U.S. patent application number 13/159875 was filed with the patent office on 2011-10-20 for crystalline forms of 1,6-bis [3-(3-carboxymethylphenyl)-4-(2-alpha-d-mannopyranosyl-oxy)-phenyl] hexane.
This patent application is currently assigned to Revotar Biopharmaceuticals AG. Invention is credited to Ewald M. AYDT, Remo Kranich, Karin Vollhardt, Gerhard Wolff.
Application Number | 20110257114 13/159875 |
Document ID | / |
Family ID | 37478746 |
Filed Date | 2011-10-20 |
United States Patent
Application |
20110257114 |
Kind Code |
A1 |
AYDT; Ewald M. ; et
al. |
October 20, 2011 |
CRYSTALLINE FORMS OF 1,6-BIS
[3-(3-CARBOXYMETHYLPHENYL)-4-(2-ALPHA-D-MANNOPYRANOSYL-OXY)-PHENYL]
HEXANE
Abstract
The novel crystalline and polymorphic forms of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e have advantageous properties and can be used in pharmaceutical
and dermatological compositions.
Inventors: |
AYDT; Ewald M.; (Berlin,
DE) ; Kranich; Remo; (Berlin, DE) ; Vollhardt;
Karin; (Hennigsdorf, DE) ; Wolff; Gerhard;
(Glienicke-Nordbahn, DE) |
Assignee: |
Revotar Biopharmaceuticals
AG
Hennigsdorf
DE
|
Family ID: |
37478746 |
Appl. No.: |
13/159875 |
Filed: |
June 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12440300 |
Jan 25, 2010 |
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PCT/EP2007/059410 |
Sep 7, 2007 |
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13159875 |
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Current U.S.
Class: |
514/25 ;
536/18.2 |
Current CPC
Class: |
A61P 35/04 20180101;
A61P 37/08 20180101; A61P 35/00 20180101; A61P 1/04 20180101; C07H
15/203 20130101; A61P 9/00 20180101; A61P 9/10 20180101; A61P 11/00
20180101; A61P 11/06 20180101; A61P 17/00 20180101; A61P 25/00
20180101; A61P 31/04 20180101; A61P 17/06 20180101; A61P 29/00
20180101; A61P 9/08 20180101; A61P 37/02 20180101; A61P 19/02
20180101 |
Class at
Publication: |
514/25 ;
536/18.2 |
International
Class: |
A61K 31/7028 20060101
A61K031/7028; A61Q 19/08 20060101 A61Q019/08; A61P 35/00 20060101
A61P035/00; C07H 15/20 20060101 C07H015/20; A61P 29/00 20060101
A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 8, 2006 |
EP |
06120399.8 |
Claims
1. 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e monohydrate having the chemical formula: ##STR00002##
2. Crystalline 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e monohydrate having the chemical formula of claim 1.
3. Crystalline 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e monohydrate of claim 2, characterized by at least one of: an
X-ray powder diffraction pattern having diffraction angles (2Theta)
based on cupric K.sub..alpha.1 at approximately 5.3.degree. 2Theta,
5.6.degree. 2Theta, 17.4.degree. 2Theta, and 15.1.degree. 2Theta;
an X-ray powder diffraction pattern as substantially shown in FIG.
2; and an infrared spectrum containing peaks at 3246 cm.sup.-1,
2933 cm.sup.-1, 1728 cm.sup.-1, 1478 cm.sup.-1, 1226 cm.sup.-1,
1066 cm.sup.-1, 1017 cm.sup.-1, 982 cm.sup.-1, 800 cm.sup.-1, 686
cm.sup.1, and 605 cm.sup.-1.
4. A pharmaceutical composition comprising 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e monohydrate of claim 1 and at least one further pharmaceutically
acceptable component.
5. A pharmaceutical composition comprising crystalline 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e monohydrate of claim 2 and at least one further pharmaceutically
acceptable component.
6. A pharmaceutical composition comprising crystalline 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e monohydrate of claim 3 and at least one further pharmaceutically
acceptable component.
Description
[0001] The present invention relates to novel crystalline and/or
polymorphic forms of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (in particular in its dicarboxylic acid form), processes for
their preparation, their use and pharmaceutical compositions
comprising them.
[0002] Cell-adhesion molecule-mediated functions are part of a
complex cascade leading to the migration of circulating white blood
cells (leukocytes) from the blood stream into the surrounding
tissue (extravasation). Physiologically, leukocyte extravasation is
of critical importance for homeostasis and immuno-surveillance of
living beings including humans. Lymphocytes for example, are
constitutively leaving the blood stream into lymphatic tissues in
order to patrol for harmful antigens. Under pathological
circumstances however, e.g. local or systemic inflammation and/or
injury of the vascular system, this fundamental process is
dys-regulated, at least in part, due to an increased surface
expression of the adhesion molecules E- and P-selectin.
Consequently, the excessive leukocyte extravasation leads to a
pathological cellular infiltrate with subsequent tissue damage in
several clinically relevant settings.
[0003] Disease states such as acute lung injury (ALI), acute
respiratory distress syndrome (ARDS), asthma bronchiale (asthma),
chronic obstructive pulmonary disease (COPD), psoriasis, rheumatoid
arthritis, and sepsis are all associated with tissue inflammation
induced and perpetuated by pathologically activated leukocytes
infiltrating the respective tissue. In addition, exaggerated
leukocyte infiltration contributes to the pathogenesis of
ischemic-reperfusion injury (IRI) associated with organ
transplantation, cardiopulmonary bypass or percutaneous
transluminal angioplasty.
[0004] To extravasate, leukocytes must bind to the vascular
endothelium in order to finally transmigrate into the surrounding
tissue. Therefore, leukocytes have to attach and roll on the
endothelium (tethering and rolling). This primary event in
extravasation is mediated by the selectin family of cell-adhesion
molecules. In addition to directly binding to the endothelium,
leukocytes can adhere to other leukocytes, leukocyte-particles,
platelets or platelet-derived particles that are already attached
to the endothelium.
[0005] In addition to rolling and attachment mediated by the
interaction of leukocytes and selectins, binding to selectins may
also results in signal transduction [E. Crockett-Torabi, J.
Leukocyte Biol., 1998, 63, 1-14]. It was shown that small molecules
that bind to selectins can induce signal transduction as well [B.
Brenner et al., PNAS 1996, 93, 15376-15381].
[0006] Furthermore, selectins are also involved in leukocyte
retention in lung [D. Bock et al., Curr. Respir. Med. Rev., 2006,
2, 339-354].
[0007] The selectin family of adhesion molecules is comprised of
three structurally related calcium-dependent carbohydrate binding
cell surface proteins, E-, P- and L-selectin. E-selectin is
expressed on inflamed endothelium, P-selectin is expressed on
inflamed endothelium as well as on platelets and L-selectin is
expressed on leukocytes. Selectins are composed of an amino
terminal lectin domain, an epidermal growth factor (EGF)-like
domain, a variable number of complement receptor-related repeats, a
hydrophobic transmembrane domain and a C-terminal cytoplasmic
domain. The binding interactions leading to the adhesion of the
leukocytes are supposed to be mediated by contact of the lectin
domain of the selectins and various carbohydrate ligands on the
surface of the leukocytes. All three selectins can bind with low
affinity to the carbohydrate sialyl Lewis X (sLe.sup.X), a glycosyl
moiety present on the surface of most leukocytes. A structurally
related glycosyl moiety, sialyl Lewis a (sLe.sup.a), is
predominantly found on the surface of cancer cells [K. Okazaki et
al., J. Surg. Res., 1998, 78(1), 78-84; R. P. McEver et al.,
Glycoconjugate Journal, 1997, 14(5), 585-591]. In case of
P-selectin, a distinct high affinity glycoprotein ligand has been
described [R. P. McEver, R. D. Cummings, J. Clin. Invest., 1997,
100, 485-492], the so-called P-selectin glycoprotein ligand-1
(PSGL-1) which contributes to a high affinity selectin binding by
its sLe.sup.X moiety as well as by parts of its peptide components,
in particular sulphated tyrosine residues [R. P. McEver, Ernst
Schering Res. Found. Workshop, 2004, 44, 137-147].
[0008] PSGL-1 is one of the most important selectin ligands binding
with highest affinity to P-selectin, but it also binds to E- and
L-selectin [G. Constantin; Drug News Perspect; 2004; 17(9);
579-586]. It is a homodimeric sialomucin predominantly expressed on
leukocytes.
[0009] In inflammatory diseases, dys-regulated extravasation is, at
least in part, mediated due to an increased cell surface expression
of E- and P-selectin. In contrast to their low basal expression, E-
and P-selectin expression is upregulated during inflammation,
leading to a substantial recruitment of leukocytes into the
inflamed tissue. Although selectin-mediated cell adhesion is
required for fighting infection, there are various situations in
which such cell adhesion is undesirable or excessive, resulting in
severe tissue damage instead of repair. In the case of many acute
as well as chronic inflammatory disorders (e.g., asthma, COPD,
psoriasis, etc.), an association between infiltration of activated
leukocytes into the tissue simultaneously with a marked elevation
of tissue expression of corresponding adhesion molecules,
particularly E- and P-selectin, has been demonstrated [Muller et
al., J. Pathol., 2002, 198(2), 270-275; Di Stefano et al. Am.
Respir. Crit. Care. Med., 1994, 149(3) 803-810; Terajima et al.,
Arch. Dermatol. Res., 1998, 290, 246-252].
[0010] Leukocyte infiltration may also play a role in inflammatory
symptoms in the course of transplant and graft rejection. Also the
process of blood clotting is further promoted by
leukocyte-leukocyte and leukocyte-platelet binding, which occurs
because leukocytes possess both L-selectin and its corresponding
ligand P-glycoprotein ligand-1 (PSGL-1) and can thus interact with
themselves via PSGL-1, and they can also bind to platelets which
carry P-selectin.
[0011] In addition, selectins are involved in micro-inflammatory
processes causing ageing of the skin [P. U. Giacomoni et al.,
Micron 2004, 35, 179-184]. The signs of ageing of the skin
resulting from the effects on the skin of intrinsic and extrinsic
factors are defined by the appearance of wrinkles and fine lines,
by the yellowing of the skin which develops a wizened appearance
along with the appearance of pigmentation blemishes, by a change in
the thickness of the skin, generally resulting in a thickening of
the stratum corneum and of the epidermis and a thinning of the
dermis, by disorganization of the elastin and collagen fibers which
causes a loss of elasticity, of suppleness and of firmness, and by
the appearance of telnagiectasia.
[0012] Some of these signs are more particularly associated with
intrinsic or physiological ageing, that is so to say with "normal"
ageing associated with age, whereas others are more specific to
extrinsic ageing, that is so to say ageing caused by the
environment in general; such ageing is more particularly
photo-ageing due to exposure to the sun, to light or to any other
radiation. Other factors causing ageing of the skin are atmospheric
pollution, wounds, infections, traumatisms, anoxia, cigarette
smoke, hormonal status, neuropeptides, electromagnetic fields,
gravity, lifestyle (e.g. excessive consumption of alcohol),
repetitive facial expressions, sleeping positions, and
psychological stressors. Intrinsic and extrinsic factors of ageing
of the skin share common mechanisms [P. U. Giacomoni et al.,
Biogerontology 2004, 2, 219-229]. These factors trigger the
micro-inflammatory cycle where selectins are involved.
[0013] There is a strong medical, cosmetic (including skin care),
and dermatological need for novel highly potent anti-inflammatory
and anti-micro-inflammatory compounds for the treatment,
prophylaxis, and/or diagnosis of various indications or conditions
where inflammatory or micro-inflammatory conditions play a
role.
[0014] Most of the available anti-inflammatory pharmaceutical
therapies, which are available on the market, comprise
corticosteroids or NSAIDs (non steroidal anti-inflammatory drugs)
having several serious drawbacks/side effects, and target different
steps of the inflammatory cascade. Various cosmetic and
dermatological compositions (including for skin care) intended
inter alia to prevent or treat ageing of the skin are known.
However, these compounds also have side effects, consisting of
stinging and redness, which the user finds unpleasant. Thus, there
remains a need for anti-ageing agents which are at least as
effective as the known compounds, but do not exhibit their
drawbacks.
[0015] Unlike the established strategies to treat, prevent, or
diagnose inflammatory or micro-inflammatory indications or
conditions, modulating the selectin function is a novel concept
intervening the micro-/inflammation cascade at a very early stage
and treating, preventing, and/or diagnosing inflammatory or
micro-inflammatory indications or conditions according to the
present inventions represents a strategy without the drawbacks
known from other strategies.
[0016] The compound 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of the formula (I)) is described, for example, in U.S.
Pat. No. 5,919,768; I. Scott et al., Carbohydrate Research 317
(1-4), 1999, 210-216; T. Kogan et al., J. Medicinal Chemistry
41(7), 1998, 1099-1111; U.S. Pat. No. 5,712,387 and EP-A 0 840 606,
which are incorporated herein by reference. The compound of formula
I has several valuable pharmacological properties. It acts as
pan-selectin antagonist and inhibits leukocyte extravasation. Since
leukocyte extravasation is a key step in the pathogenesis of most
inflammatory disorders or conditions the compounds of formula (I)
offer the opportunity to be developed in a variety of inflammatory
and micro-inflammatory indications and conditions. The compound of
formula (I) can be used for the prophylaxis, treatment, and
diagnosis of inflammatory disorders and for the treatment and
prophylaxis of cosmetic and dermatological conditions where
micro-inflammatory conditions are involved.
