such as pharmacodynamic
character of the particular agent, and its mode and
route of administration; the recipient's age, weight,
and health; nature and extent of symptoms; kind of
concurrent treatmenti frequency of treatment; and
desired effect. For use in the treatment of said
diseases or conditions, the compounds of this
invention can be orally administered daily at a
dosage of the active ingredient of 0.002 to 200 mg/kg
of body weight. Ordinarily, a dose of 0.01 to 10
mg/kg in divided doses one to four times a day, or in
sustained release formulation will be effective in
obtaining the desired pharmacological effect.
Dosage forms (compositions) suitable for
administration contain from about 1 mg to about 100
mg of active ingredient per unit. In these
pharmaceutical compositions, the active ingredient
will ordinarily be present in an amount of about 0.5
to 95% by weight based on the total weight of the
composition.
The active ingredient can be administered orally
is solid dosage forms, such as capsules, tablets and
powdersi or in liquid forms such as elixirs, syrups,
and/or suspensions. The compounds of this invention
can also be ~mi ni stered parenterally in sterile
liquid dose formulations.
Gelatin capsules can be used to contain the
active ingredient and a suitable carrier such as but
not limited to lactose, starch, magnesium stearate,
steric acid, or cellulose derivatives. Similar
diluents can be used to make compressed tablets. Both
tablets and capsules can be manufactured as sustained
CA 02249~98 1998-09-22
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release products to provide for continuous release of
medication over a-period of time. Compressed tablets
can be sugar-coated or film-coated to mask any
unpleasant taste, or used to protect the active
ingredients from the atmosphere, or to allow
selective disintegration of the tablet in the
gastrointestinal tract.
Liquid dose forms for oral administration can
contain coloring or flavoring agents to increase
patient acceptance.
In general, water, pharmaceutically acceptable
oils, saline, aqueous dextrose (glucose), and related
sugar solutions and glycols, such as propylene glycol
or polyethylene glycol, are suitable carriers for
parenteral solutions. Solutions for parenteral
administration preferably contain a water soluble
salt of the active ingredient, suitable stabilizing
agents, and if necessary, butter substances.
Antioxidizing agents, such as sodium bisulfite,
sodium sulfite, or ascorbic acid, either alone or in
combination, are suitable stabilizing agents. Also
used are citric acid and its salts, and EDTA. In
addition, parenteral solutions can contain
preservatives such as benzalkonium chloride, methyl-
or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described
in "Remington's Pharmaceutical Sciences", A. Osol, a
standard reference in the field.
Useful pharmaceutical dosage-forms for
30 ~mi nistration of the compounds of this invention can
be illustrated as follows:
C~DS1]1 es
A large number of units capsules are prepared
by filling standard two-piece hard gelatin capsules
each with 100 mg of powdered active ingredient, 150
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W097/3~46 PCT~S97/04828
mg lactose, 50 mg cellulose, and 6 mg magnesium
-stearate.
.~oft Gel~ti n C~
A mixture of active ingredient in a digestible
oil such as soybean, cottonseed oil, or olive oil is
prepared and injected by means of a positive
displacement was pumped into gelatin to form soft
gelatin capsules containing 100 mg of the active
ingredient. The capsules were washed and dried.
T~hlet.~
A large number of tablets are prepared by
conventional procedures so that the dosage unit was
100 mg active ingredient, 0.2 mg of colloidal silicon
dioxide, 5 mg of magnesium stearate, 275 mg of
microcrystalline cellulose, 11 mg of starch, and 98.8
mg lactose. Appropriate coatings may be applied to
lncrease palatability or delayed adsorption.
The compounds of this invention may also be used
as reagents or standards in the biochemical study of
neurological function, dysfunction, and disease.
