1. The use of a compound of formula
34
a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein
A is CH, CR4 or N,
n is 0, 1, 2, 3 or 4:
Q is hydrogen or NR1R2;
R1 and R2 are each independently selected from hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl wherein each of the aforementioned C1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C1-6alkyl)amino, aryl and Het; or
R1 and R2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-12alkyl)aminoC1-4alkylidene;
R3 is hydrogen, aryl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with C1-6alkyloxycarbonyl; and
each R4 independently is hydroxy, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy or C1-6alkyl substituted with cyano or aminocarbonyl;
R5 is hydrogen or C1-4alkyl;
L is C1-10alkyl, C3-10alkenyl, C3-10alkynyl, C3-7cycloalkyl, or C1-10alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl, indanyl, indolyl, and phenyl, wherein said phenyl, indanyl, and indolyl may be substituted with one, two, three, four, or where possible five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, C1-6alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy, and C1-6alkylcarbonyl; or L is X1R6 or X2AlkR7 wherein
R6 and R7 each independently are phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy, and trihalomethyl; and
X1 and X2 are each independently NR3, NHNH, NN, O, S, S(O) or S(O)2;
Alk is C1-4alkanediyl;
aryl is phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, nitro, and trifluoromethyl;
Het is an aliphatic or aromatic heterocyclic radical, said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy;
for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
2. The use of a compound-as claimed in claim 1 wherein n is at least 1 and at least one R4 is cyano.
3. The use of a compound as claimed in claim 1 or 2 wherein the compound has the formula
35
4. The use of a compound as claimed in any one of claims 1 to 3 wherein the compound has the formula
36
5. A compound of formula
37
a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein L, Q, R3, R4, R5, and A are as defined under formula (I), and R4 is halo, C1-6alkyl, cyano, aminocarbonyl, nitro, trihalomethyl, trihalomethyloxy or C1-6alkyl substituted with cyano or aminocarbonyl;
n is 0, 1, 2, or 3;
with the proviso that Q and L are other than anilino, 2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino, 3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino, 2-(C1-6alkyl)-anilino, 4-(C1-6alkyl)-anilino, 3-chloro-anilino, 4-bromo-anilino, 4-nitro-anilino, and 4-chloro-anilino.
6. A compound as claimed in claim 5 wherein the compound has the formula
38
7. A compound as claimed in claim 6 wherein L and Q are other than anilino, 2,4,6-trinitro-anilino, 4-(C1-6alkyl)-anilino, 4-bromo-anilino, 4-nitro-anilino, and 4-chloro-anilino.
8. A compound as claimed in claim 6 or 7 wherein R4 is cyano, aminocarbonyl or C1-6alkyl substituted with cyano or aminocarbonyl.
9. A compound as claimed in any one of claims 5 to 8 wherein L is 2,6-dichlorobenzyl, or L is X1R6 wherein X1 is NR3, S or O and R6 is 2,4,6-trichlorophenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methylphenyl, 2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoro-methyl-phenyl, 2,6-dichloro-phenyl, 2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, 4-cyano-2,6-dimethyl-phenyl; or L is X2 AlkR7 wherein X2Alk is NHCH2 and R7 phenyl.
10. A compound as claimed in any one of claims 5 to 9 wherein Q is hydrogen, L is X1R6 wherein X1 is NH and R6 is 2,4,6-trimethyl-phenyl or 4-cyano-2,6-dimethylphenyl, the NR3(optionally substituted phenyl or pyridyl) moiety represents p-cyano-anilino and is in the 2 position of the pyrimidine ring.
11. A compound as claimed in any one of claims 5 to 10 wherein R4 is halo, cyano, aminocarbonyl, or cyanoC1-6alkyl; n is zero, A is CH, R3 is hydrogen; R5 is hydrogen or methyl; Q is hydrogen or NHR1; and L contains phenyl, 2,4,6-trichloro-phenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoro-methyl-phenyl, 2,6-dichloro-phenyl, 2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl. 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, or 4-cyano-2,6-dimethyl-phenyl.
