Title of Invention

A PROCESS FOR THE PREPARATION OF N-METHYL-N-[(IS)-PHENYL-2-((3S)-3-HYDROXYPYRROLIDIN-1-YL) ETHYL]-2, 2-DIPHENYLACETAMIDE HYDROCHLORIDE AND THE COMPOUND THEREOF

Abstract Process for the preparation of N-methyl-N-[(IS)-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl) ethyl]-2, 2-diphenylacetamide hydrochloride, characterized in that 1-[(IS)-3- hydroxypyrroIidin-1-yl]-(2S)-2-methyl-amino-2-phenylethane and diphenylacetyl chloride are reacted with one another at low temperatures, in particular at -5 to 10°C, by slowly adding diphenylacetyl chloride dissolved in a solvent to the 1-[(IS)-2-hydroxypyrrolidin-1- yl]-(2S)-2-methylamino-2-phenylethane dissolved in the same solvent and initially introduced into the apparatus while maintaining the temperature, and following the reaction recrystallizing the crude product obtained from a hot solvent and the product obtained from the said process.
Full Text The present invention relates to a hovel heat-
stable form of N-methyl-N- [(1S)-1-phenyl-2-((3S)-3-
hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide and
to a process for the preparation and isolation of this
compound in this novel form, and to use for the produc-
tion of medicaments which contain this compound and/or
one of its physiologically acceptable salts.
Compounds of this structural formula and also the
abovementioned compound and suitable processes for their
preparation are described in the Of fenlegungsschrift
DE 42 15 213 A1.
It has been found that the compound N-methyl-N-
[(1S) -1-phenyl-2- ( (3S) -3-hydroxypyrrolidin-1-yl)ethyl] -
2,2-diphenylacetamide, which is already known from Patent
Application DE 42 15 213 Al, is a pharmaceutically
particularly active compound which is very particularly
suitable as a medicament for the treatment of inflamma-
tory bowel disorders. In particular, this compound can be
employed and is effective in this indication, as it
simultaneously alleviates the pain associated with this
disorder and in the acute case of an intestinal occlusion
threatening or produced by the inflammatory bowel dis-
order again normalizes the motoricity of the intestine or
sets it in motion again without causing noticeable side
effects.
Attempts to prepare [lacuna] according to the
process known from DE 42 15 213 Al have shown that this
compound is obtained in various forms.
It was therefore the object of the invention to
make available N-methyl-N-[(1S)-1-phenyl-2-((3S) -3-
hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide in
heat-stable form and to provide a process for the prep-
aration of this compound, by means of which a heat-stable
product is obtained which is stable on storage and
suitable for the production of pharmaceutical formula-
tions .

The invention thus relates to heat-stable,
storable N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyr-
rolidin-1-yl)ethyl] -2,2-diphenylacetamide and to its use
as a medicament for the treatment of inflammatory bowel
disorders and also to pharmaceutical preparations which
contain this compound as a constituent and can therefore
be employed for the effective treatment of inflammatory
bowel disorders and the disease symptoms associated
therewith, and for the treatment of severe pain, in
particular of hypersensitivity to pain.
The invention likewise relates to the use of this
compound as a medicament for the treatment of pain and
hypersensitivity to pain occurring in back complaints,
burn injuries, sunburn and rheumatic disorders, and also
inflammatory reactions occurring in this context. The
invention also relates to the use of this medicament for
the treatment of post-operative pain, hypersensitivity
reactions to pain, and the ileus frequently occurring
after abdominal operations. The invention further relates
to the use of the corresponding compound in pharmaceuti-
cal formulations for the treatment of neurodermatitis.
This invention moreover relates to a process for
the preparation of heat-stable, storable N-methyl-N-
t (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl)ethyl] -
2,2-diphenylacetamide.
The compound according to the invention and its
physiologically acceptable salts exhibit particularly
good analgesic actions. In this connection, they antagon-
ize, in particular, inflammation-related hyperalgesias,
but are also effective in the control of the actual
inflammatory event, so that they have a broad spectrum of
action.
Experiments have shown that the compound accord-
ing to the invention is active in the "writhing test" on
mice or rats (method cf. Siegmund et al., Proc. Soc. Exp.
Biol. 95, (1957), 729-731). The analgesic action as such
can be further demonstrated in the "tail-flick test" on
mice or rats (methodology cf. d'Amour and Smith, J.
Pharmacol. Exp. Ther. 72, (1941), 74-79) and further in

