Note: Descriptions are shown in the official language in which they were submitted.
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AMINOTETRALINS AS 5-HTlDa AGONISTS
BACKGROUND OF THE INVENTION
This invention relates to novel substituted
aminotetralins useful as 5-HT1D agonists.
Over the last several years it has become
apparent that serotonin (5-hydroxytryptamine; 5-HT) is
associated directly or indirectly with a number of
physiological phenomena, including appetite, memory,
thermo-regulation, sleep, sexual behavior, anxiety,
depression, and hallucinogenic behavior [Glennon, R.A.,
J. Med. Chem. 30, 1 (1987) ] .
5-HT receptors have been identified in the
central nervous system (CNS; brain and spinal cord) and
in peripheral tissues including the gastrointestinal
tract, lung, heart, blood vessels, and various other
smooth muscle tissues.
It has been recognized that there are multiples
types of 5-HT receptors. These receptors have been
classificed as 5-HT1, 5-HT2 and 5-HT3 receptors, with the
former being further divided into the sub-classes 5-HT1A,
5-HT18, 5-HT1C, 5-HT1D, 5-HT1E, and 5-HT1F~
Within the 5-HT1 receptor class, several
subtypes have been distinguished on the basis of their
pharmacological binding profiles, second messenger
coupling and physiological roles. One such subtype, the
5-HT1D receptor, was originally defined as a particular
type of [3H]5-HT binding site in the bovine caudate
(Heuring and Peroutka, J. Neurosci., 7:894 (1987)).
Few ligands have selectivity for 5-HT1D
receptors. Sumatriptan possesses limited 5-HT1D
selectivity. GR 127935 has also been identified as a
patent and selective 5-HT1D receptor antagonist. Hayer,
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et al., Pharmacological Reviews, Vol. 46, No. 2, pp. 157-
203 (1994) .
Molecular cloning has demonstrated that
pharmacologically defined 5-HT1D receptors are encloded
by two separate but closely related genes, designated 5-
HTlDa and 5-HT1D~, which are members of the GPRC
superfamily. These receptors display highly conserved
transmembrane homology (75%) and similar binding
properties and second messenger coupling (inhibition of
adenylate cyclase). Leonhardt, S., et al., J. Neurochem,
53:465-471 (1989).
The 5-HTlDa receptor is a species homolog of
the 5-HT1D receptor of bovine calif caudate and guinea-
pig brain. Hartig, et al., supra.
The 5-HT1B and 5-HTlDa receptors have recently
been shown to be species homologues of the same receptor
subtype. They display similarities in their
pharmacology, second messenger coupling, and anatomical
distribution. The 5-HT1B subtype appears to be confined
to rat, mouse, and opossum whereas 5-HT1D~ sites have
been demonstrated in human, pig, guinea pig and calf.
Adham, N., et al., Mol. Pharmacol., 41:1-7 (1992).
The rat 5-HTlB receptor differs from its human
counterpart at only 4% of its transmembrane amino acids,
but its pharmacological binding properties are
dramatically different from those of the human 5-HT1DB
receptor. Hartig, et al., Trends Pharmacol. ci.,
13:152-159 (1992).
We have now discovered a further class of
compounds which have selective 5-HTlDa agonist activity
useful in treatment of dementia, Parkinson's Disease,
appetite modulation, anxiety, migraine, sexual
dysfunction, irritative bladder symptoms of benign
prostatic hyperplasia, urge incontinence and excessive
bladder activity caused by bacterial cystitis,
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interstitial cystitis, radiation/chemotherapy-induced
cystitis, outlet obstruction, neurogenic bladder, spinal
cord injury, stroke, and nocturnal enurisis.
. It is desirable to develop new compounds and
treatments for these 5-HTiDa mediated diseases.
This invention provides a compound of formula I
R3
7 g\ 1 2 NR1R.2
16 ~/ 4 3
(I)
wherein:
R1 and R2 are each individually hydrogen or -(C1-
C6)alkyl;
R3 is -(C2-Cg)alkenyl, -(CH2)q(C3-C8)cycloalkyl -
(CH2)n~(CH2)pRS,
( CH2 ) ( CH2 )
-A-B~ ~-A-H
I ; or I
substituted with one substituent selected from the group
consisting of -(C1-C6)alkyl and -(C3-Cg)cycloalkyl;
where A-H is >C=CH- or >CR4CH2-;
D is -CH2- or oxygen;
R4 is hydrogen or -OH;
R5~ is -(C3-Cg)cycloalkyl, or phenyl substituted with
one substituent selected from the group consisting of halo,
~ 25 -(C1-C6)alkyl and (C1-C6)alkoxy;
m is an integer from 1 to 5 both inclusive;
~ n is an integer from 0 to 4 both inclusive;
p is an integer from i to 7 both inclusive; and
q is an integer from 0 to 4 both inclusive;
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or a pharmaceutically acceptable salt or optical
isomer thereof;
provided that when D is oxygen, >A-B is not >C=CH-;
and when R4 is -OH, D is oxygen.
This invention also provides a pharmaceutical
formulation comprising a compound of formula I in
association with one or more pharmaceutically acceptable
diluents, carriers and excipients.
This invention further provides a method of
activating the 5-HTlDa receptor comprising administering
to a mammal in need of such treatment a therapeutically
effective amount of a compound of formula II
3'
R
2 NR1R2
16~ 4 3
(II)
wherein:
R1 and R2 are each individually hydrogen or
-(C1-C6)alkyl;
R3~ is -(C1-C8)alkyl, -(CH2)q(C3-Cg)cycloalkyl,
-(C2-Cg)alkenyl,
-(C1-Cg)alkan-1-ol-1-yl, -(CH2)n0(CH2)pRS~,
(CH2) (CH2)".,
D-A-B~ ~-A- ~~'J~B
I ; or I
substituted with one substituent selected from the group
consisting of -(C1-C6)alkyl and -(C3-Cg)cycloalkyl;
where A-B is >C=CH- or >CR4CH2-;
D is -CH2- or oxygen;
R4 is hydrogen or -OH;
R5~ is -(C1-C6)alkyl, -(C3-Cg)cycloalkyl, -(C1-
Cg)alkoxy, phenyl or phenyl substituted with one substituent
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selected from the group consisting of halo, -(CZ-Cg)alkyl
and (Cl-C6)alkoxy;
m is an integer from 1 to 5 both inclusive;
n is an integer from 0 to 4 both inclusive;
p is an integer from 1 to 7 both inclusive; and
q is an integer from 0 to 4 both inclusive;
or a pharmaceutically acceptable salt or optical isomer
thereof ;
provided that when D is oxygen, >A-B is not >C=CH.-.
This invention also provides a method of
alleviating the pathological effects of 5-HTlDa receptor-
activated diseases which comprises administering to a
mammal in need of such treatment a therapeutically
effective amount of the compound of formula II.
A still further aspect of the invention is a
method of treating a mammal suffering from or susceptible
to any condition activated by the 5HTlDa receptor of the
type represented by dementia, Parkinson~s disease,
anxiety, migraine, appetite modulation, sexual
dysfunction, irritative bladder symptoms of benign
prostatic hyperplasia, urge incontinence and excessive
bladder activity caused by bacterial cystitis,
interstitial cystitis, radiation/chemotherapy-induced
cystitis, outlet obstruction, neurogenic bladder, spinal
cord injury, stroke and nocturnal enurisis which
comprises administering to said mammal a therapeutically-
effective amount of a compound of formula (II).
Other objects, features and advantages of the
present invention will become apparent from the
subsequent description and the appended claims.
Definitions:
As used herein, the term, ~~(C1-Cg)alkyl" by
itself or as part of another substituent means, unless
otherwise defined, a straight or branched chain
monovalent hydrocarbon radical such as methyl, ethyl, n-
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propyl, isopropyl, n-butyl, tertiary butyl, isobutyl,
sec-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl,
octyl and the like. The term "(C1-Cg)alkyl" encompasses
" (C1_C6) alkyl" .
The term "halo" means chloro, fluoro, bromo or
iodo.
The term "(C1-Cg)alkoxy" denotes a straight or
branched alkyl chain having one to six carbon atoms attached
to the remainder of the molecule by an oxygen atom. Typical
(C1-C6) alkoxy groups include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy,
neopentoxy and the like.
The term "(C3-C8) cycloalkyl" referes to a
hydrocarbon ring having the stated number of carbon
atoms. Typical (C3-Cg) cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl.
The term, "(C2-Cg)alkenyl," as used herein,
means a straight chain or branched monovalent hydrocarbon
group attached to the tetralin ring at any point on the
chain, having the stated number range of carbon atoms and
one double bond on the carbon attached to the tetralin
ring. Typical groups include vinyl, prop-1-en-1-yl,
isoprop-1-en-1-yl, n-but-2-en-2-yl, tertiary but-1-en-1-
yl, isobut-1-en-1-yl, n-pent-1-en-1-yl, isopent-1-en-1-
yl, pent-1-en-1-yl, hept-3-en-3-yl, hex-2-en-2-yl, oct-2-
en-2-yl and the like.
The term, "(C1-Cg)alkan-1-ol-1-yl" means a
straight or branched chain monovalent hydrocarbon radical
having the stated number of carbon atoms attached to the
tetralin ring at the 1-position of the chain and,
further, having an hydroxy group attached to the 1-
position of the chain. Such groups include methan-1-ol-
1-yl, ethan-1-ol-1-yl, n-propan-1-ol-1-yl, isopropan-ol-
1-yl, n-butan-1-ol-1-yl, tertiary butan-1-ol-1-yl,
isobutan-1-ol-1-yl, sec-butan-1-ol-1-yl, n-pentan-1-ol-1-
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yl, isopentan-1-ol-1-yl, neopentan-1-ol-1-yl, heptan-1-
ol-1-yl, hexan-1-ol-.1-yl, octan-1-ol-1-yl and the like.
