U.S. patent application number 09/380608 was filed with the patent office on 2002-01-17 for propanolamine derivatives.
Invention is credited to Hashimoto, Norio, Okamoto, Takumi, Sakurai, Minoru, Takasugi, Hisashi, Taniguchi, Kiyoshi, Tomishima, Yasuyo, Tsubaki, Kazunori.
Application Number | 20020006956 09/380608 |
Document ID | / |
Family ID | 3799962 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020006956 |
Kind Code |
A1 |
Taniguchi, Kiyoshi ; et
al. |
January 17, 2002 |
Propanolamine derivatives
Abstract
This invention relates to new propanolamine derivatives
presented by the following formula [I]: 1 wherein R.sup.1 is
hydrogen or lower alkenyloxy, R.sup.2 is carboxy(lower)alkoxy or
protected carboxy(lower)alkoxy, R.sup.3 is hydrogen or N-protective
group, n is an integer of 1 or 2, and salts thereof which have gut
selective sympathomimetic, anti-ulcerous, anti-pancreatitis,
lipolytic and anti-pollakisuria activities, to processes for the
preparation thereof and to a pharmaceutical composition comprising
the same.
Inventors: |
Taniguchi, Kiyoshi;
(Suma-ku, JP) ; Sakurai, Minoru; (Toyonaka-shi,
JP) ; Hashimoto, Norio; (Ibaraki-shi, JP) ;
Okamoto, Takumi; (Toyonaka-shi, JP) ; Tsubaki,
Kazunori; (Uji-shi, JP) ; Tomishima, Yasuyo;
(Kita-ku, JP) ; Takasugi, Hisashi; (Sakai-shi,
JP) |
Correspondence
Address: |
Oblon Spivak McClelland
Maier & Neustadt
Fourth Floor
1755 Jefferson Davis Highway
Arlington
VA
22202
US
|
Family ID: |
3799962 |
Appl. No.: |
09/380608 |
Filed: |
September 15, 1999 |
PCT Filed: |
March 17, 1998 |
PCT NO: |
PCT/JP98/01112 |
Current U.S.
Class: |
514/510 ;
514/567; 560/43; 560/45; 562/452 |
Current CPC
Class: |
C07C 217/30 20130101;
C07C 217/34 20130101; C07C 2602/12 20170501; C07C 217/74 20130101;
Y02P 20/55 20151101; C07C 2602/10 20170501; C07C 215/64
20130101 |
Class at
Publication: |
514/510 ;
514/567; 560/43; 560/45; 562/452 |
International
Class: |
A61K 031/665 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 17, 1997 |
AU |
PO5659 |
Claims
What we claim is:
1. A compound of the formula 5wherein R.sup.1 is hydrogen or lower
alkenyloxy, R.sup.2 is carboxy(lower)alkoxy or protected
carboxy(lower)alkoxy, R.sup.3 is hydrogen or n-protective group, n
is an integer of 1 or 2, and salts thereof.
2. A compound of claim 1, wherein R.sup.1 is hydrogen or lower
alkenyloxy, R.sup.2 is carboxy(lower)alkoxy or lower
alkoxycarbonyl(lower)alkoxy, R.sup.3 is hydrogen or ar(lower)alkyl,
and n is an integer of 1 or 2.
3. A process for preparing a compound of the formula: 6wherein
R.sup.1 is hydrogen or lower alkenyloxy, R.sup.2 is
carboxy(lower)alkoxy or protected carboxy(lower)alkoxy, R.sup.3 is
hydrogen or N-protective group, and n is an integer of 1 or 2, or
salts thereof, which comprises (a) reacting a compound of the
formula: 7 with a compound of the formula: 8 or its salt to provide
a compound of the formula: 9 or its salt, in the above formulas,
R.sup.1, R.sup.2, R.sup.3 and n are each as defined above, or (b)
subjecting a compound of the formula 10 or its salt to elimination
reaction of the N-protective group to provide a compound of the
formula: 11 or its salt, in the above formulas, R.sup.1, R.sup.2
and n are each as defined above, and R.sub.a.sup.3 is N-protective
group.
4. A pharmaceutical composition comprising a compound of claim 1 or
pharmaceutically acceptable salt thereof, as an active ingredient,
in association with a pharmaceutically acceptable, substantially
non-toxic carrier or excipient.
5. A medicament comprising a compound of claim 1 or
pharmaceutically acceptable salt thereof, as an active
ingredient.
6. A compound of claim 1 or pharmaceutically acceptable salt
thereof for use as a medicament.
7. Use of a compound of claim 1 or pharmaceutically acceptable salt
thereof as .beta..sub.3 adrenergic receptor agonist.
8. A method for the treatment and/or prevention of spasm or
hyperanakinesia; gastric ulcer, duodenal ulcer or peptic ulcer
caused by non steroidal anti-inflammatory drugs; dysuria; or
pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia,
hypertension, atherosclerosis, glaucoma, metancholia or depression,
which comprises administering
Description
TECHNICAL FIELD
[0001] This invention relates to new propanolamine derivatives and
salts thereof which are useful as a medicament.
BACKGROUND ART
[0002] Some propanolamine derivatives having spasmolytic activity
and relaxing activity on smooth muscle contraction have known as
described, for example, in PCT International Publication
WO94/25427.
DISCLOSURE OF INVENTION
[0003] This invention relates to new propanolamine derivatives and
salts thereof.
[0004] More particularly, it relates to new propanolamine
derivatives and salts thereof which have gut selective
sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and
anti-pollakisuria activities, to processes for the preparation
thereof, to a pharmaceutical composition comprising the same and to
a method of using the same therapeutically in the treatment and/or
prevention of gastrointestinal disorders caused by smooth muscle
contractions in human beings or animals, and more particularly to a
method for the treatment and/or prevention of spasm or
hyperanakinesia in case of irritable bowel syndrome, gastritis,
gastric ulcer, duodenal ulcer, enteritis, cholecystopathy,
cholangitis, urinary calculus and the like; for the treatment
and/or prevention of ulcer such as gastric ulcer, duodenal ulcer,
peptic ulcer, ulcer caused by non steroidal anti-inflammatory
drugs, or the like; for the treatment and/or prevention of dysuria
such as pollakisuria, urinary incontinence or the like in case of
nervous pollakisuria, neurogenic bladder dysfunction, nocturia,
unstable bladder, cystospasm, chronic cystitis, chronic prostatitis
or the like; and for the treatment and/or prevention of
pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia,
hypertension, atherosclerosis, glaucoma, melancholia, depression
and the like.
[0005] One object of this invention is to provide new and useful
propanolamine derivatives and salts thereof which have gut
selective sympathomimetic, anti-ulcerous, lipolytic and
anti-pollakisuria activities.
[0006] Another object of this invention is to provide processes for
the preparation of said propanolamine derivatives and salts
thereof.
[0007] A further object of this invention is to provide a
pharmaceutical composition comprising, as an active ingredient,
said propanolamine derivatives and salts thereof.
[0008] Still further object of this invention is to provide a
therapeutical method for the treatment and/or prevention of
aforesaid diseases in human beings or animals, using said
propanolamine derivatives and salts thereof.
[0009] The object propanolamine derivatives of this invention are
new and can be represented by the following general formula [I]:
2
[0010] wherein
[0011] R.sup.1 is hydrogen or lower alkenyloxy,
[0012] R.sup.2 is carboxy(lower)alkoxy or protected
carboxy(lower)alkoxy,
[0013] R.sup.3 is hydrogen or N-protective group,
[0014] n is an integer of 1 or 2,
[0015] and salts thereof (Hereinafter, these propanolamine
derivatives may be mentioned as the object compound [I]).
[0016] The object compound [I] or its salt can be prepared by the
following processes.
[0017] Process 1 3
[0018] Process 2 4
[0019] wherein
[0020] R.sup.1, R.sup.2, R.sup.3 and n are each as defined above,
and R.sub.a.sup.3 is N-protective group.
[0021] In the above and subsequent description of the present
specification, suitable examples of the various definition to be
included within the scope of the invention are explained in detail
in the following.
