U.S. patent number RE39,667 [Application Number 11/017,635] was granted by the patent office on 2007-05-29 for 3,3-diphenylpropylamines, their use and preparation.
This patent grant is currently assigned to Pfizer Health AB. Invention is credited to Rolf A. Johansson, Pinchas Moses, Lisbeth Nilvebrant, Bengt A. Sparf.
United States Patent |
RE39,667 |
Johansson , et al. |
May 29, 2007 |
3,3-Diphenylpropylamines, their use and preparation
Abstract
The invention relates to 3,3-diphenylpropylamines of formula
(I), wherein R.sup.1 signifies hydrogen or methyl, R.sup.2 and
R.sup.3 independently signify hydrogen, methyl, methoxy, hydroxy,
carbamoyl, sulphamoyl or halogen, and X represents a tertiary amino
group of formula (II), wherein R.sup.4 and R.sup.5 signify
non-aromatic hydrocarbyl groups, which may be the same or different
and which together contain at least three carbon atoms, and wherein
R.sup.4 and R.sup.5 may form a ring together with the amine
nitrogen, their salts with physiologically acceptable acids and,
when the compounds can be in the form of optical isomers, the
racemic mixture and the individual enantiomers. The invention also
relates to methods for their preparation, pharmaceutical
compositions containing the novel compounds, and the use of the
compounds for preparing drugs ##STR00001##
Inventors: |
Johansson; Rolf A. (Huddinge,
SE), Moses; Pinchas (Satsjo-Boo, SE),
Nilvebrant; Lisbeth (Bromma, SE), Sparf; Bengt A.
(Trangsund, SE) |
Assignee: |
Pfizer Health AB (Stockholm,
SE)
|
Family
ID: |
20387730 |
Appl.
No.: |
11/017,635 |
Filed: |
November 5, 1993 |
PCT
Filed: |
November 05, 1993 |
PCT No.: |
PCT/SE93/00927 |
371(c)(1),(2),(4) Date: |
May 05, 1995 |
PCT
Pub. No.: |
WO94/11337 |
PCT
Pub. Date: |
May 26, 1994 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
08432113 |
May 5, 1995 |
05559269 |
Sep 24, 1996 |
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Foreign Application Priority Data
Current U.S.
Class: |
564/443; 546/240;
564/165; 564/86; 564/316; 548/578 |
Current CPC
Class: |
C07C
217/62 (20130101); C07C 215/54 (20130101); A61P
25/02 (20180101) |
Current International
Class: |
C07C
215/76 (20060101); A61K 31/135 (20060101) |
Field of
Search: |
;514/603,620,648
;564/86,165,316,443 |
References Cited
[Referenced By]
U.S. Patent Documents
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3446901 |
May 1969 |
Jones et al. |
4139537 |
February 1979 |
Diamond et al. |
5382600 |
January 1995 |
Jonsson et al. |
5686464 |
November 1997 |
Johansson et al. |
6538035 |
March 2003 |
Gillberg et al. |
|
Foreign Patent Documents
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1 216 318 |
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May 1966 |
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DE |
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111894 |
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Oct 1968 |
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DK |
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1169944 |
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Nov 1969 |
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GB |
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1169945 |
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Nov 1969 |
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GB |
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215 499 |
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Sep 1967 |
|
SE |
|
WO-89/06644 |
|
Jul 1989 |
|
WO |
|
WO-94/11337 |
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May 1994 |
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WO |
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Other References
Nilvebrant et al. "Tolterodine--a new bladder selective muscarinic
. . . " CA 126:271639 (1997). cited by examiner .
Trilateral project B3b "Reach through claims" (2001). cited by
examiner .
Wilbraham "Organic and biological chemistry" p. 268-269 (1984).
cited by examiner .
Markaryan et al., Chemical Abstracts 97:120105n, vol. 97 (1982), p.
20. cited by other .
Strehike et al., Chemical Abstracts 91:107943r, vol. 91 (1979), p.
580. cited by other .
Atwal et al., Substituted 1,2,3,4-Tetrahydroaminonaphthols:
Antihypertensive Agents, Calcium Channel Blockers, and Adrenergic
Receptor Blockers with Catecholamine-Depleting Effects. Journal of
Medicinal Chemistry 30:627-635 (1987). cited by other.
|
Primary Examiner: Chang; Celia
Attorney, Agent or Firm: Connolly Bove Lodge & Hutz,
LLP
Claims
We claim:
1. A 3,3-diphenylpropylamine of formula I ##STR00014## wherein
R.sup.1 represents hydrogen or methyl, R.sup.2 and R.sup.3
independently represent hydrogen, methyl, methoxy, hydroxy,
carbamoyl, sulphamoyl or halogen, and X represents a tertiary amino
group of formula II ##STR00015## wherein R.sup.4 and R.sup.5
represent non-aromatic hydrocarbyl groups, which are the same or
different and which together contain at least three carbon atoms,
and wherein R.sup.4 and R.sup.5 may form a ring together with the
amine nitrogen; or a physiologically acceptable acid salt thereof
.Iadd.with the proviso that the 3,3-diphenylpropylamine of formula
I is not
(+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylami-
ne.Iaddend..
2. The 3,3-diphenylpropylamine according to claim 1, wherein each
of R.sup.4 and R.sup.5 independently represents a saturated
hydrocarbyl group.
3. The 3,3-diphenylpropylamines according to claim 1 wherein at
least one of R.sup.4 and R.sup.5 comprises a branched carbon
chain.