##STR00001##
[0017] The compound of formula (I) may also be administered to
treat other diseases that are associated with cell-cell adhesion.
As the compound of formula (I) modulates the binding of E-selectin
or P-selectin or L-selectin, any disease that is related to this
interaction may potentially be treated by the modulation of this
binding interaction.
[0018] The compound of formula (I) is also useful for the
treatment, diagnosis, and prophylaxis of some forms of cancer,
including lung and colon cancer, for instance. Furthermore, the
compound of formula (I) can be used for the treatment, diagnosis,
and prophylaxis of diseases or conditions where selectins mediated
leukocyte retention is involved, e.g. in lung diseases [D. Bock et
al., Curr. Respir. Med. Rev., 2006, 2, 339-354].
[0019] The compound of formula (I) and its physiologically
tolerable salts are suitable as active pharmaceutical ingredients
(API) for the prevention, treatment, and diagnosis of various
inflammatory or micro-inflammatory diseases or conditions. The
compound of formula (I) and/or its physiologically tolerable salts
are preferably employed for this in the form of pharmaceutical
preparations which are tailored with respect to their composition
and the dosage form to the medicinal effects desired in the
specific case.
[0020] For example it can be used in the form of (1) solid
preparations such as tablets (e.g. compressed, layered, sugar, film
or enteric coated, chewable, delayed or extended release,
sublingual, buccal or effervescent) or capsules (e.g. hard filled
or soft gelatine) or in the form of (2) liquid preparations such as
oral solutions, emulsions and suspensions, parenteral solutions
e.g. for injections and infusions, including lyophilized powders
and ready-to-use injections, or ophthalmic solutions or in the form
of (3) semi-solid formulations for topical administration such as
ointments, creams, gels, or microemulsions.
[0021] In addition, specialized formulations like liposomes and
related forms, micellar solutions, microspheres, nanoparticles or
therapeutic systems, e.g. transdermal therapeutic systems, implants
or pumps, inhalative dosage forms, biodegradable or bioerodible
polymer systems, surgical or edible foams, soft or hydro gels,
microsponges, are also possible dosage forms.
[0022] Furthermore the compound of formula (I) may be used for
treating ageing of the skin caused by extrinsic and intrinsic
factors. The signs of skin ageing are defined by the appearance of
wrinkles and fine lines, by the yellowing of the skin which
develops a wizened appearance along with the appearance of
pigmentation blemishes, by a change in the thickness of the skin,
generally resulting in a thickening of the stratum corneum and of
the epidermis and a thinning of the dermis, by disorganization of
the elastin and collagen fibers which causes a loss of elasticity,
of suppleness and of firmness, and by the appearance of
telangiectasia.
[0023] Surprisingly, it turned out that the compound of formula (I)
can occur in a number of different crystal modifications which can
be prepared specifically by adjustment of the reaction conditions
and/or of the crystallization conditions and which differ in their
physicochemical properties. These crystal modifications differ, for
example, in their solubility, rate of dissolution or the behavior
during pharmaceutical processing and allow the production of
pharmaceutical preparations having different property profiles
starting from a single parent compound.
[0024] The herein described crystalline forms differ from
previously described solid forms of the compound of formula (I).
According to the published descriptions, the compound of formula
(I) has been isolated as white solid with a melting point of
115-117.degree. C. [U.S. Pat. No. 5,919,768, or T. P. Kogan et al.,
J. Med. Chem. 1998, 41, 1099-1111] indicating, as compared to the
melting points indicated below, different solid forms with
different physicochemical properties. In the present invention the
term "polymorph" is used to describe true polymorphs, amorphous
forms, mixtures of polymorphs and pseudo polymorphs, such as
hydrates and solvates.
[0025] The present invention relates to a polymorph of the compound
of formula (I) selected from the group of polymorphs of FORM 1,
FORM 2, FORM 3, FORM 4, FORM 5 and FORM 6.
[0026] The present invention also relates to a crystalline
polymorph which consists of FORM 1 and is further characterized in
that it provides an X-ray powder diffraction pattern which shows
the following diffraction angles (2Theta) based on cupric
K.sub..alpha.1 at approximately 4.8.degree. (strong peak). The
indicated X-ray diffraction data were obtained from crystal powders
at a Stoe powder diffraction system, type P with transmission
geometry (STOE & Cie. GmbH, Darmstadt, Germany). Some of the
measures are made on a Siemens D5000 diffractometer using Cu
K.sub..alpha.1 radiation (40 kV, 40 mA). The indicated diffraction
angles 2Theta of the X-ray reflections as well as the indicated
relative reflection intensities are values rounded to a multiple of
0.5.degree..
[0027] X-ray reflections which have a rounded relative intensity of
more than 50% of the intensity of the strongest reflection are
designated here as strong X-ray reflections. X-ray reflections
which have a rounded relative intensity of 15% or more, but less
than or equal 50% of the intensity of the strongest reflection are
designated here as medium-strong X-ray reflections. X-ray
reflections which have a rounded relative intensity of more than
25% and less or equal 50% of the intensity of the strongest
reflection are designated here as stronger medium X-ray
reflections.
[0028] A crystalline polymorph which consists of FORM 2 is further
characterized in that it provides an X-ray powder diffraction
pattern for this crystalline form which shows the following
diffraction angles (2Theta) based on cupric K.sub..alpha.1 [0029]
at approximately 5.3.degree. (strong peak), [0030] at approximately
5.6.degree. (strong peak), [0031] at approximately 17.4.degree.
(strong peak), and [0032] at approximately 15.1.degree. (medium
peak) is also subject of this invention.
[0033] Another embodiment of this invention is a crystalline
polymorph which consists of FORM 3 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1 [0034] at approximately
5.3.degree. (strong peak), [0035] at approximately 5.6.degree.
(strong peak), [0036] at approximately 4.2.degree. (medium peak),
[0037] at approximately 4.3.degree. (medium peak), and [0038] at
approximately 4.8.degree. (medium peak).
[0039] Another embodiment of this invention is a crystalline
polymorph which consists of FORM 4 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1: [0040] at approximately
16.8.degree. (strong peak), [0041] at approximately 26.5.degree.
(strong peak), [0042] at approximately 19.7.degree. (stronger
medium peak), and [0043] at approximately 21.5.degree. (stronger
medium peak).
[0044] Another embodiment of this invention is a crystalline
polymorph which consists of FORM 5 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1: [0045] at approximately
5.2.degree. (strong peak), [0046] at approximately 5.6.degree.
(strong peak), [0047] at approximately 21.4.degree. (strong peak),
[0048] at approximately 16.5.degree. (stronger medium peak), [0049]
at approximately 18.7.degree. (stronger medium peak), [0050] at
approximately 20.0.degree. (stronger medium peak), and [0051] at
approximately 20.6.degree. (stronger medium peak).
[0052] Another embodiment of this invention is a polymorph which
consists of FORM 6 and is further characterized in that it provides
an X-ray powder diffraction pattern for this amorphous form which
shows the following diffraction angles (2Theta) based on cupric
K.sub..alpha.1: 19.6.degree. (one broad peak).
[0053] A further embodiment of this invention is a crystalline
polymorph which consists of FORM 1 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1 [0054] at approximately
4.8.degree. (strong peak), [0055] at approximately 16.6.degree.
(medium peak), and [0056] at approximately 16.8.degree. (medium
peak).
[0057] Another embodiment of this invention is a crystalline
polymorph which consists of FORM 2 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1 [0058] at approximately
5.3.degree. (strong peak), [0059] at approximately 5.6.degree.
(strong peak), [0060] at approximately 17.4.degree. (strong peak),
[0061] at approximately 9.9.degree. (medium peak), [0062] at
approximately 10.3.degree. (medium peak), [0063] at approximately
13.8.degree. (medium peak), [0064] at approximately 15.0.degree.
(medium peak), [0065] at approximately 16.3.degree. (medium peak),
[0066] at approximately 16.6.degree. (medium peak), [0067] at
approximately 18.7.degree. (medium peak), [0068] at approximately
19.1.degree. (medium peak), [0069] at approximately 19.2.degree.
(medium peak), [0070] at approximately 19.8.degree. (medium peak),
[0071] at approximately 20.1.degree. (medium peak), [0072] at
approximately 20.4.degree. (medium peak), [0073] at approximately
20.7.degree. (medium peak), [0074] at approximately 21.5.degree.
(medium peak), [0075] at approximately 24.3.degree. (medium peak),
[0076] at approximately 24.8.degree. (medium peak), [0077] at
approximately 25.5.degree. (medium peak), and [0078] at
approximately 26.5.degree. (medium peak).
[0079] A further embodiment of this invention is a crystalline
polymorph which consists of FORM 3 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1 [0080] at approximately
5.3.degree. (strong peak), [0081] at approximately 5.6.degree.
(strong peak), [0082] at approximately 4.2.degree. (medium peak),
[0083] at approximately 4.8.degree. (medium peak), [0084] at
approximately 7.2.degree. (medium peak), [0085] at approximately
9.9.degree. (medium peak), [0086] at approximately 10.3.degree.
(medium peak), [0087] at approximately 10.6.degree. (medium peak),
[0088] at approximately 11.7.degree. (medium peak), [0089] at
approximately 13.8.degree. (medium peak), [0090] at approximately
15.1.degree. (medium peak), [0091] at approximately 16.3.degree.
(medium peak), [0092] at approximately 16.6.degree. (medium peak),
[0093] at approximately 16.9.degree. (medium peak), [0094] at
approximately 17.4.degree. (medium peak), [0095] at approximately
18.8.degree. (medium peak), [0096] at approximately 19.1.degree.
(medium peak), [0097] at approximately 19.3.degree. (medium peak),
[0098] at approximately 19.8.degree. (medium peak), [0099] at
approximately 20.0.degree. (medium peak), [0100] at approximately
20.1.degree. (medium peak), [0101] at approximately 20.4.degree.
(medium peak), [0102] at approximately 20.7.degree. (medium peak),
[0103] at approximately 21.5.degree. (medium peak), [0104] at
approximately 24.3.degree. (medium peak), [0105] at approximately
24.8.degree. (medium peak), [0106] at approximately 25.5.degree.
(medium peak), and [0107] at approximately 26.5.degree. (medium
peak).
[0108] Another embodiment of this invention is a crystalline
polymorph which consists of FORM 4 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1: [0109] at approximately
4.3.degree. (strong peak), [0110] at approximately 16.8.degree.
(strong peak), [0111] at approximately 26.5.degree. (strong peak),
[0112] at approximately 11.7.degree. (stronger medium peak), [0113]
at approximately 18.2.degree. (stronger medium peak), [0114] at
approximately 19.7.degree. (stronger medium peak), and [0115] at
approximately 21.5.degree. (stronger medium peak).
[0116] Another embodiment of this invention is a crystalline
polymorph which consists of FORM 5 and is further characterized in
that it provides an X-ray powder diffraction pattern for this
crystalline form which shows the following diffraction angles
(2Theta) based on cupric K.sub..alpha.1: [0117] at approximately
5.2.degree. (strong peak), [0118] at approximately 5.6.degree.
(strong peak), [0119] at approximately 21.4.degree. (strong peak),
[0120] at approximately 10.2.degree. (stronger medium peak), [0121]
at approximately 16.5.degree. (stronger medium peak), [0122] at
approximately 17.3.degree. (stronger medium peak), [0123] at
approximately 18.7.degree. (stronger medium peak), [0124] at
approximately 20.0.degree. (stronger medium peak), [0125] at
approximately 20.6.degree. (stronger medium peak), [0126] at
approximately 23.4.degree. (stronger medium peak), and [0127] at
approximately 23.6.degree. (stronger medium peak).
[0128] A particular subject of this invention is a crystalline
polymorph which provides an X-ray powder diffraction pattern
substantially in accordance with FIG. 1.
[0129] A crystalline polymorph which provides an X-ray powder
diffraction pattern substantially in accordance with FIG. 2 is also
subject of this invention.
[0130] Another subject of this invention is a crystalline polymorph
which provides an X-ray powder diffraction pattern substantially in
accordance with FIG. 3.
[0131] Another subject of this invention is a crystalline polymorph
which provides an X-ray powder diffraction pattern substantially in
accordance with FIG. 4.
[0132] Another subject of this invention is a crystalline polymorph
which provides an X-ray powder diffraction pattern substantially in
accordance with FIG. 5.
[0133] Another subject of this invention is an amorphous polymorph
which provides an X-ray powder diffraction pattern substantially in
accordance with FIG. 6.
[0134] Two X-ray powder diffraction pattern diagrams are normally
substantial in accordance if the strong and medium reflections of
both diffraction patterns are identical or show 2Theta angles with
a shift of maximal 2Theta.+-.0.2.degree..
[0135] Further details regarding the X-ray diffraction diagrams
which can also serve for further characterization of the FORM 1,
FORM 2, FORM 3, FORM 4, FORM 5 and FORM 6 are specified below.
[0136] The X-ray diffraction diagrams obtained under the conditions
indicated are shown in FIGS. 1 to 6. In the figures, the
diffraction angle 2Theta (in .degree.) is plotted in the abscissa
direction and the relative intensity (in %) is plotted in the
ordinate direction.
