U.S. patent application number 14/471147 was filed with the patent office on 2014-12-18 for 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazoline-6-yloxy]-1,4-di- aza-spiro[5.5]undecane-5-one dimaleate, use thereof as a medicament and method for the production thereof.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. The applicant listed for this patent is Guenther HUCHLER, Markus OSTERMEIER, Waldemar PFRENGLE, Peter SIEGER. Invention is credited to Guenther HUCHLER, Markus OSTERMEIER, Waldemar PFRENGLE, Peter SIEGER.
Application Number | 20140371226 14/471147 |
Document ID | / |
Family ID | 43896655 |
Filed Date | 2014-12-18 |
United States Patent
Application |
20140371226 |
Kind Code |
A1 |
PFRENGLE; Waldemar ; et
al. |
December 18, 2014 |
9-[4-(3-CHLORO-2-FLUORO-PHENYLAMINO)-7-METHOXY-QUINAZOLINE-6-YLOXY]-1,4-DI-
AZA-SPIRO[5.5]UNDECANE-5-ONE DIMALEATE, USE THEREOF AS A MEDICAMENT
AND METHOD FOR THE PRODUCTION THEREOF
Abstract
The present invention relates to a compound of formula (I),
##STR00001## which has valuable pharmacological properties,
particularly an inhibiting effect on signal transduction mediated
by tyrosine kinases, processes for stereoselectively preparing
these compounds, particularly pharmaceutical formulations suitable
for inhalation and their use for the treatment of diseases,
particularly tumoral diseases, benign prostatic hyperplasia and
diseases of the lungs and airways.
Inventors: |
PFRENGLE; Waldemar;
(Biberach an der Riss, DE) ; HUCHLER; Guenther;
(Hochdorf, DE) ; OSTERMEIER; Markus; (Biberach an
der Riss, DE) ; SIEGER; Peter; (Mittelbiberach,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PFRENGLE; Waldemar
HUCHLER; Guenther
OSTERMEIER; Markus
SIEGER; Peter |
Biberach an der Riss
Hochdorf
Biberach an der Riss
Mittelbiberach |
|
DE
DE
DE
DE |
|
|
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
43896655 |
Appl. No.: |
14/471147 |
Filed: |
August 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13359807 |
Jan 27, 2012 |
8853225 |
|
|
14471147 |
|
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Current U.S.
Class: |
514/249 |
Current CPC
Class: |
A61P 1/00 20180101; C07D
241/38 20130101; A61P 11/00 20180101; A61P 37/02 20180101; A61P
43/00 20180101; A61P 13/08 20180101; A61P 35/00 20180101; A61P
37/08 20180101; A61P 11/06 20180101; C07D 239/70 20130101; A61P
1/04 20180101; A61P 17/06 20180101; C07D 403/12 20130101 |
Class at
Publication: |
514/249 |
International
Class: |
C07D 241/38 20060101
C07D241/38 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 1, 2011 |
EP |
11 152 895.6 |
Claims
1-2. (canceled)
3. A method for the treatment of inflammatory or allergic diseases
of the airways comprising administering a therapeutically effective
amount of the compound of formula (I), characterized in that
reflections in the X-ray powder diagram occur at d.sub.hkl values
of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 .ANG., optionally in
the form of a tautomer thereof, to a patient in need thereof
##STR00034##
4-18. (canceled)
19. The method according to claim 3, wherein the inflammatory or
allergic disease of the airways is selected from chronic
bronchitis, chronic obstructive bronchitis (COPD), asthma,
bronchiectasis, allergic or non-allergic rhinitis or sinusitis,
cystic fibrosis, .alpha.1-antitrypsin deficiency, or coughs,
pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
Description
[0001] The present invention relates to the compound of formula
(I),
##STR00002##
which has valuable pharmacological properties, particularly an
inhibiting effect on signal transduction mediated by tyrosine
kinases, processes for stereoselectively preparing this compound,
particularly pharmaceutical formulations suitable for inhalation
and their use for the treatment of diseases, particularly tumoral
diseases, benign prostatic hyperplasia and diseases of the lungs
and airways.
BACKGROUND TO THE INVENTION
[0002] Quinazoline derivatives are known from the prior art as
active substances for example for the treatment of tumoral diseases
and also diseases of the lungs and airways. Processes for preparing
quinazoline derivatives are described in WO03082290 and WO07068552.
WO2009098061 discloses the base (compound (II)) of the dimaleate
salt according to the invention (compound (I)).
[0003] The aim of the present invention is to provide a salt of
9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-di-
aza-spiro[5.5]undecan-5-one which by virtue of its pharmaceutical
efficacy as a tyrosine-kinase inhibitor is suitable for use in the
therapeutic field, i.e. for the treatment of pathophysiological
processes that are caused by the hyperfunction of
tyrosine-kinases.
[0004] A further aim is to provide a compound that meets the
requirements for physical and chemical stability and other
properties, such as for example crystalline stability, the absence
of polymorphism and low hygroscopicity, particularly with regard to
the absence of polymorphism, that are imposed on an active
substance of a medicament. Another aim of the present invention is
to provide a stereoselective process for preparing the compound
according to the invention.
DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1: X-ray powder diagram of compound (I)
[0006] FIG. 2: DSC/TG schemes of compound (I)
[0007] FIG. 3: Sorption isotherms of compound (I): a.) kinetic
plot, b.) isothermic plot
DETAILED DESCRIPTION OF THE INVENTION
[0008] The present invention solves the above-mentioned problems by
providing the compound of formula (I) that is suitable in
particular for oral administration, which is highly crystalline,
has low hygroscopicity and low polymorphism, the pharmaceutical
formulation thereof and the method of synthesis described
hereinafter. By crystalline stability is meant, within the scope of
the present invention, that X-ray powder diagrams of the compound
of formula (I) have sharp reflections with high intensity up to the
upper 2.theta. range, preferably up to 20-40.degree. 2.theta..
[0009] By low hygroscopicity is meant, within the scope of the
present invention, that in sorption experiments on the compound of
formula (I) a water uptake of less than 1% is observed in the
humidity range of 10-90% investigated.
[0010] By low polymorphism is meant, within the scope of the
present invention, that after recrystallization from different
solvents of the compound of formula (I) a maximum of 5 other
crystal modifications, preferably a maximum of 3 other crystal
modifications, particularly preferably no other crystal
modifications are obtained.
[0011] The invention relates to a compound of formula (I)
##STR00003##
optionally in the form of the tautomers, solvates or hydrates
thereof.
[0012] A crystalline compound of formula (I) is preferred wherein
reflections occur in the X-ray powder diagram with d.sub.hkl values
of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 .ANG..
[0013] The invention further relates to the above-mentioned
compound for use as a medicament, preferably for the treatment of
inflammatory or allergic diseases of the airways, particularly
preferably for the treatment of chronic obstructive bronchitis
(COPD) and/or chronic bronchitis.
[0014] The compound of formula (I) is useful for treating diseases,
preferably selected from among acute bronchitis, bronchitis caused
by bacterial or viral infection or fungi or helminths, allergic
bronchitis, toxic bronchitis, asthma (intrinsic or allergic),
pediatric asthma, bronchiectasis, allergic alveolitis, allergic or
non-allergic rhinitis, chronic sinusitis, cystic fibrosis or
mucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonary
emphysema, interstitial lung diseases, alveolitis, hyperreactive
airways, nasal polyps, pulmonary oedema, pneumonitis of different
origins, e.g. radiation-induced or caused by aspiration or
infectious pneumonitis, collagenoses such as lupus erythematodes,
systemic scleroderma, sarcoidosis and Boeck's disease, and for
treating complications in asthma and COPD triggered by viral,
bacterial or other causes, for treating viral or bacterial
infections of the airways or lungs.
[0015] It is also preferred to use the compound of formula (I) in
cases of inflammatory or allergic complaints in which autoimmune
reactions are involved.