4. The 3,3-diphenylpropylamine according to claim 1, wherein X is a
moiety selected from the group consisting of formulas a) to h):
##STR00016##
5. The 3,3-diphenylpropylamine according to claim 1, wherein the
HOCH.sub.2-group is in the 5-position on the phenyl ring, R.sup.2
is hydrogen and R.sup.3 is hydrogen or hydroxy.
6. The 3,3-diphenylpropylamines according to claim 1, selected from
N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine,
its salts with physiologically acceptable acids, racemates thereof
and individual enantiomers thereof.
.[.7. A pharmaceutical composition comprising an effective amount
of a 3,3-diphenylpropylamine according to claim 1 and a compatible
pharmaceutical carrier..].
8. A method for preparing a 3,3-diphenylpropylamine according to
claim 1, comprising: a) reducing the group R.sup.6CO of a
3,3-diphenylpropylamine of formula III ##STR00017## wherein R.sup.1
to R.sup.3 and X are as defined above, R.sup.6 is hydrogen or
R.sup.7O, where R.sup.7 is hydrogen, alkyl, alkenyl, alkynyl or
aryl, and any hydroxy groups may be protected, such as by
methylation or benzylation, or b) reacting a reactively esterified
3,3-diphenylpropanol of formula IV ##STR00018## wherein R.sup.1 to
R.sup.3 are as defined above, any hydroxy groups may be protected,
and wherein Y is a leaving group, with an amine of formula V H--X V
wherein X is as defined above, or c) reducing a
3,3-diphenylpropionamide of formula VI ##STR00019## wherein R.sup.1
to R.sup.3 and X are as defined above and any hydroxy groups may be
protected, or d) N-methylating a secondary 3,3-diphenylpropylamine
of formula VII ##STR00020## wherein R.sup.1 to R.sup.3 and X are as
defined above and any hydroxy groups may be protected, and wherein
Z has the same meaning as R.sup.4 and R.sup.5 with the exception of
methyl, or e) reducing a 3,3-diphenylpropenamine of formula VIIIa
or a 3,3-diphenylpropylamine of formula VIIIb ##STR00021## wherein
R.sup.1 to R.sup.3 and X are as defined above and any hydroxy
groups may be protected, and W signifies a hydroxy group or a
halogen atom, or f) reacting a diphenylpropylamine of formula IX
##STR00022## wherein R.sup.1 to R.sup.3 and X are as defined above,
and Hal is halogen, with formaldehyde or a formaldehyde equivalent,
or g) oxidizing the methyl group of a diphenylpropylamine of
formula X ##STR00023## wherein R.sup.1 to R.sup.3 and X are as
defined above, and i) when necessary splitting off hydroxy
protecting groups in the compounds obtained, if desired after mono-
or di-halogenation of one or both of the phenyl rings, and/or ii)
if desired converting the obtained bases of formula I into salts
thereof with physiologically acceptable acids, or vice versa,
and/or iii) if desired separating an obtained mixture of optical
isomers into the individual enantiomers, and/or iv) if desired
methylating an ortho-hydroxy group in an obtained compound of
formula I, wherein R.sup.1 is hydrogen and/or R.sup.3 is
hydroxy.
9. The 3,3-diphenylpropylamine according to claim 1, wherein said
compound is in the form of a racemic mixture of optical
isomers.
10. The 3,3-diphenylpropylamine according to claim 1, wherein said
compound is an individual enantiomer.
11. The 3,3-diphenylpropylamine according to claim 2, wherein
R.sup.4 and R.sup.5 independently represent a C.sub.1-8-alkyl group
or adamantyl and the total number of carbon atoms contained in
R.sup.4 and R.sup.5 is at least four carbon atoms.
12. The 3,3-diphenylpropylamine according to claim 11, wherein
R.sup.4 and R.sup.5 independently represent a C.sub.1-6-alkyl
group.
13. The 3,3-diphenylpropylamine according to claim 5, wherein
R.sup.3 is in the 2-position on the phenyl ring.
14. A method for treating .[.acetylcholine-mediated.]. disorders
.Iadd.of the bladder .Iaddend.which comprises administering to a
patient in need thereof .[.an.]. .Iadd.a therapeutically
.Iaddend.effective amount of a 3,3-diphenylpropylamine as claimed
in claim 1.
15. The method according to claim 14, wherein said disorder is
urinary incontinence.
.Iadd.16. The compound
(+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylami-
ne, or a physiologically acceptable acid salt thereof, which is
free of the compound
(+)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine,
or a physiologically acceptable acid salt thereof..Iaddend.
.Iadd.17. A method for treating disorders of the bladder which
comprises administering to a patient in need thereof a
therapeutically effective amount of the compound as claimed in
claim 16..Iaddend.
Description
The present invention relates to novel therapeutically active
compounds, methods for their preparation, pharmaceutical
compositions containing the novel compounds, and the use of the
compounds for preparing drugs.
WO 89/06644 discloses 3,3-diphenylpropylamines having
anticholinergic activity. In accordance with the present invention
novel therapeutically active compounds have now been found, some of
which are formed as metabolites in mammals when treated with the
3,3-diphenylpropylamines disclosed in the above-mentioned WO
publication. These metabolites have at least as favourable
anti-cholinergic properties as the parent compounds and can thus be
used for the control of events mediated by acetylcholine, like
urination.