the "hot plate test" (cf. Schmauss and Yaksh, J.
Pharmacol. Exp. Ther. 228, (1984), 1-12 and the
literature cited there). Particularly strong actions are
to be observed on rats in the carrageenan-induced
hyperalgesia model (cf. Bartoszyk and Wild, Neuroscience
Letters 101 (1989) 95) . In this context, this compound
shows no or only a small tendency to physical dependence.
Additionally, by means of corresponding experi-
ments carried out by familiar methods, pronounced anti-
inflammatory, diuretic, anticonvulsive and neuropro-
tective actions were demonstrated. The compound exhibits
a high affinity with respect to the binding behaviour to
kappa-receptors.
In contrast to other compounds having a similar
spectrum of action, the compound according to the inven-
tion is particularly suitable for use in pharmaceutical
preparations for the treatment of inflammatory bowel
disorders, as in addition to the analgesic and anti-
inflammatory action it is suitable for normalizing
disorders of the intestinal motoricity produced by the
disorder. In particular, it is suitable for getting the
bowel movements going again if, due to the inflammatory
bowel disorder, intestinal obstruction threatens or has
already occurred. This action can also be employed for
the treatment of postoperative ileus and the pain associ-
ated therewith.
On account of the pharmacological activity
described above, the compound according to the invention
has proved particularly suitable in the treatment of
burns, namely both of burns due to the action of heat or
flames and also of severe sunburn. In particular, in
addition to the actual pain and hypersensitivity
reactions to pain, inflammatory processes can addition-
ally be influenced in these indications by the adminis-
tration of suitable pharmaceutical preparations which
comprise the active compound according to the invention.
Also, the reflex ileus occurring in the case of the most
severe burns can be prevented or treated.
In this connection, indications have also been

found which point to an advantageous action in the
treatment of allergies to the sun, especially as under
the influence of the compound according to the invention
allergic skin reactions rapidly fade and the itching
associated therewith rapidly subsides. Corresponding
positive results were also found in the treatment of
neurodermatitis. In particular, the itching of the skin
in this disorder subsides under the action of the above-
mentioned active compound and inflammatory reactions
occurring due to the disorder are favourably influenced.
Furthermore, this active compound has proved
particularly effective in the treatment of rheumatic
disorders and of back conditions. It is particularly
advantageous in this connection that it is both active
against the pain associated therewith and positively
affects the inflammatory processes occurring in rheumatic
disorders and thus contributes to an improvement in the
general condition of the patient. In this context, it has
advantageously been shown that normal motoricity of the
gastrointestinal tract is not adversely affected.
In all indication areas described here, the use
of N-methyl-N-[(1S)-1-pbenyl-2-((3S)-3-hydroxypyrrolidin-
1-yl)ethyl]-2,2-diphenylacetamide hydrochloride as a
medicament has emerged as particularly effective in all
sorts of preparation forms.
Chemical and physical investigations for the
characterization of this compound according to the
invention have shown that it is contained in various
forms, depending on preparation and storage.
In detail, to date four different forms have been
found, which differ from one another significantly. Type
1 is a solvate. This form is readily converted into
another crystal type, which is designated in the follow-
ing text as type II. On slow heating of type I a release
of solvent takes place. The X-ray diffractometry, IR
analysis and the melting point data then correspond to
those of type II.
The compound prepared by the previously known
process described in the earlier application

