U.S. patent application number 11/738692 was filed with the patent office on 2007-08-16 for quinoline 3-amino chroman derivatives.
Invention is credited to Jonathan Laird Gross, Nicole Theriault Hatzenbuhler, Gary Paul Stack, Dahui Zhou.
Application Number | 20070191417 11/738692 |
Document ID | / |
Family ID | 33436707 |
Filed Date | 2007-08-16 |
United States Patent
Application |
20070191417 |
Kind Code |
A1 |
Hatzenbuhler; Nicole Theriault ;
et al. |
August 16, 2007 |
QUINOLINE 3-AMINO CHROMAN DERIVATIVES
Abstract
Quinoline 3-amino chroman derivatives and compositions
containing such compounds are disclosed. Methods for using the
quinoline 3-amino chroman derivatives and compositions containing
such compounds in the treatment of serotonin disorders are
disclosed. Also disclosed are processes for preparing quinoline
3-amino chroman derivatives.
Inventors: |
Hatzenbuhler; Nicole Theriault;
(Bridgewater, NJ) ; Zhou; Dahui; (East Brunswick,
NJ) ; Stack; Gary Paul; (Ambler, PA) ; Gross;
Jonathan Laird; (Robbinsville, NJ) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
CIRA CENTRE, 12TH FLOOR
2929 ARCH STREET
PHILADELPHIA
PA
19104-2891
US
|
Family ID: |
33436707 |
Appl. No.: |
11/738692 |
Filed: |
April 23, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10835128 |
Apr 29, 2004 |
7227023 |
|
|
11738692 |
Apr 23, 2007 |
|
|
|
60466583 |
Apr 30, 2003 |
|
|
|
Current U.S.
Class: |
514/291 |
Current CPC
Class: |
A61P 25/32 20180101;
A61P 25/00 20180101; A61P 25/36 20180101; C07D 491/04 20130101;
A61P 25/24 20180101; A61P 43/00 20180101; A61P 25/22 20180101; A61P
15/10 20180101; A61P 3/04 20180101 |
Class at
Publication: |
514/291 |
International
Class: |
A61K 31/44 20060101
A61K031/44 |
Claims
1. A method of treating a patient suspected of suffering from a
serotonin-related disorder, comprising the step of administering to
the patient a therapeutically effective amount of a compound of
formula I: ##STR7## or a pharmaceutically acceptable salt thereof;
wherein R.sup.1 is hydrogen, alkyl having 1 to 6 carbon atoms,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
methylcyclopropyl, or methylcyclobutyl; R.sup.2 is hydrogen or
alkyl having 1 to 6 carbon atoms; R.sup.3 is hydrogen, fluoro,
chloro, bromo, iodo, cyano at either the 5- or 6-position; and n is
an integer from 2 to 4.
2. A method according to claim 1, wherein said serotonin-related
disorder is depression, anxiety, panic disorder, post-traumatic
stress disorder, premenstrual dysphoric disorder, attention deficit
disorder, obsessive compulsive disorder, social anxiety disorder,
generalized anxiety disorder, obesity, anorexia nervosa, bulimia
nervosa, vasomotor flushing, cocaine addiction, alcohol addiction,
or sexual dysfunction.
3. The method of claim 2 wherein said serotonin-related disorder is
depression.
4. A method of inhibiting serotonin uptake in a patient in need
thereof, comprising the step of administering to the patient a
therapeutically effective amount of the compound of formula I:
##STR8## or a pharmaceutically acceptable salt thereof; wherein
R.sup.1 is hydrogen, alkyl having 1 to 6 carbon atoms, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, or
methylcyclobutyl; R.sup.2 is hydrogen or alkyl having 1 to 6 carbon
atoms; R.sup.3 is hydrogen, fluoro, chloro, bromo, iodo, cyano at
either the 5- or 6-position; and n is an integer from 2 to 4.
5. A method of antagonizing 5-HT.sub.1A receptors in a patient in
need thereof, comprising the step of administering to the patient a
therapeutically effective amount of the compound of formula I:
##STR9## or a pharmaceutically acceptable salt thereof; wherein
R.sup.1 is hydrogen, alkyl having 1 to 6 carbon atoms, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, or
methylcyclobutyl; R.sup.2 is hydrogen or alkyl having 1 to 6 carbon
atoms; R.sup.3 is hydrogen, fluoro, chloro, bromo, iodo, cyano at
either the 5- or 6-position; and n is an integer from 2 to 4.
6. A method of treating a patient suspected of suffering from a
serotonin disorder, comprising the step of administering to the
patient a therapeutically effective amount of the compound of
formula II: ##STR10## or a pharmaceutically acceptable salt
thereof; wherein R.sup.1 is hydrogen, alkyl having 1 to 6 carbon
atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
methylcyclopropyl, or methylcyclobutyl; R.sup.2 is hydrogen or
alkyl having 1 to 6 carbon atoms; R.sup.3 is hydrogen, fluoro,
chloro, bromo, iodo, cyano at either the 5- or 6-position; and n is
an integer from 2 to 4.
7. A method according to claim 6, wherein said serotonin disorder
is depression, anxiety, panic disorder, post-traumatic stress
disorder, premenstrual dysphoric disorder, attention deficit
disorder, obsessive compulsive disorder, social anxiety disorder,
generalized anxiety disorder, obesity, anorexia nervosa, bulimia
nervosa, vasomotor flushing, cocaine addiction, alcohol addiction,
or sexual dysfunction.
8. The method of claim 7 wherein said serotonin disorder is
depression.
9. A method of inhibiting serotonin uptake in a patient in need
thereof, comprising the step of administering to the patient a
therapeutically effective amount of the compound of formula II:
##STR11## or a pharmaceutically acceptable salt thereof; wherein
R.sup.1 is hydrogen, alkyl having 1 to 6 carbon atoms, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, or
methylcyclobutyl; R.sup.2 is hydrogen or alkyl having 1 to 6 carbon
atoms; R.sup.3 is hydrogen, fluoro, chloro, bromo, iodo, cyano at
either the 5- or 6-position; and n is an integer from 2 to 4.
10. A method of antagonizing 5-HT.sub.1A receptors in a patient in
need thereof, comprising the step of administering to the patient a
therapeutically effective amount of the compound of formula II:
##STR12## or a pharmaceutically acceptable salt thereof; wherein
R.sup.1 is hydrogen, alkyl having 1 to 6 carbon atoms, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, or
methylcyclobutyl; R.sup.2 is hydrogen or alkyl having 1 to 6 carbon
atoms; R.sup.3 is hydrogen, fluoro, chloro, bromo, iodo, cyano at
either the 5- or 6-position; and n is an integer from 2 to 4.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims benefit of Provisional
Application Ser. No. 60/466,583, filed Apr. 30, 2003, the
disclosure of which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel quinoline 3-amino
chroman derivatives, processes for preparing such derivatives, and
the use of such derivatives to treat a variety of psychological
disorders. Preferred compounds of this invention display activity
both as serotonin reuptake inhibitors and as 5-HT.sub.1A receptor
agonists, and are useful in the treatment of serotonin-related
disorders.
BACKGROUND OF THE INVENTION
[0003] Major depressive disorder affects an estimated 340 million
people worldwide. Depression is the most frequently diagnosed
psychiatric disorder and, according to the World Health
Organization, is the fourth greatest public health problem. If left
untreated, the effects of depression can be devastating, robbing
people of the energy or motivation to perform everyday activities
and, in some cases, leading to suicide. Symptoms of the disorder
include feelings of sadness or emptiness, lack of interest or
pleasure in nearly all activities, and feelings of worthlessness or
inappropriate guilt. In addition to the personal costs of
depression, the disorder also has been estimated to result in more
than $40 billion in annual costs in the United States alone, due to
premature death, lost productivity, and absenteeism.
[0004] Selective serotonin reuptake inhibitors (SSRIs) have had
significant success in treating depression and related illnesses
and have become among the most prescribed drugs since the 1980s.
