OA16485A - 9-[4-(3-chlor-2-fluor-phenylamino)-7methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof. - Google Patents
9-[4-(3-chlor-2-fluor-phenylamino)-7methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate, use thereof as a drug, and production thereof. Download PDFInfo
- Publication number
- OA16485A OA16485A OA1201300297 OA16485A OA 16485 A OA16485 A OA 16485A OA 1201300297 OA1201300297 OA 1201300297 OA 16485 A OA16485 A OA 16485A
- Authority
- OA
- OAPI
- Prior art keywords
- formula
- compound
- optionally
- hydroxy
- tautomers
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- JPFLINXTDIKQQV-SPIKMXEPSA-N (Z)-but-2-enedioic acid;9-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxy-1,4-diazaspiro[5.5]undecan-5-one Chemical compound OC(=O)\C=C/C(O)=O.OC(=O)\C=C/C(O)=O.C=12C=C(OC3CCC4(CC3)C(NCCN4)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F JPFLINXTDIKQQV-SPIKMXEPSA-N 0.000 title description 2
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- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229960000797 oxitropium Drugs 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-M oxolane-2-carboxylate Chemical compound [O-]C(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-M 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 201000004681 psoriasis Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960002720 reproterol Drugs 0.000 description 1
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- 229960002052 salbutamol Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 230000003248 secreting Effects 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 229960002578 sitaxentan Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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- 238000009492 tablet coating Methods 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 230000001960 triggered Effects 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 201000006704 ulcerative colitis Diseases 0.000 description 1
- 229940117960 vanillin Drugs 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The invention relates to a compound of formula (I),
Description
Boehringer Ingelheim International GmbH
9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazoline-6-yloxy]-1,4-diazaspiro[5.5]undecane-5-one dimaleate, use thereof as a médicament and method for the production thereof
The présent invention relates to the compound of formula (I),
Cl
OH
OH
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 ofthe lungs and airways.
BACKGROUND TO THE INVENTION
Quinazoline dérivatives 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 dérivatives are described in W003082290 and WO07068552. W02009098061 discloses the base (compound (II)) of the dimaleate sait according to the invention (compound (I)).
The aim of the présent invention is to provide a sait of 9-[4-(3-chloro-2-fluorophenylamino)-7-methoxy-quïnazolin-6-yloxy]-1,4-diaza-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 hyperfunctîon of tyrosine-kinases.
The compound prepared in the présent invention is supposed to meet the requirements for physical and chemical stability and other properties, such as for example crystalline vS''' 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 médicament
A further aim of the présent invention is to provide a stereoselective process for preparing the compound according to the invention.
DESCRIPTION OF THE DRAWINGS
Table 1: X-ray reflections up to 30 ° 2 Θ inclusive intensities (standardised) of compound (I)
Figure 1: X-ray powder diagram of compound (I)
Figure 2: DSC/TG schemes of compound (I)
Figure 3: Sorption isothemns of compound (I): a.) kinetic plot, b.) isothermic plot
DETAILED DESCRIPTION OF THE INVENTION
The présent invention solves the above-mentioned problème 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 présent invention, that X-ray powder diagrams of the compound of formula (I) hâve sharp reflections with high intensity up to the upper 2 Θ range, preferably up to 20 40 0 2 Θ.
By low hygroscopicity is meant, within the scope of the présent 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.
By low polymorphism is meant, within the scope of the présent invention, that after recrystallisation 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.
The invention relates to a compound of formula (I)
optionally in the form of the tautomers, solvatés or hydrates thereof.
A crystalline compound of formula (I) is preferred wherein reflections occur in the X-ray powder diagram with dhki values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 A.
The invention further relates to the above-mentioned compound for use as a médicament, preferably for the treatment of inflammatory or allergie diseases of the airways, particularly preferably for the treatment of chronic obstructive bronchitis (COPD) and/or chronic bronchitis.
It is also préférable to use the compound of formula (I), the disease in question being one that is selected from among acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergie bronchitis, toxic bronchitis, asthma (intrinsic or allergie), paediatric asthma, bronchiectasis, allergie alveolitis, allergie 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, collagénoses 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.
it is also preferred to use the compound of formula (I) in cases of inflammatory or allergie complaints in which autoimmune reactions are involved.
It is also preferred to use the compounds of formula (I) in cases of a disease in the form of benign or malignant tumours.
The invention further relates to a process for the stereoselective préparation of the compound of formula (I), optionally in the form of the tautomers, solvatés or hydrates thereof: /*/
the process comprising reaction steps (A) to (M), wherein (A) dénotés the reaction of 1,4-cyclohexanedione-mono-ethyleneketal to form a compound of formula (1)
(B) is the reaction of a compound of formula (1) to form the compound of for- mula (2)
Xpç xHCI (2), (C) is the reaction of a compound of formula (2) to form the compound of formula (3)
(3) (D) is the reaction of a compound of formula (3) with a protective group reagent to form the compound of formula (4)
(E) is the réduction of a compound of formula (4) to form the compound of formula (5)
(F) is the reaction of a compound of formula (5) to form a compound of formula (6)
HO
(6) (G) is the reaction of a compound of formula (6) with a compound of formula (13) to form a compound of formula (7)
(13)
(7) (H) is the reaction of a compound of formula (7) to form a compound of formula (8a) or its tautomeric form (8b),
(I) is the chlorination of the compound of formula (8a) or (8b) to form a com- pound of formula (9)
(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 (11 A)
(11)
(L) is the cleaving of another protective group to form the compound of formula (II)
(II) (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, solvatés or hydrates thereof,
OH
OH while process steps (A) to (M) take place successively in the sequence indicated.
