1. A compound according to Formula I
or a pharmaceutically acceptable salt or solvate thereof, wherein
X is C(O), SO or SO2,
Y is CH or N;
n=0, 1, 2, 3 or 4;
A 4-A7 are independently N or CR4, CR5, CR6 or CR7, respectively, with the proviso that no more than two of the four positions A4-A7 can be simultaneously N, wherein A4 is N, A5 is CR5, A6 is CR6, and A7 is CR7;
R1 is (i) (C3-7)cycloalkyl or (C3-5)heterocycloalkyl, both optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H2NC(O)\u2014, (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl and (C1-3)alkoxy are optionally substituted with one or more halogens; (ii) (C2-9)heteroaryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H2NC(O)\u2014, (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl and (C1-3)alkoxy are optionally substituted with one or more halogens; or (iii) (C6-14)aryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H2NC(O)\u2014, (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy are optionally substituted with one or more halogens;
R2 is C(O)OH, 5-tetrazoylyl, HOC(CF3)2, C(O)OH(C1-10)alkyl, (C1-10)alkylsulfoxyaminocarbonyl; or carbamoyl;
R3 is hydrogen, halogen, cyano, nitro, hydroxy, (C1-3)alkylC(O)O\u2014, (C1-4)alkyl, or (C1-4)alkoxy, wherein (C1-4)alkyl and (C1-4)alkoxy are optionally substituted with one or more halogen;
R4-R7 independently are H, halogen, amino, cyano, hydroxy, (C1-3)alkoxy, (C1-4)alkyl, (C0-10)alkyl)aminocarbonyl, (di)(C1-6)alkylaminocarbonyl or amino(C1-4)alkyl, wherein (C1-3)alkoxy, (C1-4)alkyl, (C0-10)alkyl)aminocarbonyl, (di)(C1-6)alkylaminocarbonyl and amino(C1-4)alkyl are optionally substituted with one or more halogen, hydroxyl or (C1-3)alkoxy; or a group having the formula
\u2003optionally substituted with one or more of the following: (C1-10)alkyl, halogen, amino, cyano, hydroxy, (C1-3)alkoxy, and wherein m is 1, 2, 3, or 4.
2. A compound according to Formula Ia
or a pharmaceutically acceptable salt or solvate thereof, wherein
X represents C(O), SO or SO2,
Y is CH or N;
A4-A7 are independently N or CR4, CR5, CR6 or CR7, respectively, with the proviso that no more than two of the four positions A4-A7 can be simultaneously N, wherein A4 is N, A5 is CR5, A6 is CR6, and A7 is CR7;
R1 is (C3-7)cycloalkyl or (C3-5)heterocycloalkyl, both optionally substituted with one or more groups selected from halogen, amino, cyano, hydroxy, H2NC(O)\u2014, or (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4alkyl or (C1-3)alkoxy, all optionally substituted with one or more halogens or;
R1 is (C2-9)heteroaryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H2NC(O)\u2014, or (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy, all optionally substituted with one or more halogens or;
R1 is (C6-14)aryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, H2NC(O)\u2014, or (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy, all optionally substituted with one or more halogens;
R2 is C(O)OH, 5-tetrazoylyl, or HOC(CF3)2;
R3 is independently selected from hydrogen, halogen, cyano, nitro or (C1-4)alkyl, optionally substituted with one or more halogens; and
R4-R7 independently are H, halogen, amino, cyano, hydroxy, (C1-3)alkoxy, (C1-4alkyl, optionally substituted with one or more halogens.
3. The compound of claim 1, wherein Y is N.
4. The compound of claim 3, wherein
X is C(O) or SO2;
R1 is (i) (C3-7)cycloalkyl or (C3-5)heterocycloalkyl, both optionally substituted with one or more groups selected from (C1-4)alkyl or halogen; (ii) (C2-9)heteroaryl, optionally substituted with one or more groups selected from halogen, amino or (C1-4)alkyl; or (iii) (C6-14)aryl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (C1-3)alkoxycarbonyl, (C1-4)alkyl, (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (C1-4)alkyl and (C1-3)alkoxy are optionally substituted with one or more halogens.
5. The compound of claim 4, wherein
R1 is (C2-9)heteroaryl or (C6-14)aryl, both optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (C1-3)alkoxycarbonyl, (C1-4)alky or (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (C1-4)alkyl and (C1-3)alkoxy are optionally substituted with one or more halogens.