DE 4215 213 A1 is obtained as type II and has a melting
range of 196-200 °C (see also Bioorganic & Medicinal
Chemistry Letters 4 (5) , 679 (1994) and has a heat of
fusion of 100 J/g.
A form designated as type III is obtained if type
II is stored under extreme conditions at an atmospheric
humidity of approximately 73 to 95%.
A modification characterized in the following as
type IV has, compared with that of type II, a melting
range of approximately 220-226°C and a heat of fusion of
approximately 120-128 J/g.
The higher melting point and the higher heat of
fusion of the compound according to the invention show
that the thermodynamically stable crystal modification is
present, the two crystal modifications II and IV obtained
being monotropic to one another.
This state of affairs can be confirmed by further
observations. On very rapid cooling of a melt obtained
from the thermodynamically unstable crystal modification
(m.p. 196-200°C) from 210°C to -78°C and storage at -78°C
for 5 hours the thermostable compound (221-226°C) slowly
crystallizes out.
In the case of these two types, not only their
melting behaviour differs. They also differ in their
storage stabilities. After storage of type II in a drying
oven at 170 °C a partial conversion into type IV was
detected. During DSC determination (DSC = Differential
Scanning Calorimetry) of the crystal modification of type
II, on slow heating above the melting point at
approximately 200°C, the crystal type IV which melts at
approximately 220-226°C crystallizes out. Crystal type IV
is also detected when a melt of type II (just above
200°C) is suddenly cooled and stored at room temperature
for a period of 12 to 16 hours. While type II has
therefore proved to be metastable, type IV is the
thermodynamically stable modification. By means of
specific crystallization tests, it was found that by
addition of seed crystals of type IV only the crystal
modification IV is obtained. In contrast to this.

however, by seeding with seed crystals of type II the
crystal modification IV is especially obtained.
Additionally, the solubility of the crystal type IV in
aqueous solution is lower than that of type II. It is
approximately 45 to 70% of the solubility of type II.
After seven months' storage of the compound
prepared by the process described in the earlier
application DE 4515213 A1 at room temperature, it was
possible to determine a start of conversion to the
thermostable crystal modification IV. That is to say, the
compound prepared by the process described in this
invention is stable on storage in contrast to the other
crystal modification.
In the presence of solvents (e.g. water), the
compound prepared can form solvates.
When using the compound according to the inven-
tion with the crystal modification of the type II in
pharmaceutical formulations, on relatively long storage
a change in the crystal modifications can occur.
Previous investigations of the pharmaceutical
activity have so far shown it to be relatively indepen-
dent of the crystal modification, which, however, does
not exclude differences due to a possibly modified
bioavailability. For use in solid pharmaceutical formula-
tions, care must therefore be taken that the stable
crystal modification of the type IV is employed, or that
when using the type II additives are employed by means of
which a long-term stabilization of this crystal type is
effected.
Surprisingly, it now appeared that not only the
manner of working up of the crude product obtained by the
actual reaction has an influence on the crystal modifica-
tion, but that even the conditions under which the
starting materials react with one another are important
for this. It was found that in this case, in particular,
the reaction temperatures and the solvent conditions play
a part.
In detail, it has been shown that the crystal-
lization type IV is obtained if the reaction of the

starting materials 1-[(1S)-3-hydroxypyrrolidin-1-yl] -
(2S)-2-methylamino-2-phenylethane and diphenylacetyl
chloride is carried out at low temperatures, in particu-
lar at -5 to 10°C, preferably at 0 to 8°C.
It has furthermore proved advantageous for this
purpose that the molar ratio of the starting materials 1-
C(1S) -3-hydroxypyrrolidin-1-yl] - (2S) -2-methylamino-2-
phenylethane and diphenylacetyl chloride to one another
is 1:0.75 to 1:1.65, preferably 1:1.1 to 1:1.3.
The molar ratio of the starting compounds 1-
[(1S) -3-hydroxypyrrolidin-1-yl] - (2S) -2-methylamino-2-
phenylethane and diphenylacetyl chloride to the solvent
used should in this case be selected such that the
starting materials are in solution, but the solvent if
possible is present only in a small excess. If tetra-
hydrofuran is selected as a solvent, it has proved
advantageous if the molar ratio of the abovementioned
starting materials and the solvent to one another is
approximately (0.8-1.2): (0.9-1.3):(14-22). A ratio of
(0.9-1.1):(1-1.2):(16-19) has proved particularly
effective.
A very slow addition of the diphenylacetyl
chloride dissolved in one part of the solvent used has
proved particularly advantageous, namely in particular
while maintaining a low temperature. To complete the
reaction, stirring is continued for some time at the same
temperature, but if possible for not longer than approxi-
mately 4 hours. A period of stirring of 1.5 to 2.5 hours
has emerged as optimum.
To purify the crude product obtained in this
manner, it is recrystallized from a suitable solvent. In
this context it is advantageous to select the amount of
solvent such that the product crystallizes even in the
hot solvent.
When using ethanol, this is achieved at molar
ratios of approximately one mol of product relative to 75
to 125 mol, in particular 85 to 115 mol, of solvent.
Depending on the choice of the solvent from which
it is recrystallized, the purified product is

