U.S. patent application number 10/948827 was filed with the patent office on 2005-02-24 for benzoylguanidine salt and hydrates thereof.
This patent application is currently assigned to Boehringer Ingelheim Pharma GmbH & Co. KG. Invention is credited to Eickmeier, Christian, Herter, Rolf, Koerner, Volkmar, Rall, Werner, Sieger, Peter.
Application Number | 20050043320 10/948827 |
Document ID | / |
Family ID | 27214290 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050043320 |
Kind Code |
A1 |
Eickmeier, Christian ; et
al. |
February 24, 2005 |
Benzoylguanidine salt and hydrates thereof
Abstract
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidine
hydrochloride and its hydrates, processes for preparing this
benzoylguanidine salt and its hydrates, pharmaceutical compositions
containing this benzoylguanidine salt and its hydrates, and its use
in treating diseases, particularly those in which inhibition of the
cellular Na.sup.+/H.sup.+ exchange is of therapeutic benefit.
Inventors: |
Eickmeier, Christian;
(Mittelbiberach, DE) ; Sieger, Peter;
(Mittelbiberach, DE) ; Rall, Werner;
(Mittelbiberach, DE) ; Koerner, Volkmar;
(Biberach, DE) ; Herter, Rolf; (Biberach,
DE) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877
US
|
Assignee: |
Boehringer Ingelheim Pharma GmbH
& Co. KG
Ingelheim
DE
|
Family ID: |
27214290 |
Appl. No.: |
10/948827 |
Filed: |
September 23, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10948827 |
Sep 23, 2004 |
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10731825 |
Dec 9, 2003 |
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10948827 |
Sep 23, 2004 |
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10057597 |
Jan 25, 2002 |
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6730678 |
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60281344 |
Apr 4, 2001 |
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Current U.S.
Class: |
514/254.01 ;
544/373 |
Current CPC
Class: |
C07D 207/416 20130101;
C07D 403/02 20130101; C07D 207/34 20130101 |
Class at
Publication: |
514/254.01 ;
544/373 |
International
Class: |
A61K 031/496; C07D
043/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 15, 2001 |
DE |
101 06 970 |
Claims
We claim:
1.
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanid-
ine hydrochloride 1 3
2. A pharmaceutical composition comprising: (a) the compound
according to claim 1; and (b) a pharmaceutically acceptable
excipient.
3. A method of treating diseases in which inhibition of the
cellular Na.sup.+/H.sup.+ exchange is of therapeutic benefit in a
patient in need thereof, the method comprising administering to the
patient an effective amount of the compound according to claim
1.
4. The method according to claim 3, wherein the compound according
to claim 1 is administered in the form of an aqueous injectable
solution, a tablet, a suppository, an ointment, a transdermal
plaster, an inhalation aerosol, or a nasal spray.
5. A method of treating diseases in which inhibition of the
cellular Na.sup.+/H.sup.+ exchange is of therapeutic benefit in a
patient in need thereof, the method comprising administering to the
patient an effective amount of a hydrate of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluo-
romethylbenzoylguanidine hydrochloride 1 4
6. A method of treating diseases in which inhibition of the
cellular Na.sup.+/H.sup.+ exchange is of therapeutic benefit in a
patient in need thereof, the method comprising administering to the
patient an effective amount of a monohydrate of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-tri-
fluoromethylbenzoylguanidine hydrochloride 1 5
7. A method of treating diseases in which inhibition of the
cellular Na.sup.+/H.sup.+ exchange is of therapeutic benefit in a
patient in need thereof, the method comprising administering to the
patient an effective amount of a hemihydrate of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-tri-
fluoromethylbenzoylguanidine hydrochloride 1 6
8. The method according to claim 5, wherein the a hydrate of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidin-
e hydrochloride 1 is administered in the form of an aqueous
injectable solution, a tablet, a suppository, an ointment, a
transdermal plaster, an inhalation aerosol, or a nasal spray.
9. The method according to claim 6, wherein the monohydrate of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidin-
e hydrochloride 1 is administered in the form of an aqueous
injectable solution, a tablet, a suppository, an ointment, a
transdermal plaster, an inhalation aerosol, or a nasal spray.