6. The compound of claim 5 wherein R1 is phenyl, naphthyl, pyridinyl, quinolinyl, benzooxadiazolyl, thiophenyl, or isoxazolyl, each optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (C1-3)alkoxycarbonyl, (C1-4)alkyl or (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (C1-4)alkyl and (C1-3)alkoxy are optionally substituted with one or more halogens.
7. The compound of claim 6, wherein R1 is phenyl, optionally substituted with one or more groups selected from halogen, amino, cyano, nitro, hydroxy, (C1-3)alkoxycarbonyl, (C1-4)alkyl or (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (C1-4)alkyl and (C1-3)alkoxy are optionally substituted with one or more halogens.
8. The compound of claim 7, wherein R2 is C(O)OH.
9. The compound of claim 1 having Formula Ib
or a pharmaceutically acceptable salt or solvate thereof.
10. The compound of claim 9 having Formula Ic
or a pharmaceutically acceptable salt or solvate thereof, wherein,
X is C(O) or SO2
R8 is selected from halogen, amino, cyano, nitro, hydroxy, H2NC(O)\u2014, (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy, wherein (C1-3)alkoxycarbonyl, (di)(C1-6)alkylaminocarbonyl, (C1-4)alkyl or (C1-3)alkoxy are optionally substituted with one or more halogens; and
x is 0, 1, 2, 3, 4 or 5.
11. The compound of claim 10 having Formula Id
or a pharmaceutically acceptable salt or solvate thereof.
12. The compound of claim 11 having Formula Ie
or a pharmaceutically acceptable salt or solvate thereof.
13. A compound according to claim 1 selected from:
4-(1-(2,6-dichlorbenzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)benzoic acid;
4-(1-(2-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)benzoic acid;
4-(1-(2,6-dichlorobenzoyl)-1H-pyrrolo3,2-bpyridin-3-yl)benzoic acid;
4-(1-(2,6-dichlorobenzoyl)-1H-pyrazolo4,3-cpyridin-3-yl)benzoic acid;
methyl4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-3-fluorobenzoate;
sodium4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-3-fluorobenzoate;
3-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)benzoic acid;
2-(4-(1(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)phenyl)acetic acid;
(2-chloro-6-(trifluoromethyl)phenyl)(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-1H-pyrazolo4,3-bpyridin-1-yl)methanone;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-3-methylbenzoic acid;
3-chloro-4(1-(2-chloro6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin3-yl)-2-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-2methoxybenzoic acid;
2-chloro-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-5-fluorobenzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-2,5-difluorobenzoic acid;
5-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-2-hydroxybenzoic acid;
4-(1-(2-fluoro-6-methoxybenzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)benzoic acid;
3-fluoro-4-(1-(2-fluoro-6-methoxybenzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-2-hydroxybenzoic acid;
2-acetoxy-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)benzoic acid;
4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyeazolo4,3-bpyridin-3-yl)-3-fluorobenzoic acid;
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable excipients.
15. The pharmaceutical composition of claim 14, which further comprises at least one additional therapeutically active agent.
16. 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo4,3-bpyridin-3-yl)-3-fluorobenzoic acid, having the formula
17. A pharmaceutically acceptable salt of the compound of claim 16.
18. A pharmaceutical composition comprising the compound of claim 16 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
19. The pharmaceutical composition of claim 18, which further comprises at least one additional therapeutically active agent.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A composition suitable for oral administration comprising a casing that disintegrates in a gastric pH range and that contains
pellets, particles, granules or agglomerates that have a mean diameter ranging between 50 and 2,500 \u03bcm and comprising:
a) an inner matrix layer comprising
an active substance other than a peptide, protein, peptide or protein derivative, or peptide or protein conjugate,
a lipophilic matrix with a melting point of over 37\xb0 C.; and
a mucoadhesive polymer; and
b) a film-applied outer coating, consisting essentially of an anionic polymer or copolymer, and, optionally, one or more pharmaceutically customary excipients,
wherein the active substance in the inner matrix layer has a water-solubility as defined in the German Pharmacopeia DAB 10 of at least 30 parts by volume of water for 1 part by weight of the active substance,
wherein the lipophilic matrix with its active substance is embedded in a matrix made from the mucoadhesive polymer used jointly with an acid or a buffer system which is present in the matrix or in or on a core to which the matrix is applied, which matrix comprises a chitosan and is adjusted to pH 5.0-5.5 by means of the acid or a buffer system, and is combined with a film-applied outer coating which begins to dissolve in the range of pH 6.0 to 8.0.