[0016] It is also preferred to use the compounds of formula (I) in
cases of a disease in the form of benign or malignant tumours.
[0017] The invention further relates to a process for the
stereoselective preparation of the compound of formula (I),
optionally in the form of the tautomers, solvates or hydrates
thereof:
##STR00004## [0018] the process comprising reaction steps (A) to
(M), wherein [0019] (A) denotes the reaction of
1,4-cyclohexanedione-mono-ethyleneketal to form a compound of
formula (1)
[0019] ##STR00005## [0020] (B) is the reaction of a compound of
formula (1) to form the compound of formula (2)
[0020] ##STR00006## [0021] (C) is the reaction of a compound of
formula (2) to form the compound of formula (3)
[0021] ##STR00007## [0022] (D) is the reaction of a compound of
formula (3) with a protective group reagent to form the compound of
formula (4)
[0022] ##STR00008## [0023] (E) is the reduction of a compound of
formula (4) to form the compound of formula (5)
[0023] ##STR00009## [0024] (F) is the reaction of a compound of
formula (5) to form a compound of formula (6)
[0024] ##STR00010## [0025] (G) is the reaction of a compound of
formula (6) with a compound of formula (13) to form a compound of
formula (7)
[0025] ##STR00011## [0026] (H) is the reaction of a compound of
formula (7) to form a compound of formula (8a) or its tautomeric
form (8b),
[0026] ##STR00012## [0027] (I) is the chlorination of the compound
of formula (8a) or (8b) to form a compound of formula (9)
[0027] ##STR00013## [0028] (J)+(K) are the reaction of the compound
of formula (9) with 3-chloro-2-fluoraniline and the cleaving of a
protective group to form a compound of formula (11) or (11A)
[0028] ##STR00014## [0029] (L) is the cleaving of another
protective group to form the compound of formula (II)
[0029] ##STR00015## [0030] (M) is the reaction of the compound of
formula (II) with maleic acid to form a compound of formula (I),
optionally in the form of the tautomers, solvates or hydrates
thereof,
[0030] ##STR00016## [0031] while process steps (A) to (M) take
place successively in the sequence indicated.
[0032] The invention further relates to a process for the
stereoselective preparation of the compound of formula (I),
optionally in the form of the tautomers, solvates or hydrates
thereof, comprising process steps (A) to (M),
wherein process steps (J+K) are replaced by steps (N+O), where
[0033] (N+O) is the cleaving of a protective group of the compound
of formula (9) to form the compound of formula (12) and subsequent
reaction with 3-chloro-2-fluoraniline to form the compound of
formula (11) or (11A)
[0033] ##STR00017## [0034] In a preferred process for the
stereoselective preparation of a compound of formula (I), the
process consists of process steps (I), (J), (K), (L), and (M) or of
process steps (I), (N), (O), (L) and (M), while process steps (I)
to (M) in each case take place successively in the order indicated.
[0035] Another preferred process for the stereoselective
preparation of a compound of formula (II) is characterized in that
the process consists of process steps (I), (J), (K) and (L), or of
process steps (I), (N), (O) and (L), while process steps (I) to (L)
in each case take place successively in the order indicated.
[0036] Particularly preferred is process step (G).
[0037] Also particularly preferred is process step (I). [0038] The
invention further relates to the intermediate of formula (6),
optionally in the form of the tautomers, solvates or hydrates
thereof. [0039] The invention further relates to the intermediate
of formula (7), optionally in the form of the tautomers, solvates
or hydrates thereof. [0040] The invention further relates to the
intermediate of formula (8), optionally in the form of the
tautomers, solvates or hydrates thereof. [0041] The invention
further relates to the intermediate of formula (9), optionally in
the form of the tautomers, solvates or hydrates thereof. [0042] The
invention further relates to the intermediate of formula (11) or
(11A), optionally in the form of the tautomers, solvates or
hydrates thereof.
[0043] The invention further relates to a pharmaceutical
composition containing a compound of formula (I). An orally
administered pharmaceutical composition containing a compound of
formula (I) is preferred. [0044] In another aspect the invention
relates to medicament combinations which contain, in addition to a
compound of formula (I) according to claim 1, as a further active
substance, one or more compounds selected from among the categories
of the betamimetics, anticholinergics, corticosteroids,
PDE4-inhibitors, LTD4-receptor antagonists, LTB4-receptor
antagonists, inhibitors of MAP kinases, bradykinin receptor
antagonists, endothelin receptor antagonists, CXCR1 and/or CXCR2
receptor antagonists, and antitussives, or double or triple
combinations thereof.
[0045] In process steps A, C to L and N alternative reagents may be
used, which are selected from among the reagents listed below:
In process step [0046] A: in addition to ethylenediamine and
chloroform: [0047] preferably benzyltriethylammonium chloride/NaOH,
tetrabutylammonium chloride/KOH, benzyltriethylammonium
chloride/KOH, tetrabutylammonium chloride/NaOH, particularly
preferably benzyltriethylammonium chloride/NaOH; C: preferably
alkoxide bases selected from among NaO.sup.tBu, KO.sup.tBu and
NaOEt, carbonate bases selected from among Cs.sub.2CO.sub.3,
K.sub.2CO.sub.3, Li.sub.2CO.sub.3 and Na.sub.2CO.sub.3,
particularly preferably sodium methoxide; [0048] D: in addition to
di-tert-butyldicarbonate and DMAP (4-(dimethylamino)-pyridine):
[0049] preferably K.sub.2CO.sub.3, Cs.sub.2CO.sub.3,
Li.sub.2CO.sub.3 and Na.sub.2CO.sub.3, particularly preferably
K.sub.2CO.sub.3; [0050] E: preferably NaBH.sub.4 and LiBH.sub.4,
particularly preferably NaBH.sub.4; [0051] F: in addition to
trifluoroacetic anhydride: [0052] as base preferably triethylamine,
Hunig base, N-methylmorpholine and N,N-diethylaniline, particularly
preferably triethylamine; [0053] G: in addition to
3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one: [0054] preferably
triphenylphosphine/diisopropyl azodicarboxylate,
triphenylphosphine/diethyl azodicarboxylate,
tributylphosphine/1,1'-(azodicarbonyl)dipiperidine, particularly
preferably triphenylphosphine/diisopropyl azodicarboxylate; [0055]
H: catalysts, preferably selected from among Pd/C and Pd(OH).sub.2,
particularly preferably Pd/C; [0056] I: preferably
N-chlorosuccinimide/triphenylphosphane (in combination), oxalyl
chloride, thionyl chloride, phosphorus oxychloride, phosphorus
pentachloride, carbon tetrachloride/triphenylphosphane,
dichlorotriphenylphosphorane and P,P-dichlorophenylphosphine oxide,
particularly preferably N-chlorosuccinimide/triphenylphosphane (in
combination); [0057] J+K: in addition to 3-chloro-2-fluooraniline:
[0058] preferably HCl, methanesulphonic acid, ethanesulphonic acid,
p-toluenesulphonic acid and HBr, particularly preferably HCl;
[0059] L: preferably ethanolamine, ammonia and Ba(OH).sub.2,
particularly preferably ethanolamine; [0060] I+N: preferably
N-chlorosuccinimide/triphenylphosphane (in combination), HCl,
oxalyl chloride, thionyl chloride, phosphorus oxychloride,
phosphorus pentachloride, carbon tetrachloride/triphenylphosphane,
dichlorotriphenylphosphorane, P,P-dichlorophenylphosphine oxide,
methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic
acid and HBr, particularly preferably
N-chlorosuccinimide/triphenylphosphane (in combination) and
HCl.