Useful compounds for practicing the present
. invention includes pharmaceutically acceptable acid
addition salts of the compounds defined by the above
formulae I and II. Since the compounds of formula I are
amines, they are basic in nature and accordingly react
with any of a number of inorganic and organic acids to
form pharmaceutically acceptable acid addition salts.
Acids commonly employed to form such salts are
inorganic acids, such as hydrocholoric acid, hydrobomic
acid, hydroiodic acid, sulfuric acid, phosphoric acid,
and the like, and organic acids, such as
p-toluenesulfonic, methanesulfonic acid, oxalic acid,
p-bromophenylsulfonic acid, carbonic acid, succinic acid,
citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable
salts thus are the sulfate, pyrosolfate, bisulfate,
sulfite, bisulfite, phosphate, monohydrogensphosphate,
dihydrogenphosphate, metaphosphate, chloride, bromide,
iodide, acetate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caproate, heptanoate,
propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumariate, maleate, butyne-1,4-dioate, hexyne-
1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
phthalate, sulfonate, xylenesulfonate, phenylacetate,
phenylpropionate, phenylbutyrate, citrate, lactate, y-
hydroxybutyrate, glycollate, tartrate, methanesulfonate,
propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-
. sulfonate, mandelate, and the like. Preferred
pharmaceutically acceptable acid addition salts are those
formed with mineral acids such as hydrochloric acid and
hydrobromic acid.
The compounds of the instant invention may have
one stereocenter at the 2-position, and possibly more
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stereocenters, depending on the R3 substituent at the
8-position; and may be isolated in optically active and
racemic forms. The optically active isomers of the
racemates of invention are also considered within the
scope of Formulae I and II. Such optically active
isomers may be prepared from their respective optically
active precursors following the procedure described
below, or by resolving the racemic mixtures. These
resolutions can typically be carried out in the presence
of a resolving agent, by chromatography or by repeated
cyrstallization.
Procedures for separating racemates into their
individual isomers can be found in references such as
Jacques, et al., Enantiomers, Racemates and Resolutions,
(John Wiley and Sons, New York 1981).
The term "amino-protecting group" is used
herein as a.t is frequently used in synthetic organic
chemistry, to refer to a group which will prevent an
amino group from participating in a reaction carried out
on some other functional group of the molecule, but which
can be removed from the amine when it is desired to do
so. In a similar fashion, the term "hydroxy protecting
group" refers to a removable group which will prevent a
hydroxy group from participating in a reaction performed
on the molecule. Such groups are discussed by T. W.
Greene in chapters 2 and 7 of Protective Groups in
Organic Synthesis, John Wiley and Sons, New York, 1981,
and by J. W. Barton in chapter 2 of Protective Groups in
Organic Chemistrv, J. F. W. McOmie, ed., Plenum Press,
New York, 1973, which are incorporated herein by
reference in their entirety. Examples of amino
protecting groups include benzyl and substituted benzyl
such as 3,4-dimethoxybenzyl, _o-nitrobenzyl, and
triphenylmethyl; those of the formula -COOR where R
includes such groups as methyl, ethyl, propyl, isopropyl,
2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl,
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t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-
nitrobenzyl, _o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl
groups and substituted acyl such as formyl, acetyl,
. chloroacetyl, dichloroacetyl, trichloroacetyl,
trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other
groups such as methanesulfonyl, p-toluenesulfonyl, p-
bromobenzenesulfonyl, p-nitrophenylethyl, and g-
toluenesulfonylaminocarbonyl. A preferred amino-blocking
group is t-butoxycarbonyl.
Examples of hydroxy protecting groups include
ether and substituted ether forming groups such as
methyl, methoxymethyl, t-butoxymethyl, 1-ethoxyethyl and
benzyl; silyl ether forming groups such as
trimethylsilyl, triethylsilyl and methyl-
diisopropylsilyl; ester forming groups such as formate,
acetate and trichloroacetate and carbonate groups, such
as methyl, 2,2,2-trichloroethylcarbonate and p-
nitrophenyl carbonates.
The term °urinary incontinence~~ includes
bacterial cystitis, interstitial cystitis,
radiation/chemotherapy induced cystitis, outlet
obstruction, neurogenic bladder, incontinence due to
spinal cord injury and stroke, and nocturnal enurisis.
Preferred substituent groups of compounds of
formulae I and II include the following:
(a) R1 and R2 are each independently hydrogen;
(b) R1 and R2 are each independently -(C1-C6)alkyl;
(c) R3 is -(C1-Cg)alkyl ;
(d) R3 is -(CH2)n~(CH2)pRS;
(e) R3 is -(C2-Cg}alkenyl;
(CHI
D-A-
( f } R3 is
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(CHI
D-A-
(g) R3 is ~ ,substituted with one substituent
selected from the group consisting of
-(C1-Cg)alkyl or -(C3-Cg)cycloalkyl;
(h) R5 is -(C3-Cg)cycloalkyl;
(i) R5 is phenyl substituted with one substituent
selected from the group consisting of
-(C1-C~)alkyl or (C1-C6)alkoxy;
(j) R5 is phenyl substituted with halo;
(k) A-B is >C=CH-;
(1) A-B is >CR4CH2-;
(m) D is CH2;
(n) D is oxygen;
(o) m is 2-4;
(p) n is 1;
(q) p is 2; and
(r) q is 0 or 1.
A preferred genus of compounds include those
compounds of formula I where:
R1 and R2 are each individually hydrogen or
-(C1-C6)alkyl;
(CHI
D-A
R3 is ~ ; and
m is 2 or 3.
Of this preferred genus, compounds where A-B is
>C=CH- are more preferred.
Still another preferred group of compounds
include those where A-B is >CR4CH2- and D is -CH2-.
The most preferred compound of the instant
invention is 2-N,N-dimethylamino-8-(2-methylcyclopent-1-
yl)tetralin hydrochloride.
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Further typical examples of compounds of
formula I which are useful in the present invention
include:
2-N-methylamino-8-ethyltetralin;
2-N,N-dipropylamino-8-isopropyltetralin;
2-N-methyl-N-ethyl-8-pentyltetralin;
2-N,N-di-t-butylamino-8-isobutyltetralin;
2-N-ethyl-N-hexyl-8-octyltetralin;
2-N,N-dipropylamino-8-methyltetralin;
2-N-butylamino-8-eth-1-en-1-yltetralin;
2-N,N-dimethylamino-8-isoprop-1-en-1-yltetralin;
2-N-ethyl-N-methyl-8-but-1-en-1-yltetralin;
2-N,N-diethylamino-8-pent-1-en-1-yltetralin;
2-N-propylamino-8-hept-1-en-lyltetralin;
2-N-methyl-N-butyl-8-cyclopropylmethyloxymethyltetralin;
2-N,N-di-t-butyl-8-(2-cyclobutylethyl)oxymethyltetralin;
2-N-pentylamino-8-(2-(3-
cyclopentylpropyl)oxy)ethyltetralin;
2-N-methyl-N-hexyl-8-(4-cyclohexylbutyl)oxytetralin;
2-N-methyltetralin-8-(4-(7-
cyclooctylheptyl)oxy)butyltetralin;
2-N,N-dimethylamino-8-(3-(3-
chlorophenyl)propyl)oxymethyltetralin;
2-N-ethyl-N-methylamino-8-(4-(4-
methylphenyl)butyl)oxytetralin;
2-N-pentylamino-8-(3-(2-
methoxyphenyl)methyloxy)propyltetralin;
2-N,N-diethylamino-8-(4-(3-(3~
fluorophenyl)propyl)oxy)butyltetralin;
2-N-t-butyl-N-methylamino-8-(5-(4-
- ethylphenyl)pentyl)oxytetralin;
2-N-hexylamino-8-(5-(2-
propoxyphenyl)heptyl)oxymethyltetralin;
2-N,N-dipropyl-8- (2- (6- (3-
propylphenyl)hexyl)oxy)ethyltetralin;
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2-N-methyl-N-butylamino-8-(4-(4-
bromophenyl)butyl)oxymethyltetralin;
2-N-isopropylamino-8-(2-(2-
hexylphenyl)ethyl)oxymethyltetralin;
2-N,N-diethyl-8-(3-(3-butoxyphenyl))
2-N-ethyl-N-propylamino-8-cyclobutyltetralin;
2-N-t-butylamino-8-cyclopentyltetralin;
2-N,N-diethylamino-8-cycloheptyltetralin;
2-N-methyl-N-hexylamino-8-cyclooctyltetralin;
2-N-isopentylamino-8-cycloprop-1-en-1-yltetralin;
2,N,N-dibutylamino-8-cyclohex-1-en-1-yltetralin;
2-N-hexyl-N-ethylamino-8-cyclopent-1-en-1-yltetralin;
2-N-isobutylamino-8-(1'-hydroxy)cyclobutyltetralin;
2-N,N-dipentylamino-8(1'-hydroxy)cyclooctyltetralin; and
2-N-propyl-N-methylamino-8-(1'-
hydroxy)cycloheptyltetralin.
synthesis Methods
All of the reactions described in the following
schemes are preferably conducted under an inert gas such
as nitrogen.
The compounds of formula I where R3 or R3' is
(CHI (CHI
D-A- D-A
-(C2-C8)alkenyl, ~ or ~ substituted with
-(C1-C6)alkyl or -(C3-Cg)cycloalkyl; where A-B is >C=CH-
or >CR4CH2- and D is -CH2- can be prepared according to
the following reaction Scheme I.
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Scheme I
Hr Li
\ NR1R2 \ NR1R2 O
(a)
/ ~' / +Ra Rb ---a
(1) (la)
H(
a
1R2
(C)
(2) / (3)
\(d) Re ~e)
NR1R2
f~
{4)
one of Ra or Rb is H and the other is -
(CH2)q(C3-Cg)cycloalkyl, or
Ra and Rb taken together are with the carbon to
which they are attached are {C3-Cg)alkyl
CHI C:H~
D-A-B' D-p_
or , or substituted ~ where A-B is >CR4CH2-,
D is -CH2- and R4 is -OH;
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Rc and Rd taken together with the carbon to
(CHI
c
D-A-
which they are attached are (C2-Cg)alkenyl or ~ or
(CHI
c
D-A-
substituted ~ , where A-B is >C=CH- and D is -CH2-;
(CHI
c
D-A-
Re is -(C1-Cg)alkyl, ~ or substituted
(CHI
c
D-A-
~ ; where A-B is >CR4CH2-, D is -CH2- and R4 is
hydrogen.