[0137] FORM 1, FORM 2, FORM 3, FORM 4, FORM 5 and FORM 6 of the
compound of formula (I) are all white solids which are excellently
filterable.
[0138] While FORM 1 of the present invention appears as a white
powder, what qualifies it for better solubility in several media
like water or surfactants (e.g. for the production of a
microemulsion) or for powder inhaling, FORM 2 and FORM 3 of the
present invention appear as white free flowing solids what
qualities them for a comfortable handling during manufacturing
processes or for processing them into a medicinal or skin care,
cosmetic, or dermatological product. The solids are stable on
storage at the customary temperatures and also at medium to higher
atmospheric humidity.
[0139] Depending on the crystal modification, they have differences
in pharmaceutical related properties, e.g. water solubility.
Therefore, they are particularly advantageously suitable for use in
pharmaceutical preparations, in particular for the production of
solid, semi-solid or liquid formulations which are intended, for
example, for parenteral administration, but also for the production
of pharmaceutical dosage forms to be administered orally or
topically.
[0140] The invention comprises FORM 1, FORM 2, FORM 3, FORM 4, FORM
5 and FORM 6 of compound of formula (I) both in solvent-free from
and in the form of solvates, for example hydrates or adducts with
alcohols such as isopropanol or ethanol.
[0141] A crystalline polymorph which consists of FORM 1 and
provides an infrared spectrum containing peaks at 3404 cm.sup.-1,
2931 cm.sup.-1, 1707 cm.sup.-1, 1500 cm.sup.-1, 1479 cm.sup.-1,
1245 cm.sup.-1, 1228 cm.sup.-1, 1136 cm.sup.-1, 1095 cm.sup.-1,
1050 cm.sup.-1, 818 cm.sup.-1, 801 cm.sup.-1, and 690 cm.sup.-1 is
also subject of this invention.
[0142] The present invention also relates to a crystalline
polymorph which consists of FORM 2 and provides an infrared
spectrum containing peaks at 3246 cm.sup.-1, 2933 cm.sup.-1, 1728
cm.sup.-1, 1478 cm.sup.-1, 1226 cm.sup.-1, 1066 cm.sup.-1, 1017
cm.sup.-1, 982 cm.sup.-1, 800 cm.sup.-1, 686 cm.sup.-1, and 605
cm.sup.-1.
[0143] The present invention also relates to an amorphous polymorph
which consists of FORM 6 and provides an infrared spectrum
containing peaks at 3387 cm.sup.-1, 2928 cm.sup.-1, 2855 cm.sup.-1,
1710 cm.sup.-1, 1607 cm.sup.-1, 1478 cm.sup.-1, 1223 cm.sup.-1,
1115 cm.sup.-1, 977 cm.sup.-1, 890 cm.sup.-1, 797 cm.sup.-1, and
703 cm.sup.-1.
[0144] The pharmacological properties of the polymorphs of compound
of formula (I) such as FORM 1, FORM 2, FORM 3, FORM 4, FORM 5 or
FORM 6 and their possible uses for the therapy, diagnosis, and/or
prophylaxis of disorders are not the same.
[0145] However, if the substances are present at the same
concentrations in the blood (circulation), in the lymphatic system,
in the target man or in the target cell in dissolved form they tend
to have the same properties, independent of the original form of
the solid. Thus the polymorphs have corresponding properties to
those which are described inter alia in U.S. Pat. No. 5,919,768 and
U.S. Pat. No. 5,712,387 and EP-A 0 840 606.
[0146] Like the compound of formula (I) as described therein, the
polymorphs of compound of formula (I) such as FORM 1, FORM 2, FORM
3, FORM 4, FORM 5 and the amorphous FORM 6 modulate the action of
selectins.
[0147] The action of FORM 1, FORM 2, FORM 3, FORM 4, FORM 5 and
FORM 6 can be investigated, for example, in the pharmacological
models which are described in U.S. Pat. No. 5,919,768, U.S. Pat.
No. 5,712,387 or EP-A 0 840 606. The activity of the crystalline
forms can also be shown by using other methods known in the prior
art.
[0148] The present invention also relates to the use of a
crystalline polymorph of the compound of formula (I) for the
preparation of a pharmaceutical composition. Due to the differences
in solubility, the polymorphic forms can provide various
formulations.
[0149] The amount used of a crystalline polymorph of the compound
of formula (I) corresponds to the amount required to obtain the
desired result using the pharmaceutical compositions.
[0150] The amount can be varied to a large extent. It depends on
the derivative used, the individual on whom it is applied, and the
time of this application. To provide an order of magnitude, in the
pharmaceutical compositions according to the invention, the
crystalline polymorphs of the compound of formula (I) may be
administered in an amount representing from 0.001% to 40% by
weight, preferentially 0.005% to 30% by weight and more
preferentially from 0.01% to 20% by weight, but depending on the
nature of the pharmaceutical preparation the content can also be,
for example, higher than 40% by weight.
[0151] A pharmaceutical composition comprising a polymorph of
compound of formula (I) such as FORM 1, FORM 2, FORM 3, FORM 4,
FORM 5 and/or FORM 6 and at least one further pharmaceutically
acceptable component is also subject of this invention.
[0152] The pharmaceutical composition contains, for example, a
polymorph of compound of formula (I), e.g. FORM 1 and a
pharmaceutically acceptable component, or FORM 2 and a
pharmaceutically acceptable component, or FORM 3 and a
pharmaceutically acceptable component, or, for example, two of the
crystalline polymorphs according to the invention such as FORM 1
and 2, or FORM 1 and 3, or FORM 2 and 3, in each case together with
a pharmaceutically acceptable component.
[0153] The pharmaceutical composition can be manufactured using
standard technologies, which are known to the person skilled in the
art. For this, one or more polymorphs of compound of formula (I)
according to the invention are brought into a suitable dosage form
together with one or more pharmaceutical components.
[0154] The pharmaceutical composition of the present invention may
include one or more of the polymorphs of compound of formula (I)
formulated together with one or more physiologically acceptable
carriers, adjuvants or vehicles, which are collectively referred to
herein as components, e.g. for parenteral injection, for oral
administration in solid or liquid form, for rectal or topical
administration and the like.
[0155] The compositions can e.g. be administered to humans and
animals either orally, rectally, parenterally (intravenously,
intramuscularly, or subcutaneously), intracistemally,
intravaginally, intraperitoneally, locally (powders, ointments or
drops), or as a buccal or by inhalation (nebulized, or as nasal
sprays).
[0156] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and non-aqueous carriers, diluents,
solvents or vehicles include water, ethanol, polyol, (propylene
glycol, polyethylene glycol, glycerol and the like), suitable
mixtures thereof, vegetable oils (such as olive or cannola oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0157] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents. Prevention
of the action of microorganisms can be ensured by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium
chloride and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, for example, aluminum monostearate and
gelatin.
[0158] If desired, and for more effective distribution, the
crystalline polymorphs of compound of formula (I) can be
incorporated into slow or timed release or targeted delivery
systems such as polymer matrices, liposomes and microspheres. They
may be sterilized, for example, by filtration through a
bacteria-retaining filter, or by incorporating sterilizing agents
in the form of sterile water, or some other sterile injectable
medium immediately before use.
[0159] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, glucose, mannitol and silicic acid, (b) binders,
as for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for
example, glycerol, (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates and sodium carbonate, (e) solution
retarders, as for example, paraffin, (f) absorption accelerators,
e.g. quaternary ammonium compounds, (g) wetting agents, as for
example, cetyl alcohol and glycerol monostearate, (h) adsorbents,
as for example, kaolin and bentonite, and (i) lubricants, as for
example, talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In
the case of capsules, tablets and pills, the dosage forms may also
comprise buffering agents.
[0160] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. Solid dosage forms such
as tablets, dragees, capsules, pills and granules can be prepared
with coatings and shells, such as enteric coatings and others well
known in the art. They may contain opacifying agents, and can also
be of such composition that they release the active compound or
compounds in a certain part of the intestinal tract in a delayed
manner. Examples of embedding compositions that can be used are
polymeric substances and waxes.
[0161] The active compounds can also be in microencapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0162] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active crystalline
polymorphs of compound of formula (I), the liquid dosage forms may
contain inert diluents commonly used in the art such as water or
other solvents, solubilizing agents and emulsifiers, as for
example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate, benzyl alcohol, benzyl benzoate, propylene glycol,
1,3-butylene glycol, dimethylformamide, oils, in particular,
cottonseed oil, groundnut oil, corn germ oil, olive oil, cannola
oil, castor oil and sesame seed oil, glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan or
mixtures of these substances, and the like.
[0163] Besides such inert diluents, the compositions can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0164] Suspensions, in addition to the active compounds, may
contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth or mixtures of these substances and the
like.
[0165] Compositions for rectal administrations are preferably
suppositories, which can be prepared by mixing the compounds of the
present invention with suitable nonirritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository
wax, which are solid at ordinary temperatures but liquid at body
temperature and therefore melt in the rectal or vaginal cavity and
release the active pharmaceutical ingredient.
[0166] Dosage forms for topical administration of a compound of
this invention include ointments, powders, sprays and
inhalants.
[0167] The active pharmaceutical ingredient is admixed under
sterile conditions with a physiologically acceptable carrier and
any needed preservatives, buffers or propellants as may be
required. Ophthalmic formulations, eye ointments, suspensions,
powders and solutions are also contemplated as being within the
scope of this invention.
[0168] The polymorphs of compound of formula (I) according to this
invention can also be administered in the form of liposomes. As is
known in the art, liposomes are generally derived from
phospholipids or other lipid substances. Liposomes are formed by
mono or multilamellar hydrated liquid crystals that are dispersed
in an aqueous medium. Any nontoxic, physiologically acceptable and
metabolizable lipid capable of forming liposomes can be used. The
present compositions in liposome form can contain, in addition to
the selectin binding inhibitors of the present invention,
stabilizers, preservatives, excipients and the like. The preferred
lipids are the phospholipids and the phosphatidyl cholines
(lecithins), both natural and synthetic. Methods to form liposomes
are well known in the art.
[0169] Actual dosage levels of active pharmaceutical ingredient in
the compositions of the present invention may be varied so as to
obtain an amount of active pharmaceutical ingredient that is
effective to obtain the desired therapeutic response for a
particular composition and method of administration.
[0170] The selected dosage level, therefore, depends on the desired
therapeutic effect, on the route of administration, on the desired
duration of treatment and other factors.
[0171] The total daily dosage of the compounds of this invention
administered to a host in single or divided doses may be in the
range of about 0.3 mg to about 50 mg per kilogram of body weight.
Dosage unit compositions may contain such submultiples thereof as
may be used to make up the daily dosage. It will be understood,
however, that the specific dose level for any particular patient,
whether human or other animal, will depend upon a variety of
factors including the body weight, general health, sex, diet, time
and route of administration, rates of absorption and excretion,
combination with other drugs and the severity of the particular
disease being treated.
[0172] The pharmaceutical composition comprising at least one
polymorph of compound of formula (I) such as FORM 1, FORM 2, FORM
3, FORM 4, FORM 5 and/or FORM 6 can be used for the treatment,
diagnosis, and/or prophylaxis of inflammatory diseases or
conditions. Thus, another subject of this invention is the use of
pharmaceutical composition comprising a (crystalline) polymorph of
compound of formula (I) such as FORM 1, FORM 2, FORM 3, FORM 4,
FORM 5 or FORM 6 for the treatment, diagnosis and/or prophylaxis of
inflammatory diseases or conditions.
[0173] Furthermore, the pharmaceutical compositions may comprise
additional active pharmaceutical ingredients. The present invention
therefore relates to pharmaceutical composition comprising a
(crystalline) polymorph of compound of formula (I) such as FORM 1,
FORM 2, FORM 3, FORM 4, FORM 5 or FORM 6 and at least one further
active pharmaceutical ingredient.
[0174] Favorable, but nevertheless optional active pharmaceutical
ingredients, which may be used are all active pharmaceutical
ingredients customary or suitable for pharmaceutical applications.
Exemplary, possible other active pharmaceutical ingredients are
other substances having anti-inflammatory activity such as:
histamine receptor targeted molecules (e.g. 2-methylhistamine,
dimaprit, or imetit, ketofifen, promethazine), kinin modulators,
modulators of eicosanoid synthesis, nonsteroidal anti-inflammatory
drugs (NSAIDs) (e.g. aspirin, acetaminophen, ibuprofen, ketoprofen,
naproxen, indomethacin, piroxam, diflunisal, celecoxib, apazone),
xanthine oxidase targeted molecules (e.g. allopurinol),
.beta..sub.2 adrenergic receptor targeted molecules (e.g.
albuterol, levalbuterol, metaproterenol, terbutaline, pirbuterol,
salmeterol xinafoate, formoterol, arformoterol, carmoterol,
indacaterol, salbutamol, GSK-159797, GSK-685698, GSK-597901,
GSK-159802, 642444, 678007, LAS-34273, LAS-35201, TD-5742),
muscarinic receptor modulators (e.g. tiotropiumbromide,
ipratropiumbromide, AD237), leukotriene-receptor modulators (e.g.
zafirlukast, montelukast, prantukast), LTB.sub.4-modulators (e.g.