[0061] The use of the following solvents selected from the group
specified in each case is preferred in the process steps described
above:
[0062] In process step
A: CH.sub.2Cl.sub.2, CHCl.sub.3, THF (tetrahydrofuran) and dioxane;
B: HOAc, dioxane, H.sub.2O and aqueous solutions of the following
solvents selected from among EtOH, THF, iPrOH, MeOH,
NMP(N-methyl-2-pyrrolidone) and DMF (dimethylformamide); C:
ACN(CH.sub.3CN), EtOH, MeOH, iPrOH, H.sub.2O, THF and NMP;
D: ACN, EtOH and NMP;
[0063] E: H.sub.2O, MeOH, EtOH, THF and dioxane; F: Me-THF, THF,
toluene, CH.sub.2Cl.sub.2 and dioxane; G: THF, NMP, dioxane, DMF
and CH.sub.2Cl.sub.2; H: iPrOH, dioxane, EtOH, MeOH, THF and NMP;
I: dioxane/ACN and THF/dioxane; J: ACN, dioxane, THF and EtOH; K:
ACN, dioxane, THF and EtOH; L: EtOH, MeOH, iPrOH and dioxane;
M: EtOH, MeOH and H.sub.2O;
[0064] N: dioxane/ACN and THF/dioxane O: EtOH, n-PrOH, dioxane and
NMP
[0065] The process steps described above are preferably carried out
in the following temperature ranges:
[0066] In process step:
A: preferably -15 to 40.degree. C., particularly preferably 0 to
20.degree. C.; B: preferably 0 to 100.degree. C., particularly
preferably 75 to 100.degree. C.; C: preferably 0 to 65.degree. C.,
particularly preferably 15 to 30.degree. C.; D: preferably 10 to
80.degree. C., particularly preferably 15 to 35.degree. C.; E:
preferably 0 to 40.degree. C., particularly preferably 0 to
15.degree. C.; F: preferably -10 to 60.degree. C., particularly
preferably 0 to 35.degree. C.; G: preferably 10 to 65.degree. C.,
particularly preferably 45 to 60.degree. C.; H: preferably 20 to
85.degree. C., particularly preferably 70 to 85.degree. C.; I:
preferably 20 to 100.degree. C., particularly preferably 70 to
95.degree. C.; J: preferably 20 to 100.degree. C., particularly
preferably 50 to 85.degree. C.; K: preferably 20 to 100.degree. C.,
particularly preferably 50 to 85.degree. C.; L: preferably 50 to
80.degree. C., particularly preferably 70 to 80.degree. C.; M:
preferably 0 to 75.degree. C., particularly preferably 0 to
70.degree. C. N: preferably 20 to 100.degree. C., particularly
preferably 50 to 85.degree. C.; O: preferably 50 to 100.degree. C.,
particularly preferably 70 to 80.degree. C.;
[0067] Preferably, protective groups selected from among benzyl,
Cbz, trifluoracetyl and Boc, particularly trifluoracetyl and Boc,
are used.
[0068] The abbreviation Boc used in the above formulae denotes
tertiary butyl carbamate and Cbz denotes benzyloxycarbonyl.
[0069] Scheme 1 illustrates the synthesis according to the
invention. All the compounds are shown in the form of their
bases.
##STR00018## ##STR00019## ##STR00020##
[0070] The following Examples serve to illustrate the processes
carried out by way of example for preparing the compound of formula
(I). These Examples are to be understood as being an illustration
of the invention, without limiting it to their subject-matter.
Example 1
1,4-dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one
##STR00021##
[0071] Process Step a
[0072] 15.1 kg of 50% sodium hydroxide solution are added dropwise
at 5.degree. C. to a mixture of 437 g benzyltriethylammonium
chloride and 2700 ml ethylenediamine in 19.2 L dichloromethane.
Then a solution of 6000 g of
1,4-cyclohexanedione-mono-ethyleneketal and 6100 g chloroform in
4.8 L dichloromethane within the next 4.5 h is added dropwise at
5-15.degree. C. The dropping funnel is rinsed with 3 L
dichloromethane. After 15 h, 18 L water and 39 L dichloromethane
are added at 15-25.degree. C. The phases are separated and the
aqueous phase is extracted with 20 L dichloromethane. The combined
organic phases are concentrated by distillation. After 72 L solvent
have been distilled off, 48 L isopropanol are added to the
suspension and then a further 30 L solvent are distilled off. After
cooling to 3.degree. C. the precipitate is filtered off and washed
twice with 7.5 L cold isopropanol. After drying at 50.degree. C. in
vacuo, 6144 g of product is obtained.
[0073] Mass spectrum (ESI.sup.+): m/z=227 [M+H].sup.+
Example 2
1,4-diaza-spiro[5.5]undecane-5,9-dione
##STR00022##
[0074] Process Step B
[0075] 14.5 kg of 4M HCl in dioxane are added dropwise within 15
min to 6085 g
1,4-dioxa-9,12-diaza-dispiro[4.2.5.2]pentadecan-13-one in 25 kg
acetic acid at 80-100.degree. C. The dropping funnel is rinsed with
3 kg acetic acid. After 140 min the suspension is cooled to
20.degree. C. After 2 h the precipitate is filtered off and washed
twice with 12 L dioxane. After drying at 60.degree. C. in vacuo,
5333 g of product is obtained as the hydrochloride.
[0076] Mass spectrum (ESI.sup.+): m/z=183 [M+H].sup.+
Process Step C
[0077] 5200 g of 1,4-diaza-spiro[5.5]undecane-5,9-dione
hydrochloride in 52 L acetonitrile are combined with 4370 ml 30%
sodium methoxide solution in methanol at RT within 3 h. The
dropping funnel is rinsed with 1 L methanol. 250 g sodium carbonate
are added and the mixture is stirred for 16 h. 30 L solvent are
distilled off and after the addition of 20 L acetonitrile the
suspension is filtered. The filter cake is washed with 10 L
acetonitrile. 22 L solvent are distilled off from the filtrate and
the residue that contains the product is further reacted directly
in the next step.
Example 3
tert-butyl 5,9-dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylate
##STR00023##
[0078] Process Step D
[0079] 6573 g potassium carbonate and 145 g
4-(dimethylamino)-pyridine are added to the residue from the
previous mixture which contains the
1,4-diaza-spiro[5.5]undecane-5,9-dione. Then within 30 min 6487 g
di-tert-butyldicarbonate in 8 L acetonitrile is added dropwise. The
dropping funnel is rinsed with 2 L acetonitrile. After 100 min the
mixture is added to 20 L water at 10.degree. C. It is rinsed with 2
L water, 5 L acetonitrile and 16 L toluene. After phase separation
the organic phase is combined with 10 L toluene. 55 L solvent are
distilled off. After the addition of 30 L methylcyclohexane and 10
L toluene the mixture is inoculated with product and the suspension
is stirred for 14 h at 20-30.degree. C. 20 L methylcyclohexane are
added and the mixture is cooled to -5.degree. C. After 2.5 h the
precipitate is filtered off and washed with 100 L
methylcyclohexane. After drying at 50.degree. C. in vacuo, 5160 g
of product is obtained.
[0080] Mass spectrum (ESI.sup.+): m/z=283 [M+H].sup.+
Example 4
tert-butyl(cis)-9-hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-4-carboxylate
##STR00024##
[0081] Process Step E
[0082] 201 g sodium borohydride in 5 L water are added dropwise at
3.degree. C. within 17 min to a mixture of 5000 g of tert-butyl
5,9-dioxo-1,4-diaza-spiro[5.5]undecane-4-carboxylate in 35 L water.
The dropping funnel is rinsed with 1.4 L water. After 15 min, 30 L
methyl-tetrahydrofuran are added. After the addition of 10 L of
sat. potassium carbonate solution the phases are separated and the
aqueous phase is extracted with 20 L methyl-tetrahydrofuran. The
combined organic phases are washed with 1 L sat. saline solution.