Compound (1), 8-bromo aminotetralin, is first
treated with an organo-lithium reagent, preferably n-
butyl lithium, to form the activated intermediate (la).
The reaction is carried out in a suitable solvent,
preferably tetrahydrofuran or diethylether, at a
temperature of about -78°C and is substantially complete
in 5 to 60 minutes.
In an aldol reaction, starting at a temperature
of about -78°C, and gradually allowing to warm to a
temperature of about 0°C, the lithiated intermediate (la)
is treated with an alkyl ketone or aldehyde or cyclic
ketone of the formula RaCORb, where
one of Ra or Rb is hydrogen and the other is
-(CH2)q(C3-C8)cycloalkyl, or
Ra and Rb taken together with the carbon to which they
(CHI
c
D-A-
are attached form -(C1-Cg)alkyl, or ~ or
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(CHI
D-A-
substituted ~ where A-B is >CR4CH2-, D is -CH2- and
(CHI
C
R4 is hydrogen, to form product (2). where R3 is D-A-
(CH~
c
D-A-
or substituted ~ , A-B is >CR4CH2-, D is -CH2- and
R4 is hydroxy. At temperatures of about 0°C, the
reaction is substantially complete in about 10 minutes to
an hour.
Dehydration of (2) is achieved using
trifluoroacetic acid to prepare product (3) where R3 is
CHI
D-A-
-(C2-C6)alkenyl, -(CH2)q(C3-Cg)cycloalkyl, ~ or
(CHI
D-A-
substituted ~ ; where A-H is >C=CH- and D is -CH2-.
Hydride reduction of (2), preferably using
triethylsilane with trifluoroacetic acid or alternately,
triethylsilane with a Lewis acid such as boron
trifluoride etherate, can be employed to prepare (4),
(CHI
D-A-
compounds of formula I where R3 or R3~ is ~ or
(CHI
D-A-
substituted ~ where A-B is >CR4CH2-, D is -CH2-,
and R4 is hydrogen. Alternately, compound (3) can be
hydrogenated by refluxing in an alcohol solvent with
ammonium formate and palladium on carbon to prepare (4).
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In step (b), for compounds where R3 or R3~ is
methyl, the lithiated intermediate (la) is treated with
dimethylformamide instead a compound of formula RaCORb.
Compounds of formula I where R3 or R3~ is
(CHI
c
D-A-
-(CH2)n0(CH2)pRS, -(CH2)n0(CH2)pRS~ or ~ where A-B
is >CR4CH2-, D is oxygen, R4 is hydrogen and n is 1 to 4,
both inclusive, can be prepared as follows in scheme II.
Scheme II
Br Li
\ NR1R2 \ ~1R2
-~ / + XRf
(1} (la)
Rf
\ NR1R2
(5)
X is a halogen;
(CHI
D-A-
Rf is -(CH2)n0(CH2)pRS, ~ or
(CHI
c
D-A-
substituted ~ where A-B- is >CR4CH2-, D is oxygen and
R4 is hydrogen.
Following the procedure outlined in Scheme I, step
(a) above, the brominated aminotetralin (1) is first
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activated by treatment with an organo-lithium reagent, such
as n-butyl lithium to form (la). The activated intermediate
(la) is then C-alkylated with an alkyl halide of the formula
XRf where X is a halogen and Rf is -(CH2)n0(CH2)pRS,
' (CH~ (CHI
c c
D-A-~ D_A_
-(CH2)n0(CH2)pRS~ ~ or substituted ~ where A-H-
is >CR4CH2-, D is oxygen and R4 is hydrogen.
When R3 is -(CH2)n0(CH2)pR5 or -(CH2)n0(CH2)pRS~
the halide starting material XRf may be prepared by reacting
an appropriately substituted alcohol, HO(CH2)n0(CH2)pR5 or
HO(CH2)n0(CH2)pRS~ with methoxymethyl chloride and a base,
such as diisopropylethylamine or sodium or potassium
carbonate in an organic solvent, such as methylene chloride
or chloroform to form the methoxy intermediate. The methoxy
group may then be replaced with an appropriate halogen,
preferably chlorine, by reacting the intermediate with a
halogenating agent such as boron trichloride.
(CHI
- - D-A-
For compounds where R3 or R3~ is ~ and D is
oxygen, the alkyl halide starting material, XRf, can be
0
(CH2) r
prepared by reacting a heterocyclic alkene, , where
r is an integer from 1 to 4 both inclusive, with a
halogenating agent, such as hydrogen chloride gas to give
X O
(CH2)r
Compounds of formula I where R3 or R3~ is
-(CH2)n0(CH2)pR5 or -(CH2)n0(CH2)pRS~ and n is zero, can
be prepared as described in Scheme III as follows.
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Scheme III
OH ORg
~1R2
NR1R2
/ ~ ~ /
(6)
Rg is -(CH2)pR5 or -(CH2)pRS~
An appropriately substituted phenol (6) is 0-
alkylated with an alkyl halide of the formula X(CH2)pR5 or
X(CH2)pRS~ where X is preferably chlorine, in the presence
of a base, such as potassium hydroxide or potassium
carbonate and a catalyst such as potassium iodide, to form
product (7). The reaction is preferably conducted in a
solvent, such as ethanol, or solvent system, such as
dimethoxyformamide/acetone.
Compounds of formula I may have one or two
stereocenters; one at the 2- position of the tetralin
ring and the other at the 8-position. Racemates of
(CHI
D-A-
compounds of formula I, where R3 or R3~ is ~ and D
is oxygen, may be converted to their respective (R) and
(S) enantiomers in a diasteroselective synthesis as
described in Scheme IV below.
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Scheme IV
O
O~ ( CH ) CH30 ~ ~ OPG
2 m (a) ~ N (CH~ +
(8) CH3 (9)
O ( CH2 ) m~OPG
1 2
~NR R ~ ,,. NR1R2
/ (~ ~ ( c?
/
(la> (lo>
HO ( CH2 ) m~OPG PGO ( CH2 ) m~OH
,,. ~1R2 ~ ,,. NR1R2
(d) ~ (e)
/ ,,. / --
(11) (12)
H
PGO ( CH2 ) m~~0
,,. NR1R2
( f~
(13)
i
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HOL
~'~~y--,~H
HO ( CH2 ) m~~0 O ( CH2 ) m
,,. NR1R2 ~ ,,. NR1R2
.~---~ ( /
(14) (15)
0 (CH2)m
,,. NR1R2
(16)
PG is an hydroxy protecting group
Starting material (8) is first treated with
methoxymethyl amine and trimethyl aluminum, at
temperatures of about -15°C. The terminal hydroxy is
protected using, for example, butyldiphenylsilane to
prepare intermediate (9). Intermediate (9) is then
coupled with lithiated starting material (la), preferably
at temperatures of from about -78°C to 0°C, in a solvent
such as tetrahydrofuran, to prepare (10).
Stereospecific reduction of the carbonyl of
(10) can be achieved by treatment with (-)DIP-C1
((-)dimethylaminoisopropyl chloride) hydrochloride to
produce the (R) enantiomer (11). The reaction is
preferably conducted at temperatures of about -25°C and
is substantially complete in 1 to 3 days.
Protection of the alpha hydroxy can be
accomplished by treating (11) with a selective hydroxy-
protecting group, such as benzoylchloride, followed by
removal of the silyl hydroxy-protecting group on the
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omega hydroxy, using, for example, tetrabutylammonium
fluoride to prepare (12).
Reduction of the omega hydroxy can then be
readily accomplished using pyridinum chlorochromate to
prepare (13). Removal of the alpha hydroxy protecting
group and cyclization of (13) can then be accomplished by
treatment with a strong base, such as sodium hydroxide.
Reduction of (15) is achieved using triethyl
silane and trifluoroacetic acid to yield (16).
To achieve the (S) enantiomer, stereospecific
reduction of the carbonyl of intermediate (11) can be
accomplished using (S)-1,3,3-triphenyltetrahydro-1H,3H-
pyrrolo[1,2-C][13,2]oxazaborole and boron trihydride in
step (d) Scheme IV above instead of DIP-C1.
The intermediates and final products may be
isolated and purified by conventional techniques, for
example by concentration of the solvents, followed by
washing of the residue with water, then purification by
conventional techniques such as chromatography or
recrystallization.
It will be readily appreciated by the skilled
artisan that the starting materials which are not
described are either commercially available or can be
readily prepared by known techniques from commercially
available starting materials. All other reactants used
to prepare the compounds in the instant invention are
commercially available.
The pharmaceutically acceptable acid addition
salts are typically formed by reacting an aminotetralin
of formula I with an equimolar or excess amount of acid,
preferably hydrochloric acid. The reactants are
generally combined in a mutual solvent, such as diethyl
ether or benzene, and the salt. normally precipitates out
of solution within about one hour to 10 days, and can be
isolated by filtration.
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The following examples further illustrate the
preparation of the compounds of this invention. The
examples are illustrative only and are not intended to
limit the scope of the invention in any way.
The following abbreviations are used in the
Examples below.