Some of the most widely known SSRIs are fluoxetine, sertraline,
paroxetine, fluvoxamine and citalopram. Although they have a
favorable side effect profile compared to tricyclic antidepressants
(TCAs), they have their own particular set of side effects due to
the non-selective stimulation of serotonergic sites. They typically
have a slow onset of action, often taking several weeks to produce
their full therapeutic effect. Furthermore, they have generally
been found to be effective in less than two-thirds of patients.
[0005] SSRIs are believed to work by blocking the neuronal reuptake
of serotonin, increasing the concentration of serotonin in the
synaptic space, and thus increasing the activation of postsynaptic
serotonin receptors. Although a single dose of a SSRI can inhibit
the neuronal serotonin transporter, and thus would be expected to
increase synaptic serotonin, clinical improvement has generally
been observed only after long-term treatment. It has been suggested
that the delay in onset of antidepressant action of the SSRIs is
the result of an increase in serotonin levels in the vicinity of
the serotonergic cell bodies. This excess serotonin is believed to
activate somatodendritic autoreceptors, i.e., 5-HT.sub.1A
receptors, reduce cell firing activity and, in turn, decrease
serotonin release in major forebrain areas. This negative feedback
limits the increment of synaptic serotonin that can be induced by
antidepressants acutely. Over time, the somatodendritic
autoreceptors become desensitized, allowing the full effect of the
SSRIs to be expressed in the forebrain. This time period has been
found to correspond to the latency for the onset of antidepressant
activity [Perez, V., et al., The Lancet, 1997, 349: 1594-1597].
[0006] In contrast to the SSRIs, a 5-HT.sub.1A agonist or partial
agonist acts directly on postsynaptic serotonin receptors to
increase serotonergic neurotransmission during the latency period
for the SSRI effect. Accordingly, the 5-HT.sub.1A partial agonists
buspirone and gepirone [Feiger, A., Psychopharmacol. Bull., 1996,
32(4): 659-665; Wilcox, C., Psychopharmacol. Bull., 1996, 32(93):
335-342] and the 5-HT.sub.1A agonist flesinoxan [Grof, P.,
International Clinical Psychopharmacology, 1993, 8(3): 167-172]
have shown efficacy in clinical trials for the treatment of
depression. Furthermore, such agents are believed to stimulate the
somatodendritic autoreceptors, thus hastening their desensitization
and decreasing the SSRI latency period. An agent with a dual
mechanism of antidepressant action would be expected to have
greater efficacy and thus reduce the number of patients refractory
to treatment. Indeed, buspirone augmentation to standard SSRI
therapy has been shown to produce marked clinical improvement in
patients initially unresponsive to standard antidepressant therapy
[Dimitriou, E., J. Clinical Psychopharmacol., 1998, 18(6):
465-469].
[0007] Lacking from the current therapy regime, however, is a
single compound that effectively displays the dual mechanism of
antidepressant action.
SUMMARY OF THE INVENTION
[0008] This invention provides novel quinoline 3-amino chroman
derivatives. In preferred embodiments, the compounds of this
invention inhibit serotonin reuptake and/or are agonists or partial
agonists at the 5-HT.sub.1A receptor. Such preferred compounds are
thus useful in the treatment of diseases affected by disorders of
serotonin-affected neurological systems, such as depression,
anxiety, panic disorder, post-traumatic stress disorder,
premenstrual dysphoric disorder, attention deficit disorder,
obsessive compulsive disorder, social anxiety disorder, generalized
anxiety disorder, obesity, anorexia nervosa, bulimia nervosa,
vasomotor flushing, cocaine addiction, alcohol addiction, and
sexual dysfunction.
[0009] In one aspect, the present invention provides, quinoline
3-amino chroman derivatives having formula I or II: ##STR1##
[0010] or a pharmaceutically acceptable salt thereof;
[0011] wherein R.sup.1 is hydrogen, alkyl having 1 to 6 carbon
atoms, cyclopropyl, cyclolbutyl, cyclopentyl, cyclohexyl,
methylcyclopropyl, or methylcyclobutyl;
[0012] R.sup.2 is hydrogen or alkyl having 1 to 6 carbon atoms;
[0013] R.sup.3 is hydrogen, fluoro, chloro, bromo, iodo, cyano at
either the 5- or 6-position; and
[0014] n is an integer from 2 to 4.
[0015] In another aspect, the present invention is directed to
compositions comprising a compound of formula I or II and one or
more pharmaceutically acceptable carriers.
[0016] Also provided methods for blocking the neuronal reuptake of
serotonin and/or modulating the activity of 5-HT.sub.1A receptors
through in vitro or in vivo administration of an effective amount
of one or more compound according to the invention. In this
respect, such compounds preferably function as 5-HT.sub.1A
agonists.
[0017] The present invention also provides methods of treating a
patient suspected of suffering from a serotonin-related disorder,
comprising the step of administering to the patient a
therapeutically effective amount of a compound of formula I or
II.
[0018] In yet another aspect, the present invention is also
directed to methods of inhibiting the uptake of serotonin in a
patient in need thereof, comprising the step of administering to
the patient a therapeutically effective amount of a compound of
formula I or II.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0019] The term "alkyl", as used herein, refers to an aliphatic
hydrocarbon chain and includes, but is not limited to, straight and
branched chains containing from 1-12 carbon atoms, preferably 1-6
carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl,
i-butyl and t-butyl are encompassed by the term alkyl.
[0020] This invention relates to both the R and S stereoisomers of
the 3-amino-chroman, as well as to mixtures of the R and S
stereoisomers. Throughout this application, the name of the product
of this invention, where the absolute configuration of the
3-amino-chromans is not indicated, is intended to embrace the
individual R and S enantiomers as well as mixtures thereof.
[0021] Where a stereoisomer is preferred, it may, in some
embodiments, be provided substantially free of the corresponding
enantiomer. Thus, "an enantiomer substantially free of the
corresponding enantiomer" refers to a compound that is isolated or
separated via separation techniques or prepared free of the
corresponding enantiomer. "Substantially free", as used herein,
refers to a compound made up of a significantly greater proportion
of one stereoisomer. Stereoisomers may be isolated in pure form
from racemic mixtures by standard separation techniques.
[0022] Preferred among the above noted R.sup.1 groups are hydrogen
and alkyl groups having 1 to 3 carbon atoms, with propyl being
particularly preferred. Preferred R.sup.2 groups are hydrogen and
methyl, and preferred R.sup.3 groups are hydrogen, fluoro, and
cyano, with fluoro being particularly preferred at the 5-position
of the indole. Preferred compounds are those of formula I or II in
which R.sup.1 is hydrogen or propyl, R.sup.2 is hydrogen, R.sup.3
is 5-fluoro, and n is an integer of 2, 3 or 4.
[0023] The following compounds are particularly preferred: [0024]
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine; [0025]
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quinolin-
-2-amine; [0026]
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyrano[3,2-f-
]quinolin-2-amine; [0027]
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quin-
olin-2-amine; [0028]
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quin-
olin-2-amine; [0029]
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyrano[3-
,2-f]quinolin-2-amine; [0030]
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyrano[3-
,2-f]quinolin-2-amine; [0031]
N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-2,3-dihydro-1H-pyrano[3,2-f]quinolin--
2-amine; [0032]
N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-N-propyl-2,3-dihydro-1H-pyrano[3,2-f]-
quinolin-2-amine; [0033]
3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine; [0034]
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]-
quinolin-3-amine; [0035]
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-3,4-dihydro-2H-pyrano[2,3-f-
]quinolin-3-amine; [0036]
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]quin-
olin-3-amine; [0037]
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]quin-
olin-3-amine; [0038]
N-[4-(5-fluoro-1H-indol-3-yl)butyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin--
3-amine; and [0039]
N-[4-(5-fluoro-1H-indol-3-yl)butyl]-N-propyl-3,4-dihydro-2H-pyrano[2,3-f]-
quinolin-3-amine; and pharmaceutical salts thereof.