LY293111, SB201146, BIIL315ZW), modulators of LTB.sub.4-synthesis
(e.g. BAYx1005), modulators of leukotriene synthesis (e.g.
zileuton), recombinant monoclonal anti-IgE antibodies (e.g.
omalizumab), IL-1 receptor modulators, glucocorticoids (e.g.
cortisol, cortisone, prednisolon, dexamethason, betamethason,
fluocinoid, fluocortolon, diflucortolon-21-valerat, ciclesonid,
roleponide palmitate, mometasone furoate). modulators of PDE.sub.4
(e.g. cilomilast, roflumilast, BAY 19-8004, NVP-ABE171), modulators
of IL-2 transcription (e.g. ciclosporine A, tacrolismus,
sirolismus), modulators of IL-2 receptor (e.g. basiliximab,
daclizumab), modulators of retinoid acid receptor (RAR) (e.g.
acitretin, tazaroten, adapalen, Ro444753), modulators of RXR (e.g.
bexaroten), modulators of CXCR2 (e.g. SB225002, SB265610),
modulators of CCR3 (e.g. Ro1164875, Ro3202947), modulators of
chemokine receptor (e.g. SB297006, SB238437, UCB35625), modulators
of cytokines (e.g. SCH55700, infiximab, etanercept, BION-1),
modulators of cytokine receptor (e.g. altrucincept), cytokines
(e.g. IL-10, IL-12), modulators of Adenosine receptor (e.g.
EPI2010, CGS21680, GW328267), modulators of the complement system
(e.g. C5a/C3a receptor antagonists), modulators of the ICAM-family,
modulators of VCAM-1, modulators of PECAM-1, modulators of
integrins (e.g. natalizumab, efalizumab), modulators of
TNF/TNF-receptor (e.g. infliximab, etanercept, adalimumab),
modulators of TNF-alpha converting enzyme (TACE) (e.g. PKF 242-484,
PKF241-466), modulators of matrix-metaloproteinase (MMP) (e.g. PKF
242-484, PKF241-466, BAY 15-7496, RS 113456), modulators of serine
proteases (e.g. ZD0892), modulators of elastases (e.g. ONO 6818),
modulators of glycoproteins (e.g. intergrilin), modulators of JAM
family, modulators of MIF, modulators of signalling pathways (e.g.
cilomilast, rofumilast, sildenafil, gefitinib, erlotinib),
modulators of NF-kB pathway, modulators of P38 mitogen-activated
protein (MAP) kinase pathway (e.g. SB203580, SB 239063), modulators
of Jak/STAT pathway, modulators of protein kinases (e.g.
rapamycin), modulators of proteasome/signalosome (e.g. velcade),
modulators of sphingosin-1 phosphate receptor (e.g. FTY720),
modulators of IL-17 pathway, modulators of Toll-like receptor,
modulators of proliferator-activated receptor (PPAR) (e.g.
rosiglitazone), modulators of platelet activating factor (PAF)
pathway, modulators of 5HT3 (e.g. ondansetron, granisetron,
dolasetron), modulators of INF-.gamma., modulators of IL2R
alpha-chain (e.g. basiliximab, daclizumab), modulators of CD3
(T-cell) (e.g. OKT3=muronomab CD3), modulators of glycosylation,
modulators of iNOS, modulators of tryptase (e.g. APC366,
AMG-126737, MOL6131), ATP-sensitive potassium channel openers (e.g.
SDZ217-744, KCO912), antisense oligonucleotides (e.g. GATA-3),
cromolyn sodium, nedocromil sodium, theophylline, polyphenols (e.g.
gallic acid and derivates thereof, epicatechins,
epigallocatechines), derivatives of vitamin D (e.g. calcitriol,
calcipotriol, tacalcitol), all trans retinoic acid (ATRA),
derivatives of vitamin A (e.g. tretinoin, isotretinoin),
dithranole, azelaic acid, benzoylperoxide, erythromycin,
clindamicyn, minocycline, tetracycline, and derivatives of
5-amino-salicylic acid (e.g. sufasalazin, olsalazin).
[0175] Possible other advantageous pharmaceutical compositions are
also obtained if antioxidants are used as additives or active
pharmaceutical ingredients. According to this invention, the
pharmaceutical compositions may comprise one or more antioxidants.
Favorable, but nevertheless optional antioxidants which may be used
are all antioxidants customary or suitable for pharmaceutical
applications, e.g.
amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and
derivatives thereof, imidazoles (e.g. urocanic acid) and
derivatives thereof, peptides such as D,L-carnosine, D-carnosine,
L-carnosine and derivatives thereof (e.g. anserine), carotenoids,
carotenes (e.g. .alpha.-carotene, .beta.-carotene, lycopene) and
derivatives thereof, gallates (e.g. propyl gallate, dodecyl
gallate, octyl gallate) and derivates thereof, lipoic acid and
derivatives thereof (e.g. dihydrolipoic acid), aurothioglucose,
propylthiouracil and other thiols (e.g. thioredoxin, glutathione,
cysteine, cystine, cystamine and the glycosyl, N-acetyl methyl,
ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl
.gamma.-linoleyl, cholesteryl and glyceryl esters thereof) and
salts thereof dilauryl thiodipropionate, distearyl
thiodipropionate, thiodipropionic acid and derivatives thereof
(esters, ethers, peptides, lipids, nucleotides, nucleosides and
salts), sulfoximine compounds (e.g. butbionine sulfoximines,
homocysteine sulfoximine, buthionine sulfones, penta-, hexa-,
heptathionine sulfoximine) in very low tolerated doses, and also
(metal) chelating agents (e.g. a-hydroxy fatty acids, palmitic
acid, phytic acid, lactoferrin), a-hydroxy acids (e.g. citric acid,
lactic acid, malic acid), humic acid, bile acid, bile extracts,
bilirubin, EDTA, EGTA and derivatives thereof, unsaturated fatty
acids and derivatives thereof (e.g. .gamma.-linolenic acid,
linoleic acid, oleic acid), folic acid and derivatives thereof,
ubiquinone and ubiquinol and derivatives thereof, vitamin C and
derivatives (e.g. ascorbyl palmitate, Mg ascorbyl phosphate,
ascorbyl acetate), tocopherols and derivatives (e.g. vitamin E
acetate), vitamin A and derivatives (vitamin A palmitate) and
coniferyl benzoate of benzoin resin, manic acid and derivatives
thereof, ferulic acid and derivatives thereof, butylhydroxytoluene,
butylhydroxyanisole, nordihydroguaiacic acid, nordihydroguaiaretic
acid, trihydroxybutyrophenone, uric acid and derivatives thereof,
mannose and derivatives thereof, zinc and derivatives thereof (e.g.
ZnO, ZnS0.sub.4), selenium and derivatives thereof (e.g.
selenomethionine), stilbenes and derivatives thereof (e.g. stilbene
oxide, trans-stilbene oxide) and the derivatives (salts, esters,
ethers, sugars, nucleotides, nucleosides, peptides and lipids) of
these listed active ingredients which are suitable according to the
invention.
[0176] A further embodiment of this invention is the use of a
pharmaceutical composition comprising a (crystalline) polymorph of
compound of formula (I) such as FORM 1, FORM 2, FORM 3, FORM 4,
FORM 5 or FORM 6 and at least one further active pharmaceutical
ingredient for the treatment, diagnosis and/or prophylaxis of
inflammatory diseases or conditions.
[0177] A pharmaceutical composition comprising a (crystalline)
polymorph of compound of formula (I) such as FORM 1, FORM 2, FORM
3, FORM 4, FORM 5 or FORM 6 and at least one further
pharmaceutically acceptable component or a pharmaceutical
composition comprising a crystalline polymorph of compound of
formula (I) such as FORM 1, FORM 2, FORM 3, FORM 4, FORM 5 or FORM
6 and at least one further pharmaceutically acceptable component as
well as at least one further active pharmaceutical ingredient for
the treatment, diagnosis, and/or prophylaxis of chronic obstructive
pulmonary disease (COPD), acute lung injury (ALI), cardiopulmonary
bypass, acute respiratory distress syndrome (ARDS), septic shock,
sepsis, chronic inflammatory diseases such as psoriasis, atopic
dermatitis, and rheumatoid arthritis, and reperfusion injury that
occurs following heart attacks, strokes, atherosclerosis, and organ
transplants, traumatic shock, multi-organ failure, autoimmune
diseases like multiple sclerosis, percutaneous transluminal
angioplasty, asthma, and inflammatory bowel diseases, Crohn's
disease, and metastasis of cancers, where cell adhesion involving
sLe.sup.a is involved, is also subject of the present
invention.
[0178] In each case, an effective amount of the polymorphs of
compound of formula (I) is administered either alone or as part of
a pharmaceutically active composition to a patient in need of such
treatment. It is also recognized that a combination of the crystal
modifications of the compound of formula I with e.g. other
anti-inflammatory drugs may be administered to a patient in need of
such administration. The crystalline polymorphs of compound of
formula (I) may also be administered to treat other diseases that
are associated with cell-cell adhesion.
[0179] As the compound of formula (I) modulates the binding of
E-selectin or P-selectin or L-selectin, any disease that is related
to this interaction may potentially be treated by the modulation of
this binding interaction. In addition, the crystalline polymorphs
of compound of formula (I) can be used for the prophylaxis,
diagnosis, and treatment of conditions where cell adhesion
involving sLe.sup.a, such as metastasis of certain cancers, is
involved. Furthermore, the crystalline polymorphs of compound of
formula (I) can be used for the treatment, diagnosis, and/or
prophylaxis of diseases or conditions where selectins mediated
leukocyte retention is involved, e.g. in lung diseases.
[0180] Another subject of this invention is a process for the
preparation of a polymorph according to claim 1 characterized in
that at least one of the following process is applied: [0181] a)
Dissolution of compound of formula (I) in water or in an organic
solvent or in a surfactant or in an ionic liquid or in a mixture of
any of the aforementioned media under exposure of heat followed by
precipitation or crystallization under cooling of the solution. or
[0182] b) Dissolution of compound of formula (I) in water or in an
organic solvent or in a surfactant or in an ionic liquid or in a
mixture of any of the aforementioned media under exposure of heat
followed by crystallization through evaporation. or [0183] c)
Dissolution of compound of formula (I) in a solvent followed by
fast precipitation or crystallization by addition of an anti
solvent to the solution. or [0184] d) Crystallization from a
solution of compound of formula (I) by addition of a seed crystal.
or [0185] e) Titration of compound of formula (I) with an aqueous
solution of a base (e.g. sodium hydroxide, potassium hydroxide,
sodium bicarbonate etc.) followed by treatment with an adsorbent
agent (e.g. functionalized resin, charcoal, fused alumina etc.)
followed by precipitation by addition of an aqueous solution of an
acid (e.g. hydrochloric acid, sulfuric acid etc.) or [0186] f)
Exposure of heat and/or pressure and/or vapor to compound of
formula (I).
[0187] The present invention also relates to a process for the
preparation of FORM 1 of compound of formula (I) characterized in
that the following process steps are applied: [0188] a) Add
compound of formula (I) to a mixture of water and a lower alcohol
(e.g. ethanol or isopropyl alcohol) in a reactor. [0189] b) Heat
the mixture to a temperature of about 10.degree. C. under its
atmospheric boiling point and stir until dissolution. [0190] c)
Cool the reaction mixture to a temperature between 0.degree. C. and
25.degree. C. and stir the reaction mixture between 0.degree. C.
and 25.degree. C. for 30 minutes up to 20 hours. [0191] d) Filter
the suspension. [0192] e) Wash the filter cake with a mixture of
water and a lower alcohol (e.g. ethanol or isopropyl alcohol)
previously cooled to a temperature between 0.degree. C. and
25.degree. C. [0193] f) Suspend the wet filter cake obtained from
the filtration in a mixture of water and a lower alcohol (e.g.
ethanol or isopropyl alcohol) in a reactor. [0194] g) Heat the
mixture to a temperature of about 10.degree. C. under its
atmospheric boiling point and stir until dissolution. [0195] h)
Transfer the reaction mixture from the reactor into another actor,
through a filter with a maximum porosity of 1 .mu.m. [0196] i) Wash
the filtration line with a mixture of water and a lower alcohol
(e.g. ethanol or isopropyl alcohol) previously heated to a
temperature of about 10.degree. C. under its atmospheric boiling
point. [0197] j) Concentrate the mixture, under vacuum. [0198] k)
Set the solution's Karl Fischer at a value between 30% and 60%, by
addition of water. [0199] l) Cool the reaction mixture to a
temperature between 0.degree. C. and 25.degree. C. and stir the
reaction mixture between 0.degree. C. and 25.degree. C. for 30
minutes up to 20 hours. [0200] m) Filter the suspension. [0201] n)
Wash the filter cake with a mixture of water and a lower alcohol
(e.g. ethanol or isopropyl alcohol) previously cooled to a
temperature between 0.degree. C. and 25.degree. C. [0202] o) Add
the filter cake from step 14 above into a reactor charged with
water. [0203] p) Add (in relation to the amount of compound of
formula (I)) at least 2 molar equivalents of a 1M aqueous solution
of sodium hydroxide, prepared by dissolution of pure sodium
hydroxide in water and stir the mixture until total dissolution.