The invention further relates to a process for the stereoselective préparation of the compound of formula (I), optionally in the form of the tautomers, solvatés or hydrates thereof, comprising process steps (A) to (M), wherein process steps (J+K) are replaced by steps (N+O), where (N+O) is the cleaving of a protectîve group of the compound of formula (9) to form the compound of formula (12) and subséquent reaction with 3-chloro-2-fluoraniline to form the compound of formula (11) or (11 A)
In a preferred process for the stereoselective préparation 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.
Another preferred process for the stereoselective préparation of a compound of formula (II) is characterised in that the process consists of process steps (I), (J), (K) and vx/'”' (L), or of process steps (l),(N), (O) and (L), while process steps (I) to (L) in each case take place successively in the order indicated.
Particularly preferred is process step (G).
Also particularly preferred is process step (I).
The invention further relates to the intermediate of formula (6), optionally in the form of the tautomers, solvatés or hydrates thereof.
The invention further relates to the intermediate of formula (7), optionally in the form of the tautomers, solvatés or hydrates thereof.
The invention further relates to the intermediate of formula (8), optionally in the form of the tautomers, solvatés or hydrates thereof.
The invention further relates to the intermediate of formula (9), optionally in the form of the tautomers, solvatés or hydrates thereof.
The invention further relates to the intermediate of formula (11) or (11 A), optionally in the form of the tautomers, solvatés or hydrates thereof.
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.
In another aspect the invention relates to médicament 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, cortîcosteroids, PDE4-inhibitors, LTD4-receptor antagoniste, 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.
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
A: in addition to ethylenediamine and chloroform :
preferably benzyltriéthylammonium chloride /NaOH, tetrabutylammonium chloride/ KOH, benzyltriéthylammonium chloride /KOHJetrabutylammonium chloride/ NaOH, particularly preferably benzyltriéthylammonium chloride/ NaOH; —
C: | preferably alkoxîde bases selected from among NaO'Bu, KO'Bu and NaOEt, carbonate bases selected from among CS2CO3, K2CO3, Li2CO3 and Na2CO3i particularly preferably sodium methoxide; |
D: | in addition to di-tert-butyldicarbonate and DMAP (4-(dimethylamino)-pyridine): preferably K2CO3,Cs2CO3, Li2CO3 and Na2CO3, particularly preferably K2CO3; |
E: F: | preferably NaBH4 and LiBH4, particularly preferably NaBH4; in addition to trifluoroacetic anhydride: as base preferably triethylamine, Hünig base, N-methylmorpholine and N,Ndiethylaniline, particularly preferably triethylamine; |
G: | in addition to 3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4-one: preferably triphenylphosphine/ diisopropyl azodicarboxylate, triphenylphosphine/ diethyl azodicarboxylate, tributylphosphine/ 1,T-(azodicarbonyl)dipiperidine, particularly preferably triphenylphosphine/ diisopropyl azodicarboxylate; |
H: I: | catalysts, preferably selected from among Pd/C and Pd(OH)2, particularly preferably Pd/C; preferably N-chlorosuccinimide/triphenylphosphane (in combination), oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotrîphenylphosphorane and P,P-dichlorophenylphosphine oxide, particularly preferably N-chlorosuccinimide/ triphenylphosphane (in combination); |
J+K: L: | in addition to 3-chloro-2-fluooraniline: preferably HCl, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic acid and HBr, particularly preferably HCl; preferably ethanolamine, ammonia and Ba(OH)21 particularly preferably ethanolamine; |
l+N: | preferably N-chlorosuccinimide/triphenylphosphane (in combination), HCl, oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, carbon tetrachloride/triphenylphosphane, dichlorotrîphenylphosphorane, P,P-dichlorophenylphosphine oxide, methanesulphonic acid, ethanesulphonic acid, ptoluenesulphonic acid and HBr, particularly preferably Nchlorosuccinimide/triphenylphosphane (in combination) and HCl. |
The use of the following solvents selected from the group specified in each case is preferred in the process steps described above:
In process step
A: CH2CI2, CHCI3, THF (tetrahydrofuran) and dioxane;
B: HOAc, dioxane, H2O and aqueous solutions of the following solvents selected from among EtOH, THF, ÎPrOH, MeOH, NMP (N-methyl-2-pyrrolidone) and DM F (dimethylformamide);
C: ACN (CH3CN), EtOH, MeOH, ÎPrOH, H2O, THF and NMP;
D: ACN, EtOH and NMP;
E: H2O, MeOH, EtOH, THF and dioxane;
F: Me-THF, THF, toluene, CH2CI2 and dioxane;
G: THF, NMP, dioxane, DMF and CH2CI2:
H: ÎPrOH, 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, ÎPrOH and dioxane;
M: EtOH, MeOH and H2O;
N: dioxane/ACN and THF/dioxane
O: EtOH, n-PrOH, dioxane and NMP
The process steps described above are preferably carried out in the following température ranges:
In process step:
A: preferably -15 to 40°C, particularly preferably 0 to 20°C;
B: preferably 0 to 100°C, particularly preferably 75 to 100°C;
C: preferably 0 to 65°C, particularly preferably 15 to 30°C;
D: preferably 10 to 80°C, particularly preferably 15 to 35°C;
E: preferably 0 to 40°C, particularly preferably 0 to 15°C;
F: preferably -10 to 60°C, particularly preferably 0 to 35°C;
G: preferably 10 to 65°C, particularly preferably 45 to 60°C;
H: preferably 20 to 85°C, particularly preferably 70 to 85°C;
I: preferably 20 to 100°C, particularly preferably 70 to 95°C;
J: preferably 20 to 100°C, particularly preferably 50 to 85°C;
K: preferably 20 to 100°C, particularly preferably 50 to 85°C;
L: preferably 50 to 80°C, particularly preferably 70 to 80°C; y/y''''
M: preferabiy Ο to 75°C, partîcularly preferabiy 0 to 70°C.
