Combination therapies employing ace inhibitors and uses thereof for the treatment of diabetic disorders
The present invention includes use of an angiotensin-converting enzyme (ACE) inhibitor in combination with a vitamin B6 related compound for the treatment of diabetes and diabetic related disorders and in particular the treatment of diabetic hypertension.
1 . A method of treating or inhibiting hypertension in a diabetic patient of comprising administering a therapeutically effective amount of an angiotensin converting enzyme (ACE) inhibitor and a vitamin B6 related compound.
2 . The method according to claim 1 , wherein the vitamin B6 related compound is selected from a group consisting of: pyridoxal, pyridoxal-5′-phosphate, pyridoxamine, a 3-acylated analogue of pyridoxal, a 3-acylated analogue of pyridoxal-4,5-aminal, a pyridoxine phosphate analogue, and a mixture thereof.
3 . The method according to claim 1 , wherein the vitamin B6 related compound is pyridoxal-5-phosphate.
4 . The method according to claim 2 , wherein the 3-acylated analogue of pyridoxal is:
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
5 . The method according to claim 2 , wherein the 3-acylated analogue of pyridoxal-4,5-aminal is
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy,alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl; and
R 2 is a secondary amino group, or a pharmaceutically accpetable acid addition salt thereof.
6 . The method according to claim 2 , wherein the pyridoxine phosphate analogue is selected from a group consisting:
(a)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R6 in which R6 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
(b)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen, alkyl, aryl, aralkyl,
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R6 in which R6 is hydrogen, alkyl, aryl or aralkyl;
n is 1 to 6; and
(c)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, CH 2 OH—, —CH 3 , —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, or alkanoyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R6 are hydrogen; or
R 5 and R6 are halo;
R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R8 is hydrogen, alkyl, aryl, or aralkyl.
7 . The method according to claim 2 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is between 1 and 1000 mg per kg body weight per day.
8 . The method according to claim 2 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is an amount selected from a group consisting of: 100 mg per kg body weight per day, 300 mg per kg body weight per day, and 1000 mg per kg body weight per day.
9 . The method according to claim 1 , wherein the ACE inhibitor is selected from a group consisting of: benazepril; captopril; cilazapril; enalapril; enalaprilat; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril; and a mixture thereof.
10 . The method according to claim 1 , wherein the ACE inhibitor is lisinopril and the therapeutically effective amount of lisinopril is between 5 and 40 mg per day.
11 . The method according to claim 10 , wherein the therapeutically effective amount of lisinopril is 20 mg per day.
12 . The method according to claim 1 , wherein the ACE inhibitor is captopril and the therapeutically effective amount of captopril is between 25 and 150 mg per day.
13 . The method according to claim 1 , wherein the ACE inhibitor is enalapril and the therapeutically effective amount of enalapril is between 5 and 40 mg per day.
14 . The method according to claim 1 , wherein the ACE inhibitor is ramipril and the therapeutically effective amount of ramipril is between 1.25 and 10 mg per day.
15 . The method according to claim 1 , wherein the ACE inhibitor is trandolapril and the therapeutically effective amount of trandolapril is between 1 and 4 mg per day.
16 . The method according claim 1 , wherein the diabetic patient is an insulin dependent diabetic patient.
17 . The method according to claim 1 , wherein the diabetic patient is a non-insulin dependent diabetic patient.
18 . A method of improving kidney function in a diabetic patient comprising administering a therapeutically effective amount of an ACE inhibitor and a vitamin B6 related compound.
19 . The method according to claim 18 , wherein the vitamin B6 related compound is selected from a group consisting: pyridoxal, pyridoxal-5′-phosphate, pyridoxamine, a 3-acylated analogue of pyridoxal, a 3-acylated analogue of pyridoxal-4,5-aminal, a pyridoxine phosphate analogue, and a mixture thereof.
20 . The method according to claim 18 , wherein the vitamin B6 related compound is pyridoxal-5-phosphate.
21 . The method according to claim 19 , wherein the 3-acylated analogue of pyridoxal is:
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
22 . The method according to claim 19 , wherein the 3-acylated analogue of pyridoxal-4,5-aminal is
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy,alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl; and
R 2 is a secondary amino group, or a pharmaceutically accpetable acid addition salt thereof.
23 . The method according to claim 19 , wherein the pyridoxine phosphate analogue is selected from a group consisting:
(a)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R6 in which R6 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
(b)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen, alkyl, aryl, aralkyl,
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R6 in which R6 is hydrogen, alkyl, aryl or aralkyl;
n is 1 to 6; and
(c)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, CH 2 OH—, —CH 3 , —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, or alkanoyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R 6 are hydrogen; or
R 5 and R6 are halo;
R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.