.Iadd.WO 89/06644 discloses 3,3-diphenylpropylamines of formula Ia
##STR00002## wherein R.sup.1a signifies hydrogen or methyl,
R.sup.2a, R.sup.3a and R.sup.4a independently signify hydrogen,
methyl, methoxyl, hydroxy, carbamoyl, sulphanoyl or halogen, and Xa
represents a tertiary amino group of formula ##STR00003## wherein
R.sup.5a and R.sup.6a signify non-aromatic hydrocarbol groups,
which may be the same or different and which together contain at
least three carbon atoms, preferably at least four carbon atoms,
especially at least five carbon atoms, and where R.sup.5a and
R.sup.6a may form a ring together with the amine nitrogen, said
ring preferably having no other hetero atom than the amine
nitrogen, and physiologically acceptable acid salts
thereof..Iaddend.
The novel compounds of the present invention are represented by the
general formula I ##STR00004## wherein R.sup.1 signifies hydrogen
or methyl, R.sup.2 and R.sup.3 independently signify hydrogen,
methyl, methoxy, hydroxy, carbamoyl, sulphamoyl or halogen, and X
represents a tertiary amino group of formula II ##STR00005##
wherein R.sup.4 and R.sup.5 signify non-aromatic hydrocarbyl
groups, which may be the same or different and which together
contain at least three carbon atoms, preferably at least four
carbon atoms, especially at least five carbon atoms, and wherein
R.sup.4 and R.sup.5 may form a ring together with the amine
nitrogen, said ring preferably having no other heteroatom than the
amine nitrogen.
The compounds of formula I can form salts with physiologically
acceptable acids, organic and inorganic, and the invention
comprises the free bases as well as the salts thereof. Examples of
such acid addition salts include the hydrochloride, hydrobromide,
hydrogen fumarate, and the like.
When the novel compounds are in the form of optical isomers, the
invention comprises the racemic mixture as well as the individual
isomers as such.
In the compounds of formula I, R.sup.2 is preferably hydrogen, and
R.sup.3 is preferably hydrogen or hydroxy.
R.sup.2 is preferably in 3-, 4- or 5-position.
R.sup.3 is preferably in 2-position with respect to the propylamine
group.
The HOCH.sub.2-group is preferably in 5-position.
Preferably, each of R.sup.4 and R.sup.5 independently signifies
C.sub.1-8-alkyl, especially C.sub.1-6-alkyl, or adamantyl, R.sup.4
and R.sup.5 together comprising at least three, preferably at least
four carbon atoms. R.sup.4 and R.sup.5 may carry one or more
hydroxy groups, and they may be joined to form a ring together with
the amine nitrogen atom.
Presently preferred tertiary amino groups X in formula I include
the following groups a)-h): ##STR00006##
Preferably, R.sup.4 and R.sup.5 are both isopropyl.
A presently preferred specific compound of formula I is
N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine.
The compounds of formula I may, in accordance with the present
invention, be prepared by per se conventional methods, and
especially by a) reducing the group R.sup.6CO in a
3,3-diphenylpropylamine of formula III ##STR00007## wherein R.sup.1
to R.sup.3 and X are as defined above, R.sup.6 is hydrogen or
R.sup.7O, where R.sup.7 is hydrogen, (preferably lower) alkyl,
alkenyl, alkynyl or aryl (such as phenyl) and any hydroxy groups
may be protected, such as by methylation or benzylation, or b)
reacting a reactively esterified 3,3-diphenylpropanol of formula IV
##STR00008## wherein R.sup.1 to R.sup.3 are as defined above and
any hydroxy groups may be protected, and wherein Y is a leaving
group, preferably halogen or an alkyl or arylsulphonyloxy group,
with an amine of formula V H--X wherein X is as defined above, or
c) reducing a 3,3-diphenylpropionamide of formula VI ##STR00009##
wherein R.sup.1 to R.sup.3 and X are as defined above and any
hydroxy groups may be protected, preferably using a complex metal
hydride, or d) N-methylating a secondary 3,3-diphenylpropylamine of
formula VII ##STR00010## wherein R.sup.1 to R.sup.3 and X are as
defined above and any hydroxy groups may be protected, and wherein
Z has the same meaning as R.sup.4 and R.sup.5 with the exception of
methyl, Z preferably being a hydrocarbyl group comprising at least
three carbon atoms, the N-methylation preferably being carried out
using formaldehyde or formic acid, or e) reducing a
3,3-diphenylpropenamine of formula VIIIa or a
3,3-diphenylpropylamine of formula VIIIb ##STR00011## wherein
R.sup.1 to R.sup.3 and X are as defined above and any hydroxy
groups may be protected, and W signifies a hydroxy group or a
halogen atom, preferably by means of catalytic hydrogenation, f)
reacting a 3,3-diphenylpropylamine of formula IX ##STR00012##
wherein R.sup.1 to R.sup.3 and X are as defined above, and Hal is
halogen, with formaldehyde or a formaldehyde equivalent (such as
s-trioxane), or g) oxidizing the methyl group of a
diphenylpropylamine of formula X ##STR00013## wherein R.sup.1 to
R.sup.3 and X are as defined above, and i) when necessary splitting
off hydroxy protecting groups in the compounds obtained, if desired
after mono- or di-halogenation of one or both of the phenyl rings,
and/or ii) if desired converting the obtained bases of formula I
into salts thereof with physiologically acceptable acids, or vice
versa, and/or iii) if desired separating an obtained mixture of
optical isomers into the individual enantiomers, and/or iv) if
desired methylating an ortho-hydroxy group in an obtained compound
of formula I, wherein R.sup.1 is hydrogen and/or R.sup.3 is
hydroxy.
