U.S. patent application number 09/931431 was filed with the patent office on 2002-04-04 for prodrug acid esters of [2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethansulfony- l]phenol.
Invention is credited to Alanine, Alexander, Buettelmann, Bernd, Fischer, Holger, Huwyler, Joerg, Jaeschke, Georg, Neidhart, Marie-Paule Heitz, Pinard, Emmanuel, Wyler, Rene.
Application Number | 20020040037 09/931431 |
Document ID | / |
Family ID | 8169594 |
Filed Date | 2002-04-04 |
United States Patent
Application |
20020040037 |
Kind Code |
A1 |
Alanine, Alexander ; et
al. |
April 4, 2002 |
Prodrug acid esters of
[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethansulfony- l]phenol
Abstract
The invention is a compound of the formula 1 wherein R is a)
--C(O)(CH.sub.2).sub.nC(O)OH, b) 2 wherein R.sup.1 is
--N(R.sup.2)(R.sup.3), or is a five or six member aromatic or
non-aromatic heterocyclic ring having one or more heteroatoms
selected from nitrogen, oxygen or sulfur, unsubstituted or
substituted by lower alkyl, c) --P(O)(OH).sub.2, or is d)
--C(O)(CH.sub.2).sub.nNHC(O)(CH.sub.2).sub.nN(R.sup.2)(R.sup.3);
and R.sup.2/R.sup.3 are hydrogen or lower alkyl; n is 1, 2, 3 or 4;
or a pharmaceutically acceptable acid addition salt thereof.
Inventors: |
Alanine, Alexander;
(Schlierbach, FR) ; Buettelmann, Bernd;
(Schopfheim, DE) ; Fischer, Holger; (Grellingen,
CH) ; Neidhart, Marie-Paule Heitz; (Hagenthal le Bas,
FR) ; Huwyler, Joerg; (Burg, CH) ; Jaeschke,
Georg; (Basle, CH) ; Pinard, Emmanuel;
(Linsdorf, FR) ; Wyler, Rene; (Zuerich,
CH) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8169594 |
Appl. No.: |
09/931431 |
Filed: |
August 16, 2001 |
Current U.S.
Class: |
514/317 ;
514/253.12; 514/89; 544/360; 546/216; 546/24 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/28 20180101; A61P 25/18 20180101; C07D 211/42 20130101;
A61P 25/04 20180101; A61P 25/14 20180101; A61P 25/16 20180101; A61P
25/22 20180101; A61P 25/00 20180101; A61P 25/24 20180101; C07F 9/59
20130101 |
Class at
Publication: |
514/317 ; 514/89;
514/253.12; 546/24; 544/360; 546/216 |
International
Class: |
A61K 031/675; A61K
031/496; A61K 031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 21, 2000 |
EP |
00117918.3 |
Claims
1. A compound of the formula 24wherein R is a)
--C(O)(CH.sub.2).sub.nC(O)- OH, b) 25 wherein R.sup.1 is
--N(R.sup.2)(R.sup.3) or a five or six member aromatic or
non-aromatic heterocyclic ring containing one or more heteroatoms
selected from nitrogen, oxygen or sulfur, said ring being
unsubstituted or substituted by lower alkyl, c) --P(O)(OH).sub.2,
or is d)
--C(O)(CH.sub.2).sub.nNHC(O)(CH.sub.2).sub.nN(R.sup.2)(R.sup.3);
R.sup.2/R.sup.3 are hydrogen or lower alkyl; and n is 1, 2, 3 or 4;
or a pharmaceutically acceptable acid addition salt thereof:
2. A compound of formula I of claim 1, wherein R is
--C(O)(CH.sub.2).sub.nC(O)OH.
3. A compound of claim 2, which is succinic acid
mono-{(3S,4S)-4-[2-(4-ben-
zyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl} ester.
4. A compound of formula I of claim 1, wherein R is 26and R.sup.1
is as in claim 1.
5. A compound of claim 4, wherein R.sup.1 is morpholinyl.
6. A compound of claim 5 wherein the compound is
4-morpholin-4-yl-methyl-b- enzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfony-
l]-phenyl ester.
7. A compound of claim 5, wherein the compound is
3-morpholin-4-ylmethyl-b- enzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfony-
l]-phenyl ester.
8. A compound of claim 4 wherein R.sup.1 is
4-methyl-piperazinyl.
9. The compound of claim 8, wherein the compound is
4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-h-
ydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester.
10. A compound of claim 8, wherein the compound is
3-(4-methyl-piperazin-1- -ylmethyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-e-
thanesulfonyl]-phenylester.
11. A compound of claim 4 wherein R.sup.1 is --N(R.sup.2)(R.sup.3),
wherein R.sup.2 and R.sup.3 are as in claim 1.
