Novel compounds with high therapeutic index

Abstract

The present invention is directed to novel therapeutic compounds comprised of an amino acid bonded to a medicament or drug having a hydroxy, amino, carboxy or acylating derivative thereon. These high therapeutic index derivatives have the same utility as the drug from which they are made, and they have enhanced pharmacological and pharmaceutical properties. In fact, the novel drug derivatives of the present invention enhance at least one therapeutic quality, as defined herein. The present invention is also directed to pharmaceutical compositions containing same.

1 . A compound or the pharmaceutically acceptable salt thereof, wherein a drug having a functionality selected from the group consisting of hydroxy, amino, carboxy or acylating derivative of said carboxy group is bonded to an amino acid wherein the drug is selected from the consisting of 5-HETE, Abacavir, Acarbose, Acebutolol, Acetaminophen, Adefovir, Albuterol, Alfaprostol acid, Amlodipine, Amoxicillin, Amphotericin B, Amprenavir, Arachidonic Acid, Aspirin, Atenolol, Atorvastatin, Atropine, Atovaquone, Baclofen, Benazeprilat, Beraprost, Bexarotene, Bicalutamide, Biperiden, Bisoprolol, Bitolterol, Brinzolamide, Bupivacaine, Buprenorphine, Bupropion, Butorphanol, Candesartan, Capacitabine, Captopril, Carbidopa, Carboprost, Carnitine, Carteolol, Carvedilol, Cefdinir, Cefditoren, Ceftazimide, Cefpodoxime, Cefuroxime, Cerivastatin, Chloramphenicol, Cisapride, Clofibrate, Cloprostenol, Clorazepic Acid, Cycloserine, Cyclosporine, Cytarabine, Dextroamphetamine, Diclofenac, Didanosine, Divalproex, Efavirenz, Enalaprilat, Ephedrine, Eplerenone, Eprosartan, Esmolol, Estramustine, Ethambutol, Ethchlorvynol, Ethotoin, Etidocaine, Etoposide, Ezetimibe, Famciclovir, Fenofibrate, Fenoprofen, Fenprostalene acid, Fibric acid derivatives, Finasteride, Flavoxate, Fluprostenol, Fluoxetine, Flurbiprofen, Fluticasone, Fluvastatin, Fosinoprilat, Frovatriptan, Fulvestrant, Gemprost Acid, Goserelin, Hydroxychloroquine, Hydroxyzine, Hyoscyamine, Ibuprofen, Ibutilide, Indapamide, Indinavir, Ipratropium, Irinotecan, Isosorbide, Isradipine, Ketoprofen, Ketorolac, Labetalol, Lamivudine, Lansoprazole, Latanoprost Acid, Leukotrienes (LTA 4 , LTB 4 , LTC 4 , LTD 4  and LTE 4 ) Leuprolide, Levobunolol, Levodopa, Levorphanol, Limaprost, γ-Linolenic Acid, Liothyronine, Lisinopril, Lopinavir, Lorazepam, Lovastatin, Medroxyprogesterone, Mefloquine, Megestrol, Mephobarbital, Mepivacaine, Metaproterenol, Metformin, Methamphetamine, Methohexital, Methotrexate, Methylprednisolone, Metolazone, Metoprolol, Mexiletine, Miglitol, Moexiprilat, Mometasone, Montelukast, Mycophenolate Acid, Nadolol, Nalbuphine, Naproxen, Naratriptan, Nateglinide, Nelfinavir, Niacin, Nicotinic Acid, Nicotinamide, Nicardipine, Nimidipine, Nisoldipine, Norgestimate, Octreotide, Ofloxacin, Olmesartan, Omeprazole, Ozagrel, Paclitaxel, Pantothenic Acid, Paroxetine, Penbutolol, Penciclovir, Pentazocine, Pentobarbital, Perindoprilat, Phenylephrine, Phenylpropanolamine, Pindolol, Pioglitazone, Pirbuterol, Pramipexole, Pravastatin, Propafenone, Propofol, Propoxyphene, Propranolol, Prostacyclin, Prostaglandins (E 1 , E 2  and F 2α ), Prostanoic Acid, Pseudoephedrine, Quinacrine, Quinaprilat, Quinethazone, Quinidine, Quinine, Ramiprilat, Reboxetine, Repaglinide, Ribavirin, Ritonavir, Ropivacaine, Rosaprostol, Rosuvastatin, Salmeterol, Salsalate, Sertraline, Simavastatin, Sotalol, Sulfa Drugs, Sulfasalazine, Sumitriptan, Tacrolimus, Tazorotene, Telmesartan, Tenofovir, Terbutaline, Tiagabine, Timolol, Tirofiban, Tocainide, Tramadol, Trandolaprilat, Tranylcypromine, Treprostinil, Triamcinolone, Trimoprostil, Troglitazone, Unoprostone, Valproic Acid, Valsartan, Venlafaxine, Vidarabine, Warfarin, Zalcitabine, Zidovudine, Zileuton and Zolmitriptan or a pharmaceutically acceptable salt of any of said drug and wherein the amino acid is L-Hyp, L-Ser, L-Tyr, L-Lys, L-Leu, L-Ile, Gly, L-Asp, L-Glu, L-Met, L-Ala, L-Val, L-Pro, L-His, L-Nor, L-Arg, L-Phe, L-Trp, L-Car, L-Ort, GABA, L-Cys, or Thr. 
     
