U.S. patent application number 15/155897 was filed with the patent office on 2016-09-08 for novel compounds as respiratory stimulants for treatment of breathing control disorders or diseases.
The applicant listed for this patent is GALLEON PHARMACEUTICALS, INC.. Invention is credited to SCOTT L. DAX, SEAN PENG, RICHARD WOODWARD.
Application Number | 20160256463 15/155897 |
Document ID | / |
Family ID | 46162783 |
Filed Date | 2016-09-08 |
United States Patent
Application |
20160256463 |
Kind Code |
A1 |
DAX; SCOTT L. ; et
al. |
September 8, 2016 |
NOVEL COMPOUNDS AS RESPIRATORY STIMULANTS FOR TREATMENT OF
BREATHING CONTROL DISORDERS OR DISEASES
Abstract
The present invention includes a composition comprising a
compound, such as a 2,4,6-triamino-1,3,5-triazine,
2,4,6-triaminopyrimidine,
2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine or
2,4-diamino-7H-pyrrolo[2,3-d]pyrimidine, that is useful in the
treatment of breathing control diseases or disorders in a subject
in need thereof. The present invention also includes a method of
treating a respiratory disease or disorder in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of a pharmaceutical composition of the invention.
The present invention further includes a method of preventing
destabilizing or stabilizing breathing rhythm in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of a pharmaceutical composition of the
invention.
Inventors: |
DAX; SCOTT L.; (LANDENBERG,
PA) ; WOODWARD; RICHARD; (PHOENIXVILLE, PA) ;
PENG; SEAN; (AMBLER, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALLEON PHARMACEUTICALS, INC. |
DOYLESTOWN |
PA |
US |
|
|
Family ID: |
46162783 |
Appl. No.: |
15/155897 |
Filed: |
May 16, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13306349 |
Nov 29, 2011 |
9351972 |
|
|
15155897 |
|
|
|
|
61494268 |
Jun 7, 2011 |
|
|
|
61417777 |
Nov 29, 2010 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 11/16 20180101; C07D 405/14 20130101; A61K 31/519 20130101;
A61P 7/06 20180101; C07D 239/50 20130101; A61K 45/06 20130101; C07D
498/06 20130101; C07D 487/04 20130101; C07D 405/12 20130101; A61K
31/505 20130101; A61K 31/57 20130101; A61M 16/0465 20130101; C07D
403/12 20130101; A61P 7/00 20180101; A61K 31/5355 20130101; A61M
16/06 20130101; C07D 409/12 20130101; C07D 251/66 20130101; C07D
413/04 20130101; A61K 31/53 20130101; A61P 11/00 20180101; C07D
401/14 20130101; A61K 31/522 20130101 |
International
Class: |
A61K 31/53 20060101
A61K031/53; C07D 413/04 20060101 C07D413/04; A61K 31/5355 20060101
A61K031/5355; C07D 409/12 20060101 C07D409/12; C07D 403/12 20060101
C07D403/12; C07D 401/14 20060101 C07D401/14; C07D 405/14 20060101
C07D405/14; C07D 498/06 20060101 C07D498/06; C07D 239/50 20060101
C07D239/50; A61K 31/505 20060101 A61K031/505; C07D 487/04 20060101
C07D487/04; A61K 31/519 20060101 A61K031/519; A61M 16/04 20060101
A61M016/04; A61M 16/06 20060101 A61M016/06; C07D 251/66 20060101
C07D251/66 |
Claims
1-34. (canceled)
35. A compound of formula (I), or a salt or solvate thereof:
##STR00117## wherein the compound of formula (I) is selected from
the group consisting of: (i) Y is N, bond b.sup.1 is nil, Z is H,
bond b.sup.2 is a single bond, A is CH, and the compound is a
compound of formula (II-a): ##STR00118## (ii) Y is N, bond b.sup.1
is nil, Z is nil, bond b.sup.2 is nil, and A is a bond, and the
compound is a compound of formula (II-b): ##STR00119## wherein
R.sup.1 is selected from the group consisting of alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
and substituted heteroaryl; R.sup.2 is selected from the group
consisting of alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted
phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted
aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl,
substituted heteroarylalkyl, heteroaryl and substituted heteroaryl;
or R.sup.1 and R.sup.2 combine as to form a biradical selected from
the group consisting of 3-hydroxy-pentane-1,5-diyl,
6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl
and pentane-1,5-diyl; R.sup.3 is selected from the group consisting
of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, --NR.sup.1R.sup.2, --C(O)OR.sup.1,
and aryl; R.sup.4 is selected from the group consisting of H,
alkyl, and substituted alkyl; R.sup.5 is selected from the group
consisting of alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, --NR.sup.1R.sup.2,
--C(O)OR.sup.1, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic; or R.sup.3
and R.sup.5 combine as to form a biradical selected from the group
consisting of 3,6,9-trioxa-undecane-1,11-diyl and
3,6-dioxa-octane-1,8-diyl; and X is O.
36. The compound of claim 35, wherein R.sup.3 is selected from the
group consisting of alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, and substituted alkenyl.
37. The compound of claim 35, wherein R.sup.5 is selected from the
group consisting of alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, and substituted alkenyl.
38. The compound of claim 35, wherein the salt is selected from the
group consisting of sulfate, hydrogen sulfate, hydrochloric,
hydrobromic, hydriodic, nitric, carbonic, sulfuric, phosphoric,
aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,
carboxylic, and sulfonic.
39. The compound of claim 35, wherein the salt is selected from the
group consisting of hydrogen sulfate and hydrochloride.
40. A pharmaceutical composition comprising at last one compound of
claim 35 and at least one pharmaceutically acceptable carrier.
41. A method of preventing or treating a breathing control disorder
or disease in a subject in need thereof, the method comprising
administering to the subject a therapeutically effective amount of
at least one compound of formula (I) or a salt or solvate thereof:
##STR00120## wherein the compound of formula (I) is selected from
the group consisting of: (i) Y is N, bond b.sup.1 is nil, Z is H,
bond b.sup.2 is a single bond, A is CH, and the compound is a
compound of formula (II-a): ##STR00121## (ii) Y is N, bond b.sup.1
is nil, Z is nil, bond b.sup.2 is nil, and A is a bond, and the
compound is a compound of formula (II-b): ##STR00122## wherein
R.sup.1 is selected from the group consisting of alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
and substituted heteroaryl; R.sup.2 is selected from the group
consisting of alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted
phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted
aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl,
substituted heteroarylalkyl, heteroaryl and substituted heteroaryl;
or R.sup.1 and R.sup.2 combine as to form a biradical selected from
the group consisting of 3-hydroxy-pentane-1,5-diyl,
6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl
and pentane-1,5-diyl; R.sup.3 is selected from the group consisting
of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, --NR.sup.1R.sup.2, --C(O)OR.sup.1,
and aryl; R.sup.4 is selected from the group consisting of H,
alkyl, and substituted alkyl; R.sup.5 is selected from the group
consisting of alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, --NR.sup.1R.sup.2,
--C(O)OR.sup.1, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic; or R.sup.3
and R.sup.5 combine as to form a biradical selected from the group
consisting of 3,6,9-trioxa-undecane-1,11-diyl and
3,6-dioxa-octane-1,8-diyl; and X is O.
42. The method of claim 41, wherein the breathing control disorder
or disease is selected from the group consisting of respiratory
depression, sleep apnea, apnea of prematurity,
obesity-hypoventilation syndrome, primary alveolar hypoventilation
syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and
chronic obstructive pulmonary disease (COPD); wherein the
respiratory depression is caused by an anesthetic, a sedative, an
anxiolytic agent, a hypnotic agent, alcohol or a narcotic.
43. The method of claim 41, wherein the subject is further
administered at least one additional agent useful for treating the
breathing disorder or disease.
44. The method of claim 43, wherein the at least one additional
agent is selected from the group consisting of acetazolamide,
almitrine, theophylline, caffeine, methyl progesterone, a
serotonergic modulator, a cannabinoid and an ampakine.
45. The method of claim 41, wherein the at least one compound is
administered in conjunction with the use of a mechanical
ventilation device or positive airway pressure device on the
subject.
46. The method of claim 41, wherein the at least one compound is
part of a pharmaceutically acceptable composition further
comprising at least one pharmaceutically acceptable carrier.
47. The method of claim 41, wherein the subject is a mammal.
48. The method of claim 47, wherein the mammal is a human.
49. The method of claim 41, wherein the at least one compound is
administered to the subject by at least one route selected from the
group consisting of inhalational, topical, oral, buccal, rectal,
vaginal, intramuscular, subcutaneous, transdermal, intrathecal and
intravenous.
50. The method of claim 41, wherein the at least one compound is
selected from the group consisting of:
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XX),
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylami-
ne (XXII), N-(4-Cyclopropylmethyl)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV),
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine (XXVII), N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX),
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI),
N-(Bis-4,6-(cyclopropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxyla-
mine (XXXIII),
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine
(XXXV),
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hyd-
roxylamine (LIII),
6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine
(LVII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine (LXIV),
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamin-
e (LXVIII),
6-((Benzyloxy)(isopropyl)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-triazine-2-
,4-diamine (LXXII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxyla-
mine (LXXVI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxyla-
mine (LXXXII),
6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-d-
iamine (LXXXIV),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl--
hydroxylamine (XCI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamin-
e (XCVI),
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triaz-
in-2-yl)-N,O-dimethyl-hydroxylamine (CIII),
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV),
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-O,N-dimethyl-hydroxylamine (CVII),
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine (CIX),
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXI),
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXIII),
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine (CXV), and
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(1-
9),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII).
51. A method of preventing destabilization or stabilizing breathing
rhythm in a subject in need thereof, the method comprising
administering to the subject a therapeutically effective amount of
at least one compound of formula (I), or a salt or solvate thereof:
##STR00123## wherein the compound of formula (I) is selected from
the group consisting of: (i) Y is N, bond b.sup.1 is nil, Z is H,
bond b.sup.2 is a single bond, A is CH, and the compound is a
compound of formula (II-a): ##STR00124## (ii) Y is N, bond b.sup.1
is nil, Z is nil, bond b.sup.2 is nil, and A is a bond, and the
compound is a compound of formula (II-b): ##STR00125## wherein
R.sup.1 is selected from the group consisting of alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
and substituted heteroaryl; R.sup.2 is selected from the group
consisting of alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted
phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted
aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl,
substituted heteroarylalkyl, heteroaryl and substituted heteroaryl;
or R.sup.1 and R.sup.2 combine as to form a biradical selected from
the group consisting of 3-hydroxy-pentane-1,5-diyl,
6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl
and pentane-1,5-diyl; R.sup.3 is selected from the group consisting
of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
alkenyl, substituted alkenyl, --NR.sup.1R.sup.2, --C(O)OR.sup.1,
and aryl; R.sup.4 is selected from the group consisting of H,
alkyl, and substituted alkyl; R.sup.5 is selected from the group
consisting of alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, --NR.sup.1R.sup.2,
--C(O)OR.sup.1, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic; or R.sup.3
and R.sup.5 combine as to form a biradical selected from the group
consisting of 3,6,9-trioxa-undecane-1,11-diyl and
3,6-dioxa-octane-1,8-diyl; and X is O.
52. The method of claim 51, wherein the destabilization is
associated with a breathing control disorder or disease selected
from the group consisting of respiratory depression, sleep apnea,
apnea of prematurity, obesity-hypoventilation syndrome, primary
alveolar hypoventilation syndrome, dyspnea, altitude sickness,
hypoxia, hypercapnia and chronic obstructive pulmonary disease
(COPD); wherein the respiratory depression is caused by an
anesthetic, a sedative, an anxiolytic agent, a hypnotic agent,
alcohol or a narcotic.
53. The method of claim 51, wherein the subject is further
administered at least one additional agent useful for treating the
breathing disorder or disease.
54. The method of claim 53, wherein the at least one additional
agent is selected from the group consisting of acetazolamide,
almitrine, theophylline, caffeine, methyl progesterone, a
serotonergic modulator, a cannabinoid and an ampakine.
55. The method of claim 51, wherein the at least one compound is
administered in conjunction with the use of a mechanical
ventilation device or positive airway pressure device on the
subject.
56. The method of claim 51, wherein the at least one compound is
part of a pharmaceutically acceptable composition further
comprising at least one pharmaceutically acceptable carrier.
57. The method of claim 51, wherein the subject is a mammal.
58. The method of claim 57, wherein the mammal is a human.
59. The method of claim 51, wherein the at least one compound is
administered to the subject by at least one route selected from the
group consisting of inhalational, topical, oral, buccal, rectal,
vaginal, intramuscular, subcutaneous, transdermal, intrathecal and
intravenous route.
60. The method of claim 51, wherein the at least one compound is
selected from the group consisting of:
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XX),
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylami-
ne (XXII), N-(4-Cyclopropylmethyl)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV),
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine (XXVII), N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX),
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI),
N-(Bis-4,6-(cyclopropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxyla-
mine (XXXIII),
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine
(XXXV),
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hyd-
roxylamine (LIII),
6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine
(LVII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine (LXIV),
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamin-
e (LXVIII),
6-((Benzyloxy)(isopropyl)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-triazine-2-
,4-diamine (LXXII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxyla-
mine (LXXVI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxyla-
mine (LXXXII),
6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-d-
iamine (LXXXIV),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl--
hydroxylamine (XCI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamin-
e (XCVI),
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triaz-
in-2-yl)-N,O-dimethyl-hydroxylamine (CIII),
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV),
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-O,N-dimethyl-hydroxylamine (CVII),
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine (CIX),
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXI),
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXIII),
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine (CXV), and
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(1-
9),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII). a salt
thereof and mixtures thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is entitled to priority under 35
U.S.C. .sctn.119(e) to U.S. Provisional Patent Applications No.
61/417,777, filed Nov. 29, 2010, and No. 61/494,268, filed Jun. 7,
2011, all of which are hereby incorporated by reference in their
entireties herein.
BACKGROUND OF THE INVENTION
[0002] Normal control of breathing is a complex process that
involves the body's interpretation and response to chemical stimuli
such as carbon dioxide, pH and oxygen levels in blood, tissues and
the brain. Breathing control is also affected by wakefulness (i.e.,
whether the patient is awake or sleeping). Within the brain
medulla, there is a respiratory control center that interprets the
various signals that affect respiration and issues commands to the
muscles that perform the work of breathing. Key muscle groups are
located in the abdomen, diaphragm, pharynx and thorax. Sensors
located centrally and peripherally then provide input to the
brain's central respiration control areas that enables response to
changing oxygen requirements.
[0003] Normal respiratory rhythm is maintained primarily by the
body's rapid response to changes in carbon dioxide levels
(CO.sub.2). Increased CO.sub.2 levels signal the body to increase
breathing rate and depth, resulting in higher oxygen levels and
subsequent lower CO.sub.2 levels. Conversely, low CO.sub.2 levels
can result in periods of apnea (no breathing) since the stimulation
to breathe is absent. This is what happens when a person
hyperventilates.
[0004] In addition to the role of the brain, breathing control is
the result of feedback from both peripheral and central
chemoreceptors, but the exact contribution of each is unknown.
[0005] There are many diseases in which loss of normal breathing
rhythm is a primary or secondary feature of the disease. Examples
of diseases with a primary loss of breathing rhythm control are
apneas (central, mixed or obstructive; where the breathing
repeatedly stops for 10 to 60 seconds) and congenital central
hypoventilation syndrome. Secondary loss of breathing rhythm may be
due to chronic cardio-pulmonary diseases (e.g., heart failure,
chronic bronchitis, emphysema, and impending respiratory failure),
excessive weight (e.g., obesity-hypoventilation syndrome), certain
drugs (e.g., anesthetics, sedatives, anxiolytics, hypnotics,
alcohol, and narcotic analgesics and/or factors that affect the
neurological system (e.g., stroke, tumor, trauma, radiation damage,
and ALS). In chronic obstructive pulmonary diseases where the body
is exposed to chronically low levels of oxygen, the body adapts to
the lower pH by a kidney mediated retention of bicarbonate, which
has the effect of partially neutralizing the CO.sub.2/pH
respiratory stimulation. Thus, the patient must rely on the less
sensitive oxygen-based system.
[0006] In particular, loss of normal breathing rhythm during sleep
is a common condition. Sleep apnea is characterized by frequent
periods of no or partial breathing. Key factors that contribute to
these apneas include decrease in CO.sub.2 receptor sensitivity,
decrease in hypoxic ventilatory response sensitivity (e.g.,
decreased response to low oxygen levels) and loss of"wakefulness."
Normal breathing rhythm is disturbed by apnea events, resulting in
hypoxia (and the associated oxidative stress) and eventually severe
cardiovascular consequences (high blood pressure, stroke, heart
attack). Snoring has some features in combination with sleep apnea.
The upper airway muscles lose their tone resulting in the sounds
associated with snoring but also inefficient airflow, which may
result in hypoxia.
[0007] The ability of a mammal to breathe, and to modify breathing
according to the amount of oxygen available and demands of the
body, is essential for survival. There are a variety of conditions
in which breathing is compromised that are characterized by, or due
to, either a primary or secondary cause. Estimates for U.S.
individuals afflicted with conditions wherein there is compromised
respiratory control include sleep apneas (15-20 millions);
obesity-hypoventilation syndrome (5-10 millions); chronic heart
disease (5 millions); chronic obstructive pulmonary disease
(COPD)/chronic bronchitis (10 millions); drug-induced
hypoventilation (2-5 millions); and mechanical ventilation weaning
(0.5 million).
[0008] There is a need in the art for novel chemical compounds that
can be used to restore all or part of the body's normal breathing
control system in response to changes in CO.sub.2 and/or oxygen,
with minimal side effects. Such compounds would be of benefit in
decreasing the incidence and severity of breathing control
disturbances. The present invention addresses and meets these
needs.
BRIEF SUMMARY OF THE INVENTION
[0009] The invention includes a composition comprising at least one
compound of formula (I):
##STR00001##
wherein:
[0010] R.sup.1 and R.sup.2 are independently H, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
or substituted heteroaryl; or R.sup.1 and R.sup.2 combine as to
form a biradical selected from the group consisting of
3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl,
propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
[0011] R.sup.3 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, or aryl;
[0012] R.sup.4 is H, alkyl, or substituted alkyl;
[0013] R.sup.5 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, --OR.sup.1,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, or substituted
heterocyclic; or R.sup.3 and R.sup.5 combine as to form a biradical
selected from the group consisting of
3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;
[0014] R.sup.6 is H, alkyl, substituted alkyl or alkenyl;
[0015] X is a bond, O or NR.sup.4; and,
[0016] Y is N, CR.sup.6 or C; wherein: [0017] if Y is N or
CR.sup.6, then bond b.sup.1 is nil and: (i) Z is H, bond b.sup.2 is
a single bond, and A is CH; or, (ii) Z is nil, bond b.sup.2 is nil,
and A is a single bond; and, [0018] if Y is C, then bond b.sup.1 is
a single bond, and: (i) Z is CH.sub.2, bond b.sup.2 is a single
bond, and A is CH; or, (ii) Z is CH, bond b.sup.2 is a double bond,
and A is C; or a salt thereof.
[0019] In one embodiment, R.sup.3 is H, alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, or substituted
alkenyl. In another embodiment, R.sup.5 is H, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, or acyl.
[0020] In one embodiment, the at least one compound of formula (I)
is selected from the group consisting of: (i) Y is N, bond b.sup.1
is nil, Z is H, bond b.sup.2 is a single bond, A is CH, and the at
least one compound is a compound of formula (II-a) or a salt
thereof:
##STR00002##
and (ii) Y is N, bond b.sup.1 is nil, Z is nil, bond b.sup.2 is
nil, and A is a bond, and the compound of the invention is a
1,3,5-triazine of formula (II-b) or a salt thereof:
##STR00003##
[0021] In one embodiment, the at least one compound of formula (I)
is selected from the group consisting of: (i) Y is CR.sup.6, bond
b.sup.1 is nil, Z is H, bond b.sup.2 is a single bond, A is CH, and
the at least one compound is a compound of formula (III-a) or a
salt thereof:
##STR00004##
and (ii) Y is CR.sup.6, bond b.sup.1 is nil, Z is nil, bond b.sup.2
is nil, and A is a bond, and the compound of the invention is a
pyrimidine of formula (III-b) or a salt thereof:
##STR00005##
[0022] In one embodiment, Y is C, bond b.sup.1 is a single bond, Z
is CH.sub.2, bond b.sup.2 is a single bond, A is CH, and said at
least one compound is a compound of formula (IV) or a salt
thereof:
##STR00006##
[0023] In one embodiment, Y is C, bond b.sup.1 is a single bond, Z
is CH, bond b.sup.2 is a double bond, A is C, and said at least one
compound is a compound of formula (V) or a salt thereof:
##STR00007##
[0024] In one embodiment, the at least one compound is selected
from the group consisting of:
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XX),
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylami-
ne (XXII), N-(4-Cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV),
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine (XXVII), N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX),
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI),
4,6-Bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamin-
e hydrochloride (XXXIII),
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine
(XXXV),
N-(4-(Methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)pr-
opionamide (XL),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
(XLI),
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
(XLIII), N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
(XLV),
6-(Methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine
(XLVII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine
(XLVIII),
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-h-
ydroxylamine (LIII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine
(LV), 6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine
(LVII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl--
hydroxylamine (LXIV),
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamin-
e (LXVIII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine
(LXX),
6-((Benzyloxyxisopropyl)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-tria-
zine-2,4-diamine (LXXII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxyla-
mine (LXXVI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxyla-
mine (LXXXI),
6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-d-
iamine (LXXXIV),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl--
hydroxylamine (XCI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamin-
e (XCVI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethy-
l)-hydroxylamine (C),
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propylamino-[1,3,5]triazin-2-yl)-N-
,O-dimethyl-hydroxylamine (CIII),
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV),
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-O,N-dimethyl-hydroxylamine (CVII),
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine (CIX),
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXI),
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXIII),
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine (CXV),
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(-
19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine
(XLVI),
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhyd-
razine (XLIX), a salt thereof and mixtures thereof. In another
embodiment, the salt is hydrogen sulfate or hydrochloride.
[0025] In one embodiment, the at least one compound is
2,6-bis-(N-n-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
or a salt thereof. In another embodiment, the salt is hydrogen
sulfate or hydrochloride.
[0026] In one embodiment, the at least one compound is selected
from the group consisting of:
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXVI),
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyr-
imidine (CXXVIII),
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXXI),
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d-
]pyrimidine (CXXXVI),
2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX),
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]-
pyrimidine (CLII),
8-(7-Methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicycl-
o[3.2.1]octan-3-ol (CLV), a salt thereof and mixtures thereof. In
another embodiment, the salt is hydrogen sulfate or
hydrochloride.
[0027] In one embodiment, the at least one compound is selected
from the group consisting of:
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylami-
ne (CXLI),
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N-
,O-dimethyl-hydroxylamine (CLVIII),
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hy-
droxylamine (CLX),
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hyd-
roxylamine (CLXII),
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxy-
lamine (CLXIV),
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
(CLXVI),
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl-
)-hydrazine (CLXVIII),
N,N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hy-
drazine (CLXX), a salt thereof and mixtures thereof. In another
embodiment, the salt is hydrogen sulfate or hydrochloride.
[0028] In one embodiment, the composition further comprises at
least one pharmaceutically acceptable carrier.
[0029] The invention also includes a method of preventing or
treating a breathing control disorder or disease in a subject in
need thereof. The method comprises the step of administering to the
subject an effective amount of a pharmaceutical formulation
comprising at least one pharmaceutically acceptable carrier and at
least one compound of formula (I):
##STR00008##
wherein
[0030] R.sup.1 and R.sup.2 are independently H, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
or substituted heteroaryl; or R.sup.1 and R.sup.2 combine as to
form a biradical selected from the group consisting of
3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl,
propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
[0031] R.sup.3 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, or aryl;
[0032] R.sup.4 is H, alkyl, or substituted alkyl;
[0033] R.sup.5 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, --OR.sup.1,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, or substituted
heterocyclic; or R.sup.3 and R.sup.5 combine as to form a biradical
selected from the group consisting of
3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;
[0034] R.sup.6 is H, alkyl, substituted alkyl or alkenyl;
[0035] X is a bond, O or NR.sup.4; and,
[0036] Y is N, CR.sup.6 or C; wherein: [0037] if Y is N or
CR.sup.6, then bond b.sup.1 is nil and: (i) Z is H, bond b.sup.2 is
a single bond, and A is CH; or, (ii) Z is nil, bond b.sup.2 is nil,
and A is a single bond; and, [0038] if Y is C, then bond b.sup.1 is
a single bond, and: (i) Z is CH.sub.2, bond b.sup.2 is a single
bond, and A is CH; or, (ii) Z is CH, bond b.sup.2 is a double bond,
and A is C; or a salt thereof.
[0039] In one embodiment, the breathing control disorder or disease
is selected from the group consisting of respiratory depression,
sleep apnea, apnea of prematurity, obesity-hypoventilation
syndrome, primary alveolar hypoventilation syndrome, dyspnea,
altitude sickness, hypoxia, hypercapnia and chronic obstructive
pulmonary disease (COPD), wherein the respiratory depression is
caused by an anesthetic, a sedative, an anxiolytic agent, a
hypnotic agent, alcohol or a narcotic. In another embodiment, the
subject is further administered a composition comprising at least
one additional compound useful for treating said breathing disorder
or disease. In yet another embodiment, the at least one additional
compound is selected from the group consisting of acetazolamide,
almitrine, theophylline, caffeine, methyl progesterone, a
serotonergic modulator, a cannabinoid and an ampakine. In yet
another embodiment, the formulation is administered in conjunction
with the use of a mechanical ventilation device or positive airway
pressure device on the subject. In yet another embodiment, the
subject is a mammal. In yet another embodiment, the mammal is a
human. In yet another embodiment, the formulation is administered
to the subject by an inhalational, topical, oral, buccal, rectal,
vaginal, intramuscular, subcutaneous, trans dermal, intrathecal or
intravenous route.
[0040] In one embodiment, the at least one compound is selected
from the group consisting of:
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine, N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine,
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-(Methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionami-
de,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine,
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
6-(Methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylami-
ne,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine,
6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydrox-
ylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxyla-
mine, 6-((Benzyloxy)(isopropyl)
amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxyla-
mine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydr-
oxylamine,
6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-tria-
zine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl--
hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamin-
e,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydr-
oxylamine,
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine,
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine,
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(1-
9),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine,
2,6-Bis-(N-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine,
2-(n-Propyl)
amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(i-propyl)
amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidine,
2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]-
pyrimidine,
8-(7-Methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicycl-
o[3.2.1]octan-3-ol,
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylami-
ne,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]-pyrimidin-4-yl)-N,O-dim-
ethyl-hydroxylamine,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hy-
droxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hyd-
roxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxy-
lamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine-
,
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydraz-
ine,
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl-
)-hydrazine, a salt thereof and mixtures thereof.
[0041] The invention also includes a method of preventing
destabilization or stabilizing breathing rhythm in a subject in
need thereof. The method comprises the step of administering to
thed subject an effective amount of a pharmaceutical formulation
comprising at least one pharmaceutically acceptable carrier and at
least one compound of formula (I):
##STR00009##
wherein
[0042] R.sup.1 and R.sup.2 are independently H, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
or substituted heteroaryl; or R.sup.1 and R.sup.2 combine as to
form a biradical selected from the group consisting of
3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl,
propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
[0043] R.sup.3 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, or aryl;
[0044] R.sup.4 is H, alkyl, or substituted alkyl;
[0045] R.sup.5 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, --OR.sup.1,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, or substituted
heterocyclic; or R.sup.3 and R.sup.5 combine as to form a biradical
selected from the group consisting of 3,6,9-trioxa-undecane-1,
11-diyl and 3,6-dioxa-octane-1,8-diyl;
[0046] R.sup.6 is H, alkyl, substituted alkyl or alkenyl;
[0047] X is a bond, O or NR.sup.4; and,
[0048] Y is N, CR.sup.6 or C; wherein: [0049] if Y is N or
CR.sup.6, then bond b.sup.1 is nil and: (i) Z is H, bond b.sup.2 is
a single bond, and A is CH; or, (ii) Z is nil, bond b.sup.2 is nil,
and A is a single bond; and, [0050] if Y is C, then bond b.sup.1 is
a single bond, and: (i) Z is CH.sub.2, bond b.sup.2 is a single
bond, and A is CH; or, (ii) Z is CH, bond b.sup.2 is a double bond,
and A is C; or a salt thereof.
[0051] In one embodiment, the destabilization is associated with a
breathing control disorder or disease selected from the group
consisting of respiratory depression, sleep apnea, apnea of
prematurity, obesity-hypoventilation syndrome, primary alveolar
hypoventilation syndrome, dyspnea, altitude sickness, hypoxia,
hypercapnia and chronic obstructive pulmonary disease (COPD),
wherein the respiratory depression is caused by an anesthetic, a
sedative, an anxiolytic agent, a hypnotic agent, alcohol or a
narcotic. In another embodiment, the subject is further
administered a composition comprising at least one additional
compound useful for treating said breathing disorder or disease. In
yet another embodiment, the at least one additional compound is
selected from the group consisting of acetazolamide, almitrine,
theophylline, caffeine, methyl progesterone, a serotonergic
modulator, a cannabinoid and an ampakine. In yet another
embodiment, the formulation is administered in conjunction with the
use of a mechanical ventilation device or positive airway pressure
device on the subject. In yet another embodiment, the subject is a
mammal. In yet another embodiment, the mammal is a human. In yet
another embodiment, the formulation is administered to the subject
by an inhalational, topical, oral, buccal, rectal, vaginal,
intramuscular, subcutaneous, trans dermal, intrathecal or
intravenous route. In yet another embodiment, the at least one
compound is selected from the group consisting of:
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine, N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine,
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-(Methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionami-
de,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine,
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
6-(Methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylami-
ne,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine,
6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydrox-
ylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxyla-
mine, 6-((Benzyloxy)(isopropyl)
amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxyla-
mine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydr-
oxylamine,
6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-tria-
zine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl--
hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamin-
e,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydr-
oxylamine,
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine,
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine,
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(-
19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine,
2,6-Bis-(N-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine,
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidi-
ne, 2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]-
pyrimidine,
8-(7-Methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicycl-
o[3.2.1]octan-3-ol,
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylami-
ne,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dime-
thyl-hydroxylamine,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hy-
droxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hyd-
roxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxy-
lamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine-
,
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydraz-
ine,
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl-
)-hydrazine, a salt thereof and mixtures thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] For the purpose of illustrating the invention, there are
depicted in the drawings certain embodiments of the invention.
However, the invention is not limited to the precise arrangements
and instrumentalities of the embodiments depicted in the
drawings.
[0053] FIG. 1 is a graph illustrating results of plethysmography
experiments which monitored minute ventilation in the
opioid-treated rat upon administration of Compound (XXXVI) [labeled
as cmpd (A)].
[0054] FIGS. 2A-2B illustrate arterial blood gas analysis results
for administration of Compound (XXXVI) [labeled as cmpd (A)] in the
opioid-treated rat. FIG. 2A--PaCO.sub.2 (mmHg); FIG. 2B--SaO.sub.2
(%).
[0055] FIG. 3 is a graph illustrating results of plethysmography
experiments monitoring minute ventilation in the rat upon
administration of Compound (XXXVI) [labeled as cmpd (A)] under
conditions of hypoxia.
[0056] FIG. 4 is a graph illustrating end-tidal CO.sub.2 and minute
ventilation in the opioid-treated monkey upon administration of
Compound (XXXVI) [labeled as cmpd (A)].
[0057] FIG. 5 is a graph illustrating the dose-dependent effect of
Compound (XXXVI) [labeled as cmpd (A)] and Compound (L) [labeled as
cmpd (B)] on minute ventilation, in terms of maximum peak response,
in the rat.
[0058] FIG. 6 is a graph illustrating the dose-dependent effect of
Compound (XXXVI) [labeled as cmpd (A)] and Compound (CXXI) [labeled
as cmpd (C)] on minute ventilation, in terms of maximum peak
response, in the rat.
[0059] FIGS. 7A-7D illustrate the dose-dependent effect of Compound
(L) [labeled as cmpd (B)] on blood gases and pH in the
opioid-treated rat. FIG. 7A--pH; FIG. 7B--SaO.sub.2; FIG.
7C--pO.sub.2; FIG. 7D--pCO.sub.2.
[0060] FIGS. 8A-8D illustrate the dose-dependent effect of Compound
(CXLII) [labeled as cmpd (D)] on blood gases and pH in the
opioid-treated rat. FIG. 8A--pO.sub.2; FIG. 8B--SaO.sub.2; FIG.
8C--pCO.sub.2; FIG. 8D--pH.
[0061] FIG. 9 is a graph illustrating the effect of Compound
(CXLII) [labeled as cmpd (D)] in the minute ventilation of the
opioid-treated rat.
[0062] FIG. 10 illustrates the .sup.1H-NMR spectrum for Compound
(XXXVI) in DMSO-d.sub.6 at 25.degree. C.
[0063] FIG. 11 illustrates the .sup.13C-NMR spectrum for Compound
(XXXVI) in DMSO-d.sub.6 at 25.degree. C.
[0064] FIG. 12 illustrates the FTIR spectrum for Compound
(XXXVI).
[0065] FIG. 13 illustrates the thermal analysis by DSC of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI).
[0066] FIG. 14 illustrates the X-ray diffraction spectrum of
Compound (XXXVI).
[0067] FIG. 15 is a graph illustrating the effect of Compound
(XXXVI) on reversing the effects of midazolam on minute ventilation
(MV) in the rat.
[0068] FIG. 16 is a graph illustrating the effect of Compound
(XXXVI) on reversing the effects of midazolam on tidal volume (TV)
in the rat.
[0069] FIG. 17 is a graph illustrating the effect of Compound
(XXXVI) on reversing the effects of midazolam on respiratory
frequency (f) in the rat.
[0070] FIG. 18 is a graph illustrating the effect of Compound
(XXXVI) infusion on the minute volume response to acute hypercapnia
(3% CO.sub.2).
DETAILED DESCRIPTION OF THE INVENTION
[0071] The present invention relates in one aspect to the
unexpected discovery that the compounds of the invention are
respiratory stimulants and useful in the treatment of breathing
control disorders or diseases.
DEFINITIONS
[0072] As used herein, each of the following terms has the meaning
associated with it in this section.
[0073] Unless defined otherwise, all technical and scientific terms
used herein generally have the same meaning as commonly understood
by one of ordinary skill in the art to which this invention
belongs. Generally, the nomenclature used herein and the laboratory
procedures in animal pharmacology, pharmaceutical science,
separation science and organic chemistry are those well-known and
commonly employed in the art.
[0074] As used herein, the articles "a" and "an" refer to one or to
more than one (i.e. to at least one) of the grammatical object of
the article. By way of example, "an element" means one element or
more than one element.
[0075] As used herein, the term "about" will be understood by
persons of ordinary skill in the art and will vary to some extent
on the context in which it is used. As used herein when referring
to a measurable value such as an amount, a temporal duration, and
the like, the term "about" is meant to encompass variations of
.+-.20% or .+-.10%, more preferably .+-.5%, even more preferably
.+-.1%, and still more preferably .+-.0.1% from the specified
value, as such variations are appropriate to perform the disclosed
methods.