12. A compound of claim 11, wherein the compound is
4-aminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phe-
nyl ester.
13. A compound of claim 11, wherein the compound is
3-methylaminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperid-
in-1-yl)-ethanesulfonyl]-phenyl ester.
14. A compound of claim 11, wherein the compound is
4-methylaminomethyl-benzoic acid (3S
,4S)-4-[2-(4-benzyl-3-hydroxy-piperi-
din-1-yl)-ethanesulfonyl]-phenyl ester.
15. A compound of formula I of claim 1, wherein R is
--P(O)(OH).sub.2.
16. A compound of claim 15, wherein the compound is phosphoric acid
mono-{(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-ph-
enyl} ester.
17. A compound of formula I of claim 1, wherein R is
--C(O)(CH.sub.2).sub.2NHC(O)(CH.sub.2).sub.2NH.sub.2.
18. A compound of claim 17, wherein the compound is
3-(3-amino-propionylamino)-propionic acid
(3S,4S)-4-[2-(4-benzyl-3-hydrox-
y-piperidin-1-yl)-ethanesulfonyl]-phenyl ester.
Description
FIELD OF INVENTION
[0001] The present invention is generally related to acid esters of
[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethansulfonyl]phenol, and
more particularly to acid esters that enhance the solubility of the
parent compound and are hydrolyzed under in vivo conditions thus
serving as prodrugs for the parent compound.
BACKGROUND
[0002] A prodrug is in most cases a pharmacologically inactive
derivative of a parent drug molecule that requires spontaneous or
enzymatic transformation within the body in order to release the
active drug, and that has improved delivery properties over the
parent drug molecule. It has been shown that a molecule with
optimal structural configuration and physicochemical properties for
eliciting the desired therapeutic response at its target site does
not necessarily possess the best molecular form and properties for
its delivery to its point of ultimate action. Usually, only a minor
fraction of doses administered reaches the target area and since
most agents interact with non-target sites as well, an inefficient
delivery may result in undesirable side effects. This fact of
differences in transport and in situ effect characteristics for
many drug molecules is the basic reason why bioreversible chemical
derivatization of drugs, i.e., prodrug formation is a means by
which a substantial improvement in the overall efficacy of drugs
can often be achieved.
[0003] Prodrugs are designed to overcome pharmaceutically and/or
pharmacokinetically based problems associated with the parent drug
molecule that would otherwise limit the clinical usefulness of the
drug. The advantage of a prodrug lies in its physical properties,
such as enhanced water solubility for parenteral administration at
physiological pH compared to the parent drug, or it enhances
absorption from the digestive tract, or it may enhance drug
stability for long-term storage.
[0004] In recent years several types of bioreversible derivatives
have been exploited for utilization in designing prodrugs. Using
esters as a prodrug type for drugs containing carboxyl or hydroxyl
function is most popular. Further well-known are prodrug
derivatives of peptides, 4-imidazolidinones and the like, described
in Drugs of the Future, 1991, 16(5), 443-458 or N-oxides, described
for example in U.S. Pat. No. 5,691,336.
[0005] Compounds of formula 3
[0006] are known as NMDA (N-methyl-D-aspartate)-receptor-subtype
selective blockers. Compounds of formula II have limited water
solubility at physiological pH, not allowing bolus injections. A
similar compound of formula II is generically described in WO
95/25721, wherein the formula does not contain a hydroxy group on
the piperidine ring. These compounds are described to possess
activities on the glutamat receptor or AMPA receptor for the
treatment of diseases which are related to these receptors.
[0007] Similar compounds are described in EP 824 098, in which the
piperidine ring is substituted by a hydroxy group in 4-position.
These compounds are described to possess activities on the NMDA
receptor and are useful in the treatment of acute forms of
neurodegeneration caused, for example, by stroke and brain trauma,
and chronic forms of neurodegeneration such as Alzheimer's disease,
Parkinson's disease, ALS (amyotrophic lateral sclerosis),
neurodegeneration associated with bacterial or viral infections and
acute/chronic pain. Furthermore, it is known from WO 00/75109, that
the compound of formula II is a good NMDA receptor subtype specific
blocker, neuroprotective in vivo and less active as blockers of the
hERG potassium channels and thus is much less likely to have
pro-arrhythmic activity in man.
[0008] Under pathological conditions of acute and chronic forms of
neurodegeneration overactivation of NMDA receptors is a key event
for triggering neuronal cell death. NMDA receptors are composed of
members from two subunit families, namely NR-1 (8 different splice
variants) and NR-2 (A to D) originating from different genes.