12. A compound as claimed in claim 5 wherein the compound is
4-4-amino-6-(2,6-dichlorophenyl)methyl-2-pyrimidinylaminobenzonitrile;
6-(2,6-dichlorophenyl)methyl-N2-(4-fluorophenyl)-2,4-pyrimidinediamine;
4-4-(2,4-dichlorophenyl)methyl-6-(4-hydroxybutyl)amino-2-pyrimidinylamino-benzonitrile;
4-4-(2,6-dichlorophenyl)methyl-6-(3-hydroxypropyl)amino-2-pyrimidinylamino-benzonitrile;
N-2-(4-cyanophenyl)amino-6-(2,6-dichlorophenyl)methyl-4-pyrimidinyl-acetamide;
N-2-(4-cyanophenyl)amino-6-(2,6-dichlorophenyl)methyl-4-pyrimidinyl-butanamide;
4-2-amino-6-(2,6-dichlorophenoxy)-4-pyrimidinylaminobenzonitrile;
4-4-(2,6-dichlorophenyl)methyl-6-(2-hydroxy-2-phenylethyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-(2,6-dichlorophenyl)methyl-6-3-(2-oxo-1-pyrrolidinyl)propylamino-2-pyrimidinylaminobenzontrile;
4-4-(2,6-dichlorophenyl)methyl-6-2-(2-hydroxyethoxy)ethylamino-2-pyrimidinylaminobenzontrile;
4-4-(2,6-dichlorophenyl)methyl-6-(2,3-dihydroxypropyl)amino-2-pyrimidinyl-aminobenzonitrile;
4-4-(2,6-dichlorophenyl)methyl-6-(hydroxyamino)-2-pyrimidinylamino-benzonitrile;
4-4-(2-cyanoethyl)amino-6-(2,6-dichlorophenyl)methyl-2-pyrimidinylamino-benzonitrile;
4-4-(2,6-dichlorophenyl)methyl-6-2-(1-pyrrolidinyl)ethylamino-2-pyrimidinylaminobenzonitrile;
4-4-amino-6-(2,6-dichlorophenyl)methyl-5-methyl-2-pyrimidinylamino-benzonitrile;
N2-(4-bromophenyl)-6-(2,6-dichlorophenyl)methyl-5-methyl-2,4-pyrimidinediamine;
4-4-(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-2-(2,4,6-trimethylphenyl)amino-4-pyrimidinylaminobenzonitrile;
4-4-(2,6-dimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-(2,4,6-trimethylphenoxy)-2-pyrimidinylaminobenzonitrile;
4-4-(2,6-dichlorophenyl)thio-2-pyrimidinylaminobenzonitrile;
4-4-2,6-dibromo-4-(1-methylethyl)phenylamino-2-pyrimidinylaminobenzonitrile;
4-4-2,6-dichloro-4-(trifluoromethyl)phenylamino-2-pyrimidinylaminobenzonitrile;
4-4-(2,4-dichloro-6-methylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-2-(cyanophenyl)amino-4-pyrimidinylamino-3,5-dimethylbenzonitrile;
4-4-(2,4-dibromo-6-fluorophenyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-amino-6-(2,6-dichlorophenyl)methyl-5-methyl-2-pyrimidinylaminobenzeneacetonitrile;
4-4-methyl(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-(2,4,6-trichlorophenyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-(2,4,6-trimethylphenyl)thio-2-pyrimidinylaminobenzonitrile;
4-4-(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-amino-6-(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-2-amino-6-(2,4,6-trimethylphenyl)amino-4-pyrimidinylaminobenzonitrile;
4-4-(2-bromo-4-chloro-6-methylphenoxy)-2-pyrimidinylaminobenzonitrile;
4-4-(4-chloro-2,6-dimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
3,5-dichloro-4-2-(4-cyanophenyl)amino-4-pyrimidinylaminobenzonitrile;
4-4-2,6-dichloro-4-(trifluoromethoxy)phenylamino-2-pyrimidinylaminobenzonitrile;
4-4-(2,4-dibromo-3,6-dichlorophenyl)amino-2-pyrimidinylaminobenzonitrile;
4-4-(2,6-dibromo-4-propylphenylamino-2-pyrimidinylaminobenzonitrile;
4-4-(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzamide;
4-4-(4-(1,1-dimethylethyl)-2,6-dimethylphenyl)amino-2-pyrimidinylaminobenzonitrile;
4-2-(4-cyanophenyl)amino-4-pyrimidinyloxy-3,5-dimethylbenzonitrile;
4-4-(4-chloro-2,6-dimethylphenyl)amino-5-methyl-2-pyrimidinylaminobenzonitrile;
4-2-(4-cyanophenyl)amino-5-methyl-4-pyrimidinylamino-3,5-dimethylbenzonitrile;
4-4-4-(1,1-dimethylethyl)-2,6-dimethylphenylamino-5-methyl-2-pyrimidinylaminobenzonitrile;
4-4-((4-bromo-2,6-dimethylphenyl)amino-5-methyl-2-pyrimidinylaminobenzonitrile;
4-5-methyl-4-(2,4,6-trimethylphenyl)thio-2-pyrimidinylaminobenzonitrile;
4-4-(2,6-dibromo-4-propylphenyl)amino-5-methyl-2-pyrimidinylaminobenzonitrile;
4-4-(2,4,6-trimethylphenyl)amino-2-pyrimidinylaminobenzamide, N3-oxide;
N2-(4-chlorophenyl)-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine;
4-4-2,6-dibromo-4-(1-methylethyl)phenylamino-5-methyl-2-pyrimidinylaminobenzonitrile;