[0040] Scheme I: General Scheme to Produce Compounds of Formula I
or II
[0041] The compounds of the invention are prepared by conventional
methods. The appropriate 3-bromoalkyl indole 2 is combined with a
quinoline 3-aminochroman derivative 1a or 1b in a solvent such as
dimethyl sulfoxide in the presence of triethylamine and heated to a
temperature of 80-100.degree. C. for several hours as illustrated
in Scheme I below. This is followed by reductive amination using
sodium cyanoborohydride and the desired alkyl aldehyde to introduce
the appropriate alkyl chain R.sup.1 on the basic nitrogen if
desired. ##STR2##
[0042] Alternatively, a 3-aminoalkyl indole can be used as starting
material and combined with a quinoline chroman 3-carbonyl in the
presence of a reducing agent such as sodium cyanoborohydride or
sodium triacetoxyborohydride to generate the desired product of
Formula I or II (where R.sup.1 is H). This is followed by a second
reductive amination using sodium cyanoborohydride and the desired
alkyl aldehyde to introduce the appropriate alkyl chain R.sup.1 on
the basic nitrogen if desired. The compounds of the invention may
be resolved into their enantiomers by conventional methods.
[0043] The 3-bromoalkyl indoles required to prepare the compounds
of the invention are known compounds, and can be prepared by
generally following the procedures taught by U.S. Pat. Nos.
5,750,724, 6,121,307 and 6,313,114. The
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine 1a and
3,4,-dihydro-2H-pyrano[2,3-f]quinolin-3-amine 1b are novel
compounds, and can be prepared by the procedure illustrated below
in Schemes II and III, respectively.
Scheme II: Preparation of
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine
[0044] The 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine 1a is
prepared according to Scheme II. The commercially available
6-hydroxyquinoline 3 is first protected with an allyl group, and
the resulting 6-allyloxyquinoline 4 subjected to Claisen
rearrangement by heating in p-xylene to generate
5-allyl-quinolin-6-ol 5. The resulting phenol is protected with a
suitable protecting group, such as benzyl, and the resulting
product 6,5-allyl-6-benzyloxy-quinoline converted to the
3-(6-benzyloxy-quinoline-5-yl)-propane-1,2-diol 7 using the
Sharpless Catalytic Asymmetric Dihydroxylation reagent,
AD-mix-.alpha.. The diol is then converted to the bromoacetate 8
upon heating in 30% HBr in acetic acid, simultaneously cleaving the
benzyl protecting group. Cyclization to 9 is achieved under basic
conditions using sodium hydride. Cleavage of the acetyl group under
basic conditions produced 10,
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-ol quantitatively. The
tosylate 11 is then generated using p-toluenesulfonyl chloride in
pyridine, and converted to the azide 12 with sodium azide in DMF.
The azide is finally reduced by treatment with triphenylphosphine
in THF--H.sub.2O to provide the
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine 1a suitable for the
preparation of some of the derivatives claimed in this invention.
##STR3## ##STR4## Scheme III: Preparation of
3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine
[0045] The 3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine 1b is
prepared according to Scheme III. The commercially available
5-hydroxyquinoline 13 is first protected with an allyl group, and
the resulting 5-allyloxyquinoline 14 subjected to Claisen
rearrangement by heating in p-xylene to generate
6-allyl-quinolin-5-ol 15. The resulting phenol is protected with a
suitable protecting group, such as benzyl, and the resulting
product 16, 6-allyl-5-benzyloxy-quinoline converted to the
3-(5-benzyloxy-quinoline-6-yl)-propane-1,2-diol 17 using the
Sharpless Catalytic Asymmetric Dihydroxylation reagent,
AD-mix-.alpha.. The diol is then converted to the bromoacetate 18
upon heating in 30% HBr in acetic acid, simultaneously cleaving the
benzyl protecting group. Cyclization to 19 is achieved under basic
conditions using sodium hydride. Cleavage of the acetyl group under
basic conditions produced 20,
3,4-dihydro-2H-pyrano[2,3f]quinolin-3-ol quantitatively. The
tosylate 21 is then generated using p-toluenesulfonyl chloride in
pyridine, and converted to the azide 22 with sodium azide in DMF.
The azide is finally reduced by treatment with triphenylphosphine
in THF--H.sub.2O to provide the
3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine 1b suitable for the
preparation of some of the derivatives claimed in this invention.
##STR5## ##STR6## All enantiomers were separated by high
performance liquid chromatography (HPLC) using a chiral column.
[0046] The terms "effective amount", "therapeutically effective
amount" and "effective dosage" as used herein, refer to the amount
of a compound of formula I or II that, when administered to a
patient, is effective to at least partially ameliorate a condition
form which the patient is suspected to suffer. Such conditions
include, but are not limited to, depression, anxiety, panic
disorder, post-traumatic stress disorder, premenstrual dysphoric
disorder, attention deficit disorder, obsessive compulsive
disorder, social anxiety disorder, generalized anxiety disorder,
obesity, anorexia nervosa, bulimia nervosa, vasomotor flushing,
cocaine addiction, alcohol addiction, and sexual dysfunction.
[0047] The term "pharmaceutically acceptable salt", as used herein,
refers to salts derived from organic and inorganic acids such as,
for example, acetic, lactic, citric, cinnamic, tartaric, succinic,
fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,
hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,
pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic,
salicylic, benzoic, and similarly known acceptable acids.
[0048] The term "patient", as used herein, refers to a mammal,
preferably a human.
[0049] The terms "administer", "administering" or "administration",
as used herein, refer to either directly administering a compound
or composition to a patient, or administering a prodrug derivative
or analog of the compound to the patient, which will form an
equivalent amount of the active compound or substance within the
patient's body.
[0050] Compounds of formula I and II have been found to act as
serotonin reuptake inhibitors and to have an affinity for the
5-HT.sub.1A reuptake transporter. They are therefore useful in the
treatment of diseases affected by disorders of the serotonin
affected neurological systems, including, but not limited to,
depression, anxiety, panic disorder, post-traumatic stress
disorder, premenstrual dysphoric disorder, attention deficit
disorder, obsessive compulsive disorder, social anxiety disorder,
generalized anxiety disorder, obesity, anorexia nervosa, bulimia
nervosa, vasomotor flushing, cocaine addiction, alcohol addiction,
and sexual dysfunction. The present invention thus provides
pharmaceutical compositions comprising at least either one compound
of formula I or one compound of formula II, mixtures thereof, and
optionally one or more pharmaceutically acceptable carriers,
excipient, or diluents. The term "carrier", as used herein, shall
encompass carriers, excipients, and diluents.
[0051] Examples of such carriers are well known to those skilled in
the art and are prepared in accordance with acceptable
pharmaceutical procedures, such as, for example, those described in
Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R.
Gennaro, Mack Publishing Company, Easton, Pa. (1985), which is
incorporated herein by reference in its entirety. Pharmaceutically
acceptable carriers are those that are compatible with the other
ingredients in the formulation and biologically acceptable.
[0052] The compounds of this invention may be administered orally
or parenterally, neat or in combination with conventional
pharmaceutical carriers. Applicable solid carriers can include one
or more substances which may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents or
encapsulating materials. They are formulated in conventional
manner, for example, in a manner similar to that used for known
antihypertensive agents, diuretics and .beta.-blocking agents. Oral
formulations containing the active compounds of this invention may
comprise any conventionally used oral forms, including tablets,
capsules, buccal forms, troches, lozenges and oral liquids,
suspensions or solutions. In powders, the carrier is a finely
divided solid, which is an admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to 99% of the active
ingredient.
[0053] Capsules may contain mixtures of the active compound(s) with
inert fillers and/or diluents such as the pharmaceutically
acceptable starches (e.g. corn, potato or tapioca starch), sugars,
artificial sweetening agents, powdered celluloses, such as
crystalline and microcrystalline celluloses, flours, gelatins,
gums, etc.