[0022] The term "lower" is intended to mean a group having 1 to 6
carbon atom(s), unless otherwise provided.
[0023] Suitable "lower alkenyl" moiety in the term "lower
alkenyloxy" may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or
3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or
5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)-methyl-1-(or
2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3-
or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which
preferable example may be C.sub.2-C.sub.4 alkenyl, and more
preferable example may be propenyl.
[0024] Suitable "lower alkoxy" moiety in the terms of
"carboxy(lower)alkoxy" and "protected carboxy(lower)alkoxy" may be
a straight or branched one such as methoxy, ethoxy, propoxy,
isopropoxy, butoxy, pentyloxy or the like, in which preferable one
is C.sub.1-C.sub.4 ones and more preferably methoxy.
[0025] Suitable "protected carboxy" moiety in the term "protected
carboxy(lower)alkoxy" may include esterified carboxy and the like.
And suitable example of said esterified carboxy may be substituted
or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl,
2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.],
substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl,
4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted
or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl,
phenethyloxycarbonyl, benzhydryloxycarbonyl,
4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable
one is lower alkoxycarbonyl.
[0026] "N-Protective group" may be common N-protective group such
as acyl, for example, substituted or unsubstituted lower alkanoyl
[e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl,
lower alkoxycarbonyl [e.g. tert-butoxycarbonyl,
tert-amyloxycarbonyl, etc.], substituted or unsubstituted
aralkyloxycarbonyl [e.g. benzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted
arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.],
nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl, etc.] or
the like, in which preferable one is phenyl(lower)alkyl such as
benzyl.
[0027] Preferred embodiments of the object compound [I] are as
follows:
[0028] R.sup.1 is hydrogen or lower alkenyloxy,
[0029] R.sup.2 is carboxy(lower)alkoxy or esterified
carboxy(lower)alkoxy,
[0030] R.sup.3 is hydrogen or ar(lower)alkyl, and
[0031] n is an integer of 1 or 2.
[0032] More preferred embodiments of the object compound [I] are as
follows:
[0033] R.sup.1 is hydrogen or lower alkenyloxy,
[0034] R.sup.2 is lower alkoxycarbonyl(lower)alkoxy,
[0035] R.sup.3 is hydrogen or benzyl, and
[0036] n is an integer of 1 or 2 (more preferably an integer of
2).
[0037] Suitable salts of the object propanolamine derivatives [I]
are pharmaceutically acceptable salts and include conventional
non-toxic salts such as an inorganic acid addition salt [e.g.
hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic
acid addition salt [e.g. formate, acetate, trifluoroacetate,
oxalate, maleate, fumarate, tartrate, methanesulfonate,
benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt
[e.g. sodium salt, potassium salt, etc.] or the like.
[0038] The processes for preparing the object compound [I] are
explained in detail in the following.
[0039] Process 1
[0040] The object compound [I] or its salt can be prepared by
reacting a compound [II] with a compound [III] or its salt.
[0041] Suitable salt of the compound [III] may be the same as those
exemplified for the compound [I].
[0042] The reaction is preferably carried out in the presence of a
base such as an alkali metal carbonate [e.g. sodium carbonate,
potassium carbonate, etc.], an alkaline earth metal carbonate [e.g.
magnesium carbonate, calcium carbonate, etc.], an alkali metal
bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.],
tri(lower)alkylamine [e.g. trimethylamine, triethylamine, etc.],
picoline or the like.
[0043] The reaction is usually carried out in a conventional
solvent, such as an alcohol [e.g. methanol, ethanol, propanol,
isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any
other organic solvent which does not adversely influence the
reaction.
[0044] The reaction temperature is not critical, and the reaction
can be carried out under cooling to heating.
[0045] Process 2
[0046] The object compound [Ib] or its salt can be prepared by
subjecting a compound [Ia] or its salt to elimination reaction of
the N-protective group.
[0047] Suitable salts of the compounds [Ia] and [Ib] may be the
same as those exemplified for the compound [I].
[0048] This reaction is carried out in accordance with a
conventional method such as hydrolysis, reduction or the like.
[0049] The hydrolysis is preferably carried out in the presence of
a base or an acid including Lewis acid.
[0050] Suitable base may include an inorganic base and an organic
base such as an alkali metal [e.g. sodium, potassium, etc.], an
alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide
or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g.
trimethylamine, triethylamine, etc.], picoline,
1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
[0051] Suitable acid may include an organic acid [e.g. formic acid,
acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic
acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic
acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen
fluoride, etc.] and an acid addition salt compound [e.g. pyridine
hydrochloride, etc.].
[0052] The elimination using trihaloacetic acid [e.g.
trichloroacetic acid, trifluoroacetic acid, etc.] or the like is
preferably carried out in the presence of cation trapping agents
[e.g. anisole, phenol, etc.].
[0053] The reaction is usually carried out in a solvent such as
water, an alcohol [e.g. methanol, ethanol, etc.], methylene
chloride, chloroform, tetrachloromethane, tetrahydrofuran, a
mixture thereof or any other solvent which does not adversely
influence the reaction. A liquid base or acid can be also used as
the solvent. The reaction temperature is not critical and the
reaction is usually carried out under cooling to heating.
[0054] The reduction method applicable for the elimination reaction
may include chemical reduction and catalytic reduction.
[0055] Suitable reducing agents to be used in chemical reduction
are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic
compound [e.g. chromium chloride, chromium acetate, etc.] and an
organic or inorganic acid [e.g. formic acid, acetic acid, propionic
acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric
acid, hydrobromic acid, etc.].
[0056] Suitable catalysts to be used in catalytic reduction are
conventional ones such as platinum catalysts [e.g. platinum plate,
spongy platinum, platinum black, colloidal platinum, platinum
oxide, platinum wire, etc.], palladium catalysts [e.g. spongy
palladium, palladium black, palladium oxide, palladium on carbon,
colloidal palladium, palladium on barium sulfate, palladium on
barium carbonate, etc.], nickel catalysts [e.g. reduced nickel,
nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced
cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron,
Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney
copper, Ullman copper, etc.] and the like.
[0057] In case that the N-protective group is benzyl, the reduction
is preferably carried out in the presence of a combination of
palladium catalysts [e.g. palladium black, palladium on carbon,
etc.] and formic acid or its salt [e.g. ammonium formate,
etc.].
[0058] The reduction is usually carried out in a conventional
solvent which does not adversely influence the reaction such as
water, an alcohol [e.g. methanol, ethanol, propanol, etc.],
chlorobenzene, N,N-dimethylformamide, or a mixture thereof.
Additionally, in case that the above-mentioned acids to be used in
chemical reduction are in liquid, they can also be used as a
solvent. Further, a suitable solvent to be used in catalytic
reduction may be the above-mentioned solvent, and other
conventional solvent such as diethyl ether, dioxane,
tetrahydrofuran, etc. or a mixture thereof.
[0059] The reaction temperature of this reduction is not critical
and the reaction is usually carried out under cooling to
heating.
[0060] The compounds obtained by the above processes can be
isolated and purified by a conventional method such as
pulverization, recrystallization, column chromatography,
reprecipitation, or the like, and converted to the desired salt in
conventional manners, if necessary.
[0061] It is to be noted that the compound [I] and the other
compounds may include one or more stereoisomers due to asymmetric
carbon atoms, and all of such isomers and mixture thereof are
included within the scope of this invention.
[0062] It is further to be noted that isomerization or
rearrangement of the object compound [I] may occur due to the
effect of the light, acid, base or the like, and the compound
obtained as the result of said isomerization or rearrangement is
also included within the scope of the present invention.
[0063] It is also to be noted that the solvating form of the
compound [I] (e.g. hydrate, etc.) and any form of the crystal of
the compound [I] are included within the scope of the present
invention.