4-2-(4-cyanophenyl)amino-5-methyl-4-pyrimidinylamino-3,5-dimethylbenzonitrile;
a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as defined in any one of claims 5 to 12.
14. A process for preparing a pharmaceutical composition as defined in claim 13 characterized in that a therapeutically effective amount of a compound as defined in any one of claims 5 to 12 is intimately mixed with a pharmaceutically acceptable carrier.
15. A process for preparing a compound as defined in claim 5, characterized by
a) reacting an intermediate of formula (II-A) wherein W1 is a suitable leaving group with an amino derivative of formula (III) optionally in a solvent under a reaction-inert atmosphere, and optionally in the presence of an acid
39
wherein Q, R3, R4, R4, R5, A, n, and L are as defined in claim 5;
b) reacting an intermediate of formula (II-B) wherein W1 is a suitable leaving group with an amino derivative of formula (VI) optionally in a solvent under a reaction-inert atmosphere, and optionally in the presence of an acid
40
c) reacting an intermediate HX1R6 with an intermediate of formula (II-C) in a suitable solvent optionally in the presence of a suitable acid or base; thus obtaining compounds of formula (I) wherein L is X1R6, said compounds being represented by formula (I-c).
41
or if desired, converting compounds of formula (I) into each other following art-known transformations, and further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or into a therapeutically active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and, if desired, preparing stereochemically isomeric forms or N-oxides thereof.
16. A compound as claimed in claim 5 for use as a medicine.
17. The combination of a compound of formula (I) as defined in claim 1 and another antiretroviral compound.
18. The combination of a compound of formula (I) as defined in claim 5 and another antiretroviral compound.
19. A combination as claimed in claim 17 or 18 for use as a medicine.
20. A product containing (a) a compound of formula (I) as defined in claim 1, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment.
21. A product containing (a) a compound of formula (I) as defined in claim 5, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment.
22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I) as defined in claim 1, and (b) another antiretroviral compound.
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I) as defined in claim 5, and (b) another antiretroviral compound.
24. A compound of formula (II-B)
42
wherein R3, R4, R4, n, A, and L are as defined in claim 5 and W1 is a halogen.
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. An implantable device, comprising:
at least one lead comprising an atrial electrode configured for sensing and pacing an atrium of a heart;
a pulse generator coupled to the at least one lead;
a detector coupled to the at least one lead and configured to detect elevated atrial interval rates indicative of atrial arrhythmia based on atrial events occurring within a post-ventricular atrial refractory period (PVARP) during an atrial arrhythmia;
memory configured to define a detection window having a length and a satisfaction criterion; and
a controller coupled to the pulse generator, the detector and the memory, respectively, the controller configured to inhibit the pulse generator from delivering pacing signals to the atrium and from delivering atrial arrhythmia therapy in response to detecting the elevated atrial interval rates, and wherein the detector detects atrial intervals while delivery of the pacing signals to the atrium and the atrial arrhythmia therapy are inhibited, the controller further configured to classify the atrial intervals in the detection window and declare an atrial episode in response to satisfying the detection window by evaluating the atrial intervals in the detection window with respect to the satisfaction criterion.