NaHC03 is sodium bicarbonate
Na2S04 is sodium sulfate
NH40H is ammonium hydroxide
HC1 is hydrochloric acid
MgS04 is magnesium sulfate
CH2C12 is methylene chloride
MeOH is methanol
NaOH is sodium hydroxide
DMAP dimethylaminopyridine
THF is tetrahydrofuran
N-HuLi is n-butyllithium
Et3SiH is triethylsilane
BF3 is borom trifluoride
CF3COOH trifluoroacetic acid
EtOH is ethanol
Pd/C is palladium on carbon
NH40H is ammonium hydroxide
NH4C02H is ammonium formate
AlMe3 is trimethyl aluminum
Na2C03 is sodium carbonate
BH3 is borane
Et20 is diethylether
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Example 1
(R)-2-N,N-dimethylamino-8-methyltetralin hydrochloride
CH3 CH3
,,,,N~CH3
A. Preparation of (R)-2-N,N-dimethylamino-8-
f ormyltetralin
[Reaction under nitrogen atmosphere, using flame
dried glassware)
To 1.0048 of (+)-(R)-2-N,N-dimethylamino-8-
bromotetralin, dissolved in 15 mL of dry THF and chilled
to -78°C in a dry ice/acetone bath, was added 3.45 mL
(1.6 M) of n-BuLi, and the mixture was allowed to stir
for one hour. Anhydrous dimethylformamide (0.46 mL) was
then added via syringe. The reaction was allowed to
slowly return to room temperature. Water was added and
the mixture was extracted witra ethyl acetate. The
organic layers were dried over MgS04 and concentrated to
leave a yellow oil that was purified by silica gel flash
column chromatography using a solvent mixture (10% MeOH,
0.5% NH40H in CH2C12) to give 683 mg of (R)-2-N,N-
dimethylamino-8-formyltetralin (85%), which was used for
next step without further characterization.
B. Preparation of (R)-2-N,N-dimethylamino-8-
methyltetralin hydrochloride
The compound of part A, above (660 mg) was dissolved
in 8 mL of dry CH2C12 and 9.3 mL of Et3SiH was added. To
this vigorously stirring solution was bubbled BF3 gas via
syringe. The resulting solution oiled out to a yellow
sludge and the solution cleared from yellow to a clear
liquid. The reaction was allowed to stir overnight.
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After quenching with 20 mL of saturated NaHC03 and
diluting with 50 mL of CH2C12, the layers were separated
and the organic layer was washed with brine. The
organics were then dried over MgS04, filtered, and
evaporated to recover an oily yellow solid. The crude
product was purified by silica gel flash column
chromatography using a solvent mixture (6.5% MeOH, 0.5%
NH40H in CH2C12). The HC1 salt was made from this oily
residue and recrystallized from hot EtOH and Et20.
M.P.: 180-181°C dec
HRMS Calculated: 190.1596
Found: 190.157
Example 2
(R)-2-N,N-dimethylamino-8-(cyclobut-1-en-1-yl)tetralin
CH3
\ ,,,,N.CHs
A. Preparation of (R)-2-N,N-dimethylamino-8-(1~-
hydroxy)cyclobutyltetralin hydrochloride
[Reaction under nitrogen atmosphere, using flame
dried glassware]
By substantially following the procedure in Example
1, part A, using 1.50g of (+)-(R)-2-N,N-dimethylamino-8-
bromotetralin, 5.2 ml of n-BuLi (1.6M, l.4eq) and 0.75 mL
of cyclobutanone (1.7 eq.), subtitled compound was
prepared, 1.09g (75%).
B. Preparation of (R)-2-N,N-dimethylamino-8-(cyclobut-
1-en-1-yl)tetralin hydrochloride
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Compound of part A above (1.09g) was dissolved in 20
mL of dry CH2C12 and chilled to 0°C. CF3COOH, 2.2 mL,
was then added dropwise. The reaction stirred for 15
minutes at 0°C before it was allowed to warm to room
temperature over 2.3 hours. The reaction was quenched
with 20 mL of NaOH (2N) and 80 mL of CH2C12. The organic
phase was washed with water, dried over MgS04, filtered,
and evaporated to give 1.07g of as a crude oil. Flash
column purification over silica gel using a solvent
mixture (6.5% MeOH, 0.5% NH40H in CH2C12) afforded 827 mg
of (R)-2-N,N-dimethylamino-8-(cyclobut-1-enyl)tetralin.
The HC1 salt was made with 205 mg of the material. The
salt was recrystallized from hot EtOH and (ether/hexane)
to recover 159 mg of (R)-2-N,N-dimethylamino-8-(cyclobut-
1-en-1-yl)tetralin hydrochloride.
M.P.: 196-197°C dec
Elemental Analysis:
Calculated: C 72.85; H 8.41; N 5.31
Found C 72.59; H 8.37; N 5.43
Example 3
(R)-2-N,N-dimethylamino-8-(prop-1-en-2-yl tetralin)
hydrochloride
H3C CHZ
CH3
\ ,,.N.CHs
Title compound was prepared substantially according
to the procedure of Example 2 using 1.50g (5.9 mmol) of
(+)-(R)-2-N,N-dimethylamino-8-bromotetralin and 0.74 mL
of acetone to give 682 mg of (R)-2-N,N-dimethylamino-8-
(prop-1-en-2-yl-tetralin) as a free base which was
converted to the HC1 salt.
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M.P.: 168 - 170°C
Elemental Analysis:
Calculated: C 71.55; H 8.81; N 5.56
Found: C 71.66; H 8.95; N 5.57
Example 4
(R)-2-N,N-dimethylamino-8-(cyclooct-1-en-1-yl)tetralin
hydrochloride
CH3
,,,N~CH3
to
Title compound was prepared substantially according
to the procedure of Example 2 using 1.708 (6.71 mmol) of
(+)-(R)-2-N,N-dimethylamino-8-bromotetralin and 1.5 mL of
cyclooctanone to give 444 mg of (R)-2-N,N-dimethylamino-
8-(cyclooct-1-en-1-yl)tetralin, and was recovered as the
HC1 salt.
M.P.: 174 - 276°C
Elemental Analysis
Calculated: C 75.09; H 9.45; N 4.38
Found: C 75.06; H 9.21; N 4.48
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Example 5
(R)-2-N,N-dimethylamino-8-(pent-2-en-3-yl)tetralin
hydrochloride
~H3
N
~ CH3
Title compound was prepared substantially according
to the procedure of Example 2 using 953mg (3.75 mmol) of
(+)-(R)-2-N,N-dimethylamino-8-bromotetralin and 0.68 mL
of diethyl ketone to give 373 mg of (R)-2-N,N-
dimethylamino-8-(pent-2-en-3-yl)tetralin hydrochloride.
M.P.: 158 -160°C
Elemental Analysis:
Calculated: C 72.96; H 9.37; N 5.01
Found: C 72.74; H 9.22; N 5.07
Example 6
(R,S), (R,R)-2-N,N-dimethylamino-8-(3-methylcyclopent-1-
en-1-yl)tetralin hydrochloride
~H3
N~ CH3
Title compounds were prepared substantially
according to the procedure of Example 2 using 602mg (2.37
mmol) of (+)-(R)-2-N,N-dimethylamino-8-bromotetralin and
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4.03 mL of 3-methylcyclopentanone to give 229 mg of a
mixture of two diasteromers of (R,S),(R,R)-2-N,N-
dimethylamino-8-(3-methylcylopent-1-en-1-yl)tetralin
hydrochloride which was isolated as the HC1 salt.
M.P.: 160 -162°C
Elemental Analysis:
Calculated: C 73.82; H 9.13; N 5.01
Found: C 74.08; H 8.98; N 4.80
Example 7
(R)-2-N,N-dimethylamino-8-cyclobutyltetralin
hydrochloride
~H3
,,~ N~CH3
The compound of Example 2, 621 mg, was dissolved in
30 mL of MeOH along with 200 mg of Pd/C (5%) and 10
equivalents of ammonium formate. The mixture was stirred
at reflux for 5 hours before allowing it to cool to room
temperature. The resulting mixture was filtered over
diatomaceous earth and the filter cake was rinsed with
warm methanol. The filtrate was concentrated and
redissolved in methylene chloride. The organic layer was
washed with water (pH ~11) and brine, and then dried over
magnesium sulfate, filtered, and evaporated. The crude
oil was made into its corresponding HC1 salt and
recrystallized from hot EtOH and (ether/hexanes) to
recover 150 mg (R)-2-N,N-dimethylamino-8-
cyclobutyltetralin hydrochloride.
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M.P.: 155 -156°C
Elemental Analysis
Calculated: C 72.29; H 9.10; N 5.27
Found: C 72.50; H 9.15; N 5.57
Example 8
(R,S),(R,R)-2-N,N-dimethylamino-8-(2
cyclopentylcyclopent-1-yl)tetralin hydrochloride
~H3
N
~ CH3
Title compound was prepared substantially according
to the procedure of Examples 2 and 7 using 466 mg of (+)-
(R)-2-N,N-dimethylamino-8-bromotetralin and 0.616 mL of
(R,S)-2-cyclopentyl cyclopeatanine. A mixture of two
diastereomers (R,S),(R,R)-2-N,N-dimethylamino-8-(2-
cyclopentylcyclopent-1-yl)tetralin, 108 mg, was isolated
as the HC1 salt.
M.P.: 172 -174°C
Elemental Analysis
Calculated: C 76.38; H 9.32; N 4.05
Found: C 76.13; H 9.59; N 3.97
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Example 9
(R,S),(R,R)-2-N,N-dimethylamino-8-(2-methylcyclopent-1
yl)tetralin hydrochloride
H3C CH3
,,. NCH
3
Title compound was prepared substantially according
to the procedure of Examples 2 and 7 using 400 mg (1.57
mmol) of (+)-(R)-2-N,N-dimethylamino-8-bromotetralin and
0.202 mL of 2-methylcyclopentanone to give 39 mg of a
mixture of two diastereomers (R,S),(R,R)-2-N,N-
dimethylamino-8-(2-methylcyclopent-1-yl)tetralin which
was isolated as the HC1 salt.
M.P.: 181 - 183°C
Elemental Analysis
Calculated: C 73.57; H 9.60; N 4.77
Found: C 73.29; H 9.64; N 4.69
Example 10
(R)-2-N,N-dimethylamino-8-cyclohexylmethyl tetralin
hydrochloride
~H3
N~CH3
Title compound was prepared substantially according
to the procedure of Examples 2 and 7 using 627 mg (2.47
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mmol) of (+)-(R)-2-N,N-dimethylamino-8-bromotetralin and
0.509 mL cyclohexanecarboxaldehyde to give (R)-2-N,N-
dimethylamino-8-cyclohexylmethyltetralin, 356 mg of which
was isolated as the HC1 salt.