     
         2 . The compound according to  claim 1  wherein the drug is Acarbose, Glimepiride, Metformin, Miglitol, Nateglinide, Pioglitazone, Repaglinide, or Troglitazone. 
     
     
         3 . The compound according to  claim 1  wherein the drug is Adefovir, Amoxicillin, AmphotericinB, Amprenavir, Abacavir, Ethambutol, Atovaquone, Cefdinir, Cefditoren, Ceftazimide, Cefpodoxime, Cefuroxime, Chloramphenicol, Quinine, Tenofovir, Vidarabine, Zalcitabine, Zidovudine, Mefloquine, Quinidine, Didanosine, Efavirenz, Famciclovir, Sulfa Drugs, Ribavirin, Ritonavir, Indinavir, Lamivudine, Lopinavir, Nelfinavir, Cycloserine, Ofloxacin or Penciclovir. 
     
     
         4 . The compound according to  claim 1  wherein the drug is Amlodipine, Acebutolol, Atenolol, Benazeprilat, Beraprost, Candesartan, Captopril, Bisoprolol, Carvedilol, Enalaprilat, Ephedrine, Eplerenone, Eprosartan, Esmolol, Fibric acid derivatives, Fosinoprilat, Isradipine, Metolazone, Labetalol, Metoprolol, Moexiprilat, Isosorbide, Mexiletine, Nadolol, Fenofibrate, Indapamide, Lisinopril, Nicardipine, Nisoldipine, Olmesartan, Penbutolol, Perindoprilat, Pindolol, Sotalol, Propafenone, Propranolol, Prostacyclin, Prostaglandins (EI, E2 and F 2α ), Prostanoic Acid, Quinaprilat, Quinethazone, Ramiprilat, Telmisartan, Phenylephrine, Tirofiban, Tocainide, Trandolaprilat, Valsartan, or Ibutilide. 
     
     
         5 . The compound according to  claim 1  wherein the drug is Rosuvastatin, Simavastatin, Fluvastatin, Cerivastatin, Pravastatin, Ezetimibe, Nicotinic Acid, Niacin, Clofibrate, Lovastatin or Atorvastatin. 
     
     
         6 . The compound according to  claim 1  wherein the drug is Aspirin, Butorphanol, Acetaminophen, Diclofenac, Fenoprofen, Flurbiprofen, Frovatriptan, Ibuprofen, Ketoprofen, Ketorolac, Levorphanol, Methylprednisolone, Nalbuphine, Naproxen, Naratriptan, Nicotinamide, Pentazocine, Propoxyphene, Salsalate, Sumitriptan, Tramadol or Zolmitriptan. 
     