N: preferabiy 20 to 100°C, partîcularly preferabiy 50 to 85°C;
O: preferabiy 50 to 100°C, partîcularly preferabiy 70 to 80°C;
Preferabiy, protective groups selected from among benzyl, Cbz, trifluoracetyl and Boc, partîcularly trifluoracetyl and Boc, are used.
The abbreviatîon Boc used in the above formulae dénotés tertiary butyl carbamate and Cbz dénotés benzyloxycarbonyl.
io Scheme 1 illustrâtes the synthesis according to the invention. Ail the compounds are shown in the form of their bases.
Scheme 1 (part 1 of 2) Synthesis of compound (I) NJ''
(7)
Scheme 1 (part 2 of 2)
(l)
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
NH (1)
Process step A
15.1 kg of 50% sodium hydroxide solution are added dropwise at 5°C to a mixture of 437 g benzyltriéthylammonium 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 515°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°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 hâve been distilled off, 48 L isopropanol are added to the suspension and then a further 30 L solvent are distilled off. After cooling to 3qC the precipitate is filtered off and washed twice with 7.5 L cold isopropanol. After drying at 50°C in vacuo, 6144 g of product is obtaîned.
Mass spectrum (ESI*): m/z = 227 [M+HJ*
Example 2
1,4-diaza-spiro[5.5]undecane-5,9-dione
O.
NH (3)
Process step B
14.5 kg of 4M HCl in dioxane are added dropwise within 15 min to 6085 g 1,4-dioxa-9,12diaza-dispiro[4.2.5.2]pentadecan-13-one in 25 kg acetic acid at 80-100°C. The dropping funnel is rinsed with 3 kg acetic acid. After 140 min the suspension is cooled to 20°C. After 2h the precipitate is filtered off and washed twice with 12 L dioxane. After drying at 60°C in vacuo, 5333 g of product is obtained as the hydrochloride.
Mass spectrum (ESf): m/z = 183 [M+H]+
Process step C
5200 g of 1,4-diaza-spiro[5.5]undecane-5,9-dione hydrochoride in 52 L acetonitrile are combined with 4370 ml 30% sodium methoxide solution in methanol at RT within 3h. 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
O.
(4)
Process step D
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°C. It is rinsed with 2 L water, 5 L acetonitrile and 16 L toluene. After phase séparation 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°C. 20 L methylcyclo17 hexane are added and the mixture is cooled to -5°C. After 2.5h the precipitate is filtered off and washed with 10 L methylcyclohexane. After drying at 50°C in vacuo, 5160 g of product is obtained.
Mass spectrum (ESI+): m/z = 283 [M+H]+
Example 4 tert-butyl (cis)-9-hydroxy-5-oxo-1,4-diaza-spiro[5.5]undecane-4-carboxylate
HO (5)
Process step E
201 g sodium borohydride in 5 L water are added dropwise at 3°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 methyltetrahydrofuran 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 methyltetrahydrofuran. 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.
Mass spectrum (ESI*): m/z = 285 [M+H]+
Example 5 tert-butyl (cis)-9-hydroxy-5-oxo-1 -(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4carboxylate
(6)
Process step F
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°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°C within 50 min. After 1h at 2°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°C in the circulating air dryer 5299 g of product is obtained as a cis/trans mixture.
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°C it is inoculated with product. After 3h at 1°C the precipitate is centrifuged off and washed with 8 L cold toluene. After drying at 55°C in vacuo 4398 g of product is obtained, which still contains approx. 4% trans product.