Members from the two subunit families show a distinct distribution
in different brain areas. Heteromeric combinations of NR- 1 members
with different NR-2 subunits result in NMDA receptors, displaying
different pharmacological properties. Possible therapeutic
indications for NMDA receptor subtype specific blockers include
acute forms of neurodegeneration caused, e.g., by stroke or brain
trauma; chronic forms of neurodegeneration such as Alzheimer's
disease, Parkinson's disease, Huntington's disease or ALS
(amyotrophic lateral sclerosis); neurodegeneration associated with
bacterial or viral infections, diseases such as schizophrenia,
anxiety and depression and acute/chronic pain.
SUMMARY
[0009] The present invention relates to a compound of the formula
4
[0010] wherein
[0011] R is
[0012] a) --C(O)(CH.sub.2).sub.nC(O)OH,
[0013] b) 5
[0014] wherein R.sup.1 is --N(R.sup.2)(R.sup.3) and R.sup.2/R.sup.3
are hydrogen or lower alkyl, or is a five or six member aromatic or
non-aromatic heterocyclic ring containing one or more heteroatoms
selected from nitrogen, sulfur or oxygen, unsubstituted or
substituted by lower alkyl,
[0015] c) --P(O)(OH).sub.2, or is
[0016] d)
--C(O)(CH.sub.2).sub.nNHC(O)(CH.sub.2).sub.nN(R.sup.2)(R.sup.3);
and
[0017] n is 1,2,3 or 4;
[0018] or a pharmaceutically acceptable acid addition salt
thereof.
[0019] It has been found that compounds of formula I may be used as
prodrugs of compounds of formula 6
[0020] which are NMDA (N-methyl-D-aspartate)-receptor-subtype
selective blockers.
[0021] It has surprisingly been shown that the compounds of the
invention of formula I fulfill all requirements of a good prodrug.
Specifically, it has been shown that compounds of the invention
have up to 10-fold higher solubility over the parent compound at
physiological pH. Additionally the compounds of the invention have
an unexpected stability in solution at room temperature up to 48 h
but also demonstrate a fast hydrolysis in plasma.
[0022] The present invention is a novel compound of formula I, its
use as a prodrug in the treatment or prophylaxis of diseases caused
by overactivation of respective NMDA receptor subtypes, which
include acute forms of neurodegeneration caused, e.g., by stroke or
brain trauma; chronic forms of neurodegeneration such as
Alzheimer's disease, Parkinson's disease, Huntington's disease or
ALS (amyotrophic lateral sclerosis); neurodegeneration associated
with bacterial or viral infections, and diseases such as
schizophrenia, anxiety, depression and acute/chronic pain, the use
of these compounds for manufacture of corresponding medicaments,
processes for the manufacture of these novel compounds and
medicaments, containing them.
[0023] The most preferred indication in accordance with the present
invention is the treatment or prevention of stroke.
DETAILED DESCRIPTION
[0024] The following definitions of the general terms used in the
present description apply irrespective of whether the terms in
question appear alone or in combination.
[0025] As used herein, the term "lower alkyl" denotes a straight-
or branched-chain alkyl group containing from 1-7 carbon atoms, for
example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl,
t-butyl and the like.
[0026] Preferred lower alkyl groups are groups with 1-4 carbon
atoms.
[0027] The term "five or six member aromatic or non-aromatic
heterocyclic ring containing one or more hetero atoms selected from
nitrogen, sulfur or oxygen, unsubstituted or substituted by lower
alkyl" denotes, for example pyrrol-1-yl, imidazol-1-yl,
piperidin-1-yl, piperazin-1-yl or morpholin-4-yl. Preferred are
piperazin-1-yl or morpholin-4-yl. It is preferred that the
heterocyclic rings contain one or two hetero atoms.
[0028] The term "physiological pH" means a pH of around 7,
preferably about 7.4.
[0029] Exemplary preferred are compounds of formula 1, in which R
is --C(O)(CH.sub.2).sub.nC(O)OH and n is 2, for example the
following compound:
[0030] Succinic acid mono- {(3
S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1--
yl)-ethanesulfonyl]-phenyl} ester.
[0031] Further preferred are compounds of formula 1, in which R is
7
[0032] and R.sup.1 is as above. Especially preferred are compounds
wherein R.sup.1 is morpholinyl, 4-methyl-piperazinyl or
--N(R.sup.2)(R.sup.3) with R.sup.2 and R.sup.3 as above.
[0033] Examples of such compounds when R.sup.1 is morpholinyl
are:
[0034] 4-morpholin-4-ylmethyl-benzoic acid (3
S,4S)-4-[2-(4-benzyl-3-hydro- xy-piperidin-
1-yl)-ethanesulfonyl]-phenyl ester; and
[0035] 3-morpholin-4-ylmethyl-benzoic acid (3
S,4S)-4-[2-(4-benzyl-3-hydro-
xy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester.
