Use of amine carboxyboranes as therapeutic delivery of carbon monoxide and as general drug delivery system in the presence of reactive oxygen species

Patent metadata

Field	Value
Publication number	US-10676490-B2
Application number	US-201615742463-A
Country	US
Kind code	B2
Filing date	Jul 7, 2016
Priority date	Jul 7, 2015
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

Disclosed is a method of delivering therapeutic carbon monoxide to the cells and tissues of a patient which comprises administering thereto a compound of the formula XBY1Y2C(O)V (I) or pharmaceutically acceptable salts thereof. In addition, disclosed is a method of delivering a drug to a diseased cell or tissue by administering a compound of formula I either wherein at least one of X is a drug containing an amino group or V is a drug containing an amino group or hydroxyl group less a hydrogen on the amino or hydroxyl group. Further disclosed are novel compounds of Formula I.

First claim

What is claimed is:

1. A compound of the formula
XBY1Y2C(O)V  I

or pharmaceutically acceptable salts,
where
each of Y1 and Y2 is H;
V is O − , OR1 or NR1R2 or is a first drug, which drug has an amino function or an alcohol moiety thereon in which a hydrogen atom of the alcohol or amine is not present;
R1 and R2 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl or Ar—N(R3)C(O)R4 or is a first drug, which drug has an amino function or an alcohol moiety thereon in which a hydrogen atom of the alcohol or amine is not present;
Ar is aryl;
each R3 and R4 are independently hydrogen or lower alkyl;
X is a second drug selected from Hexamethylenetetramine, Memantine, Amantadine, Aripiprazole, Rosuvastatin, Pregabalin, Scopolamine, Sitagliptin, Glatiramer acetate, Abacavir, Abiraterone, Amlodipine, Amphetamine, Anastrozole, Atazanavir, Atomoxetine, Azacitidine, Bendamustine, Bortezomib, Buprenorphine, Celecoxib, Cinacalcet, Ciprofloxacin, Clopidogrel, Dabigatran, Dacarbazine, Darunavir, Dasatinib, Desvenlafaxine, Dexlansoprazole, Dexmethylphenidate, Dipyridamole, Duloxetine, Emtricitabine, Epinephrine, Erlotinib, Escitalopram, Esomeprazole, Eszopiclone, Fentanyl, Fingolimod, Formoterol, Guanfacine, Hydrocodone, Imatinib, Imiquimod, Lamivudine, Lenalidomide, Levothryoxine, Lidocaine, Linezolid, Lisdexamfetamine, Mesalazine, Metformin, Methylphenidate, Metoprolol, Minocycline, Naloxone, Nebivolol, Niacin, Nilotinib, Octreotide Acetate, Olanzapine, Olmesartan, Oseltamivir, Oxycodone, Oxymorphone, Paliperidone, Palonosetron, Pemetrexed, Pioglitazone, Piperacillin, Prasugrel, Quetiapine, Rabeprazole, Raloxifene, Raltegravir, Ranolazine, Regadenoson, Rifaximin, Rilpivirine, Risedronic Acid, Risperidone, Ritonavir, Rivastigmine, Rizatriptan, Salbutamol, Salmeterol, Saxagliptin, Sevelamer, Sildenafil, Solifenacin, Sunitinib, Tazobactam, Telaprevir, Temozolomide, Tenofovir, ThioTEPA, Tolterodine, Valganciclovir, Valsartan, Varenicline, Vismodegib, Ziprasidone, or Zoledronic Acid, or a pharmaceutically acceptable salt thereof;
wherein R1, R2, R3, and R4 groups being independently unsubstituted or substituted with lower alkyl, halo, lower alkoxy, heterocyclic, cycloalkyl, nitro, carboxy, carbalkoxy, C(O)NR8R9, C(O)R8, or OC(O)R8, where R8 and R9 are independently hydrogen or lower alkyl.

2. The compound according to claim 1 , wherein V is O − , OH or is a first drug, which drug has an amino function or an alcohol moiety thereon in which a hydrogen atom of the alcohol or amine function of said drug is not present or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein V is a drug containing a hydroxy group, or an amino group less a hydrogen atom on the hydroxy group or amino group or pharmaceutically acceptable salt of said drug.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier therefor.

5. The compound according to claim 1 , wherein V is a first drug, which drug has an amino function or an alcohol moiety thereon in which a hydrogen atom of the alcohol or amine function of said drug is not present or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein the second drug is Hexamethylenetetramine.