M.P.: 234 - 235°C
Elemental Analysis
Calculated: C 74.12; H 9.82; N 4.55
Found: C 73.89; H 9.68; N 4.40
Example 11
(R)-2-N,N-dimethylamino-8-cyclooctyltetralin
hydrochloride
CH3
,,,N~CH3
Title compound was prepared substantially according
to the procedure of Example 7 using 303 mg (1.07 mmol) of
(R)-2-N,N-dimethylamino-8-cyclooct-1-en-1-yl-tetralin
hydrochloride. Title compound, 210 mg, was recovered as
the HCl salt.
M.P.: 171 - 173°C
Elemental Analysis:
Calculated: C 74.02; H 10.02; N 4.35
Found: C 74.40; H 9.97; N 4.55
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Example 15
(R)-2-N,N-dimethylamino-8-methoxyethoxymethyl tetralin
hydrochloride
CH20CH2CH20CH3
,~~ N ( CH3 ) 2
To a stirred solution of (+)-(R)-2-N,N-
dimethylamino-8-bromotetralin (1.67 mmol) in 9 mL of THF
was added n-butyllithium (1.76 mmol) at -78°C under
nitrogen. After stirring for 45 minutes,
methoxyethoxymethyl chloride (1.75 mmol) was added. The
resulting mixture was stirred at -78°C for 15 minutes and
then gradually warmed to room temperature over a period
of 1 hour. Ten ml of 5% NaHC03 solution was added. The
mixture was extracted with CH2C12 (15 mL x 3). The
combined organic layer was dried (Na2S04), filtered, and
then concentrated. The crude residue was purified by
flash chromatogrphy using a mixture of solvents (NH40H,
0.5%; MeOH, 7%; in CH2C12) to give 382.7 mg (87%) of
title compound.
MS (m/e) : 263 (M+) .
HCl salt of the product has melting point of 147-148°C.
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Example 13
(R,S),(R,R)-2-N,N-dimethylamino-8-(tetrahydropyran-2
yl)tetralin hydrochloride
,~N(CH3)Z
A. Preparation of 2-chlorotetrahydropyran
The starting material of 2-chlorotetrahydropyran was
synthesized by reported procedures (R. A. Earl, L.H.
Townsend; Synthesis, 1972, 1140). Dihydropyran (300
mmol) and CH2C12 (25 mL) were placed in a flask. HCl gas
was bubbled through the precooled mixture (-78°C) for 30
minutes. The mixture was then slowly warmed to room
temperature. Distillation of the crude product
(44°C/water aspirator) gave 20.48 (56% purity) of
2-chlorotetrahydropyran.
B. Preparation of (R,S)(R,R)-2-N,N-dimethylamino-8-
(tetrahydropyran-2-yl)tetralin hydrochloride
To a stirred solution of (+)-(R)-2-N,N-
dimethylamino-8-bromotetralin (1.10 mmol) in 5 mL of THF
was added n-butyllithium (1.32 mmol) at -78°C under
nitrogen. After stirring for 45 minutes, 2-
chlorotetrahydropyran (1.20 mmol) was added. The
resulting mixture was stirred at -78°C for 15 minutes and
then gradually warmed to room temperature over a period
of 1 hour. Ten mL of 5% NaHC03 solution was added. The
mixture was extracted with CH2C12 (15 mL x 3). The
combined organic layer was dried (Na2S04), filtered, and
then concentrated. The crude residue was purified by
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flash chromatography using a mixture of solvent (NH40H,
0.5%; MeOH, 7%; in CH2C12) to give 116.4 mg (45%) of
title compound a mixture of two diastereoisomers. HC1
salts of the products were prepared.
MS (m/e) : 296 (M+) .
Elemental Analysis:
Calculated: C 69.02; H 8.86; N 4.73
Found: C 69.21; H 9.10; N 4.67
Example 14
(R)-2-N,N-dimethylamino-8-(tetrahydrofuran-2-yl)tetralin
hydrochloride
N(CH3)2
A. Preparation of 2-chlorotetrahydrofuran.
Subtitled product was prepared substantially
according to the procedures reported in part A of Example
16. Thus, the reaction of dihydrofuran (400 mmol) and
HC1 gas in CH2C12 gave 28.2g (66%) of 2-
chlorotetrahydrofuran.
B. Preparation of (R)-2-N,N-dimethylamino-8-
(tetrahydrofuran-2-yl)tetralin hydrochloride
Using substantially the same procedure as in Example
13, part B, the reaction of (+)-(R)-2-N,N-dimethylamino-
8-bromotetralin (1.28 mmol) with n-butyllithium (1.54
mmol) and 2-chlorotetrahydrofuran (1.53 mmol) in 5 mL of
THF gave 175.1 mg (56%) of title compound as a mixture of
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the two diastereoisomers. HC1 salts of the products were
prepared.
MS (m/e) : 246° (M+) .
Elemental Analysis:
Calculated: C 68.19; H 8.58; N 4.97
Found: C 68.38; H 8.68; N 4.85
Examp:Le 15
(R)-2-N,N-dimethylamino-8-(1'-hydroxycyclohexyl)tetralin
hydrobromide
N (CH3) 2
To a stirred solution of (+)-(R}-2-N,N-
dimethylamino-8-bromotetralin (4.17 mmol) in 15 mL of
THF, was added n-butyllithium (1.6 M in hexanes, 5.76
mmol) at -78°C under nitrogen. After stirring for 45
minutes, cyclohexanone (6.37 mmol) was added. The
resulting mixture was stirred at -78°C for 30 minutes and
then gradually warmed to room temperature over a period
of 30 minutes. The reaction mixture was quenched with 5%
NaHC03 solution (25 mL), then extracted with CH2C12 (20
mL x 3). The combined organic layer was dried (Na2S04),
filtered, and then concentrated. The crude residue was
purified by flash chromatography using a mixture of
NH40H, MeOH, CH2C12 (0.5% . 9% . 90.5%) to give 751.6 mg
(66%) of title compound as an oil.
MS (m/e) : 256° (M+-H20) .
HBr salt of the product has melting point of 210-211°C.
i
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Example 16
(R)-2-N,N-dimethylamino-8-(1'-hydroxy
cycloheptyl)tetralin hydrobromide
,,. N ( CH3 ) 2
Following substantially the same procedure as
described in Example 15, the reaction of (+)-(R)-2-N,N-
dimethylamino-8-bromotetralin (4.06 mmol) with n-
butyllithium (5.66 mmol) and cycloheptanone (6.10 mmol)
in 15 mL of THF gave 696.8 mg (60%) of title compound.
MS (m/e): 270° (M+-H20)
HBr salt of the products has melting point of 186-187°C.
Example 17
(R)-2-N,N-dimethylamino-8-(cyclohex-1-en-1-yl)tetralin
hydrochloride
,,, N(CH3)2
/
A mixture of the compound of Example 15 (1.29 mmol)
and trifluoroborane etherate (1.38 mmol) in 10 mL of
CH2C12 was stirred at room temperature for 5 minutes.
NaOH solution (1N, lOmL) was added. The product was
extracted with CH2C12. The extract was dried, filtered,
and concentrated. The crude residue was purified by
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flash chromatography using a mixture of NH40H, MeOH, and
CH2C12 (0.5 . 10 . 120) to give 56% yield of title
compound.
The HC1 salt of the product has melting point of 190-
191°C.
Elemental Analysis:
Calculated: C 74.08; H 8.98; N 4.80
Found: C 74.29; H 8.89; N 5.01
Example 18
(R)-2-N,N-dimethylamino-8-(cyclohept-1-en-1-yl)tetralin
hydrochloride
,, N{CH3)2
/ J
Using a substantially same procedure as described in
Example 17, using (1.67 mmol) of the compound of Example
16, and trifluoroacetic acid (0.3 mL) in 8 mL of CH2C12
gave 80% yield of title compound.
HC1 salt of the product has melting point of 160-161°C.
Elemental Analysis:
Calculated: C 74.61; H 9.23; N 4.58
Found: C 74.85; H 9.25; N 4.78
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Example 19
(R)-2-N,N-dimethylamino-8-(cyclopent-1-en-1-yl) tetralin
hydrochloride
N(CH3)2
A. Preparation of (R)-8-(1'-hydroxy)cyclopentyl-2-N,N-
dimethylaminotetralin
(R)-8-(1'-hydroxy)cyclopentyl-2-N,N-
dimethylaminotetralin was prepared substantially
according to the procedures described in Example 15 using
(+)-(R}-2-N,N-dimethyamino-8-bromotetralin (5.99 mmol}
with n-butyllithium (8.32 mmol) and cyclopentanone (10.17
mmol) in 17 mL of THF to give 815.6 mg (53%) of sub-
titled product.
B. Preparation of (R)-2-N,N-dimethylamino-8-
(cyclopentyl-1-en-1-yl)tetralin hydrochloride
Using a substantially same procedure as described in
Example 17, (3.07 mmol) of the compound of part A, above,
and trifluoroacetic acid (1.5 mL) in 20 mL of CH2C12 gave
659.2 mg (800) of title compound.
HCL salt of the product has melting point of 184-185°C.
Elemental Analysis:
Calculated: C 73.49; H 8.71; N 5.04
Found: C 73.27; H 8.51; N 5.27
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Example 20
(R)-2-N,N-dimethylamino-8-cyclopentyltetralin
hydrochloride
\ ,,, N(CH3)2
To a stirred solution of the compound of Example 20
(0.41 mmol) and EtSiH (0.63 mmol) in 11 mL of CH2C12, was
added trifluoroborane etherate (0.81 mmol) at room
temperature. The resulting mixture was stirred at room
temperature for 2 hours. Saturated Na2C03 (15 mL) was
added. The product was extracted with CH2C12. The
extract was dried, filtered, and concentrated. The crude
residue was purified by flash chromatography using a
mixture of NH40H, MeOH, CH2C12 (0.5 . 5 . 95) to give
73.0 mg (73%) of title compound.