precipitated in crystalline form in the modification of
the type IV even after brief cooling. When using ethanol,
it is the case after cooling to temperatures of
approximately 55 to 45°C. It has proved advantageous in
this case to maintain this temperature during the entire
crystallization.
It has proved particularly advantageous in the
case of the compound according to the invention that it
obviously cannot pass through the blood-brain barrier on
account of its structure and therefore exhibits no
dependence potential. Also, until now (no side effects
have been found which would restrict the use of the
advantageous actions for the claimed indications in any
way.
The compound according to the invention and its
physiologically acceptable salts can therefore be used
for the production of pharmaceutical preparations by
bringing them into the suitable dose form together with
at least one excipient or auxiliary and, if desired, with
one or more further active compounds. The preparations
thus obtained can be employed as medicaments in human or
veterinary medicine. Suitable excipients are organic or
inorganic substances which are suitable for enteral (e.g.
oral or rectal) or parenteral administration and do not
react with the novel compound, for example water,
vegetable oils, benzyl alcohols, polyethylene glycols,
glycerol triacetate and other fatty acid glycerides,
gelatin, soya lecithin, carbohydrates such as lactose or
starch, magnesium atearate, talc or cellulose.
For oral administration, in particular tablets,
coated tablets, capsules, syrups, juices or drops are
used. Of interest are especially coated tablets and
capsules having enteric coatings or capsule shells. For
rectal administration, suppositories are used, and for
parenteral administration, solutions, preferably oily or
aqueous solutions, and also suspensions, emulsions or
implants are used.
The active compound claimed according to the
invention can also be lyophilized and the lyophilizate

obtained used, for example, for the production of injec-
tion preparations.
The preparations indicated can be sterilized
and/or contain auxiliaries such as preservatives, stabi-
lizers and/or wetting agents, emulsifiers, salts for
affecting the osmotic pressure, buffer substances,
colourants and/or flavourings. If desired, they can also
contain one or more further active compounds, e.g. one
or more vitamins, diuretics or antiinflammatories.
The compound I according to the invention is
generally administered in analogy to other known prepara-
tions available commercially for the indications claimed,
preferably in doses of between about 1 mg and 50 mg, in
particular between 5 and 30 mg, per dose unit. The daily
dose is preferably between about 0.02 and 20 mg/kg, in
particular 0.2 and 0.4 mg/kg of body weight.
The specific dose for each individual patient
depends, however, on all sorts of factors, for example
on the age, body weight, general state of health and sex,
on the diet, on the time and route of administration, and
on the excretion rate, pharmaceutical combination and
severity of the particular disorder to which the therapy
applies. Oral administration is preferred.
In the following, examples are given which serve
to illustrate the invention, but do not restrict the
invention to the examples given.
In the following text all temperatures are
indicated in °C.
Comparison Example
N-Methyl-N- t (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-
yl)ethyl]-2,2-dlphenylacetamide hydrochloride (type II)
22 g of 1- [ (1S) -3-hydroxypyrrolidin-1-yl] - (2S) -2-
methylamino-2-phenylethane are initially introduced into
a 500 ml apparatus and dissolved in 150 ml of tetrahydro-
furan. While stirring, a solution consisting of 150 ml of
tetrahydrofuran and 24.1 g of diphenylacetyl chloride is
added dropwise at 10-20°C in the course of one hour, a
precipitate being formed at the start which, however.