[0064] The object compound [I] and salts thereof possess gut
selective sympathomimetic, anti-ulcerous, anti-pancreatitis,
lipolytic and anti-pollakisuria activities, and are useful for the
treatment and/or prevention of gastrointestinal disorders caused by
smooth muscle contractions in human beings or animals, and more
particularly to methods for the treatment and/or prevention of
spasm or hyperanakinesia in case of irritable bowel syndrome,
gastritis, gastric ulcer, duodenal ulcer, enteritis,
cholecystopathy, cholangitis, urinary calculus and the like; for
the treatment and/or prevention of ulcer such as gastric ulcer,
duodenal ulcer, peptic ulcer, ulcer caused by non steroidal
anti-inflammatory drugs, or the like; for the treatment and/or
prevention of dysuria such as pollakisuria, urinary incontinence or
the like in case of nervous pollakisuria, neurogenic bladder
dysfunction, nocturia, unstable bladder, cystospasm, chronic
cystitis, chronic prostatitis or the like; and for the treatment
and/or prevention of pancreatitis, obesity, diabetes, glycosuria,
hyperlipidemia, hypertension, atherosclerosis, glaucoma,
melancholia, depression and the like.
[0065] In order to illustrate the usefulness of the object compound
[I], the pharmacological data of the object compound [I] are shown
in the following.
[0066] Test 1
[0067] Effect on isolated rat distal colon:
[0068] (1) Test Method
[0069] Male SD rats (180-230 g) were used. Animals were fasted for
24 hours prior to experiment. Distal colon was removed immediately
after sacrifice and placed in an organ bath containing 25 ml Tyrode
solution aerating with 95% O.sub.2, 5% CO.sub.2 at 37.degree. C.
The strip was mounted under 0.5 g tension and spontaneous
contractions were recorded isometrically. After the mobility was of
a uniform size, test compound was added to an organ bath and the
contractions were observed over a 30 minutes period. Effect of test
compound was calculated by comparing contractions before and after
test compound.
1 (2) Test Result: Test Compound (Example No.) IC.sub.50 (M) 1 4.2
.times. 10.sup.-9
[0070] Test 2
[0071] Effect on isolated non-pregnant rat uterus:
[0072] (1) Test Method
[0073] Female SD rats (150-180 g) were used. 48 and 24 hours prior
to use, rats were given estradiol (ovahormon benzoat: Trademark,
Teikoku Hormone Mfg. Co., Ltd.) subcutaneously at a dose of 40
.mu.g/rat to induce oestrus. The animals were killed and uteri were
removed. Each strip was placed in an organ bath containing 25 ml
Locke solution aerating with 95% O.sub.2, 5% CO.sub.2 at 37.degree.
C. under 1 g tension. Contractions were recorded isometrically.
After the spontaneous contractions were of a uniform size, test
compound was added to organ bath. The motility was observed over a
20 minutes period. Effect of test compound was calculated by
comparing contractions before and after test compound.
2 (2) Test Result: Test Compound (Example No.) IC.sub.50 (M) 1 3.7
.times. 10.sup.-7
[0074] For therapeutic purpose, the compound [I] and a salt thereof
of the present invention can be used in a form of pharmaceutical
preparation containing one of said compounds, as an active
ingredient, in admixture with a pharmaceutically acceptable carrier
such as an organic or inorganic solid, semi-solid or liquid
excipient suitable for oral, parenteral or external (topical)
administration. The pharmaceutical preparations may be capsules,
tablets, dragees, granules, suppositories, solutions, lotion,
inhalant, ophthalmic preparations, suspension, emulsion, ointment,
gel, or the like. If desired, there may be included in these
preparations, auxiliary substances, stabilizing agents, wetting or
emulsifying agents, buffers and other commonly used additives.
[0075] While the dosage of the compound [I] will vary depending
upon the age and condition of the patient, an average single dose
of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and
1000 mg of the compound [I] may be effective for treating the
above-mentioned diseases. In general, amounts between 0.1 mg/body
and about 1,000 mg/body may be administered per day.
[0076] The following Preparations and Examples are given for the
purpose of illustrating this invention.
Preparation 1
[0077] A suspension of (2S)-3-phenoxy-1,2-epoxypropane (300 mg) (IL
FARMACO, 50 (10), 643 (1995)),
N-benzyl-(1-hydroxy-6,7,8,9-tetrahydro-5H--
benzocyclohepten-6-yl)amine (535 mg), and ytterbium(III)
trifluoromethanesulfonate (372 mg) in dichloromethane (15 ml) was
stirred at room temperature for 3 days and partitioned between
ethyl acetate and aqueous sodium bicarbonate. The organic layer was
separated, washed with brine, dried over sodium sulfate, and
evaporated in vacuo. The residue was chromatographed
(dichloromethane-methanol) over silica gel (16 g) to afford
(2S)-1-[N-benzyl-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-
-6-yl)amino]-3-phenoxy-2-propanol (747 mg) as a colorless oil.
[0078] IR (KBr): 3359, 1244 cm.sup.-1
[0079] NMR (CDCl.sub.3, .delta.): 1.15-1.35 (1H, m), 1.55-2.4 (5H,
m), 2.55-3.35 (6H, m), 3.64-3.98 (4H, m), 4.85 (1H, br), 6.58 (1H,
d, J=8.0 Hz), 6.75 (1H, d, J=7.4 Hz), 6.82-6.99 (4H, m), 7.15-7.31
(8H, m)
[0080] (+) APCI MS m/z: 418 (M.sup.++1)
[0081] Preparation 2
[0082] The following compound was obtained according to a similar
manner to that of Preparation 1.
(2S)-1-[N-Benzyl-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)am-
ino]-3-phenoxy-2-propanol
[0083] IR (KBr): 3386, 1244 cm.sup.-1
[0084] NMR (CDCl.sub.3, .delta.): 1.2-2.3 (5H, m), 2.45-3.07 (6H,
m), 3.64-4.11 (5H, m), 4.0 (1H, br), 6.51-6.60 (2H, m), 6.82-7.01
(4H, m), 7.21-7.30 (8H, m)
[0085] (+) APCI MS m/z: 418 (M.sup.++1)
EXAMPLE 1
[0086] A suspension of 60% sodium hydride (54 mg, washed with
n-hexane) in N,N-dimethylformamide (1 ml) was added slowly to a
stirred solution of
(2S)-1-[N-benzyl-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-6-yl)a-
mino]-3-phenoxy-2-propanol (512 mg) in N,N-dimethylformamide (5 ml)
under ice cooling and the resulting mixture was stirred at the same
temperature for 30 minutes. A solution of ethyl bromoacetate (225
mg) in N,N-dimethylformamide (1 ml) was added dropwise therein at
the same temperature and the mixture was stirred at the same
temperature for 4 hours. The reaction mixture was diluted with
water and extracted with ethyl acetate. The extract was washed
twice with brine, dried over magnesium sulfate, and evaporated in
vacuo to afford
(2S)-1-[N-benzyl-(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocycl-
ohepten-6-yl)amino]-3-phenoxy-2-propanol (0.59 g) as a crude
oil.
[0087] IR (Film): 3450, 1759, 1734, 1246 cm.sup.-1
[0088] NMR (CDCl.sub.3, .delta.): 1.22-1.33 (4H, m), 1.45-2.4 (5H,
m), 2.5-3.15 (5H, m), 3.45 (1H, m), 3.64-3.95 (4H, m), 4.25 (2H, q,
J=7.1 Hz), 4.58 (2H, s), 6.60 (1H, d, J=8.2 Hz), 6.81-7.08 (5H, m),
7.21-7.31 (7H, m)
[0089] (+) APCI MS m/z: 504 (M.sup.++1)
EXAMPLE 2
[0090] The following compound was obtained according to a similar
manner to that of Example 1.