HC1 salt of the product has melting point of 158-159°C.
MS (m/e): 244° (M+H).
Example 21
(R)-2-N,N-dimethylamino-8-cyclohexyltetralin
hydrochloride
\ ,, N(CHs)2
l~
The compound of Example 17 (1.29 mmol) was
hydrogenated (60 PSI H2) in ethanol (25 mL) in the
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presence of catalyst Pd/C (5%, 80 mg) for 12 hours. The
crude mixture was filtered and then evaporated. The
residue was purified by flash chromatography using a
mixture of NH40H, methanol, and CH2C12 (0.5 . 6 . 94) to
give 243.2 mg (73%) of title product.
HCl salt of the product has melting point of 213-214°C.
Elemental Analysis:
Calculated: C 73.57; H 9.60; N 4.78
Found: C 73.49; H 9.57; N 4.96
Example 22
(R}-2-N,N-dimethylamino-8-cycloheptyltetralin
hydrochloride
\ ,, N(CHs)2
The compound of Example 18 (1.08 mmol) was
hydrogenated (60 PSI H2) in ethanol (25 mL) in the
presence of catalyst Pd/C (5%, 75 mg) for 12 hours. The
crude mixture was filtered and then evaporated. The
residue was purified by flash chromatography using a
mixture of NH40H, methanol, and CH2C12 (0.5 . 6 . 94) to
give 211.7 mg (73%) of title product.
HC1 salt of the product has melting point of 192-193°C.
Elemental Analysis:
Calculated: C 74.12; H 9.82; N 4.55
Found: C 73.93; H 9.76; N 4.78
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Example 23
2-(R)-2'-(S)-N,N-dimethylamino-8-(tetrahydrofuran-2
yl)tetralin hydrochloride
O
,,, N(CH2CH2CH3)2
A. Preparation of N-methyl-N-methoxy-4-t-
butyldiphenylsilyloxybutylamide
To a stirred solution of n-methyl-N-methoxyamine
hydrochloride (107.12 mmol) in 100 mL of CH2C12, was
added 2.0 M solution of AlMe3 (62.5 mmol) at -15°C under
nitrogen. After the mixture was stirred for 40 minutes,
y-butyrolactone (31.25 mmol) was added at -15°C. The
resulting mixture was stirred at room temperature for 2.5
hours. HC1 solution (1 N) was added dropwise until all
the precipitate was dissolved. The mixture was extracted
with CH2C12/MeOH (9:1; 50 mL x 8). The combined organic
layer was dried, filtered, and concentrated. Without
further purification, the crude residue containing N-
methyl-N-methoxy-4-hydroxybutylamide was treated with
chloro-t-butyldiphenylsilane (34.6 mmol) and imidazole
(38.19 mmol) in the presence of DMAP (1.23 mmol) and DMF
(50 mL) at room temperature under nitrogen for 13 hours.
Upon aqueous workup, the crude residue was purified by
flash chromatography using a mixture of hexanes and ethyl
acetate (4:1) to give subtitled product (7.98 g) in 66%
overall yield.
B. Preparation of (+)-(R)-2-N,N-dimethylaminotetralin-
8-yl-(3'-t-butyldiphenylsilyloxy)propylketone
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To a stirred solution of (+)-(R)-2-N,N-
dimethylamino-8-bromotetralin (1.36 mmol) in 6 mL of THF
was added n-butyllithium (1.6 M in hexanes, 1.6 mmol) at
-78°C under nitrogen. After stirred for 30 minutes, the
compound of part A (1.43 mmol) in 4 mL of THF was added.
The resulting mixture was stirred at -78°C for 20 minutes
and then at room temperature for 2 hours. After aqueous
workup, the crude residue was purified by flash
chromatography using a mixture of NH40H, CH2C12 and MeOH
(0.5 . 6 . 94) to give subtitled product (170 mg) in 25%
yield.
C. Preparation of 2-(R)-1'-(S)-2-N,N-dimethylamino-8-
(1'-hydroxy-3'-t-
butyldiphenylsilyloxy)propyltetralin
To a stirred solution of the compound of part B,
above, (0.67 mmol) in 1.5 mL of THF was added (-)-DIP-
C1(0.81 mmol) at 25°C. After the mixture was stirred for
3 days, the solvent was removed by evaporation. The
residue was purified by flash chromatography using a
mixture of NH40H, MeOH, and CH2C12 (0.5 . 8 . 92) to give
107.6 mg (32%) of subtitled product.
D. Preparation of 2-(R)-1'-(S)-2-N,N-dimethylamino-8-
(1'-benzoyloxy-3'-t-butyldiphenylsilyloxy)propyl
tetralin
To a stirred solution of the compound of part C
(0.64 mmol) in 6 mL of CH2C12 were added 0.2 mL of
pyridine and 0.1 mL of benzoyl chloride (0.86 mmol). The
mixture was stirred at room temperature for 3 hours.
Saturated Na2C03 (10 mL) was added. The product was
extracted with CH2C12. The extract was dried, filtered,
and concentrated. The residue was purified by flash
chromatography using a mixture of NH40H, MeOH, and CH2C12
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(0.5 . 8 . 92) to give subtitled product (0.64 mmol)
(363.9 mg) in 94% yield.
E. Preparation of 2-(R)-1'-(S)-2-N,N-dimethylamino-8-
(1'-benzoyloxy-3'-hydroxy)propyltetralin
To a stirred solution of the compound of part D
(0.60 mmol) in 6 mL of THF was added tetrabutylammonium
fluoride (1.20 mmol). The mixture was stirred at room
temperature for 5 hours. After aqueous workup, the crude
residue was purified by flash chromatography using a
mixture of NH40H, MeOH, and CH2C12 (0.5 . 10 . 90) to
give subtitled product (0.54 mmol) in 91% yield.
F. Preparation of 2'-(R)-4-(S)-4-[2'-N,N-
dimethylaminotetralin]-8'-yl-4-
benzoyloxybutyraldehyde
To a stirred solution of the compound of part E
(0.207 mmol) in CH2C12 (2 mL) was added pyridinium
chlorochromate (0.414 mmol) at room temperature. The
mixture was stirred for 45 minutes. NaOH solution (2N)
was added to basify the mixture (pH = 12). The product
was extracted with CH2C12. The extract was dried,
filtered, and concentrated. Purification of the residue
by flash chromatography using a mixture of NH40H, MeOH,
and CH2C12 (0.5 . 8 . 92) gave subtitled product (21.8
mg) in 29% yield.
G. Preparation of 2-(R)-2'-(S)-2-N,N-dimethylamino-8
(5'-hydroxytetrahydrofuran-2'-yl)tetralin
To a stirred solution of the compoind of part F
(21.8 mg) in MeOH (3 mL) was added NaOH (1N, 3 mL). The
mixture was stirred at room temperature for 50 minutes.
The product was extracted with CH2C12 (10 mL x 3). The
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extract was dried, filtered, and concentrated to give
15.5 mg of subtitled product as a crude product.
H. Preparation of 2-(R}-2'-(S)-N,N-dimethylamino-8-
(tetrahydrofuran-2-yl)tetralin hydrochloride
To a stirred solution of the compound of part G,
above, (15.5 mg, 0.06 mmol) in 3 mL of CH2C12 were added
Et3SiH (0.2 mL) and trifluoroacetic acid (0.2 mL). The
mixture was stirred at room temperature for 10 minutes.
NaOH solution was added until the pH equaled 12-14. The
product was extracted with CH2C12 (10 mL x 3). The
combined organic layer was dried, filtered, and
concentrated. The residue was purified by flash
chromatography using a mixture of NH40H, MeOH, and CH2C12
(0.5 . 8 . 92) to give title product (8.2 mg) in 57%
yield.
MS (m/e): 246 (M+ H).
HC1 salt of the product has melting point of 186-188°C.
Example 24
2-(R)-2'(R)-N,N-dimethylamino-8-(tetrahydrofuran-2
yl)tetralin hydrochloride
O
,,, N(CH2CH2CH3)2
A. Preparation of 2-(R)-1'-(R)-2-N,N-dimethylamino-8-
(1'-hydroxy-3'-t-butyldiphenylsilyloxy)
propyltetralin
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To a stirred solution of (+)-(R)-2-N,N-
dimethylaminotetralin-8-yl-(3'-t-
butyldiphenylsilyloxy)propylketone (0.47 mmol) (Example
. 30, Part B) and (S)-1,3,3-triphenyltetrahydro-iH, 3H-
pyrrolo[1,2-C][1,3,2]oxazaborole (0.09 mmol) in 6 mL of
THF was added HH3 solution in THF (0.50 mmol) at 0°C
under nitrogen. The mixture was stirred for 30 minutes.
The solvent was evaporated and the residue was dissolved
in ether (10 mL) and methanol (10 mL). Diethanolamine (2
mL) was added. The mixture was heated to reflux for 14
hours. NH40H solution was added to basify the mixture.
The product was extracted with CH2C12. The extract was
dried, filtered, and concentrated. T a residue was
purified by flash chromatography using a mixture of
NH40H, MeOH, and CH2C12 (0.5 .. 6 . 94) to give 88.5 mg of
subtitled product.
B. Preparation of 2-(R)-1'-{R)-2-N,N-dimethylamino-8-
(1'-benzoyloxy-3'-t-butyldiphenylsilyloxy)propyl
tetralin
To a stirred solution of the compound of part A
(0.568 mmol) in 8 mL of CH2C12 were added 0.3 mL of
pyridine and 0.1 mL of benzoyl chloride (0.86 mmol). The
mixture was stirred at room temperature for 3 hours.