The organic phase is separated off and diluted with 27.5 L
methyl-tetrahydrofuran. 55 L solvent are distilled off. Then 15 L
methyl-tetrahydrofuran are added and 15 L solvent are distilled
off. Then 20 L methyl-tetrahydrofuran are added and 20 L solvent
are distilled off. Then 20 L methyl-tetrahydrofuran are added and
20 L solvent are distilled off. The residue which contains the
product is further reacted directly in the next step.
[0083] Mass spectrum (ESI.sup.+): m/z=285 [M+H].sup.+
Example 5
tert-butyl(cis)-9-hydroxy-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro-
[5.5]undecane-4-carboxylate
##STR00025##
[0084] Process Step F
[0085] 11.1 L triethylamine are added to the organic phase from the
previous mixture. Then 5170 ml trifluoroacetic anhydride are added
dropwise within 30 min at 3-25.degree. C. After 15 min 12.4 L
methanol are added. After 1 h, 30 L solvent are distilled off in
vacuo. Then 15.3 L methanol are added and 8 L of solvent are
distilled off in vacuo. 12.4 L methanol are added and 35 L water
are added dropwise at 1-10.degree. C. within 50 min. After 1 h at
2.degree. C. the precipitate is centrifuged off and washed with 10
L of a 2:1 mixture of water and methanol and then again washed with
10 L water. After drying at 55.degree. C. in the circulating air
dryer 5299 g of product is obtained as a cis/trans mixture.
[0086] This crude product is suspended in 70 L toluene. Then 500 ml
solvent are distilled off and then 10 L toluene are added. The
solution is cooled and at 52.degree. C. it is inoculated with
product. After 3 h at 1.degree. C. the precipitate is centrifuged
off and washed with 8 L cold toluene. After drying at 55.degree. C.
in vacuo 4398 g of product is obtained, which still contains
approx. 4% trans product.
[0087] Mass spectrum (ESI.sup.+): m/z=381 [M+H].sup.+
Example 6
tert-butyl(trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-ylo-
xy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carbox-
ylate
##STR00026##
[0088] Process Step G
[0089] 2471 ml diisopropyl azodicarboxylate is added dropwise,
within 100 min, to a mixture of 3500 g
tert-butyl(cis)-9-hydroxy-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spir-
o[5.5]undecane-4-carboxylate, 2362 g
3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one and 3292 g
triphenylphosphine in 45 L tetrahydrofuran at 50-55.degree. C. The
dropping funnel is rinsed with 4 L tetrahydrofuran and 30 L solvent
are distilled off in vacuo. Then, during the continuous addition of
60 L ethanol, a further 30 L solvent are distilled off at normal
pressure. It is inoculated with product and left to cool slowly to
RT. After 19 h, the precipitate is filtered off and washed with 15
L ethanol. After drying at 50.degree. C. in vacuo, 4710 g of
product is obtained.
[0090] Mass spectrum (ESI.sup.+): m/z=645 [M+H].sup.+
Example 7
tert-butyl(trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,-
2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate
##STR00027##
[0091] Process Step H
[0092] 470 g palladium (10%) on charcoal are added to a mixture of
4700 g
tert-butyl(trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yl-
oxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carbo-
xylate in 33 L isopropanol and 33 L dioxane. After 4 h
hydrogenation at 80.degree. C. the mixture is filtered at
60.degree. C. and washed with a mixture of 10 L isopropanol and 10
L dioxane. 58 L solvent are distilled off from the filtrate in
vacuo and 32 L tert-butylmethylether are added. After 2 h at
0-5.degree. C. the precipitate is filtered off and washed with 15 L
tert-butylmethylether. After drying at 50.degree. C. in vacuo 4153
g of product is obtained.
[0093] Mass spectrum (ESI.sup.+): m/z=555 [M+H].sup.+
Example 8
tert-butyl(trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-
-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate
##STR00028##
[0094] Process Step I
[0095] 1590 g N-chlorosuccinimide in 20 L acetonitrile are added to
a mixture of 5500 g
tert-butyl(trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2-
,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate and
3122 g triphenylphosphine in 24 L dioxane at 60.degree. C. within
one minute. The dropping funnel is rinsed with 4 L acetonitrile and
the mixture is heated to 80-90.degree. C. for 30 min. The mixture
containing the product is used directly in the next step.
Example 9
tert-butyl(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazoli-
n-6-yloxy]-5-oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-
-carboxylate
##STR00029##
[0096]
(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-
-yloxy]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one
hydrochloride
##STR00030##
[0097] Process Step J+K
[0098] After 20 min at 50-60.degree. C. 1733 g
3-chloro-2-fluoraniline are added to the mixture. The dropping
funnel is rinsed with 2 L acetonitrile. Then 7.8 kg 4 M
hydrochloric acid in dioxane are added and the mixture is stirred
for 45 min at 55-80.degree. C. After cooling to 1.degree. C. the
precipitate is filtered off and washed with 10 L ethanol. The
precipitate is suspended in 40 L ethanol and combined with 290 g
3-chloro-2-fluoroaniline. The suspension is stirred for 45 min at
70-80.degree. C. and then for 13 h at RT. The precipitate is
filtered off and washed with L ethanol. After drying at 60.degree.
C. in vacuo 4853 g of product is obtained as the hydrochloride.
[0099] Mass spectrum (ESI.sup.+): m/z=582 [M+H].sup.+
or: Process step O
[0100] A mixture of 3.42 g
(trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-1-(2,2,2-trifluoro-acet-
yl)-1,4-diaza-spiro[5.5]undecan-5-one and 1.25 g
3-chloro-2-fluoroaniline in 40 ml of ethanol is heated to
80.degree. C. for 2 h. After the suspension has been cooled to
20.degree. C. and stirred for 16 h the precipitate is filtered off
and washed with 10 mL ethanol and 10 mL tert-butylmethylether.
After drying at 100.degree. C. in vacuo, 3.28 g of product is
obtained.
[0101] Mass spectrum (ESI.sup.+): m/z=582 [M+H].sup.+
Example 10
(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-
-1,4-diaza-spiro[5.5]undecan-5-one
##STR00031##
[0102] Process Step L
[0103] A mixture of 4700 g
(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy-
]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one and
5150 g ethanolamine in 47 L ethanol is heated to 75-80.degree. C.
for 17 h. After the suspension has been cooled to 20.degree. C. the
precipitate is filtered off and washed with 15 L ethanol. After
drying at 60.degree. C. in vacuo, 3776 g of product is obtained as
the mono-ethanol solvate.
[0104] Mass spectrum (ESI.sup.+): m/z=486 [M+H].sup.+
[0105] 1H NMR (400 MHz, DMSO): 9.60 (1H, s; 8.37 (1H, s); 7.82 (1H,
s); 7.44-7.55 (2H, m), 7.37 (1H, s); 7.28 (1H, t); 7.22 (1H, s);
4.63-4.69 (1H, m); 4.33 (1H, t); 3.96 (3H, s); 3.41-3.49 (2H, m);
3.11-3.16 (2H, m); 2.82-2.87 (2H, m); 2.30 (1H, s); 2.14-2.23 (2H,
m); 1.84-1.97 (4H, m); 1.44-1.51 (2H, m); 1.06 (3H, t).
Example 11
(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-
-1,4-diaza-spiro[5.5]undecan-5-one dimaleic acid compound
##STR00032##
[0106] Process Step M
[0107] A solution of 1680 g maleic acid in 7 L ethanol and 7 L
water is added at 77.degree. C. to 3500 g
(trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy-
]-1,4-diaza-spiro[5.5]undecan-5-one mono-ethanol solvate in 18 L of
ethanol. The dropping funnel is rinsed with 3 L ethanol. The
solution is inoculated with product at 66.degree. C. and after 5
min 35 L ethanol are added dropwise to the suspension. The
suspension is cooled to 20.degree. and stirred for 1 h at this
temperature. Then it is cooled to 1.degree. C. and stirred for 16 h
at this temperature. The precipitate is filtered off and washed
twice with 10 L ethanol. After drying at 60.degree. C. in vacuo,
4362 g of product is obtained.
