The present invention provides nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof and a process for making thereof. The compounds have inhibitory activity on the phosphorylation of kinases, which inhibits the activity of such kinases. The invention also provides intermediate compounds useful in the process, as well as final products produced by the process, and salts or prodrugs thereof. The invention further provides a method of inhibiting kinases and treating disease states in a mammal by inhibiting the phosphorylation of kinases comprising administering an effective amount of a compound according to the invention to a patient in need thereof.
|
0. 22. A process for preparing a compound of formula A:
##STR00036##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O-CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2—C═CH and —O(—CH2)n —R3; wherein one of the R2 and R4 groups is —O(—CH2)n—R3 and the remaining R2 or R4 group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 is a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising:
nitrating the compound according to formula iii, or its position isomer, to yield a compound according to formula iv, or its position isomer, at a suitable temperature in solvent as follows:
##STR00037##
0. 23. A process for preparing a compound of formula A:
##STR00038##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O—CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2—C═CH and —O(—CH2)n—R3; wherein one of the R2 and R4 groups is —O(—CH2)n —R3 and the remaining R2 or R4 group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 is a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising:
reacting the compound of formula iv, or its position isomer, with an amine containing compound selected from the group consisting of piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine for the appropriate R3 group, in the presence of a basic catalyst and a
solvent to replace the l1 group with an R3 group, and provide a compound of formula v, or its position isomer, as follows:
##STR00039##
0. 26. A process for preparing a compound of formula A:
##STR00044##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O—CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2—C═CH and —O(—CH2)n—R3; wherein one of the R2 and R4 groups is —O(—CH2)n —R3 and the remaining R2 or group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 is a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising:
replacing the hydroxy group of the compound of formula vii, or its position isomer, with a leaving group Q to provide a compound of formula viii, or its position isomer, as follows:
##STR00045##
0. 24. A process for preparing a compound of formula A:
##STR00040##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O—CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2C═CH and —O(—CH2)n—R3; wherein one of the R2 and R4 groups is —O(—CH2)n—R3 and the remaining R2 or R4 group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 is a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising:
reducing the nitro group on the compound of formula v, or on its position isomer, to an amino group and thereby producing a compound of formula vi, or its position isomer, as follows:
##STR00041##
0. 25. A process for preparing a compound of formula A:
##STR00042##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy 5-isoquinolyloxy;
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O—CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2—C═CH and —O(—CH2)n—R3; wherein one of the R2 and R4 groups is —O(—CH2)n —R3 and the remaining R2 or R4 group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising:
reacting the compound of formula vi, or its position isomer with ammonium formate and formamide at a suitable temperature to produce a cyclized quinazoline derivative of formula vii, or its position isomer, as follows:
##STR00043##
0. 27. A process for preparing a compound of formula A:
##STR00046##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O—CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2—C═CH and —O(—CH2)n—R3; wherein one of the R2 and R4 groups is —O(—CH2)n —R3 and the remaining R2 or R4 group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 is a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine 4-methyl-piperidine and 2-methyl-piperidine,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising:
reacting the compound of formula viii, or its position isomer, with a compound of the formula IX, or a salt thereof, to provide a compound of formula x, or its position isomer, as follows:
##STR00047##
0. 21. A process for preparing a compound of formula A:
##STR00034##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O—CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2—C═CH and —O(—CH2)n—R3; wherein one of the R2 and R4 groups is —O(—CH2)n —R3 and the remaining R2 or R4 group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 is a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising:
etherifying the hydroxy group of a compound of formula I or its position isomer with a compound of formula ii wherein l1 is a leaving group, under basic etherification conditions in the presence of an appropriate solvent to produce a compound of formula iii or its position isomer as follows:
##STR00035##
0. 36. A process for preparing a compound of formula x: e####
##STR00057##
and all pharmaceutically acceptable salts and hydrates thereof, wherein
R1 is a member selected from the group consisting of: —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy; R4 is a member selected from the group consisting of: hydrogen, —O—CH3, —O(—CH2) —CH3, —O(—CH2)2 —CH3, —O—CH2 —CH═CH2, —O—CH2 —C≡CH and —O(—CH2)n —R3; n is 2 to 5; R3 is a member selected from the group consisting of: piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, comprising at least one of: (a) etherifying the hydroxy group of a compound of formula I with a compound of formula ii, under basic etherification conditions in the presence of an appropriate solvent to produce a compound of formula iii as follows:
##STR00058##
(b) nitrating the compound according to formula iii to yield a compound according to formula iv at a suitable temperature in a solvent as follows:
##STR00059##
(c) reacting the compound of formula iv with an amine containing compound selected from the group consisting of piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, in the presence of a catalyst and a solvent to provide a compound of formula v as follows:
##STR00060##
(d) reducing the nitro group on the compound of formula v to an amino group and thereby producing a compound of formula vi as follows:
##STR00061##
(e) reacting the compound of formula vi with ammonium formate and formamide at a suitable temperature to produce a cyclized quinazoline derivative of formula vii as follows:
##STR00062##
(f) replacing the hydroxy group of the compound of formula vii with a leaving group Q to provide a compound of formula viii as follows:
##STR00063##
and further converting the product of said step(s) to a compound of formula x or
(g) reacting the compound of formula viii with a compound of the formula IX, or a salt thereof, to provide a compound of formula x as follows:
##STR00064##
wherein each of l1, l2 or Q is independently selected from the group consisting of halogen, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy.
