NOVEL HIGH PENETRATION DRUGS AND THEIR COMPOSITIONS THEREOF FOR TREATMENT OF PARKINSON DISEASES

• US 20160002157A1
• Filed: 09/15/2015
• Published: 01/07/2016
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Techfields Pharma Co ltd
• Original Assignee: Suzhou Techfields Medical Limited
• Inventors: YU, Chongxi, XU, Lina
• Granted Patent: US 9,718,766 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 217/60 linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 219/06 having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 219/10 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
• CPC Class Codes: C07C 219/14 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 219/28 having amino groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 219/32 having amino groups bound to carbon atoms of six-membered aromatic rings and esterified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• CPC Class Codes: C07C 229/12 to carbon atoms of acyclic carbon skeletons
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 229/58 having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
• CPC Class Codes: C07C 237/06 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 237/08 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 237/20 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 2602/08 : the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 271/16 : to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/22 : to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 327/30 : having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07C 327/36 : Esters of dithiocarboxylic acids
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/62 : attached in position 4
• CPC Class Codes: C07D 321/12 : Eight-membered rings
• CPC Class Codes: C07D 455/02 : containing not further condensed quinolizine ring systems
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07K 5/0806 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0823 : and Pro-amino acid; Derivatives thereof

Abstract

One aspect of the invention provides a composition of novel high penetration compositions (HPC) or a high penetration prodrug (HPP) for treatment of Parkinson'"'"'s disease. The HPCs/HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPCs/HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

Claims

1. A compound comprising a structure selected from the group consisting of Structure Pro-L-Dopa-1, Structure Pro-L-Dopa-2, Structure Pro-L-Dopa-3, Structure Pro-L-Dopa-4, Structure Pro-L-Dopa-5, Structure Pro-dopamine-1, Structure Pro-dopamine-2, Structure Pro-dopamine-3, Structure Pro-dopamine-4, and Structure Pro-dopamine-5:

2. A pharmaceutical composition comprising a high penetration prodrug according to claim 1;

a compound comprising a structure selected from the group consisting of Structure NSAID-1, Structure NSAID-2, Structure NSAID-3, Structure NSAID-4, Structure NSAID-5, Structure NSAID-6, Structure NSAID-7, Structure NSAID-8, Structure NSAID-9, Structure NSAID-10, Structure NSAID-11, Structure NSAID-12, and Structure NSAID-13;

an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa;

a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone; and

a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, the pharmaceutically acceptable carrier being selected from the group consisting of alcohol, acetone, ester, cellulose, mannitol, croscarmellose sodium, vegetable oil, hydroxypropyl methylcellulose, water, and aqueous solution.

4. A pharmaceutical composition comprising one or more high penetration pro-drugs of levodopa and/or dopamine according to claim 1, and one or more high penetration prodrugs of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and any combinations thereof.