2. The composition of claim 1, wherein the active substance and the substance or substances forming the lipophilic matrix do not differ from each other in their water-solubility as defined in the German Pharmacopeia DAB 10 by more than \xb150%, in their distribution coefficient defined in Annexe V to EU Directive No. 67548EEC Point A.8 by more than \xb160%, andor in their HLB value as measured by Marszall’s method by more than \xb180%.
3. The composition of claim 1, wherein the mucoadhesive polymer and the substance or substances forming the lipophilic matrix either have the same ionic character, or\u2014if they have opposite ionic characters\u2014the mucoadhesive polymer is present in a form neutralized to an extent of at least 50%.
4. The composition of claim 1, wherein 80-100 wt-% of the lipophilic matrix is formed by a substance with an HLB value of 0-15 or by a mixture of substances with a mean HLB value of 0-15, and can contain 0-20 wt-% of pharmaceutically customary excipients, especially stabilizers, thickeners or adsorbents.
5. The composition of claim 1, wherein the substance or substances forming the lipophilic matrix are selected from the group consisting of oils, fats, mono-, di- or triglycerides, fatty acids, fatty alcohols, including their salts, ether derivatives, ester derivatives or amide derivatives, phospholipids, lecithins, emulsifiers, lipoids, fat-soluble vitamins and surfactants.
6. The composition of claim 1, wherein the lipophilic matrix contains one of the following lipid preparations: Imwitor 308 (glyceryl monocaprylate containing over 80% of the monoester), Imwitor 312 (glyceryl monolaurate containing over 90% of the monoester), Imwitor 491 glyceryl monostearate (C16+C18) containing over 90% of the monoesters, Imwitor 900 P (glyceryl monostearate containing 40-55% of the monoester and 40-60% of C18 compound), Imwitor 900 K (glyceryl monostearate containing 40-55% of the monoester and 60-80% of C18 compound), Imwitor 742 (medium-chain C8 and C10 glycerides containing 45-55% of monoesters), Imwitor 928 (partial glycerides formed with saturated C10-C18 fatty acids of plant origin, where the main component is C12 compound and the monoester content is 34-36%), C8 and C10 glycerides, sodium caprylate or sodium caprate.
7. The composition of claim 1, wherein the active substance is soluble in the lipophilic matrix to an extent of at least 10%.
8. The composition of claim 1, wherein the amount of the inner matrix layer a) in the lipophilic matrix that contains the active substance is 5-60 wt-%.
9. The composition of claim 1, wherein the casing that disintegrates in the gastric pH range is a capsule, a tablet, a reconstitutable powder formulation, or a sachet.
10. The composition of claim 1, wherein the properties of the outer coating are adjusted by the appropriate choice of the anionic polymer or copolymer and formulation or of its excipients with and of its layer thickness, in such a way that it\u2014the outer coating\u2014dissolves in the gut at a pH of 4.0-8.0 within 10-60 minutes, so that the lipophilic matrix embedded\u2014with its active substance\u2014in the mucoadhesive matrix layer is exposed, can bind to the intestinal mucosa and can release the active substance there; the mucoadhesive polymer is so chosen that, when the pH is within \xb10.5 pH units from the pH value at which the outer coating begins to dissolve, it possesses a mucoadhesive action \u03b7b of 150-1000 mPa\xb7sec and a water absorption of 10-750% in 15 minutes, and the active substance constitutes at most 90 wt-% of the lipophilic matrix.
11. The composition of claim 1, wherein the film-applied outer coating is cellulose glycolate, cellulose acetate phthalate (CAP, cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxy propyl methyl cellulose phthalate (HPMCP, HP50, HP55), hydroxy propyl methyl cellulose acetate succinate (HPMCAS-LF, -MF -HF), polyvinyl acetate phthalate (PVAP), vinyl acetate-vinylpyrrolidone copolymer (PVAc), a 9:1 vinyl acetate:crotonic acid copolymer (VAC:CRA) andor shellac.
12. The composition of claim 1, wherein the film-applied outer coating consists of a (meth)acrylate copolymer containing 5-60 wt-% of monomers with anionic groups.
13. The composition of claim 1, the layer thickness of the outer coating is from 20 to 200 \u03bcm.
14. The composition of claim 1, the inner layer a) contains an efflux pump inhibitor andor a penetration promoting agent.