goes into solution again in the course of the reaction.
Towards the end of the reaction a precipitate is again
formed. The mixture is stirred at room temperature for a
further 12 hours. It is then cooled to about 5°C and the
precipitated product is filtered off with suction. The
separated product is washed with about 100 ml of tetra-
hydrofuran and dried. In this way, 39 g of crude product
are obtained. This is recrystallized using about 250 ml
of ethanol and 1 g of active carbon.
Yield: 33 g of N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-
hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenyl-
acetamide hydrochloride (73.2% of theory)
Melting point: 196-200°C
Heat of fusion: 100 J/g
pK,: 7.4
Solubility in water at 20°C: 1.16 g/100 ml
Solubility in methanol at 20°C: 6.31 g/100 ml
Example 1
N-Methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-
yl)ethyl]-2.2-diphenylacetamide hydrochloride (type IV)
A solution consisting of 10.5 g of diphenylacetyl
chloride and 17 ml of tetrahydrofuran is slowly added
dropwise with stirring in the course of 75 minutes to a
reaction solution, cooled to 0 to 8°C, consisting of 9 g
of 1-[(IS)-3-hydroxypyrrolidin-1-yl]-(2S)-2-methylamino-
2-phenylethane and 40 ml of tetrahydrofuran. The mixture
is then stirred at the same temperature for a further
120 °C [sic]. The reaction product depositing in the
course of this as a precipitate is filtered off with
suction and dried. In this manner 17 g of crude product
are obtained, which are recrystallized from 180 ml of
ethanol. During this recrystallization, the product
prepared is deposited at 50°C as the stable crystal
type IV.
Yield: 13 g of N-methyl-N-[ (1S)-1-phenyl-2-((3S)-3-
hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenyl-
acetamide hydrochloride (70.6% of theory)
Melting point: 220-225°C
Heat of fusion: 124 J/g

pKa: 7.4
Solubility in water at 20°C: 0.76 g/100 ml
Solubility in methanol at 20°C: 4.26 g/100 ml
The following examples relate to pharmaceutical
preparations:
Example A: Injection vials
A solution of 100 g of an active compound of the
formula I and 5 g of disodium hydrogen phosphate are
adjusted to pH 6.5 in 3 1 of double-distilled water using
2N hydrochloric acid, sterile filtered, filled into
injection vials, lyophilized under sterile conditions and
aseptically sealed. Each injection vial contains 5 mg of
active compound.
Example B: Suppositories
A mixture of 20 g of an active compound of the
formula I is fused with 100 g of soya lecithin and 1400 g
of cocoa butter, poured into moulds and allowed to cool.
Each suppository contains 20 mg of active compound.
Example C: Solution
A solution is prepared from 1 g of an active
compound of the formula I, 9.38 g of NaH3PO4.2H3O, 28.48 g
of NA2HPO4. 12H2O and 0.1 g of benzalkonium chloride in
940 ml of double-distilled water. The solution is
adjusted to pH 6.8, made up to 1 1 and sterilized by
irradiation.
Example D; Ointment
500 mg of an active compound of the formula I are
mixed with 99.5 g of petroleum jelly under aseptic
conditions.
Example E; Tablets
A mixture of 1 kg of active compound, 4 kg of
lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1
kg of magnesium stearate is compressed in a customary
manner to give tablets in such a way that each tablet
contains 10 mg of active compound.
Example F; Coated tablets
Analogously to Example E, tablets are pressed
which are then coated in a customary manner with a
coating of sucrose, potato starch, talc, tragacanth and

colourant.
Example G; Capsules
2 kg of active compound are filled into hard
gelatin capsules in the customary manner such that each
capsule contains 20 mg of the active compound.
Example H; Ampoules
A solution of 1 kg of active compound in €0 1 of
double-distilled water iS sterile filtered, filled into
ampoules, lyophilized under sterile conditions and
aseptically sealed. Each ampoule contains 10 mg of active
compound.

WE CLAIM :
1. Process for the preparation of N-methyl-N-[(IS)-phenyl-2-((3S)-3-
hydroxypyrrolidin-1-yl) ethyl]-2, 2-diphenylacetamide hydrochloride,
characterized in that
(a) 1-[(IS)-3-hydroxypyrrolidin-1-yl]-(2S)-2-methyl-amino-2-
phenylethane and diphenylacetyl chloride are reacted with one
another at low temperatures, in particular at -5 to 10°C, by
(b) slowly adding diphenylacetyl chloride dissolved in a solvent to the
1-[(IS)-2-hydroxypyrrolidin-1-yl]-(2S)-2-methylamino-2-
phenylethane dissolved in the same solvent and initially
introduced into the apparatus while maintaining the temperature,
and
(c) following the reaction recrystallizing the crude product obtained
from a hot solvent.
2. N-Methyl-N-[(IS)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,
2-diphenylacetamide hydrochloride as prepared by the process as
claiamed in claim 1 wherein, the thermodynamically stable crystal
modification has a melting point of 220-225°C.