[0108] Mass spectrum (ESI.sup.+): m/z=486 [M+H].sup.+
[0109] .sup.1H NMR (400 MHz, DMSO): 8.50 (1H, s); 8.24 (1H, s);
7.93 (1H, s); 7.50-7.57 (2H, m), 7.29-7.35 (1H, m); 7.27 (1H, s);
6.15 (4H, s); 4.65-4.71 (1H, m); 3.98 (3H, s); 3.45-3.51 (2H, m);
3.39-3.44 (2H, m); 2.38-2.48 (2H, m); 2.06-2.15 (2H, m); 1.83-2.02
(4H, m).
Example 12
(trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-1-(2,2,2-trifluoro-acety-
l)-1,4-diaza-spiro[5.5]undecan-5-one
##STR00033##
[0110] Process Step I+N
[0111] 19.6 g N-chlorosuccinimide in 240 mL acetonitrile are added
at 60.degree. C. within two minutes to a mixture of 60 g
tert-butyl(trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2-
,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate and
37.5 g triphenylphosphine in 300 mL dioxane. The mixture is heated
to 80-90.degree. C. for 100 min. After 20 min at 50-60.degree. C.,
84 mL of 4 M hydrochloric acid in dioxane are added to the mixture
and the mixture is stirred for 3 h at 50-85.degree. C. After
stirring for 17 h at ambient temperature the mixture is cooled to
5.degree. C. and the precipitate is filtered off. The filter cake
is washed with a 1:1 mixture of dioxane/acetonitrile and with
tert-butylmethylether. After drying at 50.degree. C., 40 g of
product is obtained.
[0112] Mass spectrum (ESI.sup.+): m/z=473 [M+H].sup.+
Collection of Data
[0113] The following equipment and test conditions are used to
collect the data appended hereto.
X-Ray Powder Diffractometer
[0114] STOE Stadi P X-ray powder diffractometer with a
location-sensitive detector in transmission mode with a curved
germanium (111) primary monochromator; wavelength used:
CuK.sub..alpha. with .lamda.=1.540598 .ANG.; operation of the X-ray
tube: 40 kV, 40 mA; 2.theta. range: 3-40.degree.. The complete
X-ray powder diffraction pattern of compound (I) is shown in FIG.
1. The characteristic peak positions for the X-ray powder
diffraction pattern of compound (I) is shown in Table 1 below:
TABLE-US-00001 TABLE 1 X-ray reflections to 30.degree. 2 .crclbar.
inclusive intensities (standardised) of compound (I) 2 .crclbar.
d.sub.hkl Intensity [.degree.] [.ANG.] I/I.sub.o [%] 5.76 15.34 5
6.20 14.25 12 10.00 8.84 11 10.65 8.30 22 11.52 7.68 15 12.43 7.11
26 13.89 6.37 10 14.41 6.14 4 14.95 5.92 14 15.33 5.77 27 15.68
5.65 8 16.10 5.50 10 16.61 5.33 15 17.09 5.18 14 18.06 4.91 17
18.44 4.81 13 18.92 4.69 100 19.30 4.60 17 19.60 4.53 6 20.37 4.36
51 20.70 4.29 6 21.38 4.15 26 22.41 3.96 17 23.06 3.85 49 23.64
3.76 10 24.19 3.68 7 24.67 3.61 79 25.29 3.52 8 25.68 3.47 3 26.61
3.35 13 26.94 3.31 4 27.40 3.25 21 27.67 3.22 7 28.13 3.17 6 28.68
3.11 13 29.05 3.07 6 29.55 3.02 19 29.79 3.00 7
Thermoanalysis Equipment
[0115] A DSC 822 made by Mettler Toledo is used. The following
measuring parameters are used: heating rate: 10 K/min; type of
crucible: perforated aluminium crucible; atmosphere: N.sub.2, 80
ml/min flux; typical weights: 3-10 mg.
[0116] A TGA/SDTA 851 made by Mettler Toledo which is coupled to a
Nicolet FT-IR 4700 spectrometer (for analysing the volatile
fractions) is used. The following measuring parameters are used:
heating rate: 10K/min; type of crucible: open aluminium oxide
crucible; atmosphere: N.sub.2, 20 ml/min flux; typical weights:
15-25 mg.
[0117] The melting point of compound (I) can be inferred from the
DSC/TG schemes in FIG. 2 appended hereto.
Equipment for Water Sorption Tests
[0118] A DVS-1 made by Surface Measurement Systems (=SMS) is used
to test the hygroscopic characteristics: the following humidity
profiles are used: 10-90% r.h. in 10% steps, recording both a
sorption and a desorption profile, typical weights: 10-20 mg
[0119] The corresponding diagrams (kinetic and isothermic plot) of
the different forms are shown in FIGS. 3a) and b).
Biological Test
[0120] The biological properties of compound (I) are investigated
as follows, for example:
[0121] The inhibition of the EGF-R-mediated signal transmission can
be demonstrated e.g. with cells which express human EGF-R and whose
survival and proliferation depend on stimulation by EGF or
TGF-alpha. A murine haematopoietic cell line is genetically
modified so as to express functional human EGF-R. The proliferation
of this cell line can therefore be stimulated by EGF.
[0122] The test is carried out as follows:
[0123] The cells are cultivated in RPMI/1640 medium. The
proliferation is stimulated with 20 ng/ml of human EGF (Promega).
To investigate the inhibitory activity of the compounds according
to the invention these compounds are dissolved in 100%
dimethylsulfoxide (DMSO) and added to the cultures in various
dilutions, the maximum DMSO concentration being 1%. The cultures
are incubated for 48 hours at 37.degree. C.
[0124] In order to determine the inhibitory activity of compound
(I) according to the invention the relative cell number is measured
in O.D. units using the Cell Titer 96TM AQueous NonRadioactive Cell
Proliferation Assay (Promega). The relative cell number is
calculated as a percentage of the control and the concentration of
active substance which inhibits the proliferation of the cells by
50% (IC50) is derived therefrom.
TABLE-US-00002 TABLE 2 Inhibition of the EGFR-dependent
proliferation Compound IC.sub.50 [nM] (I) 4
Indications
[0125] As has been found, the compound of formula (I) is
characterized by its versatility in the therapeutic field.
Particular mention should be made of the possible applications for
which the compound of formula (I) according to the invention is
preferably used on the basis of its pharmaceutical efficacy as a
tyrosine inhibitor.
[0126] The compound of general formula (I) according to the
invention thus inhibits signal transduction by tyrosine kinases, as
demonstrated by the example of the human EGF receptor, and is
therefore useful for treating pathophysiological processes caused
by hyperfunction of tyrosine kinases. These are e.g. benign or
malignant tumours, particularly tumours of epithelial and
neuroepithelial origin, metastasisation and the abnormal
proliferation of vascular endothelial cells (neoangiogenesis).
[0127] The compound (I) according to the invention is also useful
for preventing and treating diseases of the airways and lungs which
are accompanied by increased or altered production of mucus caused
by stimulation of tyrosine kinases, e.g. in inflammatory diseases
of the airways such as chronic bronchitis, chronic obstructive
bronchitis, asthma, bronchiectasis, allergic or non-allergic
rhinitis or sinusitis, cystic fibrosis, .alpha.1-antitrypsin
deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and
hyperreactive airways.
[0128] The compound (I) is also suitable for treating diseases of
the gastrointestinal tract and bile duct and gall bladder which are
associated with disrupted activity of the tyrosine kinases, such as
may be found e.g. in chronic inflammatory changes such as
cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in
the gastrointestinal tract or such as may occur in diseases of the
gastrointestinal tract which are associated with increased
secretions, such as Menetrier's disease, secreting adenomas and
protein loss syndrome.