10. The method according to claim 7, wherein the
4-[4-(2-pyrrolylcarbonyl)-
-1-piperazinyl]-3-trifluoromethylbenzoylguanidine hydrochloride 1
is administered in the form of an aqueous injectable solution, a
tablet, a suppository, an ointment, a transdermal plaster, an
inhalation aerosol, or a nasal spray.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
10/731,825, filed Dec. 9, 2003, which application is a continuation
of U.S. Ser. No. 10/057,597, filed Jan. 25, 2002, which claims
priority to U.S. Ser. No. 60/281,344, filed Apr. 4, 2001, and
German Patent Application No. 101 06 970.7 filed Feb. 15, 2001,
each of which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The invention relates to the hydrochloride of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidin-
e, processes for preparing it and its use in preparing a
pharmaceutical composition.
BACKGROUND OF THE INVENTION
[0003] A number of benzoylguanidine derivatives are known in the
art. Thus, for example, International Patent Application WO
00/17176 discloses benzoylguanidine derivatives which are
characterized by valuable pharmacological properties. These
compounds are effective against arrhythmias which occur in hypoxia,
for example. They may also be used for complaints connected with
ischaemia (such as cardiac, cerebral, gastrointestinal (such as
mesenteric thrombosis/embolism), pulmonary or renal ischaemia,
ischaemia of the liver, and ischaemia of the skeletal muscles).
Corresponding indications include, for example, coronary heart
disease, cardiac infarct, angina pectoris, stable angina pectoris,
ventricular arrhythmia, subventricular arrhythmias, cardiac
insufficiency, and also for assisting bypass operations, for
assisting open heart surgery, for assisting operations which
require an interruption to the blood supply to the heart and to
assist in heart transplants, embolism in the pulmonary circulation,
acute or chronic kidney failure, chronic renal insufficiency,
cerebral infarct, reperfusion damage in the restoration of blood
supply to areas of the brain after the break-up of vascular
occlusions, and acute and chronic circulatory disorders of the
brain. The abovementioned compounds may also be used in such cases
in conjunction with thrombolytic agents such as t-PA,
streptokinase, and urokinase.
[0004] During reperfusion of the ischemic heart (e.g., after an
attack of angina pectoris or a cardiac infarct) irreversible damage
may occur to cardiomyocytes in the affected region. In such cases
the compounds have a cardioprotective effect, inter alia.
[0005] The category of ischaemia should also include the prevention
of damage to transplants (e.g., as protection for the transplanted
organ, such as, for example, liver, kidney, heart, or lung, before,
during, and after implantation and during the storage of the
transplant organs), which may occur in connection with
transplantation. The compounds disclosed in WO 00/17176 are also
pharmaceutical compositions with a protective effect in carrying
out angioplastic surgical interventions on the heart and on
peripheral blood vessels.
[0006] In essential hypertension and diabetic nephropathy the
cellular sodium-proton exchange is increased. The compounds are
therefore suitable as inhibitors of this exchange for the
preventive treatment of these diseases.
[0007] The compounds are further characterized by a powerful
inhibiting effect on the proliferation of cells. Therefore, the
compounds are useful as medicaments in diseases where cell
proliferation plays a primary or secondary part and may be used as
agents against cancers, benign tumors or, for example, prostatic
hypertrophy, atherosclerosis, organ hypertrophy and hyperplasia,
fibrotic diseases, and late complications of diabetes.
[0008] The abovementioned pharmacologically valuable properties of
the benzoylguanidine derivatives disclosed in the prior art are the
main prerequisite for effective use of a compound as a
pharmaceutical composition. An active substance, however, has to
satisfy still more requirements in order to be allowed to be used
as a medicament. These parameters are largely connected to the
physico-chemical nature of the active substance.
[0009] Without being restricted thereto, examples of these
parameters are the stability of effect of the starting substance
under different ambient conditions, stability during the production
of the pharmaceutical formulation, and stability in the finished
compositions of the medicament. The pharmaceutical active substance
used to prepare the pharmaceutical compositions should therefore
have high stability which must also be guaranteed even under
different ambient conditions. This is absolutely necessary to
prevent the use of pharmaceutical compositions which contain
breakdown products of the active substance, for example, in
addition to the active substance itself. In such a case, the
content of active substance present in pharmaceutical formulations
may be lower than specified.