The oxidation in process g) above may be performed chemically,
electrochemically or enzymatically. Chemical oxidation is
advantageously performed using a metal salt or oxide like ceric
ammonium nitrate, manganese oxides, chromium oxides, vanadinium
oxides, cobalt acetate, aluminium oxide, bismuth molybdate or
combinations thereof. Chemical oxidation may also be effected by
peracids, with or without a catalyst, or with halides.
Electrochemical oxidation may be conducted with or without a
catalyst. For enzymatical oxidation, it is preferred to use
bacteria or yeast (e.g. Candida Guilliermondi, Candida
Tropicalis).
The removal of hydroxy protecting groups according to i) above can
e.g. be done by treatment with hydrobromic acid, borontribromide or
by catalytic hydrogenation.
The separation of mixtures of optical isomers, according to ii)
above, into the individual enantiomers can e.g. be achieved by
fractional crystallization of salts with chiral acids or by
chromatographic separation on chiral columns.
The starting compounds of formula III and IX may be prepared as
described in the preparation example described below. The starting
materials used in processes b) to e) and g) may be prepared as
described in the afore-mentioned WO 89/06644 (the disclosure of
which is incorporated by reference herein) with due consideration
of the disclosure in the present preparation example.
In accordance with the present invention, the compounds of formula
I, in the form of free bases or salts with physiologically
acceptable acids, can be brought into suitable galenic forms, such
as compositions for oral use, for injection, for nasal spray
administration or the like, in accordance with accepted
pharmaceutical procedures. Such pharmaceutical compositions
according to the invention comprise an effective amount of the
compounds of formula I in association with compatible
pharmaceutically acceptable carrier materials, or diluents, as is
well known in the art. The carriers may be any inert material,
organic or inorganic, suitable for enteral, percutaneous or
parenteral administration, such as: water, gelatin, gum arabicum,
lactose, microcrystalline cellulose, starch, sodium starch
glycolate, calcium hydrogen phosphate, magnesium stearate, talcum,
colloidal silicon dioxide, and the like. Such compositions may also
contain other pharmaceutically active agents, and conventional
additives, such as stabilizers, wetting agents, emulsifiers,
flavouring agents, buffers, and the like.
The compositions according to the invention can e.g. be made up in
solid or liquid form for oral administration, such as tablets,
capsules, powders, syrups, elixirs and the like, in the form of
sterile solutions, suspensions or emulsions for parenteral
administration, and the like.
The compounds and compositions can, as mentioned above, be used for
the same therapeutical indications as the compounds of the
above-mentioned WO 89/06644, i.e. for the treatment of
acetylcholine-mediated disorders, such as urinary incontinence. The
dosage of the specific compound will vary depending on its potency,
the mode of administration, the age and weight of the patient and
the severity of the condition to be treated. The daily dosage may,
for example, range from about 0.01 mg to about 4 mg per kilo of
body weight, administered singly or multiply in doses e.g. from
about 0,05 mg to about 200 mg each.
The invention will be further illustrated by the following
non-limiting example and pharmacological tests. Reference will be
made to the accompanying drawing where the only FIGURE shows
bladder pressure inhibition curves for a compound of the present
invention and a prior art compound, respectively.
GENERAL
N.M.R data were acquired on a Jeol JNM-EX 270 Fourier transform
spectrometer. Spectra were recorded with tetramethylsilane (TMS) as
internal standard at 30.degree. C. Infrared spectra were recorded
on a Perkin Elmer 599B instrument. Non-corrected melting points
were obtained on a Koeffler apparatus. Gas chromatography was
performed on a HP 5940 instrument with a 10 m HP-1 column and the
oven heated in the linear temperature gradient mode.
EXAMPLE 1
(+)-N,N-Diisopropyl-3-(2-hydroxy-5-hydroxymethyphenyl)-3-phenylpropylamin-
e (+) mandelate, and
(-)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylami-
ne (-) mandelate
a) 6-Bromo-4-phenyl-3,4-dihydro-coumarine
A solution of p-bromophenol (138 g, 0.8 mole), cinnamic acid (148
g, 1.0 mole), acetic acid (200 g) and conc. sulfuric acid was
refluxed for 2 h. Volatile material was distilled at reduced
pressure. The residual syrup was cooled and triturated with cold
water, giving a semi-crystalline mass. This was washed extensively
with water, saturated sodium carbonate and finally with water
again. The material was filtered through a sintered glass funnel,
and then mixed with an equal weight of ethanol. The slurry was
stirred at room temperature for 1 h and then filtered. The
resulting product was washed briefly with ethanol and then
diisopropyl ether. After drying, 135 g (55.7%) of the title
compound was isolated as white crystals, melting at 117.degree.
C.
b) Methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanonate
6-Bromo-4-phenyl-3,4-dihydro-coumarine (290 g, 0.96 mole) was
dissolved in a mixture of methanol (1 L) and acetone (1 L). To the
above solution were added potassium carbonate (160 g, 1.16 mole),
.alpha.-chlorotoluene (140 g, 1.1 mole) and sodium iodide (30 g,
0.47 mole), and the mixture was stirred under reflux for 3 h. The
solution was concentrated by distillation, and the residue treated
with water and extracted with diethyl ether. The ethereal layer was
washed with water, saturated sodium carbonate solution and water,
successively. The organic layer was dried over sodium sulfate,
filtered and then evaporated to give 420 g (.apprxeq.100%) of the
title compound as a light yellow oil.
c) 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanol
Methyl 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanonate (112 g,
0.26 mole) was dissolved in tetrahydrofuran (250 mL) and added
dropwise under nitrogen atmosphere to a suspension of lithium
aluminiumhydride (5.9 g, 0.16 mole) in tetrahydrofuran (250 mL).