[0076] As used herein, a "subject" may be a human or non-human
mammal. Non-human mammals include, for example, livestock and pets,
such as ovine, bovine, porcine, canine, feline and murine mammals.
Preferably, the subject is human.
[0077] In a non-limiting embodiment, the following terminology used
to report blood gas measurements is well known to those skilled in
the art and may be defined as such: minute ventilation (MV) is a
measure of breathing volume per unit time and is given herein as
mL/min; pCO.sub.2 is partial pressure of carbon dioxide (gas) in
(arterial) blood measured in mm Hg (millimeters of Hg); pO.sub.2 is
partial pressure of oxygen (gas) in (arterial) blood measured in
mmHg (millimeters of Hg); saO.sub.2 is the percentage of oxygen
saturation (dissolved oxygen gas) which correlates to the
percentage of hemoglobin binding sites in the bloodstream occupied
by oxygen; end-tidal CO.sub.2 is the measurement of exhaled carbon
dioxide gas as detected using colorimetry, capnometry, or
capnography techniques.
[0078] As used herein, the term ED.sub.50 refers to the effective
dose of a formulation that produces a given effect in 50% of the
subjects that are administered that formulation.
[0079] As used herein, a "disease" is a state of health of an
animal wherein the animal cannot maintain homeostasis, and wherein
if the disease is not ameliorated then the animal's health
continues to deteriorate.
[0080] As used herein, a "disorder" in an animal is a state of
health in which the animal is able to maintain homeostasis, but in
which the animal's state of health is less favorable than it would
be in the absence of the disorder. Left untreated, a disorder does
not necessarily cause a further decrease in the animal's state of
health.
[0081] As used herein, an "effective amount", "therapeutically
effective amount" or "pharmaceutically effective amount" of a
compound is that amount of compound that is sufficient to provide a
beneficial effect to the subject to which the compound is
administered. The term to "treat," as used herein, means reducing
the frequency with which symptoms are experienced by a patient or
subject or administering an agent or compound to reduce the
severity with which symptoms are experienced.
[0082] As used herein, the term "pharmaceutically acceptable"
refers to a material, such as a carrier or diluent, which does not
abrogate the biological activity or properties of the compound
useful within the invention, and is relatively non-toxic, i.e., the
material may be administered to an individual without causing
undesirable biological effects or interacting in a deleterious
manner with any of the components of the composition in which it is
contained.
[0083] As used herein, the language "pharmaceutically acceptable
salt" refers to a salt of the administered compound prepared from
pharmaceutically acceptable non-toxic acids and bases, including
inorganic acids, inorganic bases, organic acids, inorganic bases,
solvates, hydrates, and clathrates thereof.
[0084] As used herein, the term "composition" or "pharmaceutical
composition" refers to a mixture of at least one compound useful
within the invention with a pharmaceutically acceptable carrier.
The pharmaceutical composition facilitates administration of the
compound to a subject.
[0085] As used herein, the term "pharmaceutically acceptable
carrier" means a pharmaceutically acceptable material, composition
or carrier, such as a liquid or solid filler, stabilizer,
dispersing agent, suspending agent, diluent, excipient, thickening
agent, solvent or encapsulating material, involved in carrying or
transporting a compound useful within the invention within or to
the subject such that it may perform its intended function.
Typically, such constructs are carried or transported from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation, including
the compound useful within the invention, and not injurious to the
subject. Some examples of materials that may serve as
pharmaceutically acceptable carriers include: sugars, such as
lactose, glucose and sucrose; starches, such as corn starch and
potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter and suppository waxes; oils, such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol; polyols, such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and aluminum hydroxide; surface active agents; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol; phosphate buffer solutions; and other non-toxic compatible
substances employed in pharmaceutical formulations. As used herein,
"pharmaceutically acceptable carrier" also includes any and all
coatings, antibacterial and antifungal agents, and absorption
delaying agents, and the like that are compatible with the activity
of the compound useful within the invention, and are
physiologically acceptable to the subject. Supplementary active
compounds may also be incorporated into the compositions. The
"pharmaceutically acceptable carrier" may further include a
pharmaceutically acceptable salt of the compound useful within the
invention. Other additional ingredients that may be included in the
pharmaceutical compositions used in the practice of the invention
are known in the art and described, for example in Remington's
Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985,
Easton, Pa.), which is incorporated herein by reference.
[0086] As used herein, "treating a disease or disorder" means
reducing the frequency with which a symptom of the disease or
disorder is experienced by a subject. Disease and disorder are used
interchangeably herein.
[0087] By the term "specifically bind" or "specifically binds," as
used herein, is meant that a first molecule preferentially binds to
a second molecule (e.g., a particular receptor or enzyme), but does
not necessarily bind only to that second molecule.
[0088] As used herein, the term "alkyl," by itself or as part of
another substituent means, unless otherwise stated, a straight or
branched chain hydrocarbon having the number of carbon atoms
designated (i.e. C.sub.1-C.sub.10 means one to ten carbon atoms)
and includes straight, branched chain, or cyclic substituent
groups. Examples include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and
cyclopropylmethyl. Most preferred is (C.sub.1-C.sub.6)alkyl, such
as, but not limited to, ethyl, methyl, isopropyl, isobutyl,
n-pentyl, n-hexyl and cyclopropylmethyl.
[0089] As used herein, the term "cycloalkyl," by itself or as part
of another substituent means, unless otherwise stated, a cyclic
chain hydrocarbon having the number of carbon atoms designated
(i.e. C.sub.3-C.sub.6 means a cyclic group comprising a ring group
consisting of three to six carbon atoms) and includes straight,
branched chain or cyclic substituent groups. Examples include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. Most preferred is (C.sub.3-C.sub.6)cycloalkyl, such as,
but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
[0090] As used herein, the term "alkenyl," employed alone or in
combination with other terms, means, unless otherwise stated, a
stable mono-unsaturated or di-unsaturated straight chain or
branched chain hydrocarbon group having the stated number of carbon
atoms. Examples include vinyl, propenyl (or allyl), crotyl,
isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the
higher homologs and isomers. A functional group representing an
alkene is exemplified by --CH.sub.2--CH.dbd.CH.sub.2.
[0091] As used herein, the term "alkynyl," employed alone or in
combination with other terms, means, unless otherwise stated, a
stable straight chain or branched chain hydrocarbon group with a
triple carbon-carbon bond, having the stated number of carbon
atoms. Examples include ethynyl and propynyl, and the higher
homologs and isomers.
[0092] As used herein, the term "substituted alkyl," "substituted
cycloalkyl," "substituted alkenyl" or "substituted alkynyl" means
alkyl, cycloalkyl, alkenyl or alkynyl, as defined above,
substituted by one, two or three substituents selected from the
group consisting of halogen, --OH, alkoxy, tetrahydro-2-H-pyranyl,
--NH.sub.2, --N(CH.sub.3).sub.2, (1-methylimidazol-2-yl),
pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, --C(.dbd.O)OH,
trifluoromethyl, --C.ident.N, --C(.dbd.O)O(C.sub.1-C.sub.4)alkyl,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-C.sub.4)alkyl,
--C(.dbd.O)N((C.sub.1-C.sub.4)alkyl).sub.2, --SO.sub.2NH.sub.2,
--C(.dbd.NH)NH.sub.2, and --NO.sub.2, preferably containing one or
two substituents selected from halogen, --OH, alkoxy, --NH.sub.2,
trifluoromethyl, --N(CH.sub.3).sub.2, and --C(.dbd.O)OH, more
preferably selected from halogen, alkoxy and --OH. Examples of
substituted alkyls include, but are not limited to,
2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.
[0093] As used herein, the term "alkoxy" employed alone or in
combination with other terms means, unless otherwise stated, an
alkyl group having the designated number of carbon atoms, as
defined above, connected to the rest of the molecule via an oxygen
atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy
(isopropoxy) and the higher homologs and isomers. Preferred are
(C.sub.1-C.sub.3)alkoxy, such as, but not limited to, ethoxy and
methoxy.
[0094] As used herein, the term "halo" or "halogen" alone or as
part of another substituent means, unless otherwise stated, a
fluorine, chlorine, bromine, or iodine atom, preferably, fluorine,
chlorine, or bromine, more preferably, fluorine or chlorine.
[0095] As used herein, the term "heteroalkyl" by itself or in
combination with another term means, unless otherwise stated, a
stable straight or branched chain alkyl group consisting of the
stated number of carbon atoms and one or two heteroatoms selected
from the group consisting of O, N, and S, and wherein the nitrogen
and sulfur atoms may be optionally oxidized and the nitrogen
heteroatom may be optionally quaternized. The heteroatom(s) may be
placed at any position of the heteroalkyl group, including between
the rest of the heteroalkyl group and the fragment to which it is
attached, as well as attached to the most distal carbon atom in the
heteroalkyl group. Examples include:
--O--CH.sub.2--CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.sub.2--OH,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, and
--CH.sub.2CH.sub.2--S(.dbd.O)--CH.sub.3. Up to two heteroatoms may
be consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3, or
--CH.sub.2--CH.sub.2--S--S--CH.sub.3
[0096] As used herein, the term "heteroalkenyl" by itself or in
combination with another term means, unless otherwise stated, a
stable straight or branched chain monounsaturated or di-unsaturated
hydrocarbon group consisting of the stated number of carbon atoms
and one or two heteroatoms selected from the group consisting of O,
N, and S, and wherein the nitrogen and sulfur atoms may optionally
be oxidized and the nitrogen heteroatom may optionally be
quaternized. Up to two heteroatoms may be placed consecutively.
Examples include --CH.dbd.CH--O--CH.sub.3,
--CH.dbd.CH--CH.sub.2--OH, --CH.sub.2--CH.dbd.N--OCH.sub.3,
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3, and
--CH.sub.2--CH.dbd.CH--CH.sub.2--SH.
[0097] As used herein, the term "aromatic" refers to a carbocycle
or heterocycle with one or more polyunsaturated rings and having
aromatic character, i.e. having (4n+2) delocalized .pi. (pi)
electrons, where n is an integer.
[0098] As used herein, the term "aryl," employed alone or in
combination with other terms, means, unless otherwise stated, a
carbocyclic aromatic system containing one or more rings (typically
one, two or three rings) wherein such rings may be attached
together in a pendent manner, such as a biphenyl, or may be fused,
such as naphthalene. Examples include phenyl, anthracyl, and
naphthyl. Preferred are phenyl and naphthyl, most preferred is
phenyl.
[0099] As used herein, the term "aryl-(C.sub.1-C.sub.3)alkyl" means
a functional group wherein a one to three carbon alkylene chain is
attached to an aryl group, e.g., --CH.sub.2CH.sub.2-phenyl or
--CH.sub.2-phenyl (benzyl). Preferred is aryl-CH.sub.2-- and
aryl-CH(CH.sub.3)--. The term "substituted
aryl-(C.sub.1-C.sub.3)alkyl" means an aryl-(C.sub.1-C.sub.3)alkyl
functional group in which the aryl group is substituted. Preferred
is substituted aryl(CH.sub.2)--. Similarly, the term
"heteroaryl-(C.sub.1-C.sub.3)alkyl" means a functional group
wherein a one to three carbon alkylene chain is attached to a
heteroaryl group, e.g., --CH.sub.2CH.sub.2-pyridyl. Preferred is
heteroaryl-(CH.sub.2)--. The term "substituted
heteroaryl-(C.sub.1-C.sub.3)alkyl" means a
heteroaryl-(C.sub.1-C.sub.3)alkyl functional group in which the
heteroaryl group is substituted. Preferred is substituted
heteroaryl-(CH.sub.2)--.
[0100] As used herein, the term "heterocycle" or "heterocyclyl" or
"heterocyclic" by itself or as part of another substituent means,
unless otherwise stated, an unsubstituted or substituted, stable,
mono- or multi-cyclic heterocyclic ring system that consists of
carbon atoms and at least one heteroatom selected from the group
consisting of N, O, and S, and wherein the nitrogen and sulfur
heteroatoms may be optionally oxidized, and the nitrogen atom may
be optionally quaternized. The heterocyclic system may be attached,
unless otherwise stated, at any heteroatom or carbon atom that
affords a stable structure. A heterocycle may be aromatic or
non-aromatic in nature. In one embodiment, the heterocycle is a
heteroaryl.
[0101] As used herein, the term "heteroaryl" or "heteroaromatic"
refers to a heterocycle having aromatic character. A polycyclic
heteroaryl may include one or more rings that are partially
saturated. Examples include tetrahydroquinoline and
2,3-dihydrobenzofuryl.
[0102] Examples of non-aromatic heterocycles include monocyclic
groups such as aziridine, oxirane, thiirane, azetidine, oxetane,
thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine,
dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran,
tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine,
1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,
2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane,
homopiperazine, homopiperidine, 1,3-dioxepane,
4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.
[0103] Examples of heteroaryl groups include pyridyl, pyrazinyl,
pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl),
pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,
oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,
1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
[0104] Examples of polycyclic heterocycles include indolyl (such
as, but not limited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl,
quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited
to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl,
cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and
5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl,
1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl,
benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and
7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl,
benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and
7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not
limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl,
benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl,
carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.
[0105] The aforementioned listing of heterocyclyl and heteroaryl
moieties is intended to be representative and not limiting.
[0106] As used herein, the term "substituted" means that an atom or
group of atoms has replaced hydrogen as the substituent attached to
another group.
[0107] For aryl, aryl-(C.sub.1-C.sub.3)alkyl and heterocyclyl
groups, the term "substituted" as applied to the rings of these
groups refers to any level of substitution, namely mono-, di-,
tri-, tetra-, or penta-substitution, where such substitution is
permitted. The substituents are independently selected, and
substitution may be at any chemically accessible position. In one
embodiment, the substituents vary in number between one and four.
In another embodiment, the substituents vary in number between one
and three. In yet another embodiment, the substituents vary in
number between one and two. In yet another embodiment, the
substituents are independently selected from the group consisting
of C.sub.1-6 alkyl, --OH, C.sub.1-6 alkoxy, halo, amino, acetamido
and nitro. As used herein, where a substituent is an alkyl or
alkoxy group, the carbon chain may be branched, straight or cyclic,
with straight being preferred.
[0108] As used herein, the term "AcOH" refers to acetic acid; the
term "nBuOH" refers to n-butanol; the term "CH.sub.2Cl.sub.2"
refers to dichloromethane (also known as methylene dichloride); the
term "DMSO" refers to dimethylsulfoxide; the term "EtOAc" refers to
ethyl acetate; the term "EtOH" refers to ethanol; the term "HCl"
refers to hydrochloric acid or a hydrochloride salt; the term
"HPLC" refers to high pressure liquid chromatography; the term
"H.sub.2SO.sub.4" refers to sulfuric acid; the term "LCMS" refers
to liquid chromatography-mass spectrometry; the term "MS" refers to
mass spectrometry; the term "MeOH" refers to methanol; the term
"NaCl" refers to sodium chloride; the term "NaHCO.sub.3" refers to
sodium bicarbonate; the term "NaOH" refers to sodium hydroxide; the
term "Na.sub.2SO.sub.4" refers to sodium sulfate; the term "mpk"
refers to mg/kg; the term "NMR" refers to nuclear magnetic
resonance; the term "PE" or "pet ether" refers to petroleum ether;
the term "POCl.sub.3" refers to phosphorous oxychloride; the term
"ppm" refers to part per million; the term "xphos" refers to
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; the term
"dba" refers to trans,trans-dibenzylideneacetone.
[0109] "Instructional material," as that term is used herein,
includes a publication, a recording, a diagram, or any other medium
of expression that can be used to communicate the usefulness of the
composition and/or compound of the invention in a kit. The
instructional material of the kit may, for example, be affixed to a
container that contains the compound and/or composition of the
invention or be shipped together with a container that contains the
compound and/or composition. Alternatively, the instructional
material may be shipped separately from the container with the
intention that the recipient uses the instructional material and
the compound cooperatively. Delivery of the instructional material
may be, for example, by physical delivery of the publication or
other medium of expression communicating the usefulness of the kit,
or may alternatively be achieved by electronic transmission, for
example by means of a computer, such as by electronic mail, or
download from a website.
Compounds of the Invention
[0110] The invention includes a compound of formula (I) or a salt
thereof:
##STR00010##
wherein
[0111] R.sup.1 and R.sup.2 are independently H, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
or substituted heteroaryl; or R.sup.1 and R.sup.2 combine as to
form a biradical selected from the group consisting of
3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl,
propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
[0112] R.sup.3 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, or aryl;
[0113] R.sup.4 is H, alkyl, or substituted alkyl;
[0114] R.sup.5 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, --OR.sup.1,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, or substituted
heterocyclic; or R.sup.3 and R.sup.5 combine as to form a biradical
selected from the group consisting of
3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;
[0115] R.sup.6 is H, alkyl, substituted alkyl or alkenyl;
[0116] X is a bond, O or NR.sup.4; and,
[0117] Y is N, CR.sup.6 or C; wherein: [0118] if Y is N or
CR.sup.6, then bond b.sup.1 is nil and: [0119] (i) Z is H, bond
b.sup.2 is a single bond, and A is CH; or, (ii) Z is nil, bond
b.sup.2 is nil, and A is a single bond; and, [0120] if Y is C, then
bond b.sup.1 is a single bond, and: [0121] (i) Z is CH.sub.2, bond
b.sup.2 is a single bond, and A is CH; or, (ii) Z is CH, bond
b.sup.2 is a double bond, and A is C.
[0122] In one embodiment, R.sup.3 is H, alkyl, substituted alkyl,
alkenyl, cycloalkyl, substituted cycloalkyl, or substituted
alkenyl. In another embodiment, R.sup.5 is H, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, acyl, cycloalkyl or
substituted cycloalkyl.
[0123] In one embodiment, Y is N, bond b.sup.1 is nil, Z is H, bond
b.sup.2 is a single bond, A is CH, and the compound of the
invention is a 1,3,5-triazine of formula (II-a) or a salt
thereof:
##STR00011##
[0124] In one embodiment, Y is N, bond b.sup.1 is nil, Z is nil,
bond b.sup.2 is nil, and A is a bond, and the compound of the
invention is a 1,3,5-triazine of formula (II-b) or a salt
thereof:
##STR00012##
[0125] In one embodiment, Y is CR.sup.6, bond b.sup.1 is nil, Z is
H, bond b.sup.2 is a single bond, A is CH, and the compound of the
invention is a pyrimidine of formula (III-a) or a salt thereof:
##STR00013##
[0126] In one embodiment, Y is CR.sup.6, bond b.sup.1 is nil, Z is
nil, bond b.sup.2 is nil, and A is a bond, and the compound of the
invention is a pyrimidine of formula (III-b) or a salt thereof:
##STR00014##
[0127] In one embodiment, Y is C, bond b.sup.1 is a single bond, Z
is CH.sub.2, bond b.sup.2 is a single bond, A is CH, and the
compound of the invention is a pyrrolidinopyrimidine of formula
(IV) or a salt thereof:
##STR00015##
[0128] In one embodiment, Y is C, bond b.sup.1 is a single bond, Z
is CH, bond b.sup.2 is a double bond, A is C, and the compound of
the invention is a pyrrolopyrimidine of formula (V) or a salt
thereof:
##STR00016##
[0129] In one embodiment, the compound of formula (I) is selected
from the group consisting of:
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine, N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine,
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-(Methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionami-
de,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine,
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
6-(Methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylami-
ne,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine,
6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydrox-
ylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxyla-
mine, 6-((Benzyloxy)(isopropyl)
amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxyla-
mine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydr-
oxylamine,
6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-tria-
zine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl--
hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamin-
e,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydr-
oxylamine,
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine,
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine,
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(1-
9),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine,
2,6-Bis-(N-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine,
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidi-
ne, 2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]-
pyrimidine,
8-(7-Methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicycl-
o[3.2.1]octan-3-ol,
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylami-
ne,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dime-
thyl-hydroxylamine,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hy-
droxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hyd-
roxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxy-
lamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine-
,
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydraz-
ine,
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl-
)-hydrazine, a salt thereof and mixtures thereof.
Preparation of the Compounds of the Invention
[0130] The compounds of the invention may be prepared according to
the general methodology illustrated in the synthetic schemes
described below. The reagents and conditions described herein may
be modified to allow the preparation of the compounds of the
invention, and such modifications are known to those skilled in the
art. The scheme included herein are intended to illustrate but not
limit the chemistry and methodologies that one skilled in the art
may use to make compounds of the invention.
[0131] In one aspect, compounds of formula (I) may be prepared by
the successive additions of (i) primary amines, (ii) a
N-alkoxy-N-alkylamine or (iii) an appropriately substituted
hydrazine (H.sub.2N--NHR.sup.2 or R.sup.1HN--NHR.sup.2) to suitably
chlorinated intermediate (VI), as illustrated below in Scheme
1.
##STR00017##
[0132] In another aspect, a compound of formula (IV) or (V) may be
prepared by reductive alkylation of a suitably chlorinated
amino-pyrrolidino-pyrimidine or amino-pyrrolo-pyrimidine,
respectively (Scheme 2).
##STR00018##
[0133] In yet another aspect, a triazine compound of formula (II)
may be prepared by the successive additions of primary amines and
(i) a N-alkoxy-N-alkylamine, (ii) a hydrazine H.sub.2N--NHR.sup.2,
or (iii) a hydrazine R.sup.1HN--NHR.sup.2 to a suitably chlorinated
triazine. Under appropriate conditions, the reaction may allow the
addition of either one or two amine substituents to the triazine
ring. Alternatively, first the N-alkoxy-N-alkylamine, the hydrazine
H.sub.2N--NHR.sup.2, or the hydrazine R.sup.1HN--NHR.sup.2 may be
added to the triazine, followed by the addition of the amines.
[0134] In a non-limiting example, to a solution of
2,4,6-trichlorotriazine in an appropriate aprotic or protic solvent
containing an inorganic or organic base, is added a solution of a
primary amine (VII) and the reaction is allowed to proceed at
ambient temperature or heated, to isolate mono-amine adduct (VIII)
or bis-amine adduct (IX).
[0135] In a subsequent reaction, mono-amine adduct (VIII) is
reacted with another primary amine or a secondary amine (X) to
yield the unsymmetrical monochloro-bis-amino-triazine adduct (XI).
In a subsequent reaction, monochloro-bis-amino-triazine adduct (XI)
is reacted with (i) a N-alkoxy-N-alkylamine, (ii) a hydrazine
H.sub.2N--NHR.sup.2 or (iii) a hydrazine R.sup.1HN--NHR.sup.2 in an
appropriate aprotic or protic solvent containing an inorganic or
organic base to produce desired compounds of formula (II) (Scheme
3).
[0136] Alternatively, in a subsequent reaction, bis-amine adduct
(IX) is reacted with (i) a N-alkoxy-N-alkylamine, (ii) a hydrazine
H.sub.2N--NHR.sup.2 or (iii) a hydrazine R.sup.1HN--NHR.sup.2 in an
appropriate aprotic or protic solvent containing an inorganic or
organic base to produce desired compounds of formula (II), wherein
R.sup.3CH.sub.2 is R.sup.5 (Scheme 4).
##STR00019##
##STR00020##
[0137] In yet another aspect, the pyrimidine compound of the
formula (III) may be prepared by the successive additions of
primary amines and (i) a N-alkoxy-N-alkylamine, (ii) a hydrazine
H.sub.2N--NHR.sup.2 or (iii) a hydrazine R.sup.1HN--NHR.sup.2 to a
suitably chlorinated pyrimidine.
[0138] In a non-limiting example, to a solution of
2,4,6-trichloropyrimidine (XII) in an appropriate aprotic or protic
solvent containing an inorganic or organic base is added a solution
of a primary amine (VII) and the reaction is allowed to proceed at
ambient temperature or heated, yielding bis-amine adduct (XIII). In
a subsequent reaction, bis-amine adduct (XIII) is reacted with (i)
a N-alkoxy-N-alkylamine, (ii) a hydrazine H.sub.2N--NHR.sup.2, or
(iii) a hydrazine R.sup.1HN--NHR.sup.2 in an appropriate aprotic or
protic solvent containing an inorganic or organic base to produce
desired compounds of formula (III) (Scheme 5).
##STR00021##
[0139] In yet another aspect, a pyrrolidino-pyrimidine of formula
(IV) or a pyrrolo-pyrimidine compounds of formula (V) may be
prepared from an appropriately chlorinated
aminopyrrolidinopyrimidine or aminopyrrolopyrimidine intermediate,
respectively.
[0140] In a non-limiting example, 2-chloroacetaldehyde may be added
to a solution of 2,6-diamino-4-hydroxy-1,3-pyrimidine (XIV) in a
polar protic solvent, at ambient temperature or under heating, to
yield cyclized adduct (XV). Subsequent treatment with a
chlorinating agent, such as, but not limited to, phosphorous
oxychloride produces the chloro intermediate (XVI). Intermediate
(XVI) may be submitted to reductive alkylation with an aldehyde in
the presence of a reducing agent, such as a borohydride (in a
non-limiting example, cyanoborohydride) in a protic solvent, at
ambient temperature or elevated temperature, to produce the amino
substituted adduct (XVII). In a subsequent reaction, amino
substituted adduct (XVII) is reacted with (i) a
N-alkoxy-N-alkylamine, (ii) a hydrazine H.sub.2N--NHR.sup.2, or
(iii) a hydrazine R.sup.1HN--NHR.sup.2 in an appropriate aprotic or
protic solvent containing an inorganic or organic base to produce
desired compounds of formula (V), wherein R.sup.3 and R.sup.4 are H
(Scheme 6).
##STR00022##
[0141] In a non-limiting example, a pyrrolidinopyrimidine compound
of the formula (IV) may be prepared from the corresponding
pyrrolopyrimidine analog via reduction (Scheme 7).
##STR00023##
Salts
[0142] The compounds described herein may form salts with acids,
and such salts are included in the present invention. In one
embodiment, the salts are pharmaceutically acceptable salts. The
term "salts" embraces addition salts of free acids that are useful
within the methods of the invention. The term "pharmaceutically
acceptable salt" refers to salts that possess toxicity profiles
within a range that affords utility in pharmaceutical applications.
Pharmaceutically unacceptable salts may nonetheless possess
properties such as high crystallinity, which have utility in the
practice of the present invention, such as for example utility in
process of synthesis, purification or formulation of compounds
useful within the methods of the invention.
[0143] Suitable pharmaceutically acceptable acid addition salts may
be prepared from an inorganic acid or from an organic acid.
Examples of inorganic acids include sulfate, hydrogen sulfate,
hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric,
and phosphoric acids (including hydrogen phosphate and dihydrogen
phosphate). Appropriate organic acids may be selected from
aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,
carboxylic and sulfonic classes of organic acids, examples of which
include formic, acetic, propionic, succinic, glycolic, gluconic,
lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
trifluoromethanesulfonic, 2-hydroxyethanesulfonic,
p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,
alginic, .beta.-hydroxybutyric, salicylic, galactaric and
galacturonic acid.
[0144] Suitable pharmaceutically acceptable base addition salts of
compounds of the invention include, for example, metallic salts
including alkali metal, alkaline earth metal and transition metal
salts such as, for example, calcium, magnesium, potassium, sodium
and zinc salts. Pharmaceutically acceptable base addition salts
also include organic salts made from basic amines such as, for
example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. All of these salts may be prepared from the corresponding
compound by reacting, for example, the appropriate acid or base
with the compound.
Combination Therapies
[0145] In one embodiment, the compounds of the invention are useful
in the methods of present invention in combination with at least
one additional compound useful for treating breathing control
disorders. These additional compounds may comprise compounds of the
present invention or other compounds, such as commercially
available compounds, known to treat, prevent, or reduce the
symptoms of breathing disorders. In embodiment, the combination of
at least one compound of the invention or a salt thereof and at
least one additional compound useful for treating breathing
disorders has additive, complementary or synergistic effects in the
treatment of disordered breathing, and in the treatment of
sleep-related breathing disorders.
[0146] In a non-limiting example, the compounds of the invention or
a salt thereof may be used in combination with one or more of the
following drugs: acetazolamide, almitrine, theophylline, caffeine,
methylprogesterone and related compounds, serotonergic modulators,
cannabinoids (such as but not limited to dronabinol), and compounds
known as ampakines. Non-limiting examples of ampakines are the
pyrrolidine derivative racetam drugs such as piracetam and
aniracetam; the "CX-" series of drugs which encompass a range of
benzoylpiperidine and benzoylpyrrolidine structures, such as CX-516
(6-(piperidin-1-yl-carbonyl)quinoxaline), CX-546
(2,3-dihydro-1,4-benzodioxin-7-yl-(1-piperidyl)-methanone), CX-614
(2H,3H,6aH-pyrrolidino(2,1-3',2')-1,3-oxazino-(6',5'-5,4)benzo(e)1,4-diox-
an-10-one), CX-691
(2,1,3-benzoxadiazol-6-yl-piperidin-1-yl-methanone), CX-717,
CX-701, CX-1739, CX-1763, and CX-1837; benzothiazide derivatives
such as cyclothiazide and IDRA-21
(7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxide); biarylpropylsulfonamides such as LY-392,098,
LY-404,187
(N-[2-(4'-cyanobiphenyl-4-yl)propyl]propane-2-sulfonamide),
LY-451,646 and LY-503,430
(4'-{(1S)-1-fluoro-2-[(isopropylsulfonyl)amino]-1-methylethyl}-N-methylbi-
phenyl-4-carboxamide).
[0147] A synergistic effect may be calculated, for example, using
suitable methods such as, for example, the Sigmoid-E.sub.max
equation (Holford & Scheiner, 19981, Clin. Pharmacokinet. 6:
429-453), the equation of Loewe additivity (Loewe & Muischnek,
1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the
median-effect equation (Chou & Talalay, 1984, Adv. Enzyme
Regul. 22: 27-55). Each equation referred to above may be applied
to experimental data to generate a corresponding graph to aid in
assessing the effects of the drug combination. The corresponding
graphs associated with the equations referred to above are the
concentration-effect curve, isobologram curve and combination index
curve, respectively.
Methods of the Invention
[0148] In one aspect, the present invention includes a method of
preventing or treating a breathing control disorder or disease in a
subject in need thereof. The method includes the step of
administering to the subject an effective amount of a
pharmaceutical formulation comprising at least a pharmaceutically
acceptable carrier and at least one compound of formula (I):
##STR00024##
[0149] R.sup.1 and R.sup.2 are independently H, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted
alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted
phenylalkyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl
or substituted heteroaryl; or R.sup.1 and R.sup.2 combine as to
form a biradical selected from the group consisting of
3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl,
propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
[0150] R.sup.3 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, or aryl;
[0151] R.sup.4 is H, alkyl, or substituted alkyl;
[0152] R.sup.5 is H, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, substituted alkenyl, --OR.sup.1,
--NR.sup.1R.sup.2, --C(O)OR.sup.1, acyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, or substituted
heterocyclic; or R.sup.3 and R.sup.5 combine as to form a biradical
selected from the group consisting of
3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;
[0153] R.sup.6 is H, alkyl, substituted alkyl or alkenyl;
[0154] X is a bond, O or NR.sup.4; and,
[0155] Y is N, CR.sup.6 or C; wherein: [0156] if Y is N or
CR.sup.6, then bond b.sup.1 is nil and: [0157] (i) Z is H, bond
b.sup.2 is a single bond, and A is CH; or, (ii) Z is nil, bond
b.sup.2 is nil, and A is a single bond; and, [0158] if Y is C, then
bond b.sup.1 is a single bond, and: [0159] (i) Z is CH.sub.2, bond
b.sup.2 is a single bond, and A is CH; or, (ii) Z is CH, bond
b.sup.2 is a double bond, and A is C; or a salt thereof.
[0160] In another aspect, the present invention includes a method
of preventing destabilization of or stabilizing breathing rhythm in
a subject in need thereof. The method includes the step of
administering to the subject an effective amount of a
pharmaceutical formulation comprising at least a pharmaceutically
acceptable carrier and at least one compound of formula (I) or a
salt thereof.
[0161] In one embodiment, administering the formulation of the
invention stabilizes the breathing rhythm of the subject. In
another embodiment, administering the formulation of the invention
increases minute ventilation in the subject.
[0162] In one embodiment, the destabilization is associated with a
breathing control disorder or disease.
[0163] In one embodiment, the breathing disorder or disease is
selected from the group consisting of narcotic-induced respiratory
depression, anesthetic-induced respiratory depression,
sedative-induced respiratory depression, anxiolytic-induced
respiratory depression, hypnotic-induced respiratory depression,
alcohol-induced respiratory depression, analgesic-induced
respiratory depression, sleep apnea, apnea of prematurity,
obesity-hypoventilation syndrome, primary alveolar hypoventilation
syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and
chronic obstructive pulmonary disease (COPD). In another
embodiment, the respiratory depression is caused by an anesthetic,
a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a
narcotic.
[0164] In one embodiment, the subject is further administered at
least one additional compound useful for treating the breathing
disorder or disease. In another embodiment, the at least one
additional compound is selected from the group consisting of
acetazolamide, almitrine, theophylline, caffeine,
methylprogesterone and related compounds, a serotonergic modulator,
a cannabinoid, and an ampakine. In yet another embodiment, the
formulation is administered to the subject in conjunction with the
use of a mechanical ventilation device or positive airway pressure
device. In one embodiment, the formulation is administered to the
subject by an inhalational, topical, oral, buccal, rectal, vaginal,
intramuscular, subcutaneous, transdermal, intrathecal or
intravenous route. In another embodiment, the subject is a mammal
including but not limited to mouse, rat, ferret, guinea pig,
monkey, dog, cat, horse, cow, pig and other farm animals. In one
embodiment, the subject is a human. In another embodiment, the at
least one compound of formula (I) is selected from the group
consisting of:
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine, N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(Bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine,
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
N-(4-(Methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionami-
de,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine,
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine,
6-(Methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylami-
ne,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine,
6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine,
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydrox-
ylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxyla-
mine,
6-((Benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-di-
amine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hyd-
roxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxyla-
mine, 6-(Methyl
(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl--
hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamin-
e,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydr-
oxylamine,
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine,
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine,
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine,
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine,
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(1-
9),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine,
2,6-Bis-(N-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine,
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine,
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidi-
ne, 2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine,
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]-
pyrimidine,
8-(7-Methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicycl-
o[3.2.1]octan-3-ol,
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylami-
ne,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dime-
thyl-hydroxylamine,
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hy-
droxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hyd-
roxylamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxy-
lamine,
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine-
,
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydraz-
ine,
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl-
)-hydrazine, a salt thereof and mixtures thereof.
Pharmaceutical Compositions and Formulations
[0165] The invention also encompasses the use of pharmaceutical
compositions of at least one compound of the invention or a salt
thereof to practice the methods of the invention.
[0166] Such a pharmaceutical composition may consist of at least
one compound of the invention or a salt thereof, in a form suitable
for administration to a subject, or the pharmaceutical composition
may comprise at least one compound of the invention or a salt
thereof, and one or more pharmaceutically acceptable carriers, one
or more additional ingredients, or some combination of these. The
at least one compound of the invention may be present in the
pharmaceutical composition in the form of a physiologically
acceptable salt, such as in combination with a physiologically
acceptable cation or anion, as is well known in the art.
[0167] In an embodiment, the pharmaceutical compositions useful for
practicing the method of the invention may be administered to
deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In another
embodiment, the pharmaceutical compositions useful for practicing
the invention may be administered to deliver a dose of between 1
ng/kg/day and 500 mg/kg/day.
[0168] The relative amounts of the active ingredient, the
pharmaceutically acceptable carrier, and any additional ingredients
in a pharmaceutical composition of the invention will vary,
depending upon the identity, size, and condition of the subject
treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0169] Pharmaceutical compositions that are useful in the methods
of the invention may be suitably developed for inhalational, oral,
rectal, vaginal, parenteral, topical, transdermal, pulmonary,
intranasal, buccal, ophthalmic, intrathecal, intravenous or another
route of administration. A composition useful within the methods of
the invention may be directly administered to the brain, the
brainstem, or any other part of the central nervous system of a
mammal. Other contemplated formulations include projected
nanoparticles, liposomal preparations, resealed erythrocytes
containing the active ingredient, and immunologically-based
formulations. The route(s) of administration will be readily
apparent to the skilled artisan and will depend upon any number of
factors including the type and severity of the disease being
treated, the type and age of the veterinary or human patient being
treated, and the like.
[0170] The formulations of the pharmaceutical compositions
described herein may be prepared by any method known or hereafter
developed in the art of pharmacology. In general, such preparatory
methods include the step of bringing the active ingredient into
association with a carrier or one or more other accessory
ingredients, and then, if necessary or desirable, shaping or
packaging the product into a desired single- or multi-dose
unit.
[0171] As used herein, a "unit dose" is a discrete amount of the
pharmaceutical composition comprising a predetermined amount of the
active ingredient. The amount of the active ingredient is generally
equal to the dosage of the active ingredient that would be
administered to a subject or a convenient fraction of such a dosage
such as, for example, one-half or one-third of such a dosage. The
unit dosage form may be for a single daily dose or one of multiple
daily doses (e.g., about 1 to 4 or more times per day). When
multiple daily doses are used, the unit dosage form may be the same
or different for each dose.
[0172] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for ethical administration to
humans, it will be understood by the skilled artisan that such
compositions are generally suitable for administration to animals
of all sorts. Modification of pharmaceutical compositions suitable
for administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design and
perform such modification with merely ordinary, if any,
experimentation. Subjects to which administration of the
pharmaceutical compositions of the invention is contemplated
include, but are not limited to, humans and other primates, mammals
including commercially relevant mammals such as cattle, pigs,
horses, sheep, cats, and dogs.
[0173] In one embodiment, the compositions of the invention are
formulated using one or more pharmaceutically acceptable excipients
or carriers. In one embodiment, the pharmaceutical compositions of
the invention comprise a therapeutically effective amount of at
least one compound of the invention and a pharmaceutically
acceptable carrier. Pharmaceutically acceptable carriers, which are
useful, include, but are not limited to, glycerol, water, saline,
ethanol and other pharmaceutically acceptable salt solutions such
as phosphates and salts of organic acids. Examples of these and
other pharmaceutically acceptable carriers are described in
Remington's Pharmaceutical Sciences (1991, Mack Publication Co.,
New Jersey).
[0174] The carrier may be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (for example,
glycerol, propylene glycol, and liquid polyethylene glycol, and the
like), suitable mixtures thereof, and vegetable oils. The proper
fluidity may be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersion and by the use of surfactants. Prevention
of the action of microorganisms may be achieved by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, sodium chloride, or polyalcohols such as mannitol
and sorbitol, in the composition. Prolonged absorption of the
injectable compositions may be brought about by including in the
composition an agent that delays absorption, for example, aluminum
monostearate or gelatin. In one embodiment, the pharmaceutically
acceptable carrier is not DMSO alone.
[0175] Formulations may be employed in admixtures with conventional
excipients, i.e., pharmaceutically acceptable organic or inorganic
carrier substances suitable for oral, parenteral, nasal,
inhalational, intravenous, subcutaneous, transdermal enteral, or
any other suitable mode of administration, known to the art. The
pharmaceutical preparations may be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure buffers, coloring, flavoring and/or aromatic
substances and the like. They may also be combined where desired
with other active agents, e.g., other analgesic agents. As used
herein, "additional ingredients" include, but are not limited to,
one or more ingredients that may be used as a pharmaceutical
carrier.
[0176] The composition of the invention may comprise a preservative
from about 0.005% to 2.0% by total weight of the composition. The
preservative is used to prevent spoilage in the case of exposure to
contaminants in the environment. Examples of preservatives useful
in accordance with the invention included but are not limited to
those selected from the group consisting of benzyl alcohol, sorbic
acid, parabens, imidurea and combinations thereof. A particularly
preferred preservative is a combination of about 0.5% to 2.0%
benzyl alcohol and 0.05% to 0.5% sorbic acid.
[0177] The composition preferably includes an antioxidant and a
chelating agent which inhibit the degradation of the compound.
Preferred antioxidants for some compounds are BHT, BHA,
alpha-tocopherol and ascorbic acid in the preferred range of about
0.01% to 0.3% and more preferably BHT in the range of 0.03% to 0.1%
by weight by total weight of the composition. Preferably, the
chelating agent is present in an amount of from 0.01% to 0.5% by
weight by total weight of the composition. Particularly preferred
chelating agents include edetate salts (e.g. disodium edetate) and
citric acid in the weight range of about 0.01% to 0.20% and more
preferably in the range of 0.02% to 0.10% by weight by total weight
of the composition. The chelating agent is useful for chelating
metal ions in the composition which may be detrimental to the shelf
life of the formulation. While BHT and disodium edetate are the
particularly preferred antioxidant and chelating agent respectively
for some compounds, other suitable and equivalent antioxidants and
chelating agents may be substituted therefore as would be known to
those skilled in the art.
[0178] Liquid suspensions may be prepared using conventional
methods to achieve suspension of the active ingredient in an
aqueous or oily vehicle. Aqueous vehicles include, for example,
water, and isotonic saline. Oily vehicles include, for example,
almond oil, oily esters, ethyl alcohol, vegetable oils such as
arachis, olive, sesame, or coconut oil, fractionated vegetable
oils, and mineral oils such as liquid paraffin. Liquid suspensions
may further comprise one or more additional ingredients including,
but not limited to, suspending agents, dispersing or wetting
agents, emulsifying agents, demulcents, preservatives, buffers,
salts, flavorings, coloring agents, and sweetening agents. Oily
suspensions may further comprise a thickening agent. Known
suspending agents include, but are not limited to, sorbitol syrup,
hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone,
gum tragacanth, gum acacia, and cellulose derivatives such as
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose. Known dispersing or wetting agents
include, but are not limited to, naturally-occurring phosphatides
such as lecithin, condensation products of an alkylene oxide with a
fatty acid, with a long chain aliphatic alcohol, with a partial
ester derived from a fatty acid and a hexitol, or with a partial
ester derived from a fatty acid and a hexitol anhydride (e.g.,
polyoxyethylene stearate, heptadecaethyleneoxycetanol,
polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan
monooleate, respectively). Known emulsifying agents include, but
are not limited to, lecithin, and acacia. Known preservatives
include, but are not limited to, methyl, ethyl, or n-propyl
para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known
sweetening agents include, for example, glycerol, propylene glycol,
sorbitol, sucrose, and saccharin. Known thickening agents for oily
suspensions include, for example, beeswax, hard paraffin, and cetyl
alcohol.
[0179] Liquid solutions of the active ingredient in aqueous or oily
solvents may be prepared in substantially the same manner as liquid
suspensions, the primary difference being that the active
ingredient is dissolved, rather than suspended in the solvent. As
used herein, an "oily" liquid is one which comprises a
carbon-containing liquid molecule and which exhibits a less polar
character than water. Liquid solutions of the pharmaceutical
composition of the invention may comprise each of the components
described with regard to liquid suspensions, it being understood
that suspending agents will not necessarily aid dissolution of the
active ingredient in the solvent. Aqueous solvents include, for
example, water, and isotonic saline. Oily solvents include, for
example, almond oil, oily esters, ethyl alcohol, vegetable oils
such as arachis, olive, sesame, or coconut oil, fractionated
vegetable oils, and mineral oils such as liquid paraffin.
[0180] Powdered and granular formulations of a pharmaceutical
preparation of the invention may be prepared using known methods.
Such formulations may be administered directly to a subject, used,
for example, to form tablets, to fill capsules, or to prepare an
aqueous or oily suspension or solution by addition of an aqueous or
oily vehicle thereto. Each of these formulations may further
comprise one or more of dispersing or wetting agent, a suspending
agent, and a preservative. Additional excipients, such as fillers
and sweetening, flavoring, or coloring agents, may also be included
in these formulations.
[0181] A pharmaceutical composition of the invention may also be
prepared, packaged, or sold in the form of oil-in-water emulsion or
a water-in-oil emulsion. The oily phase may be a vegetable oil such
as olive or arachis oil, a mineral oil such as liquid paraffin, or
a combination of these. Such compositions may further comprise one
or more emulsifying agents such as naturally occurring gums such as
gum acacia or gum tragacanth, naturally-occurring phosphatides such
as soybean or lecithin phosphatide, esters or partial esters
derived from combinations of fatty acids and hexitol anhydrides
such as sorbitan monooleate, and condensation products of such
partial esters with ethylene oxide such as polyoxyethylene sorbitan
monooleate. These emulsions may also contain additional ingredients
including, for example, sweetening or flavoring agents.
[0182] Methods for impregnating or coating a material with a
chemical composition are known in the art, and include, but are not
limited to methods of depositing or binding a chemical composition
onto a surface, methods of incorporating a chemical composition
into the structure of a material during the synthesis of the
material (i.e., such as with a physiologically degradable
material), and methods of absorbing an aqueous or oily solution or
suspension into an absorbent material, with or without subsequent
drying.
Administration/Dosing
[0183] The regimen of administration may affect what constitutes an
effective amount. The therapeutic formulations may be administered
to the patient either prior to or after the onset of a breathing
disorder event. Further, several divided dosages, as well as
staggered dosages may be administered daily or sequentially, or the
dose may be continuously infused, or may be a bolus injection.
Further, the dosages of the therapeutic formulations may be
proportionally increased or decreased as indicated by the
exigencies of the therapeutic or prophylactic situation.
[0184] Administration of the compositions of the present invention
to a patient, preferably a mammal, more preferably a human, may be
carried out using known procedures, at dosages and for periods of
time effective to treat a breathing control disorder in the
patient. An effective amount of the therapeutic compound necessary
to achieve a therapeutic effect may vary according to factors such
as the activity of the particular compound employed; the time of
administration; the rate of excretion of the compound; the duration
of the treatment; other drugs, compounds or materials used in
combination with the compound; the state of the disease or
disorder, age, sex, weight, condition, general health and prior
medical history of the patient being treated, and like factors
well-known in the medical arts. Dosage regimens may be adjusted to
provide the optimum therapeutic response. For example, several
divided doses may be administered daily or the dose may be
proportionally reduced as indicated by the exigencies of the
therapeutic situation. A non-limiting example of an effective dose
range for a therapeutic compound of the invention is from about
0.01 mg/kg and 50 mg/kg of body weight/per day. One of ordinary
skill in the art would be able to study the relevant factors and
make the determination regarding the effective amount of the
therapeutic compound without undue experimentation.
[0185] The compound can be administered to an animal as frequently
as several times daily, or it may be administered less frequently,
such as once a day, once a week, once every two weeks, once a
month, or even less frequently, such as once every several months
or even once a year or less. It is understood that the amount of
compound dosed per day may be administered, in non-limiting
examples, every day, every other day, every 2 days, every 3 days,
every 4 days, or every 5 days. For example, with every other day
administration, a 5 mg per day dose may be initiated on Monday with
a first subsequent 5 mg per day dose administered on Wednesday, a
second subsequent 5 mg per day dose administered on Friday, and so
on. The frequency of the dose will be readily apparent to the
skilled artisan and will depend upon any number of factors, such
as, but not limited to, the type and severity of the disease being
treated, the type and age of the animal, etc.
[0186] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient that is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0187] A medical doctor, e.g., physician or veterinarian, having
ordinary skill in the art may readily determine and prescribe the
effective amount of the pharmaceutical composition required. For
example, the physician or veterinarian could start doses of the
compounds of the invention employed in the pharmaceutical
composition at levels lower than that required in order to achieve
the desired therapeutic effect and gradually increase the dosage
until the desired effect is achieved.
[0188] In particular embodiments, it is especially advantageous to
formulate the compound in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the patients to be treated; each unit containing a
predetermined quantity of therapeutic compound calculated to
produce the desired therapeutic effect in association with the
required pharmaceutical vehicle. The dosage unit forms of the
invention are dictated by and directly dependent on (a) the unique
characteristics of the therapeutic compound and the particular
therapeutic effect to be achieved, and (b) the limitations inherent
in the art of compounding/formulating such a therapeutic compound
for the treatment of breathing disorders in a patient.
[0189] In one embodiment, the compositions of the invention are
administered to the patient in dosages that range from one to five
times per day or more. In another embodiment, the compositions of
the invention are administered to the patient in range of dosages
that include, but are not limited to, once every day, every two,
days, every three days to once a week, and once every two weeks. It
will be readily apparent to one skilled in the art that the
frequency of administration of the various combination compositions
of the invention will vary from subject to subject depending on
many factors including, but not limited to, age, disease or
disorder to be treated, gender, overall health, and other factors.
Thus, the invention should not be construed to be limited to any
particular dosage regime and the precise dosage and composition to
be administered to any patient will be determined by the attending
physical taking all other factors about the patient into
account.
[0190] Compounds of the invention for administration may be in the
range of from about 1 .mu.g to about 7,500 mg, about 20 .mu.g to
about 7,000 mg, about 40 .mu.g to about 6,500 mg, about 80 .mu.g to
about 6,000 mg, about 100 .mu.g to about 5,500 mg, about 200 .mu.g
to about 5,000 mg, about 400 .mu.g to about 4,000 mg, about 800
.mu.g to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg
to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to
about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500
mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about
60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to
about 150 mg, and any and all whole or partial increments
thereinbetween.
[0191] In some embodiments, the dose of a compound of the invention
is from about 0.5 .mu.g and about 5,000 mg. In some embodiments, a
dose of a compound of the invention used in compositions described
herein is less than about 5,000 mg, or less than about 4,000 mg, or
less than about 3,000 mg, or less than about 2,000 mg, or less than
about 1,000 mg, or less than about 800 mg, or less than about 600
mg, or less than about 500 mg, or less than about 200 mg, or less
than about 50 mg. Similarly, in some embodiments, a dose of a
second compound as described herein is less than about 1,000 mg, or
less than about 800 mg, or less than about 600 mg, or less than
about 500 mg, or less than about 400 mg, or less than about 300 mg,
or less than about 200 mg, or less than about 100 mg, or less than
about 50 mg, or less than about 40 mg, or less than about 30 mg, or
less than about 25 mg, or less than about 20 mg, or less than about
15 mg, or less than about 10 mg, or less than about 5 mg, or less
than about 2 mg, or less than about 1 mg, or less than about 0.5
mg, and any and all whole or partial increments thereof.
[0192] In one embodiment, the present invention is directed to a
packaged pharmaceutical composition comprising a container holding
a therapeutically effective amount of a compound of the invention,
alone or in combination with a second pharmaceutical agent; and
instructions for using the compound to treat, prevent, or reduce
one or more symptoms of breathing disorder in a patient.
[0193] The term "container" includes any receptacle for holding the
pharmaceutical composition. For example, in one embodiment, the
container is the packaging that contains the pharmaceutical
composition. In other embodiments, the container is not the
packaging that contains the pharmaceutical composition, i.e., the
container is a receptacle, such as a box or vial that contains the
packaged pharmaceutical composition or unpackaged pharmaceutical
composition and the instructions for use of the pharmaceutical
composition. Moreover, packaging techniques are well known in the
art. It should be understood that the instructions for use of the
pharmaceutical composition may be contained on the packaging
containing the pharmaceutical composition, and as such the
instructions form an increased functional relationship to the
packaged product. However, it should be understood that the
instructions may contain information pertaining to the compound's
ability to perform its intended function, e.g., treating,
preventing, or reducing a breathing disorder in a patient.
Routes of Administration
[0194] Routes of administration of any of the compositions of the
invention include inhalational, oral, nasal, rectal, parenteral,
sublingual, transdermal, transmucosal (e.g., sublingual, lingual,
(trans)buccal, (trans)urethral, vaginal (e.g., trans- and
perivaginally), (intra)nasal, and (trans)rectal), intravesical,
intrapulmonary, intraduodenal, intragastrical, intrathecal,
subcutaneous, intramuscular, intradermal, intra-arterial,
intravenous, intrabronchial, inhalation, and topical
administration.
[0195] Suitable compositions and dosage forms include, for example,
tablets, capsules, caplets, pills, gel caps, troches, dispersions,
suspensions, solutions, syrups, granules, beads, transdermal
patches, gels, powders, pellets, magmas, lozenges, creams, pastes,
plasters, lotions, discs, suppositories, liquid sprays for nasal or
oral administration, dry powder or aerosolized formulations for
inhalation, compositions and formulations for intravesical
administration and the like. It should be understood that the
formulations and compositions that would be useful in the present
invention are not limited to the particular formulations and
compositions that are described herein.
Oral Administration
[0196] For oral application, particularly suitable are tablets,
dragees, liquids, drops, suppositories, or capsules, caplets and
gelcaps. Other formulations suitable for oral administration
include, but are not limited to, a powdered or granular
formulation, an aqueous or oily suspension, an aqueous or oily
solution, a paste, a gel, toothpaste, a mouthwash, a coating, an
oral rinse, or an emulsion. The compositions intended for oral use
may be prepared according to any method known in the art and such
compositions may contain one or more agents selected from the group
consisting of inert, non-toxic pharmaceutically excipients which
are suitable for the manufacture of tablets. Such excipients
include, for example an inert diluent such as lactose; granulating
and disintegrating agents such as cornstarch; binding agents such
as starch; and lubricating agents such as magnesium stearate.
[0197] Tablets may be non-coated or they may be coated using known
methods to achieve delayed disintegration in the gastrointestinal
tract of a subject, thereby providing sustained release and
absorption of the active ingredient. By way of example, a material
such as glyceryl monostearate or glyceryl distearate may be used to
coat tablets. Further by way of example, tablets may be coated
using methods described in U.S. Pat. Nos. 4,256,108; 4,160,452; and
U.S. Pat. No. 4,265,874 to form osmotically controlled release
tablets. Tablets may further comprise a sweetening agent, a
flavoring agent, a coloring agent, a preservative, or some
combination of these in order to provide for pharmaceutically
elegant and palatable preparation.
[0198] Hard capsules comprising the active ingredient may be made
using a physiologically degradable composition, such as gelatin.
Such hard capsules comprise the active ingredient, and may further
comprise additional ingredients including, for example, an inert
solid diluent such as calcium carbonate, calcium phosphate, or
kaolin.
[0199] Soft gelatin capsules comprising the active ingredient may
be made using a physiologically degradable composition, such as
gelatin. Such soft capsules comprise the active ingredient, which
may be mixed with water or an oil medium such as peanut oil, liquid
paraffin, or olive oil.
[0200] For oral administration, the compounds of the invention may
be in the form of tablets or capsules prepared by conventional
means with pharmaceutically acceptable excipients such as binding
agents; fillers; lubricants; disintegrates; or wetting agents. If
desired, the tablets may be coated using suitable methods and
coating materials such as OPADRY.TM. film coating systems available
from Colorcon, West Point, Pa. (e.g., OPADRY.TM. OY Type, OYC Type,
Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type
and OPADRY.TM. White, 32K18400).
[0201] Liquid preparation for oral administration may be in the
form of solutions, syrups or suspensions. The liquid preparations
may be prepared by conventional means with pharmaceutically
acceptable additives such as suspending agents (e.g., sorbitol
syrup, methyl cellulose or hydrogenated edible fats); emulsifying
agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g.,
almond oil, oily esters or ethyl alcohol); and preservatives (e.g.,
methyl or propyl para-hydroxy benzoates or sorbic acid). Liquid
formulations of a pharmaceutical composition of the invention which
are suitable for oral administration may be prepared, packaged, and
sold either in liquid form or in the form of a dry product intended
for reconstitution with water or another suitable vehicle prior to
use.
[0202] A tablet comprising the active ingredient may, for example,
be made by compressing or molding the active ingredient, optionally
with one or more additional ingredients. Compressed tablets may be
prepared by compressing, in a suitable device, the active
ingredient in a free-flowing form such as a powder or granular
preparation, optionally mixed with one or more of a binder, a
lubricant, an excipient, a surface active agent, and a dispersing
agent. Molded tablets may be made by molding, in a suitable device,
a mixture of the active ingredient, a pharmaceutically acceptable
carrier, and at least sufficient liquid to moisten the mixture.
Pharmaceutically acceptable excipients used in the manufacture of
tablets include, but are not limited to, inert diluents,
granulating and disintegrating agents, binding agents, and
lubricating agents. Known dispersing agents include, but are not
limited to, potato starch and sodium starch glycollate. Known
surface-active agents include, but are not limited to, sodium
lauryl sulphate. Known diluents include, but are not limited to,
calcium carbonate, sodium carbonate, lactose, microcrystalline
cellulose, calcium phosphate, calcium hydrogen phosphate, and
sodium phosphate. Known granulating and disintegrating agents
include, but are not limited to, corn starch and alginic acid.
Known binding agents include, but are not limited to, gelatin,
acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and
hydroxypropyl methylcellulose. Known lubricating agents include,
but are not limited to, magnesium stearate, stearic acid, silica,
and talc.
[0203] Granulating techniques are well known in the pharmaceutical
art for modifying starting powders or other particulate materials
of an active ingredient. The powders are typically mixed with a
binder material into larger permanent free-flowing agglomerates or
granules referred to as a "granulation." For example, solvent-using
"wet" granulation processes are generally characterized in that the
powders are combined with a binder material and moistened with
water or an organic solvent under conditions resulting in the
formation of a wet granulated mass from which the solvent must then
be evaporated.
[0204] Melt granulation generally consists in the use of materials
that are solid or semi-solid at room temperature (i.e. having a
relatively low softening or melting point range) to promote
granulation of powdered or other materials, essentially in the
absence of added water or other liquid solvents. The low melting
solids, when heated to a temperature in the melting point range,
liquefy to act as a binder or granulating medium. The liquefied
solid spreads itself over the surface of powdered materials with
which it is contacted, and on cooling, forms a solid granulated
mass in which the initial materials are bound together. The
resulting melt granulation may then be provided to a tablet press
or be encapsulated for preparing the oral dosage form. Melt
granulation improves the dissolution rate and bioavailability of an
active (i.e. drug) by forming a solid dispersion or solid
solution.
[0205] U.S. Pat. No. 5,169,645 discloses directly compressible
wax-containing granules having improved flow properties. The
granules are obtained when waxes are admixed in the melt with
certain flow improving additives, followed by cooling and
granulation of the admixture. In certain embodiments, only the wax
itself melts in the melt combination of the wax(es) and
additives(s), and in other cases both the wax(es) and the
additives(s) will melt.
[0206] The present invention also includes a multi-layer tablet
comprising a layer providing for the delayed release of one or more
compounds useful within the methods of the invention, and a further
layer providing for the immediate release of one or more compounds
useful within the methods of the invention. Using a
wax/pH-sensitive polymer mix, a gastric insoluble composition may
be obtained in which the active ingredient is entrapped, ensuring
its delayed release.
Parenteral Administration
[0207] As used herein, "parenteral administration" of a
pharmaceutical composition includes any route of administration
characterized by physical breaching of a tissue of a subject and
administration of the pharmaceutical composition through the breach
in the tissue. Parenteral administration thus includes, but is not
limited to, administration of a pharmaceutical composition by
injection of the composition, by application of the composition
through a surgical incision, by application of the composition
through a tissue-penetrating non-surgical wound, and the like. In
particular, parenteral administration is contemplated to include,
but is not limited to, subcutaneous, intravenous, intraperitoneal,
intramuscular, intrasternal injection, and kidney dialytic infusion
techniques.
[0208] Formulations of a pharmaceutical composition suitable for
parenteral administration comprise the active ingredient combined
with a pharmaceutically acceptable carrier, such as sterile water
or sterile isotonic saline. Such formulations may be prepared,
packaged, or sold in a form suitable for bolus administration or
for continuous administration. Injectable formulations may be
prepared, packaged, or sold in unit dosage form, such as in ampules
or in multi-dose containers containing a preservative. Formulations
for parenteral administration include, but are not limited to,
suspensions, solutions, emulsions in oily or aqueous vehicles,
pastes, and implantable sustained-release or biodegradable
formulations. Such formulations may further comprise one or more
additional ingredients including, but not limited to, suspending,
stabilizing, or dispersing agents. In one embodiment of a
formulation for parenteral administration, the active ingredient is
provided in dry (i.e., powder or granular) form for reconstitution
with a suitable vehicle (e.g., sterile pyrogen-free water) prior to
parenteral administration of the reconstituted composition.
[0209] The pharmaceutical compositions may be prepared, packaged,
or sold in the form of a sterile injectable aqueous or oily
suspension or solution. This suspension or solution may be
formulated according to the known art, and may comprise, in
addition to the active ingredient, additional ingredients such as
the dispersing agents, wetting agents, or suspending agents
described herein. Such sterile injectable formulations may be
prepared using a non-toxic parenterally-acceptable diluent or
solvent, such as water or 1,3-butane diol, for example. Other
acceptable diluents and solvents include, but are not limited to,
Ringer's solution, isotonic sodium chloride solution, and fixed
oils such as synthetic mono- or di-glycerides. Other
parentally-administrable formulations which are useful include
those which comprise the active ingredient in microcrystalline
form, in a liposomal preparation, or as a component of a
biodegradable polymer system. Compositions for sustained release or
implantation may comprise pharmaceutically acceptable polymeric or
hydrophobic materials such as an emulsion, an ion exchange resin, a
sparingly soluble polymer, or a sparingly soluble salt.
Topical Administration
[0210] An obstacle for topical administration of pharmaceuticals is
the stratum corneum layer of the epidermis. The stratum corneum is
a highly resistant layer comprised of protein, cholesterol,
sphingolipids, free fatty acids and various other lipids, and
includes cornified and living cells. One of the factors that limit
the penetration rate (flux) of a compound through the stratum
corneum is the amount of the active substance that can be loaded or
applied onto the skin surface. The greater the amount of active
substance which is applied per unit of area of the skin, the
greater the concentration gradient between the skin surface and the
lower layers of the skin, and in turn the greater the diffusion
force of the active substance through the skin. Therefore, a
formulation containing a greater concentration of the active
substance is more likely to result in penetration of the active
substance through the skin, and more of it, and at a more
consistent rate, than a formulation having a lesser concentration,
all other things being equal.
[0211] Formulations suitable for topical administration include,
but are not limited to, liquid or semi-liquid preparations such as
liniments, lotions, oil-in-water or water-in-oil emulsions such as
creams, ointments or pastes, and solutions or suspensions.
Topically administrable formulations may, for example, comprise
from about 1% to about 10% (w/w) active ingredient, although the
concentration of the active ingredient may be as high as the
solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0212] Enhancers of permeation may be used. These materials
increase the rate of penetration of drugs across the skin. Typical
enhancers in the art include ethanol, glycerol monolaurate, PGML
(polyethylene glycol monolaurate), dimethylsulfoxide, and the like.
Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol,
laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar
lipids, or N-methyl-2-pyrrolidone.
[0213] One acceptable vehicle for topical delivery of some of the
compositions of the invention may contain liposomes. The
composition of the liposomes and their use are known in the art
(for example, see Constanza, U.S. Pat. No. 6,323,219).
[0214] In alternative embodiments, the topically active
pharmaceutical composition may be optionally combined with other
ingredients such as adjuvants, antioxidants, chelating agents,
surfactants, foaming agents, wetting agents, emulsifying agents,
viscosifiers, buffering agents, preservatives, and the like. In
another embodiment, a permeation or penetration enhancer is
included in the composition and is effective in improving the
percutaneous penetration of the active ingredient into and through
the stratum corneum with respect to a composition lacking the
permeation enhancer. Various permeation enhancers, including oleic
acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic
acids, dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone,
are known to those of skill in the art. In another aspect, the
composition may further comprise a hydrotropic agent, which
functions to increase disorder in the structure of the stratum
corneum, and thus allows increased transport across the stratum
corneum. Various hydrotropic agents such as isopropyl alcohol,
propylene glycol, or sodium xylene sulfonate, are known to those of
skill in the art.
[0215] The topically active pharmaceutical composition should be
applied in an amount effective to affect desired changes. As used
herein "amount effective" shall mean an amount sufficient to cover
the region of skin surface where a change is desired. An active
compound should be present in the amount of from about 0.0001% to
about 15% by weight volume of the composition. More preferable, it
should be present in an amount from about 0.0005% to about 5% of
the composition; most preferably, it should be present in an amount
of from about 0.001% to about 1% of the composition. Such compounds
may be synthetically- or naturally derived.
Buccal Administration
[0216] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for buccal
administration. Such formulations may, for example, be in the form
of tablets or lozenges made using conventional methods, and may
contain, for example, 0.1 to 20% (w/w) of the active ingredient,
the balance comprising an orally dissolvable or degradable
composition and, optionally, one or more of the additional
ingredients described herein. Alternately, formulations suitable
for buccal administration may comprise a powder or an aerosolized
or atomized solution or suspension comprising the active
ingredient. Such powdered, aerosolized, or aerosolized
formulations, when dispersed, preferably have an average particle
or droplet size in the range from about 0.1 to about 200
nanometers, and may further comprise one or more of the additional
ingredients described herein. The examples of formulations
described herein are not exhaustive and it is understood that the
invention includes additional modifications of these and other
formulations not described herein, but which are known to those of
skill in the art.
Rectal Administration
[0217] A pharmaceutical composition of the invention may be
prepared, packaged, or sold in a formulation suitable for rectal
administration. Such a composition may be in the form of, for
example, a suppository, a retention enema preparation, and a
solution for rectal or colonic irrigation.
[0218] Suppository formulations may be made by combining the active
ingredient with a non-irritating pharmaceutically acceptable
excipient which is solid at ordinary room temperature (i.e., about
20.degree. C.) and which is liquid at the rectal temperature of the
subject (i.e., about 37.degree. C. in a healthy human). Suitable
pharmaceutically acceptable excipients include, but are not limited
to, cocoa butter, polyethylene glycols, and various glycerides.
Suppository formulations may further comprise various additional
ingredients including, but not limited to, antioxidants, and
preservatives.
[0219] Retention enema preparations or solutions for rectal or
colonic irrigation may be made by combining the active ingredient
with a pharmaceutically acceptable liquid carrier. As is well known
in the art, enema preparations may be administered using, and may
be packaged within, a delivery device adapted to the rectal anatomy
of the subject. Enema preparations may further comprise various
additional ingredients including, but not limited to, antioxidants,
and preservatives.
Additional Administration Forms
[0220] Additional dosage forms of this invention include dosage
forms as described in U.S. Pat. Nos. 6,340,475, 6,488,962,
6,451,808, 5,972,389, 5,582,837, and 5,007,790. Additional dosage
forms of this invention also include dosage forms as described in
U.S. Patent Applications Nos. 20030147952, 20030104062,
20030104053, 20030044466, 20030039688, and 20020051820. Additional
dosage forms of this invention also include dosage forms as
described in PCT Applications Nos. WO 03/35041, WO 03/35040, WO
03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO
01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO
97/47285, WO 93/18755, and WO 90/11757.
Controlled Release Formulations and Drug Delivery Systems
[0221] Controlled- or sustained-release formulations of a
pharmaceutical composition of the invention may be made using
conventional technology. In some cases, the dosage forms to be used
can be provided as slow or controlled-release of one or more active
ingredients therein using, for example, hydropropylmethyl
cellulose, other polymer matrices, gels, permeable membranes,
osmotic systems, multilayer coatings, microparticles, liposomes, or
microspheres or a combination thereof to provide the desired
release profile in varying proportions. Suitable controlled-release
formulations known to those of ordinary skill in the art, including
those described herein, can be readily selected for use with the
pharmaceutical compositions of the invention. Thus, single unit
dosage forms suitable for oral administration, such as tablets,
capsules, gelcaps, and caplets, that are adapted for
controlled-release are encompassed by the present invention.
[0222] Most controlled-release pharmaceutical products have a
common goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
level of the drug, and thus can affect the occurrence of side
effects.
[0223] Most controlled-release formulations are designed to
initially release an amount of drug that promptly produces the
desired therapeutic effect, and gradually and continually release
of other amounts of drug to maintain this level of therapeutic
effect over an extended period of time. In order to maintain this
constant level of drug in the body, the drug must be released from
the dosage form at a rate that will replace the amount of drug
being metabolized and excreted from the body.
[0224] Controlled-release of an active ingredient can be stimulated
by various inducers, for example pH, temperature, enzymes, water,
or other physiological conditions or compounds. The term
"controlled-release component" in the context of the present
invention is defined herein as a compound or compounds, including,
but not limited to, polymers, polymer matrices, gels, permeable
membranes, liposomes, or microspheres or a combination thereof that
facilitates the controlled-release of the active ingredient.
[0225] In certain embodiments, the formulations of the present
invention may be, but are not limited to, short-term, rapid-offset,
as well as controlled, for example, sustained release, delayed
release and pulsatile release formulations.
[0226] The term sustained release is used in its conventional sense
to refer to a drug formulation that provides for gradual release of
a drug over an extended period of time, and that may, although not
necessarily, result in substantially constant blood levels of a
drug over an extended time period. The period of time may be as
long as a month or more and should be a release that is longer that
the same amount of agent administered in bolus form.
[0227] For sustained release, the compounds may be formulated with
a suitable polymer or hydrophobic material which provides sustained
release properties to the compounds. As such, the compounds for use
the method of the invention may be administered in the form of
microparticles, for example, by injection or in the form of wafers
or discs by implantation.
[0228] In a preferred embodiment of the invention, the compounds of
the invention are administered to a patient, alone or in
combination with another pharmaceutical agent, using a sustained
release formulation.
[0229] The term delayed release is used herein in its conventional
sense to refer to a drug formulation that provides for an initial
release of the drug after some delay following drug administration
and that may, although not necessarily, includes a delay of from
about 10 minutes up to about 12 hours.
[0230] The term pulsatile release is used herein in its
conventional sense to refer to a drug formulation that provides
release of the drug in such a way as to produce pulsed plasma
profiles of the drug after drug administration.
[0231] The term immediate release is used in its conventional sense
to refer to a drug formulation that provides for release of the
drug immediately after drug administration.
[0232] As used herein, short-term refers to any period of time up
to and including about 8 hours, about 7 hours, about 6 hours, about
5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour,
about 40 minutes, about 20 minutes, or about 10 minutes and any or
all whole or partial increments thereof after drug administration
after drug administration.
[0233] As used herein, rapid-offset refers to any period of time up
to and including about 8 hours, about 7 hours, about 6 hours, about
5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour,
about 40 minutes, about 20 minutes, or about 10 minutes, and any
and all whole or partial increments thereof after drug
administration.
Mechanical Devices
[0234] In one aspect of the invention, a method of treating a
patient lacking normal breathing and normal breathing control
comprises administering the composition useful within the invention
as described herein, and additionally treating the patient using a
device for treatment of a lack of normal breathing. Such devices
include, but are not limited to, ventilation devices, CPAP and
BiPAP devices.
[0235] Mechanical ventilation is a method to mechanically assist or
replace spontaneous breathing. Mechanical ventilation is typically
used after an invasive intubation, a procedure wherein an
endotracheal or tracheostomy tube is inserted into the airway. It
is normally used in acute settings, such as in the ICU, for a short
period of time during a serious illness. It may also be used at
home or in a nursing or rehabilitation institution, if patients
have chronic illnesses that require long-term ventilation
assistance. The main form of mechanical ventilation is positive
pressure ventilation, which works by increasing the pressure in the
patient's airway and thus forcing air into the lungs. Less common
today are negative pressure ventilators (for example, the "iron
lung") that create a negative pressure environment around the
patient's chest, thus sucking air into the lungs. Mechanical
ventilation is often a life-saving intervention, but carries many
potential complications including pneumothorax, airway injury,
alveolar damage, and ventilator-associated pneumonia. For this
reason the pressure and volume of gas used is strictly controlled,
and reduced as soon as possible. Types of mechanical ventilation
are: conventional ventilation, high frequency ventilation,
non-invasive ventilation (non-invasive positive pressure
pentilation or NIPPV), proportional assist ventilation (PAV),
adaptive support ventilation (ASV) and neurally adjusted
ventilatory assist (NAVA).
[0236] Non-invasive ventilation refers to all modalities that
assist ventilation without the use of an endotracheal tube.
Non-invasive ventilation is primarily aimed at minimizing patient
discomfort and the complications associated with invasive
ventilation, and is often used in cardiac disease, exacerbations of
chronic pulmonary disease, sleep apnea, and neuromuscular diseases.
Non-invasive ventilation refers only to the patient interface and
not the mode of ventilation used; modes may include spontaneous or
control modes and may be either pressure or volume modes. Some
commonly used modes of NIPPV include:
[0237] (a) Continuous positive airway pressure (CPAP): This kind of
machine has been used mainly by patients for the treatment of sleep
apnea at home, but now is in widespread use across intensive care
units as a form of ventilation. The CPAP machine stops upper airway
obstruction by delivering a stream of compressed air via a hose to
a nasal pillow, nose mask or full-face mask, splinting the airway
(keeping it open under air pressure) so that unobstructed breathing
becomes possible, reducing and/or preventing apneas and hypopneas.
When the machine is turned on, but prior to the mask being placed
on the head, a flow of air comes through the mask. After the mask
is placed on the head, it is sealed to the face and the air stops
flowing. At this point, it is only the air pressure that
accomplishes the desired result. This has the additional benefit of
reducing or eliminating the extremely loud snoring that sometimes
accompanies sleep apnea.
[0238] (b) Bi-level positive airway pressure (BIPAP): Pressures
alternate between inspiratory positive airway pressure (IPAP) and a
lower expiratory positive airway pressure (EPAP), triggered by
patient effort. On many such devices, backup rates may be set,
which deliver IPAP pressures even if patients fail to initiate a
breath.
[0239] (c) Intermittent positive pressure ventilation (IPPV), via
mouthpiece or mask.
[0240] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures, embodiments, claims, and
examples described herein. Such equivalents were considered to be
within the scope of this invention and covered by the claims
appended hereto. For example, it should be understood, that
modifications in reaction conditions, including but not limited to
reaction times, reaction size/volume, and experimental reagents,
such as solvents, catalysts, pressures, atmospheric conditions,
e.g., nitrogen atmosphere, and reducing/oxidizing agents, with
art-recognized alternatives and using no more than routine
experimentation, are within the scope of the present
application.
[0241] It is to be understood that, wherever values and ranges are
provided herein, the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
all values and ranges encompassed by these values and ranges are
meant to be encompassed within the scope of the present invention.
Moreover, all values that fall within these ranges, as well as the
upper or lower limits of a range of values, are also contemplated
by the present application. The description of a range should be
considered to have specifically disclosed all the possible
sub-ranges as well as individual numerical values within that range
and, when appropriate, partial integers of the numerical values
within ranges. For example, description of a range such as from 1
to 6 should be considered to have specifically disclosed sub-ranges
such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2
to 6, from 3 to 6 etc., as well as individual numbers within that
range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies
regardless of the breadth of the range.
[0242] The following examples further illustrate aspects of the
present invention. However, they are in no way a limitation of the
teachings or disclosure of the present invention as set forth
herein.
EXAMPLES
[0243] The invention is now described with reference to the
following Examples. These Examples are provided for the purpose of
illustration only, and the invention is not limited to these
Examples, but rather encompasses all variations that are evident as
a result of the teachings provided herein.
Materials:
[0244] Unless otherwise noted, all remaining starting materials
were obtained from commercial suppliers and used without
purification. Final products are typically isolated as
hydrochloride acid addition salts unless noted otherwise.
Example 1
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrochloride (XX)
##STR00025##
[0245] 2-Chloro-N-(4,6-bis-methylamino)-[1,3,5]triazine (XIX)
[0246] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (5.0 g, 27 mmol) was
dissolved in acetone (35 mL) and poured into ice-water (50 mL) to
form a very fine suspension. A solution of N-methylamine
hydrochloride (3.66 g, 54 mmol) in water (20 mL) was added and the
temperature maintained at approximately 0.degree. C. To this
mixture, 2N NaOH (54 mL, 108 mmol) was added in a dropwise manner
to keep the temperature between 0.degree. C. and 5.degree. C. The
mixture was stirred 30 min at ambient temperature for an additional
60 min at 50.degree. C. The precipitate was filtered and washed
with water (3.times.25 mL). After drying over anhydrous calcium
chloride under high vacuum,
2-chloro-N-(4,6-bis-methylamino)-[1,3,5]triazine (XIX) was isolated
as a white powder (4.2 g, 89% yield). LCMS (ESI) m/z=174
(M+H).sup.+.
N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrochloride (XX)
[0247] A mixture of 2-chloro-N-(4,
6-bis-methylamino)-[1,3,5]triazine (XIX) (1.74 g, 10 mmol),
N,O-dimethylhydroxylamine hydrochloride (3.88 g, 40 mmol) and DIPEA
(7.74 g, 60 mmol) in EtOH (200 mL) was heated at 100.degree. C. for
16 h, after which the solvent was removed under reduced pressure.
The residue was dissolved in EtOAc (150 mL), washed with water (100
mL) and brine solution (100 mL), and then dried over
Na.sub.2SO.sub.4. The solvent was removed under reduced pressure.
The crude product was purified by flash column chromatography (pet
ether/ethyl acetate=5/1 to 5/3) to yield 899 mg (23%) of the
desired product. The isolated free amine (380 mg, 2 mmol) was
placed into H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (6 mL)
was added. The resultant solution was subjected to lyophilization
to yield the desired product,
N-(4,6-bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxy-
lamine hydrochloride (XX), as a white solid (468 mg). LCMS (ESI)
m/z=199 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO): .delta. (ppm)
12.20-12.50 (br, 1H), 8.48-8.62 (m, 2H), 3.76-3.86 (m, 3H),
3.29-3.39 (m, 3H), 2.76-2.93 (m, 6H).
Example 2
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrochloride (XXII)
##STR00026##
[0248] 2-Chloro-N-(4,6-bis-ethylamino)-[1,3,5]triazine (XXI)
[0249] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (5.0 g, 27 mmol) was
dissolved in acetone (35 mL) and poured into ice-water (50 mL) to
form a very fine suspension. A solution of ethylamine (2.43 g, 54
mmol) in water (20 mL) was added and the temperature maintained at
approximately 0.degree. C. To this mixture, 2N NaOH (27 mL, 54
mmol) was added in a dropwise manner to keep the temperature
between 0.degree. C. and 5.degree. C. The mixture was stirred for
30 min at ambient temperature, and for additional 60 min at
50.degree. C. The precipitate was filtered off, washed with water
(3.times.25 mL). After drying over anhydrous calcium chloride under
high vacuum, 2-chloro-N-(4, 6-bis-ethylamino)-[1,3,5]triazine (XXI)
was isolated as a white powder (5.0 g, 92% yield). LCMS (ESI)
m/z=202 (M+H).sup.+.
N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrochloride (XXII)
[0250] A mixture of 2-chloro-N-(4,
6-bis-ethylamino)-[1,3,5]triazine (XXI) (4.03 g, 20 mmol),
N,O-dimethylhydroxylamine hydrochloride (9.7 g, 100 mmol) and DIPEA
(1.806 g, 140 mmol) in EtOH (200 mL) was heated at 100.degree. C.
for 16 h. After this time, the solvent was removed under reduced
pressure. The residue was dissolved in EtOAc (400 mL), washed with
water (100 mL) and a brine solution (100 mL), then dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
by flash column chromatography (pet ether/ethyl acetate=5/1 to 5/2)
to yield 811 mg (18%) of the desired product. The isolated free
amine (811 mg, 3.58 mmol) was dissolved in H.sub.2O (10 mL) and 0.5
M HCl solution in H.sub.2O (7.2 mL) was added. The resultant
solution was lyophilized to yield the desired product,
N-(4,6-bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrochloride (XXII) as a white solid (938 mg). LCMS (ESI) m/z=227
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO): .delta. (ppm) 12.40-12.80
(br, 1H), 8.58-8.87 (m, 2H), 3.76-3.78 (m, 4H), 3.34-3.37 (m, 6H),
1.10-1.16 (m, 6H).
Example 3
N-(4-Cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV)
##STR00027##
[0251] 2, 4-Dichloro-N-(6-n-propylamino)-[1,3,5]triazine
(XXIII)
[0252] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (20 g, 109 mmol) was
dissolved in acetone (100 mL) and poured into ice-water (50 mL) to
form a very fine suspension. A solution of propan-1-amine (7.1 g,
120 mmol) in water (20 mL) was added and the temperature maintained
at approximately 0.degree. C. To this mixture, 2N NaOH (60 mL, 120
mmol) was added in a dropwise manner to keep the temperature
between -5.degree. C. and 0.degree. C. The mixture was stirred at
0.degree. C. for 60 min. The precipitate was filtered off and
washed with water (3.times.25 mL). After drying over calcium
chloride under high vacuum,
2,4-dichloro-N-(6-n-propylamino)-[1,3,5]triazine (XXIII) was
isolated as a white powder (18 g, 80% yield). LCMS (ESI) m/z=208
(M+H).sup.+.
2-Chloro-N-(4-cyclopropylmethyl)-N-(6-n-propylamino)
[1,3,5]triazine (XXIV)
[0253] 2,4-Dichloro-N-(6-n-propylamino)-[1,3,5]triazine (XXIII) (18
g, 87 mmol) was dissolved in acetone (100 mL) and poured into
ice-water (50 mL) to form a very fine suspension. A solution of
cyclopropylmethanamine (6.7 g, 95 mmol) in acetone (30 mL) was
added and the temperature was maintained at approximately 0.degree.
C. To this mixture, 2N NaOH (44 mL, 88 mmol) was added in a
dropwise manner to keep the temperature between 0.degree. C. and
5.degree. C. The mixture was stirred for 30 min at ambient
temperature and for an additional 60 min at 50.degree. C. The
precipitate was filtered off, washed with water (3.times.25 mL).
After drying over anhydrous calcium chloride under high vacuum,
2-chloro-N-(4-cyclopropylmethyl)-N-(6-n-propylamino)
[1,3,5]triazine (XXIV) was isolated as a white powder (12 g, 57%
yield). LCMS (ESI) m/z=242 (M+H).sup.+.
N-(4-Cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride
(XXV)
[0254] A mixture of
2-chloro-N-(4-cyclopropylmethyl)-N-(6-n-propylamino)
[1,3,5]triazine (XXIV) (1.5 g, 6.2 mmol), N,O-dimethylhydroxylamine
hydrochloride (3.0 g, 31.0 mmol) and DIPEA (6.5 g, 49.6 mmol) in
EtOH (50 mL) was heated at 100.degree. C. for 16 h, after the
solvent was removed under reduced pressure. The residue was
dissolved in EtOAc (400 mL), washed with water (100 mL), then with
a brine solution (100 mL) and dried over Na.sub.2SO.sub.4. The
crude was purified by flash column chromatography (pet ether/ethyl
acetate=5/1 to 5/2). The solvent was removed under reduced pressure
to yield 500 mg (26%) of the desired product. The isolated free
amine (500 mg, 1.88 mmol) was dissolved in H.sub.2O (10 mL) and 0.5
M aqueous HCl solution (4.0 mL) was added. The resultant solution
was subjected was subjected to lyophilization to yield the desired
product, N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (XXV,
520 mg) as a brown oil. LCMS (ESI) m/z=267 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO): .delta. (ppm) 11.80-12.10 (br, 1H), 8.68-8.85 (m,
2H), 3.77 (s, 3H), 3.15-3.36 (m, 7H), 1.49-1.55 (m, 2H), 1.23 (s,
1H), 0.85-0.93 (m, 3H), 0.43-0.49 (m, 2H), 0.22-0.25 (m, 2H).
Example 4
N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hyd-
roxylamine (XXVII)
##STR00028##
[0255] 2,4-Dichloro-N-(6-n-propylamino)-[1,3,5]triazine (XXII)
[0256] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (20 g, 109 mmol) was
dissolved in acetone (100 mL) and poured into ice-water (50 mL) to
form a very fine suspension. A solution of propan-1-amine (7.1 g,
120 mmol) in water (20 mL) was added and the temperature maintained
at approximately 0.degree. C. To this mixture was added 2 N NaOH
(60 mL, 120 mmol) in a dropwise manner to keep the temperature
between -5.degree. C. and 0.degree. C. The mixture was then stirred
at 0.degree. C. for 60 min. The precipitate was filtered off,
washed with water (3.times.25 mL). After drying over anhydrous
calcium chloride under high vacuum,
2,4-dichloro-N-(6-n-propylamino)-[1,3,5]triazine (XXIII) was
isolated as a white powder (18 g, 80% yield). LCMS (ESI) m/z=208
(M+H).sup.+.
2-Chloro-N-(4-ethylamino)-N-(6-n-propylamino)-[1,3,5]triazine
(XXVI)
[0257] 2,4-Dichloro-N-(6-n-propylamino)-[1,3,5]triazine (XXIII)
(4.0 g, 19.5 mmol) was dissolved in acetone (40 mL) and poured into
ice-water (40 mL) to form a very fine suspension. A solution of
ethanamine hydrochloride (1.91 g, 23.4 mmol) in water (10 mL) was
added and the temperature was maintained at approximately 0.degree.
C. A solution of NaOH (2.34 g, 58.5 mmol) in water (10 mL) was
added in a dropwise manner to keep the temperature between
0.degree. C. and 5.degree. C. The mixture was then stirred 40 min
at room temperature and concentrated. The precipitate was filtered
off, washed with water (3.times.25 mL). After drying over calcium
chloride under high vacuum, the desired product,
2-chloro-N-(4-ethylamino)-N-(6-n-propylamino)-[1,3,5]triazine
(XXVI) was isolated as a white powder (3.89 g, 92% yield). LCMS
(ESI) m/z=216 (M+H).sup.+.
N-(4-Ethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride
(XXVII)
[0258] A mixture of
2-chloro-N-(4-ethylamino)-N-(6-n-propylamino)-[1,3,5]triazine
(XXVI) (2 g, 9.3 mmol), N,O-dimethylhydroxylamine hydrochloride
(4.5 g, 46.5 mmol) and DIPEA (8.4 g, 65.1 mmol) in EtOH (20 mL) was
heated at 100.degree. C. for 16 h, after which time the solvent was
removed under reduced pressure. The residue was dissolved in EtOAc
(150 mL), washed with water (100 mL), washed with a brine solution
(100 mL) and then dried over Na.sub.2SO.sub.4. The solvent was
removed under reduced pressure and the residue was purified by
flash column chromatography (pet ether/ethyl acetate=10/1 to 2/1)
to yield the desired product (820 mg, 37%). The isolated free amine
(820 mg, 3.42 mmol) was dissolved in H.sub.2O (10 mL), and 0.5 M
aqueous HCl solution (11 mL) was added. The resultant solution was
subjected to lyophilization to yield the desired product,
N-(4-ethylamino)-N-(6-n-propylamino)
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride
(XXVII), as a colorless oil (944 mg). LCMS (ESI) m/z=241
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO): .delta. (ppm) 12.25-12.75
(br, 1H), 8.71-8.75 (m, 2H), 3.75-3.92 (m, 6H), 3.25-3.37 (m, 4H),
1.50-1.55 (m, 2H), 1.09-1.16 (m, 3H), 0.87-0.94 (m, 3H).
Example 5
N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX)
##STR00029##
[0259] 2-Chloro-N-(4, 6-bis-(2-methylpropylamino)-[1,3,5]triazine
(XXVIII)
[0260] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (5.0 g, 27 mmol) was
dissolved in acetone (35 mL) and poured into ice-water (50 mL) to
form a very fine suspension. A solution of 2-methylpropan-1-amine
(4.0 g, 54 mmol) in acetone (20 mL) was added and the temperature
was maintained at approximately 0.degree. C. To this mixture, 2 N
NaOH (27 mL, 54 mmol) was added in a dropwise manner to keep the
temperature between 0.degree. C. and 5.degree. C. The mixture was
stirred for 30 min at ambient temperature and for an additional 60
min at 50.degree. C. The precipitate was filtered off, washed with
water (3.times.25 mL). After drying over calcium chloride under
high vacuum, 2-chloro-N-(4,
6-bis-(2-methylpropylamino)-[1,3,5]triazine (XXVIII) was isolated
as white powder (6.0 g, 87% yield). LCMS (ESI) m/z=258
(M+H).sup.+.
N-(Bis-4,6-(2-methylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride
(XXIX)
[0261] A mixture of 2-chloro-N-(4,
6-bis-(2-methylpropylamino)-[1,3,5]triazine (XXVIII) (2.57 g, 10
mmol), N,O-dimethylhydroxylamine hydrochloride (1.94 g, 20 mmol)
and DIPEA (5.16 g, 40 mmol) in EtOH (100 mL) was heated at
100.degree. C. for 16 h, after which time the solvent was removed
under reduced pressure. The residue was dissolved in EtOAc (200
mL), washed with water (2.times.100 mL), washed with a brine
solution (100 mL) and then dried over Na.sub.2SO.sub.4. The solvent
was removed under reduced pressure. The residue was purified by
flash column chromatography (pet ether/ethyl acetate=5/1) to yield
the desired product (920 mg, 33%). The isolated free amine (920 mg,
3.3 mmol) was dissolved in H.sub.2O (10 mL) and 0.5 M aqueous HCl
solution (6.6 mL) was added. The resultant solution was subjected
to lyophilization to yield the desired product,
N-(bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydrox-
ylamine hydrochloride (XXIX) as a white solid (1.0 g). LCMS (ESI)
m/z=283 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO): .delta. (ppm)
12.55-12.60 (br, 1H), 8.57-8.77 (br, 2H), 3.78 (s, 3H), 3.40-3.45
(m, 3H), 3.11-3.19 (m, 4H), 1.80-1.86 (m, 2H), 0.89-0.94 (m,
12H).
Example 6
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride
(XXXI)
##STR00030##
[0262]
N-(4,6-Dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXY)
[0263] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (30 g, 163 mmol) was
dissolved in acetone (300 mL), and N,O-dimethylhydroxylamine
hydrochloride (15.8 g, 163 mmol) and DIPEA (42 g, 326 mmol) were
added and the mixture then stirred at 0.degree. C. for 1 h. The
solution was concentrated and the residue was treated with EtOAc
(750 mL), washed with water (100 mL), and the organic layer was
dried with Na.sub.2SO.sub.4. The volatiles were removed in vacuo
and the residue was purified by flash column chromatography (pet
ether/ethyl acetate=50/1 to 10/1) to yield the desired product,
N-(4,6-dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX), as a white solid (25 g, 73% yield). LCMS (ESI) m/z=210
(M+H).sup.+.
N-(Bis-4,6-(2,2-dimethylpropylamino))
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXI)
[0264] A mixture of
N-(4,6-dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX) (1 g, 4.78 mmol), 2,2-dimethylpropan-1-amine (832.5 mg, 9.57
mmol) and DIPEA (1.85 g, 14.34 mmol) in EtOH (20 mL) was heated at
100.degree. C. for 16 h, after which time the solvent was removed
under reduced pressure. The residue was dissolved in EtOAc (40 mL),
washed with water (20 mL) and with a brine solution (20 mL), dried
over Na.sub.2SO.sub.4, and then concentrated. The crude product was
purified by flash column chromatography (pet ether/ethyl
acetate=20/1 to 5/1) to yield the desired product (1.4 g, 95%). The
isolated free amine (1.4 g, 4.52 mmol) was dissolved in H.sub.2O
(10 mL) and 0.5 M HCl solution in H.sub.2O (14.5 mL) was added, and
the resultant solution was subjected to lyophilization to yield the
desired product,
N-(bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine hydrochloride, as a white solid (1.67 g). LCMS (ESI)
m/z=311 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO): .delta. (ppm)
12.40-12.70 (br, 1H), 8.52-8.81 (m, 2H), 3.75-3.79 (m, 3H),
3.33-3.36 (m, 3H), 3.14-3.21 (m, 4H), 0.89-0.96 (m, 18H).
Example 7
4,6-Bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrochloride (XXXIII)
##STR00031##
[0265] 2-Chloro-N-(4, 6-bis-(cyclopropylamino)-[1,3,5]triazine
(XXXII)
[0266] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (40 g, 217 mmol) was
dissolved in 200 mL of acetone and poured into ice-water (250 mL)
to form a very fine suspension. A solution of cyclopropanamine
(24.8 g, 435 mmol) was added with stirring at 0.degree. C. To this
mixture, 2N NaOH (218 mL, 435 mmol) was added dropwise at a rate to
keep the temperature between 0.degree. C. and 5.degree. C. The
resultant mixture was stirred for 30 min at ambient temperature and
then for an additional 60 min at 50.degree. C. The precipitate was
filtered off, washed with water (3.times.100 mL). After drying over
calcium chloride under high vacuum, chloro-N-(4,
6-bis-(cyclopropylamino)-[1,3,5]triazine (XXXII) was isolated as a
white powder (46 g, 93% yield). LCMS (ESI) m/z=226 (M+H).sup.+.
4,6-Bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXXIII)
[0267] A mixture of chloro-N-(4,
6-bis-(cyclopropylamino)-[1,3,5]triazine (XXXII) (2.25 g, 10 mmol),
N,O-dimethylhydroxylamine hydrochloride (1.94 g, 20 mmol) and DIPEA
(5.16 g, 40 mmol) in EtOH (100 mL) was heated at 100.degree. C. for
16 h, and the solvent was then removed under reduced pressure. The
residue was dissolved in EtOAc (200 mL), washed with water
(2.times.100 mL) and brine (100 mL) then dried over
Na.sub.2SO.sub.4. The solvent was removed under reduced pressure.
The residue was purified by flash column chromatography (pet
ether/ethyl acetate=3/1) to yield 1.0 g (40%) of the desired
product. The isolated free amine (1.0 g, 4.0 mmol) was dissolved in
H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (8 mL) and then the
solution was lyophilized to yield
N-(4,6-bis-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylami-
ne hydrochloride (XXXIII) as a white solid (1.05 g). LCMS (ESI)
m/z=251 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO): .delta. (ppm)
12.00-12.80 (br, 1H), 8.70-9.50 (br, 2H), 3.76 (s, 3H), 3.28-3.38
(m, 3H), 2.69-2.89 (m, 2H), 0.59-0.81 (m, 8H).
Example 8A
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXXV)
Example 9A
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI)
##STR00032##
[0268] 2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine
(XXXIV)
[0269] A 2 M NaOH solution (82 mL, 162.68 mmol) was added in a
dropwise manner to a suspension of 2,4,6-trichloro-1,3,5-triazine
(XVIII) (15.00 g, 81.34 mmol) and n-propylamine (13.4 mL, 162.68
mmol) in acetone (300 mL) and water (15 mL) at 0.degree. C. The
reaction mixture was heated at 50.degree. C. for 3 h and then
cooled. Water (100 mL) was added to the reaction mixture; the
resultant precipitate was filtered, washed with water, ethyl ether
and dried to yield 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (15.88 g, 85%
yield).
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXXIV)
[0270] A mixture of 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (10.00 g, 43.53
mmol), N,O-dimethylhydroxylamine hydrochloride (8.49 g, 87.06 mmol)
and NaOH (3.13 g, 78.35 mmol) in 1,4-dioxane (120 mL) and water (30
mL) was heated at 60.degree. C. for 6 h, after which the volatiles
were removed under reduced pressure. Saturated NaHCO.sub.3 solution
(500 mL) was added to the residue and the mixture was extracted
with EtOAc (3.times.200 mL). The combined organic extracts were
washed with water (300 mL), then with a brine solution (300 mL) and
dried over Na.sub.2SO.sub.4. The solvent was removed under reduced
pressure and the resultant residue was filtered through silica gel
using eluent CH.sub.2Cl.sub.2/EtOH (9/1 v/v) to yield
N-(4,6-bis-n-propylamino
[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) (9.96 g,
90% yield).
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI)
[0271] Concentrated (95%) H.sub.2SO.sub.4 (0.72 mL, 12.74 mmol) was
added in a dropwise manner to a solution of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXXV, 3.24 g, 12.74 mmol) in 1,4-dioxane (100 mL) at 0.degree. C.
The mixture was stirred for 0.5 h at room temperature, volatiles
were removed under reduced pressure. The residue was co-evaporated
with dry toluene (3.times.25 mL). The resulting white residue was
crystallized from ethanol/ethyl ether to yield
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,
hydrogen sulfate (XXXVI, 3.86 g, 86% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO): .delta. (ppm) 12.0-11.2 (1H, br s),
8.7-8.3 (0.7H, br s), 8.10 (0.3H, br s), 7.8-7.3 (1H, m), 3.78 (3H,
s), 3.40-3.20 (7H, m), 1.61-1.45 (4H, m), 0.93-0.84 (6H, m). ESI-MS
(m/z) 255 [M+H]; melting point: 134-135.degree. C.
Example 8b
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXXV)
Example 9b
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI)
##STR00033##
[0272] Stage 1: 2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine
(XXXIV)
[0273] Summary: Di-chloro displacement by 2 equivalents of
n-propylamine. In one embodiment, two or more equivalence of
n-propylamine produced only the bis-propylamine derivative of the
starting material. The reaction progress was monitored by HPLC and
the desired intermediate (2-chloro-4,6-bispropylamino-s-triazine)
was precipitated. In-process QC Tests were performed.
[0274] A suitable glass reactor vessel equipped with a mechanical
stirrer, thermocouple, condenser, addition funnel and a temperature
control mantle was charged with 8 L of acetone followed by 1 kg
(5.42 moles) of cyanuric chloride. The stirring mixture was
pre-cooled to 15.degree. C. and n-propylamine (at ambient
temperature) was added slowly via addition funnel, to maintain the
temperature below 45.degree. C. A 2M NaOH solution was prepared and
was added to the mixture at a rate to maintain the temperature
below 45.degree. C. The pH of the mixture was acidic (approximately
pH=4) and 6N NaOH was added to adjust the pH to 8-9. The mixture
was stirred at 40-50.degree. C. for 0.5 h and the reaction was
monitored for completion by IPC HPLC analysis. The reaction was
deemed complete when <2% of cyanuric chloride was detected.
Analysis was repeated every hour until reaction was complete.
[0275] After reaction was complete, WFI (sterile water) was added
slowly to maintain temperature below 50.degree. C. The resulting
suspension was allowed to cool to room temperature while stirring
overnight. The solids were filtered through a polypropylene filter
cloth and washed with acetone/water (1:2) followed by 1.5 L of
MTBE. The solids were dried on the filter (assisted by vacuum) then
placed in a vacuum oven (45.+-.5.degree. C., >29'' Hg) for a
minimum of 6 h to give <0.5% in change in weight loss. A sample
was collected for analytical testing (QC HPLC analysis and Karl
Fisher analysis); 2 g was collected for QA retain. The product
produced in Stage 1 was a white solid. This powder was transferred
from drying pans to poly bag with nylon tie, double bagged and
placed into fiber drum; label and submit to QA for quarantine
storage.
Stage 2:
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydrox-
ylamine (XXXV)
[0276] Summary: Chloro displacement by 1 equivalent of
N-methoxymethylamine. The reaction progress was monitored by HPLC
and precipitation of desired product free base was accomplished by
adding water and cooling. In-process QC Tests were pre-formed. The
free base was converted to the corresponding sulfate salt with
crystallization and the final product was subjected to vacuum oven
drying. In-process QC Tests were performed as well as finished
product QC testing.
[0277] A suitable round-bottom flask equipped with a mechanical
stirrer, thermocouple, condenser, and a heating mantle was charged
with 6 L of N,N-dimethylacetamide (DMA) followed by 1 kg (4.35
moles) of 6-chloro-N,N-dipropyl-[1,3,5]-triazine-2,4-diamine (Stage
1 Product). Added to this stirring mixture at room temperature, was
K.sub.2CO.sub.3 (1.2 kg, 6.53 moles, 2 eq.), with rinsing with a
small quantity of additional DMA. To this, was added
N,O-dimethylhydroxylamine hydrochloride (0.637 kg, 8.71 moles, 1.5
eq.) in portions over .about.5-10 minutes to reduce foaming (and
while maintaining the temperature below 60.degree. C.) with rinsing
using a small quantity of additional DMA. The mixture was heated to
75-80.degree. C. and stir for a minimum of 0.5 hours. Once at
75-80.degree. C., the reaction was monitored for completion by
HPLC. The mixture was cooled to below 65.degree. C. and water (12
L) was added. The resulting suspension was allowed to cool to room
temperature while stirring overnight (18 h). The resultant solids
were filtered and washed with 1.2 L of water. The filter cake to
air-dry one hour and a sample for OVI amine GC analysis was
obtained. The remaining solids were vacuum oven dried (45.degree.
C., >29'' Hg) for a minimum of 6 hours (NMT 1% weight change).
The desired product (free base) was a dense white solid. An IPC
sample for testing was obtained.
[0278] MEK (14.3 L) was added to 1 kg (3.93 moles) of the free base
obtained above. The mixture was stirred and heated to 45.degree. C.
then filtered through a 5.mu. inline filter into a suitable
reactor. Concentrated H.sub.2SO.sub.4 (4.13 moles, 1.05 eq based on
pre-filtered weight) was added slowly via addition funnel to
maintain temperature below 50.degree. C. The mixture was then
cooled to 20.degree. C. overnight. The mixture was then further
cooled to 10.degree. C., stirred for 0.5 h and then filtered. The
solid product cake was washed with MEK (2 L), air dried on the
filter (vacuum assisted) for a minimum of 2 h then placed in a
vacuum oven (>29'' Hg @45.degree. C.) and dried for a minimum of
6 h to give
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI) as a white solid.
Stage 1:
[0279] IPC Test 1: Temperature Chart Recording during
additions--
[0280] Maintain temperature control specified in process steps
IPC Test 2: IPC HPLC analysis--
[0281] Reaction is complete when <2% of cyanuric chloride is
detected.
[0282] Repeat analysis every hour until reaction is complete.
[0283] Contact supervisor if reaction is not complete after third
sample.
Stage 1 Product QC Testing:
[0284] QC HPLC analysis--
[0285] Record results of assay of cyanuric chloride and
2-chloro-4,6-bispropylamino-s-triazine
[0286] Karl Fisher--
[0287] Record results
Stage 2:
Step 1: Reaction:
[0288] IPC Test 1: Temperature Chart Recording during
additions--
[0289] Maintain temperature control specified in process steps
IPC Test 2: IPC HPLC analysis--
[0290] Reaction is complete when <2% of
2-chloro-4,6-bispropylamino-s-triazine is detected.
[0291] Repeat analysis every hour until reaction is complete.
[0292] Contact supervisor if reaction is not complete after third
sample.
IPC Test 3: Residual amine analysis (by GC)-- n-Propylamine and
N,O-dimethylhydoxylamine levels NMT 0.1% IPC Test 4: Weight Change
during drying--
[0293] NMT 1%
IPC Test 5: IPC HPLC analysis--
[0294] Purity by HPLC (AUC) record results
Step 2: Salt Formation and Crystallization
[0295] IPC Test 1: Temperature Chart Recording during concentrated
sulfuric acid addition--
[0296] Maintain temperature control specified in process step
IPC Test 2: OVI of MEK and DMAc by GC--
[0297] NMT 800 ppm each
IPC Test 4: Weight Change during drying--
[0298] NMT 1%
Proton Nuclear Magnetic Resonance (NMR) Spectroscopy
[0299] .sup.1H NMR data of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI) was obtained as a solution in DMSO-d.sub.6
at 400 MHz and is presented in FIG. 10 and shift assignments are
presented in Table 1.
TABLE-US-00001 TABLE 1 .sup.1H Chemical shift assignments for
(XXXVI) in DMSO-d6 at 25.degree. C. Resonance Peak .delta.1H (ppm)
Assignment 1 0.88 13, 17 2 1.53 12, 16 3 3.30 11, 15 4 3.35 18 5
3.77 9 6 [7.42, 8.70] 10, 14
Carbon-13 NMR Spectroscopy
[0300] .sup.13C NMR data of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI) was obtained as solutions in DMSO-d.sub.6
at 100 MHz and is presented in FIG. 11 and shift assignments are
presented in Table 2.
TABLE-US-00002 TABLE 2 .sup.13C Chemical shift assignments for
(XXXVI) in DMSO-d6 at 25.degree. C. Resonance .delta.13C peak (ppm)
Assignment 1 11.25 13, 17 2 21.88 12, 16 3 34.08 18 4 42.24 11, 15
5 61.86 9 6 154.63 2 7 155.79 4, 6
Fourier Transform Infrared (FTIR) Spectroscopy
[0301] The FTIR spectrum of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI) is presented in Table 3 and FIG. 12.
TABLE-US-00003 TABLE 3 FTIR spectrum of (XXXVI) Wavenumber (cm-1)
Assignment 3284 N-H stretch 2850-2960 C-H stretch 1615-1700 C = N
bend 1536-1656 N-H bend 1020-1340 C-N stretch
High and Low Resolution Mass Spectrometry
[0302] The mass obtained from Liquid Chromatography-Mass
Spectrometry (LCMS) was 254 amu, which agrees with the theoretical
mass of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI). High-resolution results obtained through
direct injection are presented in Table 4.
TABLE-US-00004 TABLE 4 Mass spec results for (XXXVI) Calculated
Theoretical Molecular Weight Exact Mass Formula 254.1863 254.1855
C.sub.11H.sub.22N.sub.6O
Chromatographic Purity
[0303] The HPLC chromatographic purity of the RS was determined to
be 100.0% by area, with no related substances detected.
Water by Determination
[0304] The water content was determined to be 0.04% by Karl Fischer
titration.
Elemental Analysis
[0305] Elemental analysis of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI) was obtained and is presented in Table
5.
TABLE-US-00005 TABLE 5 Elemental analysis results for (XXXVI)
Element Theoretical (%) Result (%) C 37.49 37.64 H 6.86 6.83 N
23.85 23.73
Thermal Analysis by Differential Scanning Calorimetry (DSC)
[0306]
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxyl-
amine hydrogen sulfate (XXXVI) was analyzed from 25.degree. C. to
250.degree. C., at a rate of 10.degree. C. per minute as per cUSP
<891>/EP 2.2.34 and was found to have endotherms at
90.19.degree. C., 126.38.degree. C., and 138.30.degree. C. FIG.
13.
X-Ray Powder Diffraction
[0307] XRPD diffraction pattern of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI) was obtained and is consistent with Form
A; presented in FIG. 14.
Counterion Content
[0308]
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxyl-
amine hydrogen sulfate (XXXVI) was found to contain 27.13% sulfate
content by titration.
pH of Aqueous Solution
[0309] A 1% aqueous solution of
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (XXXVI) yielded a pH of 1.89.
Physical Description
[0310]
N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxyl-
amine hydrogen sulfate (XXXVI) was determined to be a white
solid.
Example 10
N-(4-(Methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamid-
e (XL)
##STR00034##
[0311] 6-Amino-2,4-dichloro-[1,3,5]triazine (XXXVII)
[0312] 2,4,6-Trichloro-1,3,5-triazine (XVIII) (10.0 g, 55 mmol) was
dissolved in acetone (80 mL) and poured into ice-water (80 mL) to
form a very fine suspension. To this mixture, 1 N ammonium
hydroxide solution (108 mL, 109.4 mmol) was added at 0.degree. C.
The reaction was stirred for 30 min at ambient temperature and for
additional 60 min at 25.degree. C. The precipitate was filtered
off, washed with water (3.times.25 mL). After drying over calcium
chloride under high vacuum, 6-amino-2,4-dichloro-[1,3,5]triazine
(XXXVII) was isolated as white powder (7.4 g, 82% yield). LCMS
(ESI) m/z=165 (M+H).sup.+.
6-Amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII)
[0313] 6-Amino-2,4-dichloro-[1,3,5]triazine (XXXVII) (30.0 g, 187
mmol) was dissolved in acetone (100 mL) and poured into ice-water
(100 mL) to form a very fine suspension. To this mixture, a
solution of propan-1-amine (11.0 g, 187 mmol) in acetone (20 mL)
was added at 0.degree. C. To this reaction, 2 N NaOH (94 mL, 187
mmol) was added dropwise at a rate to keep the temperature between
0.degree. C. and 5.degree. C. The mixture was stirred for 30 min at
ambient temperature and for an additional 60 min at 50.degree. C.
The mixture was concentrated and then the precipitate was filtered
off and washed with water (3.times.100 mL). After drying over
calcium chloride under high vacuum,
6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) was
isolated as a white powder (35 g, 100% yield). LCMS (ESI) m/z=188
(M+H).sup.+.
N-(6-Amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX)
[0314] A mixture of
6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) (5 g,
26.65 mmol), N,O-dimethylhydroxylamine hydrochloride (13 g, 133.24
mmol) and DIPEA (27.5 g, 213.2 mmol) in EtOH (100 mL) was heated at
100.degree. C. for 16 h, after which time the solvent was removed
under reduced pressure. The residue was dissolved in EtOAc (400
mL), which was washed with water (200 mL) and then with a brine
solution (200 mL) and finally dried over Na.sub.2SO.sub.4. The
solvent was removed under reduced pressure to yield
N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamin-
e (XXXIX) as a white solid (5 g, 89% yield). LCMS (ESI) m/z=213
(M+H).sup.+.
N-(4-(Methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamid-
e (XL)
[0315]
N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydrox-
ylamine (XXXIX) (5 g, 23.58 mmol) was dissolved in THF (50 mL).
Propionyl chloride (3.25 g, 35.38 mmol) and DIPEA (5.47 g, 42.44
mmol) were added at 0.degree. C. The resultant mixture was stirred
at ambient temperature for 10 min, then stirred at 70.degree. C.
for 16 h, after which time the solvent was removed under reduced
pressure. The residue was dissolved in EtOAc (250 mL), and this
extract was washed with water (80 mL) and then with a brine
solution (80 mL), and lastly dried over Na.sub.2SO.sub.4. The
solvent was removed under reduced pressure and the crude product
was purified by flash column chromatography (pet ether/ethyl
acetate=5/1 to 2/1) to yield 930 mg (15%) of the desired product.
The isolated free amine (930 mg, 3.47 mmol) was dissolved in
H.sub.2O (10 mL) and 0.5 M HCl solution in H.sub.2O (10.4 mL) and
then the solution was lyophilized to yield
N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)prop-
ionamide (XL) as a colorless oil (1.06 g). LCMS: (ESI) m/z=269
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO): .delta. (ppm) 12.23 (s,
1H), 8.25-9.45 (m, 2H), 3.76-3.84 (m, 3H), 3.30-3.44 (m, 5H),
2.55-2.56 (m, 1H), 2.21-2.22 (m, 1H), 1.53-1.58 (m, 2H), 0.88-1.08
(m, 6H).
Example 11
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
(XLI)
Example 12
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
hydrochloride (XLII)
##STR00035##
[0316] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine
(XXXIV)
[0317] A 2 M NaOH solution (163 mL, 325.36 mmol) was added in a
dropwise manner to a suspension of 2,4,6-trichloro-1,3,5-triazine
(XVIII) (30.0 g, 162.68 mmol) and n-propylamine (26.8 mL, 325.36
mmol) in acetone (600 mL) and water (30 mL) at 0.degree. C.
(water-ice/NaCl bath). The ice bath was removed and the reaction
mixture was heated at 50.degree. C. for 3 h, then cooled. Water
(200 mL) was added to the reaction mixture; the precipitate was
filtered, washed with water (200 mL) and dried over P.sub.2O.sub.5
at 40.degree. C. for 20 h to yield 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV, 33.6 g, 90% yield).
400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) 7.80 (0.85H, t, J=5.5 Hz),
7.76-7.66 (1H, m), 7.49 (0.15H, t, J=5.5 Hz), 3.22-3.11 (4H, m),
1.55-1.42 (4H, m), 0.88-0.82 (6H, m). ESI-MS (m/z): 230, 232
[M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
(XLI)
[0318] A mixture of
6-chloro-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine (XXXIV) (2.30 g,
10.01 mmol), O-methyl-hydroxylamine hydrochloride (1.67 g, 20.02
mmol) and NaOH (0.72 g, 18.00 mmol) in 1,4-dioxane (30 mL) and
water (6 mL) was heated at 60.degree. C. for 3 h. After this time,
NaOH (0.72 g, 18.00 mmol) was added and the reaction mixture was
heated for another 3 h. The volatiles were removed under reduced
pressure. Saturated NaHCO.sub.3 solution (100 mL) was added to the
residue, the mixture was extracted with EtOAc (3.times.25 mL). The
combined organic extracts were washed with water (50 mL), brine (50
mL) and dried over Na.sub.2SO.sub.4. The solvent was removed under
reduced pressure and the crude product was purified by flash column
chromatography using gradient elution from CH.sub.2Cl.sub.2/EtOH
(99:1) to CH.sub.2Cl.sub.2/EtOH (95:5) to yield 2.17 g (90%) of
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
(XLI). ESI-MS (m/z): 241 [M+H].sup.+
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
hydrochloride (XLII)
[0319] A 2M HCl/ethyl ether (4.5 mL, 9.00 mmol) was added to the
solution
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
(XLI) (2.17 g, 9.03 mmol) in 1,4-dioxane (5 mL) at 0.degree. C. The
mixture was stirred for 0.5 h at 0.degree. C., volatiles were
removed under reduced pressure to yield
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine
hydrochloride (XLII) in quantitative yield. 400 MHz .sup.1H NMR
(DMSO-d.sub.6, ppm) 12.5-11.5 (2H, br s), 8.49 (1H, br s), 8.34
(1H, br s), 3.71 (3H, s), 3.34-3.16 (4H, m), 1.59-1.46 (4H, m),
0.94-0.83 (6H, m). ESI-MS (m/z) 241 [M+H].sup.+.
Example 13
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
(XLIII)
Example 14
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
hydrochloride salt (XLIV)
##STR00036##
[0320]
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
[0321] A mixture of 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (2.00 g, 8.71 mmol),
O-allyl-hydroxylamine hydrochloride (1.91 g, 17.42 mmol) and NaOH
(0.70 g, 17.42 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was
heated at 60.degree. C. for 4 h. The volatiles were removed under
reduced pressure. Saturated NaHCO.sub.3 solution (100 mL) was added
to the residue and the mixture was extracted with EtOAc (3.times.25
mL). The combined organic extracts were washed with water (50 mL),
brine (50 mL) and dried over Na.sub.2SO.sub.4. The solvent was
removed under reduced pressure and the crude product was purified
by flash column chromatography using gradient elution from
CH.sub.2Cl.sub.2/EtOH (99:1) to CH.sub.2Cl.sub.2/EtOH (95:5) to
yield
O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
(XLIII, 2.05 g, 88% yield). ESI-MS (m/z) 267 [M+H].sup.+.
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
hydrochloride
[0322]
O-Allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
hydrochloride (XLIV) was prepared from
O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
(XLIII) and 2M HCl/ethyl ether as described in Example 12. 400 MHz
.sup.1H NMR (DMSO-d.sub.6, ppm) 11.7-10.0 (1H, m), 7.9-7.1 (2H, m),
6.09-5.92 (1H, m), 5.39-5.18 (2H, m), 4.35 (2H, d, J=6.0 Hz),
3.28-3.11 (4H, m), 1.56-1.42 (4H, m), 0.91-0.81 (6H, m). ESI-MS
(m/z): 267 [M+H].sup.+. MP: 130-132.degree. C.
Example 15
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV)
##STR00037##
[0324] N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine
(XLV) was prepared from 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and hydroxylamine
hydrochloride as described in Example 13 (99% yield). 400 MHz
.sup.1H NMR (DMSO-d.sub.6, ppm) 9.0-8.6 (1H, br s), 8.39-8.14 (1H,
s), 6.89-6.55 (2H, m), 3.23-3.06 (4H, m), 1.54-1.40 (4H, m), 0.84
(6H, t, J=7.4 Hz). ESI-MS (m/z): 227 [M+H].sup.+. MP:
138-141.degree. C.
Example 16
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine
(XLVI)
[0325]
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine
(XLVI) may be prepared from 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and
N,N-dimethylhydrazine as described in Example 19.
##STR00038##
Example 17
6-(Methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine
(XLVII)
##STR00039##
[0327]
6-(Methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine
(XLVII) may be prepared from
6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) and
N,O-dimethylhydroxylamine as described in Example 10.
Example 18
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine
(XLVIII)
##STR00040##
[0329]
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine
(XLVIII) was prepared from 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and
N-methyl-hydroxylamine hydrochloride as described in Example 13
(90% yield). 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 8.93 (1H, s),
6.92-6.43 (2H, m), 3.23-3.07 (7H, m), 1.55-1.38 (4H, m), 0.84 (6H,
t, J=7.4 Hz). ESI-MS (m/z) 241 [M+H].sup.+.
Example 19
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N'-dimethyl-hydrazine
(XLIX)
Example 20
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N'-dimethyl-hydrazine
hydrogen sulfate (L)
##STR00041##
[0330]
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N'-dimethyl-hydrazine
(XLIX)
[0331] A mixture of 2-chloro-N-(4,
6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (2.50 g, 10.88 mmol),
N,N'-dimethyl-hydrazine dihydrochloride (2.89 g, 21.76 mmol) and
NaOH (2.18 g, 54.40 mmol) in 1,4-dioxane (40 mL) and water (20 mL)
was heated at 60.degree. C. for 18 h. The volatiles were removed
under reduced pressure. Saturated NaHCO.sub.3 solution (100 mL) was
added to the residue, the mixture was extracted with EtOAc
(3.times.50 mL). The combined organic extracts were washed with
water (75 mL), brine (75 mL) and dried over Na.sub.2SO.sub.4. The
solvent was removed under reduced pressure and the crude product
was purified by flash column chromatography using gradient elution
(CH.sub.2Cl.sub.2/EtOH (99:1) to CH.sub.2Cl.sub.2/EtOH (95:5)) to
yield
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N'-dimethyl-hydrazine
(1.17 g, 42%). 200 MHz .sup.1H NMR (DMSO-d.sub.6, ppm): 6.81-6.44
(2H, m), 5.31 (1H, br s), 3.24-3.08 (4H, m), 3.05 (3H, s),
2.47-2.40 (3H, m), 1.57-1.37 (4H, m), 0.84 (6H, t, J=7.4 Hz).
ESI-MS (m/z): 254 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N'-dimethyl-hydrazine
hydrogen sulfate (L)
[0332] 95% H.sub.2SO.sub.4 (0.26 mL, 4.62 mmol) was added dropwise
to the solution of
6-(N,N'-dimethyl-hydrazino)-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
(XLIX) (1.17 g, 4.62 mmol) in 1,4-dioxane (10 mL) at 0.degree. C.
The mixture was stirred for 0.5 h at room temperature; volatiles
were removed under reduced pressure. The residue was co-evaporated
with dry toluene (3.times.25 mL) to yield
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N'-dimethyl-hydrazine
hydrogen sulfate (L) in quantitative yield. 400 MHz .sup.1H NMR
(DMSO-d.sub.6, ppm) 8.48-8.32 (1H, m), 7.9-7.7 (0.5H, br s),
7.70-7.61 (0.5H, m), 3.34-3.20 (4H, m), 3.21 (1.5H, s), 3.17 (1.5H,
s), 2.52 (1.5H, s), 2.51 (1.5H, s, overlapped with DMSO), 1.59-1.46
(4H, m), 0.93-0.82 (6H, m). ESI-MS (m/z): 254 [M+H].sup.+.
Example 21
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamin-
e (LIII)
Example 22
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamin-
e hydrogen sulfate salt (LIV)
##STR00042##
[0333] Formaldehyde O-benzyl-oxime (LI)
[0334] A NaOH (1.25 g, 31.32 mmol) solution in water (6 mL) was
added to the mixture of O-benzyl-hydroxylamine hydrochloride (5.00
g, 31.32 mmol) and formaldehyde (.about.37 wt. % in H.sub.2O) (2.3
mL, 31.32 mmol) in toluene (40 mL). The reaction mixture was
stirred at room temperature for 1 h. After this time, the organic
phase was separated and the water phase was extracted with
dichloromethane (3.times.30 mL). The combined organic phases were
dried over Na.sub.2SO.sub.4, and concentrated in vacuo to yield
formaldehyde O-benzyl-oxime (LI, 4.15 g, 98%). 400 MHz .sup.1H NMR
(CDCl.sub.3, ppm) 7.40-7.29 (5H, m), 7.09 (1H, d, J=8.2 Hz), 6.47
(1H, d, J=8.2 Hz), 5.14 (2H, s).
O-Benzyl-N-methyl-hydroxylamine (LII)
[0335] A 1M HCl/EtOH solution (50 mL) was added dropwise to the
solution of formaldehyde O-benzyl-oxime (3.85 g, 28.48 mmol) in
EtOH at 0.degree. C. The mixture was stirred at room temperature
for 1 hour, volatiles were removed in vacuo. The residue was
dissolved in dichloromethane (100 mL), washed with saturated
NaHCO.sub.3 solution (75 mL), water (75 mL), and dried over
Na.sub.2SO.sub.4. The product was purified by flash column
chromatography using gradient elution from petroleum ether/EtOAc
(9:1) to petroleum ether/EtOAc (7:1) to yield
O-benzyl-N-methyl-hydroxylamine (1.72 g, 44%). 200 MHz .sup.1H NMR
(CDCl.sub.3, ppm) 7.40-7.27 (5H, m), 5.53 (1H, br s), 4.71 (2H, s),
2.73 (3H, s).
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamin-
e (LIII)
[0336] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
and O-benzyl-N-methyl-hydroxylamine (LII) were reacted as described
in Example 13 to yield
O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylami-
ne (LIII) (29% yield). 200 MHz .sup.1H NMR (DMSO-d.sub.6, ppm)
7.52-7.28 (5H, m), 7.07-6.67 (2H, m), 4.93 (2H, s), 3.26-3.03 (7H,
m), 1.58-1.39 (4H, m), 0.85 (6H, t, J=7.2 Hz). ESI-MS (m/z): 331
[M+H].sup.+.
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamin-
e hydrogen sulfate (LIV)
[0337]
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydro-
xylamine (LIII) was reacted with 95% H.sub.2SO.sub.4 as described
in Example 20 to yield
O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylami-
ne hydrogen sulfate (LIV) in quantitative yield. 400 MHz .sup.1H
NMR (DMSO-d.sub.6, ppm) 12.0-10.9 (1H, br s), 8.7-8.3 (1H, br s),
7.56-7.46 (2H, m), 7.46-7.37 (2.5H, m), 7.36-7.30 (0.5H, m),
5.07-4.95 (2H, m), 3.44-3.16 (7H, m), 1.61-1.45 (4H, m), 0.94-0.82
(6H, m). ESI-MS (m/z): 331 [M+H].sup.+.
Example 23
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine
(LV)
Example 24
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine
hydrogen sulfate (LVI)
##STR00043##
[0338]
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylami-
ne (LV)
[0339] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
and N-isopropyl-hydroxylamine hydrochloride were reacted as
described in Example 13 to yield
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine
(LV) (61% yield). ESI-MS (m/z): 269 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine
hydrogen sulfate (LVI)
[0340]
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylami-
ne hydrogen sulfate (LVI) was prepared from
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine
(LV) and 95% H.sub.2SO.sub.4 as described in Example 20 (95%
yield). 200 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 11.5-11.1 (1H, br
s), 10.66-10.40 (1H, m), 8.45 (1H, s), 7.75-7.36 (1H, m), 4.77-4.55
(1H, m), 3.30-3.16 (4H, m), 1.61-1.44 (4H, m), 1.17 (6H, t, J=7.0
Hz), 0.89 (3H, t, J=7.3 Hz), 0.86 (3H, t, J=7.3 Hz). ESI-MS (m/z)
269 [M+H].sup.+. M.P.: 154-156.degree. C.
Example 25
6-[1,2]Oxazinan-2-yl-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
(LVII)
Example 26
6-[1,2]Oxazinan-2-yl-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
hydrogen sulfate (LVIII)
##STR00044##
[0341]
6-[1,2]Oxazinan-2-yl-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
(LVII)
[0342] An ACE.RTM. pressure tube was charged with
2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.50
g, 6.53 mmol), N-ethyldiisopropylamine (19.59 mmol), 1,2-oxazinane
hydrochloride (1.61 g, 13.06 mmol) and tetrahydrofuran. The
reaction mixture was heated at 100.degree. C. for 2 h, then cooled
and poured into saturated NaHCO.sub.3 solution (50 mL). The
suspension was extracted with EtOAc (3.times.25 mL). The combined
organic extracts were washed with water (50 mL), brine (50 mL) and
dried over Na.sub.2SO.sub.4. The solvent was removed under reduced
pressure and the crude product was purified by flash column
chromatography using gradient elution from CH.sub.2Cl.sub.2/EtOH
(99:1) to CH.sub.2Cl.sub.2/EtOH (95:5) to yield
6-[1,2]oxazinan-2-yl-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
(LVII) (1.63 g, 89%). ESI-MS (m/z): 281 [M+H].sup.+.
6-[1,2]Oxazinan-2-yl-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
hydrogen sulfate (LVIII)
[0343]
6-[1,2]Oxazinan-2-yl-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
hydrogen sulfate (LVIII) was prepared from
6-[1,2]oxazinan-2-yl-N,N'-dipropyl-[1,3,5]triazine-2,4-diamine
(LVII) and 95% H.sub.2SO.sub.4 as described in Example 20.
Quantitative yield was isolated. 400 MHz .sup.1H-NMR (DMSO-d.sub.6,
ppm) 11.6-11.3 (1H, br s), 8.61-8.41 (0.8H, m), 8.18-8.03 (0.2H,
m), 7.63-7.28 (1H, m), 4.14-4.08 (2H, m), 3.92-3.81 (2H, m,
overlapped with water), 3.36-3.19 (4H, m), 1.86-1.78 (2H, m),
1.77-1.68 (2H, m), 1.6-1.45 (4H, m), 1.60-1.45 (6H, m). ESI-MS
(m/z): 281 [M+H].sup.+. M.P.: 134-137.degree. C.
Example 27
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyla-
mine (LXIV)
Example 28
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyla-
mine hydrogen sulfate (LXV)
2-Isopropoxy-isoindole-1,3-dione (LIX)
[0344] Diethyl azodicarboxylate (14.5 mL, 73.56 mmol) was added
dropwise at 0.degree. C. to a stirred suspension of propan-2-ol
(4.7 mL, 61.30 mmol), triphenylphosphine (19.30 g, 73.56 mmol), and
N-hydroxyphthalimide (10.00 g, 61.30 mmol) in THF (50 mL). The
mixture was stirred at room temperature for 20 h and evaporated to
dryness. The product was purified by flash column chromatography
using gradient elution from petroleum ether/EtOAc (9:1) to
petroleum ether/EtOAc (5:1) to yield
2-isopropoxy-isoindole-1,3-dione (LIX, 10.92 g, 87%). 400 MHz
.sup.1H NMR (DMSO-d.sub.6, ppm): 7.86 (4H, s), 4.44 (1H, septet,
J=6.2 Hz), 1.28 (6H, d, J=6.2 Hz).
##STR00045## ##STR00046##
O-Isopropyl-hydroxylamine hydrochloride (LX)
[0345] A mixture of 2-isopropoxy-isoindole-1,3-dione (LIX, 10.78 g,
52.50 mmol) and hydrazine monohydrate (5.1 mL, 105.00 mmol) in
CH.sub.2Cl.sub.2 (60 mL) was stirred at room temperature for 20 h.
The reaction mixture was filtered. The filtrate was washed with
water (70 mL), brine (70 mL) and dried over Na.sub.2SO.sub.4. After
removing the drying agent via filtration, 4M HCl/1,4-dioxane (13.8
mL, 55.00 mmol) was added and the volatiles was removed under
reduced pressure to yield O-isopropyl-hydroxylamine hydrochloride
(LX, 3.91 g, 67% yield). 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm)
11.04 (3H, br s), 4.35 (1H, septet, J=6.2 Hz), 1.21 (6H, d, J=6.2
Hz).
O-Benzyl-N-isopropoxy carbamate (LXI)
[0346] To a pre-cooled (0.degree. C.) solution of
O-isopropyl-hydroxylamine hydrochloride (3.89 g, 34.87 mmol) in
CH.sub.2Cl.sub.2 (150 mL) was added N,N-diisopropyl-ethylamine
(14.4 mL, 87.18 mmol) and benzyl chloroformate (5.0 mL, 34.87
mmol). The resulting solution was stirred at room temperature for 5
h. At this time the solution was washed twice with saturated
aqueous NaHCO.sub.3 (30 mL) and dried over Na.sub.2SO.sub.4. The
product was purified by flash column chromatography using gradient
elution from petroleum ether/EtOAc (95:5) to petroleum ether/EtOAc
(6:1) to yield O-benzyl-N-isopropoxycarbamate (LXI, 4.98 g, 68%).
400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 10.22 (1H, s), 7.42-7.29
(5H, m), 5.07 (2H, s), 3.89 (1H, septet, J=6.2 Hz), 1.11 (6H, d,
J=6.2 Hz).
O-Benzyl-N-methyl-N-isopropoxy carbamate (LXII)
[0347] An ACE.RTM. pressure tube was charged with benzyl
isopropoxycarbamate (4.98 g, 23.80 mmol), anhydrous K.sub.2CO.sub.3
(4.94 g, 35.70 mmol), methyl iodide (6.7 mL, 107.10), and anhydrous
acetone (30 mL). The reaction mixture was heated at 70.degree. C.
for 24 h. The reaction mixture was filtered, and the acetone was
evaporated. The resulting slurry was dissolved in EtOAc, washed
with water (3.times.50 mL), dried (Na.sub.2SO.sub.4), and filtered.
The solvent was removed to yield benzyl isopropoxy(methyl)carbamate
(4.96 g, 93%). 400 MHz 1H-NMR (DMSO-.sub.d6, ppm) 7.41-7.30 (5H,
m), 5.12 (2H, s), 4.08 (1H, septet, J=6.2 Hz), 3.08 (3H, s), 1.12
(6H, d, J=6.2 Hz).
O-Isopropyl-N-methyl-hydroxylamine hydrochloride (LXIII)
[0348] O-Benzyl-N-methyl-Nisopropoxy carbamate (4.96 g, 22.22 mmol)
and 33% HBr/AcOH (45 mL) were stirred at room temperature for 20
min. Saturated solution of NaHCO.sub.3 (400 mL) was added, the
suspension was extracted with CH.sub.2Cl.sub.2 (3.times.150 mL).
The combined organic extracts were dried over Na.sub.2SO.sub.4.
After removal of the drying agent via filtration, 4M
HCl/1,4-dioxane (6.7 mL, 26.65 mmol) was added, and the volatiles
was removed under reduced pressure to yield
O-isopropyl-N-methyl-hydroxylamine hydrochloride (2.09 g, 75%). 400
MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 12.3-11.7 (2H, br s), 4.49 (1H,
septet, J=6.1 Hz), 2.77 (3H, s), 1.12 (6H, d, J=6.1 Hz).
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyla-
mine (LXIV)
[0349] A mixture of
2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.65
g, 16.61 mmol), O-isopropyl-N-methyl-hydroxylamine hydrochloride
(LXIII, 2.09 g, 16.61 mmol) and NaOH (0.66 g, 16.61 mmol) in
1,4-dioxane (50 mL) and water (5 mL) was heated at 100.degree. C.
for 16 h. The volatiles were then removed under reduced pressure.
Saturated NaHCO.sub.3 solution (50 mL) was added to the residue and
the mixture was extracted with EtOAc (3.times.50 mL). The combined
organic extracts were washed with water (50 mL), brine (50 mL) and
dried over Na.sub.2SO.sub.4. The solvent was removed under reduced
pressure and the crude product was purified by flash column
chromatography using gradient elution from CH.sub.2Cl.sub.2/EtOH
(99:1) to CH.sub.2Cl.sub.2/EtOH (95:5) to yield
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine (LXIV, 1.93 g, 95%). ESI-MS (m/z): 283 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyla-
mine hydrogen sulfate (LXV)
[0350] To a solution
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine (LXIV, 1.93 g, 6.83 mmol) in 1,4-dioxane (6 mL) at 0.degree.
C. was added 95% H.sub.2SO.sub.4 (0.36 mL, 6.83 mmol) in a
drop-wise manner. The mixture was stirred for 0.5 h at room
temperature and then the volatiles were removed under reduced
pressure. The residue was co-evaporated with dry toluene
(3.times.25 mL) to yield
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxyl-
amine hydrogen sulfate (.about.quantitative yield). 400 MHz
.sup.1H-NMR (DMSO-d.sub.6, ppm) 11.3-10.7 (1H, br s), 8.8-8.4 (1H,
br s), 8.2-8.0 (0.3H, br s), 8.04-7.65 (0.7H, m), 4.43-4.28 (1H,
m), 3.42-3.18 (7H, m), 1.64-1.44 (4H, m), 1.25 (6H, d, J=6.1 Hz),
0.94-0.82 (6H, m). ESI-MS (m/z): 283 [M+H].sup.+.
Example 29
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine
(LXVIII)
Example 30
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine
hydrogen sulfate (LXIX)
##STR00047##
[0351] O-Benzyl-N-vinyl-hydroxylamine (LXVI)
[0352] Acetaldehyde (24.7 mL, 44.2 mmol) was added dropwise to the
cooled solution (0.degree. C.) of O-benzyl-hydroxylamine
hydrochloride (7.00 g, 43.85 mmol) in water (100 mL) and MeOH (20
mL). The reaction mixture was stirred for 16 h. The volatiles were
removed under reduced pressure, and the water suspension was
extracted with EtOAc (2.times.75 mL). The combined organic extracts
were washed with brine, and then dried over Na.sub.2SO.sub.4 and
evaporated to yield O-benzyl-N-vinyl-hydroxylamine (LXVI) in
quantitative yield. 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 7.48
(0.5H, q, J=5.8 Hz), 7.39-7.26 (5H, m), 6.86 (0.5H, q, J=5.5 Hz),
5.06 (1H, s), 4.97 (1H, s), 1.78 (1.5H, d, J=5.5 Hz), 1.76 (1.5H,
d, J=5.8 Hz).
O-Benzyl-N-ethyl-hydroxylamine (LXVII)
[0353] To a solution of O-benzyl-N-vinyl-hydroxylamine (LXVI, 6.52
g, 43.70 mmol) in AcOH (10 mL), NaCNBH.sub.3 (11.00 g, 175.05 mmol)
was added in portions. The reaction mixture was stirred at room
temperature for 1 h. The mixture was neutralized (pH 7) with 1N
NaOH and extracted with EtOAc (3.times.75 mL). The combined organic
extracts were washed with saturated NaHCO.sub.3 solution
(2.times.100 mL), dried over Na.sub.2SO.sub.4, and purified by
flash column chromatography (eluent:petroleum ether/EtOAc (9:1) to
petroleum ether/EtOAc (1:4)) to yield
O-benzyl-N-ethyl-hydroxylamine (LXVII, 2.10 g, 32%). 400 MHz
.sup.1H NMR (DMSO-d.sub.6, ppm) 7.36-7.24 (5H, m), 6.50 (1H, t,
J=6.4 Hz), 4.60 (2H, s), 2.81 (2H, qd, J=7.0, 6.4 Hz), 0.98 (3H, t,
J=7.0 Hz).
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine
(LXVIII)
[0354] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
and O-benzyl-N-ethyl-hydroxylamine (LXVII) were reacted as
described in Example 13 to afford
O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamin-
e (LXVIII, 38% yield). 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm)
7.51-7.45 (2H, m), 7.40-7.30 (3H, s), 6.97-6.85 (1H, m), 6.79-6.67
(1H, m), 4.97-4.87 (1H, m), 3.72-3.53 (2H, m), 3.23-3.11 (4H, m),
1.56-1.43 (4H, m), 1.13-1.00 (3H, m), 0.89-0.80 (6H, m). ESI-MS
(m/z): 345 [M+H].sup.+.
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine
hydrogen sulfate (LIX)
[0355]
O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydrox-
ylamine (LXVIII) was reacted with 95% H.sub.2SO.sub.4 as described
in Example 9 to yield
O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylami-
ne hydrogen sulfate (LXIX) in quantitative yield. 400 MHz .sup.1H
NMR (DMSO-d.sub.6, ppm) 12.0-11.0 (1H, br s), 8.7-8.0 (1H, m),
7.57-7.30 (5H, m), 5.07-4.95 (2H, m), 3.89-3.68 (2H, m), 3.39-3.14
(4H, m), 1.63-1.42 (4H, m), 1.23-1.07 (3H, m), 0.94-0.77 (6H, m).
ESI-MS (m/z): 345 [M+H].sup.+.
Example 31
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine
(LXX)
Example 32
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine
hydrogen sulfate (LXXI)
##STR00048##
[0356]
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylami-
ne (LXX)
[0357] 2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
and O-isopropyl-hydroxylamine hydrochloride were reacted as
described in Example 13 (80% yield). ESI-MS (m/z): 269
[M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine
hydrogen sulfate (LXX)
[0358]
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylami-
ne (LXX) was reacted with 95% H.sub.2SO.sub.4 as described in
Example 20 (quantitative yield). 400 MHz .sup.1H NMR (DMSO-d.sub.6,
ppm) 11.5-10.7 (1H, m), 8.6-7.5 (3H, m), 4.08 (1H, septet, J=6.2
Hz), 3.38-3.13 (4H, m), 1.61-1.44 (4H, m), 1.21 (6H, d, J=6.2 Hz),
0.94-0.81 (6H, m). ESI-MS (m/z): 269 [M+H].sup.+.
Example 33
6-((Benzyloxy)(isopropyl)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-triazine-2,-
4-diamine (LXXII)
Example 34
6-((Benzyloxy)(isopropyl)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-triazine-2,-
4-diamine hydrogen sulfate (LXXIII)
##STR00049##
[0360]
6-((Benzyloxy)(isopropyl)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-tria-
zine-2,4-diamine (LXXII) was prepared by reacting
2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and
O-benzyl-N-isopropyl-hydroxylamine as exemplified in Example 13.
The corresponding hydrogen sulfate (LXXIII) was prepared as
described in Example 20.
Example 35
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylam-
ine (LXXVI)
Example 36
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylam-
ine hydrogen sulfate (LXXVII)
##STR00050##
[0361] O-Benzyl-N-ethyl-N-isopropoxy-carbamate (LXXIV)
[0362] An ACE.RTM. pressure tube was charged with benzyl
isopropoxycarbamate (4.08 g, 19.50 mmol), anhydrous K.sub.2CO.sub.3
(4.04 g, 29.25 mmol), ethyl iodide (7.0 mL, 87.75 mmol), and
anhydrous acetone (30 mL). The reaction mixture was heated at
70.degree. C. for 24 h. Ethyl iodide (7.0 mL, 87.75 mmol) and
K.sub.2CO.sub.3 (4.04 g, 29.25 mmol) were added and the reaction
mixture was heated for 24 h. The reaction mixture was filtered, and
the acetone was evaporated. The resulting slurry was dissolved in
EtOAc (150 mL), washed with water (3.times.50 mL), dried
(Na.sub.2SO.sub.4), and filtered. The solvent was removed to yield
O-benzyl-N-ethyl-N-isopropoxy-carbamate (3.86 g, 83%). 400 MHz
.sup.1H NMR (DMSO-d.sub.6, ppm) 7.41-7.30 (5H, m), 5.12 (2H, s),
4.05 (1H, septet, J=6.2 Hz), 3.46 (2H, q, J=7.0 Hz), 1.12 (6H, d,
J=6.2 Hz), 1.06 (3H, t, J=7.0 Hz).
N-Ethyl-O-isopropyl-hydroxylamine hydrochloride (LXXV)
[0363] O-Benzyl-N-ethyl-N-isopropoxy-carbamate was reacted with
HBr/AcOH as described for the preparation of compound LXIII in
Example 27 (yield 71%). 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm)
11.7-11.2 (2H, br s), 4.41 (1H, septet, J=6.1 Hz), 3.16 (2H, q,
J=7.2 Hz), 1.24 (6H, d, J=6.1 Hz), 1.19 (3H, t, J=7.2 Hz).
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylam-
ine (LXXVI)
[0364] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
was reacted with N-ethyl-O-isopropyl-hydroxylamine hydrochloride
(LXXV) as described in Example 13, yielding
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxyla-
mine (LXXVI) (88% yield). ESI-MS (m/z): 297 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylam-
ine hydrogen sulfate (LXXVII)
[0365]
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hyd-
roxylamine (LXXVI) was reacted with 95% H.sub.2SO.sub.4 as
described in Example 20 (quantitative yield). 400 MHz .sup.1H NMR
(DMSO-d.sub.6, ppm) 12.0-10.8 (1H, m), 8.7-8.4 (1H, br s),
8.27-7.78 (1H, m), 4.39-4.25 (1H, m), 3.90-3.76 (2H, m), 3.39-3.15
(4H, m), 1.62-1.45 (4H, m), 1.25 (6H, d, J=6.1 Hz), 1.18-1.10 (3H,
m), 0.95-0.82 (6H, m). ESI-MS (m/z): 297 [M+H].sup.+.
Example 37
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylam-
ine (LXXXII)
Example 38
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylam-
ine hydrogen sulfate (LXXXIII)
##STR00051##
[0366] O-Benzyl-N-isobutoxy carbamate (LXXIX)
[0367] O-isobutyl-hydroxylamine hydrochloride (LXXVIII) was reacted
with benzyl chloroformate as described for the preparation of
compound LXI in Example 27, yielding O-benzyl-N-isobutoxy carbamate
(LXXIX) (87% yield). 400 MHz .sup.1H NMR (CDCl.sub.3, ppm)
7.36-7.23 (5H, m), 5.11 (2H, s), 3.58 (2H, d, J=6.6 Hz), 1.89 (1H,
septet, J=6.7 Hz), 0.86 (6H, d, J=6.7 Hz).
O-Benzyl-N-methyl-N-isobutoxy carbamate (LXXX)
[0368] O-Benzyl-N-isobutoxycarbamate was reacted with methyl
iodide, as described for the preparation of compound LXII in
Example 27, affording O-benzyl-N-methyl-N-isobutoxycarbamate in 78%
yield. 400 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) 7.41-7.30 (5H, m),
5.12 (2H, s), 3.59 (2H, d, J=6.6 Hz), 3.09 (3H, s), 1.80 (1H,
septet, J=6.7 Hz), 0.87 (6H, d, J=6.7 Hz).
O-Isobutyl-N-methyl-hydroxylamine hydrochloride (LXXXI)
[0369] O-Benzyl-N-methyl-N-isobutoxycarbamate was reacted with
HBr/AcOH as described for the preparation of compound LXIII in
Example 27 (38% yield). 200 MHz .sup.1H NMR (DMSO-d.sub.6, ppm)
12.5-11.4 (2H, br s), 3.84 (2H, d, J=6.6 Hz), 2.81 (3H, s), 1.90
(1H, septet, J=6.7 Hz), 0.89 (6H, d, J=6.7 Hz).
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylam-
ine (LXXXII)
[0370] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
was reacted with O-isobutyl-N-methyl-hydroxylamine hydrochloride as
described in Example 13, affording LXXXII in 82% yield. ESI-MS
(m/z) 297 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylam-
ine hydrogen sulfate (LXXXII)
[0371]
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hyd-
roxylamine (LXXXII) was reacted with 95% H.sub.2SO.sub.4 as
described in Example 20 (quantitative yield). 400 MHz .sup.1H-NMR
(DMSO-d.sub.6, ppm) 12.0-10.7 (1H, br s), 8.7-7.6 (2H, m),
3.82-3.72 (2H, m), 3.41-3.20 (7H, m), 2.11-1.82 (11H, m), 1.62-1.44
(4H, m), 1.00-0.82 (12H, m). ESI-MS (m/z): 297 [M+H].sup.+.
Example 39
6-(Methyl(thiophen-2-ylmethoxy)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-triaz-
ine-2,4-diamine (LXXXIV)
Example 40
6-(Methyl(thiophen-2-ylmethoxy)amino)-N.sup.2,N.sup.4-dipropyl-1,3,5-triaz-
ine-2,4-diamine hydrogen sulfate (LXXXV)
##STR00052##
[0373]
6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-
-2,4-diamine (LXXXIV) may be prepared by reacting
2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and
O-(thiophen-2-yl-methyl)-N-methyl-hydroxylamine as exemplified in
Example 13.
Example 41
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-h-
ydroxylamine (XCI)
Example 42
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl-O-cyclopropylmethyl-N-methyl-hy-
droxylamine hydrogen sulfate (XCII)
##STR00053## ##STR00054##
[0374] 2-Cyclopropylmethoxy-isoindole-1,3-dione (LXXXVI)
[0375] N-Hydroxyphthalimide and cyclopropyl-methanol were reacted
as described for compound LIX in Example 27, to afford LXXXVI in
87% yield. 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 7.86 (4H, s),
3.97 (2H, d, J=7.4 Hz), 1.22-1.11 (1H, m), 0.61-0.48 (2H, m),
0.34-0.22 (2H, m).
O-Cyclopropylmethyl-hydroxylamine hydrochloride (LXXXVII)
[0376] 2-Cyclopropylmethoxy-isoindole-1,3-dione was reacted with
hydrazine as described for compound LX in Example 27 (LXXXVII, in
67% yield). 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 10.95 (3H, br
s), 3.83 (2H, d, J=7.4 Hz), 1.12-1.01 (1H, m), 0.62-0.50 (2H, m),
0.35-0.24 (2H, m).
O-Benzyl-N-cyclopropylmethoxy carbamate (LXXXVIII)
[0377] O-Cyclopropylmethyl-hydroxylamine hydrochloride was reacted
with benzyl chloroformate as described for compound LXI in Example
27 (LXXXVIII, in 88% yield). 400 MHz .sup.1H-NMR (DMSO-d.sub.6,
ppm) 10.37 (1H, br s), 7.41-7.30 (5H, m), 5.08 (2H, s), 3.54 (2H,
d, J=7.2 Hz), 1.06-0.92 (1H, m), 0.54-0.41 (2H, m), 0.25-0.13 (2H,
m).
O-Benzyl-N-methyl-N-cyclopropylmethoxy-carbamate (LXXXIX)
[0378] O-Benzyl N-cyclopropylmethoxy carbamate and methyl iodide
were reacted as described for compound LXII in Example 27 (LXXXIX,
in 95% yield). 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 7.42-7.30
(5H, m), 5.11 (2H, s), 3.62 (2H, d, J=7.2 Hz), 3.11 (3H, s),
1.06-0.93 (1H, m), 0.54-0.41 (2H, m), 0.26-0.13 (2H, m).
O-Cyclopropylmethyl-N-methyl-hydroxylamine hydrochloride (XC)
[0379] O-Benzyl-N-methyl-N-cyclopropylmethoxy carbamate was reacted
with HBr/AcOH as described for compound LXIII in Example 27,
yielding XC in 77% yield. 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm)
11.96 (2H, br s), 3.91 (2H, d, J=7.4 Hz), 2.80 (3H, s), 1.13-1.01
(1H, m), 0.63-0.50 (2H, m), 0.37-0.25 (2H, m).
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-h-
ydroxylamine (XCI)
[0380] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
was reacted with O-cyclopropylmethyl-N-methyl-hydroxylamine
hydrochloride (XC) as described in Example 13, yielding (XCI) in
99% yield. 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 6.91-6.77 (1H,
m), 6.75-6.58 (1H, m), 3.77-3.64 (2H, m), 3.21-3.09 (7H, m),
1.54-1.41 (4H, m), 1.11-1.00 (1H, m), 0.88-0.80 (6H, m), 0.56-0.44
(2H, m), 0.32-0.20 (2H, m). ESI-MS (m/z) 295 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-h-
ydroxylamine hydrogen sulfate (XCII)
[0381]
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-m-
ethyl-hydroxylamine (XCI) was reacted with 95% H.sub.2SO.sub.4 as
described in Example 20, yielding (XCII) in quantitative yield. 400
MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) 11.6-11.0 (1H, br s), 8.7-8.4
(0.7H, br s), 8.2-8.0 (0.3H, br s), 7.89-7.42 (1H, m), 3.88-3.77
(2H, m), 3.42-3.18 (7H, m), 1.62-1.45 (4H, m), 1.24-1.13 (1H, m),
0.95-0.82 (6H, m), 0.61-0.52 (2H, m), 0.38-0.28 (2H, m). ESI-MS
(m/z) 295 [M+H].sup.+.
Example 43
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine
(XCVI)
Example 44
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine
hydrogen sulfate (XCVII)
##STR00055##
[0382] tert-Butyl ethoxycarbamate (XCIII)
[0383] A solution of saturated Na.sub.2CO.sub.3 solution (45.0 mL)
was added dropwise at room temperature to a solution of
O-ethyl-hydroxylamine (1.76 g, 18.0 mmol) and di-tert-butyl
dicarbonate (5.13 g, 23.67 mmol) in dichloromethane (45.0 mL) and
stirred for 24 h. Water was added, the mixture pH was adjusted to 2
by adding 6N HCl, and the resulting system was extracted with
dichloromethane (3.times.50 mL). The combined organic extracts were
dried over Na.sub.2SO.sub.4 and evaporated. The crude product was
purified by flash column chromatography using gradient elution from
petroleum ether/EtOAc (98:2) to petroleum ether/EtOAc (95:5) to
yield tert-butyl ethoxycarbamate (XCIII) (2.62 g, 90%). 400 MHz
.sup.1H NMR (DMSO-d.sub.6, ppm) 9.89 (1H, s) 3.72 (2H, q, J=7.0 Hz)
1.40 (9H, s) 1.10 (3H, t, J=7.0 Hz).
tert-Butyl ethoxy(methyl)carbamate (XCIV)
[0384] A solution of tert-butyl ethoxycarbamate (XCIII, 2.48 g,
15.38 mmol) in DMF (10 mL) was added dropwise to the suspension of
60% sodium hydride (0.66 g, 16.92 mmol) in DMF (5 mL) at 0.degree.
C. After 30 min. methyl iodide (1.95 mL, 31.32 mmol) in DMF (10 mL)
was added, and the reaction mixture was stirred at room temperature
for 24 h. Water (100 mL) was added and the product was extracted
with ethyl acetate (3.times.50 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo to yield tert-butyl
ethoxy(methyl)carbamate (XCIV, 2.34 g, 87%). 400 MHz .sup.1H NMR
(DMSO-d.sub.6, ppm) 3.81 (2H, q, J=7.0 Hz), 3.00 (3H, s), 1.41 (9H,
s), 1.12 (3H, t, J=7.0 Hz).
O-Ethyl-N-methyl-hydroxylamine hydrochloride (XCV)
[0385] A solution of 4M HCl/1,4-dioxane (25 mL) was added in
portions to tert-butyl ethoxy(methyl)carbamate (XCIV, 2.34 g, 13.35
mmol) at 0.degree. C. The mixture was stirred at room temperature
for 4 h. The volatiles removed in vacuo and the residue was
triturated with ethyl ether and filtered to yield a solid
(O-ethyl-N-methyl-hydroxylamine hydrochloride, XCV, 1.35 g,
91%).
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine
(XCVI)
[0386] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
was reacted with O-ethyl-N-methyl-hydroxylamine hydrochloride as
described in Example 13, to yield XCVI in 93% yield. ESI-MS (m/z)
269 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine
hydrogen sulfate (XCVII)
[0387]
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydrox-
ylamine (XCVI) was reacted with 95% H.sub.2SO.sub.4 as described in
Example 20, to afford (XCVII) in 91% yield. 400 MHz .sup.1H NMR
(DMSO-d.sub.6, ppm) 11.7-10.8 (1H, br s), 8.79-7.34 (2H, m),
4.09-3.98 (2H, m), 3.40-3.20 (7H, m), 1.61-1.46 9 (4H, m), 1.27
(3H, t, J=7.1 Hz), 0.94-0.84 (6H, m). 400 MHz .sup.1HNMR (D.sub.2O,
ppm) 3.99-3.88 (2H, m), 3.34-3.13 (7H, m), 1.52-1.39 (4H, m), 1.14
(3H, t, J=7.1 Hz), 0.76 (6H, t, J=7.5 Hz). ESI-MS (m/z): 269
[M+H].sup.+. M.P.: 84-86.degree. C.
Example 45
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxy-
lamine (C)
Example 46
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxy-
lamine hydrogen sulfate (CI)
##STR00056##
[0388] 2-(2,2-Difluoro-ethoxy)-isoindole-1,3-dione (XCVIII)
[0389] N-Hydroxyphthalimide and 2,2-difluoro-ethanol were reacted
as described for compound LXI in Example 27, affording XCVIII in
52% yield. 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm) 7.92-7.85 (4H,
m), 6.34 (1H, tt, J=54.4, 3.9 Hz), 4.46 (2H, td, J=14.1, 3.9
Hz).
O-(2,2-Difluoro-ethyl)-hydroxylamine hydrochloride (XCIX)
[0390] 2-(2,2-Difluoro-ethoxy)-isoindole-1,3-dione was reacted with
hydrazine as described for compound LX in Example 27, affording
XCIX in 73% yield. 400 MHz .sup.1H NMR (DMSO-d.sub.6, ppm)
12.3-10.3 (3H, br s), 6.38 (1H, tt, J=54.0, 3.3 Hz), 4.34 (2H, td,
J=14.7, 3.3 Hz).
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxy-
lamine (C)
[0391] 2-Chloro-N-(4, 6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV)
was reacted with O-(2,2-difluoro-ethyl)-hydroxylamine hydrochloride
as described in Example 13, affording C in 59% yield. 400 MHz
.sup.1H NMR (DMSO-d.sub.6, ppm) 9.91-9.56 (1H, m), 7.00-6.90 (1H,
m), 6.89-6.67 (1H, m), 6.48-6.13 (1H, m, 4.12-3.98 (2H, m),
3.20-3.09 (4H, m), 1.53-1.41 (4H, m), 0.88-0.80 (6H, m). ESI-MS
(m/z) 291 [M+H].sup.+.
N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxy-
lamine hydrogen sulfate (CI)
[0392]
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)--
hydroxylamine (C, 1.02 g, 3.51 mmol) was reacted with 95%
H.sub.2SO.sub.4 (0.19 mL, 3.51 mmol) in diethyl ether (3 mL) at
0.degree. C. Two drops of EtOH were added, and the resultant
crystals were filtered, washed with diethyl ether, and dried to
yield
N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydrox-
ylamine hydrogen sulfate (CI) (1.26 g, 93%). 400 MHz .sup.1H NMR
(DMSO-d.sub.6, ppm) 11.8-10.5 (1H, m) 8.8-8.4 (0.3H, br s)
8.36-7.53 (1.7H, m) 6.50-6.08 (1H, m) 4.28-4.07 (2H, m) 3.39-3.13
(4H, m) 1.64-1.42 (4H, m) 0.97-0.78 (6H, m). ESI-MS (m/z) 291
[M+H].sup.+. M.P.: 91-93.degree. C.
Example 47
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N-
,O-dimethyl-hydroxylamine (CIII)
Example 48
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N-
,O-dimethyl-hydroxylamine hydrochloride (CIV)
##STR00057##
[0393]
2-Chloro-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydr-
oxylamine (CII)
[0394] 2,4-Dichloro-N-(6-n-propylamino)-[1,3,5]triazine (XXIII) (18
g, 87 mmol) was dissolved in acetone (100 mL) and poured into
ice-water (50 mL) to form a very fine suspension. A solution of
N,O-dimethylhydroxylamine hydrochloride (9.3 g, 95 mmol) in water
(30 mL) was added, while keeping the temperature at 0.degree. C.
(ice bath). To this mixture, 2N NaOH (44 mL, 88 mmol) was added
dropwise at a rate adjusted to keep the temperature between
0.degree. C. and 5.degree. C. The reaction was stirred for 30 min
at ambient temperature and for additional 60 min at 50.degree. C.
The resultant precipitate was filtered off, and washed with water
(3.times.25 mL). After drying over calcium chloride under high
vacuum,
2-chloro-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine (CII, 12 g, 60%) was isolated as a white powder. LCMS
(ESI) m/z=232 (M+H).sup.+.
4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N-
,O-dimethyl-hydroxylamine (CIII)
[0395] A mixture of
2-chloro-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylam-
ine (CII, 1.5 g, 6.5 mmol), N,N-dimethylethane-1,2-diamine (3.5 g,
39 mmol) and DIPEA (2.5 g, 20 mmol) in EtOH (30 mL) was heated at
100.degree. C. for 16 h. The solvent was then removed under reduced
pressure. The residue was dissolved in EtOAc (80 mL), washed with
water (2.times.50 mL) and then with a brine solution (50 mL) and
lastly, dried over Na.sub.2SO.sub.4. The solvent was removed under
reduced pressure. The residue was purified by flash column
chromatography (DCM/MeOH=20/1 to 5/1) to yield
4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)--
N,O-dimethyl-hydroxylamine (620 mg, 33%).
4-N-(2-Dimethylaminoethyl)amino-6-N-(propyl)amino-[1,3,5]triazin-2-yl)-N,O-
-dimethyl-hydroxylamine hydrochloride (CIV)
[0396]
4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin--
2-yl)-N,O-dimethyl-hydroxylamine (610 mg, 2.1 mmol) was dissolved
in H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (6.6 mL) and the
solution was lyophilized to yield
4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)--
N,O-dimethyl-hydroxylamine hydrochloride (CIV, 630 mg) as a
colorless oil. LCMS (ESI) m/z=284 (M+H).sup.+. .sup.1H NMR (500
MHz, DMSO) .delta. (ppm) 10.55-10.88 (br, 1H), 8.70-9.10 (m, 2H),
4.37-4.43 (m, 5H), 3.76-3.87 (m, 7H), 2.84-2.88 (m, 6H), 1.60-1.64
(m, 2H), 0.94-1.02 (m, 3H).
Example 49
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propylamino-[1,3,5]t-
riazin-2-yl)-N,O-dimethyl-hydroxylamine (CV)
Example 50
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]-
triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (CVI)
##STR00058##
[0397]
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino--
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV)
[0398]
2-Chloro-6-N-(n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydr-
oxylamine (CII) (400 mg, 2.9 mmol), DIPEA (5.16 g, 40 mmol) and
3-(1-methyl-1H-imidazol-2-yl)propan-1-amine (J. Heterocyclic Chem.,
2005, 42:1011-15) (732 mg, 3.2 mmol) in EtOH (50 mL) were heated at
100.degree. C. for 16 h. After this time, the solvent was removed
under reduced pressure. The residue was dissolved in DCM/MeOH (400
mL/200 mL), washed with water (50 mL) then dried over
Na.sub.2SO.sub.4. The solvent was removed under reduced pressure.
The crude product was purified by flash column chromatography
(DCM/MeOH=50/1 to 10/1) to yield
4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV, 210 mg, 22%).
4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n
propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
hydrochloride (CVI)
[0399]
4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino--
[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV) (210 mg, 0.63
mmol) was dissolved in H.sub.2O (10 mL) and 0.5 M aqueous HCl
solution (1.3 mL), and the solution was lyophilized to yield
4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5-
]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (CVI, 210
mg) as a yellow oil. LCMS (ESI) m/z=335 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO) .delta. (ppm) 14.40-14.55 (br, 1H), 8.60-8.80 (m,
2H), 7.57-7.62 (m, 2H), 3.77-3.83 (m, 6H), 3.28-3.42 (m, 7H),
2.80-2.84 (m, 2H), 1.95-2.10 (m, 2H), 1.53-1.56 (m, 2H), 0.89-0.93
(m, 3H).
Example 51
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triaz-
in-2-yl)-N,O-dimethyl-hydroxylamine (CVII)
Example 52
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triaz-
in-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (CVIII)
##STR00059##
[0400]
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,-
5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CVII)
[0401]
2-Chloro-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydr-
oxylamine (CII) (1 g, 4.5 mmol),
(1-methyl-1H-imidazol-2-yl)methanamine (600 mg, 5.4 mmol) and
K.sub.2CO.sub.3 (1.24 g, 9 mmol) in EtOH (50 mL) were heated at
100.degree. C. for 16 h. The reaction mixture was filtered, and the
volatiles were removed under reduced pressure. The residue was
dissolved in EtOAc (100 mL), washed with water (30 mL) and then
with a brine solution (30 mL), and lastly dried over
Na.sub.2SO.sub.4. The solvent was removed under reduced pressure.
The crude product was purified by flash column chromatography
(DCM/MeOH=20/1 to 8/1) to yield
4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine (CVII, 650 mg, 47%).
4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triaz-
in-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (CVIII)
[0402]
4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,-
5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CVII, 650 mg, 2.1 mmol)
was dissolved in H.sub.2O (10 mL) and 0.5 M aqueous HCl solution
(6.3 mL). The resultant solution was subjected to lyophilization to
yield
4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]tria-
zin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (CVIII, 389 mg)
as a colorless oil. LCMS (ESI) m/z=307 (M+H).sup.+. .sup.1H NMR
(500 MHz, DMSO) .delta. (ppm) 14.65-14.85 (br, 1H), 8.70-9.20 (m,
2H), 7.62-7.70 (m, 2H), 4.87-4.91 (m, 2H), 3.75-3.89 (m, 9H),
3.31-3.40 (m, 3H), 1.55-1.56 (m, 2H), 0.85-0.96 (m, 3H).
Example 53
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl--
hydroxylamine (CIX)
Example 54
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl--
hydroxylamine hydrochloride (CX)
##STR00060##
[0403]
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine (CIX)
[0404]
N-(4,6-Dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX) (7 g, 33.5 mmol), N,N-dimethyl-ethane-1,2-diamine (6.05 g,
68.7 mmol) and K.sub.2CO.sub.3 (10.2 g, 73.7 mmol) in THF (250 mL)
were heated at 70.degree. C. for 5 h, after which time the solvent
was removed under reduced pressure. The residue was purified by
reverse flash column chromatography to yield
4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine (270 mg, 3%).
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl--
hydroxylamine hydrochloride (CX)
[0405]
4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine (270 mg, 0.86 mmol) was dissolved in H.sub.2O
(10 mL) and 0.5 M aqueous HCl solution (2 mL), and the resultant
solution was lyophilized to yield
4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-
-hydroxylamine hydrochloride (290 mg) as a colorless oil. LCMS
(ESI) m/z=313 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta.
(ppm) 10.20-10.60 (br, 1H), 7.17-7.25 (m, 2H), 3.54-3.76 (m, 7H),
3.01-3.25 (m, 7H), 2.72 (s, 12H).
Example 55
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine (CXI)
Example 56
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine hydrochloride (CXII)
##STR00061##
[0406]
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dime-
thyl-hydroxylamine (CXI)
[0407]
N-(4,6-Dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX) (1 g, 4.78 mmol), pyridin-4-ylmethanamine (1.14, 10.52 mmol)
and DIPEA (1.85 g, 14.34 mmol) in EtOH (80 mL) were heated at
100.degree. C. for 16 h, after which the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography to yield
4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXI) (450 mg, 27%).
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine hydrochloride (CI)
[0408]
4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dime-
thyl-hydroxylamine (CXI) (450 mg, 1.28 mmol) was dissolved in
H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (3.84 mL), and the
resultant solution was lyophilized to yield
4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine hydrochloride (497 mg) as a yellow solid. LCMS (ESI)
m/z=353 (M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. (ppm)
8.79-8.89 (m, 4H), 7.98-8.20 (m, 4H), 5.04 (s, 2H), 4.85 (s, 2H),
3.90-3.95 (m, 3H), 3.50 (s, 1H), 3.33 (s, 2H).
Example 57
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine (CXIII)
Example 58
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine hydrochloride salt (CXIV)
##STR00062##
[0409]
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dime-
thyl-hydroxylamine (CXII)
[0410]
N-(4,6-Dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX) (1 g, 4.78 mmol), 3-methoxypropan-1-amine (936 mg, 10.52
mmol) and DIPEA (1.85 g, 14.34 mmol) in EtOH (50 mL) were heated at
100.degree. C. for 16 h, after which time the solvent was removed
under reduced pressure. The residue was dissolved in EtOAc (200
mL), washed with water (50 mL) and then with a brine solution (50
mL) and lastly dried over Na.sub.2SO.sub.4. The solvent was removed
under reduced pressure. The crude product was purified by flash
column chromatography (pet ether/ethyl acetate=5/1 to 1/2) to yield
4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine (CXIII) (1.4 g, 93%).
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hy-
droxylamine hydrochloride (CXIV)
[0411]
4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dime-
thyl-hydroxylamine (CXIII, 1.4 g, 4.46 mmol) was dissolved in
H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (13.4 mL), and the
resultant solution was lyophilized to yield
4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-h-
ydroxylamine hydrochloride (1.56 g) as a colorless oil. LCMS (ESI)
m/z=315 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta. (ppm)
12.10-12.60 (br, 1H), 8.55-8.74 (m, 2H), 3.75-3.86 (m, 3H),
3.35-3.45 (m, 11H), 3.22-3.25 (m, 5H), 2.77 (s, 1H), 1.72-1.76 (m,
4H).
Example 59
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dim-
ethyl-hydroxylamine (CXV)
Example 60
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dim-
ethyl-hydroxylamine hydrochloride (CXVI)
##STR00063##
[0412]
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)--
N,O-dimethyl-hydroxylamine (CXV)
[0413]
N-(4,6-Dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX) (1 g, 4.78 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (1.21
g, 10.52 mmol) and DIPEA (1.85 g, 14.34 mmol) in EtOH (50 mL) were
heated at 100.degree. C. for 16 h, after which time the solvent was
removed under reduced pressure. The residue was dissolved in EtOAc
(200 mL), washed with water (50 mL) and then with a brine solution
(50 mL) and lastly dried over Na.sub.2SO.sub.4. The solvent was
removed under reduced pressure. The crude product was purified by
flash column chromatography (PE/EA=5/1 to 1/1) to afford
4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine (CXV) (1.5 g, 85%).
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dim-
ethyl-hydroxylamine hydrochloride (CXVI)
[0414]
4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)--
N,O-dimethyl-hydroxylamine (CXV) (1.5 g, 4.1 mmol) was dissolved in
H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (12.3 mL), and the
resultant solution was lyophilized to yield
4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-di-
methyl-hydroxylamine (CXVI) hydrochloride (1.65 g) as a white
solid. LCM: (ESI) m/z=367 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO)
.delta. (ppm) 12.30-12.70 (br, 1H), 8.65-8.80 (m, 2H), 3.77-3.86
(m, 7H), 3.20-3.35 (m, 11H), 1.75-1.78 (m, 2H), 1.56-1.58 (m, 4H),
1.20-1.23 (m, 4H).
Example 61
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(19-
),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII)
Example 62
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(19-
),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine hydrochloride
(CXVIII)
##STR00064##
[0415]
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18-
),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII)
[0416]
N-(4,6-Dichloro[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine
(XXX) (1.63 g, 7.8 mmol) in EtOH (100 mL) was added to
2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))diethanamine (Org.
Biomol. Chem. 2005, 3:2255-61) (1.5 g, 7.8 mmol) and DIPEA (2.01 g,
15.6 mmol). The reaction was heated at 100.degree. C. for 3 h,
after which time the solvent was removed under reduced pressure.
The residue was dissolved in EtOAc (200 mL), washed with water
(2.times.100 mL) and then with a brine solution (100 mL) and lastly
dried over Na.sub.2SO.sub.4. The solvent was removed under reduced
pressure and the residue was purified by flash column
chromatography (DCM/MeOH=50/1 to 20/1) to yield
N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(1-
9),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII) (700 mg)
as a colourless oil (yield 27%).
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(19-
),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine hydrochloride
(CXVIII)
[0417]
N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18-
),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII) (700
mg, 2.1 mmol) was dissolved in H.sub.2O (10 mL) and 0.5 M aqueous
HCl solution (4.3 mL), and the resultant solution was lyophilized
to yield
N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(1-
9),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine hydrochloride
(CXVIII) (750) mg as a colorless oil. LCMS: (ESI) m/z=329
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta. (ppm) 11.50-12.60
(br, 1H), 8.61 (s, 2H), 3.77 (s, 3H), 3.30-3.62 (m, 16H), 3.30 (s,
3H).
Example 63
2,6-Bis-(N-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
(CXX)
Example 64
2,6-Bis-(N-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (CXXI)
##STR00065##
[0418] 4-Chloro-2,6-bis-[N-n-propylamino]-1,3-pyrimidine (CXIX)
[0419] 2,4,6-Trichloro-pyrimidine (5.00 g, 27.26 mmol) and
n-propylamine (13.5 mL, 163.56 mmol) in EtOH were heated at
60.degree. C. for 24 h and then cooled. The volatiles were removed
under reduced pressure. Water (100 mL) was added and the resulting
suspension was extracted with CH.sub.2Cl.sub.2 (3.times.75 mL). The
combined organic extracts were washed with water (150 mL), then
with a brine solution (100 mL) and dried over Na.sub.2SO.sub.4. The
solvent was removed under reduced pressure to yield
4-chloro-2,6-bis-[N-n-propylamino]-1,3-pyrimidine (CXIX) (5.78 g,
93%). 200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm) 7.26-7.04 (1H, m)
7.04-6.81 (1H, m) 5.69 (1H, s) 3.26-3.01 (4H, m) 1.60-1.36 (4H, m)
0.87 (3H, t, J=7.4 Hz) 0.85 (3H, t, J=7.4 Hz); ESI-MS (m/z) 229,
231 [M+H].sup.+.
(2,6-Bis-N-[n-propylamino]-pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
(CXX)
[0420] 4-Chloro-2,6-bis-[N-n-propylamino]-1,3-pyrimidine (CXIX)
(5.78 g, 25.27 mmol), N,O-dimethylhydroxylamine hydrochloride (4.93
g, 50.54 mmol) and NaOH (2.02 g, 50.54 mmol) in 1,4-dioxane (400
mL) and water (20 mL) were heated at 60.degree. C. for 24 h.
N,O-Dimethylhydroxylamine hydrochloride (4.93 g, 50.54 mmol) and
NaOH (3.03 g, 75.81 mmol) were added to the reaction mixture and
heating was continued for 3 days at 110.degree. C. The volatiles
were removed under reduced pressure. Saturated NaHCO.sub.3 solution
(50 mL) was added to the residue and the mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.75 mL). The combined organic extracts
were washed with water (150 mL) and dried over Na.sub.2SO.sub.4.
The solvent was removed under reduced pressure, and the residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/EtOH
(25/1)) to yield
(2,6-bis-N-[n-propylamino]-pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
(CXX) (1.2 g, 19%/). 200 MHz .sup.1H-NMR (DMSO-d.sub.6, ppm)
6.57-6.45 (1H, m) 6.13 (1H, t, J=5.5 Hz) 5.34 (1H, s) 3.59 (3H, s)
3.20-3.04 (4H, m) 3.03 (3H, s) 1.58-1.37 (4H, m) 0.87 (3H, t, J=7.1
Hz) 0.84 (3H, t, J=7.1 Hz).
(2,6-Bis-N-[n-propylamino]-pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (CXXI)
[0421]
(2,6-Bis-N-[n-propylamino]-pyrimidin-4-yl)-N,O-dimethyl-hydroxylami-
ne (1.20 g, 4.74 mmol) in 1,4-dioxane (15 mL) was treated with 95%
H.sub.2SO.sub.4 (0.27 mL, 4.74 mmol) in a dropwise manner at
0.degree. C. The mixture was stirred at room temperature for 0.5 h
and then the volatiles were removed under reduced pressure. The
resulting residue was co-evaporated with dry toluene (3.times.5 mL)
to yield
(2,6-bis-N-[n-propylamino]-pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
hydrogen sulfate (CXXI) in quantitative yield. 400 MHz H-NMR
(DMSO-d.sub.6, ppm) 11.3-10.5 (1H, m), 8.29 (0.4H, br s), 7.38
(0.6H, br s), 5.48-5.20 (1H, m), 3.70 (3H, s), 3.36-3.21 (5H, m),
3.20-3.08 (2H, m), 1.61-1.48 (4H, m), 0.9 (6H, t, J=7.4 Hz). ESI-MS
(m/z) 254 [M+H].sup.+; melting point: 123-126.degree. C.
Example 65
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXVI)
Example 66
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CXXVII)
##STR00066##
[0422]
2-(t-Butyl-dimethylsilyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine
(CXXII)
[0423] To a dichloromethane solution (100 mL) of
2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.7 g, 52 mmol) was
added Et.sub.3N (26 g, 260 mmol) and the mixture was stirred at
-30.degree. C. After this time, TBDMSOTf (15.1 g, 57.2 mmol) was
added in a slow dropwise manner and the resultant reaction was
stirred at ambient temperature for 1.5 h. The observed solid
material completely dissolved to form a light brown solution. The
mixture was then quenched with 1 N NaOH (100 mL) and extracted with
DCM (250 mL). The organic layer was washed with H.sub.2O (150 mL)
and then with a brine solution (150 mL) and dried over
Na.sub.2SO.sub.4. The solvents were removed in vacuo and the
residue was purified by flash column chromatography (PE/EtOAc=10/1
to 5/1) to afford
2-(t-butyl-dimethylsilyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine
(CXXII, 11.4 g, 79%) as a light yellow solid. LCMS: (ESI) m/z=283
(M+H).sup.+.
2-(t-Butyl-dimethylsilyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXIII)
[0424]
2-(t-Butyl-dimethylsilyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine
(CXXII) (700 mg, 2.5 mmol), 0.18 mL (3.5 mmol) of methyl iodide in
DMF (10 mL), and K.sub.2CO.sub.3 (552 mg, 4 mmol) were reacted at
ambient temperature for 15 h. After addition of H.sub.2O (10 mL),
the reaction was extracted with EtOAc (100 mL), and the organic
layer was washed with a brine solution (10 mL), and dried over
Na.sub.2SO.sub.4. The solvents were removed in vacuo, and the
residue was purified by flash column chromatography (PE/EtOAc=10/1
to 5/1) to afford
2-(t-butyl-dimethylsilyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXIII) (750 mg, 100%) as a light yellow oil. LCMS (ESI) m/z=297
(M+H).sup.+.
2-(n-Propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXIV)
[0425] Under a nitrogen atmosphere
2-(t-butyl-dimethylsilyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXIII, 5.0 g, 17 mmol) and 1-iodopropane (4.3 g, 25 mmol) were
dissolved in DMF (20 mL). The reaction mixture was cooled to
0.degree. C. with vigorous stirring, then NaH (1 g of a 60%
dispersion in mineral oil, 21 mmol) was added. The mixture was
stirred for 10 min. and water (50 mL) was slowly added to quench
the reaction. The aqueous solution was extracted with EtOAc (200
mL), and the organic layer was washed with water (50 mL) and with a
brine solution (50 mL), and lastly, dried over anhydrous
Na.sub.2SO.sub.4. After evaporation of volatiles, a yellow oily
residue (5.7 g) was isolated. The residue was dissolved in
Et.sub.2O (50 mL) and concentrated hydrochloric acid (10 mL) was
added at 0.degree. C. with stirring. The mixture was reacted for an
additional 10 min. After this time, the solution was extracted with
EtOAc (200 mL) and 1N NaOH (200 mL). The organic layer was washed
with H.sub.2O (150 mL) and then with a brine solution (150 mL) and
lastly, dried over Na.sub.2SO.sub.4. The solvents were removed in
vacuo and the resultant residue was purified by flash column
chromatography (PE/EtOAc=10/1 to 5/1) to afford
2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (3.78
g, 100%) of the desired product as a yellow solid. LCMS: (ESI)
m/z=225 (M+H).sup.+.
2-(n-Propyl)amino-4-(i-propyl)amino-7-methyl-pyrrolo[2,
3-d]pyrimidine (CXXV)
[0426] To a solution of
2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (1.6
g, 7.1 mmol) in n-butanol (10 mL) was added potassium carbonate
(4.9 g, 35.5 mmol), followed by propan-2-amine (632 mg, 10.7 mmol).
The mixture was stirred in an autoclave equipped with a stirrer at
140.degree. C. for 16 h. After cooling to room temperature, water
was added (20 mL), and the mixture was extracted with EtOAc
(3.times.50 mL). The combined organic layers were washed with water
and then with a brine solution, and lastly dried over anhydrous
Na.sub.2SO.sub.4. The volatiles were removed in vacuo and the
residue was purified by flash column chromatography (PE/EtOAc=3/1)
to yield
2-(n-propyl)amino-4-(i-propyl)amino-7-methyl-pyrrolo[2,3-d]pyrimidine
(1.2 g, 75%) as a yellow solid. LCMS: (ESI) m/z=248
(M+H).sup.+.
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXVI)
[0427] To the solution of
2-(n-propyl)amino-4-(i-propyl)amino-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXV, 1.0 g, 4 mmol) in EtOAc (50 mL) were added 10% Pd/C (1.0 g)
and AcOH (2.43 g, 40 mmol). The mixture was attached to a
hydrogenation apparatus and the system was evacuated and then
refilled with hydrogen. The reaction was stirred at ambient
temperature for 48 h. After this time, the mixture was filtered
over 10 g of silica-gel on a glass-filter. The filtrate was
concentrated and the residue was purified by flash column
chromatography (DCM/MeOH=50/1 to 10/1) to yield
2-(n-propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXVI, 500 mg, 50%) as a yellow solid.
2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CXXVII)
[0428] The isolated free amine (CXXVI, 500 mg, 2 mmol) was
dissolved in H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (4
mL), and the solution was lyophilized to yield
2-(n-propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CXXVII, 525 mg) as a brown solid. LCMS (ESI) m/z=250
(M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. (ppm) 3.80 (s,
1H), 3.58 (t, J=8.5 Hz, 2H), 3.23-3.29 (m, 2H), 2.88 (s, 3H), 2.77
(t, J=8.5 Hz, 2H), 1.52-1.56 (m, 2H), 1.15 (d, J=6.5 Hz, 6H), 0.89
(d, J=7.5 Hz, 3H).
Example 67
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXVIII)
Example 68
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CXXIX)
##STR00067##
[0429]
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXVII)
[0430] To
2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (1.0
g, 4.5 mmol) (CXXIV) in n-butanol (20 mL) was added potassium
carbonate (3.7 g, 27 mmol) and dimethylamine hydrochloride (1.0 g
(22 mmol). The mixture was stirred in an autoclave equipped with a
stirrer at 120.degree. C. for 16 h. After cooling to room
temperature, water was added (20 mL), and the mixture was extracted
with EtOAc (3.times.50 mL). The combined organic layers were washed
with water and then with a brine solution, and dried over anhydrous
Na.sub.2SO.sub.4. The solvents were removed in vacuo and the
residue was purified by flash column chromatography (PE/EtOAc=6/1)
to yield
2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXVII, 800 mg, 76%) as a yellow solid. LCMS (ESI) m/z=234
(M+H).sup.+.
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXVIII)
[0431] To the solution of
2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXVII, 800 mg, 3.4 mmol) in EtOAc (30 mL) was added 10% Pd/C (1.0
g) and AcOH (3 mL), and the mixture was attached to a hydrogenation
apparatus. The system was evacuated and then refilled with
hydrogen. The mixture was stirred at ambient temperature for 48 h.
The mixture was filtered through 10 g of silica-gel on a
glass-filter. The filtrate was concentrated and the residue was
purified by flash column chromatography (EtOAc/MeOH=25/1) to yield
2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXVIII, 600 mg, 75%).
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CXXIX)
[0432]
2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimi-
dine (CXXVIII, 600 mg, 2.6 mmol) was dissolved in H.sub.2O (10 mL)
and 0.5 M aqueous HCl solution (5.2 mL), and the solution was
lyophilized to yield
2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimi-
dine hydrochloride (CXXIX, 600 mg) as a yellow solid. LCMS (ESI)
m/z=236 (M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. (ppm) 3.66
(t, J=9.0 Hz, 2H), 3.40 (t, J=7.0 Hz, 2H), 3.33 (s, 1H), 3.23 (t,
J=9.5 Hz, 2H), 3.17 (s, 5H), 3.00 (s, 3H), 1.63-1.67 (m, 2H), 1.00
(t, J=7 Hz, 3H).
Example 69
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXXI)
Example 70
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CXXXII)
##STR00068##
[0433]
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidi-
ne (CXXXI)
[0434] To a solution of
2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXX) (2.0 g, 9.13 mmol) in EtOAc (50 mL) was added 10% Pd/C (2.1
g) and AcOH (8 mL), and the mixture was attached to a hydrogenation
apparatus. The system was evacuated and refilled with hydrogen. The
mixture was stirred at ambient temperature for 48 h. The mixture
was filtered through 10 g of silica-gel on a glass-filter. The
filtrate was concentrated and the residue was purified by flash
column chromatography (DCM/MeOH=60/1 to 10/1) to yield
2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(CXXXI, 700 mg, 43%) as a yellow solid.
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CXXXII)
[0435]
2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidi-
ne (CXXX, 700 mg, 3.2 mmol) was dissolved in H.sub.2O (10 mL) and
0.5 M aqueous HCl solution (7 mL), and the solution was lyophilized
to yield
2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine
(717 mg) as a brown solid. LCMS: (ESI) m/z=222 (M+H).sup.+. .sup.1H
NMR (500 MHz, MeOD) .delta. (ppm) 3.50 (t, J=8.5, 2H), 3.22 (t,
J=7.0 Hz, 2H), 2.79 (s, 6H), 2.68 (t, J=9.0 Hz, 2H), 1.43-1.51 (m,
2H), 0.81 (t, J=8.0 Hz, 3H).
Example 71
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidin-
e (CXXXVI)
Example 72
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidin-
e hydrochloride salt (CXXXVII)
##STR00069##
[0436]
2-(t-Butyl-dimethylsilyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]py-
rimidine (CXXXIII)
[0437]
2-(t-Butyl-dimethylsilanyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidi-
ne (CXXII) (5 g, 17.7 mmol), 2-iodopropane (4.5 g, 26.6 mmol) and
K.sub.2CO.sub.3 (4.3 g, 26.6 mmol) in DMF (20 mL) were reacted at
ambient temperature for 15 h. After addition of H.sub.2O (50 mL) to
the reaction mixture, the aqueous solution was extracted with EtOAc
(300 mL) and the organic layer was washed with a brine solution (50
mL) and dried with Na.sub.2SO.sub.4. The solvents were removed in
vacuo and the residue was purified by flash column chromatography
(pet ether/EtOAc=10/1 to 5/1) to afford
2-(t-butyl-dimethylsilyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]p-
yrimidine (CXXXIII, 5.7 g, 100%) as a light yellow oil. LCMS: (ESI)
m/z=325 (M+H).sup.+.
2-(n-Propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine
(CXXXIV)
[0438] Under nitrogen atmosphere,
2-(t-butyl-dimethylsilanyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimi-
dine (5.7 g, 17.6 mmol) and 1-iodopropane (4.5 g (26.4 mmol) were
dissolved in DMF (20 mL). The reaction mixture was cooled to
0.degree. C. with vigorous stirring, and NaH (1.06 g of a 60%
dispersion in mineral oil, 26.4 mmol) of (60%) was added. The
mixture was stirred for 10 min, and then water (50 mL) was slowly
added to quench the reaction. The mixture was extracted with EtOAc
(300 mL) and the organic layer was washed with water (50 mL) and
then with a brine solution (50 mL), and lastly, dried over
anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, a
yellow oily residue was isolated (6.5 g). The residue was dissolved
in Et.sub.2O (50 mL), concentrated hydrochloric acid (10 mL) was
added at 0.degree. C. with stirring, and the mixture was stirred
for an additional 10 min. After the reaction was completed, the
solution was extracted with EtOAc (200 mL) and 1N NaOH (200 mL).
The organic layer was washed with H.sub.2O (150 mL) and then with a
brine solution (150 mL) and dried over Na.sub.2SO.sub.4. The
solvents in vacuo and the residue was purified by flash column
chromatography (PE/EtOAc=10/1 to 5/1) to yield
2-(n-propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine
(CXXXIV, 4.5 g, !00%) as a yellow solid. LCMS (ESI) m/z=253
(M+H).sup.+.
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolo[2,3-d]pyrimidine
(CXXXV)
[0439] To
2-(n-propyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine
(CXXXIV, 3.0 g, 12 mmol) in n-butanol (10 mL) was added
propan-2-amine (1.05 g, 18 mmol) and potassium carbonate (2.5 g, 18
mmol). The resulting mixture was stirred in an autoclave equipped
with a stirrer at 140.degree. C. for 16 h. After cooling to room
temperature, water was added (20 mL), and the mixture was extracted
with EtOAc (3.times.50 mL). The combined organic layers were washed
with water and then with a brine solution and dried over anhydrous
Na.sub.2SO.sub.4. After the solvents were removed in vacuo, the
residue was purified by flash column chromatography (PE/EtOAc=5/1
to 3/1) to yield
2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolo[2,3-d]pyrimidine
(CXXXV, 1.2 g, 36%) as a yellow solid. LCMS: (ESI) m/z=276
(M+H).sup.+.
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidin-
e (CXXXVI)
[0440] To a solution of
2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolo[2,3-d]pyrimidine
(1.0 g, 3.6 mmol) in EtOAc (10 mL) were added 10% Pd/C (1.0 g) and
AcOH (2.43 g, 40 mmol). The mixture was attached to a hydrogenation
apparatus. The system was evacuated and refilled with hydrogen gas.
The mixture was stirred at ambient temperature for 48 h, and
filtered through 10 g of silica-gel on a glass-filter. The filtrate
was concentrated and the residue was purified by flash column
chromatography (DCM/MeOH=100/1 to 20/1) to yield
2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidi-
ne (CXXXVI) (800 mg, 79%) as a yellow solid.
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidin-
e hydrochloride (CXXXVII)
[0441]
2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolo[2,3-d]pyrimi-
dine (200 mg, 0.72 mmol) was dissolved in H.sub.2O (10 mL) and 0.5
M aqueous HCl solution (1.5 mL) and then the solution was
lyophilized to yield
2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]py-
rimidine hydrochloride (225 mg, 95%) as a yellow solid. LCMS (ESI)
m/z=278 (M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. (ppm) 4.36
(s, 1H), 3.90 (s, 1H), 3.67 (t, J=8.5 Hz, 2H), 3.30 (t, J=7.5 Hz,
2H), 2.84 (t, J=8.5 Hz, 2H), 1.60-1.66 (m, 2H), 1.24 (d, J=6.0 Hz,
6H), 1.21 (d, J=6.0 Hz, 6H), 0.98 (t, J=7.5 Hz, 3H).
Example 73
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamin-
e (CXLI)
Example 74
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamin-
e hydrochloride (CXLII)
##STR00070##
[0442] 2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3d]pyrimidine
(CXXXVIII)
[0443] To the solution of 2,4-diamino-6-hydroxypyrimidine (50 g,
397 mmol) in H.sub.2O (750 mL) was added 2-chloroacetaldehyde (40%
in H.sub.2O, 85 g, 437 mmol) in a dropwise manner at 0.degree. C.
The mixture was stirred at 65.degree. C. for 2 h and then heated at
100.degree. C. until the reaction was complete. The resultant
solids were filtered and the remaining residue was heated at reflux
in EtOH (750 mL). The additional solids were filtered and the
mother liquor was concentrated to afford
2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3d]pyrimidine (CXXXVIII) as
a yellow solid 40 g (.about.67%, .about.70% purity). LCMS (ESI)
m/z=151 (M+H).sup.+.
2-Amino-4-chloro-7H-pyrrolo[2,3d]pyrimidine (CXXXIX)
[0444] 2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3d]pyrimidine
(CXXXVIII, 25 g, 167 mmol) was suspended in POCl.sub.3 (200 mL) and
cooled in an ice bath. The mixture was slowly warmed and heated up
to 120.degree. C. for 3 h. After this time, the volatiles (excess
POCl.sub.3) were evaporated the under vacuum. To this residue was
added ice water (200 mL) and the resultant solid was filtered to
afford 2-amino-4-chloro-7H-pyrrolo[2,3d]pyrimidine (CXXXIX) as a
yellow solid (20 g, .about.71%, .about.75% purity). LCMS (ESI)
m/z=169 (M+H).sup.+.
4-Chloro-2-n-propylamino-7H-pyrrolo[2,3d]pyrimidine (CXL)
[0445] To a solution of 2-amino-4-chloro-7H-pyrrolo[2,3d]pyrimidine
(CXXXIX, 26 g, 155 mmol) and n-propionaldehyde (27 g, 464 mmol) in
MeOH (600 mL) was added AcOH (50 mL). The reaction was stirred at
ambient temperature for 30 min. After this time, NaBH.sub.3CN (49
g, 775 mmol) was added in portions at -20.degree. C. for 30 min.
The resultant mixture was stirred at 80.degree. C. for 3 h and the
volatiles were removed. The resultant residue was extracted with
EtOAc (3.times.300 mL) and the combined organics were washed with a
brine solution (2.times.100 mL). The organic layer was dried over
Na.sub.2SO.sub.4, concentrated and purified via silica-gel column
chromatography (pet ether/EtOAc (5/1)) to afford
4-chloro-2-propylamino-7H-pyrrolo[2,3d]pyrimidine (CXL) as a yellow
solid (6 g, 18%). LCMS (ESI) m/z=211 (M+H).sup.+.
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamin-
e (CXLI)
[0446] To a solution of
4-chloro-2-propylamino-7H-pyrrolo[2,3d]pyrimidine (CXL, 1.0 g, 4.8
mmol) in n-BuOH (5 mL) was added potassium carbonate (3.3 g, 5.0
eq.) and N,O-dimethylhydroxylamine hydrochloride (1.1 g, 4.0 eq.).
The mixture was stirred in an autoclave equipped with a stirrer at
100.degree. C. for 8 h. After cooling to ambient temperature, water
was added (20 mL) and the mixture was extracted with EtOAc
(3.times.25 mL). The combined organic layers were washed with water
and then with a brine solution, and dried over anhydrous
Na.sub.2SO.sub.4. The solvents were removed in vacuo and the
resultant residue was purified by flash column chromatography (pet
ether/EtOAc=5/1) to yield
N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylami-
ne (CXLI, 500 mg, 45%).
N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamin-
e hydrochloride (CXLII)
[0447]
N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydro-
xylamine (CXLI, 500 mg, 2.1 mmol) was dissolved in H.sub.2O (10 mL)
and 0.5 M aqueous HCl solution (5 mL). The solution was then
lyophilized to yield
N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydro-
xylamine hydrochloride as a white solid (CXLII, 550 mg). LCMS (ESI)
m/z=236 (M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. (ppm) 6.74
(d, J=3.5 Hz, 1H), 6.41 (d, J=4.0 Hz, 1H), 3.80 (s, 3H), 3.35 (s,
3H), 3.28-3.35 (m, 2H), 1.59-1.62 (m, 2H), 0.97 (t, J=7.0 Hz,
3H).
Example 75
2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX)
Example 76
2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CL)
5-Allyl-2-amino-4,6-dihydroxypyrimidine (CXLIII)
[0448] Guanidine hydrochloride (27 g, 0.28 mol) was added to cold
absolute EtOH (200 mL) and NaOEt (30% in ethanol) (200 mL), and the
mixture was stirred at 0.degree. C. for 10 min. After this time,
diethyl allylmalonate (55 g, 0.28 mol) was added. The reaction
mixture was then stirred at room temperature for 18 h.
Acidification with 3N HCl precipitated the crude product (pH=6).
The solid was collected by filtration and washed with ethanol.
Recrystallization from water afforded 29 g (62%) of pure
5-allyl-2-amino-4,6-dihydroxypyrimidine (CXLIII). LCMS (ESI)
m/z=168 (M+H).sup.+.
##STR00071##
5-Allyl-2-amino-4,6-chloropyrimidine (CXLIV)
[0449] 5-Allyl-2-amino-4,6-dihydroxypyrimidine (4.9 g, 28.0 mmol)
was added in small portions to a solution of PCl.sub.5 (6.6 g, 29.5
mmol) in POCl.sub.3 (180 mL) at 60.degree. C., and diethylaniline
(3 g) was added dropwise. The temperature was raised to 120.degree.
C. The reaction mixture was heated at reflux overnight before it
was evaporated to dryness. Hot water (100.degree. C.) (100 mL) was
added slowly to the residue, and the resulting suspension was
cooled and extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The
combined organic layers were washed with cold water three times
until the aqueous extract was above pH=5. The organic layer was
dried (Na.sub.2SO.sub.4) and evaporated to dryness in vacuo. The
resultant residue was purified by column chromatography (EtOAc/pet
ether=1:10) to afford 5-allyl-2-amino-4,6-chloropyrimidine (CXLIV,
2.5 g, 42%). LCMS (ESI) m/z=204 (M+H).sup.+.
2-(2-Amino-4,6-chloropyrimidin-5-yl)ethanal (CXLV)
[0450] 5-Allyl-2-amino-4,6-chloropyrimidine (1 g, 4.9 mmol) was
dissolved in ethyl acetate (40 mL) and reacted with ozone gas at
-78.degree. C. for about 1 h (about 5% ozone at a rate of 1 L/min).
The reaction was monitored by TLC (pet ether/AcOEt=3/l (v/v)), and
once the starting material was consumed, the reaction mixture was
flushed with oxygen for 10 min. At this time, NaI (3 g) and glacial
acetic acid (3 mL) were added simultaneously to the cold reaction
mixture, and the temperature was allowed to warm up to 20.degree.
C. with continuous stirring over a 60-min period. Sodium
thiosulfate solution (67 g/100 mL of H.sub.2O) was added to the
reaction mixture until it became colorless. The resulting mixture
was diluted with water (30 mL) and extracted with CH.sub.2Cl.sub.2
(4.times.70 mL). The combined organic extracts were washed
successively with H.sub.2O (4.times.30 mL), a saturated NaHCO.sub.3
solution (30 mL) and with a brine solution (30 mL) and lastly,
dried over anhydrous Na.sub.2SO.sub.4). After filtration and
evaporation, 2-(2-amino-4,6-chloropyrimidin-5-yl)ethanal (CXLV, 1.1
g, 87%) was isolated as a white solid with .about.80% purity. LCMS
(ESI) m/z=207 (M+H).sup.+.
2-Amino-4-chloro-7-(4-methoxy)benzyl-pyrrolidino[2,3-d]pyrimidine
(CXLVI)
[0451] A solution of 2-(2-amino-4,6-chloropyrimidin-5-yl)ethanal
(CXLV, 1.2 g, 5.8 mmol) and para-methoxybenzylamine (PMBNH.sub.2)
(1.6 g, 11.6 mmol) in THF (20 mL) and AcOH (2 mL) was stirred at
ambient temperature for 30 min. To this mixture was added
NaBH(OAc).sub.3 (6.2 g, 29 mmol) in portions and the reaction was
stirred overnight. The mixture was concentrated in vacuo, and
extracted with EtOAc (3.times.80 mL). The combined organic extracts
were then washed with a brine solution (2.times.50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum.
The resultant residue was purified by flash column chromatography
(pet ether/EtOAc=10/1) to afford
2-amino-4-chloro-7-(4-methoxy)benzyl-pyrrolidino[2,3-d]pyrimidine
(CXLVI, 950 mg, 52%) as a yellow solid (52%). LCMS (ESI) m/z=291
(M+H).sup.+.
2-n-Propylamino-4-chloro-7-(4-methoxy)benzyl-pyrrolidino[2,3-d]pyrimidine
(CXLVII)
[0452]
2-Amino-4-chloro-7-(4-methoxy)benzyl-pyrrolidino[2,3-d]pyrimidine
(CXLVI, 950 mg, 3.3 mmol) and propionaldehyde (575 mg, 16.5 mmol)
in MeOH (30 mL) and AcOH (3 mL) were stirred at ambient temperature
for 30 min. At this time, NaBH.sub.3CN (1.0 g, 16.5 mmol) was added
in portions and the reaction was then heated at 85.degree. C. for
16 h. After cooling, the mixture was evaporated, and extracted with
EtOAc (2.times.50 mL). The combined organics were then washed with
a brine solution (2.times.50 mL). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuum.
The resultant residue was purified by flash column chromatography
(PE/EtOAc=10/1) to afford
2-n-propylamino-4-chloro-7-(4-methoxy)benzyl-pyrrolidino[2,3-d]pyrimidine
(CXLVII, 920 mg, 85%). LCMS (ESI) m/z=333 (M+H).sup.+.
2-n-Propylamino-4-chloro-7H-pyrrolidino[2,3-d]pyrimidine
(CXLVIII)
[0453] A solution of
2-n-propylamino-4-chloro-7-(4-methoxy)benzyl-pyrrolidino[2,3-d]pyrimidine
(CXLVII, 920 mg, 3.2 mmol) in TFA (5 mL) was heated at 85.degree.
C. for 3 h. After cooling the mixture was evaporated and extracted
with EtOAc (2.times.50 mL). The combined organics were washed with
a brine solution (2.times.50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum. The resultant residue was
purified by flash column chromatography (pet ether/EtOAc=5/1) to
afford 2-n-propylamino-4-chloro-7H-pyrrolidino[2,3-d]pyrimidine
(CXLVIII, 500 mg, 85%) as a colorless solid. LCMS (ESI) m/z=213
(M+H).sup.+.
2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX)
[0454] 2-n-Propylamino-4-chloro-7H-pyrrolidino[2,3-d]pyrimidine
(CXLVIII, 500 mg, 2.38 mmol) was dissolved in n-butanol (5 mL), and
potassium carbonate (1.64 g, 5.0 eq.) and propan-1-amine (923 mg,
4.0 eq.) were added. The mixture was stirred in an autoclave
equipped with a stirrer at 100.degree. C. for 72 h. After cooling
to room temperature, 20 mL of water was added, and the mixture was
extracted with EtOAc (3.times.20 mL). The combined organic layers
were washed with water and with a brine solution, and dried over
anhydrous Na.sub.2SO.sub.4. After removal of the solvents in vacuo,
the resultant residue was purified by preparative HPLC to yield
2-n-propylamino-4-chloro-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX,
210 mg, 37% yield).
2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CL)
[0455] 2-n-Propylamino-4-chloro-7H-pyrrolidino[2,3-d]pyrimidine
(CXLIX, 210 mg, 0.89 mmol) was dissolved in H.sub.2O (5 mL) and 0.5
M aqueous HCl solution (2.0 mL), and the solution was lyophilized
to yield 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine
hydrochloride (CL, 242 mg, 95% yield) as an orange solid. LCMS
(ESI) m/z=236 (M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta.
(ppm) 3.72 (t, J=9.0 Hz, 2H), 3.30-3.34 (m, 4H), 2.90 (t, J=9.0 Hz,
2H), 1.61-1.65 (m, 4H), 0.96-0.99 (m, 6H).
Example 77
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]p-
yrimidine (CLII)
Example 78
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]p-
yrimidine hydrochloride (CLIII)
##STR00072##
[0456]
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolo[2,3--
d]pyrimidine (CLI)
[0457] 2-(n-Propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXIV) (1.6 g, 7.1 mmol) was added to n-butanol (10 mL) followed
by potassium carbonate (4.9 g, 35.5 mmol) and piperidin-4-ol
hydrochloride (632 mg, 10.7 mmol). The mixture was stirred in an
autoclave equipped with a stirrer at 130.degree. C. for 16 h. After
cooling to room temperature, water was added (20 mL), and the
mixture was extracted with EtOAc (3.times.50 mL). The combined
organic layers were washed with water and then with a brine
solution, and dried over anhydrous Na.sub.2SO.sub.4. The solvents
were removed in vacuo and the residue was purified by flash column
chromatography (pet ether/EtOAc=3/1) to yield
2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolo[2,3-d]pyri-
midine (1.2 g, 75%) as a yellow solid. LCMS (ESI) m/z=290
(M+H).sup.+.
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]p-
yrimidine (CLII)
[0458] To the solution of
2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolo[2,3-d]pyri-
midine (CLI, 1.0 g, 4 mmol) in EtOAc (50 mL) were added 10% Pd/C
(1.0 g) and AcOH (2.43 g, 40 mmol). The mixture was attached to a
hydrogenation apparatus. The system was evacuated and refilled with
hydrogen gas. The mixture was stirred at ambient temperature for 48
h. The mixture was filtered through 10 g of silica-gel on a
glass-filter. The filtrate was concentrated and the residue was
purified by flash column chromatography (DCM/MeOH=50/1 to 10/1) to
yield
2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]-
pyrimidine (CLII, 500 mg, 50% yield) as a yellow solid.
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]p-
yrimidine hydrochloride (CLIII)
[0459]
2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[-
2,3-d]pyrimidine (CLII, 500 mg, 2 mmol) was dissolved in H.sub.2O
(10 mL) and 0.5 M HCl solution in H.sub.2O (4 mL) and the solution
was lyophilized to yield
2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]-
pyrimidine hydrochloride (525 mg) as a yellow solid. LCMS (ESI)
m/z=292 (M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. (ppm)
4.12-4.15 (m, 2H), 3.80-3.82 (m, 1H), 3.40 (t, J=8.0 Hz, 2H), 3.29
(t, J=7.0 Hz, 2H), 3.08-3.14 (m, 2H), 3.02 (t, J=8.0 Hz, 2H), 2.84
(s, 3H), 1.86-1.90 (m, 2H), 1.58-1.62 (m, 2H), 1.46-1.51 (m, 2H),
0.97 (t, J=4.0 Hz, 3H).
Example 79
8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo-
[3.2.1]octan-3-ol (CLV)
Example 80
8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo-
[3.2.1]octan-3-ol hydrochloride (CLVI)
##STR00073##
[0460]
8-(7-Methyl-2-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-azab-
icyclo[3.2.1]octan-3-ol (CLIV)
[0461] To a solution of
2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CXXIV) (1.0 g, 4.5 mmol) in n-butanol (10 mL) were added DIPEA
(1.0 g, 7.8 mmol) and 8-aza-bicyclo[3.2.1]octan-3-ol hydrochloride
(1.1 g, 6.7 mmol). The mixture was stirred at 125.degree. C. for 16
h. After cooling to room temperature, water (20 mL) was added, and
the mixture was extracted with EtOAc (3.times.50 mL). The combined
organic layers were washed with water and then with a brine
solution, and dried over anhydrous Na.sub.2SO.sub.4. The solvents
were removed in vacuo and the resultant residue was purified by
flash column chromatography (pet ether/EtOAc=6/1) to yield
8-(7-methyl-2-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-a-
zabicyclo[3.2.1]octan-3-ol (CLIV) (800 mg, 57% yield) as a yellow
solid. LCMS (ESI) m/z=316 (M+H).sup.+.
8-(7-Methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo-
[3.2.1]octan-3-ol (CLV)
[0462] To a solution of
2-(n-propyl)amino-4-(4-hydroxy-1-aza-bicyclo[3.2.1]octan-1-yl)-7-methyl-p-
yrrolo[2,3-d]pyrimidine (CLIV, 1.00 g, 3.2 mmol) in EtOAc (10 mL)
were added 10% Pd/C (1.0 g) and AcOH (3 mL). The mixture was
attached to a hydrogenation apparatus. The system was evacuated and
refilled with hydrogen. The mixture was stirred at ambient
temperature for 48 h. The mixture was filtered through 10 g of
silica-gel on a glass-filter. The filtrate was concentrated and the
residue was purified by flash column chromatography
(EtOAc/MeOH=50/1) to yield
8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicycl-
o[3.2.1]octan-3-ol (CLV) (500 mg, 49% yield) as a yellow solid.
8-(7-Methyl-2-(propylamino)pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[-
3.2.1]octan-3-ol hydrochloride (CLVI)
[0463]
8-(7-Methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-aza-
bicyclo[3.2.1]octan-3-ol (CLV, 200 mg, 0.63 mmol) was dissolved in
H.sub.2O (10 mL) and 0.5 M aqueous HCl solution (1.3 mL), and the
solution was lyophilized to yield
8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicycl-
o[3.2.1]octan-3-ol hydrochloride (CLVI) (224 mg) as a yellow solid.
LCMS (ESI) m/z=318 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta.
(ppm) 4.55 (br, 2H), 3.90 (s, 1H), 3.60 (t, J=8.0 Hz, 2H), 3.27 (t,
J=6.5 Hz, 2H), 3.00 (t, J=9.0 Hz, 2H), 2.92 (s, 3H), 2.27 (d, J=7.0
Hz, 2H), 1.90-1.95 (m, 4H), 1.69 (s, 1H), 1.66 (s, 1H), 1.49-1.54
(m, 2H), 0.92 (t, J=7.0 Hz, 3H).
Example 81
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-
-hydroxylamine (CLVIII)
Example 82
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-
-hydroxylamine hydrochloride (CLIX)
##STR00074##
[0464]
2-(Propen-2-yl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CLVII)
[0465] Under a nitrogen atmosphere,
2-(t-butyl-dimethylsilanyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidi-
ne (CXXIII) (7.5 g, 25 mmol) was dissolved in DMF (100 ml) and
3-iodoprop-1-ene (6.38 g, 38 mmol) was added. The mixture was
cooled to 0.degree. C. with vigorous stirring, then NaH (1.5 g of a
60% dispersion in mineral oil, 38 mmol) was added. The mixture was
stirred for 30 min, and water (50 mL) was slowly added to quench
the reaction. The aqueous mixture was extracted with EtOAc (300 mL)
and the organic layer was washed with water (100 mL) and then with
a brine solution (100 mL), and dried over anhydrous
Na.sub.2SO.sub.4. After evaporation, 8.6 g of a yellow oily residue
was isolated. This material was dissolved in Et.sub.2O (100 mL),
and concentrated hydrochloric acid (20 mL) was added at 0.degree.
C. with stirring. The mixture was then stirred for an additional 10
min. The mixture was extracted with EtOAc (200 mL) and 1N NaOH (200
mL). The organic layer was separated and washed with H.sub.2O (150
mL) and with a brine solution (150 mL) and dried over anhydrous
Na.sub.2SO.sub.4. The solvents were removed in vacuo and the
resultant residue was purified by flash column chromatography (pet
ether/EtOAc=10/1 to 5/1) to yield
2-(propen-2-yl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (6
g, 100% yield) as a yellow solid. LCMS: (ESI) m/z=223
(M+H).sup.+.
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-
-hydroxylamine (CLVIII)
[0466] To
2-(propen-2-yl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CLVII, 500 mg, 2.38 mmol) were added n-butanol (5 mL), potassium
carbonate (1.64 g, 5.0 eq.) and N,O-dimethylhydroxylamine
hydrochloride (923 mg, 4.0 eq.). The mixture was stirred in an
autoclave equipped with a stirrer at 100.degree. C. for 8 h. After
cooling to room temperature, water (20 mL) was added, and the
mixture was extracted with EtOAc (3.times.20 mL). The combined
organic layers were washed with water and with a brine solution and
dried over anhydrous Na.sub.2SO.sub.4. The solvents were then
removed in vacuo and the resultant residue was purified by flash
column chromatography (pet ether/EtOAc=3/1) to yield
N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethy-
l-hydroxylamine (CLVIII, 310 mg, 55% yield).
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,
O-dimethyl-hydroxylamine hydrochloride (CLIX)
[0467]
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-d-
imethyl-hydroxylamine (310 mg, 1.32 mmol) was dissolved in H.sub.2O
(5 mL) and 0.5 M aqueous HCl solution (2.7 mL), and the solution
was lyophilized to yield
N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,-
O-dimethyl-hydroxylamine hydrochloride (CLIX, 325 mg) as a white
solid. LCMS (ESI) m/z=248 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO)
.delta. (ppm) 12.60-14.80 (br, 1H), 7.70-8.70 (br, 1H), 7.06 (s,
1H), 6.55 (s, 1H), 5.90-5.94 (m, 1H), 5.31 (d, J=17.0 Hz, 1H), 5.17
(d, J=10.5 Hz, 1H), 4.06 (s, 2H), 3.84 (s, 3H), 3.70 (s, 3H), 3.53
(s, 3H).
Example 83
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hyd-
roxylamine (CLX)
Example 84
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hyd-
roxylamine hydrochloride (CLXI)
##STR00075##
[0468]
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-met-
hyl-hydroxylamine (CLX)
[0469]
2-(2-Propen-2-yl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine
(CLVII) (700 mg, 3.15 mmol) was dissolved in n-butanol, and
potassium carbonate (2.2 g, 5.0 eq.) and O-methylhydroxylamine
hydrochloride (768 mg, 4.0 eq.) were added. The mixture was stirred
in an autoclave equipped with a stirrer at 100.degree. C. for 12 h.
After cooling to room temperature, water (20 mL) was added, and the
mixture was extracted with EtOAc (3.times.25 mL). The combined
organic layers were washed with water and a brine solution, and
dried over anhydrous Na.sub.2SO.sub.4. The solvents were removed in
vacuo and the resultant residue was purified by flash column
chromatography (pet ether/EtOAc=5/1) to yield
N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hy-
droxylamine (370 mg, 46% yield).
N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hyd-
roxylamine hydrochloride (CLXI)
[0470]
N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-met-
hyl-hydroxylamine (370 mg, 1.59 mmol) was dissolved in H.sub.2O (5
mL) and 0.5 M aqueous HCl solution (2 mL), and the solution was
lyophilized to yield
N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-met-
hyl-hydroxylamine hydrochloride (383 mg) as a white solid. LCMS
(ESI) m/z=234 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta.
(ppm) 12.40-13.00 (br, 1H), 7.70-8.10 (br, 1H), 7.04 (d, J=3.5 Hz,
1H), 6.49 (d, J=3.0 Hz, 1H), 5.94-5.99 (m, 1H), 5.32 (d, J=17.0 Hz,
1H), 5.17 (d, J=10.5 Hz, 1H), 4.04 (s, 2H), 3.85 (s, 3H), 3.61 (s,
3H).
Example 85
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydr-
oxylamine (CLXII)
Example 86
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydr-
oxylamine hydrochloride (CLXIII)
##STR00076##
[0471]
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimeth-
yl-hydroxylamine (CLXII)
[0472] The desired compound was prepared from
4-chloro-2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine and
N,O-dimethyl-hydroxylamine as described in Example 73. LCMS: (ESI)
m/z=250 (M+H).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
(ppm) 7.70 (s, 1H), 7.02 (s, 1H), 6.52 (s, 1H), 3.82 (s, 3H), 3.67
(s, 3H), 3.53 (s, 3H), 3.34 (t, J=8.5 Hz, 2H), 1.54-1.59 (m, 2H),
0.93 (t, J=8.5 Hz, 3H).
Example 87
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxyl-
amine (CLXIV)
Example 88
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxyl-
amine hydrochloride (CLXV)
##STR00077##
[0473] N-(2-n-Propylamino-7
methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine
(CLXIV)
[0474] The desired compound was prepared from
4-chloro-2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine and
O-methyl-hydroxylamine as described in Example 73. LCMS (ESI)
m/z=236 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta. (ppm)
12.50 (s, 1H), 8.10 (s, 1H), 7.05 (s, 1H), 6.01 (s, 1H), 3.85 (s,
3H), 3.60 (s, 3H), 3.36 (s, 1H), 3.34 (t, J=6.5 Hz, 2H), 1.58-1.62
(in, 2H), 0.96 (t, J=7.5 Hz, 3H).
Example 89
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
(CLXVI)
Example 90
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
hydrochloride (CLXVII)
##STR00078##
[0475]
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
(CLXVI)
[0476] To a solution of
4-chloro-2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine (CXXIV,
1.0 g, 4.5 mmol) in ethanol (70 mL) was added hydrazine (14 mL) and
the mixture was heated at refluxed for 3 h. After cooling to room
temperature, the solvents were removed in vacuo. The residue was
purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH=30/1) to yield
N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
(CLXVI, 1.0 g, 80% yield).