     
         7 . The compound according to  claim 1  wherein the drug is Finasteride, 5-HETE, Bicalutamide, Cytarabine, Estramustine, Capecitabine, Estramustine, Goserelin, Fulvestrant, Etoposide, Leuprolide, Alfaprostol acid, Megestrol, Methotrexate or Paclitaxel. 
     
     
         8 . The compound according to  claim 1  wherein the drug is Biperiden, Carbidopa, Levodopa, Pramipexole, or Atropine. 
     
     
         9 . The compound according to  claim 1  wherein the drug is Baclofen, Limaprost, Fluprostenol, Brinzolamide, Carteolol, Latanoprost Acid, Gemprost Acid, Levobunolol, Timolol or Unoprostone. 
     
     
         10 . The compound according to  claim 1  wherein the drug is Clorazepic Acid, Buprenorphine, Bupropion, Fluoxetine, Lorazepam, Pantothenic Acid, Paroxetine, Sertraline, Venlafaxine, Phenylpropanolamine, Valproic Acid, Reboxetine or Tranylcypromine. 
     
     
         11 . The compound according to  claim 1  wherein the drug is Ethotoin, Mephobarbital, Pentobarbital or Tiagabine. 
     
     
         12 . The compound according to  claim 1  wherein the drug is Bitolterol, Albuterol, Hydroxyzine, Fexofenadine, Fluticasone, Ipratropium, Ozagrel, Leukotrienes (LTA 4 , LTB 4 , LTC 4 , LTD 4  and LTE 4 ), Metaproterenol, Montelukast, Mometasone, Pirbuterol, Pseudoephedrine, Salmeterol, Terbutaline, Treprostinil or Zileuton. 
     
     
         13 . The compound according to  claim 1  wherein the drug is Flavoxate, Hyoscyamine, Lansoprazol, Cisapride, Omeprazole, Octreotide, Rosaprostol, Trimoprostil or Irinitecan. 
     
     
         14 . The compound according to  claim 1  wherein the drug is Hydroxychloroquine, Sulfasalazine or Quinacrine. 
     
     
         15 . The compound according to  claim 1  wherein the drug is Norgestimate or Medroxyprogesterone. 
     
     
         16 . The compound according to  claim 1  wherein the drug is Etidocaine, Ethchlorvynol, Mepivacaine, Methohexital, Propofol, Ropivacaine, or Bupivacaine. 
     
     
         17 . The compound according to  claim 1  wherein the drug is Methamphetamine, Dextroamphetamine or Pemoline. 
     
     
         18 . The compound according to  claim 1  wherein the drug is Mycophenolate Acid or Cyclosporine. 
     
     
         19 . The compound according to  claim 1  wherein the drug is Bexarotene, Tacrolimus, Tazorotene or Triamcinolone. 
     
     
         20 . The compound according to  claim 1  wherein the drug is Nimodipine, Carboprost, Carnitine or Warfarin. 
     
     
         21 . The compound according to  claim 1  wherein the drug is Arachidonic Acid, Linolenic Acid or Liothyronine. 
     
     
         22 . The compound according to  claim 1  wherein the drug is Fenprostalene acid, or Cloprostenol. 
     
     
         23 . The compound according to  claim 1  wherein the drug is Atorvastatin, Aspirin, Amlodipine Albuterol, Valsartan, Albuterol, Ipratropium, Olmesartan, Abacavir, Lamivudin, Adefovir, Buprenorphine, Benazeprilat, Bupriopion, Clopidogrel, Candesartan, Cefuroxime, Cerivastatin, Clofibrate, Ciprofloxacine, dexamethorphan, Carvedilol, Cyclosporine, Capacitabine, Divalproex, Dextroamphitamine, Diclofenac, Enalaprilat, Eprosartan, Efafirenz, Tenofovir, Ezitimible, Simvastatin, Tenovofir, Famciclovir, Fenofibrate, Fluvastaatin, Fosinoprilat, Fulvestrant, Fluticasone Salmenterol, Fenofibrate, Fluticasone, Fenofibrate, Finasteride, Flucasone+Salmet, Fluticason, Goserelin, Hydroxychloroquine, Ibuprofen, Irinotecan, Ketoprofen, Ketorolac, Labetalol, Lansoprazole, Latanoprost Acid, Lorazepam, Lovastatin, Lopinavir, Ritonavir, Lanzoprazol, MedroxyProgesterone, Mometazone, Metformin, Montelukast, Methylphenidate, Metalazone, Methylphenidate, Mycophenolate, Naproxen, Naratriptan, Nelfinavir, Nicotinamide, Niacin, Olmesartan, Pravastatin, Propofol, Pioglitazone, Repaglinide, Rosuvastatin, Ritonavir, Salmeterol, Simavastatin, Sumitriptan, Sulfa Drugs, Trandolaprilat, Tacrolimus, Telmesartan, Tenofovir, Triamcinolone, Valsartan, Venlafaxine, Valproic Acid, Warfarin, Zolmitriptan, or Zidovudin. 
     