Mass spectrum (ESI+): m/z = 381 [M+H]+
Example 6 tert-butyl (trans)-9-(3-benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate
O (?) «r-
Process step G
2471 ml dîisopropyl 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-diazaspiro[5.5]undecane-4-carboxylate, 2362 g 3-benzyl-6-hydroxy-7-methoxy-3H-quinazolin-4one and 3292 g triphenylphosphine in 45 L tetrahydrofuran at 50-55°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 éthanol, 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 éthanol. After drying at 50°C in vacuo, 4710 g of product is obtained.
Mass spectrum (ESI+): m/z = 645 [M+Hf
Ëxample 7 tert-butyl (trans)-9-(4-hydroxy-7-methoxy-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoroacetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate
Process step H
470 g palladium (10%) on charcoal are added to a mixture of 4700g tert-butyl (trans)-9-(3benzyl-7-methoxy-4-oxo-3,4-dihydro-quinazolin-6-yloxy)-5-oxo-1-(2,2,2-trifluoro-acetyl)-
1,4-diaza-spiro[5.5]undecane-4-carboxylate in 33 L isopropanol and 33 L dioxane. After 4 h hydrogénation at 80°C the mixture is filtered at 60°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°C the precipitate is filtered off and washed with 15 L tert-butylmethylether. After drying at 50°C in vacuo 4153 g of product is obtained.
Mass spectrum (ESI+): m/z = 555 [M+Hf
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
Cl (9)
Process step I
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)-1,4diaza-spiro[5.5]undecane-4-carboxylate and 3122 g triphenylphosphine in 24 L dioxane at 60°C within one minute. The dropping funnel is rinsed with 4 L acetonitrile and the mixture is heated to 80-90°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-quinazolin-6-yloxy]- 5oxo-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecane-4-carboxylate
Cl (1°) (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1 -(2,2,2trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one hydrochloride
Process step J+K
After 20 min at 50-60°C 1733 g 3-chloro-2-fluoranilin 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°C. After cooling to 1°C the precipitate is filtered off and washed with 10 L éthanol. The precipitate is suspended in 40 L éthanol and combined with 290 g 3-chloro-2-fluoroaniline. The suspension is stirred for 45 min at 70-80°C and then for 13 h at RT. The precipitate is filtered off and washed with 10 L éthanol. After drying at 60°C in vacuo 4853 g of product is obtained as the hydrochloride. Mass spectrum (ESI*): m/z = 582 [M+H]+ or:
Process step O
A mixture of 3.42 g (trans)-9-(4-chloro-7-methoxy-quinazolin-6-yloxy)-1-(2,2,2-trifluoroacetyl)-1,4-diaza-spiro[5.5]undecan-5-one and 1.25 g 3-chloro-2-fluoroaniline in 40 ml of éthanol is heated to 80°C for 2 h. After the suspension has been cooled to 20°C and stirred for 16 h the precipitate is filtered off and washed with 10 mL éthanol and 10 mL tert-butylmethylether. After drying at 100°C in vacuo, 3.28 g of product is obtained.
Mass spectrum (Ε5Γ): m/z = 582 [M+H]+ sf/
Example 10 (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one
Process step L
A mixture of 4700 g (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6yloxy]-1-(2,2,2-trifluoro-acetyl)-1,4-diaza-spiro[5.5]undecan-5-one and 5150 g ethanolamine in 47 L éthanol is heated to 75-80°C for 17 h. After the suspension has been cooled to 20°C the precipitate is filtered off and washed with 15 L éthanol. After drying at 60°C in vacuo, 3776 g of product is obtained as the mono-ethanol solvaté.
Mass spectrum (ESI+): m/z = 486 [M+H]+
1H NMR (400 MHz, DMSO): 9.60 (1H, s); 8.37 (1H, s); 7.82 (1 H, s); 7.44-7.55 (2H, m), 7.37 (1H, s); 7.28 (1H, t); 7.22 (1H, s); 4.63-4.69 (1 H, m); 4.33 (1 H, t); 3.96 (3H, s); 3.413.49 (2H, m); 3.11-3.16 (2H, m); 2.82-2.87 (2H, m); 2.30 (1H, s); 2.14-2.23 (2H, m); 1.841.97 (4H, m); 1.44-1.51 (2H, m); 1.06 (3H, t).
Example 11 (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quînazo1in-6-yloxy]-1,4-diazaspiro[5,5]undecan-5-one dimaleic acid compound
Process step M
A solution of 1680 g maleic acid in 7 L éthanol and 7 L water is added at 77°C to 3500 g (trans)-9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diazaspiro[5.5]undecan-5-one mono-ethanol solvaté in 18 L of éthanol. The dropping funnel is rinsed with 3 L éthanol. The solution is inoculated with product at 66°C and after 5 min 35 L éthanol are added dropwise to the suspension. The suspension is cooled to 20° and stirred for 1 h at this température. Then it is cooled to 1°C and stirred for 16 h at this température. The precipitate is filtered off and washed twice with 10 L éthanol. After drying at 60°C in vacuo, 4362 g of product is obtained.
