Biphenyl derivatives and methods for preparing same
Inventors
Kim, Soon-Hoe • Im, Weon-Bin • CHO, Chong-Hwan • Choi, Sun-Ho • Park, Jung-Sang • Kim, Mi-Yeon • Choi, Sung-Hak • Lee, Min-Jung • Cho, Kang-Hun
Assignees
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Publication Number
US-9828339-B2
Publication Date
2017-11-28
Expiration Date
Abstract
Provided are biphenyl derivatives having the structure of Formula 1: stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein R1 is hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, or C1-C6 alkoxy; R2, R3 and R4 are each independently hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or —C(O)R6; R5 is hydrogen or C1-C6 alkyl; n is 0 or 1; and R6 is hydrogen or amino, methods for preparing the same, and a pharmaceutical composition containing the same. The biphenyl derivatives having the structure of Formula 1 act as muscarinic M3 receptor antagonists, and thus are useful for the prevention or treatment of a disease selected from among chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia, and hyper-salivation syndromes.
Core Innovation
The invention relates to biphenyl derivatives represented by Formula 1, including stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs. The compounds are defined by variable substituents R1, R2, R3, R4, R5, R6, and an index n that is 0 or 1, with substituents including hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, amino, nitro, cyano, and —C(O)R6.
The biphenyl derivative family includes carbamate-bearing biphenyl scaffolds with defined stereochemistry on pyrrolidine-containing side chains. The examples show specific (S) and (R) carbamate derivatives with fluoro, chloro, methoxy, difluoro, trifluoromethyl, bis(trifluoromethyl), cyano, hydroxy, amino, carbamoyl, dimethylamino, tert-butyl, and hydroxypropyl substitution patterns on the [1,1′-biphenyl] ring, together with chemical structures and 1H NMR characterization.
The disclosure presents specific named carbamate derivatives within the Formula 1 framework, including (1-methylpyrrolidin-2-yl)methyl and (1-methylpyrrolidin-2-yl)ethylamino-carbamate motifs linked to substituted biphenyl cores. It also encompasses preparation of Formula 1 compounds by reacting precursor compounds in the presence of a carbamate synthesis reagent, including defined mixtures of DPPA and triethylamine, T3P, TMSN3, triethylamine, sodium azide, tetrabutylammonium bromide, and zinc(II) triflate.
Claims Coverage
The consolidated claim coverage centers on a Formula 1 biphenyl derivative scaffold, including stereoisomers and pharmaceutically acceptable salts, defined by substituent variables R1–R6 and n (n = 0 or 1). The claim set also includes pharmaceutical composition and therapeutic-use coverage, and preparation methods. In total, the main inventive feature groupings are the compound scaffold, preparation methods, composition, and urinary therapeutic use.
Biphenyl derivative of Formula 1 with constrained substituent variables
A biphenyl derivative represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl, or C1-C6 alkoxy; R2, R3 and R4 are each independently hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or —C(O)R6; R5 is hydrogen or C1-C6 alkyl; n is 0 or 1; and R6 is hydrogen or amino.
Biphenyl derivative with narrowed substituent definitions
A biphenyl derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or halogen; R2, R3 and R4 are each independently hydrogen or halogen; and R5 is hydrogen or C1-C6 alkyl.
Named stereoisomeric carbamate selections
The compounds are selected from a group of named carbamates with explicit (R)/(S) stereochemistry and distinct biphenyl substituents corresponding to stereoisomeric forms of the compound of claim 1.
Pharmaceutical composition containing the biphenyl derivative
A pharmaceutical composition comprising the compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient together with a pharmaceutically acceptable carrier or diluent.
Preparation by carbamate synthesis reagent mixtures
A method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof, comprising reacting defined precursor compounds in the presence of a carbamate synthesis reagent mixture including DPPA and triethylamine, or T3P, TMSN3 and triethylamine, or NaN3, tetrabutylammonium bromide and zinc(II) triflate.
Treatment of urinary disorders responsive to blocking muscarinic M3 receptor activity
Treating urinary incontinence, urinary urgency, or overactive bladder in a mammal by administering a pharmaceutical composition containing the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt as an active ingredient, where the treatment is responsive to blocking muscarinic M3 receptor activity.
Overall, the claims cover a Formula 1 biphenyl derivative scaffold, including stereoisomers and pharmaceutically acceptable salts, with specific constraints on R1–R6 and n. The coverage further includes named stereoisomeric carbamates, pharmaceutical compositions, preparation methods using defined carbamate synthesis reagent mixtures, and treatment of urinary incontinence, urinary urgency, or overactive bladder responsive to blocking muscarinic M3 receptor activity.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating urinary incontinence, urinary urgency, or overactive bladder in a mammal, where the treatment is responsive to blocking muscarinic M3 receptor activity.
Preventing and/or treating muscarinic M3-related diseases.
Treating additional muscarinic M3-related conditions listed as respiratory, digestive, and neurological conditions.
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