The mixture was stirred overnight under nitrogen atmosphere. The
excess hydride was decomposed by addition of a small amount of HCl
(aq, 2M). The solution was filtered on a pad of Celatom, and the
solids were washed thoroughly with ether. The combined ethereal
solution was washed with HCl (2M), water, sodium hydroxide (2M) and
then with water again. The organic solution was dried over sodium
sulfate, filtered and evaporated to give 98.5 g (95%) of the title
compound as a colourless oil. A small fraction of the oil was
crystallized from diisopropyl ether/petroleum ether giving crystals
which melted at 70.degree. C.
d)
3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl-p-toluenesulfonate
To a solution of 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanol
(107 g, 0.24 mole) in dichloromethane (300 mL) and pyridine (75 mL)
at 0.degree. C. was added p-toluene sulfonylchloride (57 g, 0.3
mole). The solution was stirred at 0.degree. C. overnight and then
evaporated at reduced pressure and at a bath temperature below
50.degree. C. The remainder was poured onto water and then the
mixture was extracted with diethyl ether. The organic layer was
washed with water, HCl (2M) and water successively, and finally
dried over sodium sulfate. After filtration the ethereal solution
was evaporated at a bath temperature of <50.degree. C. giving
137 g (.apprxeq.100%) of
3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl-p-toluenesulfonate as
a pale yellow oil.
e)
N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine
3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl-p-toluenesulfonate
(115 g, 0.2 mole) was dissolved in a mixture of acetonitrile (150
g) and diisopropylamine (202 g, 2.0 mole) and the mixture was
refluxed for 4 days. The solution was evaporated, and to the
resulting syrup was added sodium hydroxide (2M, 200 mL). The
mixture was concentrated, cooled and then extracted with diethyl
ether. The ethereal layer was extensively washed with water. The
amine was extracted with excess sulfuric acid (1M). The aqueous
layer was washed with diethyl ether and then basified with sodium
hydroxide (11M). The mixture was then extracted with diethyl ether.
The organic layer was washed with water, dried over sodium sulfate,
filtered and then evaporated to give 78.6 g (78%) of
N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine
as a pale yellow oil. The 1-H N.M.R spectrum was in accordance with
the above structure.
f) Resolution
To a solution of
N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine
(255 g, 0.53 mole) in ethanol (750 g) was added L-(+)-tartaric acid
(80 g, 0.53 mole). When all material was dissolved, diethyl ether
(90 g) was added and crystallization commenced. After being stored
at room temperature overnight, the formed salts were filtered off,
washed with fresh ethanol-diethyl ether solution (2:1) and dried to
give 98 g of white crystals melting at 156.degree. C.
[.alpha.].sup.22=16.3.degree. (c=5.1, ethanol)
The mother liquor from the precipitation with L-(+)-tartaric acid
was evaporated. The resulting syrup was treated with sodium
hydroxide (2M) and extracted with diethyl ether. The organic phase
was washed with water, dried over sodium sulfate, filtered and then
evaporated, giving 170 g of free base. The base (170 g, 0.35 mole)
was dissolved in ethanol (500 mL), and D-(-)-tartaric acid (53 g,
0.53 mole) was added. When all had dissolved, diethyl ether (50 mL)
was added and crystallization commenced. The crystals were filtered
off and washed with fresh ethanol-diethyl ether solution giving 105
g of crystals melting at 154.degree.-155.degree. C.
[.alpha.].sup.22=16.4.degree. (c=5.0, methanol)
The mother liquor was concentrated, basified and treated as above,
yielding 80 g of free base. This base was dissolved in ethanol, and
treated with L-(+)-tartaric acid as described above, yielding
additional 20 g of the dextrorotatory form of the salt. (M.p.
156.degree. C.). In an analogous manner, 20 g of the levorotatory
form could be obtained.
The pooled dextrorotatory form was dissolved in water and basified
with sodium hydroxide (2M). The mixture was then extracted with
diethyl ether. The organic phase was washed with water, dried over
sodium sulfate, filtered and finally evaporated to give the chiral
amine (88 g) as a colourless oil. [.alpha.].sup.22=16.3.degree.
(c=5.1, ethanol)
In an analogous fashion, the levorotatory base was obtained (90 g),
[.alpha.].sup.22=-16.1.degree. (c=4.2, ethanol). The optical purity
as assessed by chromatography was >99%.
g1)
(+-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylaimi-
ne hydrochloride
A mixture of magnesium (12.2 g, 0.5 mole), ethyl bromide (2 g), and
iodine (a small crystal) in dry diethyl ether (200 mL) was warmed
until the reaction started.