Mass spectrum (ESI+): m/z = 486 [M+H]+
1H NMR (400 MHz, DMSO): 8.50 (1 H, s); 8.24 (1H, s); 7.93 (1H, s); 7.50-7.57 (2H, m), 7.29-7.35 (1 H. 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-acetyl)-1I4-diazaspiro[5.5]undecan-5-one
(12)
Process step l+N
19.6 g N-chlorosuccinimide in 240 mL acetonitrile are added at 60°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°C for 100 min. After 20 min at 50-60°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°C. After stirring for 17 h at ambient température the mixture is cooled to 5°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°C 40 g of product is obtained.
Mass spectrum (ESI*): m/z = 473 [M+Hf
Collection of data
The following equipment and test conditions are used to coilect the data appended hereto.
X-rav powder diffractometer
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.tn with λ = 1.540598 Â; operation of the X-ray tube: 40 kV, 40 mA; 2 Θ range: 3-40°.
Thermoanalysis equipment
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; atmosphère: N2, 80 ml/min flux; typical weights: 3-10 mg.
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: 10 K/min; type of crucible: open aluminium oxide crucible; atmosphère: N2, 20 ml/min flux; typical weights: 15-25 mg.
The melting point of compound (I) can be inferred from the DSC/TG schemes in Figure 2 appended hereto.
Equipment for water sorption tests
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
The correspondîng diagrams (kinetic and isothermic plot) of the different forms are shown in Figures 3a) and b). vX
Biological Test
The biological properties of compound (I) are investigated as follows, for example:
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 prolifération dépend on stimulation by EGF or TGF-alpha. A murine haematopoietic cell line is genetically modified so as to express functional human EGF-R. The prolifération of this cell line can therefore be stimulated by EGF.
The test is carried out as follows:
The cells are cultivated in RPMI/1640 medium. The prolifération 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% dimethylsulphoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures are incubated for 48 hours at 37°C.
In order to détermine 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 Prolifération Assay (Promega). The relative cell number is calculated as a percentage of the control and the concentration of active substance which inhibits the prolifération of the cells by 50% (IC50) is derived therefrom.
Table 2
Compound | Inhibition of the EGFR-dependent prolifération IC50 [nM] |
0) | 4 |
Indications
As has been found, the compound of formula (I) is characterised 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.
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 pathophysioiogical processes caused by hyperfunction of tyrosine kinases. These are e.g. benign or malignant tumours, particularly tumours of épithélial and neuroepithelial origin, metastasisation and the abnormal prolifération of vascular endothélial cells (neoangiogenesis).
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 chronîc bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergie or non-allergic rhinitis or sinusitis, cystic fibrosis, a1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
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 sécrétions, such as Ménétrier’s disease, secreting adenomas and protein loss syndrome.
ln 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. yv-—
Combinations
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 dénotés a pharmacologically active substance and is selected (for example) from among betamimetics, anticholinergics, corticosteroîds, PDE4-inhibitors, LTD4receptor (CysLTI, 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.
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:
• W dénotés a betamimetic, combined with an anticholinergic, corticosteroid, PDE4ihibitor, EGFR-inhibitor or LTD4-receptor antagonist, • W dénotés an anticholinergic, combined with a betamimetic, corticosteroid, PDE4inhibitor, EGFR-inhibitor or LTD4-receptor antagonist, • W dénotés a corticosteroid, combined with a PDE4-inhibitor, EGFR-inhibitor or LTD4receptor antagonist • W dénotés a PDE4-inhibitor, combined with an EGFR-inhibitor or LTD4-receptor antagonist • W dénotés an EGFR-inhibitor, combined with an anticholinergic.
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)-1l1-dimethyl-ethylamino]-ethyl}-4Hbenzo[1,4]oxazin-3-one, 8-(2-(2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-(2-(2-(3,5-difluoro-phenyl)-1,1-dimethylethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxyphenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, w—
8-{2-[2-(4-f luoro-phe ny I )-1,1 -dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4Hbenzo[1,4]oxazin-3-one, N-( 5-(2-(3-(4,4-dîethyl-2-oxo-4H-benzo[d][1,3]oxazin-1 -yl)-1,1 dimethyl-propylamino]-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-dimethyl-propylamino]-1hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide, N-(5-{2-[3-(4,4-diethyl-6methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1 -y I )-1,1 -dimethyl-propylamino]-1 -hydroxy-ethyl}-
2- hydroxy-phenyl)-methanesulphonamide, N-(5-{2-[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4Hbenzo[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-benziniidazol-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)-propylamino]-1-hydroxy-ethyl}-6hydroxy-4H-benzo[1,4]oxazin-3-one, 8-(2-(1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3dihydro-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)-propylamino]-
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)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide, 8hydroxy-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-quinolin-2-one, 5-((1 R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]phenyl}-ethylamino)-1 -hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one, [3-(4-{6-[(2R)-2hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy)-butyl)-5-methylphenyl]-urea, 4-((1 R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1 -hydroxyethyl)-2-hydroxymethyl-phenol, 3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide, 3-(3-{7-[(2R)-2-hydroxy-2-(4hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulphonamide,
4- ((1 R)-2-(6-(4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2hydroxymethyl-phenol, N-1-adamantanyl-2-(3-[(2R)-2-(((2R)-2-hydroxy-2-[4-hydroxy-3(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide, (1R)-5-(2-[6-(2,2-difluoro-2phenyl-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, (RlS)-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}-1hydroxy-ethyl)-2- (hydroxymethyl)phenol, (R,3)-4-(2-((6-(4,4-difluoro-4phenylbutoxy)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)-[2-({6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2(hydroxymethyl)phenol, 4-(1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1hydroxyethyl)-2-(hydroxymethyl)phenol, (R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5l5tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol, (R,S)-[5-(2-([6-(2,2-difluoro-2phenylethoxy)hexyl]amino}-1 -hydroxy-ethyl)-2- hydroxyphenyljformamide, (R,S)-4-[2-({6[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]- 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) phenyljethyl}aminoJhexylJoxyîethyOphenyljimidazolidin^^-dione, (R,S)-4-[2-({6-[2,2-difluoro-2-(3methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol, 5-((1 R)-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}-1hydroxy-ethyl)-2-(hydroxymethyl)phenol, (R,S)-(2-{[6-(2,2-difluoro-2-phenylethoxy)-4,4difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol, (R,S)-4-(2-{[6-(2,2difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy ethyl)-2- (hydroxymethyl)phenol, 3-(2-(3chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydrobenzothiazol-7-yl)-ethylamino]-ethyl}-propionamide, N-(2-diethylamlno-ethyl)-N-{2-[2-(4hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-ylethoxy)-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, solvatés 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-ptoluenesulphonate.