[0054] Useful tablet formulations may be made by conventional
compression, wet granulation or dry granulation methods and utilize
pharmaceutically acceptable diluents, binding agents, lubricants,
disintegrants, surface modifying agents (including surfactants),
suspending or stabilizing agents, including, but not limited to,
magnesium stearate, stearic acid, sodium lauryl sulfate, talc,
sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
cellulose, microcrystalline cellulose, sodium carboxymethyl
cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine,
alginic acid, acacia gum, xanthan gum, sodium citrate, complex
silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium
phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium
chloride, low melting waxes and ion exchange resins. Preferred
surface modifying agents include nonionic and anionic surface
modifying agents. Representative examples of surface modifying
agents include, but are not limited to, poloxamer 188, benzalkonium
chloride, calcium stearate, cetostearl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, colliodol silicon dioxide,
phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and
triethanolamine. Oral formulations herein may utilize standard
delay or time release formulations to alter the absorption of the
active compound(s). The oral formulation may also consist of
administering the active ingredient in water or fruit juice,
containing appropriate solubilizers or emulisifiers as needed.
[0055] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups and elixirs. The active ingredient
of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g. cellulose
derivatives, preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration. The liquid
carrier for pressurized compositions can be halogenated hydrocarbon
or other pharmaceutically acceptable propellant.
[0056] Liquid pharmaceutical compositions, which are sterile
solutions or suspensions, can be utilized by, for example,
intramuscular, intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously. Compositions for
oral administration may be in either liquid or solid form.
[0057] Preferably the pharmaceutical composition is in unit dosage
form, e.g. as tablets, capsules, powders, solutions, suspensions,
emulsions, granules, or suppositories. In such form, the
composition is sub-divided in unit dose containing appropriate
quantities of the active ingredient; the unit dosage forms can be
packaged compositions, for example, packeted powders, vials,
ampoules, prefilled syringes or sachets containing liquids. The
unit dosage form can be, for example, a capsule or tablet itself,
or it can be the appropriate number of any such compositions in
package form. Such unit dosage form may contain from 0.1 to 100 mg
of a compound of the invention and preferably from 2 to 50 mg.
Still further preferred unit dosage forms contain 5 to 25 mg of a
compound of the present invention. The compounds of the present
invention can be administered orally at a dose range of 0.01 to 100
mg/kg or preferably, at a dose range of 0.1 to 10 mg/kg. Such
compositions may be administered from 1 to 6 times a day, more
usually to 1 to 4 times a day.
[0058] When administered for the treatment or inhibition of a
particular disease state or disorder, it is understood that the
effective dosage may vary depending upon the particular compound
utilized, the mode of administration, the condition, and severity
thereof, of the condition being treated, as well as the various
physical factors related to the individual being treated. In
therapeutic application, compounds of the present invention are
provided to a patient already suffering from a disease in an amount
sufficient to cure or at least partially ameliorate the symptoms of
the disease and its complications. An amount adequate to accomplish
this is defined as a "therapeutically effective amount". The dosage
to be used in the treatment of a specific case must be subjectively
determined by the attending physician. The variables involved
include the specific condition and the size, age and response
pattern of the patient. Effective administration of the compounds
of this invention may be given at an oral dose of from about 0.1
mg/day to about 1000 mg/day. Preferably, administration will be
from about 10 mg/day to about 600 mg/day, more preferably, a
starting dose is about 5 mg/day with gradual increase in the daily
dose to about 150 mg/day, to provide the desired dosage level in
the human. Doses may be administered in a single dose or in two or
more divided doses. The projected daily dosages are expected to
vary with route of administration.
[0059] Such doses may be administered in any manner useful in
directing the active compounds herein to the recipient's
bloodstream, including orally, via implants, parentally (including
intravenous, intraperitoneal, intraarticularly and subcutaneous
injections), rectally, intranasally, topically, oculary (via eye
drops), vaginally, and transdermally.
[0060] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol. For
administration by intranasal or intrabrochial inhalation, the
compounds of this invention may be formulated into an aqueous or
partially aqueous solution.
[0061] The compounds of this invention may be administered
parenterally or intraperitoneally. Solutions or suspensions of
these active compounds as a free base or pharmaceutically
acceptable salt may be prepared in water suitably mixed with a
surfactant such as hydroxyl-propylcellulose. Dispersions may also
be prepared in glycerol, liquid polyethylene glycols and mixtures
thereof in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to inhibit the growth of
microorganisms.
[0062] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0063] The compounds of this invention can be administered
transdermally through the use of a transdermal patch. For the
purposes of this disclosure, transdermal administrations are
understood to include all administrations across the surface of the
body and the inner linings of bodily passages including epithelial
and mucosal tissues. Such administrations may be carried out using
the present compounds, or pharmaceutically acceptable salts
thereof, in lotions, creams, foams, patches, suspensions,
solutions, and suppositories (rectal and vaginal).
[0064] Transdermal administration may be accomplished through the
use of a transdermal patch containing the active compound and a
carrier that is inert to the active compound, is non-toxic to the
skin, and allows delivery of the agent for systemic absorption into
the blood stream via the skin. The carrier may take any number of
forms such as creams and ointments, pastes, gels and occlusive
devices. The creams and ointments may be viscous liquid or
semisolid emulsions of either the oil-in-water or water-in-oil
type. Pastes comprised of absorptive powders dispersed in petroleum
or hydrophilic petroleum containing the active ingredient may also
be suitable. A variety of occlusive devices may be used to release
the active ingredient into the blood stream, such as a
semi-permeable membrane covering a reservoir containing the active
ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the
literature.
[0065] The compounds of this invention may be administered rectally
or vaginally in the form of a conventional suppository. Suppository
formulations may be made from traditional materials, including
cocoa butter, with or without the addition of waxes to alter the
suppository's melting point, and glycerin. Water soluble
suppository bases, such as polyethylene glycols of various
molecular weights, may also be used.
[0066] The present invention includes prodrugs of compounds of
either formula I or formula II. "Prodrug", as used herein means a
compound which is convertible in vivo by metabolic means (e.g. by
hydrolysis) to a compound of either formula I or formula II.
Various forms of prodrugs are known in the art, for example, as
discussed in, for example, Bundgaard, (ed.), Design of Prodrugs,
Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol.
4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), "Design
and Application of Prodrugs", Textbook of Drug Design and
Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal
of Drug Deliver reviews, 8:1-38 (1992), Bundgaard, J. of
Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and
Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American
Chemical Society (1975), each of which is incorporated by reference
in its entirety.
[0067] The present invention further provides a compound of the
invention for use as an active therapeutic substance. Compounds of
the invention are of particular use in the treatment of diseases
affected by disorders of serotonin.
[0068] The present invention further provides a method for treating
depression, anxiety, panic disorder, post-traumatic stress
disorder, premenstrual dysphoric disorder, attention deficit
disorder, obsessive compulsive disorder, social anxiety disorder,
generalized anxiety disorder, obesity, anorexia nervosa, bulimia
nervosa, vasomotor flushing, cocaine addiction, alcohol addiction,
or sexual dysfunction in mammals including man, which comprises
administering to the afflicted mammal an effective amount of a
compound or a pharmaceutical composition of the invention.
EXAMPLES
[0069] The preparation of the intermediates utilized in Schemes II
and III above and representative compounds of the invention is
further illustrated below.
Example 1
Intermediate 4--6-allyloxyquinoline
[0070] To a suspension of sodium hydride (60%, 0.33 g, 8.3 mmol) in
anhydrous N,N-dimethylformamide (30 ml) was added
6-hydroxyquinoline (1.0 g, 6.9 mmol) at room temperature. The
reaction mixture was stirred for 1 hour, then allyl bromide (0.72
ml, 8.3 mmol) was added. The reaction mixture was allowed to stir
for 1 hour at room temperature, quenched with water and extracted
with methylene chloride. The organic layer was washed with water,
dried over anhydrous sodium sulfate and filtered. The solvent was
removed under vacuum. Chromatography (50% hexanes-ethyl acetate)
afforded 1.14 g (89%) of 6-allyloxyquinoline as brown oil. MS ESI
m/z 185 [M+H].sup.+.