7. The compound according to claim 1 , wherein the first drug is Acetaminophen, Rosuvastatin, Scopolamine, Glatiramer acetate, Abacavir, Abiraterone, Atorvastatin, Azacitidine, Beclomethasone Dipropionate, Bimatoprost, Budesonide, Buprenorphine, Darunavir, Dasatinib, Desvenlafaxine, Dipyridamole, Emtricitabine, Enoxaparin, Epinephrine, Ethinyl Estradiol, Etonogestrel, Everolimus, Ezetimibe, Fingolimod, Formoterol, Lamivudine, Levothyroxine, Mesalazine, Metoprolol, Minocycline, Naloxone, Nebivolol, Norgestimate, Octreotide Acetate, Olmesartan, Oxycodone, Oxymorphone, Paliperidone, Quetiapine, Raloxifine, Ranolazine, Regadenoson, Rifaximin, Salbutamol, Salmeterol, Saxagliptin, Sevelamer, Solifenacin, Tacrolimus, Testosterone, Tolterodine, Travoprost, Benzocaine, Pregabalin, Sitagliptin, Amlodipine, Amphetamine, Atomoxetine, Cinacalcet, Erlotinib, Guanfacine, Imiquimod, Lisdexamfetamine, Metformin, Methylphenidate, Oseltamivir, Pemetrexed, Valganciclovir, or Varenicline, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein V is Acetaminophen.

9. The compound according to claim 1 , wherein the compound is selected from:

10. The compound according to claim 1 , wherein the compound is:

11. A compound of the formula
XBY1Y2C(O)V  I

or pharmaceutically acceptable salts,
where
each of Y1 and Y2 is H;
V is a first drug, which drug has an amino function or an alcohol moiety thereon in which a hydrogen atom of the alcohol or amine is not present, wherein the first drug is Acetaminophen;
R1 and R2 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl or Ar—N(R3)C(O)R4 or is a first drug, which drug has an amino function or an alcohol moiety thereon in which a hydrogen atom of the alcohol or amine is not present;
Ar is aryl;
each R3 and R4 are independently hydrogen or lower alkyl;
X is a second drug, which drug contains an amino group or X is a nitrogen containing vitamin, an amino acid, a nucleotide, or X is N(R5)(R6)(R7) or a nitrogen containing heterocyclic ring containing 1, 2, 3 or 4 nitrogen atoms, wherein one nitrogen atom is bonded directly to the boron atom, said nitrogen atom being bonded directly to the boron atom being tetravalent;
R5, R6 and R7 are independently hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, aryl, aryl lower alkyl or heterocyclic or heterocyclic lower alkyl; wherein, aryl, heterocyclic, cycloalkyl, R1, R2, R3, R4, R5, R6, R7, R8, and R9 groups being independently unsubstituted or substituted with lower alkyl, halo, lower alkoxy, heterocyclic, cycloalkyl, nitro, carboxy, carbalkoxy, C(O)NR8R9, C(O)R8, or OC(O)R8, where R8 and R9 are independently hydrogen or lower alkyl,
provided that X is not ammonia, NH(CH 3 ) 2 , N(CH 3 ) 3 , or nicotine, and
further provided that either X is a drug or V is a drug having an amino or hydroxy group less a hydrogen atom on the amino or hydroxy group.

12. The compound according to claim 11 , wherein X is a second drug.

13. A compound of the formula
XBY1Y2C(O)V  I

or pharmaceutically acceptable salts,
where
each of Y1 and Y2 is H;
V is O − , OR1 or NR1R2 or is a first drug, which drug is Acetaminophen, Rosuvastatin, Scopolamine, Glatiramer acetate, Abacavir, Abiraterone, Atorvastatin, Azacitidine, Beclomethasone Dipropionate, Bimatoprost, Budesonide, Buprenorphine, Darunavir, Dasatinib, Desvenlafaxine, Dipyridamole, Emtricitabine, Enoxaparin, Epinephrine, Ethinyl Estradiol, Etonogestrel, Everolimus, Ezetimibe, Fingolimod, Formoterol, Lamivudine, Levothyroxine, Mesalazine, Metoprolol, Minocycline, Naloxone, Nebivolol, Norgestimate, Octreotide Acetate, Olmesartan, Oxycodone, Oxymorphone, Paliperidone, Quetiapine, Raloxifine, Ranolazine, Regadenoson, Rifaximin, Salbutamol, Salmeterol, Saxagliptin, Sevelamer, Solifenacin, Tacrolimus, Testosterone, Tolterodine, Travoprost, Benzocaine, Pregabalin, Sitagliptin, Amlodipine, Amphetamine, Atomoxetine, Cinacalcet, Erlotinib, Guanfacine, Imiquimod, Lisdexamfetamine, Metformin, Methylphenidate, Oseltamivir, Pemetrexed, Valganciclovir, or Varenicl

Assignees

• Univ Of Alaska Anchorage
• Univ New York State Res Found
• Florida Southwestern State College

Inventors

• Dingra Nin N
• Ayudhya Theppawut Israsena Na

Classifications

• C07F5/027 Primary

  Organoboranes and organoborohydrides · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/69 Primary

  Boron compounds · CPC title