Examples of anticholinergics which may be used here preferably include compounds which are selected from among: tiotropium salts, preferably the bromide sait, oxitropium λλ/ salts, preferably the bromide sait, flutropium salts, preferably the bromide sait, ipratropium salts, preferably the bromide sait, aclidinium salts, preferably the bromide sait, glycopyrronium salts, preferably the bromide sait, trospium salts, preferably the chloride sait, tolterodine, (3R)-1-phenethyl-3-(9H-xanthen-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octanesalts. In the above-mentioned salts the cations are the pharmacologically active constituents. As X' 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 ail the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
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 3r3',4,4'tetrafluorobenzîlate methobromide, scopine S.S’^^'-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 9fluoro-fluorene-9-carboxylate methobromide, scopine 9-hydroxy-fluorene-9- carboxylate methobromide, scopine 9-fluoro-fluorene-9-carboxylate methobromide; tropenol 9-methylfluorene-9- carboxylate methobromide, scopine 9-methyl-fluorene-9- carboxylate methobromide, cyclopropyltropine benzilate methobromide, cyclopropyltropine 2,2diphenylpropionate methobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide, cyclopropyltropine 9hydroxy-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-methylxanthene-9-carboxylate -methobromide, scopine 9-methyl-xanthene-9-carboxylate methobromide, tropenol 9-ethyl-xanthene-9-carboxylate methobromide, tropenol 9difluoromethyl-xanthene-9-carboxylate methobromide, scopine 9-hydroxymethylxanthene-9-carboxylate methobromide. The above-mentioned compounds may also be used as salts within the scope of the présent invention, while instead of the methobro31 mide, the metho-X salts may be used wherein X may hâve the meanings given hereinbefore for X'.
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-diene3.20-dione, 6-fluoro-11-hydroxy-16,17-[(1-methy!ethylidene)bis(oxy)]-21-[[4[(nitrooxy)methyl]benzoyl]oxy]-, (6-alpha,11-beta,16-alpha)- (9CI) (NCX-1024), 16,17butylidenedioxy-6,9-difluoro-11 -hydroxy-17-(methylthio)androst-4-en-3-one (ΒΡΕΙ 06541), (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11 -hydroxy-16-methyl-
3-oxo-androsta-1,4-diene-17-carbothionate, (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9dîfluoro-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-carboxylate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and dérivatives thereof, the solvatés and/or hydrates thereof. Any reference to steroids includes a reference to any salts or dérivatives, hydrates or solvatés thereof which may exist. Examples of possible salts and dérivatives of the steroids may be: alkali métal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acétates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates orfuroates.
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-(3,5dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-quinoline (D4396 (Sch-351591 )), N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3yljglyoxylic acid amide (AWD-12-281 (GW-842470)), 9-[(2-fluorophenyl)methyl]-N-methyl2-(trifluoromethyl)-9H-purin-6-amine (NCS-613), 4-[(2R)-2-[3-(cyclopentyloxy)-4methoxyphenyl]-2-phenylethyl]-pyridine (CDP-840), N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-pyridinecarboxamide (PD168787), 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1 -naphthalenyl]-1 -(2-methoxyethyl)32
2(1 H)-pyridinone (T-440), 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone (T-2585), (3-(3-cyclopenyloxy-4methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (V-11294A), beta-[3-(cyclopentyloxy)-
4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide (CDC-801 ), imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl- (D22888), 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl], (3S,5S)-2piperidinone (HT-0712), 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol (L-826141 ), N-(3,5dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, (-)p[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4methoxyphenyl)-1-(4-N,-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1 -carboxylic acid], 2carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-dîfluoromethoxyphenyl)cyclohexan-1 -ol], (R)(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(-)-ethyl[4(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, 9-cyclopentyl-5,6dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, 9cyclopentyl·5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyΓazolo[3l4-c]-1,2,4-triazolo[4,3ajpyridine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés 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-ptoluenesulphonate.