3. Compound as claimed in claim 2, having a melting point of 220-225°C.


Process for the preparation of N-methyl-N-[(IS)-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)
ethyl]-2, 2-diphenylacetamide hydrochloride, characterized in that 1-[(IS)-3-
hydroxypyrroIidin-1-yl]-(2S)-2-methyl-amino-2-phenylethane and diphenylacetyl chloride
are reacted with one another at low temperatures, in particular at -5 to 10°C, by slowly
adding diphenylacetyl chloride dissolved in a solvent to the 1-[(IS)-2-hydroxypyrrolidin-1-
yl]-(2S)-2-methylamino-2-phenylethane dissolved in the same solvent and initially
introduced into the apparatus while maintaining the temperature, and following the
reaction recrystallizing the crude product obtained from a hot solvent and the product
obtained from the said process.

Documents:

1481-cal-1996-abstract.pdf

1481-cal-1996-assignment-1.1.pdf

1481-cal-1996-assignment.pdf

1481-cal-1996-claims.pdf

1481-cal-1996-correspondence-1.1.pdf

1481-cal-1996-correspondence.pdf

1481-cal-1996-description (complete).pdf

1481-cal-1996-examination report-1.1.pdf

1481-cal-1996-examination report.pdf

1481-cal-1996-form 1-1.2.pdf

1481-cal-1996-form 1.1.pdf

1481-cal-1996-form 1.pdf

1481-cal-1996-form 18-1.1.pdf

1481-cal-1996-form 18.pdf

1481-cal-1996-form 2.pdf

1481-cal-1996-form 3-1.1.pdf

1481-cal-1996-form 3.pdf

1481-cal-1996-form 5-1.1.pdf

1481-cal-1996-form 5.pdf

1481-cal-1996-form 6-1.1.pdf

1481-cal-1996-form 6.pdf

1481-CAL-1996-FORM-27-1.pdf

1481-CAL-1996-FORM-27.pdf

1481-cal-1996-gpa-1.1.pdf

1481-cal-1996-gpa.pdf

1481-cal-1996-granted-abstract.pdf

1481-cal-1996-granted-claims.pdf

1481-cal-1996-granted-description (complete).pdf

1481-cal-1996-granted-form 1.pdf

1481-cal-1996-granted-form 2.pdf

1481-cal-1996-granted-specification.pdf

1481-cal-1996-others-1.1.pdf

1481-cal-1996-others.pdf

1481-cal-1996-priority document.pdf

1481-cal-1996-reply to examination report-1.1.pdf

1481-cal-1996-reply to examination report.pdf

1481-cal-1996-specification.pdf


Patent Number 247598
Indian Patent Application Number 1481/CAL/1996
PG Journal Number 17/2011
Publication Date 29-Apr-2011
Grant Date 26-Apr-2011
Date of Filing 20-Aug-1996
Name of Patentee TIOGA PHARMACEUTICALS, INC.
Applicant Address C/O FORWARD VENTURES, 9393 TOWNE CENTRE DRIVE, SUTIE 200, SAN DIEGO, CALIFORNIA
Inventors:
# Inventor's Name Inventor's Address
1 DR. INGE STEIN FRANKFURTER STRASSE 250, 64293 DARMSTADT
2 HOLGER BEERES FRANKFURTER STRASSE 250, 64293 DARMSTADT
3 DR. KLAUS BESCHMANN FRANKFURTER STRASSE 250, 64293 DARMSTADT
4 DR. STEFFEN NEUENFELD FRANKFURTER STRASSE 250, 64293 DARMSTADT
5 DR. ANDREW BARBER FRANKFURTER STRASSE 250, 64293 DARMSTADT
PCT International Classification Number A61K 31/40
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 19531464.6 1995-08-26 Germany