(2S)-1-[N-Benzyl-(2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclo-
hepten-6-yl)amino]-3-phenoxy-2-propanol
[0091] IR (Film): 3437, 1759, 1738, 1246 cm.sup.-1
[0092] NMR (CDCl.sub.3, .delta.): 1.22-1.45 (4H, m), 1.5-2.25 (4H,
m), 2.5-3.05 (7H, m), 3.35 (1H, br), 3.70-3.95 (4H, m), 4.27 (2H,
q, J=7.1 Hz), 4.57 and 4.58 (2H, s), 6.58-6.66 (2H, m), 6.83-7.07
(4H, m), 7.21-7.30 (7H, m)
[0093] (+) APCI MS m/z: 504 (M.sup.++1)
EXAMPLE 3
[0094] To a mixture of N-((R)-1-phenylethyl)-((6R)
-3-ethoxycarbonylmethox- y-6,7,8,9-tetrahydro-5H-benzocyclohepten
-6-yl)amine hydrochloride (2.23 g) in dichloromethane and water was
added 1N sodium hydroxide (5.5 ml), and the mixture was stirred for
30 minutes. After separation, the organic layer was dried over
anhydrous magnesium sulfate and evaporated in vacuo to give the
free amine. Under nitrogen, to a solution of the free amine and
(2R)-3-phenoxy-1,2-epoxypropane (0.34 g) in dichloromethane (22 ml)
was added ytterbium(III) trifluoromethanesulfonate (0.34 g) at
5.degree., and the mixture was stirred at room temperature for 1.5
days. The resulting mixture was poured into saturated aqueous
sodium bicarbonate solution, and extracted with ethyl acetate. The
organic layer was washed with brine, dried over magnesium sulfate,
and evaporated in vacuo. The residue was chromatographed
(hexane-ethyl acetate) over silica gel to afford
(2R)-1-[N-((R)-1-phenylethyl)-((6R) -3-ethoxycarbonylmethoxy-6,7,8-
,9-tetrahydro-5H-benzocyclohepten -6-yl)amino]-3-phenoxy-2-propanol
(2.07 g).
[0095] IR (Neat): 3444, 2929, 1758, 1496, 1245, 1166, 1041, 755
cm.sup.-1
[0096] NMR (CHCl.sub.3, .delta.): 1.30 (3H, t, J=7.1 Hz), 1.45 (2H,
d, J=6.9 Hz), 1.75-2.10 (3H, m), 2.27 (1H, d, J=12.3 Hz), 2.50-2.85
(4H, m), 3.01 (1H, dd, J=3.5, 13.8 Hz), 3.95-4.05 (4H, m), 4.28
(2H, q, J=7.1 Hz), 4.56 (2H, s), 6.29 (1H, d, J=2.6 Hz), 6.56 (1H,
dd, J=2.7, 8.2 Hz), 6.86-7.01 (4H, m), 7.23-7.43 (7H, m)
EXAMPLE 4
[0097] To a mixture of N-((S)-1-phenylethyl)-((6S)
-3-ethoxycarbonylmethox- y-6,7,8,9-tetrahydro-5H-benzocyclohepten
-6-yl)amine hydrochloride (8.1 g) in dichloromethane and water was
added 1N sodium hydroxide (20 ml), and the mixture was stirred for
20 minutes. After separation, the organic layer was dried over
anhydrous magnesium sulfate and evaporated in vacuo to give the
free amine. Under nitrogen, to a solution of the free amine and
(2S)-3-phenoxy-1,2-epoxypropane (3.9 g) in dichloromethane (120 ml)
was added tin(IV) chloride (1M in dichloromethane, 30 ml) dropwise
at -20.about.-10.degree. C., and the solution was stirred at the
same temperature for 1.5 hours. The resulting mixture was poured
into 1N hydrogen chloride and extracted with dichloromethane. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate and evaporated in vacuo. The residue was chromatographed
(hexane-ethyl acetate) over silica gel to give a less polor
diastereomer (2S)-1-[N-((S)-1-phenylethyl)
-((6S)-3-ethoxycarbonylmethoxy-6,7,8,9-tetr-
ahydro-5H-benzocyclohepten -6-yl)amino]-3-phenoxy-2-propanol (6.65
g) and a more polor diastereomer (2R)-1-[N-((S)-1-phenylethyl)
-((6S)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten
-6-yl)amino]-3-phenoxy-2-propanol (228 mg). less polor
diastereomer:
[0098] IR (Neat): 1758, 1496, 1243, 1195, 1043, 755 cm.sup.-1
[0099] NMR (CHCl.sub.3, .delta.): 1.29 (3H, t, J=7.1 Hz), 1.45 (3H,
d, J=6.9 Hz), 1.14-2.03 (4H, m), 2.27 (1H, d, J=12.6 Hz), 2.57-2.82
(5H, m), 3.01 (1H, dd, J=3.6, 13.9 Hz), 3.98-4.14 (4H, m), 4.29
(2H, q, J=7.1 Hz), 4.56 (2H, s), 6.29 (1H, d, J=2.7 Hz), 6.56 (1H,
dd, J=2.7, 8.2 Hz), 6.89-6.99 (4H, m), 7.25-7.43 (7H, m)
[0100] (+) APCI MS (m/z): 518 (M.sup.++1)
[0101] more polor diastereomer:
[0102] IR (Neat): 1758, 1496, 1243, 1195, 1041, 755 cm.sup.-1
[0103] NMR (CHCl.sub.3, .delta.): 1.31 (3H, t, J=7.1 Hz), 1.42 (3H,
d, J=6.8 Hz), 1.40-2.19 (4H, m), 2.46-2.99 (7H, m), 3.72-3.83 (1H,
m), 3.89-4.15 (4H, m), 4.28 (2H, q, J=7.1 Hz), 4.56 (2H, s), 6.47
(1H, d, J=2.7 Hz), 6.59 (1H, dd, J=2.7, 8.2 Hz), 6.86-7.00 (4H, m),
7.19-7.38 (7H, m)
[0104] (+) APCI MS (m/z): 518 (M.sup.++1)
EXAMPLE 5
[0105] The following compound was obtained according to a similar
manner to that of Example 4.
(2S)-1-[N-((R)-1-Phenylethyl)-((6R)-3-ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol
[0106] IR (Neat): 3500, 2929, 1760, 1585, 1500, 1245, 1041, 755
cm.sup.-1
[0107] NMR (CHCl.sub.3, .delta.): 1.31 (3H, t, J=7.1 Hz), 1.42 (2H,
d, J=6.8 Hz), 1.45-2.19 (4H, m), 2.46-3.00 (7H, m), 3.74-3.87 (1H,
m), 3.93-4.12 (3H, m), 4.28 (2H, d, J=7.1 Hz), 4.56 (2H, s), 6.47
(1H, d, J=2.6 Hz), 6.59 (1H, dd, J=2.7, 8.2 Hz), 6.86-7.00 (4H, m),
7.21-7.38 (7H, m)
[0108] (+) APCI MS (m/z): 518 (M+1)
Preparation 3
[0109] Under nitrogen, to the solution of 5-methoxy-1-tetralone (25
g) in dichloromethane (125 ml) were added zinc(II) iodide (0.91 g)
and trimethylsilyl nitrile (27 ml) at room temperature, and stirred
at the same temperature for 12 hours. The resulting mixture was
poured into saturated aqueous sodium bicarbonate solution, and
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium bicarbonate solution, water and brine,
dried over anhydrous magnesium sulfate, and evaporated in vacuo to
afford 6-methoxy-1-(trimethylsilanylo-
xy)-1,2,3,4-tetrahydronaphthalene -1-carbonitrile (41.3 g).
[0110] IR (Neat): 2954, 1587, 1467, 1261, 1031, 844 cm.sup.-1
[0111] NMR (CHCl.sub.3, .delta.): 0.02 (9H, s), 1.68-2.18 (4H, m),
2.49 (3H, t, J=6.3 Hz), 3.62 (3H, s), 6.57-7.17 (2H, m)
Preparation 4
[0112] Under nitrogen, to the slurry of lithium aluminum hydride
(11.4 g) in tetrahydrofuran (200 ml) was added 6-methoxy
-1-(trimethylsilanyloxy)--
1,2,3,4-tetrahydronaphthalene-1-carbonitrile (41.3 g) in
tetrahydrofuran (200 ml) dropwise at 5.degree. C., and the mixture
was stirred at the same temperature for 1 hour and at room
temperature for 2 hours. To the mixture were added sodium fluoride
(12.6 g) and water (16.2 ml) at 5.degree. C., and the mixture was
vigorously stirred at room temperature for 30 minutes. The
precipitate was removed by filtration and the filter cake was
washed with ethyl acetate-ethanol (95:5). The filtrate was
evaporated in vacuo to afford 1-aminomethyl-5-methoxy
-1,2,3,4-tetrahydronaphthalen-1-ol (28.6 g).