[0129] In addition, the compound (I) may be used to treat other
diseases caused by abnormal function of tyrosine kinases, such as
e.g. epidermal hyperproliferation (psoriasis), benign prostatic
hyperplasia (BPH), inflammatory processes, diseases of the immune
system, hyperproliferation of haematopoietic cells, the treatment
of nasal polyps, etc.
Combinations
[0130] The compound of formula (I) may be used on its own or in
combination with other active substances. These combinations may be
administered either simultaneously or sequentially. Optionally the
compound of formula (I) may also be used in combination with W,
wherein W denotes a pharmacologically active substance and is
selected (for example) from among betamimetics, anticholinergics,
corticosteroids, PDE4-inhibitors, LTD4-receptor (CysLT1, CysLT2,
CysLT3) antagonists, LTB4-receptor (BLT1, BLT2) antagonists,
inhibitors of MAP kinases such as for example p38, ERK1, ERK2,
JNK1, JNK2, JNK3 or SAP, bradykinin (BK1, BK2) receptor
antagonists, endothelin receptor antagonists, CXCR1 and/or CXCR2
receptor antagonists, and anti-tussive substances.
[0131] In addition, double or triple combinations of W may be
combined with the compounds of formula (I). Examples of
combinations of W with the compound of formula (I) might be: [0132]
W denotes a betamimetic, combined with an anticholinergic,
corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-receptor
antagonist, [0133] W denotes an anticholinergic, combined with a
betamimetic, corticosteroid, PDE4-inhibitor, EGFR-inhibitor or
LTD4-receptor antagonist, [0134] W denotes a corticosteroid,
combined with a PDE4-inhibitor, EGFR-inhibitor or LTD4-receptor
antagonist [0135] W denotes a PDE4-inhibitor, combined with an
EGFR-inhibitor or LTD4-receptor antagonist [0136] W denotes an
EGFR-inhibitor, combined with an anticholinergic.
[0137] Examples of betamimetics which may be used here preferably
include compounds which are selected from among arformoterol,
carmoterol, formoterol, indacaterol, salmeterol, albuterol,
bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,
fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin,
levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol,
orciprenalin, pirbuterol, procaterol, reproterol, rimiterol,
ritodrin, salmefamol, soterenol, sulphonterol, terbutalin,
tiaramid, tolubuterol, zinterol and
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one,
N-(5-{2-[3-(4,4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-p-
ropylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-d-
imethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamid-
e,
N-(5-{2-[3-(4,4-diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,-
1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphona-
mide,
N-(5-{2-[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-
-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-
-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propy-
lamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1--
yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propy-
lamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
N-[2-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-ph-
enyl]-ethylamino}-ethyl)-phenyl]-formamide,
8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl-
]-ethylamino}-ethyl)-1H-quinolin-2-one,
8-hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-qui-
nolin-2-one,
5-[(1R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethyla-
mino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,
[3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-
-hexyloxy}-butyl)-5-methylphenyl]-urea,
4-((1R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-et-
hyl)-2-hydroxymethyl-phenol,
3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]--
1-hexyloxy}-butyl)-benzenesulphonamide,
3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]--
heptyloxy}-propyl)-benzenesulphonamide,
4-((1R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hy-
droxy-ethyl)-2-hydroxymethyl-phenol,
N-1-adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymeth-
yl)phenyl]ethyl}amino)propyl]phenyl}acetamide,
(1R)-5-{2-[6-(2,2-difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}--
8-hydroxy-1H-quinolin-2-one,
(R,S)-4-(2-{[6-(2,2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxymethyl)phenol,
(R,S)-4-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxymethyl)phenol,
(R,S)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxymethyl)phenol,
(R,S)-4-(2-{[6-(4,4-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-
-2-(hydroxymethyl)phenol,
(R,S)-5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-
-8-hydroxyquinolin-2(1H)-one,
(R,S)-4-[2-{[6-(2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydr-
oxyethyl]-2-(hydroxymethyl)phenol,
4-(1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2--
(hydroxymethyl)phenol,
(R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5I5-tetrafluoro-6-(3-phenylp-
ropoxy)hexyl]amino}ethyl)phenol,
(R,S)-[5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl-
)-2-hydroxyphenyl]formamide,
(R,S)-4-[2-({6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydro-
xyethy]-2-(hydroxymethyl)phenol,
(R,S)--N-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl-
)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea,
3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl-
]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidin-2,4-dione,
(R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hyd-
roxyethyl]-2-(hydroxymethyl)phenol,
5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-
-hydroxyquinolin-2(1H)-one,
4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)--
2-(hydroxymethyl)phenol,
(R,S)-4-(2-{[6-(3,3-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl-
)-2-(hydroxymethyl)phenol,
(R,S)-(2-{[6-(2,2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hyd-
roxyethyl)-2-(hydroxymethyl)phenol,
(R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy
ethyl)-2-(hydroxymethyl)phenol,
3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydrox-
y-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide,
N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazo-
l-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide
7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-ethylamino)--
1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazole-2-one,
optionally in the form of the racemates, enantiomers, diastereomers
and optionally in the form of the pharmacologically acceptable acid
addition salts, solvates or hydrates thereof. Preferably, according
to the invention, the acid addition salts of the betamimetics are
selected from among hydrochloride, hydrobromide, hydriodide,
hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0138] Examples of anticholinergics which may be used here
preferably include compounds which are selected from among:
tiotropium salts, preferably the bromide salt, oxitropium salts,
preferably the bromide salt, flutropium salts, preferably the
bromide salt, ipratropium salts, preferably the bromide salt,
aclidinium salts, preferably the bromide salt, glycopyrronium
salts, preferably the bromide salt, trospium salts, preferably the
chloride salt, tolterodine,
(3R)-1-phenethyl-3-(9H-xanthen-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octan-
e-salts. In the above-mentioned salts the cations are the
pharmacologically active constituents. As X.sup.- anions the
above-mentioned salts may preferably contain chloride, bromide,
iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,
acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate
or p-toluenesulphonate, while chloride, bromide, iodide, sulphate,
methanesulphonate or p-toluenesulphonate are preferred as
counter-ions. Of all the salts the chlorides, bromides, iodides and
methanesulphonates are particularly preferred.
[0139] Other specified compounds are: tropenol
2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate
methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide,
tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol
3,3',4,4'-tetrafluorobenzilate methobromide, scopine
3,3',4,4'-tetrafluorobenzilate methobromide, tropenol
4,4'-difluorobenzilate methobromide, scopine 4,4'-difluorobenzilate
methobromide, tropenol 3,3'-difluorobenzilate methobromide, scopine
3,3'-difluorobenzilate methobromide; tropenol
9-hydroxy-fluorene-9-carboxylate methobromide, tropenol
9-fluoro-fluorene-9-carboxylate methobromide, scopine
9-hydroxy-fluorene-9-carboxylate methobromide, scopine
9-fluoro-fluorene-9-carboxylate methobromide; tropenol
9-methyl-fluorene-9-carboxylate methobromide, scopine
9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine
benzilate methobromide, cyclopropyltropine 2,2-diphenylpropionate
methobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate
methobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylate
methobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylate
methobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate
methobromide, cyclopropyltropine methyl 4,4'-difluorobenzilate
methobromide, tropenol 9-hydroxy-xanthene-9-carboxylate
methobromide, scopine 9-hydroxy-xanthene-9-carboxylate
methobromide, tropenol
9-methyl-xanthene-9-carboxylate-methobromide, scopine
9-methyl-xanthene-9-carboxylate-methobromide, tropenol
9-ethyl-xanthene-9-carboxylate methobromide, tropenol
9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine
9-hydroxymethyl-xanthene-9-carboxylate methobromide. The
above-mentioned compounds may also be used as salts within the
scope of the present invention, while instead of the methobromide,
the metho-X salts may be used wherein X may have the meanings given
hereinbefore for X.sup.-.