Example 2
Intermediate 5--5-allyl-quinolin-6-ol
[0071] A solution of 6-allyloxyquinoline (intermediate 4) (1.14 g,
6.2 mmol) in p-xylene (30 ml) was allowed to reflux for 3 days. The
organic solvent was removed under vacuum. Chromatography (30%
hexanes-ethyl acetate) afforded 0.82 g (72%) of
5-allyl-quinolin-6-ol as a white solid: mp 162-164.degree. C.
Elemental Analysis for C.sub.12H, NO: Calculated: C, 77.81; H,
5.99; N, 7.56; Found: C, 77.82; H, 5.99; N, 7.45.
Example 3
Intermediate 6--5-allyl-6-benzyloxy-quinoline
[0072] To a suspension of sodium hydride (60%, 0.7 g, 16.8 mmol) in
anhydrous N,N-dimethylformamide (80 ml) was added
5-allyl-quinolin-6-ol (intermediate 5) (2.68 g, 14 mmol) slowly at
room temperature. The reaction mixture was stirred for 1 hour, then
benzyl bromide (2.57 ml, 21 mmol) was added. The mixture was
allowed to stir for 1.5 hrs at room temperature, quenched with
water and extracted with methylene chloride. The organic layer was
washed with water, dried over anhydrous sodium sulfate and
filtered. The solvent was removed under vacuum. Chromatography (30%
hexanes-ethyl acetate) afforded 3.6 g (92%) of
5-allyl-6-benzyloxy-quinoline as a light brown oil. MS ESI m/z 276
[M+H].sup.+.
Example 4
Intermediate 7--3-(6-benzyloxy-quinolin-5-yl)propane-1,2-diol
[0073] To a solution of commercially available AD-mix-.alpha. (20.2
g) in 2-methyl-2-propanol-water (30 ml: 40 ml) was added a solution
of 5-allyl-6-benzyloxy-quinoline (intermediate 6) (4.28 g, 15.5
mmol) in 10 ml of 2-methyl-2-propanol slowly. The mixture was
allowed to stir at room temperature for 18 hours, quenched with
saturated sodium hydrogensulfide hydrate solution and extracted
with methylene chloride. The organic layer was washed with water,
dried over anhydrous sodium sulfate and filtered. The solvent was
removed under vacuum. Chromatography (15% methanol-ethyl acetate)
afforded 4.23 g (88%) of
3-(6-benzyloxy-quinolin-5-yl)propane-1,2-diol as an off-yellow
solid: mp 160-162.degree. C. Elemental Analysis for
C.sub.19H.sub.19NO.sub.3: Calculated: C, 73.77; H, 6.19; N, 4.53;
Found: C, 73.39; H, 6.14; N, 4.41.
Example 5
Intermediate 8--acetic acid
1-bromomethyl-2-(6-hydroxyquinolin-5-yl)ethyl ester
[0074] A solution of 3-(6-benzyloxy-quinolin-5-yl)propane-1,2-diol
(intermediate 7) (0.25 g) in 15 ml of hydrogen bromide (30 wt. %
solution in acetic acid) was heated at 40.degree. C. for 2 hrs. The
reaction mixture was then poured into an ice bath, neutralized with
1N NaOH, and extracted with methylene chloride. The organic layer
was washed with water, dried over anhydrous sodium sulfate and
filtered. Chromatography (3% methanol-ethyl acetate) afforded 0.17
g (65%) of acetic acid
1-bromomethyl-2-(6-hydroxyquinolin-5-yl)ethyl ester as a white
solid: mp 145.5-147.5.degree. C. MS ESI m/z 324 [M+H].sup.+.
Example 6
Intermediate 9--2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl
acetate
[0075] To a suspension of sodium hydride (60%, 0.27 g, 6.6 mmol) in
anhydrous N,N-dimethylformamide (30 ml) was added a pre-cooled
solution of acetic acid
1-bromomethyl-2-(6-hydroxyquinolin-5-yl)ethyl ester (intermediate
8) (1.96 g, 6.0 mmol) in 10 ml of N,N-dimethylformamide at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for 1
hr, quenched with water, and extracted with methylene chloride. The
organic layer was washed with water, dried over anhydrous sodium
sulfate and filtered. The solvent was removed under vacuum.
Chromatography (10% hexanes-ethyl acetate) afforded 0.89 g (61%) of
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl acetate as a white solid:
mp 125.4-127.degree. C. MS ESI m/z 244 [M+H].sup.+. Elemental
Analysis for C.sub.14H.sub.13NO.sub.3: Calculated: C, 69.12; H,
5.39; N, 5.76; Found: C, 69.12; H, 5.48; N, 5.64.
Example 7
Intermediate 10--2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-ol
[0076] To a solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl
acetate (intermediate 9) (0.49 g, 2 mmol) in methanol (20 ml) at
0.degree. C. was added potassium carbonate (0.33 g, 2.4 mmol). The
reaction mixture was stirred at 0.degree. C. for 1 hr. The reaction
mixture was poured into ice-H.sub.2O and extracted with methylene
chloride. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum to generate 0.37 g
(91%) of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-ol as a white
solid: mp 160-161.5.degree. C. MS ESI m/z 202 [M+H].sup.+.
Example 8
Intermediate 11--2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl
4-methylbenzenesulfonate
[0077] A solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-ol
(intermediate 10) (0.47 g, 2.3 mmol) and p-toluene sulfonyl
chloride (0.89 g, 4.6 mmol) in anhydrous pyridine (20 mL) was
stirred at room temperature for 2.5 days. It was then poured into
ice-H.sub.2O and extracted with methylene chloride. The organic
layer was dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. Chromatography ((15:4:1)
EtOAc-Hexane-MeOH) afforded 0.77 g (93%) of
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl 4-methylbenzenesulfonate
as an off-white solid: mp 167.5-169.5.degree. C. MS ESI m/z 356
[M+H].sup.+. Elemental Analysis for C.sub.19H.sub.17NO.sub.4S:
Calculated: C, 64.21; H, 4.82; N, 3.94; Found: C, 63.98; H, 4.79;
N, 3.84.
Example 9
Intermediate 12--2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl
azide
[0078] A solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl
4-methylbenzenesulfonate (intermediate 11) (0.58 g, 1.6 mmol) and
sodium azide (1.6 g, 24 mmol) in anhydrous N,N-dimethylformamide
(30 mL) was heated at 90.degree. C. for 14 hrs. The reaction
mixture was poured on ice-H.sub.2O and extracted with methylene
chloride. The organic layer was washed with H.sub.2O, dried over
anhydrous sodium sulfate, filtered and concentrated under vacuum.
Chromatography (10% MeOH/CH.sub.2Cl.sub.2) afforded 0.38 g (77%) of
a mixture of 2,3-dihydro-1H-pyrano[3,2f]quinolin-2-yl azide and
chromene by-product (20-25%). MS ESI m/z 227 [M+H].sup.+.
Example 10
Intermediate 1a--2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine
[0079] A solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl
azide (intermediate 12) (2.05 g, 9.1 mmol) and triphenylphosphine
(2.6 g, 9.9 mmol) in 30% water-tetrahydrofuran was allowed to
reflux for 18 hrs. The solvent was removed under vacuum.