[0113] NMR (CHCl.sub.3, .delta.): 1.64-2.12 (4H, m), 2.55-2.82 (2H,
m), 2.85 (2H, s), 3.84 (3H, s), 6.76 (1H, dd, J=1.8, 7.3 Hz),
7.05-7.34 (2H, m)
Preparation 5
[0114] To a solution of
1-aminomethyl-5-methoxy-1,2,3,4-tetrahydronaphthal- en -1-ol (26.6
g) in 1,4-dioxane (60 ml), acetic acid (24 ml) and water (210 ml)
was added sodium nitrite (9.7 g) in water (60 ml) dropwise at
5.degree. C., and the mixture was stirred at the same temperature
for 2.5 hours. The resulting mixture was diluted with ethyl acetate
and separated. The organic layer was washed with saturated aqueous
sodium bicarbonate and brine, dried over anhydrous magnesium
sulfate, and evaporated in vacuo. The residue was chromatographed
(hexane-ethyl acetate) over silica gel to afford
1-methoxy-5,7,8,9-tetrahydro-6H-benzoc- yclohepten-6-one (12.7
g).
[0115] NMR (CHCl.sub.3, .delta.): 1.84-2.04 (2H, m), 2.52 (2H, t,
J=7.0 Hz), 2.97-3.04 (2H, m), 3.70 (2H, s), 3.81 (3H, s), 6.76 (1H,
d, J=7.7 Hz), 6.81 (1H, d, J=8.4 Hz), 7.13 (1H, t, J=7.9 Hz)
[0116] (+) APCI MS (m/z): 191 (M.sup.++1), 177
Preparation 6
[0117] A solution of
1-methoxy-5,7,8,9-tetrahydro-6H-benzocyclohepten -6-one (6.0 g) and
benzylamine (3.4 ml) in toluene (60 ml) in the presence of a
catalytic amount of p-toluenesulfonic acid monohydrate was refluxed
for 2 hours to remove water as the toluene azeotrope, and then the
mixture was evaporated in vacuo. To the residue in methanol (60 ml)
was added sodium borohydride (1.2 g) under nitrogen at 5.degree.
C., and the mixture was stirred at room temperature for 12 hours.
The resulting mixture was poured into ice-cold water and stirred
for 30 minutes before adding ethyl acetate and brine. After
separation, the organic layer was washed with brine, dried over
anhydrous magnesium sulfate, and evaporated in vacuo. The residue
was chromatographed (hexane-ethyl acetate-methanol) over silica gel
to afford N-benzyl-(1-methoxy -6,7,8,9-tetrahydro-5H-benz-
ocyclohepten-6-yl)amine (7.27 g).
[0118] NMR (CHCl.sub.3, .delta.): 1.32-1.57 (2H, m), 1.70-1.93 (2H,
m), 1.95-2.15 (1H, m), 2.58-2.79 (2H, m), 2.88-3.18 (3H, m), 3.78
(3H, s), 3.78 (2H, d, J=13.0 Hz), 3.89 (1H, d, J=13.0 Hz), 6.74
(1H, d, J=8.2 Hz), 6.80 (1H, d, J=7.5 Hz), 7.07 (1H, t, J=7.8 Hz),
7.16-7.37 (5H, m)
[0119] (+) APCI MS (m/z): 282 (M.sup.++1)
Preparation 7
[0120] Under nitrogen, N-benzyl-(1-methoxy-6,7,8,9-tetrahydro
-5H-benzocyclohepten-6-yl)amine (4.5 g) in dichloromethane (45 ml)
was added boron tribromide (1M in dichloromethane, 32 ml) dropwise
at 0.degree. C., and the mixture was stirred at the same
temperature for 2 hours. The resulting mixture was poured into
ice-cold water and the precipitate was collected by filtration. The
filter cake was added to the mixture of water and ethyl acetate,
and then adjusted to pH 9 with 1N sodium hydroxide. After
separation, the organic layer was dried over anhydrous magnesium
sulfate and evaporated in vacuo to afford
N-benzyl-(1-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten
-6-yl)amine (3.72 g).
[0121] NMR (CHCl.sub.3, .delta.): 1.35-1.57 (1H, m), 1.68-2.13 (3H,
m), 2.55-3.08 (5H, m), 3.79 (1H, d, J=12.8 Hz), 3.91 (1H, d, J=12.8
Hz), 6.59 (1H, dd, J=1.2, 7.9 Hz), 6.75 (1H, d, J=6.6 Hz), 6.93
(1H, t, J=7.7 Hz), 7.17-7.36 (5H, m)
[0122] (+) APCI MS (m/z): 268 (M.sup.++1)
Preparation 8
[0123] A solution of
3-methoxy-5,7,8,9-tetrahydro-6H-benzocyclohepten -6-one (10 g) and
(R)-1-phenylethylamine (6.8 ml) in toluene (80 ml) in the presence
of a catalytic amount of p-toluenesulfonic acid monohydrate (0.10
g) was refluxed for 5 hours to remove water as the toluene
azeotrope, and then the mixture was evaporated in vacuo. To the
residue in methanol (80 ml) was added Raney nickel (NDT 90, 15 ml)
and the mixture was stirred at room temperature in the presence of
hydrogen at 3.2-4.0 kgf/cm.sup.2 for 15 hours, and filtered. After
evaporation in vacuo, the residue was dissolved in ethyl acetate
(150 ml). To the solution was added 4N hydrogen chloride in ethyl
acetate (26 ml) dropwise at 10-15.degree. C. The mixture was
stirred at 5.degree. C. for 1 hour and allowed to stand overnight
in a refrigerator. After the mixture was diluted by ether, the
precipitate was collected and the filter cake was washed with ether
and dried under reduced pressure to afford
N-((R)-1-phenylethyl)-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-
-yl)amine hydrochloride (13.7 g).
[0124] NMR (DMSO-d.sub.6, .delta.): 0.90-1.19 (1H, m), 1.68 (3H, d,
J=6.5 Hz), 1.70-2.10 (2H, m), 2.25-2.75 (4H, m), 2.90-3.33 (2H, m),
3.38-3.70 (3H, s), 4.50-4.95 (1H, m), 6.57-6.85 (2H, m), 6.92-7.05
(1H, m), 7.35-7.53 (3H, m), 7.70-7.88 (2H, m)
Preparation 9
[0125] To a mixture of
N-((R)-1-phenylethyl)-(3-methoxy-6,7,8,9-tetrahydro-
-5H-benzocyclohepten-6-yl)amine hydrochloride (13.7 g) in a mixture
of ethyl acetate and water was added 28% aqueous ammonium hydroxide
(30 ml), and the mixture was stirred for 20 minutes. After
separation, the organic layer was washed with brine (twice), dried
over anhydrous magnesium sulfate and evaporated in vacuo. To a
solution of the residue in 1-propanol (200 ml) was added L-tartaric
acid (6.8 g), and the mixture was warmed to 95.degree. C. to
dissolve it. Then the solution was slowly cooled to room
temperature, and stirred at 5.degree. C. for 1 hour. The
precipitate was collected, washed with a little amount of precooled
1-propanol and dried under reduced pressure to afford
N-((R)-1-phenylethyl)-((6R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohep-
ten -6-yl)amine L-tartaric acid (9.47 g).
[0126] NMR (DMSO-d.sub.6, .delta.): 0.97-1.25 (1H, m), 1.44 (2H, d,
J=6.5 Hz), 1.65-1.95 (2H, m), 1.97-2.15 (1H, m), 2.23-2.37 (1H, m),
2.53-2.75 (1H, m), 2.75-2.95 (1H, m), 3.06 (1H, d, J=13.5 Hz), 3.70
(3H, s), 4.38-4.53 (1H, m), 6.61 (1H, dd, J=2.6, 8.2 Hz), 6.76 (1H,
d, J=2.5 Hz), 6.94 (1H, d, J=8.2 Hz), 7.18-7.42 (3H, m), 7.55 (2H,
d, J=6.9 Hz)
Preparation 10
[0127] A mixture of N-((R)-1-phenylethyl)-((6R)-3-methoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine L-tartaric acid
(9.47 g) in a mixture of ethyl acetate and water was adjusted to
alkali with 28% aqueous ammonium hydoxide and separated. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate and evaporated in vacuo. Under nitrogen, to the residue in
dichloromethane (140 ml) was added boron tribromide (1M in
dichloromethane, 42.5 ml) dropwise at -10.about.0.degree. C., and
the mixture was stirred at the same temperature for 1 hour. The
resulting mixture was poured into ice-cold water with stirring.