[0204] q) Add an adsorbent agent (1 to 10 molar equivalents) to the
reaction mixture. [0205] r) Stir the reaction mixture until a
purity higher than or equal to 99.0% is reached (in process control
of purity by HPLC). [0206] s) Filter the reaction mixture, from the
reactor into another reactor, R2, through a filter, F1, with a
maximum porosity of 1 .mu.m. [0207] t) Wash the filter cake, with
water, passing the washings through F1 to R2. [0208] u) Charge a
mixture of water and a lower alcohol (e.g. ethanol or isopropyl
alcohol) into R2, through F1. [0209] v) Add (in relation to the
amount of sodium hydroxide in step 16) an equimolar amount of a
solution of hydrochloric acid. [0210] w) Cool the reaction mixture
to a temperature between 0.degree. C. and 25.degree. C. and stir
the reaction mixture between 0.degree. C. and 25.degree. C. for 30
minutes up to 20 hours. [0211] x) Filter the suspension. [0212] y)
Wash the filter cake with a mixture of water and a lower alcohol
(e.g. ethanol or isopropyl alcohol), previously filtered through
F1. [0213] z) Dry the product, under vacuum, at a temperature of
about 40.degree. C. to 60.degree. C. .degree. C., until water
content, by Karl Fischer, is less than 3% to obtain FORM 1 of
compound of formula (I).
[0214] The present invention also relates to a process for the
preparation of FORM 2 of compound of formula (I) characterized in
that the following process steps are applied: [0215] a) Add
compound of formula (I) to a mixture of water and a lower alcohol
(e.g. ethanol or isopropyl alcohol) in a reactor. [0216] b) Heat
the mixture to a temperature of about 10.degree. C. under its
atmospheric boiling point and stir until dissolution. [0217] c)
Cool the reaction mixture to a temperature between 0.degree. C. and
25.degree. C. and stir the reaction mixture between 0.degree. C.
and 25.degree. C. for 30 minutes up to 20 hours. [0218] d) Filter
the suspension. [0219] c) Wash the filter cake with a mixture of
water and a lower alcohol (e.g. ethanol or isopropyl alcohol)
previously cooled to a temperature between 0.degree. C. and
25.degree. C. [0220] f) Suspend the wet filter cake obtained from
the filtration in a mixture of water and a lower alcohol (e.g.
ethanol or isopropyl alcohol) in a reactor. [0221] g) Heat the
mixture to a temperature of about 10.degree. C. under its
atmospheric boiling point and stir until dissolution. [0222] h)
Transfer the reaction mixture from the reactor into another
reactor, through a filter with a maximum porosity of 1 .mu.m.
[0223] i) Wash the filtration line with a mixture of water and a
lower alcohol (e.g. ethanol or isopropyl alcohol) previously heated
to a temperature of about 10.degree. C. under its atmospheric
boiling point. [0224] j) Concentrate the mixture, under vacuum.
[0225] k) Set the solution's Karl Fischer at a value between 30%
and 60%, by addition of water. [0226] l) Cool the reaction mixture
to a temperature between 0.degree. C. and 25.degree. C. and stir
the reaction mixture between 0.degree. C. and 25.degree. C. for 30
minutes up to 20 hours. [0227] m) Filter the suspension. [0228] n)
Wash the filter cake with a mixture of water and a lower alcohol
(e.g. ethanol or isopropyl alcohol) previously cooled to a
temperature between 0.degree. C. and 25.degree. C. [0229] o) Dry
the product, under vacuum, at a temperature of about 40.degree. C.
to 60.degree. C., until water content, by Karl Fischer, is less
than 3% to obtain FORM 2 of compound of formula (I).
[0230] The present invention also relates to a process for the
preparation of FORM 3 of compound of formula (I) characterized in
that the following process steps are applied: [0231] A) Collect and
combine the filter liquor and washing solutions from the
preparation of FORM 2 above in a reactor R1. [0232] B) Concentrate
the mixture, under vacuum. [0233] C) Cool the reaction mixture to a
temperature between 0.degree. C. and 15.degree. C. and stir the
reaction mixture between 0.degree. C. and 15.degree. C. for up to 3
days in R1. [0234] D) Filter the suspension. [0235] E) Wash the
filter cake with a mixture of water and a lower alcohol (e.g.
ethanol or isopropyl alcohol) previously cooled to a temperature
between 0.degree. C. and 25.degree. C. [0236] F) Dry the product,
under vacuum, at a temperature of about 40.degree. C. to 60.degree.
C., until water content, by Karl Fischer, is less than 3% to obtain
FORM 3 of compound of formula (I).
[0237] X-ray diffraction investigations of the polymorphic forms,
FORM 1, FORM 2, and FORM 3 The X-ray diffraction diagrams of FORM
1, FORM 2, and FORM 3 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) according to the invention were
produced from crystal powders on a Stoe Powder Diffraction System,
Type P (transmission geometry) (STOE & Cie GmbH, Darmstadt,
Germany) using Cu K.sub..alpha.1 radiation.
[0238] Below, the X-ray reflections are listed in the form that the
diffraction angle 2Theta (=2.THETA. or 2.theta.) in degrees
(.degree.) is indicated at which the X-ray diffraction reflection
occurs, and behind it in brackets the relative intensity of the
reflection in percent of the intensity of the strongest reflection
whose intensity was set equal to 100%. The relative intensities are
rounded to a multiple of 0.5% of the intensity of the strongest
reflection. These rounded relative intensities also form the basis
for is the division into strong and medium-strong X-ray reflections
carried, out above and in the claims. The diffraction angles are
rounded to a multiple of 0.5.degree..
a) X-Ray reflections of FORM 1 of compound of formula (I) (2Theta
[.degree.] (relative intensity [%]))
[0239] 4.8.degree. (100.0%), 11.4.degree. (4.6%), 11.6.degree.
(6.5%), 11.6.degree. (6.5%), 11.8.degree. (5.7%), 11.9.degree.
(5.0%), 12.1.degree. (4.5%), 12.2.degree. (4.1%), 12.5.degree.
(4.0%), 12.6.degree. (3.8%), 13.1.degree. (3.7%), 13.3.degree.
(4.2%), 13.4.degree. (4.3%), 13.6.degree. (4.5%), 14.0.degree.
(3.5%), 14.3.degree. (3.5%), 14.6.degree. (3.5%), 14.7.degree.
(3.5%), 15.1.degree. (3.1%), 15.4.degree. (3.5%), 15.5.degree.
(3.3%), 15.9.degree. (3.5%), 16.4.degree. (8.3%), 16.6.degree.
(17.7%), 16.8.degree. (15.1%), 17.1.degree. (4.9%), 17.3.degree.
(4.1%), 17.6.degree. (4.5%), 17.7.degree. (6.7%), 18.1.degree.
(4.5%), 18.1.degree. (4.3%), 18.3.degree. (3.7%), 19.6.degree.
(3.5%), 19.7.degree. (3.4%), 19.8.degree. (3.0%), 20.1.degree.
(3.8%), 20.1.degree. (3.8%), 20.2.degree. (3.8%), 20.6.degree.
(4.8%), 20.7.degree. (5.8%), 20.9.degree. (3.9%), 21.2.degree.
(3.1%), 21.6.degree. (3.3%), 21.7.degree. (3.3%), 21.8.degree.
(3.0%), 22.8.degree. (4.0%), 22.9.degree. (3.9%), 23.2.degree.
(5.3%), 23.3.degree. (5.7%), 23.4.degree. (5.6%), 23.8.degree.
(3.2%), 24.1.degree. (3.8%), 24.2.degree. (3.8%), 24.6.degree.
(7.0%), 26.0.degree. (7.4%), 26.0.degree. (7.0%), 26.2.degree.
(5.9%), 27.2.degree. (2.9%), 32.9.degree. (1.6%), 33.0.degree.
(2.1%), 33.1.degree. (1.9%), 34.7.degree. (2.2%), 34.8.degree.
(2.2%), 35.1.degree. (2.3%), 35.2.degree. (2.2%), 35.4.degree.
(2.3%), 35.5.degree. (2.3%), 37.0.degree. (2.5%), 37.1.degree.
(2.3%), 37.2.degree. (1.9%), 37.8.degree. (1.6%), 37.9.degree.
(1.6%), 42.2.degree. (1.9%), 42.4.degree. (2.4%), 42.5.degree.
(2.2%), 42.6.degree. (1.9%), 48.9.degree. (1.6%), 49.0.degree.
(1.6%).
[0240] b) X-Ray reflections of FORM 2 of compound of formula (I)
(2Theta [.degree.](relative intensity [%]))
[0241] 5.3.degree. (55.6%), 5.6.degree. (100.0%), 7.2.degree.
(12.8%), 9.4.degree. (11.6%), 9.8.degree. (11.5%), 9.9.degree.
(18.3%), 10.3.degree. (29.0%), 10.6.degree. (13.5%), 11.1.degree.
(9.4%), 11.7.degree. (12.7%), 12.8.degree. (12.4%), 13.0.degree.
(10.3%), 13.8.degree. (40.2%), 14.6.degree. (11.4%), 15.1.degree.
(28.9%), 15.4.degree. (13.2%), 15.6.degree. (13.2%), 15.8.degree.
(10.7%), 15.9.degree. (12.3%), 16.3.degree. (29.2%), 16.6.degree.
(42.0%), 17.0.degree. (8.5%), 17.4.degree. (50.9%), 17.8.degree.
(10.7%), 18.8.degree. (47.1%), 19.1.degree. (30.7%), 19.2.degree.
(17.6%), 19.8.degree. (15.3%), 20.0.degree. (14.3%), 20.1.degree.
(19.6%), 20.4.degree. (17.2%), 20.7.degree. (26.7%), 21.1.degree.
(8.4%), 21.5.degree. (45.1%), 21.9.degree. (10.5%), 22.1.degree.
(7.2%), 22.2.degree. (10.0%), 22.6.degree. (7.4%), 23.3.degree.
(8.7%), 23.6.degree. (9.6%), 23.8.degree. (7.3%), 23.9.degree.
(9.4%), 24.3.degree. (15.2%), 24.6.degree. (8.6%), 24.8.degree.
(19.4%), 25.0.degree. (13.1%), 25.5.degree. (15.7%), 25.7.degree.
(11.7%), 25.8.degree. (9.8%), 26.3.degree. (10.1%), 26.5.degree.
(22.0%), 26.8.degree. (9.0%), 27.0.degree. (8.3%), 27.2.degree.
(6.3%), 27.4.degree. (7.0%), 27.7.degree. (8.4%), 27.9.degree.
(8.5%), 28.3.degree. (7.7%), 28.7.degree. (7.1%), 28.9.degree.
(5.1%), 29.7.degree. (5.1%), 30.2.degree. (6.1%), 30.8.degree.
(5.5%), 31.2.degree. (5.2%), 31.8.degree. (6.0%), 32.2.degree.
(9.2%), 32.4.degree. (3.9%), 32.5.degree. (4.0%), 3.6.degree.
(5.9%), 34.0.degree. (6.0%), 34.3.degree. (5.3%), 34.8.degree.
(4.3%), 34.8.degree. (3.6%), 35.2.degree. (6.7%), 35.5.degree.
(4.7%), 35.8.degree. (4.6%), 36.2.degree. (4.5%), 36.4.degree.
(5.2%), 36.8.degree. (3.9%), 37.0.degree. (4.8%), 37.4.degree.
(7.5%), 37.7.degree. (9.7%), 37.8.degree. (8.9%), 38.1.degree.
(4.9%), 38.4.degree. (4.9%), 38.7.degree. (4.2%), 38.9.degree.
(6.1%), 39.1.degree. (5.0%), 39.8.degree. (6.0%), 40.1.degree.
(4.1%), 40.2.degree. (4.2%), 40.6.degree. (5.9%), 40.7.degree.
(5.2%), 41.4.degree. (4.6%), 42.0.degree. (4.3%), 42.6.degree.
(3.9%), 43.6.degree. (4.0%), 43.8.degree. (3.4%), 44.4.degree.
(4.6%), 44.8.degree. (3.2%), 45.2.degree. (3.1%), 46.2.degree.
(3.1%), 46.6.degree. (2.9%), 47.0.degree. (2.6%), 47.8.degree.
(3.3%), 48.1.degree. (3.4%), 48.5.degree. (3.7%), 48.7.degree.
(3.4%), 49.0.degree. (4.0%).
c) X-Ray reflections of FORM 3 of compound of formula (I) (2Theta
[.degree.] (relative intensity [%]))
[0242] 4.2.degree. (17.6%), 4.3.degree. (20.6%), 4.8.degree.
(29.1%), 5.3.degree. (56.0%), 5.6.degree. (100.0%), 7.3.degree.
(15.3%), 9.4.degree. (14.3%), 9.9.degree. (20.6%), 10.3.degree.
(30.7%), 10.6.degree. (16.4%), 11.7.degree. (17.7%), 12.8.degree.
(14.4%), 12.9.degree. (13.4%), 13.8.degree. (37.9%), 14.1.degree.
(11.0%), 14.6.degree. (13.4%), 15.1.degree. (29.1%), 15.4.degree.
(14.5%), 15.7.degree. (14.4%), 15.9.degree. (14.3%), 16.3.degree.
(30.4%), 16.6.degree. (44.4%), 16.9.degree. (15.8%), 17.4.degree.
(48.6%), 17.8.degree. (13.6%), 18.8.degree. (46.0%), 19.1.degree.
