Polyamide compound and use thereof

Patent metadata

Field	Value
Publication number	US-11084847-B2
Application number	US-201716321430-A
Country	US
Kind code	B2
Filing date	Sep 22, 2017
Priority date	Sep 27, 2016
Publication date	Aug 10, 2021
Grant date	Aug 10, 2021

Abstract

The invention relates to a polyamide compound and a use thereof. Specifically, the invention relates to a type of polyamide compound (which preferably comprise one or more amide bonds formed by condensation of same or different L-amino acids or D-amino acids), or stereoisomers, crystalline polymorphs, solvates, metabolites, prodrugs or pharmaceutically acceptable salts or esters thereof, or pharmaceutical compositions thereof, as well as a method for preparing the polyamide compound and a use thereof in the prevention or treatment of diseases associated with κ-opioid receptor. The polyamide compound of the invention has excellent κ-opioid receptor agonistic activity and hydrophilicity, thus having a lesser ability of penetrating the blood-brain barrier and a lower capacity for entering the brain. The compound of the invention has higher selectivity for a κ-opioid receptor, lower addictiveness, improved pharmacokinetic properties, and improved safety (lower toxicity and/or fewer side effects), good patient compliance, and/or lesser propensity for developing tolerance, among other excellent medicinal properties.

First claim

The invention claimed is:

1. A compound having a structure of Formula (II):

or a stereoisomer, a crystalline polymorph, a solvate, a prodrug, or a pharmaceutically acceptable salt or ester thereof,
wherein
R a , R b and R c are substituents independently selected from the group consisting of: (CH 3 ) 2 CHCH 2 — and

R d is selected from the group consisting of: H 2 NCH 2 —, H 2 NCH 2 CH 2 —, H 2 N(CH 2 ) 2 CH 2 —, H 2 N(CH 2 ) 3 CH 2 —, H 2 N(CH 2 ) 4 CH 2 —, H 2 N(CH 2 ) 5 CH 2 —, H 2 NC(═NH)CH 2 —, H 2 NC(═NH)NHCH 2 —, H 2 NC(═NH)NHCH 2 CH 2 —, H 2 NC(═NH)NH(CH 2 ) 2 CH 2 —, and H 2 NC(═NH)NH(CH 2 ) 3 CH 2 —, wherein R d is optionally substituted with one or more of C 1-4 alkyl, and wherein R d is substituted with one or more W groups, wherein the W group is selected from the group consisting of HOCH 2 (CHOH) n CH 2 —, (HOCH 2 ) 2 CH—, —(CH 2 ) a NH 2 , and R 3 O(CH 2 CH 2 O) m CH 2 CH 2 —;
R 1 is selected from the group consisting of:

R 2 is —H;
R 3 is C 1-4 alkyl;
each n is independently an integer from 1 to 8; and,
m is an integer from 1 to 20.

2. The compound of claim 1 , or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof wherein the compound has a structure of Formula (III):

3. The compound of claim 1 , or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, wherein m is an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

4. The compound of claim 1 , or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, wherein the compound is selected from the group consisting of:
4-amino-1-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-(((R)-2,3-dihydroxypropyl)amino)hexanoyl)piperidin-4-carboxylic acid;
4-amino-1-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-(((S)-2,3-dihydroxypropyl)amino)hexanoyl)piperidin-4-carboxylic acid;
4-amino-1-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-((2-aminoethyl)amino)hexanoyl)piperidin-4-carboxylic acid;
4-amino-1-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-((3-aminoprop yl)amino)hexano yl)piperidin-4-carboxylic acid;
4-amino-1-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-((2-(2-methoxyethoxy)ethyl)amino)hexanoyl)piperidin-4-carboxylic acid;
4-amino-1-((R)-28-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-2,5,8,11,14,17,20-heptaoxa-23-azanonacosan-29-oyl)piperidin-4-carboxylic acid;
4-amino-1-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-((1,3-dihydroxypropan-2-yl)amino)hexanoyl)piperidin-4-carboxylic acid;
4-amino-1-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-(di(2-(2-methoxyethoxy)ethyl)amino)hexanoyl)piperidin-4-carboxylic acid;
8-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-(2-(methoxyethoxy)ethylamino)hexanoyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione; and
2-(6-((R)-2-((R)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamido)-6-((2-(2-methoxyethoxy)ethyl)amino) hexanoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)acetic acid.

5. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and one or more pharmaceutically acceptable carriers.

6. The pharmaceutical composition according to claim 5 , wherein the pharmaceutical composition is administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.

7. The compound, or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, according to claim 1 , wherein n is an integer from 1 to 5.

8. The compound, or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, according to claim 1 , wherein W is HOCH 2 CH(OH)CH 2 —, (HOCH 2 ) 2 CH—, —CH 2 NH 2 , —(CH 2 ) 2 NH 2 , —(CH 2 ) 3 NH 2 , CH 3 O(CH 2 CH 2 O)CH 2 CH 2 —, CH 3 O(CH 2 CH 2 O) 2 CH 2 CH 2 —, CH 3 O(CH 2 CH 2 O) 3 CH 2 CH 2 —, CH 3 O(CH 2 CH 2 O) 6 CH 2 CH 2 —, or CH 3 O(CH 2 CH 2 O) 11 CH 2 CH 2 .

9. The compound, or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, according to claim 1 , wherein the compound has a structure of Formula (III)-1:

10. The compound, or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, according to claim 9 , wherein R d is substituted with one or two W groups.

11. The compound, or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, according to claim 9 , wherein
substitution of R d with one W group forms a group, which is selected from the group consisting of: W—NHCH 2 —, W—NHCH 2 CH 2 —, W—NH(CH 2 ) 2 CH 2 —, W—NH(CH 2 ) 3 CH 2 —, W—NH(CH 2 ) 4 CH 2 —, W—NH(CH 2 ) 5 CH 2 —, W—NHC(═NH)CH 2 —, W—NHC(═NH)NHCH 2 —, W—NHC(═NH)NHCH 2 CH 2 —, W—NHC(═NH)NH(CH 2 ) 2 CH 2 —, and W—NHC(═NH)NH(CH 2 ) 3 CH 2 —, wherein W is selected from the group consisting of HOCH 2 (CHOH) n CH 2 —, (HOCH 2 ) 2 CH—, —(CH 2 ) n NH 2 , and R 3 O(CH 2 CH 2 O) m CH 2 CH 2 —, wherein
n is independently an integer from 1-8;
m is an integer from 1-20; and
R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

12. The compound, or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, according to claim 9 , wherein
substitution of R d with one W group forms a group, which is W—NH(CH 2 ) 3 CH 2 —;
wherein W is selected from the group consisting of HOCH 2 (CHOH) n CH 2 —, (HOCH 2 ) 2 CH—, —(CH 2 ) n NH 2 , and R 3 O(CH 2 CH 2 O) m CH 2 CH 2 —, wherein n is an integer from 1-8;
R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; and
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20.

13. The compound, or the stereoisomer, the crystalline polymorph, the solvate, the prodrug or the pharmaceutically acceptable salt or ester thereof, according to claim 9 , wherein
substitution of R d with one W group forms a group, which is W—NH(CH 2 ) 3 CH 2 —;
wherein the W group is HOCH 2 CHOHCH 2 —, (HOCH 2 ) 2 CH—, —CH 2 NH 2 , —(CH 2 ) 2 NH 2 , —(CH 2 ) 3 NH 2 , CH 3 O(CH 2 CH 2 O)CH 2 CH 2 —, CH 3 O(CH 2 CH 2 O) 2 CH 2 CH 2 —, CH 3 O(CH 2 CH 2 O) 3 CH 2 CH 2 —, CH 3 O(CH 2 CH 2 O) 6 CH 2 CH 2 —, or CH 3 O(CH 2 CH 2 O) 11 CH 2 CH 2 —.

14. The compound,

Assignees

• Sichuan Kelun Biotech Biopharmaceutical Co Ltd

Inventors

• Cai Jiaqiang
• Tian Qiang
• Zhao Mingliang
• Zeng Hong
• Song Hongmei
• Yu Nan
• Deng Hua
• Zhong Wei
• Yang Long
• Wu Lei
• Huang Haitao
• Wu Yongyong
• Su Donghai
• Zhou Xin
• Tan Yuting
• Wang Lichun
• Wang Jingyi

Classifications

• A61P11/14

  Antitussive agents · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• C07K5/1016 Primary

  and aromatic or cycloaliphatic · CPC title