(+)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine
(45.6 g, 0.095 mole) and ethyl bromide (32.7 g, 0.3 mole) dissolved
in dry diethyl ether (250 mL) were then added dropwise under
nitrogen atmosphere. The mixture was refluxed for 1.5 h and then
cooled in an acetone/dry-ice bath, whereupon powdered dry ice
(.apprxeq.100 g) was added gently. Tetrahydrofuran was added when
needed to prevent the mixture from solidification. The reaction
mixture was stirred for 0.5 h when ammonium chloride (200 mL, 20%
w/w) was added. The mixture was stirred vigorously until two
transparent phases were formed, and then filtered through a pad of
Celatom. The aqueous layer was washed with diethyl ether and then
acidified with hydrochloric acid to pH 1. The precipitated
semicrystalline gum was washed with water, and then transferred to
a round bottom flask. The product was dried by co-evaporation with
acetone, benzene, toluene, diisopropyl ether and methanol,
successively. The title compound (35.1 g, 77%) was isolated as
friable shiny flakes and used without any further purification.
g2)
(-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylami-
ne hydrochloride
This product was isolated in 81% yield in a corresponding way as
described above from
(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine.
h1)
(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carbomethoxyphenyl)-3-phenylprop-
ylamine
(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine
(34 g, 0.07 mole) was dissolved in methanol (300 mL) containing
sulfuric acid (6 g) and refluxed for 6 h. The solution was then
cooled and concentrated. To the mixture were added ice-water and a
slight excess of saturated sodium carbonate solution. The mixture
was then extracted with diethyl ether. The organic phase was washed
with water, dried over sodium sulfate, filtered and evaporated,
giving 30 g (93%) of crude ester. Recrystallisation from
diisopropyl ether gave white crystals melting at
85.degree.-86.degree. C. The 1-H N.M.R. spectrum was in accordance
with the above structure.
h2)
(-)-N,N-diisopropyl-3-(2-benzyloxy-5-carbomethoxyphenyl)-3-phenylprop-
ylamine
The title compound was obtained from
(-)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine
in a similar manner as described above for the dextro isomer in a
93% yield.
i1)
(-)-N,N-Diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3-phenylpro-
pylamine
(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carbomethoxyphenyl)-3-phenylpropylam-
ine (30 g, 0.065 mole) dissolved in diethyl ether (250 mL) was
added dropwise under nitrogen to a suspension of lithium
aluminiumhydride (1.9 g, 0.05 mole) in dry diethyl ether (150 mL).
The mixture was stirred overnight at room temperature, and the
excess hydride was decomposed by the addition of water (.apprxeq.5
g). The mixture was stirred for 10 min, when sodium sulfate (s) was
added. After stirring for 20 minutes, the mixture was filtered and
then evaporated to give 28.4 g of the title compound as a
colourless oil.
i2)
(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3-phenylpro-
pylamine
The title compound was obtained in an analogous fashion as
described above for the levo isomer from
(-)-N,N-diisopropyl-3-(2-benzyloxy-5-carbomethoxyphenyl)-3-phenylpropylam-
ine.
j1)
(+)-N,N-Diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropy-
lammonium (+) mandelate
(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3-phenylpropyla-
mine (28.2 g, 0,065 mole) was dissolved in methanol (300 g). Raney
Nickel (one teaspoon) was added and the mixture was hydrogenated at
atmospheric pressure until the theoretical amount of hydrogen was
consumed. The progress of the reaction was monitored by gas
chromatography. The mixture was then filtered through a pad of
Celatom, and the solvent was removed by evaporation at a bath
temperature <50.degree. C. The resulting oil was dissolved in
diethyl ether, and the ethereal solution was washed with water,
dried over sodium sulfate and evaporated giving 22.2 g of a
colourless oil. [.alpha.].sup.22=16.7.degree. (c=4.9, ethanol).
To the above oil, dissolved in 2-propanol (50 g) was added
S-(+)-mandelic acid (9.6 g, 0.06 mole) in 2-propanol (50 g). Dry
diethyl ether (50 g) was added, and the solution was left for
several hours. The resulting heavy, white crystals were filtered
off and washed with a mixture of 2-propanol and diethyl ether (1:1
v/v) and then dried, yielding 25 g of the title compound which
melted at 148.degree. C. [.alpha.].sup.22=38.3.degree. (c=5.1,
methanol).
The 1-H N.M.R. spectrum was in accordance with the above
structure.
Chiral purity as assessed by H.P.L.C. was >99%.
Elementary. Anal. Theor.: C: 73.0 H: 8.0 N: 2.8 O: 16.2 Found: C:
72.9 H: 8.1 N: 3.0 O: 16.5
j2)
(-)-N,N-Diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropy-
lammonium (-) mandelate
The title compound was obtained from
(-)-N,N-diisopropyl-3-(2-benzyloxy-5-hydroxymethylphenyl)-3-phenylpropyla-
mine in an analogous manner to that described in j1) above.
Elementary Anal. Theor.: C: 73.0 H: 8.0 N: 2.8 O: 16.2 Found: C:
73.2 H: 8.1 N: 3.0 O: 16.5
The free base had an optical rotation of
[.alpha.].sup.22=-15.5.degree. (c=5.0, ethanol).
The 1-(-)-mandelic acid salt had a m.p. of 147.degree.-148.degree.
C. and an optical rotation [.alpha.].sup.22=-37.9.degree. (c=4.7,
methanol).
The optical purity as assessed by H.P.L.C. was >99%.