15. The composition of claim 1, wherein the mucoadhesive polymer further comprises a (meth)acrylate copolymer consisting of 20-40 wt-% of methyl methacrylate and 60-80 wt-% of methacrylic acid, a cellulose, a cross-linked or non-cross-linked polyacrylic acid, a lectin, a sodium alginate andor a pectin.
16. The composition of claim 1, wherein there is a separating layer applied between the inner layer a) and the film-applied outer coating layer b).
17. The composition of claim 1, wherein the active substance formulated in the lipophilic matrix is
selected from the group consisting of Classes II and IV of the Bio-Pharmaceutical Classification System (BCS) of Prof. Amidon; andor
selected from the group consisting of antiandrogens, antidepressants, antidiabetics, antirheumatics, glucocorticoids, cytostatics, antimigraine drugs, neuroleptics, antibiotics, estrogens, vitamins, pyschopharmaceuticals, ACE inhibitors, beta-blockers, calcium channel blockers, diuretics, cardiac glycosides, antiepileptics, diureticsantiglaucoma agents, uricostatics, H2 receptor blockers and virostatics.
18. The composition of claim 1, wherein the active substance formulated in the lipophilic matrix is bicalutamide, anastrozole, glimepiride, nilutamide, bromocriptine, ketotifen, letrozole, naratriptan, ganciclovir, orlistat, mesoprostol, granisetron, pioglitazone, lamivudine, rosiglitazone, zidovudine, enalapril, atenolol, nadolol, felodipine, bepridil, furosemide, digoxin, digitoxin, carbamazepine, acetazolamide, allopurinol, cimetidine, ranitidine or oxcarbazepine.
19. A process for preparing the composition of claim 1 comprising:
(i) suspending andor dissolving the active substance in the components that form the lipophilic matrix having a melting point of over 37\xb0 C., optionally in the presence of one or more pharmaceutically customary excipients, by mixing or melting to form a lipophilic matrix containing the active substance, wherein the active substance is other than a peptide or a protein and their derivatives or conjugates;
(ii) mixing the lipophilic substance containing the active substance with the mucoadhesive polymer(s) and spraying the mixture onto a core, or subjecting the mixture to rotary agglomeration, precipitation or spraying without any core, to form prepellets, wherein the mucoadhesive polymer(s) comprise a chitosan and have been adjusted to pH 5.0-5.5 by means of the acid or a buffer system;
(iii) spraying the prepellets obtained in step (ii) from a dispersion or organic solution with an outer coating of the anionic polymer or copolymer which begins to dissolve in the range of pH 6.0 to 8.0 and which coating may optionally contain one or more plasticizers, separating agents, or other pharmaceutically customary excipients to produce pellets, particles, granules or agglomerates having a mean diameter of 50 to 2,500 \u03bcm;
(iv) incorporating the pellets, particles, granules or agglomerates obtained in step (iii) into a multiparticle pharmaceutical form.
20. The process of claim 19, wherein steps (i) and (ii) are carried out as follows:
(i) the inner matrix layer is made by preparing an emulsion, dispersion or solution of the active substance with the one or more substances for the lipophilic matrix and possibly with other pharmaceutically customary excipients, by intensely mixing the constituents in water and preparing an oil-in-water system with an average particle size of at most 60 \u03bcm,
(ii) prepellets are prepared by spraying the oil-in-water system obtained in step a) onto the mucoadhesive polymer, which may also contain admixtures of pharmaceutically customary excipients, where the ingredients are present in the form of a micronized powder, by rotary agglomeration, extrusion or granulation.
21. A composition comprising a casing, which disintegrates in the gastric pH range, and which contains numerous pellets, particles, granules or agglomerates with a mean diameter of 50-2,500 \u03bcm; wherein said pellets, particles, granules or agglomerates consist essentially of:
a) an inner matrix layer comprising an active substance other than a peptide or a protein and their derivatives or conjugates; a lipophilic matrix with a melting point of over 37\xb0 C.; and a mucoadhesive polymer,
b) a film-applied outer coating consisting essentially of an anionic polymer or copolymer, which can be optionally formulated with pharmaceutically customary excipients, which contains an active substance that has a water-solubility as defined in the German Pharmacopeia DAB 10 of at least 30 parts by volume of water for 1 part by weight of the active substance which is embedded in the lipophilic matrix,
wherein the lipophilic matrix with its active substance is embedded in a matrix made from the mucoadhesive polymer, which matrix comprises a chitosan and is adjusted to pH 5.0-5.5 by means of an acid or a buffer system, and is combined with a film-applied outer coating which begins to dissolve in the range of pH 6.0 to 8.0.