Chromatography (10% methanol-methylene chloride) afforded 1.28 g
(70%) of 2,3-dihydro-1H-pyrano[3,2f]quinolin-2-amine as an
off-white solid. It was then converted to the HCl salt by
dissolution in ethyl acetate and addition of 1M HCl/Et.sub.2O
solution (2.4 eq) to generate
2,3-dihydro-1H-pyrano[3,2f]quinolin-2-amine bis-hydrochloride salt
an off-white solid: mp>180.degree. C. MS ESI m/z 201
[M+H].sup.+. Elemental Analysis for
C.sub.12H.sub.12N.sub.2O.2.00HCl.0.30H.sub.2O; Calculated: C,
51.74; H, 5.28; N, 10.06; Found: C, 51.94; H, 5.77; N, 9.49.
Example 11
Intermediate 14--5-allyloxyquinoline
[0080] This compound was prepared generally following the procedure
above for intermediate 4, replacing 6-hydroxyquinoline with
5-hydroxyquinoline (10 g, 6.9 mmol). It was isolated in 85% yield
(10.83 g) as a brown oil. MS ESI m/z 186 [M+H].
Example 12
Intermediate 15--6-allyl-quinolin-5-ol
[0081] This compound was prepared generally following the procedure
above for intermediate 5, replacing 6-allyloxyquinoline with
5-allyloxyquinoline (intermediate 14) (10.8 g, 58 mmol). It was
isolated in 48% yield (5.18 g) as a white solid: mp 157-159.degree.
C. MS ESI m/z 186 [M+H].sup.+. Elemental Analysis for C.sub.12H,
NO: Calculated: C, 77.81; H, 5.99; N, 7.56; Found: C, 77.60; H,
5.96; N, 7.41.
Example 13
Intermediate 16--6-allyl-5-benzyloxy-quinoline
[0082] This compound was prepared generally following the procedure
above for intermediate 6, replacing 5-allyl-quinolin-6-ol with
6-allyl-quinolin-5-ol (intermediate 15) (5.17 g, 28 mmol). It was
isolated in 100% yield (based on 2 gm of recovered starting
material) as an off-white solid: mp 45-47.degree. C. MS ESI m/z 276
[M+H].sup.+. Elemental Analysis for C.sub.19H.sub.17NO: Calculated:
C, 82.88; H, 6.22; N, 5.09; Found: C, 82.80; H, 6.22; N, 5.06.
Example 14
Intermediate 17--3-(5-benzyloxy-quinolin-6-yl)-propane-1,2-diol
[0083] This compound was prepared generally following the procedure
above for intermediate 7, replacing 5-allyl-6-benzyloxy-quinoline
with 6-allyl-5-benzyloxy-quinoline (intermediate 16) (2.64 g, 9.6
mmol). It was isolated in 94% yield (9.0 g) as an off-white solid:
mp 116-118.degree. C. MS ESI m/z 310 [M+H].sup.+. Elemental
Analysis for C.sub.19H.sub.19NO.sub.3: Calculated: C, 73.77; H,
6.19; N, 4.53; Found: C, 73.82; H, 6.13; N, 4.57.
Example 15
Intermediate 18--acetic acid
1-bromomethyl-2-(5-hydroxyquinolin-6-yl)ethyl ester
[0084] This compound was prepared generally following the procedure
above for intermediate 8, replacing
3-(6-benzyloxy-quinolin-5-yl)propane-1,2-diol with
3-(5-benzyloxy-quinolin-6-yl)-propane-1,2-diol (intermediate 17)
(0.43 g, 1.39 mmol). It was isolated in 66% yield (0.3 g) as a
brown oil: MS ESI m/z 325 [M+H].sup.+.
Example 16
Intermediate 19--3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-yl
acetate
[0085] This compound was prepared generally following the procedure
above for intermediate 9, replacing acetic acid
1-bromomethyl-2-(6-hydroxyquinolin-5-yl)ethyl ester with acetic
acid 1-bromomethyl-2-(5-hydroxyquinolin-6-yl)ethyl ester
(intermediate 18) (0.3 g, 0.92 mmol). It was isolated in 67% yield
(0.15 g) as a clear oil: MS ESI m/z 244 [M+H].sup.+.
Example 17
Intermediate 20--3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-ol
[0086] This compound was prepared generally following the procedure
above for intermediate 10, replacing
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl acetate with
3,4-dihydro-2H -pyrano[2,3-f]quinolin-3-yl acetate (intermediate
19) (0.15 g, 0.62 mmol). It was isolated in 81% yield (0.10 g) as
an off-white solid: mp 182-183.5.degree. C. MS ESI m/z 202 [M+H]+.
Elemental Analysis for C.sub.12H.sub.11NO.sub.2: Calculated: C,
71.63; H, 5.51; N, 6.96; Found: C, 71.50; H, 5.45; N, 6.83.
Example 18
Intermediate 21--3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-yl
4-methylbenzenesulfonate
[0087] This compound was prepared generally following the procedure
above for intermediate 11, replacing
2,3-dihydro[3,2-f]quinolin-2-ol with
3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-ol (intermediate 20) (1.37
g, 6.8 mmol). It was isolated in 59% yield (0.2 g) as a white
solid: mp 119.degree. C./dec. Elemental Analysis for
C.sub.19H.sub.17NO.sub.4S: Calculated: C, 64.21; H, 4.82; N, 3.94;
Found: C, 63.96; H, 4.84; N, 3.83.
Example 19
Intermediate 22--3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-yl
azide
[0088] This compound was prepared generally following the procedure
above for intermediate 12, replacing
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl 4-methylbenzesulfonate
with 3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-yl
4-methylbenzenesulfonate (intermediate 21) (1.15 g, 3.2 mmol). It
was isolated in 68% yield (0.5 g) as a light brown oil: MS ESI m/z
227 [M+H].sup.+.
Example 20
Intermediate 1b--3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine
[0089] This compound was prepared generally following the procedure
above for intermediate 1a, replacing
2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-yl azide with
3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-yl azide (intermediate 22)
(0.5 g, 2.2 mmol). It was isolated in 68% yield (0.3 g) as a light
pink solid: mp 247-248.5.degree. C. MS ESI m/z 201 [M+H].sup.+.
Elemental Analysis for C.sub.12H.sub.12N.sub.2O.0.1H.sub.2O;
Calculated: C, 71.34; H, 6.09; N, 13.87; Found: C, 71.23; H, 6.08;
N, 13.70.
Example 21
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quinolin--
2-amine ("Compound 1")
[0090] A solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine
(intermediate 1a) (0.68 g, 3.4 mmol),
3-(3-bromopropyl)-5-fluoro-1H-indole (0.58 g, 2.26 mmol), and
triethylamine (0.63 mL, 4.52 mmol) in anhydrous dimethylsulfoxide
(40 mL) was stirred at 80.degree. C. for 12 hrs. The reaction
mixture was poured into ice-H.sub.2O and extracted with methylene
chloride. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. Chromatography (5%
MeOH/CH.sub.2Cl.sub.2) afforded 0.54 g (64%) of product as a brown
oil. It was converted to the HCl salt by dissolution in ethyl
acetate and addition of 1M HCl/Et.sub.2O solution (2.4 eq) to
generate
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quinolin-
-2-amine bis-hydrochloride salt as a light brown solid:
mp>180.degree. C. MS ESI m/z 376 [M+H].sup.+. Elemental Analysis
for C.sub.23H.sub.22FN.sub.3O.2.00HCl.0.25H.sub.2O; Calculated: C,
61.00; H, 5.45; N, 9.28; Found: C, 61.02; H, 5.66; N, 9.03.
Example 21a and 21b
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quino-
lin-2-amine and
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quin-
olin-2-amine ("Compounds 1a and 1b")
[0091] The enantiomers of
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quinolin-
-2-amine (example 21) were separated by chiral HPLC, isolated, and
converted to the HCl salt as described above for the racemate,
generating the following products:
[0092]
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-
-f]quinolin-2-amine bis-hydrochloride salt (example 21a) as a
yellow solid: mp 330.degree. C./dec.