0. 35. A process for preparing a compound of formula x: e####
##STR00049##
and all pharmaceutically acceptable salts and hydrates thereof wherein R1 is a member selected from the group consisting of: —CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indoylyoxy, 5-isoquinolyloxy; R4 is selected from the group consisting of: hydrogen, —O-CH3, —O(—CH2) —CH3, —O(—CH2)2 —CH3, —O—CH2 —CH═CH2, —O—CH2—C≡CH; n is 2 to 5; R3 is a member selected from the group consisting of: piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, and all pharmaceutically acceptable salts and hydrates thereof, comprising the steps of: (a) etherifying the hydroxy group of a compound of formula I with a compound of formula ii, under basic etherification conditions in the presence of an appropriate solvent to produce a compound of formula iii as follows:
##STR00050##
(b) nitrating the compound according to formula iii to yield a compound according to formula iv at a suitable temperature in a solvent as follows:
##STR00051##
(c) reacting the compound of formula iv with an amine containing compound selected from the group consisting of piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, in the presence of a catalyst and a solvent to provide a compound of formula v as follows:
##STR00052##
(d) reducing the nitro group on the compound of formula v to an amino group and thereby producing a compound of formula vi as follows:
##STR00053##
(e) reacting the compound of formula vi with ammonium formate and formamide at a suitable temperature to produce a cyclized quinazoline derivative of formula vii as follows:
##STR00054##
(f) replacing the hydroxy group of the compound of formula vii with a leaving group Q to provide a compound of formula viii as follows:
##STR00055##
(g) reacting the compound of formula viii with a compound of the formula IX, or a salt thereof, to provide a compound of formula x as follows:
##STR00056##
(h) and optionally, producing a salt or hydrate of the compound of formula x and each l1, l2 or Q is a leaving group, independently selected from the group consisting of halogen, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy and arylsulfonyloxy.
0. 1. A process for preparing a compound of formula A: e####
##STR00024##
wherein
R1is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;
R2 and R4 are each independently a member selected from the group consisting of:
hydrogen, —O—CH3, —O(—CH2)—CH3, —O(—CH2)2—CH3, —O—CH2—CH═CH2, —O—CH2—C═CH and —O(—CH2)n—R3; wherein one of the R2 and R4 groups is —O(—CH2)n —R3 and the remaining R2 or R4 group is other than —O(—CH2)n—R3;
n is 2 to 5;
R3 is a member selected from the group consisting of:
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine,
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof, comprising the steps of:
(a) etherifying the hydroxy group of a compound of formula I or its position isomer with a compound of formula ii wherein l1 is a leaving group, under basic etherification conditions in the presence of an appropriate solvent to produce a compound of formula iii or its position isomer as follows:
##STR00025##
(b) nitrating the compound according to formula iii, or its position isomer, to yield a compound according to formula iv, or its position isomer, at a suitable temperature in a solvent as follows:
##STR00026##
(c) reacting the compound of formula iv, or its position isomer, with an amine containing compound selected from the group consisting of piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine, in the presence of a catalyst and a solvent to provide a compound of formula v, or its position isomer, as follows:
##STR00027##
(d) reducing the nitro group on the compound of formula v, or on its position isomer, to an amino group and thereby producing a compound of formula vi, or its position isomer, as follows:
##STR00028##
(e) reacting the compound of formula vi, or its position isomer with ammonium formate and formamide at a suitable temperature to produce a cyclized quinazoline derivative of formula vii, or its position isomer, as follows:
##STR00029##
(f) replacing the hydroxy group of the compound of formula vii, or its position isomer, with a leaving group Q to provide a compound of formula viii, or its position isomer, as follows:
##STR00030##
(g) reacting the compound of formula viii, or its position isomer, with a compound of the formula IX, or a salt thereof, to provide a compound of formula x, or its position isomer, as follows:
##STR00031##
(h) and optionally, producing a salt, solvate, hydrate, or N-acylated, of the compound of formula x, or its position isomer.
0. 2. The process according to
0. 3. The process according to
0. 4. The process according to
0. 5. The process according to
0. 6. The process according to
0. 7. The process according to
0. 8. The process according to
0. 9. The process according to
0. 10. The process according to
0. 11. The process according to
0. 12. The process according to
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof.
0. 13. The process according to
0. 14. The process according to
0. 15. The process according to
##STR00032##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof.
0. 16. The process according to
0. 17. The process according to
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof.
0. 18. The process according to
selected from the group consisting of piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof.
0. 19. The process according to
0. 20. A process for preparing an intermediate compound having formula viii, comprising the step of replacing the hydroxy group of the compound of formula vii, or its position isomer, with a leaving group Q to provide a compound of formula viii, or its position isomer, as follows:
##STR00033##
wherein
n, R3 and R4 are defined as in
Q is a leaving group other than a hydroxyl group, which can be replaced by an amino group or other intermediary group which is subsequently replaced by an amino group, or a salt thereof.