24 . The method according to claim 20 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is between 1 and 1000 mg per kg body weight per day.
25 . The method according to claim 20 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is an amount selected from a group consisting of: 100 mg per kg body weight per day, 300 mg per kg body weight per day, and 1000 mg per kg body weight per day.
26 . The method according to claim 18 , wherein the ACE inhibitor is selected from a group consisting of: benazepril; captopril; cilazapril; enalapril; enalaprilat; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril; and a mixture thereof.
27 . The method according to claim 18 , wherein the ACE inhibitor is lisinopril and the therapeutically effective amount of lisinopril is between 5 and 40 mg per day.
28 . The method according to claim 27 , wherein the therapeutically effective amount of lisinopril is 20 mg per day.
29 . The method according to claim 18 , wherein the ACE inhibitor is captopril and the therapeutically effective amount of captopril is between 25 and 150 mg per day.
30 . The method according to claim 18 , wherein the ACE inhibitor is enalapril and the therapeutically effective amount of enalapril is between 5 and 40 mg per day.
31 . The method according to claim 18 , wherein the ACE inhibitor is ramipril and the therapeutically effective amount of ramipril is between 1.25 and 10 mg per day.
32 . The method according to claim 18 , wherein the ACE inhibitor is trandolapril and the therapeutically effective amount of trandolapril is between 1 and 4 mg per day.
33 . The method according claim 18 , wherein the diabetic patient is an insulin dependent diabetic patient.
34 . The method according to claim 18 , wherein the diabetic patient is a non-insulin dependent diabetic patient.
35 . A method of treating or inhibiting nephropathy in a diabetic patient comprising administering a therapeutically effective amount of an ACE inhibitor and a vitamin B6 related compound.
36 . The method according to claim 35 , wherein the vitamin B6 related compound is selected from a group consisting of: pyridoxal, pyridoxal-5′-phosphate, pyridoxamine, a 3-acylated analogue of pyridoxal, a 3-acylated analogue of pyridoxal-4,5-aminal, a pyridoxine phosphate analogue, and a mixture thereof.
37 . The method according to claim 35 , wherein the vitamin B6 related compound is pyridoxal-5-phosphate.
38 . The method according to claim 36 , wherein the 3-acylated analogue of pyridoxal is:
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
39 . The method according to claim 36 , wherein the 3-acylated analogue of pyridoxal-4,5-aminal is
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy,alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl; and
R 2 is a secondary amino group, or a pharmaceutically accpetable acid addition salt thereof.
40 . The method according to claim 36 , wherein the pyridoxine phosphate analogue is selected from a group consisting:
(a)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R6 in which R6 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
(b)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, aryl; or
R 2 is CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen, alkyl, aryl, aralkyl,
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R6 in which R6 is hydrogen, alkyl, aryl or aralkyl;
n is 1 to 6; and
(c)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, CH 2 OH—, —CH 3 , —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, or alkanoyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R6 are hydrogen; or
R 5 and R6 are halo;
R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.
41 . The method according to claim 37 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is between 1 and 1000 mg per kg body weight per day.
42 . The method according to claim 37 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is an amount selected from a group consisting of: 100 mg per kg body weight per day, 300 mg per kg body weight per day, and 1000 mg per kg body weight per day.
43 . The method according to claim 35 , wherein the ACE inhibitor is selected from a group consisting of: benazepril; captopril; cilazapril; enalapril; enalaprilat; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril; and a mixture thereof.
44 . The method according to claim 35 , wherein the ACE inhibitor is lisinopril and the therapeutically effective amount of lisinopril is between 5 and 40 mg per day.
45 . The method according to claim 44 , wherein the therapeutically effective amount of lisinopril is 20 mg per day.
46 . The method according to claim 35 , wherein the ACE inhibitor is captopril and the therapeutically effective amount of captopril is between 25 and 150 mg per day.
47 . The method according to claim 35 , wherein the ACE inhibitor is enalapril and the therapeutically effective amount of enalapril is between 5 and 40 mg per day.
48 . The method according to claim 35 , wherein the ACE inhibitor is ramipril and the therapeutically effective amount of ramipril is between 1.25 and 10 mg per day.
49 . The method according to claim 35 , wherein the ACE inhibitor is trandolapril and the therapeutically effective amount of trandolapril is between 1 and 4 mg per day.
50 . The method according claim 35 , wherein the diabetic patient is an insulin dependent diabetic patient.
51 . The method according to claim 35 , wherein the diabetic patient is a non-insulin dependent diabetic patient.
52 . A method of improving metabolic function in a diabetic patient comprising administering a therapeutically effective amount of an ACE inhibitor and a vitamin B6 related compound.
53 . The method according to claim 52 , wherein the metabolic function improved is selected from a group consisting of: increased insulin sensitivity, increased glycemic control, decreased insulinemia, decreased hyperglycemia, decreased hyperlipidemia and a combination thereof.
54 . The method according to claim 52 , wherein the metabolic function improved is decreased levels of low density lipoprotein (LDL) and/or increased levels of high density lipoprotein (HDL).
55 . The method according to claim 52 , wherein the metabolic function improved is decreased levels of HbA1c.
56 . The method according to claim 52 , wherein the vitamin B6 related compound is selected from a group consisting of: pyridoxal, pyridoxal-5′-phosphate, pyridoxamine, a 3-acylated analogue of pyridoxal, a 3-acylated analogue of pyridoxal-4,5-aminal, a pyridoxine phosphate analogue, and a mixture thereof.
57 . The method according to claim 52 , wherein the vitamin B6 related compound is pyridoxal-5-phosphate.
58 . The method according to claim 56 , wherein the 3-acylated analogue of pyridoxal is:
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
59 . The method according to claim 56 , wherein the 3-acylated analogue of pyridoxal-4,5-aminal is
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy,alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl; and
R 2 is a secondary amino group, or a pharmaceutically accpetable acid addition salt thereof.
60 . The method according to claim 56 , wherein the pyridoxine phosphate analogue is selected from a group consisting:
(a)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R6 in which R6 is hydrogen, alkyl, aryl; or
R 2 is CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
(b)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen, alkyl, aryl, aralkyl,
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R6 in which R6 is hydrogen, alkyl, aryl or aralkyl;
n is 1 to 6; and
(c)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, CH 2 OH—, —CH 3 , —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, or alkanoyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R6 are hydrogen; or
R 5 and R6 are halo;
R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.
61 . The method according to claim 57 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is between 1 and 1000 mg per kg body weight per day.
62 . The method according to claim 57 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is an amount selected from a group consisting of: 100 mg per kg body weight per day, 300 mg per kg body weight per day, and 1000 mg per kg body weight per day.
63 . The method according to claim 52 , wherein the ACE inhibitor is selected from a group consisting of: benazepril; captopril; cilazapril; enalapril; enalaprilat; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril; and a mixture thereof.
64 . The method according to claim 52 , wherein the ACE inhibitor is lisinopril and the therapeutically effective amount of lisinopril is between 5 and 40 mg per day.
65 . The method according to claim 64 , wherein the therapeutically effective amount of lisinopril is 20 mg per day.
66 . The method according to claim 52 , wherein the ACE inhibitor is captopril and the therapeutically effective amount of captopril is between 25 and 150 mg per day.
67 . The method according to claim 52 , wherein the ACE inhibitor is enalapril and the therapeutically effective amount of enalapril is between 5 and 40 mg per day.
68 . The method according to claim 52 , wherein the ACE inhibitor is ramipril and the therapeutically effective amount of ramipril is between 1.25 and 10 mg per day.
69 . The method according to claim 52 , wherein the ACE inhibitor is trandolapril and the therapeutically effective amount of trandolapril is between 1 and 4 mg per day.
70 . The method according claim 52 , wherein the diabetic patient is an insulin dependent diabetic patient.
71 . The method according to claim 52 , wherein the diabetic patient is a non-insulin dependent diabetic patient.
72 . A method of improving endothelial function in a diabetic patient comprising administering a therapeutically effective amount of an ACE inhibitor and a vitamin B6 related compound.
73 . The method according to claim 72 , wherein the vitamin B6 related compound is selected from a group consisting: pyridoxal, pyridoxal-5′-phosphate, pyridoxamine, a 3-acylated analogue of pyridoxal, a 3-acylated analogue of pyridoxal-4,5-aminal, a pyridoxine phosphate analogue, and a mixture thereof.
74 . The method according to claim 72 , wherein the vitamin B6 related compound is pyridoxal-5-phosphate.
75 . The method according to claim 73 , wherein the 3-acylated analogue of pyridoxal is:
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
76 . The method according to claim 73 , wherein the 3-acylated analogue of pyridoxal-4,5-aminal is
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy,alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl; and
R 2 is a secondary amino group, or a pharmaceutically accpetable acid addition salt thereof.
77 . The method according to claim 73 , wherein the pyridoxine phosphate analogue is selected from a group consisting:
(a)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R6 in which R6 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
(b)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen, alkyl, aryl, aralkyl,
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R6 in which R6 is hydrogen, alkyl, aryl or aralkyl;
n is 1 to 6; and
(c)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, CH 2 OH—, —CH 3 , —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, or alkanoyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R6 are hydrogen; or
R 5 and R6 are halo;
R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.
78 . The method according to claim 75 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is between 1 and 1000 mg per kg body weight per day.
79 . The method according to claim 75 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is an amount selected from a group consisting of: 100 mg per kg body weight per day, 300 mg per kg body weight per day, and 1000 mg per kg body weight per day.
80 . The method according to claim 72 , wherein the ACE inhibitor is selected from a group consisting of: benazepril; captopril; cilazapril; enalapril; enalaprilat; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril; and a mixture thereof.
81 . The method according to claim 72 , wherein the ACE inhibitor is lisinopril and the therapeutically effective amount of lisinopril is between 5 and 40 mg per day.
82 . The method according to claim 81 , wherein the therapeutically effective amount of lisinopril is 20 mg per day.
83 . The method according to claim 72 , wherein the ACE inhibitor is captopril and the therapeutically effective amount of captopril is between 25 and 150 mg per day.
84 . The method according to claim 72 , wherein the ACE inhibitor is enalapril and the therapeutically effective amount of enalapril is between 5 and 40 mg per day.
85 . The method according to claim 72 , wherein the ACE inhibitor is ramipril and the therapeutically effective amount of ramipril is between 1.25 and 10 mg per day.
86 . The method according to claim 72 , wherein the ACE inhibitor is trandolapril and the therapeutically effective amount of trandolapril is between 1 and 4 mg per day.
87 . The method according claim 72 , wherein the diabetic patient is an insulin dependent diabetic patient.
88 . The method according to claim 72 , wherein the diabetic patient is a non-insulin dependent diabetic patient.
89 . A method of improving vascular function in a diabetic patient comprising administering a therapeutically effective amount of an ACE inhibitor and a vitamin B6 related compound.
90 . The method according to claim 89 , wherein the vitamin B6 related compound is selected from a group consisting: pyridoxal, pyridoxal-5′-phosphate, pyridoxamine, a 3-acylated analogue of pyridoxal, a 3-acylated analogue of pyridoxal-4,5-aminal, a pyridoxine phosphate analogue, and a mixture thereof.
91 . The method according to claim 89 , wherein the vitamin B6 related compound is pyridoxal-5-phosphate.
92 . The method according to claim 90 , wherein the 3-acylated analogue of pyridoxal is:
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
93 . The method according to claim 90 , wherein the 3-acylated analogue of pyridoxal-4,5-aminal is
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy,alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl; and
R 2 is a secondary amino group, or a pharmaceutically accpetable acid addition salt thereof.
94 . The method according to claim 90 , wherein the pyridoxine phosphate analogue is selected from a group consisting:
(a)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R6 in which R6 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
(b)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen, alkyl, aryl, aralkyl,
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R6 in which R6 is hydrogen, alkyl, aryl or aralkyl;
n is 1 to 6; and
(c)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, CH 2 OH—, —CH 3 , —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, or alkanoyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R6 are hydrogen; or
R 5 and R6 are halo;
R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.
95 . The method according to claim 91 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is between 1 and 1000 mg per kg body weight per day.
96 . The method according to claim 91 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is an amount selected from a group consisting of: 100 mg per kg body weight per day, 300 mg per kg body weight per day, and 1000 mg per kg body weight per day.
97 . The method according to claim 89 , wherein the ACE inhibitor is selected from a group consisting of: benazepril; captopril; cilazapril; enalapril; enalaprilat; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril; and a mixture thereof.
98 . The method according to claim 89 , wherein the ACE inhibitor is lisinopril and the therapeutically effective amount of lisinopril is between 5 and 40 mg per day.
99 . The method according to claim 98 , wherein the therapeutically effective amount of lisinopril is 20 mg per day.
100 . The method according to claim 89 , wherein the ACE inhibitor is captopril and the therapeutically effective amount of captopril is between 25 and 150 mg per day.
101 . The method according to claim 89 , wherein the ACE inhibitor is enalapril and the therapeutically effective amount of enalapril is between 5 and 40 mg per day.
102 . The method according to claim 89 , wherein the ACE inhibitor is ramipril and the therapeutically effective amount of ramipril is between 1.25 and 10 mg per day.
103 . The method according to claim 89 , wherein the ACE inhibitor is trandolapril and the therapeutically effective amount of trandolapril is between 1 and 4 mg per day.
104 . The method according claim 89 , wherein the diabetic patient is an insulin dependent diabetic patient.
105 . The method according to claim 89 , wherein the diabetic patient is a non-insulin dependent diabetic patient.
106 . A method of treating or inhibiting vascular disease in a diabetic patient comprising administering a therapeutically effective amount an ACE inhibitor and a vitamin B6 related compound.
107 . The method according to claim 106 , wherein the vascular disease is selected from a group consisting of: peripheral vascular disease, atherothrombosis, atherosclerosis, nephropathy and retinopathy.
108 . The method according to claim 106 , wherein the vitamin B6 related compound is selected from a group consisting of: pyridoxal, pyridoxal-5′-phosphate, pyridoxamine, a 3-acylated analogue of pyridoxal, a 3-acylated analogue of pyridoxal-4,5-aminal, a pyridoxine phosphate analogue, and a mixture thereof.
109 . The method according to claim 106 , wherein the vitamin B6 related compound is pyridoxal-5-phosphate.
110 . The method according to claim 108 , wherein the 3-acylated analogue of pyridoxal is:
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl, or a pharmaceutically acceptable acid addition salt thereof.
111 . The method according to claim 108 , wherein the 3-acylated analogue of pyridoxal-4,5-aminal is
wherein,
R 1 is alkyl,
alkenyl,
in which alkyl or alkenyl
can be interrupted by nitrogen, oxygen, or sulfur, and
can be substituted at the terminal carbon by hydroxy, alkoxy, alkanoyloxy, alkanoyloxyaryl, alkoxyalkanoyl, alkoxycarbonyl, or dialkylcarbamoyloxy;
alkoxy;
dialkylamino;
alkanoyloxy;
alkanoyloxyaryl;
alkoxyalkanoyl;
alkoxycarbonyl;
dialkylcarbamoyloxy; or
aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy
aryloxy,
arylthio, or
aralkyl; and
R 2 is a secondary amino group, or a pharmaceutically accpetable acid addition salt thereof.
112 . The method according to claim 108 , wherein the pyridoxine phosphate analogue is selected from a group consisting:
(a)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R6 in which R6 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino; or
R 3 and R 4 are halo; and
R 5 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 7 in which R 7 is hydrogen, alkyl, aryl, or aralkyl;
(b)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen, alkyl, aryl, aralkyl,
R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R6 in which R6 is hydrogen, alkyl, aryl or aralkyl;
n is 1 to 6; and
(c)
wherein,
R 1 is hydrogen or alkyl;
R 2 is —CHO—, CH 2 OH—, —CH 3 , —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl; or
R 2 is —CH 2 —O alkyl- in which alkyl is covalently bonded to the oxygen at the 3-position instead of R 1 ;
R 3 is hydrogen and R 4 is hydroxy, halo, alkoxy, or alkanoyloxy; or
R 3 and R 4 can be taken together to form ═O;
R 5 and R6 are hydrogen; or
R 5 and R6 are halo;
R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.
113 . The method according to claim 109 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is between 1 and 1000 mg per kg body weight per day.
114 . The method according to claim 109 , wherein the therapeutically effective amount of the pyridoxal-5-phosphate is an amount selected from a group consisting of: 100 mg per kg body weight per day, 300 mg per kg body weight per day, and 1000 mg per kg body weight per day.
115 . The method according to claim 106 , wherein the ACE inhibitor is selected from a group consisting of: benazepril; captopril; cilazapril; enalapril; enalaprilat; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; trandolapril; and a mixture thereof.
116 . The method according to claim 106 , wherein the ACE inhibitor is lisinopril and the therapeutically effective amount of lisinopril is between 5 and 40 mg per day.
117 . The method according to claim 116 , wherein the therapeutically effective amount of lisinopril is 20 mg per day.
118 . The method according to claim 106 , wherein the ACE inhibitor is captopril and the therapeutically effective amount of captopril is between 25 and 150 mg per day.
119 . The method according to claim 106 , wherein the ACE inhibitor is enalapril and the therapeutically effective amount of enalapril is between 5 and 40 mg per day.
120 . The method according to claim 106 , wherein the ACE inhibitor is ramipril and the therapeutically effective amount of ramipril is between 1.25 and 10 mg per day.
121 . The method according to claim 106 , wherein the ACE inhibitor is trandolapril and the therapeutically effective amount of trandolapril is between 1 and 4 mg per day.
122 . The method according claim 106 , wherein the diabetic patient is an insulin dependent diabetic patient.
123 . The method according to claim 106 , wherein the diabetic patient is a non-insulin dependent diabetic patient.