     
         24 . The compound according to  claim 1  or  23  wherein the amino acid is GABA. 
     
     
         25 . The compound according to  claim 1  or  23  wherein the amino acid is L-Ort. 
     
     
         26 . The compound according to  claim 1  or  23  wherein the amino acid is L-Car. 
     
     
         27 . The compound according to  claim 1  or  23  wherein the amino acid is L-Trp. 
     
     
         28 . The compound according to  claim 1  or  23  wherein the amino acid is L-Phe. 
     
     
         29 . The compound according to  claim 1  or  23  wherein the amino acid is L-Arg. 
     
     
         30 . The compound according to  claim 1  or  23  wherein the amino acid is L-His. 
     
     
         31 . The compound according to  claim 1  or  23  wherein the amino acid is L-Pro. 
     
     
         32 . The compound according to  claim 1  or  23  wherein the amino acid is L-Pro. 
     
     
         33 . The compound according to  claim 1  or  23  wherein the amino acid is L-Val. 
     
     
         34 . The compound according to  claim 1  or  23  wherein the amino acid is L-Ala. 
     
     
         35 . The compound according to  claim 1  or  23  wherein the amino acid is L-Met. 
     
     
         36 . The compound according to  claim 1  or  23  wherein the amino acid is L-Glu. 
     
     
         37 . The compound according to  claim 1  or  23  wherein the amino acid is L-Asp. 
     
     
         38 . The compound according to  claim 1  or  23  wherein the amino acid is Gly. 
     
     
         39 . The compound according to  claim 1  or  23  wherein the amino acid is L-Ile. 
     
     
         40 . The compound according to  claim 1  or  23  wherein the amino acid is L-Leu. 
     
     
         41 . The compound according to  claim 1  or  23  wherein the amino acid is L-Lys. 
     
     
         42 . The compound according to  claim 1  or  23  wherein the amino acid is L-Tyr. 
     
     
         43 . The compound according to  claim 1  or  23  wherein the amino acid is L-Ser. 
     
     
         44 . The compound according to  claim 1  or  23  wherein the amino acid is L-Hyp. 
     
     
         45 . The compound according to  claim 1  or  23  wherein the amino acid is L-Thr. 
     
     
         46 . A compound of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof; 
         wherein CYCLO represents the residues at positions 2-11 of a cyclosporin molecule x-y is CH═CH or CH 2 CH 2  and R 2  is OAA or OGly-AA, AA is an amino acid residue without the OH groups of the carboxy group and where Gly is a glycyl residue. 
       
     
     
         47 . The compound according to  claim 46  wherein AA is naturally occurring α L-amino acid. 
     
     
         48 . The compound according to  claim 46  wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy. 
     
     
         49 . The compound according to  claim 46  wherein AA is proline, glycine, lysine or ornithine. 
     
     
         50 . The compound according to  claim 46  wherein AA is Lys or ornithine. 
     
     
         51 . The compound according to  claim 46  wherein the compound has the formula 
       
         
           
           
               
               
           
         
       
     
     
         52 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 46  and a pharmaceutically acceptable carrier therefor. 
     
     
         53 . A method of treating a patient in need of cyclosporin therapy, which method comprising administering to said patient a therapeutically effective amount of the compound according to  claim 46 . 
     
     
         54 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  or  23  and a pharmaceutically acceptable carrier therefor.