0. 28. The process of
0. 29. The process of
0. 30. The process according to
##STR00048##
wherein
R1 is a member selected from the group consisting of:
—CN, —O-methyl, —O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-t-butyl, —O-isoamyl, 1-naphthyloxy, 2-naphthyloxy, 4-indolyloxy, 5-indolyloxy, 5-isoquinolyloxy;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof.
0. 31. The process according to
0. 32. The process according to
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof.
0. 33. The process according to
piperidine, pyrrolidine, morpholine, piperazine, 4-methyl-piperidine and 2-methyl-piperidine and all pharmaceutically acceptable isomers, salts, hydrates, solvates and N-acylated derivatives thereof.
0. 34. The process according to
0. 37. The process of claim 36, wherein R4 is —O—CH3.
0. 38. The process of claim 36, wherein R1 is —O-isopropyl or —CN.
0. 39. The process of claim 36, wherein n is 3 and R3 is N-piperidine, N-pyrrolidine or morpholine.
0. 40. The process according to claim 36, wherein each leaving group l1, l2 or Q is independently selected from the group consisting of Cl, Br, p-toluenesulfonyloxy and methyl sulfonyloxy.
0. 41. The process according to claim 36, wherein the solvent in step (a) is selected from the group consisting of toluene, methanol, ethanol, ether, and THF.
0. 42. The process according to claim 36, wherein the base in step (a) is selected from the group consisting of potassium carbonate, sodium carbonate, and sodium hydroxide.
0. 43. The process according to claim 36, wherein step (a) is conducted for about 2 to about 6 hours.
0. 44. The process according to claim 36, wherein the compound in step (b) is nitrated at a temperature of from about 0° C. to about 80° C.
0. 45. The process according to claim 36, wherein the catalyst in step (c) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, and sodium iodide.
0. 46. The process according to claim 36, wherein the solvent in step (c) is selected from the group consisting of toluene, ethanol, ether, THF, glyme, diglyme, and MTBE.
0. 47. The process according to claim 36, wherein cyclization step (e) is conducted at a temperature of about 100° C. to about 200° C.
0. 48. The process according to claim 36, wherein R1 is selected from the group consisting of —CN and —O-isopropyl and n is 2 or 3.
0. 49. The process according to claim 36, wherein R1 is selected from the group consisting of —CN and —O-isopropyl, n is 2 or 3, and R3 is piperidine or pyrrolidine.
0. 50. The process according to claim 36, wherein n is 2 and R1 is —O-isopropyl or −CN.
0. 51. The process according to claim 36, wherein R4 is —O—CH3, n is 3 and R1 is —O-isopropyl or —CN.
0. 52. The process according to claim 51, wherein R3 is
##STR00065##
0. 53. The process of claim 36 further comprising producing a salt or hydrate of the compound of formula x.
0. 54. The process of claim 36 further comprising producing a salt, hydrate, or combination thereof of the compound of formula x.
|
|||||||||||||||||||
This application or when n is 1, L1 may also be —H, —CH═CH2 or —C≡CH, or when n is 0 or 2, L1 may also be —H; 2
From the results obtain from such assays, it is apparent when the compound according to the invention inhibits the occurrence of adjuvant arthritis.
Biological Test Assay Type 5
Activity on a Mesangial Proliferative Glomerulonephritis Model
Anti-rat Thy-1.1 monoclonal antibody OX-7 (Sedaren) is administered to male Wister-Kyoto rats (Charles River Japan, 160 g, 6 animals/group) in an amount of 1.0 mg/kg by intravenous administration through the tail vein. A test compound is suspended in a 0.5% solution of methylcellulose and the resulting suspension is administered to each of the rats twice a day for a period of 7 days starting on the day before the administration of OX-7. On the 7th day after the OX-7 administration, when mesangial cell growth and extracellular matrix hypertrophy become prominent, the left kidney of each rat is extirpated, fixed with 20% buffered formalin for 6 hours and wrapped in paraffin, followed by slicing. The obtained pieces are subjected to immune tissue staining using antibody PC10 (DAKO) against an intranuclear antigen of proliferative cells. After comparative staining with Methyl Green staining solution using diaminobenzidine as a color developer, the paraffin pieces are enclosed. Half of the glomeruli in a kidney piece are observed and the number of the cells in one glomerulus which are positive to the intranuclear antigen of proliferative cells are calculated. The test for the significance of difference is carried out by the Wilcoxon test.
From such results, it is apparent when the compounds according to the present invention show alleviating activity on mesangial proliferative glomerulonephritis.
Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. The examples given above are non-limiting in that one of ordinary skill in view of the above will readily envision other permutations and variations on the invention without departing from the principal concepts. Such permutations and variations are also within the scope of the present invention. All the patents, journal articles and other documents discussed or cited above are herein incorporated by reference. The invention is further illustrated with reference to the claims that follow thereto.
Scarborough, Robert M., Robinson, James, Kanter, James, Pandey, Anjali, Scarborough, legal representative, Carroll
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