1. An adjustable pickup coil matrix comprising:
a coil matrix having a plurality of selections of coils of differing effective heights and widths;
at least one contiguous magnetic pole electromagnetically associated with said coil matrix; and
a bridging control means,
wherein said bridging control means are used to create a plurality of selections of said coil matrix heights and widths used to vary said adjustable pickup coil matrix sound response.
2. The adjustable pickup coil matrix of claim 1, wherein said adjustable pickup coil matrix sound response is created by controlled summation of sound responses received from said plurality of coil matrix heights and widths, and wherein said bridging control means are used to include in said summation sound responses received from selected parts of said plurality of coil matrix heights and widths.
3. The adjustable pickup coil matrix of claim 1, wherein said adjustable pickup coil matrix is a stringed musical instrument’s adjustable pickup coil.
4. The adjustable pickup coil matrix of claim 1, wherein said adjustable pickup coil matrix is a non stringed musical instrument’s adjustable pickup coil.
5. The adjustable pickup coil matrix of claim 1, further comprising a diaphragm, and wherein said adjustable pickup coil matrix is a speaker’s adjustable coil matrix.
6. The adjustable pickup coil matrix of claim 1, further comprising a diaphragm, and wherein said adjustable pickup coil matrix is a dynamic microphone’s adjustable coil matrix.
7. The adjustable pickup coil matrix of claim 1, further comprising at least one needle, and wherein said adjustable pickup coil matrix is a phonograph cartridge adjustable coil matrix.
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 pharmaceutical composition comprising a therapeutically effective amount of a DPP-IV inhibitor, wherein the DPP-IV inhibitor is released in the lower gastrointestinal tract.
2. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is released in the ileum.
3. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is released at a pH above 7.0.
4. The pharmaceutical composition according to claim 1, wherein the composition comprises a coating.
5. The pharmaceutical composition according to claim 1, wherein the composition is a tablet or a capsule.
6. The pharmaceutical composition according to claim 5, wherein the tablet or capsule comprises a coating.
7. The pharmaceutical composition according to claim 5, wherein the tablet or capsule comprises coated pellets.
8. The pharmaceutical composition according to claim 1, wherein at least 80% of the DPP-IV inhibitor is released in the lower gastrointestinal tract.
9. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is released with a delay of 30 to 60 minutes at pH 7.0.
10. The pharmaceutical composition according to claim 1, comprising 10 to 1000 mg of the DPP-IV inhibitor.
11. The pharmaceutical composition according to claim 1, comprising 100 to 400 mg of the DPP-IV inhibitor.
12. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor exhibits a biological activity with an IC50 value below 10 \u03bcM.
13. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is a compound of formula (I)
wherein
R1 is H or CN,
R2 is \u2014C(R3,R4)\u2014(CH2)n\u2014R5, \u2014C(R3,R4)\u2014CH2\u2014NH\u2014R6, \u2014C(R3,R4)\u2014CH2\u2014O\u2014R7; or
tetralinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl, which tetralinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl group can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, CN, and CF3,
R3 is hydrogen, lower-alkyl, benzyl, hydroxybenzyl or indolylmethylene,
R4 is hydrogen or lower-alkyl, or
R3 and R4 are bonded to each other to form a ring together with the carbon atom to which they are attached and \u2014R3\u2014R4\u2014 is \u2014(CH2)2-5\u2014,
R5 is 5-membered heteroaryl, bi- or tricyclic heterocyclyl, or aminophenyl; optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, CN, CF3, trifluoroacetyl, thiophenyl, phenyl, heteroaryl and monocyclic heterocyclyl, which phenyl, heteroaryl or monocyclic heterocyclyl can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, benzyloxy, halogen, CF3, CF3\u2014O, CN and NH\u2014CO-lower-alkyl,
R6 is a) pyridinyl or pyrimidinyl, which is substituted with 1 to 3 substituents independently selected from the group consisting of aryl and heteroaryl, which aryl or heteroaryl group can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, CN, and CF3,
or b) 5-membered heteroaryl or bi- or tricyclic heterocyclyl, which 5-membered heteroaryl or bi- or tricyclic heterocyclyl can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, carbonyl, aryl and heteroaryl, which aryl or heteroaryl group can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, CN, and CF3, and which carbonyl group can optionally be substituted with lower-alkyl, lower-alkoxy, halogen, CN, CF3, aryl, or heteroaryl, which aryl or heteroaryl group can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, CN, and CF3,
R7 is aminophenyl, naphthyl or quinolinyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, CN and CF3,
X is C(R8,R9) or S,
R8 and R9 independently from each other are H or lower-alkyl,
n is 0, 1 or 2,
and pharmaceutically acceptable salts thereof.
14. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is a compound of formula (II),
wherein
R1 is \u2014C(O)\u2014N(R5)R6 or \u2014N(R5)R6;
R2, R3 and R4 are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl may optionally be substituted by lower alkoxycarbonyl, aryl or heterocyclyl;
R5 is hydrogen, lower alkyl, halogenated lower alkyl or cycloalkyl;
R6 is lower alkylsulfonyl, halogenated lower alkylsulfonyl, cycloalkylsulfonyl, lower alkylcarbonyl, halogenated lower alkylcarbonyl, cycloalkylcarbonyl; or
R5 and R6 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally mono-, di-, or tri-substituted, independently, with lower alkyl, halogenated lower alkyl, oxo, dioxo andor cyano;
and pharmaceutically acceptable salts thereof.
15. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is a compound of formula (IIIA) or (IIIB)
wherein R\u2032 represents hydroxy, C1-C7alkoxy, C1-C8-alkanoyloxy, or R5R4N\u2014CO\u2014O\u2014, where R4 and R5 independently are C1-C7alkyl or phenyl which is unsubstituted or substituted by a substitutent selected from C1-C7alkyl, C1-C7alkoxy, halogen and trifluoromethyl and where R4 additionally is hydrogen; or R4 and R5 together represent C3-C6 alkylene; and R\u2033 represents hydrogen; or R\u2032 and R\u2033 independently represent C1-C7 alkyl; in free form or in form of a pharmaceutically acceptable acid addition salt.
16. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is a compound of formula (IV)
wherein x is 0 or 1 and y is 0 or 1, provided that
x=1 when y=0 and
x=0 when y=1; and wherein
n is 0 or 1;
X is H or CN;
R1, R2, R3 and R4 are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl; all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; and R1 and R3 may optionally be taken together to form \u2014(CR5R6)m\u2014 where m is 2 to 6, and R5 and R6 are the same or different and are independently selected from hydroxy, alkoxy, H, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino, or R1 and R4 may optionally be taken together to form \u2014(CR7R8)p\u2014 wherein p is 2 to 6, and
R7 and R8 are the same or different and are independently selected from hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, halo, amino, substituted amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino, or optionally R1 and R3 together with
form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO2; or optionally R1 and R3 together with
form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring has an optional aryl ring fused thereto or an optional 3 to 7 membered cycloalkyl ring fused thereto;
including all stereoisomers thereof;
and a pharmaceutically acceptable salt thereof, or a prodrug ester thereof, and all stereoisomers thereof.
17. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is a compound of formula (V)
Ar is phenyl which is unsubstituted or substituted with 1-5 of R3, wherein R3 is independently selected from the group consisting of:
(1) halogen,
(2) C1-6 alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens,
(3) OC1-6 alkyl, which is linear or branched and is unsubstituted or substituted with 1-5 halogens, and
(4) CN;
X is selected from the group consisting of:
(1) N, and
(2) CR2;
R1 and R2 are independently selected from the group consisting of:
(1) hydrogen,
(2) CN,
(3) C1-10 alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H, and CO2C1-6alkyl, wherein the CO2C1-6 alkyl is linear or branched,
(4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H, and CO2C1-6alkyl, wherein the CO2C1-6alkyl is linear or branched, and
(5) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl, and OC1-6alkyl, wherein the C1-6alkyl and OC1-6alkyl are linear or branched and optionally substituted with 1-5 halogens;
R4 is C1-6alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO2H, and CO2C1-6alkyl, wherein the CO2C1-6alkyl is linear or branched;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
18. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is (2S)-1-{2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino-acetyl}-pyrrolidine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is (2S)-1-{1,1-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino-acetyl}-pyrrolidine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.
20. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido2,1-aisoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.
21. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is (S,S,S,S)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido2,1-aisoquinolin-3-yl)-4-methyl-pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.
22. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is (S)-1-2-((5S,7S)-3-Hydroxy-adamantan-1-ylamino)-acetyl-pyrrolidine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.
23. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is (1S,3S,5S)-2-(S)-2-Amino-2-(3-hydroxy-adamantan-1-yl)-acetyl-2-aza-bicyclo3.1.0hexane-3-carbonitrile, or a pharmaceutically acceptable salt thereof.
24. The pharmaceutical composition according to claim 1, wherein the DPP-IV inhibitor is (R)-3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-1,2,4triazolo4,3-apyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one, or a pharmaceutically acceptable salts thereof.
25. The pharmaceutical composition according to claim 1, additionally comprising a DPP-IV inhibitor which is released in the stomach or upper gut.
26. The pharmaceutical composition according to claim 25, wherein 40 to 60% of the DPP-IV inhibitor is released in the stomach or upper gut and 40 to 60% of the DPP-IV inhibitor is released in the lower gastrointestinal tract.
27. The pharmaceutical composition according to claim 26, wherein the DPP-IV inhibitor is not released in the duodenum.
28. The pharmaceutical composition according to claim 25, wherein said pharmaceutical composition is a two layer tablet.
29. A method for the treatment of diseases associated with elevated blood glucose levels, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition according to claim 1 to a human being or animal in need thereof.
30. The method according to claim 29, wherein said disease is type I diabetes mellitus, type II diabetes mellitus, diabetes secondary to pancreatic disease, diabetes related to steroid use, type III diabetes mellitus, hyperglycaemia, diabetic complications or insulin resistance.