[0140] Compounds which may be used as corticosteroids are
preferably those selected from among: beclomethasone,
betamethasone, budesonide, butixocort, ciclesonide, deflazacort,
dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol,
mometasone, prednisolone, prednisone, rofleponide, triamcinolone,
tipredane and pregna-1,4-diene-3.20-dione,
6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-21-[[4-[(nitroox-
y)methyl]benzoyl]oxy]-, (6-alpha,11-beta,16-alpha)-(9Cl)
(NCX-1024),
16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-
-3-one (RPR-106541), (S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate, (S)-(2-oxo-tetrahydro-furan-3S-yl)
6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-
-17-carbothionate, cyanomethyl
6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,-
2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxy-
late, optionally in the form of the racemates, enantiomers or
diastereomers thereof and optionally in the form of the salts and
derivatives thereof, the solvates and/or hydrates thereof. Any
reference to steroids includes a reference to any salts or
derivatives, hydrates or solvates thereof which may exist. Examples
of possible salts and derivatives of the steroids may be: alkali
metal salts, such as for example sodium or potassium salts,
sulphobenzoates, phosphates, isonicotinates, acetates,
dichloroacetates, propionates, dihydrogen phosphates, palmitates,
pivalates or furoates.
[0141] PDE4-inhibitors which may be used are preferably compounds
selected from among enprofyllin, theophyllin, roflumilast, ariflo
(cilomilast), tofimilast, pumafentrin, lirimilast, apremilast,
arofyllin, atizoram, oglemilast, tetomilast, and
5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline
(D-4418),
N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(-
trifluoromethyl)-quinoline (D-4396 (Sch-351591)),
N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyox-
ylic acid amide (AWD-12-281 (GW-842470)),
9-[(2-fluorophenylmethyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine
(NCS-613),
4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine
(CDP-840),
N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]b-
enzodiazepin-3-yl]-4-pyridinecarboxamide (PD-168787),
4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-
-2(1H)-pyridinone (T-440),
2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4--
(3-pyridinyl)-1(2H)-phthalazinone (T-2585),
(3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine
(V-11294A),
beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoind-
ole-2-propanamide (CDC-801),
imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one,
9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888),
5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenylmethyl],
(3S,5S)-2-piperidinone (HT-0712),
4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinylethy-
l]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol (L-826141),
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethox-
ybenzamide,
(-).sub.p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-met-
hylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone,
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-5-methyl-isot-
hioureido]benzyl)-2-pyrrolidone,
cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid],
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyph-
enyl)cyclohexan-1-one,
cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1--
ol],
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden-
e]acetate,
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2--
ylidene]acetate,
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4--
triazolo[4,3-a]pyridine,
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridine,
optionally in the form of the racemates, enantiomers, diastereomers
thereof and optionally in the form of the pharmacologically
acceptable acid addition salts, solvates or hydrates thereof.
According to the invention the preferred acid addition salts are
selected from among hydrochloride, hydrobromide, hydriodide,
hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0142] LTB4-receptor antagonists used here are preferably compounds
selected from among for example amebulant
(=ethyl[[4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenoxy]methyl]phen-
yl]methoxy]phenyl]iminomethyl]-carbamate), optionally in the form
of the racemates, enantiomers, diastereomers thereof and optionally
in the form of the pharmacologically acceptable acid addition
salts, solvates, prodrugs or hydrates thereof. According to the
invention the preferred acid addition salts are selected from among
hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
[0143] LTD4-receptor antagonists used here are preferably compounds
selected from among montelukast, pranlukast, zafirlukast, and
(E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl-
)-4H-1-benzopyran-4-one (MEN-91507),
4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propyl-
phenoxy]butyric acid (MN-001),
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)phenyl)thio)methylcyclopropaneacetic acid,
1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phen-
yl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneac-
etic acid,
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phen-
yl]acetic acid optionally in the form of the racemates,
enantiomers, diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts, solvates or
hydrates thereof. According to the invention the preferred acid
addition salts are selected from among hydrochloride, hydrobromide,
hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,
hydronitrate, hydromaleate, hydroacetate, hydrocitrate,
hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,
hydrobenzoate and hydro-p-toluenesulphonate.
[0144] By salts or derivatives which the LTD4-receptor antagonists
are optionally capable of forming are meant, for example: alkali
metal salts, such as for example sodium or potassium salts,
alkaline earth metal salts, sulphobenzoates, phosphates,
isonicotinates, acetates, propionates, dihydrogen phosphates,
palmitates, pivalates or furoates.
[0145] MAP Kinase inhibitors used are preferably compounds selected
from among:
bentamapimod (AS-602801), doramapimod (BIRB-796), 5-carbamoylindole
(SD-169),
6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophe-
nyl)-3-pyridinecarboxamide (VX-702),
alpha-[2-[[2-(3-pyridiny)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleaceto-
nitrile (AS-601245),
9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1.6]benzodiazo-
cine-10-carboxylic acid (CEP-1347),
4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazole-4-yl]-pyrimi-
dine (SC-409), optionally in the form of the racemates,
enantiomers, diastereomers thereof and optionally in the form of
the pharmacologically acceptable acid addition salts, prodrugs,
solvates or hydrates thereof.
[0146] Bradykinin receptor antagonists that may be used are
preferably compounds selected from among icatibant and
1-piperazinepentanaminium,
delta-amino-4-[[4-[[[2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]meth-
yl]phenyl]sulphonyl]amino]tetrahydro-2H-pyran-4-yl]carbonyl]-N,N,N-trimeth-
yl-c-oxo, chloride, hydrochloride (1:1:1), (deltaS)-(MEN-16132),
optionally in the form of the racemates, enantiomers and
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, prodrugs,
solvates or hydrates thereof.
[0147] Endothelin antagonists that may be used are preferably
compounds selected from among actelion-1, ambrisentan, sitaxsentan,
N-(2-acetyl-4,6-dimethylphenyl)-3-[[(4-chloro-3-methyl-5-isoxazolyl)amino-
]sulphonyl]-2-thiophenecarboxamide (TBC-3214) and bosentan,
optionally in the form of the racemates, enantiomers and
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, prodrugs,
solvates or hydrates thereof.
[0148] Antitussive substances that may be used are preferably
compounds selected from among hydrocodone, caramiphen,
carbetapentane and dextramethorphan, optionally in the form of the
racemates, enantiomers and diastereomers thereof and optionally in
the form of the pharmacologically acceptable acid addition salts,
prodrugs, solvates or hydrates thereof.
[0149] Substances of preferred CXCR1 and/or CXCR2 receptor
antagonists that may be used are preferably compounds such as e.g.
3-[[3-[(dimethylamino)carbonyl]-2-hydroxyphenyl]amino]-4-[[(R)-1-(5-methy-
lfuran-2-yl)propyl]amino]cyclobut-3-ene-1,2-dione (SCH-527123),
optionally in the form of the racemates, enantiomers and
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, prodrugs,
solvates or hydrates thereof.
[0150] It is preferable, according to the invention, to use the
acid addition salts of the above-mentioned betamimetics,
anticholinergics, corticosteroids, PDE4 inhibitors, LTB4 (BLT1,
BLT2) receptor antagonists, LTD4 (CysLT1, CysLT2, CysLT3) receptor
antagonists, inhibitors of MAP kinases such as for example p38,
ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, bradykinin receptor
antagonists, endothelin receptor antagonists, antitussive
substances, CXCR1 and/or CXCR2 receptor antagonists also selected
from among hydrochloride, hydrobromide, hydriodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate.
Pharmaceutical Compositions
[0151] The compound according to the invention may be administered
by oral, transdermal, inhalative, parenteral or sublingual route.