LTB4-receptor antagonists used here are preferably compounds selected from among for example amebulant (=ethyl [[4-[[3-[[4-[1-(4-hydroxyphenyl)-1methylethyl]phenoxy]methyl]phenyl]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, solvatés, prodrugs or hy drates 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-ptoluenesulphonate.
LTD4-receptor antagonists used here are preferably compounds selected from among montelukast, pranlukast, zafirlukast, and (E)-8-[2-[4-[4-(4fluorophenyl)butoxy]phenyl]ethenyl]-2-(lH-tetrazo!-5-yl)-4H-1-benzopyran-4-one (MEN91507), 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2propylphenoxyjbutyric acid (MN-001), 1-(((R)-(3-(2-(6,7-difluoro-2quinolinyl)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)phenyl)-3-(2-(1hydroxy-1-methylethyl)phenyl)propyl)thio)methyl) cyclopropaneacetic acid, [2-[[2-(4-tertbutyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés 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.
By salts or dérivatives which the LTD4-receptor antagonists are optionally capable of forming are meant, for example: alkali métal salts, such as for example sodium or potassium salts, alkaline earth métal salts, sulphobenzoates, phosphates, isonicotinates, acétates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
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-dÎfluorophenyl)-3-pyridinecarboxamide (VX-702), alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleacetonitrile (AS-601245), 9,12-epoxy-1H-dnndolo[1,2,3-fg:3',2',T-kl]pyrrolo[3,4-î][1.6]benzodiazocine10-carboxylic acid (CEP-1347), 4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1Hpyrazole-4-yl]-pyrimidine (SC-409), v/ optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvatés or hydrates thereof.
Bradykinîn 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]methyl]phenyl]sulphonyl]amino]tetrahydro-2H-pyran-4yl]carbonyl]-N,N,N-trimethyl-e-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, solvatés or hydrates thereof.
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-3methyl-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, solvatés or hydrates thereof.
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, solvatés or hydrates thereof.
Substances of preferred CXCR1 and /or CXCR2 receptor antagonists that may be used are preferably compounds such as e.g. 3-[[3-[(dimethylamino)carbonyl]-2hydroxyphenyl]amino]-4-[[(R)-1-(5-methylfuran-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, solvatés or hydrates thereof. —
It is préférable, according to the invention, to use the acid addition salts of the abovementioned betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTB4 (BLT1, BLT2) receptor antagonists, LTD4 (CysLTI, 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, hydriodtde, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
Pharmaceutical compositions
The compound according to the invention may be administered by oral, transdermal, inhalative, parentéral or sublingual route. The compound according to the invention is présent as an active ingrédient in conventional préparations, 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, émulsions, 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.
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, émulsions 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 gélatine, lubricants such as magnésium stéarate or talc and/or agents for delay ing release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
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.
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 flavourîng 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.
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 métal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
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 gélatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the dérivatives thereof.
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, magnésium stéarate, 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 préparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
The Examples which follow illustrate the présent invention without restricting its scope:
Examples of pharmaceutical formulations
A) Coated tablets containing 75 mg of active substance io Composition:
tablet core contains:
active substance | 75.0 mg |
calcium phosphate | 93.0 mg |
corn starch | 35.5 mg |
polyvinylpyrrolidone | 10.0 mg |
hydroxypropylmethylcellulose | 15.0 mg |
magnésium stéarate | 1.5 ma |
230.0 mg
Préparation:
The active substance is mixed with calcium phosphate, corn starch, polyvinyl-pyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnésium stéarate. 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 magnésium stéarate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape.
Weight of core: 230 mg die: 9 mm, convex
The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.
Weight of coated tablet: 245 mg. vZ'
B) Tablets containing 100 mg of active substance
Composition:
tablet contains:
active substance | 100.0 mg |
lactose | 80.0 mg |
corn starch | 34.0 mg |
polyvinylpyrrolidone | 4.0 mg |
magnésium stéarate | 2.0 mq |
220.0 mg |
Method of Préparation:
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°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets.
Weight of tablet: 220 mg
Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.
C) Tablets containing 150 mg of active substance
Composition:
tablet contains:
active substance | 150.0 mg |
powdered lactose | 89.0 mg |
corn starch | 40.0 mg |
colloïdal silica | 10.0 mg |
polyvinylpyrrolidone | 10.0 mg |
magnésium stéarate | 1.0 mo |
300.0 mg /yZ
Préparation:
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°C, are passed through the same screen again and mixed with the specified amount of magnésium stéarate. Tablets are pressed from the mixture.
Weight of tablet: 300 mg die: 10 mm, fiat
D) Hard gélatine capsules containing 150 mo of active substance
Composition:
capsule contains:
active substance corn starch (dried) lactose (powdered)
150.0 mg approx. 180.0 mg approx. 87.0 mg magnésium stéarate
3.0 mg approx. 420.0 mg
Préparation:
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 finîshed mixture is packed into size 1 hard gélatine capsules.