Saturated Na2C03 (10 mL) was added. The product was
extracted with CH2C12. The extract was dried, filtered,
and concentrated. The residue was purified by flash
chromatography using a mixture of NH40H, MeOH, and CH2C12
(0.5 . 8 . 92) to give subtitled product (0.64 mmol)
(308.0 mg) in 90% yield.
C. Preparation of 2-(R)-1'-(R)-2-N,N-dimethylamino-8-
(1'-benzoyloxy-3'-hydroxy)propyltetralin
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To a stirred solution of the compound of part B,
above, (0.51 mmol) in 6 mL of THF was added
tetrabutylammonium fluoride (1.02 mmol). The mixture was
stirred at room temperature for 5 hours. After aqueous
workup, the crude residue was purified by flash
chromatography using a mixture of NH40H, MeOH, and CH2C12
(0.5 . 10 . 90) to give subtitled product (0.47 mmol) in
92% yield.
D. Preparation of 2'-(R)-4-(R)-4-(2'-N,N-
dimethylaminotetralin]-8'-yl-4-
benzoyloxybutyraldehyde
To a stirred solution of the compound of part C
(0.466 mmol) in CH2C12 (5 mL) was added pyridinium
chlorochromate (0.932 mmol) at room temperature. The
mixture was stirred fox 45 minutes. NaOH solution (2N)
was added to basify the mixture (pH = 12). The product
was extracted with CH2C12. The extract was dried,
filtered, and concentrated. Purification of the residue
by flash chromatography using a mixture of NH40H, MeOH,
and CH2C12 (0.5 . 8 . 92) gave subtitled product (61 mg).
E. Preparation of 2-(R)-2'-(R)-2-N,N-dimethylamino-8-
(5'-hydroxytetrahydrofuran-2'-yl)tetralin
To a stirred solution of the compound of part D (61
mg) in MeOH (10 mL) was added NaOH (1N, 6 mL). The
mixture was stirred at room temperature for 50 minutes.
The product was extracted with CH2C12 (15 mL x 3). The
extract was dried, filtered, and concentrated to give 35
mg of subtitled compound as a crude product.
F. Preparation of 2-(R)-2'-(R)-N,N-dimethylamino-8-
(tetrahydrofuran-2-yl)tetralin hydrochloride
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To a stirred solution of the compound of part E (35
mg) in 5 mL of CH2C12 were added Et3SiH (0.3 mL) and
trifluoroacetic acid (0.3 mL). The mixture was stirred
at room temperature for 10 minutes. NaOH solution was
added until pH = 12-14. The product was extracted with
CH2C12 (10 mL x 3). The combined organic layer was
dried, filtered, and concentrated. The residue was
purified by flash chromatography using a mixture of
NH40H, MeOH, and CH2C12 (0.5 . 8 . 92) to give title
product (21.0 mg) .
MS (m/e) : 245 (M+) .
HCl salt of the product has melting point of 195-197°C.
I5
Example 25
(R)-2-N,N-dimethylamino-8-(4
fluorophenyl)ethyloxymethyltetralin hydrochloride
Following substantially the same procedure as
described in Example 15, the reaction of (+)-(R)-2-N,N-
dimethylamino-8-bromotetralin (475 mg, 1.87 mm) with n-
butyllithium (2.24 mmol) and 9:-fluorophenethyl
chloromethyl ether (389 mg, 2.06 mm) in 1 mL of THF gave
88.4 mg of the desired product. '
HC1 salt of the product has melting point of 109-111°C.
Elemental Analysis:
Calculated: C 69.31; H 7.48; N 3.85
Found: C 69.56; H 7.46; N 4.04
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Example 26
(R)-2-N,N-dimethylamino-8-(4-bromophenyl)ethyloxymethyl
tetralin hydrochloride
Following substantially similar procedure as
described in Example 15, the reaction of (+)-(R)-2-N,N-
dimethylamino-8-bromotetralin (435 mg, 1.71 mmolj with n-
butyllithium (2.05 mmol) and 4-bromophenethyl
chloromethyl ether (512 mg, 1.88 mmol) in 12 mL of THF
gave 201 mg of the desired product.
HC1 salt of the product has melting point of 114-115°C.
Elemental Analysis:
Calculated: C 59.38; H 6.41; N 3.30
Found: C 59.12; H 6.21; N 3.28
Example 27
(R)-2-N,N-dimethylamino-8-(4-methoxyphenyl)ethyloxymethyl
tetralin hydrochloride
Following substantially the same procedure as
described in Example 15, the reaction of (+)-(R)-2-N,N-
dimethylamino-8-bromotetralin (395.7 mg, 1.557 mm) with
n-butyllithium (1.07 ml) and 4-methoxyphenethyl
chloromethyl ether (351 mg, 1.635 mm) in 1 mL of THF gave
117 mg of the desired product.
HC1 salt of the product has melting point of 131-132°C.
Elemental Analysis:
Calculated: C 70.84; H 8.27; N 3.59
Found: C 70.81; H 8.37; N 3.59
The method of this invention is practiced by
administering to a mammal a direct acting 5-HT1D~, agonist
or a pharmaceutically acceptable salt thereof. The
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phrase "direct acting 5-HTlDa agonist" as used in this
specification and these claims means a non-endogenous
chemical compound and includes: (1) synthetic chemical
compounds (ligands) that mimic the action of serotonin on
5-HTlDa receptors by directly activating these receptors;
and (2) partial agonists, which are synthetic chemical
compounds (ligands) that mimic the action of serotonin on
5-HTlDa receptors by directly activating these receptors
but produce a smaller maximal effect than do other
ligands that act on the same receptor. These compounds
may have activity at other receptors but must have some
component of 5-HTlDa agonist activity.
Assav Experiments
The ability of the compounds of this invention to bind
to the 5-HTlDa receptor subtype was measured essentially as
described in N. Adham, et al., Proceedings of the National
Academy of Sciences (USA), 90, 408-412 (1993).
Membrane Preparation- Membranes were prepared from
transfected Ltk- cells which were grown to 100% confluency.
The cells were washed twice with phosphate-buffered saline,
scraped from the culture dishes into 5 mL of ice-cold
phosphate-buffered saline, and centrifuged at 200 x g for 5
minutes at 4oC. The pellet was resuspended in 2.5 mL of
ice-cold Tris buffer (20 mM Tris HC1, pH=7.4 at 23~C, 5 mM
EDTA) and homogenized with a Wheaton tissue grinder. The
lysate was subsequently centrifuged at 200 x g for 5 minutes
0
at 4 C to pellet large fragments which were discarded. The
supernatant was collected and centrifuged at 40,000 x g for
20 minutes at 4~C. The pellet resulting from this
centrifugation was washed once in ice-cold Tris wash buffer
and resuspended in a final buffer containing 50 mM Tris HC1
and 0.5 mM EDTA, pH=7.4 at 23~C. Membrane preparations were
kept on ice and utilized within two hours for the
radioligand binding assays. Protein concentrations were
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determined by the method of Bradford (Anal. Biochem., 72,
248-254 (1976)).
Radioliqand Binding: [3H-5-HT] binding was performed
using slight modifications of the 5-HT1D assay conditions
reported by Herrick-Davis and Titeler (J. Neurochem., 50,
1624-1631 (1988)) with the omission of masking ligands.
Radioligand binding studies were achieved at 37oC in a total
volume of 250 mL of buffer (50 mM Tris, 10 mM MgCl2, 0.2 mM
EDTA, 10 mM pargyline, 0.1% ascorbate, pH=7.4 at 37oC) in 96
well microtiter plates. Saturation studies were conducted
using [3H]5-HT at 12 different concentrations ranging from
0.5 nM to 100 nM. Displacement studies were performed using
4.5-5.5 nM [3H]5-HT. The binding profile of drugs in
competition experiments was accomplished using 10-12
concentrations of compound. Incubation times were 30
minutes for both saturation and displacement studies based
upon initial investigations which determined equilibrium
binding conditions. Nonspecific binding was defined in the
presence of 10 mM 5-HT. Binding was initiated by the
addition of 50 mL membrane homogenates (10-20 ~,g). The
reaction was terminated by rapid filtration through
presoaked (0.5% poylethyleneimine) filters using 48R Cell
Brandel Harvester (Gaithersburg, MD). Subsequently, filters
were washed for 5 seconds with ice cold buffer (50 mM Tris
HC1, pH=7.4 at 4oC), dried and placed into vials containing
2.5 mL Readi-Safe (Beckman, Fullerton, CA) and radioactivity
was measured using a Beckman LS 5000TA liquid scintillation
counter. The efficiency of counting of [3H]5-HT averaged
between 45-50%. Binding data was analyzed by computer-
assisted nonlinear regression analysis (Accufit and
Accucomp, Lunden Software, Chagrin Falls, OH). IC50 values
were converted to Ki values using the Cheng-Prusoff equation
(Biochem. Pharmacol., 22, 3099-3108 (1973). All experiments
were performed in triplicate. Representative compounds of
the invention exhibited an Ki at the 5-HTlDa receptor of at
least 100 ~.tmol.
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As was reported by R.L. Weinshank, et al., W093/14201,
the 5-HT1D receptor is functionally coupled to a G-protein
as measured by the ability of serotonin and serotonergic
drugs to inhibit forskolin stimulated cAMP production in
NIH3T3 cells transfected with. the 5-HT1D receptor. Adenylate
cyclase activity was determined using standard techniques.
A maximal effect is achieved by serotonin. An E~x is
determined by dividing the inhibition of a test compound by
the maximal effect and determining a percent inhibition.
(N. Adham, et al., supra,; R.L. Weinshank, et al.,
Proceedings of the National Academy of Sciences (USA),
89,3630-3634 (1992)), and the references cited therein.