[.alpha.].sub.D.sup.25=+36.5.degree. (c=1% solution, DMSO). MS ESI
m/z 376 [M+H].sup.+; Elemental Analysis for
C.sub.23H.sub.22FN.sub.3O.2.00HCl.0.50H.sub.2O; Calculated: C,
60.40; H, 5.51; N, 9.19; Found: C, 60.66; H, 5.69; N, 9.12.
[0093]
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-
-f]quinolin-2-amine bis-hydrochloride salt (example 21b) as a
yellow solid: mp>460.degree. C./dec.
[.alpha.].sub.D.sup.25=-36.1.degree. (c=1% solution, DMSO). MS ESI
m/z 376 [M+H].sup.+; Elemental Analysis for
C.sub.23H.sub.22FN.sub.3O.2.00 HCl.1.25H.sub.2O; Calculated: C,
58.67; H, 5.67; N, 8.92; Found: C, 58.85; H, 5.79; N, 8.67.
Example 22
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyrano[3,2-f]-
quinolin-2-amine ("Compound 2")
[0094] To
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2--
f]quinolin-2-amine (example 21) (0.13 g, 0.34 mmol) in anhydrous
methanol (20 mL), was added propionaldehyde (0.25 mL, 3.4 mmol),
acetic acid (0.2 ml, 0.34 mmol) and sodium cyanoborohydride (0.041
g, 0.65 mmol). The reaction mixture was stirred at room temperature
overnight. The reaction mixture was quenched with 1N NaOH, and
extracted with methylene chloride. The organic layer was dried over
anhydrous sodium sulfate, filtered and concentrated under vacuum.
Chromatography (5% MeOH/CH.sub.2Cl.sub.2) afforded 0.11 g (77%) of
product as a clear oil. It was converted to the HCl salt by
dissolution in ethyl acetate and addition of 1M HCl/Et.sub.2O (2.4
eq) to generate
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyrano[3,2-f-
]quinolin-2-amine bis-hydrochloride salt as a light yellow solid:
mp>148.degree. C. MS ESI m/z 416 [M-H].sup.-. Elemental Analysis
for C.sub.26H.sub.28FN.sub.3O.2.00HCl; Calculated: C, 63.67; H,
6.17; N, 8.57; Found: C, 63.97; H, 6.48; N, 8.28.
Example 23
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyran[3,2-
-f]quinolin-2-amine ("Compound 3")
[0095] This compound was prepared generally following the procedure
above for example 22 using
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quin-
olin-2-amine (example 21a) as starting material. It was converted
to the HCl salt by dissolution in ethyl acetate and addition of 1M
HCl/Et.sub.2O (2.4 eq) to generate
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyran[3,-
2-f]quinolin-2-amine bis-hydrochloride salt as a yellow solid: mp
83.5.degree. C./dec. [.alpha.].sub.D.sup.25=-39.8 (c=1% solution,
DMSO). MS ESI m/z 418 [M+H].sup.+. Elemental Analysis for
C.sub.26H.sub.28FN.sub.3O.2.00HCl.0.50H.sub.2O; Calculated: C,
62.53; H, 6.26; N, 8.41; Found: C, 62.69; H, 6.58; N, 8.20.
Example 24
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyrano[3,-
2-f]quinolin-2-amine ("Compound 4")
[0096] This compound was prepared generally following the procedure
above for example 22 using
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-2,3-dihydro-1H-pyrano[3,2-f]quin-
olin-2-amine (example 21b) as starting material. It was converted
to the HCl salt by dissolution in ethyl acetate and addition of 1M
HCl/Et.sub.2O (2.4 eq) to generate
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-2,3-dihydro-1H-pyrano[3-
,2-f]quinolin-2-amine bis-hydrochloride salt as a yellow solid: mp
106.degree. C./dec. [.alpha.].sub.D.sup.25=+38.0.degree. (c=1%
solution, DMSO). MS ESI m/z 418 [M+H].sup.+. Elemental Analysis for
C.sub.26H.sub.28FN.sub.3O.2.00HCl; Calculated: C, 63.67; H, 6.17;
N, 8.57; Found: C, 63.32; H, 6.39; N, 8.27.
Example 25
N-[2-(5-fluoro-1H-indol-3-yl)ethyl-2,3-dihydro-1H-pyrano[3,2-f]quinolin-2--
amine ("Compound 5")
[0097] A solution of 2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-amine
(intermediate 1a) (0.42 g, 2.1 mmol),
3-(2-bromoethyl)-5-fluoro-1H-indole (0.39 g, 1.60 mmol), and
triethylamine (0.22 mL, 3.20 mmol) in anhydrous dimethylsulfoxide
(20 ml) was stirred at 100.degree. C. for 9 hrs. The reaction
mixture was poured into ice-H.sub.2O and extracted with methylene
chloride. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. Chromatography (2%
MeOH/CH.sub.2Cl.sub.2) afforded 0.22 g (38%) of product as a brown
oil. It was converted to the HCl salt by dissolution in ethyl
acetate and addition of 1M HCl/Et.sub.2O solution (2.4 eq) to
generate
N-[2-(5-fluoro-1H-indol-3-yl)ethyl-2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-
-amine bis-hydrochloride salt as a green solid: mp 91.degree.
C./dec. MS ESI m/z 362 [M+H].sup.+. Elemental analysis for
C.sub.22H.sub.20FN.sub.3O.2.00HCl.1.50H.sub.2O; Calculated: C,
57.27; H, 5.46; N, 9.11; Found: C, 57.53; H, 5.29; N, 8.64.
Example 26
N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-N-propyl-2,3-dihydro-1H-pyrano[3,2-f]q-
uinolin-2-amine ("Compound 6")
[0098] This compound was prepared generally following the procedure
above for example 22 using
N-[2-(5-fluoro-1H-indol-3-yl)ethyl-2,3-dihydro-1H-pyrano[3,2-f]quinolin-2-
-amine (example 25) as starting material. It was converted to the
HCl salt by dissolution in ethyl acetate and addition of 1M
HCl/Et.sub.2O (2.4 eq) to generate
N-[2-(5-fluoro-1H-indol-3-yl)ethyl]-N-propyl-2,3-dihydro-1H-pyrano[3,2-f]-
quinolin-2-amine bis-hydrochloride salt as a yellow solid:
[0099] mp 67.degree. C. MS ESI m/z 404 [M+H]. Elemental Analysis
for C.sub.25H.sub.26FN.sub.3O.2.00HCl.1.25H.sub.2O; Calculated: C,
60.18; H, 6.16; N, 8.42; Found: C, 60.49; H, 6.35; N, 8.16.
Example 27
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin--
3-amine ("Compound 7")
[0100] This compound was prepared generally following the procedure
above for example 21 using
3,4-dihydro-2H-pyrano[3,3-f]quinolin-3-amine (intermediate 1b) as
starting material. It was converted to the HCl salt by dissolution
in ethyl acetate and addition of 1M HCl/Et.sub.2O (2.4 eq) to
generate
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin-
-3-amine bis-hydrochloride salt as a yellow solid: mp 300.degree.
C./dec. MS (ESI) m/z 376 [M+H].sup.+. Elemental analysis for
C.sub.23H.sub.22FN.sub.3O.2.00HCl.0.25H.sub.2O; Calculated: C,
61.00; H, 5.45; N, 9.28; Found: C, 61.16; H, 5.72; N, 9.00.
Examples 27a and 27b
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4,-dihydro-2H-pyrano[2,3-f]quin-
olin-3-amine and
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]quin-
olin-3-amine ("Compounds 7a and 7b")
[0101] The enantiomers of
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin-
-3-amine (example 27) were separated by chiral HPLC, isolated, and
converted to the HCl salt as described above for the racemate,
generating the following products:
[0102]
(+)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-
-f]quinolin-3-amine bis-hydrochloride salt (example 27a) as a light
brown solid: mp 250.degree. C./dec.
[0103] [.alpha.].sub.D.sup.25=+27.14.degree. (c=1% SOLUTION, DMSO).