[0036] Further preferred are compounds of formula 1, in which R is
8
[0037] R.sup.1 is 4-methyl-piperazinyl. Examples of such compounds
are:
[0038] 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester,
[0039] 3-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (3
S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyleste-
r,
[0040] Further preferred are compounds of formula 1, in which R is
9
[0041] R.sup.1 is --N(R.sup.2)(R.sup.3) and R.sup.2/R.sup.3 are
hydrogen or lower alkyl. Examples of such compounds are:
[0042] 4-aminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperid-
in-1-yl)-ethanesulfonyl]-phenyl ester;
[0043] 3-methylaminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-p-
iperidin-1-yl)-ethanesulfonyl]-phenyl ester;and
[0044] 4-methylaminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-p-
iperidin-1-yl)-ethanesulfonyl]-phenyl ester.
[0045] Exemplary preferred are further compounds of formula 1, in
which R is --P(O)(OH).sub.2, for example the following
compound:
[0046] phosphoric acid
mono-{(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1--
yl)-ethanesulfonyl]-phenyl } ester.
[0047] Also preferred are further compounds of formula 1, in which
R is --C(O)(CH.sub.2).sub.2NHC(O)(CH.sub.2).sub.2NH.sub.2, which is
3-(3-amino-propionylamino)-propionic acid
(3S,4S)-4-[2-(4-benzyl-3-hydrox-
y-piperidin-1-yl)-ethanesulfonyl]-phenyl ester.
[0048] The present compounds of formula I and their
pharmaceutically acceptable salts can be prepared by methods known
in the art, for example, by processes described below, which
process comprises
[0049] a) reacting a compound of formula 10
[0050] to give a compound of formula 11
[0051] wherein m is 1-3 and n is 2-4, or
[0052] b) reacting a compound of formula II with
(BnO).sub.2P(H)O/CCl.sub.- 4/DMAP/Hunigs base and hydrogenating the
obtained compound to a compound of formula 12
[0053] reacting a compound of formula II with a compound of
formula
HOOC--(CH.sub.2).sub.nNHC(O)(CH.sub.2).sub.nNH-Boc IV,
[0054] cleaving off the Boc group to give a compound of formula
13
[0055] reacting a compound of formula II with a compound of formula
14
[0056] cleaving off the Boc group with TFA (trifluoroacetic acid)
to give a compound of formula 15
[0057] reacting a compound of formula 16
[0058] with morpholin or 4-methyl-piperazin to give a compound of
formula 17
[0059] and
[0060] if desired, converting the compound obtained into a
pharmaceutically acceptable acid addition salt.
[0061] In accordance with this procedure, a compound of formula I
may be prepared, for example, in accordance with reaction variant
a) as follows:
[0062] To a solution of the compound of formula II in a solvent,
such as methylene chloride, is added succinic acid or an equivalent
compound of formula III and DMAP (dimethylaminopyridine). The
reaction mixture is refluxed some hours to obtain the desired
compound of formula I-1.
[0063] In accordance with process variant b) a compound, described
in example 11, for example phosphoric acid dibenzyl ester
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester is hydrogenated at room temperature in conventional manner to
obtain a compound of formula I-2.
[0064] Process variant c) describes the process for preparation of
a compound of formula I-3. The process is carried out by reacting
the compound of formula II with a compound of formula IV, for
example with
3-(3-tert-butoxycarbonylamino-propionylamino)-propionic acid, in
the presence of DMAP (4-dimethylaminopyridine) and DAPEC
(N-(3-dimethylaminopropyl)-n-ethylcarbodiimide hydrochloride) at a
temperature of about 0.degree. C. The reaction mixture is then
treated with TFA (trifluoroacetic acid).
[0065] Furthermore, in accordance with reaction variant d) a
compound of formula I-4 is obtained. The reaction is carried out by
reaction of the compound of formula II with a compound of formula
V, for example with
3-[(tert-butoxycarbonyl-methyl-amino)-methyl]benzoic acid, in the
presence of DMAP (4-dimethylaminopyridine) and DAPEC
(N-(3-dimethylaminopropyl)-n-ethylcarbodiimide hydrochloride) and
subsequently with TFA (trifluoroacetic acid).
[0066] Process variant e) describes the preparation of compounds of
formulas I-5 or I-6. A compound of formula VI, for example
4-chloromethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1--
yl)-ethanesulfonyl]-phenyl ester is treated with morpholine or
4-methyl-piperazin in a solvent, such as methylene chloride.