[0010] The absorption of moisture reduces the content of
pharmaceutical active substance because of the increase in weight
due to the uptake of water. Pharmaceutical compositions with a
tendency to absorb moisture have to be protected from moisture
during storage, for example, by the addition of suitable drying
agents or by storing the pharmaceutical composition in an
environment which is protected from damp. Moreover, the uptake of
moisture may reduce the content of pharmaceutical active substance
during manufacture if the pharmaceutical composition is exposed to
the environment without any protection from moisture whatsoever.
Preferably, therefore, a pharmaceutical active substance should be
only slightly hygroscopic.
[0011] As the crystal modification of an active substance can
influence the activity of a pharmaceutical composition, it is
necessary to clarify any existing polymorphism of an active
substance present in crystalline form as much as possible. If there
are different polymorphic modifications of an active substance,
care must be taken to ensure that the crystalline modification of
the substance does not change in the subsequent pharmaceutical
preparation. Otherwise, this could have a detrimental effect on the
reproducible activity of the medicament. In this context, active
substances which are characterized by limited polymorphism are
preferred.
[0012] Another criterion which may be of exceptional importance in
certain circumstances, depending on the choice of formulation or on
the choice of the method of production of the formulation, is the
solubility of the active substance. If, for example, pharmaceutical
solutions are prepared (for example for infusions), it is essential
that the active substance is sufficiently soluble in
physiologically acceptable solvents. A sufficiently soluble active
substance is also very important for pharmaceutical compositions
administered orally.
[0013] The underlying aim of the present invention is to prepare a
pharmaceutical active substance which is not only characterized by
a potent pharmacological activity but also satisfies as far as
possible the physico-chemical requirements referred to above.
DETAILED DESCRIPTION OF THE INVENTION
[0014] It has been found that the abovementioned aim is achieved by
means of the compound
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethy-
lbenzoylguanidine hydrochloride 1 1
[0015] The compound of formula 1 is not hygroscopic and dissolves
readily in physiologically acceptable solvents. It is also
characterized by a high degree of stability.
[0016] The methanesulfonate of formula 1' disclosed in WO 00/17176
2
[0017] unlike the compound of formula 1, does not meet the
requirements set out hereinbefore, however.
[0018] Accordingly, in one aspect, the present invention relates to
the compound of formula 1 as such. In another aspect, the present
invention relates to the compound of formula 1 in the form of its
hydrates, preferably in the form of its monohydrate or
hemihydrate.
[0019] In another aspect, the present invention relates to the use
of the compound of formula 1 as a medicament. The present invention
further relates to the use of the compound of formula 1, optionally
in the form of its hydrates, for preparing a pharmaceutical
composition for treating diseases in which inhibitors of the
cellular Na.sup.+/H.sup.+ exchange may develop a therapeutic
benefit.
[0020] The present invention further relates to the use of the
compound of formula 1 to prepare a pharmaceutical composition for
treating cardiovascular diseases.
[0021] The present invention further relates to the use of the
compound of formula 1 to prepare a pharmaceutical composition for
treating arrhythmia such as occurs in hypoxia, for example. The
present invention further relates to the use of the compound of
formula 1 to prepare a pharmaceutical composition for treating
complaints connected with ischaemia (such as: cardiac, cerebral,
gastrointestinal (such as mesenteric thrombosis/embolism),
pulmonary, renal ischaemia, ischaemia of the liver, and ischaemia
of the skeletal muscles. The present invention further relates to
the use of the compound of formula 1 to prepare a pharmaceutical
composition for treating diseases selected from the group
consisting of coronary heart disease, cardiac infarct, angina
pectoris, stable angina pectoris, ventricular arrhythmia,
subventricular arrhythmias, cardiac insufficiency, and also for
assisting bypass operations, for assisting open heart surgery, for
assisting operations which require an interruption to the blood
supply to the heart and to assist in heart transplants, embolism in
the pulmonary circulation, acute or chronic kidney failure, chronic
renal insufficiency, cerebral infarct, reperfusion damage in the
restoration of blood supply to areas of the brain after the
dissolving of vascular occlusions and acute, and chronic
circulatory disorders of the brain. The present invention further
relates to the use of the compound of formula 1 to prepare a
pharmaceutical composition for treating diseases in which the use
of cardioprotective active substances may be of therapeutic
benefit. The present invention further relates to the use of the
compound of formula 1 to prepare a pharmaceutical composition for
treating cancers, benign tumors or, for example, prostatic
hypertrophy, atherosclerosis, organ hypertrophy and hyperplasia,
fibrotic diseases, and late complications of diabetes.
[0022] The compound of formula 1 may be used as an aqueous
injectable solution (e.g., for intravenous, intramuscular, or
subcutaneous administration), as a tablet, as a suppository, as an
ointment, as a plaster for transdermal administration, as an
aerosol for inhalation into the lungs or as a nasal spray.
[0023] The content of active substance in a tablet or a suppository
is between 5 mg and 200 mg, preferably between 10 mg and 50 mg. For
inhalation, the single dose is between 0.05 mg and 20 mg,
preferably between 0.2 mg and 5 mg. For parenteral injection, the
single dose is between 0.1 mg and 50 mg, preferably between 0.5 mg
and 20 mg. The doses specified above may be given several times a
day if necessary.
[0024] The following are some examples of pharmaceutical
preparations containing the active substance:
1 TABLETS Component Amount (mg) Compound of formula 1 18.0
magnesium stearate 1.2 maize starch 60.0 lactose 90.0
polyvinylpyrrolidone 1.5 SOLUTION FOR INJECTION Component Amount
Compound of formula 1 0.3 g sodium chloride 0.9 g water for
injections ad 100 mL
[0025] This solution can be sterilized using standard methods.
[0026] WO 00/17176 discloses possible methods of production which
can be used to synthesize the free base
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-
-3-trifluoromethylbenzoylguanidine. Starting from this compound,
the following possible methods of synthesizing the compound of
formula 1 are illustrated by way of example.
EXAMPLE 1
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidine
hydrochloride
[0027] 15.1 g of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethy-
lbenzoylguanidine is taken up in 151 mL of methanol and the
resulting suspension is cooled to about 10.degree. C. 16 mL of a
saturated ethereal HCl solution are added to this suspension which
is thus acidified to a pH of between 1 and 2. Stirring is
continued, while cooling with ice, until crystallization is
complete. The crystals are suction filtered, washed with cold
methanol, and then with cold diethyl ether. Yield: 16.19 g; melting
point: 223.degree. C. (uncorrected).
EXAMPLE 2
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidine
hydrochloride hemihydrate
[0028] 15.0 kg of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluorometh-
ylbenzoylguanidine is taken and combined with 120 L of ethyl
acetate. The suspension is heated to about 45.degree. C. and
combined with 30 L of water. The resulting mixture is stirred for
about 15 minutes and the aqueous phase is then separated off. A
solution of 3.62 kg of concentrated hydrochloric acid in 20 L of
water is added to the organic phase at a constant temperature.
Within about 1 to 2 hours, the mixture is cooled to 25.degree. C.
to 20.degree. C. The hydrochloride obtained is separated off,
washed with 50 L of ethyl acetate, and dried in vacuo at about
60.degree. C. Yield: 78%; melting point: 225.degree.
C..+-.5.degree. C. (DSC at a heating rate of 10 K/min).
EXAMPLE 3
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluoromethylbenzoylguanidine
hydrochloride monohydrate
[0029] 109.4 g of
4-[4-(2-pyrrolylcarbonyl)-1-piperazinyl]-3-trifluorometh-
ylbenzoylguanidine is suspended in 1.5 L of water and heated to
about 50.degree. C. 26.1 mL of concentrated aqueous hydrochloric
acid is diluted with 300 mL of water and added dropwise to the
preheated suspension within about 20 minutes. The mixture is
stirred for about 15 minutes at constant temperature. Then the
temperature is lowered to about 35.degree. C. with stirring over a
period of about 1.5 hours. It is then cooled to 5.degree. C. to
10.degree. C. and stirred for another hour at this temperature. The
crystals obtained are separated off, washed with a little water,
and dried in vacuo at about 50.degree. C. Yield: 116.5 g; melting
point: 180.degree. C..+-.5.degree. C. (DSC at a heating rate of 10
K/min).
* * * * *