PHARMACOLOGY
Pharmacological tests performed with one compound of the invention
and three prior art compounds disclosed in the above mentioned WO
89/06644 will now be described. The following compounds were
used:
(A)
(+)N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine,
hydrochloride (WO 89/06644);
(B) N,N-diisopropyl-3-bis-(2-hydroxyphenyl)propylamine
hydrochloride (WO 89/06644);
(C)
(+)N,N-diisopropyl-3-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyphenylpro-
pylamine, hydrochloride (WO 89/06644);
.[.(D)
N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropyl-
amine (-) mandelic acid salt (Example 1 above)..].
.Iadd.(D)
(+)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-pheny-
lpropylamine (+) mandelic acid salt (Example 1 above)..Iaddend.
Raised index numerals in the text below refer to literature
references listed at the end of the description.
MUSCARINIC RECEPTOR BINDING STUDIES
The tissue preparations and the general methods used have been
described in detail elsewhere for the parotid gland.sup.1, urinary
bladder.sup.2, heart.sup.3 and cerebral cortex.sup.3, respectively.
Male guinea pigs (250-400 g body weight) were killed by a blow on
the neck and exsanguinated. The brain was placed on ice for
dissection of the cerebral cortex (grey matter only). Urinary
bladders, hearts and parotid glands were dissected in a
Krebs-Henseleit buffer (pH 7.4) containing 1 mM phenyl methyl
sulfonyl fluoride (PMSF, a protease inhibitor). Dissected tissues
were homogenized in an ice-cold sodium-potassium phosphate buffer
(50 mM, pH 7.4) containing 1 mM PMSF, using a Polytron PT-10
instrument (bladder, heart, parotid) and a Potter-Elvehjem Teflon
homogenizer (cortex). All homogenates were finally diluted with the
ice-cold phosphate/PMSF buffer to a final protein concentration of
.ltoreq.0.3 mg/ml and immediately used in the receptor binding
assays. Protein was determined by the method of Lowry et al.
(1951).sup.4, using bovine serum albumin as the standard.
The muscarinic receptor affinities of the unlabelled compounds A to
D identified above were derived from competition experiments in
which the ability to inhibit the receptor specific binding of
(-).sup.3H-QNB (1-quinuclidinyl[phenyl-4-.sup.3H]benzilate, 32.9
Ci/mmole) was monitored as previously described.sup.3,5. Each
sample contained 10 .mu.l of (-).sup.3H-QNB (final concentration 2
nM), 10 .mu.l solution of test compound and 1.0 ml tissue
homogenate. Triplicate samples were incubated under conditions of
equilibrium, i.e., at 25.degree. C. for 60 minutes (urinary
bladder), 80 minutes (heart and cerebral cortex) or 210 minutes
(parotid gland), respectively. Non-specific binding was determined
in the presence of 10 .mu.M unlabelled atropine. Incubations were
terminated by centrifugation.sup.2, and the radioactivity in the
pellets was determined by liquid scintillation
spectrometry.sup.2.
IC.sub.50-values (concentration of unlabelled compound producing
50% inhibition of the receptor specific (-).sup.3H-QNB binding)
were graphically determined from the experimental
concentration-inhibition curves. Affinities, expressed as the
dissociation constants K.sub.i, were calculated by correcting the
IC.sub.50 for the radioligand-induced parallel shift and
differences in receptor concentration, using the method of Jacobs
et al. (1975).sup.6. The binding parameters for (-).sup.3H-QNB
(K.sub.D and receptor densities) used in these calculations were
determined in separate series of experiments.sup.1-3. The K.sub.i
values obtained for bladder, heart, parotid and cortex,
respectively, are presented in Table 1 below.
FUNCTIONAL IN VITRO STUDIES
Male guinea pigs, weighing about 300 g, were killed by a blow on
the neck and exsanguinated. Smooth muscle strips of the urinary
bladder were dissected in a Krebs-Henseleit solution (pH 7.4). The
strip preparations were vertically mounted between two hooks in
thermostatically controlled (37.degree. C.) organ baths (5 ml). One
of the hooks was adjustable and connected to a force transducer (FT
03, Grass Instruments). The Krebs-Henseleit solution was
continuously bubbled with carbogen gas (93.5% O.sub.2/6.5%
CO.sub.2) to maintain the pH at 7.4. Isometric tension was recorded
by a Grass Polygraph (Model 79D). A resting tension of
approximately 5 mN was initially applied on each muscle strip and
the preparations were allowed to stabilize for at least 45 min. The
resting tension was repeatedly adjusted and the preparations were
washed several times during the stabilization period.
Carbachol (carbamylcholine chloride) was used as the standard
agonist. In each experiment, the viability of the preparations and
the reproducibility of their contractile responses were initially
tested by three consecutive additions of a submaximal concentration
(3.times.10.sup.-6M) of carbachol. A complete
concentration-response curve to carbachol was then generated by
cumulative addition of carbachol to the organ-bath (i.e., stepwise
increase of the agonist concentration until the maximal contractile
response was reached), followed by washing out and a resting period
of at least 15 min. before a fix concentration of the test compound
(antagonist) was added to the organ-bath. After 60 min. of
incubation with the antagonist, a second cumulative
concentration-response curve to carbachol was generated. Responses
were expressed as per cent of the maximal response to carbachol.
EC.sub.50-values for carbachol in the absence (control) and
presence of antagonist were graphically derived and dose ratios (r)
were calculated. Dissociation constants, K.sub.B, for the
antagonists were calculated using equation (1).sup.7, where [A] is
the concentration of test compound. K.sub.B=[A]/r-1 (1)
The K.sub.B values obtained for compounds A, B and D identified
above are shown in Table 1 below.