The compound according to the invention is present as an active
ingredient in conventional preparations, for example in
compositions consisting essentially of an inert pharmaceutical
carrier and an effective dose of the active substance, such as for
example tablets, coated tablets, capsules, wafers, powders,
solutions, suspensions, emulsions, syrups, suppositories,
transdermal systems etc. An effective dose of the compound
according to the invention for oral administration is between 0.1
and 5000, preferably between 1 and 500, particularly preferably
between 5-300 mg/dose, when administered by intravenous,
subcutaneous or intramuscular route between 0.001 and 50,
preferably between 0.1 and 10 mg/dose. For Inhalation, according to
the invention suitable solutions are those that contain 0.01 to
1.0, preferably 0.1 to 0.5 of active substance. For inhalative
administration the use of powders, ethanolic or aqueous solutions
is preferred. It is also possible to use the compound according to
the invention as an infusion solution, preferably in a
physiological saline solution or nutrient solution.
[0152] The compound according to the invention may be used on its
own or in conjunction with other active substances according to the
invention, optionally also in conjunction with other
pharmacologically active substances. Suitable formulations include,
for example, tablets, capsules, suppositories, solutions, syrups,
emulsions or dispersible powders. Corresponding tablets may be
obtained for example by mixing the active substance(s) with known
excipients, for example inert diluents, such as calcium carbonate,
calcium phosphate or lactose, disintegrants such as maize starch or
alginic acid, binders such as starch or gelatine, lubricants such
as magnesium stearate or talc and/or agents for delaying release,
such as carboxymethyl cellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise several
layers.
[0153] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number of
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0154] Syrups containing the active substances or combinations
thereof according to the invention may additionally contain a
sweetener such as saccharine, cyclamate, glycerol or sugar and a
flavour enhancer, e.g. a flavouring such as vanillin or orange
extract. They may also contain suspension adjuvants or thickeners
such as sodium carboxymethyl cellulose, wetting agents such as, for
example, condensation products of fatty alcohols with ethylene
oxide, or preservatives such as p-hydroxybenzoates.
[0155] Solutions for injection are prepared in the usual way, e.g.
with the addition of preservatives such as p-hydroxybenzoates, or
stabilisers such as alkali metal salts of ethylenediamine
tetraacetic acid, and transferred into injection vials or
ampoules.
[0156] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[0157] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0158] For pharmaceutical use the compound according to the
invention is generally used for warm-blooded vertebrates,
particularly humans, in doses of 0.01-100 mg/kg of body weight,
preferably 0.1-15 mg/kg. For administration it may be formulated
for example with one or more conventional inert carriers and/or
diluents, e.g. with corn starch, lactose, glucose, microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid,
tartaric acid, water, water/ethanol, water/glycerol,
water/sorbitol, water/polyethylene glycol, propylene glycol,
stearyl alcohol, carboxymethylcellulose or fatty substances such as
hard fat or suitable mixtures thereof to produce conventional
galenic preparations such as plain or coated tablets, capsules,
powders, suspensions, solutions, sprays or suppositories.
[0159] The Examples which follow illustrate the present invention
without restricting its scope:
Examples of Pharmaceutical Formulations
[0160] A) Coated Tablets Containing 75 mg of Active Substance
Composition:
[0161] 1 tablet core contains:
TABLE-US-00003 active substance 75.0 mg calcium phosphate 93.0 mg
corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg
hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg
230.0 mg
Preparation:
[0162] The active substance is mixed with calcium phosphate, corn
starch, polyvinyl-pyrrolidone, hydroxypropylmethylcellulose and
half the specified amount of magnesium stearate. Blanks 13 mm in
diameter are produced in a tablet-making machine and these are then
rubbed through a screen with a mesh size of 1.5 mm using a suitable
machine and mixed with the rest of the magnesium stearate. This
granulate is compressed in a tablet-making machine to form tablets
of the desired shape. [0163] Weight of core: 230 mg [0164] die: 9
mm, convex
[0165] The tablet cores thus produced are coated with a film
consisting essentially of hydroxypropylmethylcellulose. The
finished film-coated tablets are polished with beeswax. [0166]
Weight of coated tablet: 245 mg.
B) Tablets Containing 100 mg of Active Substance
Composition:
[0167] 1 tablet contains:
TABLE-US-00004 active substance 100.0 mg lactose 80.0 mg corn
starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0
mg 220.0 mg
Method of Preparation:
[0168] The active substance, lactose and starch are mixed together
and uniformly moistened with an aqueous solution of the
polyvinylpyrrolidone. After the moist composition has been screened
(2.0 mm mesh size) and dried in a rack-type drier at 50.degree. C.
it is screened again (1.5 mm mesh size) and the lubricant is added.
The finished mixture is compressed to form tablets. [0169] Weight
of tablet: 220 mg [0170] Diameter: 10 mm, biplanar, facetted on
both sides and notched on one side.
C) Tablets Containing 150 mg of Active Substance
Composition:
[0171] 1 tablet contains:
TABLE-US-00005 active substance 150.0 mg powdered lactose 89.0 mg
corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone
10.0 mg magnesium stearate 1.0 mg 300.0 mg
Preparation:
[0172] The active substance mixed with lactose, corn starch and
silica is moistened with a 20% aqueous polyvinylpyrrolidone
solution and passed through a screen with a mesh size of 1.5 mm.
The granules, dried at 45.degree. C., are passed through the same
screen again and mixed with the specified amount of magnesium
stearate. Tablets are pressed from the mixture. [0173] Weight of
tablet: 300 mg [0174] die: 10 mm, flat
D) Hard Gelatine Capsules Containing 150 mg of Active Substance
Composition:
[0175] 1 capsule contains:
TABLE-US-00006 active substance 150.0 mg corn starch (dried)
approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium
stearate 3.0 mg approx. 420.0 mg
Preparation:
[0176] The active substance is mixed with the excipients, passed
through a screen with a mesh size of 0.75 mm and homogeneously
mixed using a suitable apparatus. The finished mixture is packed
into size 1 hard gelatine capsules. [0177] Capsule filling: approx.
320 mg [0178] Capsule shell: size 1 hard gelatine capsule.
E) Suppositories Containing 150 mg of Active Substance
Composition:
[0179] 1 suppository contains:
TABLE-US-00007 active substance 150.0 mg polyethyleneglycol 1500
550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan
monostearate 840.0 mg 2,000.0 mg
Preparation:
[0180] After the suppository mass has been melted the active
substance is homogeneously distributed therein and the melt is
poured into chilled moulds.
F) Suspension Containing 50 mg of Active Substance
Composition:
[0181] 100 ml of suspension contain:
TABLE-US-00008 active substance 1.00 g
carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05
g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g
70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100
ml
Preparation:
[0182] The distilled water is heated to 70.degree. C. The methyl
and propyl p-hydroxybenzoates together with the glycerol and sodium
salt of carboxymethylcellulose are dissolved therein with stirring.
The solution is cooled to ambient temperature and the active
substance is added and homogeneously dispersed therein with
stirring. After the sugar, the sorbitol solution and the flavouring
have been added and dissolved, the suspension is evacuated with
stirring to eliminate air. [0183] 5 ml of suspension contain 50 mg
of active substance.
G) Ampoules Containing 10 mg Active Substance
Composition:
TABLE-US-00009 [0184] active substance 10.0 mg 0.01N hydrochloric
acid q.s. double-distilled water ad 2.0 ml
Preparation:
[0185] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with common salt, filtered sterile and
transferred into 2 ml ampoules.
H) Ampoules Containing 50 mg of Active Substance
Composition:
TABLE-US-00010 [0186] active substance 50.0 mg 0.01N hydrochloric
acid q.s. double-distilled water ad 10.0 ml
Preparation:
[0187] The active substance is dissolved in the necessary amount of
0.01N HCl, made isotonic with common salt, filtered sterile and
transferred into 10 ml ampoules.
* * * * *