MS (ESI) m/z 376 [M+H].sup.+. Elemental Analysis for
C.sub.23H.sub.22FN.sub.3O.2.00HCl.1.75H.sub.2O.0.10
C.sub.4H.sub.8O.sub.2; Calculated: C, 57.51; H, 5.84; N, 8.60;
Found: C, 57.41; H, 5.50; N, 8.58.
[0104]
(-)-N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-
-f]quinolin-3-amine bis-hydrochloride salt (example 27b) as a light
brown solid: mp 250.degree. C./dec.
[.alpha.].sub.D.sup.25=-17.99.degree. (c=1% SOLUTION, DSMO). MS
(ESI) m/z 376 [M+H].sup.+. Elemental Analysis for
C.sub.23H.sub.22FN.sub.3O.2.00HCl.0.50H.sub.2O.0.25
C.sub.4H.sub.8O.sub.2.0.20 C.sub.4H.sub.10O; Calculated: C, 60.27;
H, 5.91; N, 8.50; Found: C, 59.95; H, 6.15; N, 8.58.
Example 28
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-3,4-dihydro-2H-pyrano[2,3-f]-
quinolin-3-amine ("Compound 8")
[0105] This compound was prepared generally following the procedure
above for example 22 using
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin-
-3-amine (example 27) as starting material. It was converted to the
HCl salt by dissolution in ethyl acetate and addition of 1M
HCl/Et.sub.2O (2.4 eq) to generate
N-[3-(5-fluoro-1H-indol-3-yl)propyl]-N-propyl-3,4-dihydro-2H-pyrano[2,3-f-
]quinolin-3-amine bis-hydrochloride salt as a yellow solid: mp
134.degree. C./dec. MS (ESI) m/z 418 [M+H].sup.+. Elemental
Analysis for C.sub.26H.sub.28FN.sub.3O.2.00 HCl.0.75H.sub.2O;
Calculated: C, 61.97; H, 6.30; N, 8.34; Found: C, 62.09; H, 6.60;
N, 8.20.
Example 29
N-[4-(5-fluoro-1H-indol-3-yl)butyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-
-amine ("Compound 9")
[0106] A solution of 3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine
(intermediate 1a) (0.20 g, 1.0 mmol),
3-(4-bromobutyl)-5-fluoro-1H-indole (0.19 g, 0.84 mmol), and
triethylamine (0.28 mL, 1.68 mmol) in anhydrous dimethylsulfoxide
(20 ml) was stirred at 100.degree. C. for 14 hrs. The reaction
mixture was poured into ice-H.sub.2O and extracted with methylene
chloride. The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. Chromatography (5%
MeOH/CH.sub.2Cl.sub.2) afforded 0.06 g (18%) of product as a light
brown oil and unreacted starting material. It was converted to the
HCl salt by dissolution in ethyl acetate and addition of 1M
HCl/Et.sub.2O solution (2.4 eq) to generate
N-[4-(5-fluoro-1H-indol-3-yl)butyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin--
3-amine bis-hydrochloride salt as an off-white solid: mp
173.degree. C./dec. MS ESI m/z 390 [M+H].sup.+. Elemental Analysis
for C.sub.24H.sub.24FN.sub.3O.2.00HCl.3.00 H.sub.2O; Calculated: C,
55.82; H, 6.25; N, 8.14; Found: C, 55.57; H, 6.06; N, 7.76.
Example 30
N-[4-(5-fluoro-1H-indol-3-yl)butyl]-N-propyl-3,4-dihydro-2H-pyrano[2,3-f]q-
uinolin-3-amine ("Compound 10")
[0107] This compound was prepared generally following the procedure
above for example 22 using
N-[4-(5-fluoro-1H-indol-3-yl)butyl]-3,4-dihydro-2H-pyrano[2,3-f]quinolin--
3-amine (example 29) as starting material. It was converted to the
HCl salt by dissolution in ethyl acetate and addition of 1M
HCl/Et.sub.2O solution (2.4 eq) to generate
N-[4-(5-fluoro-1H-indol-3-yl)butyl]-N-propyl-3,4-dihydro-2H-pyrano[2,3-f]-
quinolin-3-amine bis-hydrochloride salt as a light brown solid: mp
164.degree. C./dec. MS ESI m/z 432 [M+H].sup.+.
Example 31
Testing Affinity of Compounds for 5-HT Transporter
[0108] A protocol similar to that used by Cheetham et al.
(Neuropharmacol., 1993, 32: 737) was used to determine the affinity
of the compounds of the invention for the serotonin transporter.
The compound's ability to displace .sup.3H-paroxetine from male rat
cortical membranes was determined using a Tom Tech filtration
device to separate bound from free .sup.3H-paroxetine and Wallac
1205 Beta Plate.RTM. counter to quantitate bound radioactivity.
K.sub.I's thus determined for standard clinical antidepressants are
1.96 nM for fluoxetine, 14.2 nM for imipramime and 67.6 nM for
zimelidine. A strong correlation has been found between
.sup.3H-paroxetine binding in rat frontal cortex and
.sup.3H-serotonin uptake inhibition.
Example 32
Testing Affinity of Compounds for 5-HT.sub.1A Receptor
[0109] High affinity for the serotonin 5-HT.sub.1A receptor was
established by testing the claimed compound's ability to displace
[.sup.3H] 8-OH-DPAT (dipropylaminotetralin) from the 5-HT.sub.1A
serotonin receptor following a modification of the procedure of
Hall et al. (J. Neurochem 1985, 44: 1685) which utilizes CHO cells
stably transfected with human 5-HT.sub.1A receptors. The
5-HT.sub.1A affinities for the compounds of the invention are
reported below as K.sub.Is.
Example 33
Testing Agonist Activity of Compounds at the 5-HT.sub.1A
Receptor
[0110] The agonist activity at 5-HT.sub.1A receptors was
established by using a .sup.35S-GTP.gamma.S binding assay similar
to that used by Lazareno and Birdsall (Br. J. Pharmacol., 1993,
109:1120). The binding assay determines the test compound's ability
to affect the binding of .sup.35S-GTP.gamma.S to membranes
containing cloned human 5-HT.sub.1A receptors. Agonists produce an
increase in binding whereas antagonists produce no increase but
rather reverse the effects of the standard agonist 8-OH-DPAT. The
test compound's maximum stimulatory effect is represented as the
E.sub.max, while its potency is defined by the EC.sub.50.
[0111] The results of the three standard experimental test
procedures described in the preceding three examples are reported
below in Table 1. TABLE-US-00001 TABLE 1 5-HT Transporter
5-HT.sub.1A Receptor Affinity Affinity 5-HT.sub.1A Function
Compound K.sub.I (nM) K.sub.I (nM) EC.sub.50 (.mu.M) (E.sub.max) 1
1.53 62.61 0.18 (75.82) 2 6.50 91.03 2.22 (100) 1a 1.15 23.87 0.73
(100) 1b 2.50 313.80 0.12 (85.87) 3 8.00 209.55 0.63 (54.72) 4
19.00 239.20 0.30 (99.92) 5 24.00 Not tested 5.00 (30) 6 40.00
477.75 0.19 (41.27) 7 2.83 13.63 1.20 (100) 8 15.00 Not tested 1.71
(68.27) 7a 2.83 Not tested 0.32 (74.80) 7b 4.20 16.25 0.17 (100) 9
1.18 Not tested 5.94 (100) 10 12.00 Not tested Not tested
[0112] Hence, the compounds of this invention are combined
serotonin reuptake inhibitors/5-HT.sub.1A agonists, and are useful
for the treatment of depression and other conditions related to or
affected by the reuptake of serotonin and by the serotonin 1A
receptor. Other conditions may be obsessive compulsive disorder,
panic attacks, generalized anxiety disorder, sexual dysfunction,
eating disorders, addictive disorders caused by ethanol or cocaine
abuse and related illnesses.
[0113] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations or ranges and
specific embodiments therein are intended to be included.
[0114] The disclosures of each patent, patent application, and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0115] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing form the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *