Vitamin B6 Related Compounds and Methods for Recovery From Trauma

1 . A method of improving or promoting patient recovery from trauma comprising administering a therapeutically effective amount of a vitamin B6 related compound.

2 . The method according to claim 1 , wherein the trauma is caused by an adverse physiological event selected from the group consisting of: myocardial infarction, myocardial ischemia, ischemic stroke, hemorrhagic stroke, major cardiac trauma, hypertension, arteriosclerosis, aneurysm, and congestive heart failure.

3 . The method according to claim 1 , wherein the trauma is caused by a traumatic contact to the patient, said traumatic contact selected from the group consisting of:

abrasion, incision, contusion, puncture, compression, chemical burn, radiation burn, heat burn, and cold burn.

4 . The method according to claim 1 wherein the trauma is surgical trauma resulting from the patient undergoing a surgical procedure.

5 . The method according to claim 4 , wherein the surgical procedure is selected from the group consisting of: coronary bypass surgery, biopsy, heart valve replacement, atheroectomy, thrombectomy, transcatheter vascular therapy, angioplasty, vascular grafting, placement of a mechanical shunt, placement of an intravascular stent, and organ transplantation.

6 . The method according to claim 1 , wherein the vitamin B6 related compound is selected from the group consisting of pyridoxine, 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.

7 . The method according to claim 1 , wherein the vitamin B6 related compound is pyridoxal-5′-phosphate.

8 . The method according to claim 6 , 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;

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.

9 . The method according to claim 6 , 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;

aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy

aryloxy;

arylthi; or

aralkyl; and

R 7 is of the formula

wherein R 3 and R 4 are each independently alkyl, alkenyl, cycloalkyl, aryl, or, when R 3 and R 4 are taken together to form a ring with the nitrogen atom, which may optionally be interrupted by a heteroatom; or

a pharmaceutically acceptable acid addition salt thereof.

10 . The method according to claim 6 , wherein the pyridoxine phosphate analogue is selected from a group consisting of:

wherein,

R 1 is hydrogen or alkyl;

R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R 6 in which R 6 is hydrogen, alkyl, or 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;

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, or 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, or aralkyl,

R 4 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 6 in which R 6 is hydrogen, alkyl, aryl or aralkyl; and

n is 1 to 6; and

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, or 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 R 6 are halo;

R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.

11 . The method according to claim 4 , wherein the vitamin B6 related compound is administered prior to the patient undergoing the surgical procedure.

12 . The method according to claim 11 , wherein the vitamin B6 related compound is administered at least 4 hours prior to the patient undergoing the surgical procedure.

13 . The method according to claim 11 , further comprising administering a therapeutically effective amount of the vitamin B6 related compound following the surgical procedure.

14 . The method according to claim 1 , wherein the vitamin B6 related compound is administered after the trauma takes place.

15 . The method according to claim 1 , wherein the therapeutically effective amount of vitamin B6 related compound is between 1 and 1000 mg per day.

16 . The method according to claim 7 , wherein the therapeutically effective amount of pyridoxal-5′-phosphate is between 5 and 50 mg/kg patient weight per day.

17 . The method according to claim 16 , wherein the therapeutically effective amount of pyridoxal-5′-phosphate is 10 mg/kg patient weight per day.

18 . The method according to claim 4 , further comprising administering a platelet aggregation inhibitor selected from the group consisting of: a thromboxane A2 inhibitors, a glycoprotein IIb/IIIa inhibitor, an adenosine phosphate inhibitor, a fibrinogen-platelet binding inhibitor, and a platelet c-AMP phosphodiesterase inhibitor.

19 . The method according to claim 18 wherein the administration of platelet aggregation inhibitor is at a lower dosage than a standard dose that would be given in the absence of vitamin B6 related compound administration.

20 . A method of improving the success rate of surgical procedures comprising administering a therapeutically effective amount of a vitamin B6 related compound.

21 . The method according to claim 20 wherein the surgical procedure is selected from the group consisting of coronary bypass surgery, biopsy, heart valve replacement, atheroectomy, thrombectomy, trans catheter vascular therapy, angioplasty, vascular grafting, placement of a mechanical shunt, placement of an intravascular stent, and organ transplantation.

22 . The method according to claim 21 , wherein the organ transplantation is selected from the group consisting of a kidney transplant, a heart transplant, and a liver transplant.

23 . The method according to claim 20 , wherein the vitamin B6 related compound is selected from the group consisting of pyridoxine, 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.

24 . The method according to claim 20 , wherein the vitamin B6 related compound is pyridoxal 5 phosphate pyridoxal-5′-phosphate.

25 . The method according to claim 23 , 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;

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.

26 . The method according to claim 23 , 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;

aryl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy

aryloxy;

arylthi; or

aralkyl; and

R 2 is of the formula

wherein R 3 , and R 4 are each independently alkyl, alkenyl, cycloalkyl, aryl, or, when R 3 and R 4 are taken together to form a ring with the nitrogen atom, which may optionally be interrupted by a heteroatom; or

a pharmaceutically acceptable acid addition salt thereof.

27 . The method according to claim 23 , wherein the pyridoxine phosphate analogue is selected from the group consisting of:

wherein,

R 1 is hydrogen or alkyl;

R 2 is —CHO—, —CH 2 OH, —CH 3 , —CO 2 R 6 in which R 6 is hydrogen, alkyl, or 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;

wherein,

R 1 is hydrogen or alkyl;

R 2 is 13 CHO, —CH 2 OH, —CH 3 , —CO 2 R 5 in which R 5 is hydrogen, alkyl, or 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 R 6 in which R 6 is hydrogen, alkyl, aryl or aralkyl; and

n is 1 to 6; and

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 R 6 are halo; and

R 7 is hydrogen, alkyl, aryl, aralkyl, or —CO 2 R 8 in which R 8 is hydrogen, alkyl, aryl, or aralkyl.

28 . The method according to claim 20 , wherein the vitamin B6 related compound is administered prior to the patient undergoing the surgical procedure.

29 . The method according to claim 28 , wherein the vitamin B6 related compound is administered at least 4 hours prior to the patient undergoing the surgical procedure.

30 . The method according to claim 28 , wherein the step of administering a therapeutically effective amount of the vitamin B6 related compound following the surgical procedure.

31 . The method according to claim 20 , wherein the vitamin B6 related compound is administered after the trauma takes place.

32 . The method according to claim 20 , wherein the therapeutically effective amount of vitamin B6 related compound is between 1 and 1000 mg per day.

33 . The method according to claim 24 , wherein the therapeutically effective amount of pyridoxal 5′-phosphate is between 5 and 50 mg/kg patient weight per day.

34 . The method according to claim 33 , wherein the therapeutically effective amount of pyridoxal-5′-phosphate is 10 mg/kg patient weight per day.

35 . The method according to claim 20 , further comprising administering a platelet aggregation inhibitor selected from the group consisting of: a thromboxane A2 inhibitors, a glycoprotein IIb/IIIa inhibitor, an adenosine phosphate inhibitor, a fibrinogen-platelet binding inhibitor, and a platelet c-AMP phosphodiesterase inhibitor.

36 . The method according to claim 35 wherein the administration of platelet aggreghan inhibitor is at a lower dosage than a standard dose that would be given in the absence of vitamin B6 related compound administration.