Measurement of cAMP formation
Transfected NIH3T3 cells (estimated Bmax from one point
competition studies=488 fmol/mg of protein) were incubated
in DMEM, 5 mM theophylline, 10 mM HEPES (4-[2-hydroxyethyl]-
1-piperazineethanesulfonic acid) and 10 ~M pargyline for 20
minutes at 37oC, 5% C02. Drug dose-effect curves were then
conducted by adding 6 different final concentrations of
drug, followed immediately by the addition of forskolin (10
mM). Subsequently, the cells were incubated for an
additional 10 minutes at 37oC, 5% C02. The medium was
aspirated and the reaction was stopped by the addition of
100 mM HC1. To demonstrate competitive antagonism, a dose-
response curve for 5-HT was measured in parallel, using a
fixed dose of methiothepin (0.32 mM). The plates were
stored at 4oC for 15 minutes and then centrifuged for 5
minutes at 500 x g to pellet cellular debris, and the
supernatant was aliquoted and stored at -20oC before
assessment of cAMP formation by radioimmunoassay (CAMP
radioimmunoassay kit; Advanced Magnetics, Cambridge, MA).
Radioactivity was quantified using a Packard COBRA Auto
Gamma counter, equipped with data reduction software.
Representative compounds were tested and found to be
agonists at the 5-HTlDa receptor in the cAMP assay.
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Pharmaceutical Formulations of the Invention
The therapeutic and prophylactic treatments provided by
this invention are practiced by administering to a mammal in
need thereof a dose of a compound of formula I or II, or a
pharmaceutically acceptable salt thereof, that is effective
in activating the 5-HTlDa receptor.
While it is possible to administer a compound employed
in the methods of this invention directly without any
formulation, the compounds are usually administered in the
form of pharmaceutical formulation comprising a
pharmaceutically acceptable excipient and at least one
compound of the present invention. The compounds or
formulations of the present invention may be administered by
the oral and rectal routes, topically, parenterally, e.g.,
by injection and by continuous or discontinuous intra-
arterial infusion, in the form of, for example, tablets,
lozenges, sublingual tablets, sachets, cachets, elixirs,
gels, suspensions, aerosols, ointments, for example,
containing from 0.01 to 90% by weight of the active compound
in a suitable base, soft and hard gelatin capsules,
suppositories, injectable solutions and suspensions in
physiologically acceptable media, and sterile packaged
powders adsorbed onto a support material for making
injectable solutions. Such forntulations are prepared in a
manner well known in the pharmaceutical art and comprise at
least one active compound. See, e.g., REMINGTON~s
PHARMACEUTICAL SCIENCES, (16th ed. 1980) .
In making the formulations employed in the present
invention the active ingredient is usually mixed with an
excipient, diluted by an excipient or enclosed within such a
carrier which can be in the form of a capsule, sachet, paper
or other container. When the excipient serves as a diluent,
it can be a solid, semi-solid, or liquid material, which
acts as a vehicle, carrier or medium for the active
ingredient. In preparing a formulation, it may be
necessary to mill the active compound to provide the
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appropriate particle size prior to combining with the other
ingredients. If the active compound is substantially
insoluble, it ordinarily is milled to a particle size of
less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by
milling to provide a substantially uniform distribution in
the formulation, e.g. about 40 mesh.
Some examples of suitable carriers, excipients and
diluents include lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidone, cellulose,
tragacanth, gelatin, water, syrup, and methyl cellulose.
The formulations can additionally include: lubricating
agents such as talc, magnesium stearate, and mineral oil;
wetting agents; emulsifying and suspending agents;
preserving agents such as methyl- and
propylhydroxybenzoates; sweetening agents; and flavoring
agents. The compositions of the invention can be formulated
so as to provide quick, sustained or delayed release of the
active ingredient after administration to the patient by
employing procedures known in the art.
The compounds of this invention may be delivered
transdermally using known transdermal delivery systems and
excipients. Most preferably, a compound of this invention
is admixed with permeation enhancers including, but not
limited to, propylene glycol, polyethylene glycol
monolaurate, and azacycloalkan-2-ones, and incorporated into
a patch or similar delivery system. Additional excipients
including gelling agents, emulsifiers, and buffers may be
added to the transdermal formulation as desired.
For topical administration, a compound of this
invention ideally can be admixed with any variety of
excipients in order to form a viscous liquid or cream-like
preparation.
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For oral administration, a compound of this invention
ideally can be admixed with carriers and diluents and molded
into tablets or enclosed in gelatin capsules.
In the case of tablets, a lubricant may be incorporated
to prevent sticking and binding of the powdered ingredients
in the dies and on the punch of the tableting machine. For
such purpose there may be employed for instance aluminum,
magnesium or calcium stearates, talc or mineral oil.
Preferred pharmaceutical forms of the present invention
include capsules, tablets and injectable solutions.
Especially preferred are capsules and tablets.
The therapeutic and prophylactic treatments provided by
this invention are practiced by administering to a mammal in
need thereof a dose of a compound of formula I or a
pharmaceutically acceptable salt or solvate thereof that is
effective to alleviate the pathological effects of 5-HTlDa
receptor-activated diseases.
Advantageously for this purpose, formulations may be
provided in unit dosage form, preferably each dosage unit
containing from about 5 to about 500 mg (from about 5 to 50
mg in the case of parenteral or inhalation administration,
and from about 25 to 500 mg in the case of oral or rectal
administration) of a compound of Formula I. Dosages from
about 0.5 to about 300 mg/kg per day, preferably 0.5 to 20
mg/kg, of active ingredient may be administered although it
will, of course, readily be understood that the amount of
the compound or compounds of Formula I actually to be
administered will be determined by a physician, in the light
of all the relevant circumstances including the condition to
be treated, the choice of compound to be administered and
the choice of route of administration and therefore the
above preferred dosage range is not intended to limit the
scope of the present invention in any way.
The specific dose of a compound administered according
to this invention to obtain therapeutic or prophylactic
effects will, of course, be determined by the particular
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circumstances surrounding the case, including, for example,
the route of administration the age, weight and response of
the individual patient, the condition being treated and the
severity of the patient s symptoms.
In general, the compounds of the invention are most
desirably administered at a concentration that will
generally afford effective results without causing any
serious side effects and can be administered either as a
single unit dose, or if desired, the dosage may be
divided into convenient subunits administered at suitable
times throughout the day.
The following formulation examples may employ as active
compounds any of the compounds of this invention. The
examples are illustrative only and are not intended to limit
the scope of the invention in any way.
Formulation I
Hard gelatin capsules are prepared using the
following ingredients:
Quantity
(mg/capsule)
(R)-2-N-methyl-N-hexylamino-8- 250
cyclooctyltetralin
Starch, dried 200
Magnesium stearate 10
Total 460 mg
i
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Formulation 2
A tablet is prepared using the ingredients below:
Quantity
(mg/tablet)
(R)-2-N-isopentylamino-8-(1- 250
oxacyclopropyl)tetralin
Cellulose, microcrystalline 400
Silicon dioxide, fumed 10
Stearic acid 5
Total 665 mg
The components are blended and compressed to form tablets
each weighing 665 mg.
Formulation 3
An aerosol solution is prepared containing the
following components:
Weight
(R)-2-N,N-di-t-butylamino-8- 0.25
isobutyltetralin
Ethanol 25.75
Propellant 22 74.00
(Chlorodifluoromethane)
Total 100.00
The active compound is mixed with ethanol and
the mixture added to a portion of the propellant 22,
cooled to -30°C and transferred to a filling device. The
required amount is then fed to a stainless steel
container and diluted with the remainder of the
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propellant. The valve units are then fitted to the
container.
Formulation 4
Tablets, each containing 60 mg of active
ingredient, are made as follaws:
(R)-2-N-propylamino-8-kept-1-en-lyltetralin 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone (as 10% solution in 4 mg
water)
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 ma
Total 150 mg
The active ingredient, starch and cellulose are
passed through a No. 45 mesh U.S. sieve and mixed
thoroughly. The aqueous solution containing
polyvinylpyrrolidone is mixed with the resultant powder,
and the mixture then is passed through a No. 14 mesh U.S.
sieve. The granules so produced are dried at 50°C and
passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate and talc,
previously passed through a No. 60 mesh U.S. sieve, are
then added to the granules which, after mixing, are
compressed on a tablet machine to yield tablets each
weighing 150 mg.
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Formulation 5
Capsules, each containing 80 mg of active
ingredient, are made as follows:
(R)-2-N-methyl-N-propylamino-8-(4- 80 mg
bromophenyl)butyloxymethyl tetralin
Starch _ 59 mg
Microcrystalline cellulose 59 mg
Magnesium stearate 2 mg
Total 200 mg
The active ingredient, cellulose, starch, and
magnesium stearate are blended, passed through a No. 45
mesh U.S. sieve, and filled into hard gelatin capsules in
200 mg quantities.
Formulation 6
Suppositories, each containing 225 mg of active
ingredient, are made as follows:
(R)-2-N,N-dimethylamino-8-(3- 225 mg
chlorophenyl)propyloxymethyltetralin
Saturated fatty acid glycerides 2.000 ma
Total 2,225 mg
The active ingredient is passed through a No.
60 mesh U.S. sieve and suspended in the saturated fatty
acid glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2 g capacity and allowed to cool.
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Formulation 7
Suspensions, each containing 50 mg of active
ingredient per 5 ml dose, are made as follows:
(R 50 mg
(R)-2-N-ethyl-N-methylamino-8-(4-
methylphenyl)butyloxytetralin
Sodium carboxymethyl cellulose 50 mg
SY~P 1. 2 5 ml
Benzoic acid solution 0.10 ml
Flavor q,v.
Color q,v.
Purified water to total 5 ml
The active ingredient is passed through a No.
45 mesh U.S. sieve and mixed with the sodium
carboxymethyl cellulose and syrup to form a smooth paste.
The benzoic acid solution, flavor and color are diluted
with a portion of the water and added, with stirring.
Sufficient water is then added to produce the required
volume.
Formulation 8
An intravenous formulation may be prepared as
follows:
(R)-2-N,N-dipropyl-8-(3- 100 mg
propylphenyl)hexyloxyethyltetralin
hydrochloride
Isotonic saline 1,000 ml
The solution of the above ingredients generally is
administered intravenously to a subject at a rate of 1 ml
per minute.