(32.0%), 19.3.degree. (18.9%), 19.8.degree. (17.4%), 20.0.degree.
(17.9%), 20.1.degree. (21.7%), 20.4.degree. (18.5%), 20.7.degree.
(29.1%), 20.9.degree. (8.6%), 21.1.degree. (10.3%), 21.6.degree.
(47.7%), 21.9.degree. (12.4%), 22.2.degree. (11.3%), 22.6.degree.
(9.1%), 22.7.degree. (9.2%), 22.9.degree. (7.5%), 23.3.degree.
(10.8%), 23.5.degree. (11.1%), 23.9.degree. (11.2%), 24.3 (16.3%),
24.4.degree. (10.4%), 24.8.degree. (20.2%), 25.0.degree. (14.3%),
5.5.degree. (17.0%), 25.7.degree. (13.0%), 25.9.degree. (11.0%),
26.3.degree. (12.8%), 26.5.degree. (25.1%), 26.7.degree. (10.3%),
26.8.degree. (10.6%), 27.0.degree. (10.4%), 27.2.degree. (7.8%),
27.4.degree. (8.5%), 27.7.degree. (9.8%), 27.9.degree. (9.6%),
28.3.degree. (9.0%), 28.7.degree. (8.0%), 28.9.degree. (6.2%),
29.1.degree. (5.4%), 29.3.degree. (5.2%), 29.7.degree. (5.9%),
29.8.degree. (6.1%), 30.2.degree. (7.1%), 30.6.degree. (4.6%),
30.8.degree. (6.4%), 31.1.degree. (5.9%), 31.6.degree. (5.5%),
31.8.degree. (7.1%), 32.2.degree. (9.9%), 32.5.degree. (5.0%),
33.0.degree. (4.7%), 33.6.degree. (6.7%), 33.7.degree. (5.8%),
34.0.degree. (6.6%), 34.3.degree. (6.2%), 34.8.degree. (5.2%),
34.8.degree. (5.1%), 35.1.degree. (5.5%), 35.2.degree. (7.7%),
35.5.degree. (5.9%), 35.7.degree. (5.4%), 35.8.degree. (5.8%),
36.3.degree. (5.8%), 36.4.degree. (5.8%), 36.7.degree. (4.8%),
37.0.degree. (5.8%), 37.1.degree. (5.4%), 37.4.degree. (8.2%),
37.7.degree. (10.4%), 37.8.degree. (10.1%), 38.1.degree. (5.6%),
38.3.degree. (5.8%), 38.5.degree. (4.7%), 38.7.degree. (4.9%),
38.8.degree. (7.0%), 39.1.degree. (5.6%), 39.8.degree. (6.5%).
[0243] X-ray diffraction investigations of the polymorphic forms,
FORM 4, FORM 5, and FORM 6 The X-ray diffraction diagrams of FORM
4, FORM 5 and FORM 6 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) according to the invention were
collected on a Siemens D5000 diffractometer using Cu K.sub..alpha.1
radiation (40 kV, 40 mA), .THETA.-.THETA. goniometer, V20 variable
divergence and receiving slits, a graphite secondary monochromator
and scintillation counter.
[0244] Below, the X-ray reflections are listed in the form that the
diffraction angle 2Theta (=2.THETA. or 2.theta.) in degrees
(.degree.) is indicated at which the X-ray diffraction reflection
occurs, and behind it in brackets the relative intensity of the
reflection in percent of the intensity of the strongest reflection
whose intensity was set equal to 100%. The relative intensities are
rounded to a multiple of 0.5% of the intensity of the strongest
reflection. These rounded relative intensities also form the basis
for is the division into strong and medium-strong X-ray reflections
carried out above and in the claims. The diffraction angles are
rounded to a multiple of 0.5.degree..
[0245] a) X-ray reflections of FORM 4 of compound of formula (I)
(2Theta [.degree.] (relative intensity [%]))
[0246] 4.1.degree. (17.3%), 4.2.degree. (42.1%), 4.3.degree.
(52.9%), 4.4.degree. (44.3%), 4.5.degree. (21.2%), 4.6.degree.
(12.3%), 4.7.degree. (10.5%), 4.8.degree. (9.7%), 8.4.degree.
(9.7%), 8.5.degree. (11.6%), 8.6.degree. (7.3%), 11.4.degree.
(10.4%), 11.5.degree. (19.7%), 11.6.degree. (28.6%), 11.7.degree.
(31.2%), 11.8.degree. (27.3%), 11.9.degree. (24.1%), 12.0.degree.
(16.7%), 12.1.degree. (13.4%), 12.2.degree. (13.0%), 12.3.degree.
(11.0%), 12.4.degree. (9.7%), 12.5.degree. (8.9%), 16.1.degree.
(10.9%), 16.2.degree. (14.1%), 16.3.degree. (21.1%), 16.4.degree.
(36.9%), 16.5.degree. (58.1%), 16.6.degree. (79.9%), 16.7.degree.
(95.9%), 16.8.degree. (100.0%), 16.9.degree. (92.0%), 17.0.degree.
(70.2%), 17.1.degree. (47.1%), 17.2.degree. (31.5%), 17.3.degree.
(22.3%), 17.4.degree. (17.3%), 17.7.degree. (15.7%), 17.8.degree.
(20.8%), 17.9.degree. (23.5%), 18.0.degree. (26.2%), 18.1.degree.
(27.6%), 18.2.degree. (29.5%), 18.3.degree. (26.0%), 18.4.degree.
(20.6%), 19.0.degree. (21.3%), 19.1.degree. (25.4%), 19.2.degree.
(28.6%), 19.3.degree. (31.3%), 19.4.degree. (34.5%), 19.5.degree.
(38.0%), 19.6.degree. (40.2%), 19.7.degree. (43.4%), 19.8.degree.
(42.5%), 19.9.degree. (40.0%), 20.0.degree. (37.7%), 20.1.degree.
(31.4%), 0.2.degree. (26.7%), 21.2.degree. (26.3%), 21.3.degree.
(31.9%), 21.4.degree. (33.4%), 21.5.degree. (37.0%), 21.6.degree.
(34.4%), 21.7.degree. (28.9%), 21.8.degree. (23.9%), 25.4.degree.
(24.5%), 25.5.degree. (24.6%), 25.6.degree. (26.2%), 25.7.degree.
(28.0%), 25.8.degree. (31.4%), 25.9.degree. (34.1%), 26.0.degree.
(40.7%), 26.1.degree. (45.2%), 26.2.degree. (50.9%), 26.3.degree.
(56.4%), 26.4.degree. (62.5%), 26.5.degree. (64.2%), 26.6.degree.
(60.2%), 26.7.degree. (54.2%), 26.8.degree. 46.5%), 26.9.degree.
(38.6%), 27.0.degree. (33.7%), 27.1.degree. (31.3%), 27.2.degree.
(29.5%), 27.3.degree. (25.5%), 27.4.degree. 23.0%), 27.5.degree.
(21.4%).
[0247] b) X-ray reflections of FORM 5 of compound of formula (I)
(2Theta [.degree.] (relative intensity [%]))
[0248] 5.0.degree. (7.5%), 5.1.degree. (33.1%), 5.2.degree.
(68.2%), 5.3.degree. (63.0%), 5.4.degree. (32.0%), 5.5.degree.
(66.6%), 5.6.degree. (70.4%), 5.7.degree. (32.5%), 9.2.degree.
(6.9%), 9.3.degree. (8.3%), 9.4.degree. (5.6%), 9.7.degree. (7.0%),
9.8.degree. (12.0%), 9.9.degree. (13.2%), 10.0.degree. (10.6%),
10.1.degree. (22.2%), 10.2.degree. (28.2%), 10.3.degree. (21.7%),
10.4.degree. (14.7%), 10.5.degree. (17.4%), 10.6.degree. (12.2%),
10.7.degree. (6.1%), 11.4.degree. (5.3%), 11.5.degree. (9.9%),
11.6.degree. (14.4%), 11.7.degree. (13.0%), 11.8.degree. (6.8%),
12.6.degree. (6.5%), 12.7.degree. (6.3%), 13.6.degree. (9.7%),
13.7.degree. (13.6%), 13.8.degree. (12.8%), 14.4.degree. (12.4%),
14.5.degree. (14.8%), 14.6.degree. (9.9%), 14.9.degree. (13.9%),
15.0.degree. (17.0%), 15.1.degree. (14.1%), 15.6.degree. (10.1%),
15.7.degree. (18.4%), 15.8.degree. (24.3%), 15.9.degree. (21.6%),
16.0.degree. (13.7%), 16.1.degree. (13.8%), 16.2.degree. (17.4%),
16.3.degree. (22.8%), 16.4.degree. (36.7%), 16.5.degree. (45.7%),
16.6.degree. (40.7%), 16.7.degree. (24.6%), 16.8.degree. (12.9%),
17.0.degree. (11.5%), 17.1.degree. (20.6%), 17.2.degree. 31.0%),
17.3.degree. (33.1%), 17.4.degree. (23.2%), 17.5.degree. (15.1%),
18.4.degree. (15.8%), 18.5.degree. (30.2%), 18.6.degree. 45.4%),
18.7.degree. (47.4%), 18.8.degree. (36.8%), 18.9.degree. (29.8%),
19.0.degree. (28.2%), 19.1.degree. (25.6%), 19.2.degree. (19.2%),
19.3.degree. (13.7%), 19.5.degree. (12.5%), 19.6.degree. (17.7%),
19.7.degree. (28.7%), 19.8.degree. (37.8%), 19.9.degree. (47.0%),
20.0.degree. (49.5%), 20.1.degree. (43.9%), 20.2.degree. (34.5%),
20.3.degree. (31.2%), 20.4.degree. 39.4%), 20.5.degree. (46.5%),
20.6.degree. (47.0%), 20.7.degree. (35.6%), 21.0.degree. (24.0%),
21.1.degree. (28.0%), 21.2.degree. 48.8%), 21.3.degree. (85.8%),
21.4.degree. (100.0%), 21.5.degree. (90.4%), 21.6.degree. (54.2%),
21.7.degree. (32.5%), 21.8.degree. (28.5%), 21.9.degree. (26.7%),
22.0.degree. (22.1%), 22.1.degree. (18.7%), 22.2.degree. (17.5%),
22.3.degree. (14.6%), 22.4.degree. (13.9%), 22.5.degree. (14.6%),
22.6.degree. (12.6%), 22.7.degree. (11.0%), 22.8.degree. (10.4%),
23.0.degree. (13.3%), 23.1.degree. (17.3%), 23.2.degree. (22.6%),
23.3.degree. (29.3%), 23.4.degree. (31.1%), 23.5.degree. (29.2%),
23.6.degree. (23.9%), 23.7.degree. (23.7%), 23.8.degree. (23.0%),
24.3.degree. (20.6%), 24.4.degree. (22.2%), 24.5.degree. (22.4%),
24.6.degree. (22.9%), 24.7.degree. (22.9%), 24.8.degree. (24.0%),
24.9.degree. (20.9%), 25.4.degree. (16.3%), 25.5.degree. (17.1%),
25.6.degree. (16.5%), 26.0.degree. (19.5%), 26.1.degree. (25.5%),
26.2.degree. (29.5%), 26.3.degree. (30.0%), 26.4.degree. (24.1%),
26.6.degree. (21.8%), 27.1.degree. (20.2%), 27.2.degree. (21.4%),
27.3.degree. (21.0%), 27.4.degree. (18.4%), 27.5.degree. (15.9%),
27.6.degree. (12.6%), 27.7.degree. (12.6%), 28.1.degree. (12.9%),
28.2.degree. (14.0%), 28.3.degree. (14.9%), 28.4.degree. (14.6%),
28.5.degree. (14.2%), 28.7.degree. (11.8%), 29.4.degree. (8.7%),
29.5.degree. (9.5%), 29.6.degree. (8.2%).
[0249] c) No crystalline solid was observed. X-ray diffraction
diagram of FORM 6 of compound of formula (I) shows a broad peak
(2Theta) at 19.6.degree..
ATR-FT-IR Investigations of the Polymorphic Forms
[0250] The IR spectra of FORM 1, FORM 2 and FORM 3 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) according to the invention were
produced from an attenuated total reflectance Fourier transform
infra red spectrometer Spectrum One (Perkin Elmer Instruments GmbH,
Rodgau-Juegesheim, Germany). For IR measurement Sing of solid
sample were placed on the top of the ATR probe head and slightly
pressed by the adjusting screw onto the diamond window of the probe
head. Below, the IR bands are listed within a range of 4000
cm.sup.-1 and 550 cm.sup.-1 in the form that the wave numbers are
indicated at which an IR transmission occurs, and behind it in
brackets the relative intensity of the transmission in percent
compared to total transmission (100%). The relative intensities are
rounded to a multiple of 0.1%. A threshold of 2% is applied; 4 IR,
scans were applied per run. The wave numbers are rounded to a
multiple of 1 cm.sup.-1.