After stirred at 5.degree. C. for 2 hours, the precipitate was
collected. The filter cake was washed with water and dried under
reduced pressure to afford N-((R)-1-phenylethyl)-((6R)-3-hydr-
oxy-6,7,8,9-tetrahydro-5H-benzocyclohepten -6-yl)amine hydrobromide
(7.78 g).
[0128] NMR (DMSO-d.sub.6, .delta.): 0.97-1.23 (1H, m), 1.27-2.01
(3H, m), 1.61 (2H, d, J=6.6 Hz), 2.05-2.65 (3H, m), 2.89 (1H, t,
J=10.4 Hz), 3.12 (1H, d, J=13.7 Hz), 4.77-4.96 (1H, br s), 6.49
(1H, dd, J=2.4, 8.1 Hz), 6.66 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.1
Hz), 7.37-7.59 (3H, m), 7.65 (2H, d, J=6.5 Hz), 8.74-8.96 (1H, br
s), 9.17-9.50 (1H, br s)
[0129] (+) APCI MS (m/z): 282 (M.sup.++1)
Preparation 11
[0130] A mixture of N-((R)-1-phenylethyl)-((6R)-3-hydroxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)aminehydrobromide
(7.67 g), ethyl bromoacetate (3.8 ml), potassium carbonate (17.6
g), and tetrabutylammonium chloride (1.18 g) in a mixture of
dichloromethane (80 ml) and water (40 ml) was refluxed for 9 hours.
After separation, the organic layer was washed with water and
brine, dried over anhydrous magnesium sulfate, and evaporated in
vacuo. The residue was dissolved in ethyl acetate (90 ml). To the
solution was added 4N hydrogen chloride in ethyl acetate (5.6 ml),
and the mixture was stirred at 5.degree. C. for 1 hour. The
precipitate was collected, washed with a little amount of ice-cold
ethyl acetate, and dried under reduce pressure to afford
N-((R)-1-phenylethyl)
-((6R)-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro
-5H-benzocyclohepten-6-yl)amine hydrochloride (4.99 g).
[0131] NMR (DMSO-d.sub.6, .delta.): 0.95-1.42 (2H, m), 1.23 (3H, t,
J=7.1 Hz), 1.46-2.05 (3H, m), 1.67 (3H, d, J=6.5 Hz), 2.26-2.77
(4H, m), 2.99 (1H, t, J=13.4 Hz), 3.13-3.35 (1H, m), 3.37 (2H, s),
4.20 (2H, q, J=7.1 Hz), 4.70 (2H, s), 4.73-4.95 (1H, m), 6.62 (1H,
dd, J=2.6, 8.2 Hz), 6.85 (1H, d, J=2.6 Hz), 6.96 (1H, d, J=8.3 Hz),
7.32-7.48 (3H, m), 7.76 (2H, d, J=6.5 Hz), 9.17-9.39 (1H, m),
10.05-10.30 (1H, m)
[0132] (+) APCI MS (m/z): 368 (M.sup.++1)
EXAMPLE 6
[0133] A solution of (2S)-3-phenoxy-1,2-epoxypropane (140 mg) and
N-benzyl-(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten
-6-yl)amine (240 mg) in ethanol (1.36 ml) was stirred under reflux
for 2 days, cooled to room temperature, and poured into aqueous
sodium bicarbonate solution. The mixture was extracted with ethyl
acetate. The extract was washed with water and evaporated in vacuo.
The residue was chromatographed (chloroform) over silica gel (10 g)
and the eluate was treated with 4N-hydrogenchloride in ethyl
acetate to afford (2S)-l-[N-benzyl-(3-ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyc-
lohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride as a crude
oil.
[0134] A mixture of the crude oil and 10% palladium on activated
carbon (50% wet, 150 mg) in ethanol (10 ml) was stirred at room
temperature in the presence of hydrogen at an atmospheric pressure
and filtered. The filtrate was evaporated in vacuo and the residue
was washed with ether to afford
(2S)-1-[(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro
-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride
(182 mg) as a powder.
[0135] mp: 122-128.degree. C.
[0136] IR (Nujol): 3340, 3190, 2800-2350, 1740, 1220 cm.sup.-1
[0137] NMR (DMSO-d.sub.6, .delta.): 1.21 (3H, t, J=7.1 Hz,
CH.sub.3), 1.7-2.8 (8H, m, 4CH.sub.2), 2.95-3.3 (3H, m,
CH.sub.2NCH), 3.9-4.25 (5H, m, OCH.sub.2CHO, COOCH.sub.2), 4.75
(2H, s, OCH.sub.2COO), 5.9 (1H, br s, OH), 6.6-7.35 (8H, m,
aromatic H), 8.65-9.2 (3H, m)
[0138] EI MS (m/z): 413 (M.sup.+), 276, 247, 206
[0139] Anal. Calcd. for C.sub.24H.sub.31NO.sub.5.HCl.H.sub.2O: C,
61.59; H, 7.32; N, 2.99; Found: C, 61.70; H, 7.03; N, 2.97;
EXAMPLE 7
[0140] A solution of 3-(2-allyloxyphenoxy)-1,2-epoxypropane (144
mg) and (S)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro
-2-naphthalenamine (obtained from the corresponding hydrochloride
(200 mg) in a usual manner) in ethanol (5 ml) was stirred under
reflux for 2 hours, cooled to room temperature, and evaporated in
vacuo. The residue was chromatographed (ethyl acetate) over silica
gel (6.0 g) to afford an oil, which was converted to the oxalate
using oxalic acid (35.3 mg) in a usual manner to afford
3-(2-allyloxyphenoxy) -1-[((2S)-7-ethoxycarbonylmethoxy--
1,2,3,4-tetrahydronaphthalen -2-yl)amino]-2-propanol oxalate (182
mg) as a powder.
[0141] mp: 105-109.degree. C.
[0142] IR (KBr): 3325, 3190, 2800-2350, 1736 cm.sup.-1
[0143] NMR (DMSO-d.sub.6, .delta.): 1.21 (3H, t, J=7.1 Hz,
CH.sub.3), 1.74 (1H, m, CH.sub.2), 2.21 (1H, m, CH.sub.2), 2.78
(3H, m, CH.sub.2), 3.10-3.24 (3H, m, CH.sub.2), 3.42 (1H, m, NCH),
3.9-4.05 (3H, m, OCH.sub.2CHO), 4.16 (2H, q, J=7.1 Hz,
COOCH.sub.2), 4.58 (2H, d, J=5.1 Hz, OCH.sub.2C.dbd.), 4.72 (2H, s,
OCH.sub.2COO), 5.25 (1H, dd, J=17.4, 1.8 Hz, .dbd.CH.sub.2), 5.42
(1H, dd, J=17.4, 1.8 Hz, .dbd.CH.sub.2), 5.6 (1H, br, OH),
5.96-6.14 (1H, m, CH.dbd.), 6.65-6.75 (2H, m, aromatic H),
6.88-7.05 (5H, m, aromatic H)
[0144] EI MS (m/z): 455 (M.sup.+), 262
EXAMPLE 8
[0145] A mixture of (2S)-1-[N-benzyl-(1-ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy
-2-propanol (0.55 g) and 10% Pd/C (50% wet, 150 mg) in methanol (6
ml) was stirred at room temperature in the presence of hydrogen at
an atmospheric pressure for 4 hours and filtered. The filtrate was
evaporated in vacuo and the residue was chromatographed
(chloroform-ethanol) over silica gel (8 g) to afford
(2S)-1-[(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro
-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (365 mg) as a
pale yellow solid. The solid (109 mg) was treated with 4N hydrogen
chloride in ethyl acetate and powdered from ether to afford
(2S)-1-[(1-ethoxycarbonyl- methoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten -6-yl)amino]-3-phenoxy-2-p-
ropanol hydrochloride (96 mg) as a colorless amorphous powder.