5. The pharmaceutical composition according to claim 2 comprising 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylene dibenzoate hydrochloride, 4-(2-(2-(methylamino)acetamido)ethyl)-1,2,-phenylene dibenzoate acetic acid, 4-(6-methyl-4,8-dioxo-5,7-dioxa-2,9-diazadecan-11-yl)-1,2,-phenylene dibenzoate hydrobromide, 4-(2-(2-amino-3-phenylpropanamido)ethyl)-1,2,-phenylene dibenzoate hydrochloride, 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylene dibenzoate hydrochloride, 4-(2-piperidine-4-carboxamido)ethyl)-1,2,-phenylene bis(2-ethylbutanoate) hydrochloride, 4-(2-((((-octahydro-1H-quinolizin-3-yl)oxy)carbonyl)amino)ethyl)-1,2,-phenylene bis(2-ethylbutanoate)acetate, 1-(((2-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride, 1-(((2-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)ethyl)carbamoyl)oxy)ethyl isobutyrate hydrofluoride, (-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenyl benzoate hydrochloride, 5-(2-((ethoxycarbonyl)amino)ethyl)-2-(2-methylamino)acetoxy)phenyl benzoate hydrochloride, 4-(2-aminoethyl)-1,2-phenylene dibenzoate hydrochloride, (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride, (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride, (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dipentanoate hydrochloride, (S)-4-(2-amino-3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate hydrochloride, (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylene bis(2-methylpropanoate) hydrobromide, (S)-4-(2-aminoacetamido)-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate hydrochloride, 4-((2S)-3-oxo-3-(pentan-3-yloxy)-2-(pyrrolidine-2-carboxamido)propyl)-1,2-phenylene dibenzoate hydrofluoride, (S)-4-(3-isopropoxy-3-oxo-2-(piperidine-4-carboxamido)propyl)-1,2-phenylene dibenzoate hydrochloride, 4-((2S)-3-isopropoxy-3-2-(octahydro-1H-quiolizine-2-carboxamido)-3-oxopropyl)-1,2-phenylene bis(2-methylpropanoate) hydrochloride, (2S)-isopropyl 3-(3-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide, (2S)-isopropyl 3-(4-amino-2,5-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)propanoate hydrobromide, 5-((2S)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenyl benzoate hydrochloride, 4-((2S)-2-(((1-(isobutyryloxy)ethoxy)carbonyl)amino-3-isopropoxy-3-oxopropyl)-2-(2-(methylamino)acetoxy)phenyl benzoate hydrochloride, 4-((2S)-3-isopropoxy-2-((((octahydroindolizin-1-yl)oxy)carbonyl)amino)-3-oxopropyl)-1,2-phenylene dibenzoate acetate, 2-(diethylamino)ethyl 2-[(2,6-dichloro-3-methylphenyl)amino]benzoate.acetate, (Z)-2-(diethylaminoethyl)ethyl 2-(5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylidene)-1H-inden-1-yl)acetate.AcOH, 2-(dimethylamino)ethyl 2-(3-phenoxyphenyl) propionate.hydrochloride, S-(2-(dimethylamino)ethyl 2-(3-phenoxyphenyl) propanethioate hydrochloride, 2-(dipropylamino)ethyl 4-acetoxy-2′

,4′

-difluoro-[1,1′

-biphenyl]-3-carboxylate hydrochloride, 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate hydrochloride, and/or 2-(diethylamino)ethyl 2-acetoxybenzoate. hydrochloride.

6. The pharmaceutical composition according to claim 2 comprising (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate and 2-(diethylamino)ethyl 2-acetoxybenzoate.

7. The pharmaceutical composition according to claim 2 comprising (S)-4-(2-amino-3-isopropoxy-3-oxopropyl)-1,2-phenylene dibenzoate, 2-(diethylamino)ethyl 2-acetoxybenzoate, carbidopa and/or entacapone.

8. The pharmaceutical composition according to claim 2 comprising (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylene bis(2-methylpropanoate) and 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate.

9. The pharmaceutical composition according to claim 2 comprising 4-(2-(((1-((pyrrolidine-2-carbonyl)oxy)ethoxy)amino)ethyl)-1,2,-phenylene dibenzoate and 4-(dimethylamino)butyl 2-(3-phenoxyphenyl) propionate.

10. The pharmaceutical composition according to claim 2 comprising (S)-4-(2-amino-3-oxo-3-(pentan-3-yloxy)propyl)-1,2-phenylene bis(2-methylpropanoate), 2-(diethylamino)ethyl 2-(4-isobutylphenyl)propionate, carbidopa and/or entacapone.

11. The pharmaceutical composition according to claim 2 comprising (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate, and 2-(dipropylamino)ethyl 4-acetoxy-2′

,4′

-difluoro-[1,1′

-biphenyl]-3-carboxylate.

12. The pharmaceutical composition according to claim 2 comprising (S)-4-(2-amino-3-(heptan-4-yloxy)-3-oxopropyl)-1,2-phenylene dibenzoate, and 2-(dipropylamino)ethyl 4-acetoxy-2′

,4′

-difluoro-[1,1′

-biphenyl]-3-carboxylate, carbidopa and/or entacapone.

13. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 4;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

14. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 5;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

15. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 6;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

16. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 7;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

17. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 8;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

18. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 9;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

19. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 10;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

20. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 11;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

21. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 12;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.

22. A method for treating Parkinson disease in a subject comprising administering transdermally a pharmaceutical composition according to claim 13;

and administering orally an aromatic-L-amino-acid decarboxylase inhibitor selected from the group consisting of carbidopa, benserazide, difluromethyldopa, and α

-methyldopa; and

/or a catechol-O-methyl transferase inhibitor selected from the group consisting of entacapone and tolcapone;

or a pharmaceutical composition thereof.