2. The device of claim 1, wherein the controller is configured to inhibit delivery of the pacing signals in response to detecting high atrial interval rates indicative of atrial flutter.
3. The device of claim 1, wherein the controller is configured to inhibit delivery of the pacing signals in response to detecting high atrial interval rates that exceed a predefined threshold, the predefined threshold ranging between about 130 bpm and about 230 bpm.
4. The device of claim 1, wherein the detector is configured to detect a subsequent atrial event occurring before expiration of the detection window, the controller configured to initiate a subsequent detection window in response to the sensed subsequent atrial event and inhibiting delivery of a subsequent atrial pace signal during a duration of the subsequent detection window.
5. The device of claim 1, wherein the controller is configured to inhibit delivery of the pacing signals to cause an increase in a rate of detection window satisfaction.
6. The device of claim 1, wherein the detection window length is defined by a number of atrial interval samples ranging between about 20 and 60 atrial interval samples.
7. The device of claim 1, wherein the satisfaction criterion represents a predetermined number, percentage or ratio of atrial intervals classified by the controller as fast atrial intervals relative to the detection window length.
8. The device of claim 1, wherein the detection window has a second satisfaction criterion, and the controller is further configured to verify that the declared atrial episode is a sustained atrial episode in response to the detection window being satisfied by the second satisfaction criterion for subsequent atrial intervals.
9. The device of claim 8, wherein each of the satisfaction criterion and the second satisfaction criterion represents a predetermined number, percentage or ratio of atrial intervals classified by the controller as fast atrial intervals relative to the detection window length, and the second satisfaction criterion is less than the satisfaction criterion.
10. An implantable device, comprising:
at least one lead comprising an atrial electrode configured for sensing and pacing an atrium of a heart;
a pulse generator coupled to the at least one lead;
a detector coupled to the at least one lead and configured to detect atrial events occurring within a post-ventricular atrial refractory period (PVARP) during an atrial arrhythmia;
memory configured to define a detection window having a length and a satisfaction criterion; and
a controller coupled to the pulse generator, the detector and the memory, respectively, the controller configured to initiate the detection window in response to the detected atrial events, inhibit delivery of atrial pace signals for a duration of the detection window, classify, while inhibiting delivery of atrial pace signals, atrial intervals in the detection window, and declare an atrial episode in response to satisfying the detection window by evaluating the atrial intervals in the detection window with respect to the satisfaction criterion.
11. The device of claim 10, wherein the controller is configured to inhibit delivery of the atrial pace signals in response to detecting atrial interval rates indicative of atrial flutter.
12. The device of claim 10, wherein the controller is configured to inhibit delivery of the atrial pace signals in response to detecting atrial interval rates that exceed a predefined threshold, the predefined threshold ranging between about 130 bpm and about 230 bpm.
13. The device of claim 10, wherein the controller is configured to inhibit delivery of the atrial pace signals to cause an increase in a rate of detection window satisfaction.
14. The device of claim 10, wherein the controller is configured to enable delivery of the atrial pace signals to the atrium after cessation of the atrial arrhythmia.
15. The device of claim 10, wherein the detection window length ranges between 20 and 60 atrial interval samples.
16. The device of claim 10, wherein the satisfaction criterion represents a predetermined number, percentage or ratio of the atrial intervals classified as fast atrial intervals relative to the detection window length.
17. The device of claim 10, wherein the satisfaction criterion represents about 80 percent of the atrial intervals classified as fast atrial intervals.
18. The device of claim 10, wherein the controller is configured to verify that the declared atrial episode is a sustained atrial episode in response to the detection window being satisfied by a second satisfaction criterion for subsequent atrial intervals.
19. The device of claim 18, wherein each of the satisfaction criterion and second satisfaction criterion represents a predetermined number, percentage or ratio of the atrial intervals classified as fast atrial intervals relative to the detection window length, and the second satisfaction criterion is less than the satisfaction criterion.
20. The device of claim 19, wherein the satisfaction criterion represents about 80 percent of the atrial intervals classified as fast atrial intervals and the second satisfaction criterion represents about 60 percent of the subsequent atrial intervals classified as fast atrial intervals.