[0146] mp: 43-58.degree. C.
[0147] IR (KBr): 3384, 2800-2350, 1755, 1736, 1246, 1207
cm.sup.-1
[0148] NMR (DMSO-d.sub.6, .delta.): 1.15-1.3 (1H, m), 1.21 (3H, t,
J=7.1 Hz), 1.7-2.1 (2H, m), 2.25-2.42 (2H, m), 2.95-3.45 (6H, m),
4.01 (2H, m), 4.15 (2H, q, J=7.1 Hz), 4.22 (1H, m), 4.76 (2H, s),
5.9 (1H, d, J=4.8 Hz), 6.76-7.12 (6H, m), 7.31 (2H, t, J=7.8 Hz),
8.81 (1H, br), 9.12 (1H, br)
[0149] (+) APCI MS m/z: 414 (M.sup.++1)
EXAMPLE 9
[0150] A mixture of (2S)-1-[N-benzyl-(2-ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy
-2-propanol (362 mg) and 10% Pd/C (50% wet, 100 mg) in ethanol (4
ml) was stirred at room temperature in the presence of hydrogen at
an atmospheric pressure for 5 hours and filtered. The filtrate was
evaporated in vacuo and the residue was chromatographed
(dichloromethane-ethanol) over silica gel (6 g) to afford
(2S)-1-[(2-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro
-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (274 mg) as a
pale yellow oil. The oil (95 mg) and oxalic acid (20 mg) were
dissolved in ethanol and the solution was evaporated in vacuo. The
residue was powdered from ether to afford
(2S)-1-[(2-ethoxycarbonylmethoxy-6,7,8,9-te- trahydro
-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol oxalate (1:1)
(85 mg) as a colorless powder.
[0151] mp: 78.5-91.5.degree. C.
[0152] IR (KBr): 3442, 3408, 2800-2350, 1753, 1641, 1599, 1241,
1213 cm.sup.-1
[0153] NMR (DMSO-d.sub.6, .delta.): 1.21 (3H, t, J=7.1 Hz), 1.35
(1H, m), 1.8 (1H, m), 2.0 (1H, m), 2.25 (1H, m), 2.69 (2H, m),
2.95-3.25 (5H, m), 3.99 (2H, m), 4.16 (2H and 1H, q (J=7.1 Hz) and
m, respectively), 4.72 (2H, s), 5.5 (1H, br), 6.65-6.75 (2H, m),
6.94-6.99 (3H, m), 7.08-7.14 (1H, m), 7.27-7.36 (2H, m)
[0154] (+) APCI MS (m/z): 414 (M.sup.++1)
[0155] Anal. Calcd. for
C.sub.24H.sub.31NO.sub.5.C.sub.2H.sub.2O.sub.4.0.2- H.sub.2O: C,
61.58; H, 6.63; N, 2.76; Found: C, 61.51; H, 6.61; N, 2.71;
EXAMPLE 10
[0156] A solution of (2S)-1-[(1-ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol
(103 mg) in methanol (5.0 ml) and 0.1N sodium hydroxide aqueous
solution (2.5 ml) was stirred for 22 hours and evaporated in vacuo.
The residue was triturated in diethyl ether and the precipitated
powder was collected by filtration to afford sodium
[6,7,8,9-tetrahydro-6-[((2S)
-2-hydroxy-3-phenoxypropyl)amino]-5H-benzocyclohepten-1-yloxy]acetate
(98 mg) as a pale yellow powder.
[0157] mp: 65.degree. C. (dec.)
[0158] IR (KBr): 3411, 1599, 1240 cm.sup.-1
[0159] NMR (DMSO-d.sub.6, .delta.): 1.2-2.0 (4H, m), 2.45-2.85 (7H,
m), 3.12 (1H, m), 3.75-3.95 (3H, m), 4.05 (2H, s), 5.02 (1H, br d),
6.57 (1H, d, J=8.2 Hz), 6.64 (1H, d, J=7.2 Hz), 6.85-6.94 (4H, m),
7.27 (2H, t, J=8.0 Hz)
[0160] (+) APCI MS m/z: 386 (M.sup.+-Na+2)
[0161] Anal. Calcd. for C.sub.22H.sub.26NO.sub.5.H.sub.2O: C,
62.11; H, 6.63; N, 3.29; Found: C, 62.31; H, 6.59; N, 3.20;
EXAMPLE 11
[0162] The following compound was obtained according to a similar
manner to that of Example 10.
Sodium
[6,7,8,9-tetrahydro-6-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-5H-be-
nzocyclohepten-2-yloxy]acetate
[0163] mp: 166-174.degree. C.
[0164] IR (KBr): 3431, 1601, 1248 cm.sup.-1
[0165] NMR (DMSO-d.sub.6, .delta.): 1.25-1.95 (4H, m), 2.35-2.85
(7H, m), 3.25 (1H, m), 3.75-4.15 (3H, m), 4.01 (2H, s), 4.99 (1H,
br s), 6.48 (1H, dd, J=8.1, 2.5 Hz), 6.55 (1H, d, J=2.5 Hz),
6.87-6.96 (4H, m), 7.27 (2H, t, J=8.0 Hz)
[0166] (+) APCI MS m/z: 386 (M.sup.+-Na+2)
[0167] Anal. Calcd. for C.sub.22H.sub.26NO.sub.5Na.1.4H.sub.2O: C,
61.07; H, 6.71; N, 3.24; Found: C, 61.10; H, 6.42; N, 3.14;
EXAMPLE 12
[0168] A mixtur3 of
(2R)-1-[N-((R)-1-phenylethyl)-((6R)-3-ethoxycarbonylme- thoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-prop-
anol (2.0 g) and 10% palladium on activated carbon (50% wet, 0.70
g) in ethanol (24 ml) and tetrahydrofuran (12 ml) was stirred at
room temperature in the presence of hydrogen at an atmospheric
pressure for 3.5 hours, and filtered. The filtrate was evaporated
in vacuo. The residue was chromatographed (chloroform-methanol)
over silica gel to afford (2R)-1-[((6R)-3-ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzo- cyclohepten-6-yl)amino]-3-phenoxy
-2-propanol (1.37 g).
[0169] IR (KBr): 1760, 1498, 1249, 1033, 757 cm.sup.-1
[0170] NMR (CHCl.sub.3, .delta.): 1.29 (3H, t, J=7.1 Hz), 1.42-1.67
(1H, m), 1.69-1.90 (2H, m), 1.94-2.13 (1H, m), 2.69-2.97 (7H, m),
3.94-4.05 (3H, m), 4.25 (2H, d, J=7.1 Hz), 4.56 (2H, s), 6.62 (1H,
dd, J=2.7, 8.2 Hz), 6.85-7.03 (4H, m), 7.20-7.33 (2H, m)
[0171] (+) APCI MS (m/z): 414 (M.sup.++1)
EXAMPLE 13
[0172] A mixture of (2S)-1-[N-((S)-1-phenylethyl)-((6S)
-3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten
-6-yl)amino]-3-phenoxy-2-propanol (0.65 g) and 10% palladium on
activated carbon (50% wet, 0.20 g) in ethanol (6 ml) and
tetrahydrofuran (3 ml) was stirred at room temperature in the
presence of hydrogen at an atmospheric pressure for 1 hour, and
filtered. The filtrate was evaporated in vacuo. The residue was
chromatographed (chloroform-methanol) over silica gel to afford
(2S)-1-[((6S)-3-ethoxycarbonylmethoxy -6,7,8,9-tetrahydro-5H-benzo-
cyclohepten-6-yl)amino]-3-phenoxy -2-propanol (430 mg).
(2S)-1-[((6S)-3-Ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohe- pten-6-yl)amino]-3-phenoxy
-2-propanol (190 mg) was treated with 4N hydrogen chloride in ethyl
acetate to afford (2S)-1-[((6S)-3-ethoxycarbon- ylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy
-2-propanol hydrochloride (103 mg).