[0067] The salt formation is effected at room temperature in
accordance with methods which are known per se and which are
familiar to any person skilled in the art. Not only salts with
inorganic acids, but also salts with organic acids come into
consideration. Hydrochlorides, hydrobromides, sulphates, nitrates,
citrates, acetates, maleates, succinates, methan-sulphonates,
p-toluenesulphonates and the like are examples of such salts.
[0068] The following schemes 1-3 describe the processes for
preparation of the prodrugs of formula I in more detail. The
starting compound of formula II (parent compound) may be prepared
in accordance with schemes 4 to 6. The compounds, described in
these schemes, are known compounds or may be prepared by known
methods, for example in accordance with methods, described in WO
00/75109.
[0069] In the schemes the following abbreviations have been
used:
[0070] DAPEC N-(3-dimethylaminopropyl)]-n-ethylcarbodiimide
hydrochloride
[0071] DMAP 4-dimethylaminopyridine
[0072] TFA trifluoroacetic acid 18
[0073] n is 2to 4and m is 1 to 3. 19
[0074] hal is halogen, such as chloro or bromo. 20
[0075] R.sup.2 is hydrogen or lower alkyl. 21 22 23
[0076] As mentioned above, the compounds of formula I and their
pharmaceutically acceptable addition salts may be used as prodrugs
of the parent compounds of formula II, which possess valuable
pharmacological properties.
[0077] All of the compounds of the present invention were
investigated in accordance with the test given hereinafter. The
evidence, that the inventive compounds of formula I may be used as
prodrugs of their parent compounds of formula II is shown in
accordance with the description given hereinafter.
[0078] The conversion of prodrugs to the corresponding parent
compounds is due to a hydrolytic mechanism. There is well known
evidence from the literature that similar reactions occur in vivo,
hence the decision to study both the stability in plasma and blood
was taken.
Test Description
[0079] Plasma and blood samples from various species were spiked
with equimolar amounts (26.7 .mu.M) of the prodrug of the invention
and parent drug in DMSO and incubated for different time intervals
(up to 120 min) at 37.degree. C. The reaction was stopped by
protein precipitation with perchloric acid (0.5 M) followed by
centrifugation (5 min. at 15'000 g). This procedure was found to be
reliable enough at least when the drug analysis was performed
immediately after the incubation.
[0080] The concentrations of formed parent drug in the supernatant
was determined by LC-MS: The parent compound together with its
hexa-.sup.13C-labelled internal standard was enriched on a standard
bore trapping column (Lichrospher100, RP18, 5 .mu.m, 4.times.4 mm,
Merck) and separated under isocratic conditions on a narrow-bore
analytical column (Symmetry Shield, RP8, 3.5 .mu.m, 2.1.times.50
mm, Waters) by a mixture of formic acid and methanol as mobile
phase. The whole effluent (200 .mu.l/min) of the analytical column
was passed to the turbo ion spray interface without splitting.
Selected ion monitoring (SIM) in negative mode was used for single
quadrupole mass spectrometric detection. The results were expressed
as % converted to the parent compound, using the data of the parent
drug as 100%-value.
1 [0040] In the following table the results of the above mentioned
test are described. Stability Stability (2 hours) Compound of
Solubility Solubility (2 hours) human Example No. (.mu.g/ml at pH
7) (.mu.g/ml at pH 4) rat plasma plasma 1 7689 1800 <10% 10% 2
>37600 594 41% 35% 6 89 8500 7 6706 98% 91% 9 86600 100% 100% 10
26100 100% 100% Compound of 47 7750 (pH 4.8) formula II (parent
compound)
[0081] The results show that the prodrug approach of the present
invention increases the solubility at pH 7.4 (physiological pH)
compared with the parent compound (compound of formula II) thereby
substantially reducing any precipitation in plasma and local
intolerance at the injection site. An increase in solubility at
physiological pH has been clearly reached for compound 1 and 2 and
to a lesser extent for compound 6. The compounds 7, 9 and 10 were
unstable at pH 7.4 over 24 hours, therefore their solubility could
only be measured at pH 4.0. These data suggest a higher solubility
at pH 7.4 for compounds 9 and 10 than for the parent compound. The
solubility of compound 7 at pH 4.0 is similar to the parent
compound, but due to the additional charge at pH 7.4 (calculated
pKa for the benzylic amine 8.96), a higher solubility can be
assumed at this pH.
[0082] The term "stability (2 hours) rat or human plasma" of 100%
means that the prodrug of the invention in the plasma has been
converted after 2 hours completely into the parent compound. In
accordance with the test the inventive compounds of formula I are
useful as prodrugs of their parent compounds of formula II.
[0083] The compounds of formula I as well as their pharmaceutically
usable acid addition salts can be used as medicaments, e.g. in the
form of pharmaceutical preparations. The pharmaceutical
preparations can be administered orally, e.g. in the form of
tablets, coated tablets, dragees, hard and soft gelatine capsules,
solutions, emulsions or suspensions. The administration can,
however, also be effected rectally, e.g. in the form of
suppositories, or parenterally, e.g. in the form of injection
solutions.