TABLE-US-00001 TABLE 1 Test K.sub.B nm K.sub.t nM K.sub.t nM
K.sub.t nM K.sub.t nM compound bladder bladder heart parotid cortex
(A) 3.0 2.7 1.6 4.8 0.8 (B) 10.2 6.7 2.6 1.5 (C) 2.6 2.5 0.9 2.7
0.4 (D) 4.1 4.5 0.9 4.7 0.7
FUNCTIONAL IN VIVO STUDIES
a) Animal preparation
Adult cats were anaesthetized with mebumal (42 mg/kg)
intraperitoneally. When the animal was asleep, an infusion cannula
was inserted into the foreleg vein and the cat was given
alpha-chloralose. During the experiment the animal was placed on an
operation table warmed up with a feedback controlled electric pad.
The cat was tracheotomized. For blood pressure registration, a
polyethylene catheter was inserted into the femoral artery, with
the tip in aorta, and connected via a three-way stopcock to a blood
pressure transducer and a Grass polygraph. Heart rate was
registered by connecting a tachograph to a driver amplifier which
received the signal from the blood pressure transducer. Blood flow
in the central mesenteric artery was measured by an ultrasound flow
probe around the artery connected to a transonic blood flow meter
and then to a Grass polygraph for registration of the flow. For
infusion of the test substances, compounds D and A (as identified
above), a polyethylene catheter was inserted into the femoral vein
three-way stopcock to a syringe placed in an infusion pump (Sage
instrument).
Through an incision in the proximal urethra, a catheter was
inserted into the urinary bladder. At the beginning of each
experiment, this catheter was connected to an open vessel, which
was filled with 38.degree. C. tempered physiological saline and
placed above the animal. During this stabilization period the
bladder relaxed, leading to a filling of the bladder with saline,
under constant hydrostatic pressure. After the stabilization
period, the bladder catheter was connected to a pressure
transducer, for registration of intravesical pressure. Blood
pressure, heart rate, blood flow and bladder pressure were recorded
simultaneously and continuously throughout the experiment. The
animals were left for at least 45 minutes to achieve steady state
in cardiovascular variables before starting the experiment.
Bladder pressure was measured at 8 minutes after the end of
infusion of the test substance. The surgical preparation was tested
by intravenous injection of 0.25 .mu.g/kg b.w. of noradrenalin and
0.5 .mu.g/kg b.w. of acetylcholine.
b) Dosing
To study the dose-response relationship of compound D identified
above, the substance was administered at the doses 0.000
(physiological saline), 0.003, 0.010, 0.030 and 0.100 mg/kg,
respectively, with infusion during 2 minutes and an infusion volume
of 1 mL/kg. Every cat got all doses and was left to reestablish at
least 45 minutes between the 0.003 and 0.010 mg/kg doses, and 60
minutes between the 0.030 and 0.100 mg/kg doses.
c) Statistical methods and calculation
The results are presented in absolute values and calculated as mean
value.+-.standard deviation
d) Results
(i) Blood pressure
In general, intravenous administration of compound D had little or
no effect on the blood pressure except at dose of 0,3 mg/kg. This
dose caused an increase with 10% and with 6% for diastolic blood
pressure and systolic blood pressure, respectively.
(ii) Blood flow
Intravenous administration of compound D caused an increase with 8,
17 and 21% of the blood flow in superior mesenterica artery at
0.003, 0.01, and 0.03 mg/kg, respectively. Again at the highest
dose (0.3 mg/kg) a 10% increase in blood flow was observed.
(iii) Heart rate
Intravenous administration of compound D caused a decrease with 9%
at the highest dose (0.3 mg/kg).
(iv) Bladder pressure
As appears from the FIGURE, compound D of the present invention
produced a dose-dependent inhibition of the acetylcholine-induced
effect on the bladder which was about ten times more efficient than
that of prior art compound A.
REFERENCES
1. Nilvebrant, L.; Sparf, B. Muscarinic receptor binding in the
parotid gland. Different affinities of some anticholinergic drugs
between the parotid gland and ileum. Scand. J. Gastroenterol. 1982,
17 (suppl. 72), 69-77. 2. Nilvebrant, L.; Sparf, B. Muscarinic
receptor binding in the guinea pig urinary bladder. Acta Pharmacol.
et Toxicol. 1983 a, 52, 30-38. 3. Nilvebrant, L; Sparf, B.
Dicyclomine, benzhexol and oxybutynin distinguish between
sub-classes of muscarinic binding-sites. Eur. J. Pharmacol. 1986,
123, 133-143. 4. D Lowry, O. H.; Rosebrough, N. J.; Farr, A. L.;
Randall, R. J. Protein measurement with the Folin phenol reagent.
J. Biol. Chem. 1951, 193, 265-275. 5. Nilvebrant, L.; Sparf, B.
Differences between binding affinities of some antimuscarinic drugs
in the parotid gland and those in the urinary bladder and ileum.
Acta Pharmacol. et Toxicol. 1983 b, 53, 304-313. 6. Jacobs, S.;
Chang, K-J.; Custrecasas, P. Estimation of hormone receptor
affinity by competitive displacement of labelled ligand. Effects of
concentration of receptor and labelled ligand. Biochem. Biophys.
Res. Commun. 1975, 66, 687-692. 7. Schild, H. I. pAx and
competitive drug antagonism. Br. J. Pharmacol. Chemother. 1949, 4,
277-280.
* * * * *