[0251] a) Main wave numbers of FORM 1 of compound of formula (I)
(.nu. [cm.sup.-1] (relative intensity [%]))
[0252] 3404 (64.5), 2931 (64.0), 1707 (41.3), 1608 (70.0), 1500
(62.0) 1479 (61.6), 1445 (66.3), 1435 (66.7), 1400 (62.9), 1358
(67.0), 1272 (60.0), 1245 (53.8), 1228 (52.5), 1166 (70.1), 1136
(49.1), 1095 (57.4), 1050 (44.3), 1004 (54.5), 977 (39.8), 930
(67.3), 915 (66.2), 900 (65.3), 854 (69.2), 828 (63.8), 818 (52.8),
801 (58.0), 770 (69.8), 725 (68.8), 706 (61.4), 690 (57.1), 615
(60.1), 602 (67.0), 595 (68.5), 591 (64.7), 586 (61.0), 579 (67.4),
573 (64.0), 568 (70.3), 563 (69.5), 557 (72.6).
[0253] b) Main wave numbers of FORM 2 of compound of formula (I)
(.nu. [cm.sup.-1] (relative intensity [%]))
[0254] 3246 (67.2), 2933 (71.8), 2857 (75.1) 1728 (57.3), 1601
(75.4), 1499 (67.4), 1478 (62.8), 1459 (69.9), 1402 (73.0), 1323
(73.1), 1226 (46.5), 1148 (69.4), 1119 (55.4), 1096 (59.6), 1077
(56.4), 1066 (44.0), 1048 (51.8), 1017 (31.2), 997 (52.7), 982
(45.7), 920 (73.7), 899 (75.4), 875 (73.4), 843 (67.1), 826 (68.9),
817 (71.2), 800 (52.7), 785 (74.4), 759 (77.0), 747 (73.6), 720
(66.3), 704 (62.6), 686 (53.6), 660 (65.2), 640 (66.9), 627 (70.4),
605 (55.1), 580 (74.9), 575 (78.5), 568 (73.3), 561 (77.4), 555
(76.2).
[0255] c) Main wave numbers of FORM 6 of compound of formula (I)
(.nu. [cm.sup.-1] (relative intensity [%])) 3387 (88.6%), 2928
(87.5%), 2855 (91.4%), 1710 (82.4%), 1.607 (94.0%), 1500 (87.9%),
1478 (85.9%), 1367 (88.0%), 1223 (73.8%), 1115 (74.8%), 1065
(73.6%), 1048 (75.9%), 1010 (64.5%), 977 (68.0%), 908 (84.0%), 890
(82.7%), 848 (85.1%), 821 (81.2%), 797 (79.1%), 779 (84.6%), 771
(86.0%), 762 (86.7%), 752 (86.0%), 745 (85.5%), 736 (85.5%), 727
(84.1%), 719 (84.2%), 703 (75.1%), 685 (77.0%), 677 (77.5%), 668
(78.8%), 659 (80.5%).
Thermodynamic Solubility Investigations with the Polymorphic Forms
in Organic Solvents
[0256] The thermodynamic solubility of FORM 1, FORM 2, FORM 4, and
FORM 6 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was determined in several organic
solvents by suspending sufficient compound to give a maximum final
concentration. Quantification was by reverse phase HPLC with
gradient solution with reference to a standard solution of FORM B
of the compound of formula (I) at 0.25 mg/mi. The suspensions were
equilibrated at 27.degree. C. for 24 hours with shaking. All
suspensions were filtered though a glass fibre C filter. The
filtrate was then diluted by an appropriate factor in 50:50
ethanol:water apart from isopropyl myristate which was diluted in
ethanol to avoid emulsion formation.
[0257] Solubilities were calculated using the peak areas determined
by the peak found at the same retention time as the principal peak
in the standard injection. The following Table summarizes the
results:
TABLE-US-00001 TABLE EtOH IPA Triacetin Propylene Glycol PEG 300
FORM mg/ml FORM mg/ml FORM mg/ml FORM mg/ml FORM mg/ml 4 48 6 27 1
0.056 1 188 1 205 6 20 1 3.9 4 0.02 6 170 4 159 1 4.2 4 1.2 2
0.0083 4 165 6 122 2 4.2 2 0.52 6 N/A 2 104 2 102 mg/ml: Solubility
in mg/ml; N/A not available: EtOH: Ethanol; IPA: Isopropyl alcohol;
Triacetin: glycerin triacetate; PEG 300: Polyethylene glycol
300.
[0258] FORM 4 has highest solubility in ethanol, FORM 6 in IPA, and
FORM 1 in Triacetin, propylene glycol, and PEG 300. Polymorphic
conversions in the various solvents may, at least in part, impact
the solubility values obtained in this study.
Thermodynamic Solubility Investigations with the Polymorphic Forms
in Water
[0259] The thermodynamic solubility of FORM 1, FORM 2, and FORM 3
of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phen-
yl]hexane (compound of formula (I)) was determined in water by
employing the shake flask technique. The sample was added to pure
water in a Safelock-tube (Eppendorf, Germany) under vigorous
shaking until a white precipitate was formed. The saturated
solution was incubated over night at 25.degree. C. in an Eppendorf
Thermomixer operated at 700 RPM. The suspension was cleared by
centrifugation at 13.000 RPM at room temperature, and the
supernatant was carefully collected. The supernatant was further
purified by vacuum-filtration through a Millipore solubility filter
plate (Millipore, Molsheim, France).
[0260] The UV absorption of the filtrate was measured against pure
water using a Spectramax250 (Molecular Devices, Sunnyvale, Calif.)
operated with Softmax Pro v. 4.8 software, using the application
"Mscreen solubility quantify" in the ADME package. The sample
concentration was calculated using a 5-point linear calibration
line of the compound of formula (I) in acetonitrile:pure water (1:1
vol:vol). Measurements have been performed in triplicate.
[0261] The following solubilities in mg/L obtained are shown in the
Table:
TABLE-US-00002 TABLE FORM 1: 22 mg/L FORM 2: 15 mg/L FORM 3: 14
mg/L
[0262] Differential Scanning Calorimetry (DSC)
[0263] DSC data for FORM 1, FORM 2, FORM 3, FORM 4, FORM 5, and
FORM 6 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phen-
yl]hexane (compound of formula (I)) were collected on a TA
Instruments Q1000 equipped with a 50 position autosampler. The
instrument was calibrated for energy and temperature calibration
using certified indium. Typically 0.5-3 mg of each sample, in a
pin-holed aluminum pan, was heated at 10.degree. C./min. from
25.degree. C. to 235.degree. C. A nitrogen purge at 30 ml/min, was
maintained over the sample.
a) FORM 1 of Compound of Formula (I)
[0264] A single endotherm peak with onset at 136.degree. C. was
observed (FIG. 7).
b) FORM 2 of Compound of Formula (I)
[0265] A shallow endotherm peak at ca. 75.degree. C. and an
endotherm peak with onset at 158.degree. C. was observed (FIG.
8).
c) FORM 3 of Compound of Formula (I)
[0266] Three endotherm peaks were observed. The first peak occurs
at approximately 74.degree. C., followed by two peaks with onset at
138.degree. and 158.degree. C. (see FIG. 9).
d) FORM 4 of Compound of Formula (I)
[0267] Two endotherm peaks were observed, one with onset at
39.degree. C. followed by the melt at 132.degree. C. (FIG. 10).
e)
f) FORM 5 of Compound of Formula (I)
[0268] Thermal analysis showed a single melt onset at 158.degree.
C. (FIG. 11).
f) FORM 6 of Compound of Formula (I)
[0269] Thermal analysis showed a broad endotherm peak at
40-80.degree. C. (FIG. 12).
Thermo-Gravimetric Analysis (TGA)
[0270] TGA data were collected for FORM 1, FORM 2, FORM 3, FORM 4,
and FORM 6 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) on a TA Instruments Q500 TGA, equipped
with a 16 position autosampler. The instrument was temperature
calibrated using certified Alumel. Typically 5-30 mg of each sample
was loaded onto a pre-tared platinum crucible and aluminum DSC pan,
wad was heated at 10.degree. C./min from ambient temperature to
350.degree. C. A nitrogen purge at 60 ml/min was maintained over
the sample.
a) FORM 1 of Compound of Formula (I)
[0271] The thermal analysis of FORM 1 showed no weight loss prior
to degradation at high temperatures (FIG. 13).
b) FORM 2 of Compound of Formula (I)
[0272] Thermal analysis of FORM 2 showed the material was solvated
as there was a weight loss of 2.1% at about 75.degree. C. (FIG.
14).
c) FORM 3 of Compound of Formula (I)
[0273] Thermal analysis of FORM 3 showed the material was solvated
as there was a weight loss of 1.8% at about 57.degree. C. (FIG.
15).
d) FORM 4 of Compound of Formula (I)
[0274] Thermal analysis of FORM 4 suggested that FORM 4 is a
hydrate as the TGA thermogram showed a weight loss of 6.2% which
represents ca. 3 molecules of water (5.9% theoretical value)
indicating a trihydrate (FIG. 16). This assumption is supported by
the results of the Karl Fischer titration.
e) FORM 6 of Compound of Formula (I)
[0275] Thermal analysis suggested that FORM 6 is a solvate as there
was a weight loss of about 2.9% between 32-71.degree. C. A second
weight loss of about 23% between 70-110.degree. C. is observed.
(FIG. 17).
Water Determination by Karl Fischer
[0276] The content of water of FORM 2 and FORM 4 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was determined by employing the Karl
Fischer method on a Mettler Toledo DL39 Coulometer using Hydranal
Coulomat AG reagent and an argon purge. Weighed solid samples were
introduced into the vessel on a platinum TGA you which was
connected to a subseal to avoid water ingress. Approximately 10 mg
of sample was used per titration and duplicate determinants were
made.
a) FORM 2 of Compound of Formula (I)
[0277] A water content of 2.2% was observed. Taking the results of
the TGA and DSC analysis into account, FORM 2 is considered to
represent a monohydrate of the compound of formula (I).
b) FORM 4 of Compound of Formula (I)
[0278] A water content of 6.9% was observed. Taking the results of
the TGA and DSC analysis into account, FORM 2 is considered to
represent a trihydrate the compound of formula (I).
Melting Points of the Polymorphic Forms
[0279] A capillary melting point was determined for FORM 1, FORM 2,
and FORM 3 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) using standard methods known to the
person skilled in the art.
[0280] The melting points of FORM 4, FORM 5 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) were determined by the DSC method.
a) FORM 1 of Compound of Formula (I)
[0281] On average, FORM 1 of compound of formula (I) shows melting
in the following temperature range: 134.degree. C.-139.degree.
C.
b) FORM 2 of Compound of Formula (I)
[0282] On average, FORM 2 of compound of formula (I) shows melting
in the following temperature range: 158.degree. C.-161.degree.
C.
c) FORM 3 of Compound of Formula (I)
[0283] On average, FORM 3 of compound of formula (I) shows melting
in the following temperature range: 161.degree. C.-165.degree.
C.
d) FORM 4 of Compound of Formula (I)
[0284] After loss of water FORM 4 melted at 132.degree. C. In order
to prevent loosing water before melting, the DSC experiment was
conducted in a hermetic pan. A melting point of FORM 4 at
86.degree. C. was determined.
e) FORM 5 of Compound of Formula (I)
[0285] FORM 5 of compound of formula (I) shows melting at
158.degree. C.
[0286] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments,
which are given for illustration of the invention.
[0287] In the Figures enclosed to this application describe the
crystalline modifications more in detail.
[0288] FIG. 1 shows the crystalline modification of Form 1 with the
Relative Intensity (in %) shown as a function of 2Theta.
[0289] FIG. 2 shows the crystalline modification of Form 2 with the
Relative Intensity (in %) shown as a function of 2Theta.
[0290] FIG. 3 shows the crystalline modification of Form 3 with the
Relative Intensity (in %) shown as a function of 2Theta.
[0291] FIG. 4 shows the crystalline modification of Form 4 with the
Relative Intensity (in %) shown as a function of 2Theta.
[0292] FIG. 5 shows the crystalline modification of Form 5 with the
Relative Intensity (in %) shown as a function of 2Theta.
[0293] FIG. 6 shows the modification of Form 6 with the Relative
Intensity (in %) shown as a function of 2Theta.
[0294] FIG. 7 shows the Differential Scanning calorimetry (DSC) of
Form 1.
[0295] The Heat Flow (in W/g) is shown as a function of temperature
(in .degree. C.).
[0296] FIG. 8 shows the Differential Scanning calorimetry (DSC) of
Form 2
[0297] FIG. 9 shows the Differential Scanning calorimetry (DSC) of
Form 3
[0298] FIG. 10 shows the Differential Scanning calorimetry (DSC) of
Form 4
[0299] FIG. 11 shows the Differential Scanning calorimetry (DSC) of
Form 5
[0300] FIG. 12 shows the Differential Scanning calorimetry (DSC) of
Form 6
[0301] FIG. 13 shows the results of a Thermo-Gravimetric Analysis
(TGA) of Form 1
[0302] The weight (in %) is shown as a function of temperature (in
.degree. C.).
[0303] FIG. 14 shows the results of a Thermo-Gravimetric Analysis
(TGA) of Form 2
[0304] FIG. 15 shows the results of a Thermo-Gravimetric Analysis
(TGA) of Form 3
[0305] FIG. 16 shows the results of a Thermo-Gravimetric Analysis
(TGA) of Form 4
[0306] FIG. 17 shows the results of a Thermo-Gravimetric Analysis
(TGA) of Form 6.