Capsule filling: approx. 320 mg
Capsule shell: size 1 hard gélatine capsule.
E) Suppositories containing 150 mg of active substance Composition:
suppository contains:
active substance 150.0mg polyethyleneglycol 1500 550.0mg polyethyleneglycol 6000 460.0mg polyoxyethylene sorbitan monostearate ________________840.0mg
2,000.0 mg
Préparation:
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:
100 ml of suspension contain:
active substance | 1.00 g | |
carboxymethylcellulose-Na-salt | 0.10g | |
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 |
Préparation:
The distilled water is heated to 70°C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium sait of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient température 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.
ml of suspension contain 50 mg of active substance.
G) Ampoules containing 10 mg active substance
Composition:
active substance 10.0 mg
0.01 N hydrochloric acid q.s.
double-distilled water ad 2.0 ml
Préparation:
The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonie with common sait, filtered stérile and transferred into 2 ml ampoules.
H) Ampoules containing 50 ma of active substance
Composition:
active substance 50.0 mg io 0.01 N hydrochloric acid q.s.
double-distilled water ad 10.0 ml
Préparation:
The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonie with common sait, filtered stérile and transferred into 10 ml ampoules.
$ 9 M 2013
Claims (17)
- PATENT CLAIMS1. Compound of formula (I) optionally in the form of the tautomers thereof.
- 2. Crystalline compound of formula (I) according to claim 1, characterised in that reflections in the X-ray powder diagram occur at dhki values of 7.11, 5.77, 4.69, 4.36, 4.15, 3.85 and 3.61 Â.
- 3. Compound according to claim 1 or 2 for use as a médicament.
- 4. Compound according to claim 1 or 2 for the treatment of inflammatory or allergie diseases of the airways.
- 5. Process for the stereoselective préparation of the compound of formula (I) according to claim 1, optionally in the form of the tautomers thereof:characterised in that the process comprises reaction steps (A) to (M), wherein (A) is the reaction of 1,4-cyclohexanedione-mono-ethyleneketal to form a compound of formula (1) (B) is the réaction of a compound of formula (1) to form the compound of for- mula (2) xHCI (2), (C) is the reaction of a compound of formula (2) to form the compound of formula (3) (D) is the reaction of a compound of formula (3) with a protective group reagent to form the compound of formula (4) ο ο ιΠνΑ (4), (Ε) is the réduction of a compound of formula (4) to form the compound of formula (5) (5) (F) is the reaction of a compound of formula (5) to form a compound of formula (6) (6) (G) is the reaction of a compound of formula (6) with a compound of formula (13) to form a compound of formula (7) (H) (8a) or its tautomeric form (8b), μΖ' (I) is the chlorination of the compound of formula (8a) or (8b) to form a compound of formula (9) (J) + (K) is the reaction of the compound of formula (9) with3-chloro-2-fluoroaniline and the cleaving of a protective group to form a compound of formula (11) or (11 A) ν'*—15 (11) (L) is the cleaving of another protective group to form the compound of formula (II) (M) is the réaction of the compound of formula (II) with maleic acid to form a compound of formula (I), optionally in the form of the tautomers thereof, (l).wherein process steps (A) to (M) take place successively in the sequence specified.
- 6.Process according to claim 5, wherein process steps (J+K) are replaced by steps (N+O), wherein (N+O) is the cleaving of a protective group of the compound of formula (9) to form the compound of formula (12) and subséquent reaction with 3-chloro-2fluoroaniline to form the compound of formula (11) or (11 A) according to claim 6
- 7.Process according to claim 5 or 6, for the stereoselective préparation of a compound of formula (I), characterised in that the process consists of process steps (I), (J), (K), (L), and (M) or of process steps (l),(N), (O), (L) and (M), wherein the process steps (I) to (M) in each case take place successively in the sequence specified.Process according to claim 6 or 7 for the stereoselective préparation of a compound of formula (II), characterised in that the process consists of process steps (I), (J), (K) and (L), or of process steps (l),(N), (O) and (L), wherein the process steps (I) to (L) in each case take place successively in the sequence specified.
- 8.
- 9. Process step (G) according to claim 5.
- 10. Process step (I) according to claim 5.
- 11. Intermediate of formula (6) according to claim 5, optionally in the form of the tautomers thereof.
- 12. Intermediate of formula (7) according to claim 5, optionally in the form of the tautomers thereof.
- 13. Intermediate of formula (8) according to claim 5, optionally in the form of the tautomers thereof.
- 14. Intermediate of formula (9) according to claim 5, optionally in the form of the tautomers thereof.
- 15. Intermediate of formula (11 ) or {11 A) according to claim 5, optionally in the form of the tautomers thereof.
- 16. Pharmaceutical composition containing a compound of formula (I) according to claim 1.
- 17. Médicament combinations which contain, as a further active substance, in addition to one or more compounds of formula (!) according to claim 1, 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. — m n
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