[0084] The compounds of formula I and their pharmaceutically
acceptable acid addition salts can be processed with
pharmaceutically inert, inorganic or organic excipients for the
production of tablets, coated tablets, dragees and hard gelatine
capsules. Lactose, corn starch or derivatives thereof, talc,
stearic acid or its salts etc can be used as such excipients e.g.
for tablets, dragees and hard gelatine capsules.
[0085] Suitable excipients for soft gelatine capsules are e.g.
vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
[0086] Suitable excipients for the manufacture of solutions and
syrups are e.g. water, polyols, saccharose, invert sugar, glucose
etc.
[0087] Suitable excipients for injection solutions are e.g. water,
alcohols, polyols, glycerol, vegetable oils etc.
[0088] Suitable excipients for suppositories are e.g. natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
[0089] Moreover, the pharmaceutical preparations can contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, masking agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
[0090] The dosage can vary within wide limits and will, of course,
be fitted to the individual requirements in each particular case.
In general, in the case of oral administration a daily dosage of
about 10 to 1000 mg per person of a compound of formula I should be
appropriate, although the above upper limit can also be exceeded
when necessary.
[0091] The following Examples 1 to 17 illustrate the present
invention without limiting it. All temperatures are given in
degrees Celsius.
[0092] The preparation of compounds of formula I, starting with
compounds of formula II, is described generically in the
description in process variants a) to e) and in schemes 1 to 3.
Specifically, the preparation of prodrugs is described in more
detail in examples 1 to 10. Examples 11 to 17 describe the
preparation of intermediates.
EXAMPLE 1
Succinic acid
mono-{(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethan-
esulfonyl]-phenyl} ester
[0093] To a solution of 1.0 g (2.66 mmol)
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-
-piperidin-1-yl)-ethanesulfonyl]-phenol in 25 ml CH.sub.2Cl.sub.2
were added 320 mg (3.2 mmol) succinic acid and 390 mg (3.2 mmol)
dimethylaminopyridine and the reaction mixture was refluxed for 20
hours. The reaction mixture was concentrated to 10 ml and was
purified by chromatography over silica gel to give 100 mg (0.21
mmol, 7.4%) succinic acid mono-{(3
S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfon-
yl]-phenyl}ester as colorless oil.
[0094] MS: m/e=476.2 (M+H.sup.+).
EXAMPLE 2
Phosphoric acid mono-{(3
S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-et-
hanesulfonyl]-phenyl} ester
[0095] A solution of 1.20 g, (1.73 mmol) phosphoric acid dibenzyl
ester
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester in 40 ml MeOH and 6 ml water was hydrogenated at room
temperature (20 bar, 5 h). The reaction mixture was concentrated to
20 ml and 500 ml water were added. The reaction mixture was
filtered and the catalyst was washed with water. The filtrate was
concentrated under reduced pressure until the product precipitates.
The mixture was then cooled to 0.degree. C. and 200 ml MeOH were
added dropwise. After two hours the solid was filtered, washed with
cold MeOH and dried at 60.degree. C. under high vacuum to give 380
mg (0.83 mmol, 48%) of phosphoric acid mono-{(3S,4
S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl}
ester as colorless crystalls.
[0096] MS: m/e=454.4 (M-H).sup.-.
EXAMPLE 3
4-Morpholin-4-ylmethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piper-
idin-1-yl)-ethanesulfonyl]-phenyl ester
[0097] To a solution of 200 mg (0.38 mmol) 4-chloromethyl-benzoic
acid-(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phe-
nyl ester in 10 ml CH.sub.2Cl.sub.2 were added 53 .quadrature.1
(0.38 mmol) Et.sub.3N and 33 .mu.l (0.38 mmol) morpholine. After 16
hours the reaction mixture was purified by chromatography over
silica gel to give 70 mg (0.12 mmol, 32%)
4-morpholin-4-ylmethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester as a colorless solid.
[0098] MS: m/e=579.1 (M+H.sup.+).
[0099] Following the general procedure of example 3 the compounds
of example 4 to example 6 were prepared.
EXAMPLE 4
4-(4-Methyl-piperazin-1-ylmethyl)-benzoic acid (3
S,4S)-4-[2-(4-benzyl-3-h-
ydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester
[0100] The title compound was prepared from 4-chloromethyl-benzoic
acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester and 4-methylpiperazin in 27% yield as a colorless oil.
[0101] MS: m/e=592.2 (M+H.sup.+).