EXAMPLE 1
Generation of FORM 1 of Compound of Formula (I)
[0307] The following process steps are applied: [0308] 1. Charge
isopropyl alcohol and water into a reactor, R1. [0309] 2. Add, with
stirring, compound of formula (I). [0310] 3. Heat the reaction
mixture to about 45.degree. C. to 60.degree. C. [0311] 4. Stir the
reaction mixture at about 45.degree. C. to 60.degree. C. until
dissolution. [0312] 5. Cool the reaction mixture to 10.degree.
C./20.degree. C. for at least 60 to 120 minutes. [0313] 6. Stir the
reaction mixture at 15.degree. C./20.degree. C. for at least 90 to
150 minutes. [0314] 7. Filter the suspension. [0315] 8. Wash the
filter cake twice with a mixture of isopropyl alcohol and water,
previously cooled to a temperature between 20.degree. C. and
10.degree. C. [0316] 9. Charge isopropyl alcohol and water into R1.
[0317] 10. Suspend the wet product, obtained from the filtration,
in R1. [0318] 11. Heat the reaction mixture to about 45.degree. C.
to 60.degree. C. [0319] 12. Stir the reaction mixture at about
45.degree. C. to 60.degree. C. until dissolution. [0320] 13.
Transfer the reaction mixture from R1 to a reactor, R2, through a
filter with a maximum is porosity of 1 .mu.m. [0321] 14. Wash the
filtration line with a mixture of isopropyl alcohol and water,
previously heated to about 45.degree. C. to 60.degree. C. [0322]
15. Concentrate the reaction mixture, under vacuum. [0323] 16. Set
the solution's Karl Fischer at a value of 40% to 50%, by addition
of water. [0324] 17. Cool the reaction mixture to 10.degree.
C./20.degree. C. for at least 60 to 120 minutes. [0325] 18. Stir
the reaction mixture at 10.degree. C./20.degree. C. for at least 90
to 150 minutes. [0326] 19. Filter the suspension. [0327] 20. Wash
the filter cake twice with a mixture of isopropyl alcohol and
water, previously cooled to a temperature between 10.degree. C. and
20.degree. C. [0328] 21. Dry the product, under vacuum, at a
temperature of about 50.degree. C., until water content, by Karl
Fischer, is less than 1.5%.
[0329] With the above procedure compound of formula I is obtained
with a HPLC measured purity of more than 80%. [0330] 1. Charge
water into a reactor, R1. [0331] 2. Add, with stirring, dried
product from step 21 above. [0332] 3. Add (in relation to the
amount of compound of formula (I)) at least 2 molar equivalents of
a 1M aqueous solution of sodium hydroxide, prepared by dissolution
of pure sodium hydroxide in water. [0333] 4. Stir the reaction
mixture until total dissolution. [0334] 5. Add resin type D (XAD
16) (50 wt % in relation to the amount of compound of formula (I))
to the contents of R1. [0335] 6. Stir the reaction mixture for at
least 2 hours. Take samples for in process control by HPLC (purity
higher than or equal to 99.0%). [0336] 7. Filter the reaction
mixture, from R1 to a reactor. R2, through a filter, F1, with a
maximum porosity of 1 .mu.m. [0337] 8. Wash the filter cake twice,
with water, passing the washings through F1 to R2. [0338] 9. Charge
isopropyl alcohol into R2, through F1. [0339] 10. Add (in relation
to the amount of sodium hydroxide in step 3 above) an equimolar
amount of a 1M solution of hydrochloric acid, prepared by
dissolution of hydrochloric acid in water, through F1. [0340] 11.
Cool the reaction mixture to 0.degree. C./10.degree. C.
(crystallization occurs). [0341] 12. Stir the reaction mixture at
0.degree. C./10.degree. C., for at least 2 hours to 5 hours. [0342]
13. Filter the suspension. [0343] 14. Wash the filter cake twice
with a mixture of isopropyl alcohol and water, previously filtered
through F1. [0344] 15. Dry the product, under vacuum, at a
temperature of about 50.degree. C., until water content, by Karl
Fischer, is less than 1.5%.
[0345] With the above procedure compound of formula (I) is obtained
in more than 70% (w/w) yield with a HPLC measured purity of more
than 99.0% and in crystal modification Form 1.
EXAMPLE 2
Generation of FORM 2 of Compound of Formula (I)
[0346] The following process steps are applied: [0347] 1. Charge
isopropyl alcohol and water into a reactor, R1. [0348] 2. Add, with
stirring, compound of formula (I). [0349] 3. Heat the reaction
mixture to about 45.degree. C. to 60.degree. C. [0350] 4. Stir the
reaction mixture at about 45.degree. C. to 60.degree. C. until
dissolution. [0351] 5. Cool the reaction mixture to 10.degree.
C./20.degree. C. for at least 60 to 120 minutes. [0352] 6. Stir the
reaction mixture at 15.degree. C./20.degree. C. for at least 90 to
150 minutes. [0353] 7. Filter the suspension. [0354] 8. Wash the
filter cake twice with a mixture of isopropyl alcohol and water,
previously cooled to a temperature between 20.degree. C. and
10.degree. C. [0355] 9. Charge isopropyl alcohol and water into R1.
[0356] 10. Suspend the wet product, obtained from the filtration,
in R1. [0357] 11. Heat the reaction mixture to about 45.degree. C.
to 60.degree. C. [0358] 12. Stir the reaction mixture at about
45.degree. C. to 60.degree. C. until dissolution. [0359] 13.
Transfer the reaction mixture from R1 to a reactor, R2, through a
filter with a maximum porosity of 1 .mu.m. [0360] 14. Wash the
filtration line with a mixture of isopropyl alcohol and water,
previously heated to about 45.degree. C. to 60.degree. C. [0361]
15. Concentrate the reaction mixture, under vacuum. [0362] 16. Set
the solution's Karl Fischer at a value of 40% to 50%, by addition
of water. [0363] 17. Cool the reaction mixture to 10.degree.
C./20.degree. C. for at least 60 to 120 minutes. [0364] 18. Stir
the reaction mixture at 10.degree. C./20.degree. C. for at least 90
to 150 minutes. [0365] 19. Filter the suspension. [0366] 20. Wash
the filter cake twice with a mixture of isopropyl alcohol and
water, previously cooled to a temperature between 10.degree. C. and
20.degree. C. [0367] 21. Dry the product, under vacuum, at a
temperature of about 50.degree. C., until water content, by Karl
Fischer, is less than 1.5%.
[0368] With the above procedure compound of formula (I) is obtained
in more than 70% (w/w) yield with a HPLC measured purity of more
than 99.0% and in crystal modification Form 2.
EXAMPLE 3
Generation of FORM 3 of Compound of Formula (I)
[0369] The following process steps are applied: [0370] 1. Collect
and combine the filter liquor and washing solutions from the
generation of FORM 2 (see above) in a reactor, R1. [0371] 2.
Concentrate the mixture, under vacuum. [0372] 3. Cool the reaction
mixture to a temperature between 0.degree. C. and 10.degree. C. and
stir the reaction mixture between 0.degree. C. and 10.degree. C.
for 36 hours in R1. [0373] 4. Filter the suspension. [0374] 5. Wash
the filter cake triple with a mixture of water and isopropyl
alcohol, previously cooled to a temperature between 0.degree. C.
and 10.degree. C. [0375] 6. Dry the product, under vacuum, at a
temperature of about 50.degree. C., until water content, by Karl
Fischer, is less than 2%.
[0376] With the above procedure compound of formula (I) is obtained
in more than 70% (w/w) yield with a HPLC measured purity of more
than 98.0% and in crystal modification Form 3.
EXAMPLE 4
Generation of FORM 1 of Compound of Formula (I)
[0377] FORM 1 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was prepared by desolvation of FORM 4
according to the methods known to the person skilled in the art at
86.degree. C.
EXAMPLE 5
Generation of FORM 2 of Compound of Formula (I)
[0378] FORM 2 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was prepared according to the methods
principally known to the person skilled in the art by preparing
slurries of FORM 6 in a ratio 30 mg of compound of formula (I) in
0.2 ml solvent at room temperature, prior to warning the sample to
50.degree. C. Samples which formed slurries were matured for four
days on 4 hour a heat/cool between room temperature and 50.degree.
C. Solutions which were formed at 50.degree. C. were initially
cooled to room temperature followed by evaporation to dryness at
room temperature.
[0379] Here, the following solvents can be used to prepare FORM
1:
Dioxane, Diethyl ether, Ethyl acetate, IPA (isopropyl alcohol), THF
(tetrahydrofuran), DCM (dichloromethane), MIBK (methyl isobutyl
ketone), MEK (methyl ethyl ketone), n-Propanol, Ethanol, Methanol,
50% aq. Ethanol.
EXAMPLE 6
Generation of FORM 2 of Compound of Formula (I)
[0380] FORM 2 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was prepared according to the methods
known to the person skilled in the art by storing FORM 5 at
40.degree. C. and 75% relative humidity for 1 day.
EXAMPLE 7
Generation of FORM 2 of Compound of Formula (I)
[0381] FORM 2 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)), FORM 6, is prepared according to the
methods known to the person skilled in the art by slurrying FORM 4
and/or FORM 5 in either 5% or 50% aq. Isopropyl acetate (IPAc) at
40.degree. C. or more or by slurrying FORM 4 and/or FORM 5 in 10%
aq. Isopropyl acetate (IPAc) at more than 40.degree. C.
EXAMPLE 8
Generation of FORM 3 of Compound of Formula (I)
[0382] FORM 3 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was prepared according to the methods
known to the person skilled in the art by preparing slurries of
FORM 6 in a ratio 30 mg of compound of formula (I) in 0.2 ml
solvent at room temperature, prior to warming the sample to
50.degree. C. Samples which formed slurries were matured for four
days on 4 hour a heat/cool between room temperature and 50.degree.
C. Solutions which were formed at 50.degree. C. were initially
cooled to room temperature followed by evaporation to dryness at
room temperature.
[0383] Here, the following solvents can be used to prepare FORM
3:
MeCN (methyl cyanide, acetonitrile), acetone, 1-butanol, ethyl
formate, IPAc (isopropyl acetate), or MTBA (tertiary butyl methyl
ether).
EXAMPLE 9
Generation of FORM 4 of Compound of Formula (I)
[0384] FORM 4 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was prepared according to the methods
known to the person skilled in the art by preparing slurries of
FORM 6 in a ratio 30 mg of compound of formula (I) in 0.2 ml 50%
aq. IPA or water at room temperature, prior to warming the sample
to 50.degree. C. Samples which formed slurries were matured for
four days on 4 hour a heat/cool between room temperature and
50.degree. C. Solutions which were formed at 50.degree. C. were
initially cooled to room temperature followed, by evaporation to
dryness at room temperature.
EXAMPLE 10
Generation of FORM 4 of Compound of Formula (I)
[0385] FORM 4 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was prepared according to the methods
known to the person skilled in the art by storing FORM 1 at
40.degree. C. and 75% relative humidity.
EXAMPLE 11
Generation of FORM 5 of Compound of Formula (I)
[0386] FORM 5 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)) was prepared according to the methods
known to the person skilled in the art by desolvation of FORM 2 at
100.degree. C.
EXAMPLE 12
Generation of FORM 6 of Compound of Formula (I)
[0387] The amorphous form of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)), FORM 6, is prepared according to a
method generally known to the person skilled in the art by freeze
drying a methanolic solution of FORM 1 at a concentration of 20
mg/ml or by dissolving FORM 3 in an acetone water mixture and
freeze drying of the clear solution.
EXAMPLE 13
Generation of FORM 6 of Compound of Formula (I)
[0388] The amorphous form of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e, FORM 6, is prepared according to the methods known to the person
skilled in the art by lyophilisation of a mixture of FORM 1 and
FORM 2. 100 mg of material was dissolved in a minimum amount of
acetone/water (1:1; 40 ml) or t-butanol (50 ml) at 50.degree. C.
with shaking to ensure complete dissolution. The sample was then
hot filtered and rapidly cooled to -78.degree. C., before being
lyophilised overnight to remove the solvent.
EXAMPLE 14
Generation of FORM 6 of Compound of Formula (I)
[0389] The amorphous form of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e (compound of formula (I)), FORM 6, is prepared according to the
methods known to the person skilled in the art by fast evaporation
of a mixture of FORM 1 and FORM 2. 100 mg of material was dissolved
in 15 ml of methanol, before being filtered to remove any remaining
crystals. The sample was then evaporated at 50.degree. C. in vacuo
in order to remove the solvent as quickly as possible.
EXAMPLE 15
Preparation of a Microemulsion of Form 1 of Compound of Formula
(I)
[0390] 1650 g of a microemulsion having the following composition
was prepared according to the methods known to the person skilled
in the art by mixing 1.0% of FORM 1 of 1,6-Bis
[3-(3-carboxymethylphenyl)-4-(2-.alpha.-D-mannopyranosyloxy)-phenyl]hexan-
e, 8% of Taga.RTM. O2 V (surfactant, Goldschmidt GmbH), 12% of
Synperonic PE/L101 (Poloxamer 331, surfactant, Uniqema), 5% of
glyceryl triacetate (Triacetin), and qs100% of propylene
glycol/0.005 N hydrochloric acid (2:1). The pH value of the formula
was adjusted to 4.0. Preparation of the microemulsion employing
FORM 1, which shows highest solubility in both propylene glycol and
Triacetin as compared to other FORMS, gave best results.
* * * * *