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
hydrochloride (CLXVII)
[0477]
N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
(460 mg, 2.0 mmol) was dissolved in H.sub.2O (10 mL) and 0.5 M
aqueous HCl solution (4 mL), and the solution was lyophilized to
yield
N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine
hydrochloride (440 mg) as a brown solid. LCMS (ESI) m/z=221
(M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta. (ppm) 10.63 (s,
1H), 7.56 (s, 2H), 6.97 (d, J=3.0 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H),
3.58 (s, 3H), 3.33 (s, 2H), 1.56-1.61 (m, 2H), 0.95 (t, J=8.0 Hz,
3H).
Example 91
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazin-
e (CLXVIII)
Example 92
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazin-
e hydrochloride (CLXIX)
##STR00079##
[0478]
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-h-
ydrazine (CLXVIII)
[0479] To a solution of
4-chloro-2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine (CXXIV,
800 mg, 3.42 mmol) in n-butanol (5 mL) was added potassium
carbonate (2.36 g, 5.0 eq.) and methylhydrazine (630 mg, 4.0 eq.).
The mixture was stirred in an autoclave equipped with a stirrer at
100.degree. C. for 15 h. After cooling to room temperature, water
was added (20 mL), and the mixture was extracted with EtOAc
(3.times.25 mL). The combined organic layers were washed with water
and with a brine solution, and dried over anhydrous
Na.sub.2SO.sub.4. The solvents were removed in vacuo and the
resultant residue was purified by flash column chromatography (pet
ether/EtOAc=3/1 to DCM/MeOH=10/1) to yield
N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazi-
ne (CLXVIII, 220 mg, 36% yield).
N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazin-
e hydrochloride (CLXIX)
[0480]
N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-h-
ydrazine (220 mg, 0.94 mmol) was dissolved in H.sub.2O (10 mL) and
0.5 M aqueous HCl solution (2 mL), and the solution was lyophilized
to yield
N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazi-
ne hydrochloride (CLXIX, 238 mg) as a brown solid. LCMS (ESI)
m/z=235 (M+H).sup.+. .sup.1H NMR (500 MHz, DMSO) .delta. (ppm)
7.50-8.10 (br, 4H), 7.05 (s, 1H), 6.67 (s, 1H), 3.60 (s, 3H), 3.58
(s, 3H), 3.33 (s, 2H), 1.55-1.62 (m, 2H), 0.95 (t, J=7.5 Hz,
3H).
Example 93
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hyd-
razine (CLXX)
Example 94
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hyd-
razine hydrochloride (CLXXI)
##STR00080##
[0481]
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4--
yl)-hydrazine (CLXX)
[0482] To a solution of
4-chloro-2-n-propylamino-7-methyl-pyrrolo[2,3d]-pyrimidine (1.1 g,
5 mmol) and 1,1-dimethylhydrazine (450 mg, 7.5 mmol) in dioxane (30
mL) was added xphos (622 mg, 1 mmol), Pd.sub.2(dba).sub.3 (458 mg,
0.5 mmol) and Cs.sub.2CO.sub.3 (2.45 g, 7.5 mmo). The solution was
degassed by bubbling argon through it for 10 min using a syringe
needle. The mixture was then stirred at 80.degree. C. for 2 h.
After cooling to room temperature, water was added (20 mL) and the
mixture was extracted with EtOAc (3.times.40 mL). The combined
organic layers were washed with water and with a brine solution,
and dried over anhydrous Na.sub.2SO.sub.4. The solvents were
removed in vacuo and the resultant residue was purified by flash
column chromatography (DCM/MeOH=30/1 to 5/1) to yield N,
N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydr-
azine (CLXX, 100 mg, 8% yield, .about.85% purity).
N,N-Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hyd-
razine hydrochloride (CLXX)
[0483] N,
N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-
-yl)-hydrazine (100 mg, 0.4 mmol) was dissolved in H.sub.2O (5 mL)
and 0.5 M aqueous HCl solution (1 mL) and the solution was
lyophilized to yield N,
N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)--
hydrazine hydrochloride (110 mg) as a yellow oil. LCMS (ESI)
m/z=249 (M+H).sup.+. .sup.1H NMR (500 MHz, MeOD) .delta. (ppm) 6.92
(d, J=4.0 Hz, 1H), 6.50 (d, J=3.0 Hz, 1H), 3.66 (s, 3H), 3.45 (t,
J=7.5 Hz, 2H), 2.79 (s, 6H), 1.67-1.72 (m, 2H), 1.01-1.04 (m,
3H).
Example 95
Effect of Compound (XXXVI) on Opioid-Induced Respiratory Depression
in the Rat
[0484] All animal experiments were carried out according to the
U.S. law on animal care and use approved by Galleon Pharmaceuticals
Institutional Animal Care and Use Committee (IACUC). Rats with
pre-cannulated jugular vein (for administrating drugs) were
acclimated to plethysmography chambers for a minimum of 60 minutes,
or until animals were no longer restless. Each animal was dosed
with morphine sulfate (10 mg/kg), dissolved in sterile water at a
concentration of 10 mg/mL (supplied by Baxter Healthcare
Corporation), via injection into the jugular vein catheter over a
period of 5-10 seconds.
[0485] Compound (XXXVI) was dissolved in 20% hydroxypropyl
.beta.-cyclodextran (20% bcd on graph) at a concentration of 0.45
mg/mL at pH 5. After a period of 5 min, compound (XXXVI), labeled
as cmpd (A), was administered via infusion into the jugular vein at
a dose of 0.10 mg/kg/min for 20 min and then at a dose of 0.30
mg/kg/min for 20 min (e.g., 20 .mu.L/min/0.3 kg rat to yield 0.03
mpk/min).
[0486] After 20 minutes of infusion at this dose, the infusion
pumps were turned off, and all animals were given a 20 minute
recovery period, followed by a post-study analysis of rat health
and behavior. The minute ventilation data indicate that compound
(XXXVI) significantly reversed opioid-induced respiratory
depression in rat compared to vehicle. Results are illustrated in
FIG. 1.
Example 96
Effects of Morphine and Compound (XXXVI) on Blood Gases in the
Rat
[0487] Rats with pre-cannulated jugular vein and femoral arterial
catheters (for administrating drugs and obtaining blood samples
respectively) were obtained from Harlan laboratories and kept at
the animal facility at Galleon Pharmaceuticals until the
experimental procedures. All animals experiments were carried out
according to the US law on animal care and use approved by Galleon
Pharmaceuticals IACUC. Each animal was dosed with morphine sulfate
(10 mg/kg), dissolved in saline at a concentration of 10 mg/ml, via
injection into the jugular vein over a period of 20 seconds with a
20 second flush of 0.9% NaCl saline. Prior to morphine
administration, two 250 .mu.L samples of arterial blood were
aspirated from the femoral artery into a pre-heparinized syringe.
The samples were analyzed on Radiometer's ABL Flex 800, where
pO.sub.2, pCO.sub.2, pH, saO.sub.2 and other parameters were
recorded. Aspirated volumes of arterial blood were replaced by room
temperature sterile saline (.about.300 .mu.L) slowly flushed back
into the femoral arterial catheter of the rodent to prevent anemia
and/or dehydration. Morphine was then administered and 2 minutes
later another blood sample was taken.
[0488] After a period of 5 min from the administration of morphine,
compound (XXXVI), labeled as cmpd (A), was administered via
infusion into the jugular vein at a dose of 0.1, 0.3 and 1.0
mg/kg/min (dissolved in PBS buffer). The infusion started at t=15
minutes and ended at t=35 minutes. Arterial blood gas analysis
occurred at time points t=12, 18, 25, 35, 40, 45, and 50 minutes.
The data show that compound (XXXVI) significantly reverses
opioid-induced respiratory depression in rat compared to vehicle.
Results are illustrated in FIG. 2A and FIG. 2B and the accompanying
Table 6.
TABLE-US-00006 TABLE 6 pH PaCO.sub.2 PaO.sub.2 SaO.sub.2 Dose (% (%
(% (% Cmpd n (mpk/min) reversal) reversal) reversal) reversal)
XXXVI 6 1 60 94 26 62 XXXVI 11 0.3 55 72 -16 43 XXXVI 10 0.1 37 47
16 51 XXXVI 6 0.03 20 18 -2.0 42
Example 97
Hypoxic Ventilatory Response (HVR) and Effect of Compound (XXXVI)
on HVR in the Rat
[0489] Rats with a pre-cannulated jugular vein (for administrating
drugs) were acclimated to plethysmography chambers for a minimum of
60 minutes, or until animals were no longer restless. Each animal
was dosed with compound (XXXVI), labeled as cmpd (A), at 0.03
mg/kg/min via infusion into the jugular vein catheter for a period
of 50 minutes. After a period of 20 minutes, an isocapnic hypoxic
mixture (12% O.sub.2 balanced N.sub.2) was administered into all
chambers using a gas mixer (CWE inc. GSM-3 gas mixer) for 20
minutes. After this time, the gas mixer was turned off, resulting
in normal room air pumped into the chambers. Ten minutes later, the
infusion pumps were turned off, and all animals were given a 20
minute recovery period, followed by a post-study analysis of rat
health and behavior. The minute ventilation data show that compound
(XXXVI) significantly potentiates the hypoxic ventilatory response
in the rat compared to vehicle. Results are illustrated in FIG.
3.
Example 98
Effect of Compound (XXXVI) on Opioid-Induced Respiratory Depression
in the Monkey
[0490] Juvenile macaques (four-year-old Macaca fascicularis, 2 to 5
kg, n=13) were used for the study. Animal husbandry was conducted
under USDA guidelines and the protocols were approved by the
Institutional Animal Care and Use Committee of East Carolina
University.
[0491] Anesthesia was induced with 5% isoflurane and then
maintained with 1.5 to 2% isoflurane (100% O.sub.2, 2 L/min).
Antebrachial veins were cannulated. Vivometrics Lifeshirts
(Ventura, CA) were fitted to the animals for monitoring respiratory
function by inductance plethysmography. Abdomen and rib cage
deflections were calibrated using the Qualitative Diagnostic
Calibration (QDC) procedure, and tidal volume was normalized to 15
mL, which represented a typical tidal volume for these animals as
previously measured using conventional techniques. Heart rate was
monitored continuously by 3-lead ECG.
[0492] ETCO.sub.2 was measured via a neonatal nasal cannula
connected to a microstream CO.sub.2 sensor (Cardell monitor, Model
9405). SpO.sub.2 and HR were monitored by pulse oximetry using a
reflectance probe (Nelcor Max-Fast) positioned on the inner aspect
of the upper arm. HR was also determined from the ECG allowing
measurement when animal activity compromised the integrity of pulse
oximetry signals. BP was measured in anesthetized animals using a
cuff positioned on the ankle.
[0493] Compound (XXXVI) was dissolved in 20% hydroxypropyl
.beta.-cyclodextran (HPBCD) and sterile filtered using a 2.mu.
syringe filter. Compound (XXXVI), labeled as cmpd (A), was then
delivered at a rate of 0.20 mg/kg/min for 5 minutes, followed by
reduction of the infusion rate to 0.10 mg/kg/min for 10 minutes.
Minute Ventilation and end-tidal CO.sub.2 was monitored. Naloxone
HCl (0.05 mg/kg intravenous) was delivered to reverse morphine
effects and conclude the experiment. The data showed that cmpd (A)
produced a full reversal of end-tidal carbon dioxide increases
caused by the opioid, and also increased minute ventilation (FIG.
4).
Example 99
Effect of Compound (XXXVI) and (L) on Dose-Dependent Minute
Ventilation (MV) in Naive Rats
[0494] All surgical procedures were performed under anesthesia
induced by 2% isoflurane in compressed medical grade air. With rats
in supine position, the right femoral vein was catheterized using
polyethylene tubing (PE-50). This catheter was used for fluid and
drug administration. Simultaneously, the right femoral artery was
also catheterized for monitoring blood pressure. In order to
measure the respiratory parameters in spontaneously breathing rats,
trachea was intubated using 13 gauge tracheal tube (2.5 mm ID,
Instech Solomon, PA).
[0495] After establishing a stable base-line at 1.5% isoflurane,
cumulative dose-dependent (0.01, 0.03, 0.1, 0.3, 1, 3, 10 mg/kg)
ventilatory responses to compounds (XXXVI) and (L), labeled as cmpd
(A) and cmpd (B) respectively, were generated from spontaneously
breathing rats. Maximum peak minute ventilatory (MV) values at each
dose from corresponding drug were calculated and used for
generating ED.sub.50 values. The results are shown in FIG. 5. Both
compounds (XXXVI) and (L) increased minute ventilation in a
dose-dependent manner with calculated ED.sub.50 values of 0.14 and
0.13 mg/kg respectively.
Example 100
Effect of Compound (CXXI) on Dose-Dependent Minute Ventilation (MV)
in Naive Rats
[0496] Compound (CXXI), labeled as cmpd (C), was shown to increase
minute ventilation in a dose-dependent manner following the
procedure above. Results are shown in FIG. 6.
Example 101
Effects of Compound (L) in the Opioid-Treated Rat
[0497] Following the procedure in Example 6, Compound (L), labeled
as cmpd (B), was shown to reverse the effects of opioid on blood
gases and pH in the rat by increasing pH, SaO.sub.2 and pO.sub.2
and by decreasing pCO.sub.2 levels, as illustrated in FIGS.
7A-7D.
Example 102
Effects of Compound (CXLII) in the Opioid-Treated Rat
[0498] Following the procedure in Example 6, Compound (CXLII),
labeled as cmpd (D), was shown to reverse the effects of opioid on
blood gases and pH in the rat by increasing pO.sub.2 levels,
increasing (SaO.sub.2) oxygen saturation, decreasing pCO.sub.2
levels and raising pH, as illustrated in FIGS. 8A-8D.
Example 103
Effects of Compound (CXLII) on Opioid-Induced Respiratory
Depression in the Rat
[0499] Following the procedure in Example 5, Compound (CXLII),
labeled as cmpd (D), was shown to reverse opioid-induced
respiratory depression in the rat by increasing minute ventilation
(MV) as determined by plethysmography. The results are illustrated
in FIG. 9.
Example 104
Effect of Compounds on Minute Ventilation (MV) and Cardiovascular
Parameters in Naive Rats
[0500] All surgical procedures were performed under anesthesia
induced by 2% isoflurane in compressed medical grade air. With rats
in supine position, the right femoral vein was catheterized using
polyethylene tubing (PE-50). This catheter was used for fluid and
drug administration. Simultaneously, the right femoral artery was
also catheterized for monitoring blood pressure and heart rate. In
order to measure the respiratory parameters in spontaneously
breathing rats, trachea was intubated using 13 gauge tracheal tube
(2.5 mm ID, Instech Solomon, PA).
[0501] After establishing a stable base-line at 1.5% isoflurane,
compounds (typically at a dose of 1 mpk) were administered IV, and
ventilatory parameters were generated from spontaneously breathing
rats, along with cardiovascular output (mean arterial pressure
(MAP) and heart rate). Maximum peak minute ventilatory (MV)
responses (MPR), along with changes in minute ventilation versus
baseline (DMV) were obtained as shown in the tables below.
TABLE-US-00007 TABLE 7 CV MAP Heart MV (mm Rate Cmpd Structure
Formulation Dose pH MPR .DELTA.MV Hg) (B/min) (1,5)-8-(4,6-
bis(propylamino)- 1,3,5-triazin-2-yl)-8- azabicyclo[3.2.1]octan-
3-one ##STR00081## 20% HP.beta.CD 1 mpk 5 213 98 114 308
(1,5)-8-(4,6- bis(isobutylamino)- 1,3,5-triazin-2-yl)-8-
azabicyclo[3.2.1]octan- 3-one ##STR00082## 20% HP.beta.CD 1 mpk 5
237 137 117 345 N.sup.4-isopropyl-7- methyl-N.sup.2-propyl-7H-
pyrrolo[2,3-d] pyrimidine-2,4- diamine ##STR00083## 20% HP.beta.CD
1 mpk 5 402 320 118 340 6-(1-(2-(allylamino)- 7-methyl-7H-
pyrrolo[2,3-d] pyrimidin-4-yl) piperidin-4-yl)-N.sup.2,N.sup.4-
dipropyl-1,3,5- triazine-2,4-diamine ##STR00084## 20% HP.beta.CD 1
mpk 5 154 60 114 350 N.sup.4-isopropyl-7-
methyl-N.sup.2-propyl-6,7- dihydro-5H- pyrrolo[2,3-d]
pyrimidine-2,4- diamine ##STR00085## 20% HP.beta.CD 1 mpk 5 327 224
93 318 CLX, CLXI ##STR00086## 20% HP.beta.CD 1 mpk 5 182 103 96 336
CXXXI, CXXXII ##STR00087## 20% HP.beta.CD 1 mpk 4 204 130 101 348
N.sup.4,7-diisopropyl-N.sup.2- propyl-7H- pyrrolo[2,3-d]
pyrimidine-2,4- diamine ##STR00088## 20% HP.beta.CD 1 mpk 6 250 155
103 356 CXXXVI, CXXXVII ##STR00089## 20% HP.beta.CD 1 mpk 4 238 143
98 389 N.sup.4-isopropyl-N.sup.2- propyl-7H- pyrrolo[2,3-d]
pyrimidine-2,4- diamine ##STR00090## 20% HP.beta.CD 1 mpk 4 259 172
96 387 XXIX ##STR00091## 20% HP.beta.CD 1 mpk 4-6 253 161 92 371
CXLI, CXLII ##STR00092## 20% HP.beta.CD 1 mpk 4-6 264 163 93 336 XX
##STR00093## 20% HP.beta.CD 1 mpk 4-6 213 60 92 432 XXII
##STR00094## 20% HP.beta.CD 1 mpk 4-6 252 130 95 415
N.sup.2,N.sup.4-dipropyl-7H- pyrrolo[2,3-d] pyrimidine-2,4- diamine
##STR00095## 20% HP.beta.CD 1 mpk 4-6 336 164 94 427 XXV
##STR00096## 20% HP.beta.CD 1 mpk 4-6 257 126 98 430
N.sup.2-ethyl-6- (methoxyamino)-N.sup.4- propyl-1,3,5-triazine-
2,4-diamine ##STR00097## 20% HP.beta.CD 1 mpk 4-6 208 117 95 445
7-methyl-N-propyl-4- (1,2,2-trimethyl- hydrazinyl)-7H-
pyrrolo[2,3-d] pyrimidin-2-amine ##STR00098## 20% HP.beta.CD
15/65/20 1 mpk 1 mpk 4 5 175 167 83 89 93 87 372 376
N.sup.2,N.sup.4-dipropyl-6,7- dihydro-5H-pyrrolo
[2,3-d]pyrimidine-2,4- diamine ##STR00099## 20% HP.beta.CD 20%
HP.beta.CD 1 mpk 1 mpk 4 6 175 263 93 167 93 99 385 381
N.sup.2-methyl-N.sup.4,N.sup.6- dipropyl-1,3,5-
triazine-2,4,6-triamine ##STR00100## 15/65/20 1 mpk 5 145 106 92
285 6-(1,2- dimethylhydrazinyl)- N.sup.2,N.sup.4-dipropyl-1,3,5-
triazine-2,4-diamine ##STR00101## 20% HP.beta.CD 1 mpk 5 338 216 97
329 LIII, LIV ##STR00102## 20% HP.beta.CD 1 mpk 4-6 288 179 96 403
6-(methoxy (methyl)amino)- N.sup.2,N.sup.4- dipropylpyrimidine-
2,4-diamine ##STR00103## 20% HP.beta.CD 1 mpk 4-6 355 243 90 356
6-(isopropoxy (methyl)amino)- N.sup.2,N.sup.4-dipropyl-1,3,5-
triazine-2,4-diamine ##STR00104## 20% HP.beta.CD 1 mpk 271 209 98
378 6-(ethyl(isopropoxy) amino)-N.sup.2,N.sup.4- dipropyl-1,3,5-
triazine-2,4-diamine ##STR00105## 20% HP.beta.CD 1 mpk 4 308 191 89
351 6-(isobutoxy (methyl)amino)- N.sup.2,N.sup.4-dipropyl-1,3,5-
triazine-2,4-diamine ##STR00106## 20% HP.beta.CD 1 mpk 4 248 133 87
351 6-(methyl(thiophen-2- ylmethoxy)amino)-
N.sup.2,N.sup.4-dipropyl-1,3,5- triazine-2,4-diamine ##STR00107##
20% HP.beta.CD 1 mpk 4 213 110 112 411 6-((cyclopropyl
methoxy)(methyl) amino-N.sup.2,N.sup.4- dipropyl-1,3,5-
triazine-2,4-diamine ##STR00108## 20% HP.beta.CD 1 mpk 4 261 152 98
362 CLII, CLIII ##STR00109## 20% HP.beta.CD 1 mpk 4 49 0.33 79 245
XXXV, XXXVI ##STR00110## 15% DMA 85% D5W 1 mpk 5-6 207 135 87 268
XLVII ##STR00111## 20% HP.beta.CD 1 mpk 5 150.73 61.48 109.6 350.52
XLVIII ##STR00112## 15/65/20 1 mpk 5 114 30.13 98 300 XXXV, XXXVI
##STR00113## 20% HP.beta.CD 1 mpk 4-5 344 210 90 321 CLV, CLVI
##STR00114## 20% HP.beta.CD 1 mpk 4 170 57 111 349 XXXIII
##STR00115## 20% HP.beta.CD 1 mpk 4-6 147 53 89 480 LIII, LIV
##STR00116## 20% HP.beta.CD 1 mpk 4-6 288 179 96 403
TABLE-US-00008 TABLE 8 CV MAP HR Formula- MV (mmHg) (B/min)
Compound tion Dose pH MPR DMV BL DE BL DE CXX, 20% 1 mpk 4.5 355
243 107 2.3 293 17 CXXI HP.beta.CD CLXX, 20% 1 mpk 4 175 83 93 -1.0
372 -9.0 CLXXI HP.beta.CD CXLIX, 20% 1 mpk 4 175 93 93 -1.7 385 -28
CL HP.beta.CD CLXX, 15/65/20 1 mpk 5 167 89 87 1.0 376 -3.8 CLXXI
XXXV, 20% 1 mpk 5 267 164 101 -1.7 335 43 XXXVI HP.beta.CD CXLIX,
20% 1 mpk 6 263 167 99 -3 381 -18 CL HP.beta.CD XXXI 20% 1 mpk 4
140 43 101 2.6 372 2.5 HP.beta.CD CXIII, 20% 1 mpk 4 167.1 46 101
-4 368 23 CXIV HP.beta.CD CXV, 15/65/20 1 mpk 4 155.7 33.8 97 -5
374 -5 CXVI CXVII, 20% 1 mpk 4.5 143.8 15 92 -8 365 -2 CXVIII
HP.beta.CD LXXII, 20% 1 mpk 4 176 82 358 8 108 -4 LXXIII HP.beta.CD
LXXVI, 20% 1 mpk 4 308 191 351 15 89 -2 LXXVI HP.beta.CD LXXXII,
20% 1 mpk 4 248 133 351 19 87 10 LXXXIII HP.beta.CD LXXXIV, 20% 1
mpk 4 213 110 411 15 112 -1 LXXXV HP.beta.CD XCI, 20% 1 mpk 4 261
152 362 63 98 -2 XCII HP.beta.CD
Example 105
Effect of Compound (XXXVI) on Benzodiazepine-Induced Respiratory
Depression (BIRD)
[0502] In one aspect, the objective of the current study was to
evaluate the effects of an intravenous infusion of compound (XXXVI)
on respiratory depression, induced by midazolam in rats.
Procedures:
[0503] Compound (XXXVI) was dissolved in 20%
hydroxypropyl-beta-cyclodextran in sterile water, and titrated to a
pH of 4-8 using pH paper and NaOH or HCl, resulting in a clear,
stable solution at a concentration of 1.5 mg/mL. Other compounds:
morphine sulfate, supplied as 10 mg/ml solution by (Baxter, Inc)
and midazolam, supplied as 5 mg/mL solution (Hospira, Inc.)
Materials:
[0504] Male Sprague-Dawley rats (Harlan, Inc.), 250-350 g at time
of dosing, surgically prepared by Harlan with jugular vein
cannulas. 12 Chamber Plethysmography System with
temperature/humidity compensation (Epstein et al., 1980, J. Apply
Physiol. 49:1107-1115); From Buxco, Inc. (PLY 3223; Buxco, Inc,
Wilmington, N.C., USA) Biosystem XA, software, v2.11.1. Customized
12 site automated infusion system (Harvard Apparatus; Instech,
Inc)
Methods:
[0505] Rat whole body plethysmography was used to evaluate and
quantify minute ventilation and the pattern of breathing. A
respiratory waveform was generated from the exchange of air between
the animal and the chamber. This exchange induced changes in air
volume that were measured with a pressure transducer, constituting
the respiratory waveform. Atmospheric temperature and humidity were
also measured using temperature and humidity probes which sampled
chamber conditions. A compensation factor was then determined and
applied to the respiratory waveform using a standardized algorithm
(Epstein et al., 1980, J. Apply Physiol. 49:1107-1115) to
compensate for respiratory conditioning, which was reported as the
parameter COMP (see appendix).
[0506] All animals were acclimated to plethysmography chambers for
at least 1 hour, or until animals were no longer restless (up to 2
hours) prior to data collection. Bolus intravenous (IV) dosing was
administered at a rate of 5-10 seconds per dose, and catheters were
flushed with 350 .mu.L of sterile saline to be sure of complete
drug delivery. All 12 animals (6 vehicle; 6 drug treated) were
dosed simultaneously within one 60 second period. For intravenous
infusions, vehicle or test compound was prepared at a 0.1 mg/mL
stock as described, and administered with Harvard apparatus
infusion pumps. Compound (XXXVI) was given via infusion over a 30
minute period at a rate of 20 .mu.L/min/0.3 kg, to give a dose of
0.1 mg/kg/min, beginning 5 minutes after the bolus IV
administration of midazolam. None of the included studies were
performed blinded, due to the logistics of simultaneously dosing
multiple animals. All plethysmography data was recorded
automatically by the Buxco equipment.
Statistical Analysis:
[0507] Respiratory data was collected on a breath-by-breath basis
and averaged into 1 min time bins for data analysis. For each
designated acquisition phase, which is the time between doses,
percent change from pre-treatment baseline values were calculated
for each cohort on multiple ventilatory parameters including
respiratory frequency (f), tidal volume (TV), accumulated volume
(AV), minute ventilation (MV), inspiratory time (Ti), expiratory
time (Te), peak inspiratory flow (PIF), peak expiratory flow (PEF),
relaxation time (RT), end inspiratory pause (EIP), end expiratory
pause (EEP), delta volume (DV), expiratory flow at 50% TV (EF50),
rejection index (Rinx), compensation (Comp), enhanced pause (Penh),
pause (PAU), PEF rate (Rpef), relative humidity (RH), and
atmospheric temperature (Temp).
[0508] Each parameter was compared to vehicle in order to calculate
percent difference, using area under the curve (AUC) and peak
response values for each defined acquisition period using a
customized visual basic restructure analysis macro. Additionally,
percent reversal of drug induced respiratory depression by compound
was calculated using the mean respiratory depression derived from
all vehicle (or untreated) animals, compared to the mean
pre-treatment baselines of all animals in the study.
Results:
[0509] Compound (XXXVI) (0.1 mg/kg/min) reversed the BIRD induced
decrease in MV by 100 by the end of the infusion period (t=38).
Compound (XXXVI) had an effect to reverse the effects of midazolam
on MV (FIG. 15), TV (FIG. 16), AV, Te, PIF, PEF, and EEP, and had
no obvious effect on f (FIG. 17), Ti, RT, EIP, dv, EF50, Rinx,
Comp, Penh, PAU, Rpef, RH, and Temp. Small increases in minute
ventilation in all groups were often seen during IV bolus
injections which were treated as injection artifacts due to animal
arousal, and had no other apparent impact on ventilation.
[0510] Potential adverse events were monitored, and there were no
adverse behavioral effects observed following administration of
compound (XXXVI) at the doses tested. The results of these
experiments demonstrated that compound (XXXVI) reverses midazolam
induced-respiratory depression and appears to be well tolerated in
rats at the doses tested.
Example 106
Effect of Compound (XXXVI) on Hypercapnia
[0511] In one aspect, the objective of the study was to evaluate
the effects of Compound (XXXVI), administered by intravenous
infusion, on the hypercapnic ventilatory response (HCVR) in
rats.
[0512] Vehicle, 20% hydroxypropyl-beta-cyclodextran in sterile
water, was added to pre-weighed compound and mixed thoroughly,
resulting in a clear solution. A 1.5 mg/mL stock was created to
give an infusion dose of 0.10 mg/kg/min. A separate 0.45 mg/mL
stock was created to give an infusion dose of 0.03 mg/kg/min. All
compound solutions and vehicles were titrated to have a pH between
4-8, using a pH paper and titrating with NaOH or HCl solution.
[0513] Male Sprague-Dawley rats (Harlan, Inc.), 250-350 g at time
of dosing, had been surgically prepared by Harlan to contain
jugular vein cannulas. A 12 chamber plethysmography system with
temperature/humidity compensation (Epstein et al., 1980, J. Apply
Physiol. 49:1107-1115) from Buxco, Inc. (PLY 3223; Buxco, Inc,
Wilmington, N.C., USA) using Biosystem XA software, v2.11.1 and a
customized 12 site automated infusion system (Harvard Apparatus,
Instech, Inc). Gas mixer (CWE Inc.) was used for this experiment to
give concentrations of hypercapnia (3% CO.sub.2, 21% O.sub.2,
balance nitrogen). Three tanks containing 100% O.sub.2, CO.sub.2,
and nitrogen were attached to the gas mixer, with the customized
gas mixture fed to each plethysmograph at a rate of 2 L/min.
[0514] Rat whole body plethysmography was used to evaluate and
quantify minute ventilation and the pattern of breathing. A
respiratory waveform was generated from the exchange of air between
the animal and the chamber. This exchange induced changes in air
volume that were measured with a pressure transducer, constituting
the respiratory waveform (Lomask M., 2005, "Respiration measurement
in the whole body plethysmography," Buxco Inc., retrieved from
http://www dot buxco dot com/downloads/LomaskWBP dot pdf).
Atmospheric temperature and humidity were also measured using
temperature and humidity probes that sampled chamber conditions. A
compensation factor was then determined and applied to the
respiratory waveform using a standardized algorithm (Epstein et
al., 1980, J. Apply Physiol. 49:1107-1115) to compensate for
respiratory conditioning, which was reported as the parameter
COMP.
[0515] All animals were acclimated to plethysmography chambers for
at least 1 hour, or until animals were no longer restless (up to 2
hours prior to data collection). Minute ventilation (MV) was
calculated by the Biosystem XA software from direct measurements of
tidal volume (TV) and respiratory frequency (f) using the formula
MV=TV.times.f. Minute ventilation (mL/min) is a common endpoint for
evaluating ventilatory performance. The protocol included compound
(XXXVI) given as a 20 minute infusion, followed by a 20 minute
exposure to 3% hypercapnia in addition to the compound (XXXVI)
infusion. After 20 minutes of hypercapnia, the compound (XXXVI)
infusion continued for an additional 10 minutes, resulting in a
total compound (XXXVI) infusion time of 50 minutes. Each experiment
included 6 animals receiving compound (XXXVI) (0.03 or 0.10
mg/kg/min) tested against 6 animals receiving vehicle, all of which
were challenged with hypercapnia (3%). Animals were continuously
monitored and observed for adverse behavioral effects. Such
findings were recorded into laboratory notebooks for each
individual animal tested.
Statistical Analysis
[0516] Respiratory data was collected on a breath-by-breath basis
and averaged into 1 min time bins for data analysis. For each
designated acquisition phase, which is the time between doses, AUC
percent change from pre-treatment baseline values were calculated
for each cohort on multiple ventilatory parameters including,
respiratory frequency (f), tidal volume (TV), accumulated volume
(AV), minute ventilation (MV), inspiratory time (Ti), expiratory
time (Te), peak inspiratory flow (PIF), peak expiratory flow (PEF),
relaxation time (RT), end inspiratory pause (EIP), end expiratory
pause (EEP), delta volume (dV), expiratory flow at 50% TV (EF50),
rejection index (Rinx), compensation (Comp), enhanced pause (Penh),
pause (PAU), PEF rate (Rpef), relative humidity (RH), and
atmospheric temperature (Temp). Each parameter was compared to
vehicle in order to calculate percent difference, using area under
the curve (AUC) and peak response values for each defined
acquisition period using a customized visual basic restructure
analysis macro (Lopotosky, S. Galleon Buxco Restructure tool, v5.2,
2008). All of the data analysis for the single, stand-alone studies
was done using the restructure analysis macro (Lopotosky, S.
Galleon Buxco Restructure tool, v5.2, 2008). All merged data
analysis with both doses was performed in Graphpad Prism for MV,
TV, and f only, for hypercapnia studies. Additionally, percent
increase was calculated based on the cohort average immediately
prior to the hypercapnic challenge to the group's peak response.
For merged hypercapnia studies, t=62 to t=67 was used.
Results and Discussion:
[0517] Administration of compound (XXXVI) stimulated respiration in
naive animals at 0.10 mg/kg/min, with little or no effect at 0.03
mg/kg/min. Furthermore, when animals received compound (XXXVI),
exposure to hypercapnia (3% CO.sub.2) resulted in an increased MV
response in a dose dependent manner when compared to vehicle
treatment alone. Compound (XXXVI), at 0.03 or 0.1 mg/kg/min IV,
resulted in the augmentation of the hypercapnia ventilatory
response (HCVR), at the higher dose of 0.10 mg/kg/min, with no
effect at 0.03 mg/kg/min. The 0.03 mg/kg/min and vehicle groups
resulted in a 60% facilitation of the HCVR, from t=62 to t=67. The
0.10 mg/kg/min demonstrated an increase of 44% in MV during the
HCVR challenge at the same time points, in addition to an elevated
MV due to compound (XXXVI) alone. Compound (XXXVI) at 0.03
mg/kg/min against HCVR resulted in an effect on PIF only, with no
discernable change in f, TV, AV, MV, Ti, Te, PEF, RT, EIP, EEP, dv,
EF50, Rinx, Comp, penh, PAU Rpef, RH, or Temp. The 0.10 mg/kg/min
dose showed an effect on f, TV, AV, MV, Ti, Te, PIF, PEF, EIP,
EF50, Comp, and RH, with no discernable change in EEP, dV, Rinx,
Penh, PAU, Rpef, and Temp. These data suggest that compound
(XXXVI), given as an infusion, may enhance the ventilatory effects
of hypercapnia, resulting in facilitation of ventilation during
acute hypoxemia. In addition, there were no adverse clinical
observations associated with compound (XXXVI) at the doses
tested.
[0518] The disclosures of each and every patent, patent
application, and publication cited herein are hereby incorporated
herein by reference in their entirety. While this invention has
been disclosed with reference to specific embodiments, it is
apparent that other embodiments and variations of this invention
may be devised by others skilled in the art without departing from
the true spirit and scope of the invention. The appended claims are
intended to be construed to include all such embodiments and
equivalent variations.
* * * * *
References