EXAMPLE 5
3-(4-Methyl-piperazin-1-ylmethyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hy-
droxy-piperidin-1-yl)-ethanesulfonyl]-phenylester; hydrochloride(
1:3)
[0102] The title compound was prepared from 3-chloromethyl-benzoic
acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester and 4-methylpiperazin, followed by the addition of HCl in 80%
yield as a colorless solid.
[0103] MS: m/e592.2 (M+H.sup.+).
EXAMPLE 6
3-Morpholin-4-ylmethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piper-
idin-1-yl)-ethanesulfonyl]-phenyl ester; hydrochloride(1:2)
[0104] The title compound was prepared from 3-chloromethyl-benzoic
acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester and morpholine, followed by the addition of HCl in 18% yield
as a colorless solid.
[0105] MS: m/e579.1 (M+H.sup.+).
EXAMPLE 7
4-Aminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl-
)-ethanesulfonyl]-phenyl ester; hydrochloride(1:2)
[0106] A solution of 200 mg
4-(tert-butoxycarbonylamino-methyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phe-
nyl ester in 3.8 ml TFA was stirred for 1 hour at 0.degree. C. The
solvent was removed under reduced pressure and the crude product
was diluted in diethylether and 3 drops of a saturated HCl-solution
in diethylether were added. Filtration yielded 120 mg (0.22 mmol,
67%) 4-aminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phe-
nyl ester; hydrochloride(1:2) as colorless crystalls.
[0107] MS: m/e=509.4 (M+H.sup.+).
[0108] Following the general procedure of example 7 the compounds
of example 8 to example 10 were prepared.
EXAMPLE 8
3-(3-Amino-propionylamino)-propionic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-
-piperidin-1-yl)-ethanesulfonyl]-phenyl ester; 1:1 HCl
[0109] The title compound was prepared from
3-(3-tert-butoxycarbonylamino-- propionylamino)-propionic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin--
1-yl)-ethanesulfonyl]-phenyl ester in 13% yield as a colorless
solid.
[0110] MS: m/e518.2 (M+H.sup.+).
EXAMPLE 9
3-Methylaminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidi-
n-1-yl)-ethanesulfonyl]-phenyl ester hydrochloride (1:2)
[0111] The title compound was prepared from
3-(3-tert-butoxycarbonyl-methy- l-amino-methyl) benzoic acid and
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidi-
n-1-yl)-ethanesulfonyl]-phenyl ester in 93% yield as a colorless
solid.
[0112] MS: m/e=523.2 (M+H.sup.+).
EXAMPLE 10
4-Methylaminomethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidi-
n-1-yl)-ethanesulfonyl]-phenyl ester hydrochloride (1:2)
[0113] The title compound was prepared from
4-(tert-butoxycarbony-methyl-l- amino-methyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl-
)-ethanesulfonyl]-phenyl ester in 94% yield as a colorless
solid.
[0114] MS: m/e=523.2 (M+H.sup.+).
EXAMPLE 11
Phosphoric acid dibenzyl ester
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin--
1-yl)-ethanesulfonyl]-phenyl ester
[0115] To a solution of 500 mg (133 mmol)
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-
-piperidin-1-yl)-ethanesulfonyl]-phenol in 20 ml acetonitrile were
added 0.64 ml (6.7 mmol) CCl.sub.4, 16.3 mg (0.13 mmol) DMAP and
0.48 ml (2.9 mmol) N,N-diisopropylethylamine. The reaction mixture
was stirred for 15 min at room temperature and 0.43 ml (1.9 mmol)
dibenzylphosphite were added dropwise. After 20 min. 20 ml sat.
NaHCO.sub.3 solution was added and the aqueous phase was extracted
with ethylacetate (3.times.30 ml) and the combined organic layers
were washed with water, dried over MgSO.sub.4, filtrated and the
solvent was removed under reduced pressure. Purification of the
crude product by chromatography over silica gel
(ethylacetate/hexane 2/1) yielded 700 mg (11 mmol, 83%) phosphoric
acid dibenzyl ester
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesul-
fonyl]-phenyl ester as a colorless solid.
[0116] MS: m/e635.7 (M+H.sup.+).
EXAMPLE 12
4-(tert-Butoxycarbonylamino-methyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3--
hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester
[0117] To a solution of 500 mg (1.33 mmol)
(3S,4S)-4-[2-(4-benzyl-3-hydrox-
y-piperidin-1-yl)-ethanesulfonyl]-phenol in 10 ml methylenechloride
were added 368 mg (1.46 mmol)
4-(tert-butoxycarbonylamino-methyl)-benzoic acid, 16.3 mg (0.133
mmol) DMAP and 511 mg (2.66 mmol)
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and the
reaction mixture was stirred at 0.degree. C. After 1 hour, 0.5 N
HCl was added and the aqueous layer was extracted with
methylenechloride. The combined organic layers were washed with
0.5N HCl solution and brine, dried over NaSO.sub.4, filtered and
the solvent was removed under reduced pressure to give the crude
product.