[0173] IR (KBr): 3417, 1754, 1598, 1502, 1245, 1203, 1076, 755
cm.sup.-1
[0174] NMR (DMSO-d.sub.6, .delta.): 1.20 (3H, t, J=7.1 Hz),
1.17-1.40 (1H, m), 1.72-2.10 (2H, m), 2.19-2.35 (1H, m), 2.66-2.77
(2H, m), 2.98-3.45 (5H, m), 4.01 (2H, d, J=5.1 Hz), 4.16 (2H, q,
J=7.1 Hz), 4.11-4.33 (1H, m), 4.71 (2H, s), 5.92 (1H, d, J=4.7 Hz),
6.64-6.73 (1H, m), 6.83 (1H, d, J=2.5 Hz), 6.93-7.08 (4H, m), 7.31
(2H, t, J=7.9 Hz), 8.70-9.15 (2H, m)
[0175] (+) APCI MS (m/z): 414 (M.sup.++1)
EXAMPLE 14
[0176] To a solution of (2S)-1-[((6S)-3-ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy
-2-propanol (249 mg) in ethanol (1 ml) was added 1N sodium
hydroxide at 5.degree. C. After stirred at room temperature for 2
hours, the mixture was evaporated in vacuo to afford sodium
[(6S)-6-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-
-6,7,8,9-tetrahydro-5H-benzocyclohepten-3-yloxy]acetate (210
mg).
[0177] IR (KBr): 3417, 1610, 1498, 1425, 1247, 1060, 754
cm.sup.-1
[0178] NMR (D.sub.2O, .delta.): 1.35-1.58 (1H, m), 1.65-2.06 (3H,
m), 2.59-2.93 (4H, m), 3.89-4.12 (3H, m), 4.41 (2H, s), 6.65 (1H,
dd, J=2.6, 8.2 Hz), 6.80 (1H, d, J=2.6 Hz), 6.94-7.09 (5H, m),
7.30-7.42 (2H, m)
[0179] (+) APCI MS (m/z): 386 (M.sup.+-Na+2)
EXAMPLE 15
[0180] The following compounds were obtained according to a similar
manner to that of Example 13.
[0181] (1) (2S)-1-[((6R)-3-Ethoxycarbonylmethoxy-6,7,8,9-tetrahydro
-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol
hydrochloride
[0182] IR (KBr): 3446, 1749, 1504, 1243, 1207, 757 cm.sup.-1
[0183] NMR (DMSO-d.sub.6, .delta.): 1.21 (3H, t, J=7.1 Hz),
1.16-1.38 (1H, m), 1.71-2.12 (2H, m), 2.23-2.37 (1H, m), 2.65-2.74
(2H, m), 2.98-3.16 (4H, m), 3.19-3.30 (1H, m), 4.00 (2H, d, J=5.1
Hz), 4.17 (2H, q, J=7.1 Hz), 4.13-4.32 (1H, m), 4.72 (2H, s), 5.91
(1H, d, J=4.8 Hz), 6.69 (1H, dd, J=2.6, 8.3 Hz), 6.81 (1H, d, J=2.6
Hz), 6.92-7.08 (4H, m), 7.25-7.37 (2H, m), 8.58-8.90 (1H, m),
8.91-9.25 (1H, m)
[0184] (+) APCI MS (m/z): 414 (M.sup.++1)
[0185] (2) (2R)-1-[((6S)-3-Ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-be-
nzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride
[0186] IR (KBr): 3446, 1749, 1498, 1243 cm.sup.-1
[0187] NMR (DMSO-d.sub.6, .delta.): 1.21 (3H, t, J=7.1 Hz),
1.16-1.43 (1H, m), 1.70-2.13 (2H, m), 2.25-2.39 (1H, m), 2.63-2.75
(2H, m), 2.95-3.38 (5H, m), 4.00 (2H, d, J=5.1 Hz), 4.17 (2H, q,
J=7.1 Hz), 4.08-4.32 (1H, m), 4.72 (2H, s), 5.91 (1H, d, J=4.7 Hz),
6.69 (1H, dd, J=2.6, 8.2 Hz), 6.82 (1H, d, J=2.6 Hz), 6.92-7.08
(4H, m), 7.25-7.17 (2H, m), 8.65-8.90 (1H, br s), 8.97-9.28 (1H, br
s)
[0188] (+) APCI MS (m/z): 414 (M.sup.++1)
EXAMPLE 16
[0189] The following compounds were obtained according to a similar
manner to that of Example 14.
[0190] (1) Sodium
[(6R)-6-[((2R)-2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9--
tetrahydro-5H-benzocyclohepten-3-yloxy]acetate
[0191] IR (KBr): 3421, 1602, 1498, 1247, 1060, 754 cm.sup.-1
[0192] NMR (D.sub.2O, .delta.): 1.35-1.55 (1H, m), 1.63-2.05 (3H,
m), 2.55-2.97 (7H, m), 3.89-4.13 (3H, m), 4.40 (2H, s), 6.64 (1H,
dd, J=2.6, 8.2 Hz), 6.79 (1H, d, J=2.6 Hz), 6.90-7.09 (4H, m),
7.25-7.41 (2H, m)
[0193] MALDI-MS (m/z): 408 (M.sup.++1), 386
[0194] (2) Sodium
[(6S)-6-[((2R)-2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9--
tetrahydro-5H-benzocyclohepten-3-yloxy]acetate
[0195] IR (KBr): 3444, 1627, 1600, 1500, 1421, 1249, 1058, 752
cm.sup.-1
[0196] NMR (D.sub.2O, .delta.): 0.94-1.17 (1H, m), 1.10-1.70 (3H,
m), 2.19-2.65 (7H, m), 3.45-3.72 (3H, m), 3.97 (2H, s), 6.62 (1H,
dd, J=2.6, 8.2 Hz), 6.39 (1H, d, J=2.5 Hz), 6.45-6.70 (4H, m),
6.85-6.99 (2H, m)
[0197] MALDI-MS (m/z): 386 (M.sup.++1)
[0198] (3) Sodium
[(6R)-6-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-6,7,8,9--
tetrahydro-5H-benzocyclohepten-3-yloxy]acetate
[0199] IR (KBr): 3444, 1600, 1498, 1253, 1245, 1047, 752
cm.sup.-1
[0200] NMR (D.sub.2O, .delta.): 1.37-1.63 (1H, m), 1.66-2.09 (3H,
m), 2.63-3.05 (7H, m), 3.94-4.17 (3H, m), 6.66 (1H, dd, J=2.5, 8.2
Hz), 6.82 (1H, d, J=2.5 Hz), 6.93-7.11 (4H, m), 7.31-7.43 (2H,
m)
[0201] (+) APCI MS (m/z): 386 (M.sup.+-Na+2)
EXAMPLE 17
[0202] The following compound was obtained according to a similar
manner to that of Example 12.
(2R)-1-[((6S)-3-Ethoxycarbonylmethoxy
-6,7,8,9-tetrahydro-5H-benzocyclohep-
ten-6-yl)amino]-3-phenoxy-2-propanol (137 mg) was obtained.
[0203] NMR (CDCl.sub.3, .delta.): 1.29 (3H, t, J=7.1 Hz), 1.45-1.68
(1H, m), 1.71-1.93 (2H, m), 1.95-2.13 (1H, m), 2.30-3.05 (7H, m),
3.94-4.08 (3H, m), 4.26 (2H, q, J=7.1 Hz), 4.58 (2H, s), 6.64 (1H,
dd, J=2.7, 8.2 Hz), 6.76 (1H, d, J=2.7 Hz), 6.85-7.03 (4H, m),
7.21-7.33 (2H, m)
[0204] The propanolamine derivatives and salts thereof of the
object compound [I] including the object compounds of the
above-mentioned Examples possess .beta..sub.3 adrenergic receptor
stimulating activity and are useful as .beta..sub.3 adrenergic
receptor agonists which are effective in the treatment and/or
prevention of the aforesaid diseases.
* * * * *