[0118] Crystallization from diethylether yielded 280 mg (0.460
mmol, 35%) 4-(tert-butoxycarbonylamino-methyl)-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-
-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as colorless
crystalls.
[0119] MS: m/e=609.4 (M+H.sup.+).
[0120] Following the general procedure of example 12 the compounds
of example 13 to example 15 were prepared.
EXAMPLE 13
3-(3-tert-Butoxycarbonylamino-propionylamino)-propionic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester
[0121] The title compound was prepared from
(3S,4S)-4-[2-(4-benzyl-3-hydro-
xy-piperidin-1-yl)-ethanesulfonyl]-phenol and
3-(3-tert-butoxycarbonylamin- o-propionylamino)-propionic acid in
13% yield as a colorless solid.
[0122] MS: m/e=618.2 (M+H.sup.+).
EXAMPLE 14
3-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-benzoic acid (3
S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester
[0123] The title compound was prepared from
(3S,4S)-4-[2-(4-benzyl-3-hydro-
xy-piperidin-1-yl)-ethanesulfonyl]-phenol and
3-[(tert-butoxycarbonyl-meth- yl-amino)-methyl]-benzoic acid in 70%
yield as a colorless gum.
[0124] MS: m/e=623.2 (M+H.sup.+).
EXAMPLE 15
4-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl
ester
[0125] The title compound was prepared from
(3S,4S)-4-[2-(4-benzyl-3-hydro-
xy-piperidin-1-yl)-ethanesulfonyl]-phenol and
4-[(tert-butoxycarbonyl-meth- yl-amino)-methyl]-benzoic acid in 99%
yield as a light brown oil.
[0126] MS: m/e=623.2 (M+H.sup.+).
EXAMPLE 16
4-Chloromethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-y-
l)-ethanesulfonyl]-phenyl ester
[0127] To a solution of 500 mg (1.33 mmol)
(3S,4S)-4-[2-(4-benzyl-3-hydrox-
y-piperidin-1-yl)-ethanesulfonyl]-phenol in 10 ml CH.sub.2Cl.sub.2
were added 20 mg (0.16 mmol) DMAP and 162 mg (1.60 mmol) Et.sub.3N
and 302 mg (1.60 mmol) 4-chlormethylbenzoylchloride. After 1 hour
water was added and the aequous phase was extracted with
methylenechloride (3.times.20 ml). The combined organic layers were
dried over MgSO.sub.4, filtered and the solvent was removed under
reduced pressure. The crude product was purified by chromatography
over silica gel to give 280 mg (0.53 mmol, 40 %)
4-chloromethyl-benzoic acid
4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-e- thanesulfonyl]-phenyl
ester as colorless foam.
[0128] MS: m/e=528.2 (M).
[0129] Following the general procedure of example 16 the compound
of example 17 was prepared.
EXAMPLE 17
3-Chloromethyl-benzoic acid
(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-y-
l)-ethanesulfonyl]-phenyl ester
[0130] The title compound was prepared from
(3S,4S)-4-[2-(4-benzyl-3-hydro-
xy-piperidin-1-yl)-ethanesulfonyl]-phenol and
3-chlormethylbenzoylchloride in 80% yield as a colorless solid.
[0131] MS: m/e=528.1 (M).
EXAMPLE A
[0132] Tablets of the following composition are manufactured in the
usual manner:
2 mg/tablet Prodrug 5 Lactose 45 Corn starch 15 Microcrystalline
cellulose 34 Magnesium stearate 1 Tablet weight 100
EXAMPLE B
[0133] Capsules of the following composition are manufactured:
3 mg/capsule Prodrug 10 Lactose 155 Corn starch 30 Talc 5 Capsule
fill weight 200
[0134] The active substance, lactose and corn starch are firstly
mixed in a mixer and then in a comminuting machine. The mixture is
returned to the mixer, the talc is added thereto and mixed
thoroughly. The mixture is filled by machine into hard gelatine
capsules.
EXAMPLE C
[0135] Suppositories of the following composition are
manufactured:
4 mg/supp. Prodrug 15 Suppository mass 1285 Total 1300
[0136] The suppository mass is melted in a glass or steel vessel,
mixed thoroughly and cooled to 45.degree. C. Thereupon, the finely
powdered active substance is added thereto and stirred until it has
dispersed completely. The mixture is poured into suppository molds
of suitable size, left to cool, the suppositories are then removed
from the molds and packed individually in wax paper or metal
foil.
* * * * *