Patent ID: 11905287
Assignee: THE UNIVERSITY OF BRISTOL
Field: Pharmaceuticals (Chemistry)
Classification: CPC A  C  B | IPC B  C

Claim 0:
1. A process for preparing a 4-substituted cytisine analog of formula (I):, or a pharmaceutically acceptable salt, solvate and/or ester thereof, wherein:
R1 is
hydroxyl;
halogen;
optionally substituted aliphatic;
optionally substituted cycloaliphatic;
optionally substituted heterocycloaliphatic;
optionally substituted aryl;
optionally substituted heteroaryl;
—(CH2)m—NR6R7R8, wherein
R6 and R7 are each independently selected from the group consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkyl amino, N,N-dialkyl amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl or
one of R6 or R7 is —CO—R9, and the other of R6 or R7 is as defined above,
R8 is selected from the group consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkyl amino, N,N-dialkyl amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, or is absent,
R9 is selected from the group consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkyl amino, N,N-dialkyl amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl,
and m is 0, 1, 2, 3, 4 or 5,

—(CH2)m—O—(CH2)n—R10, wherein
R10 is selected from the group consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkyl amino, N,N-dialkyl amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, and
m and n are each independently 0, 1, 2, 3, 4 or 5,

—CN
—COOR12, wherein R12 is selected from the group consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkyl amino, N,N-dialkyl amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl,
—(CH2)o—CO—(CH2)p—R13, wherein
R13 is selected from the group consisting of hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkyl amino, N,N-dialkyl amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, and
o and p are each independently 0, 1, 2, 3, 4 or 5,

an amino acid or ester thereof,
acyl chloride,
a protecting group, or
cytisinyl,

R2, R3 and R4 are each independently selected from the group consisting hydrogen, halo, hydroxy, oxo, amino, amido, nitro, cyano, alkoxy, N-alkyl amino, N,N-dialkyl amino, phospho, carbonyl, carboxy, sulfoxy, sulfinyl, sulfonyl, sulfanyl, sulfamide, sulfo, mercapto, carbamoyl, methyl pivalate, trimethylsilyl, urea, thiourea, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted heteroaryl, optionally substituted haloalkyl, optionally substituted aroyl, optionally substituted heteroaroyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkenyl, amino acid or cytisine, or R4 is a protecting group, or a group having the structure —(CH2)v-FORMULA 1, wherein v is 0, 1, 2, 3, 4, 5 or 6 and FORMULA 1 is a compound of Formula (I),
the process comprising:
i) providing a compound of Formula IIa, wherein R2, R3 and R4 are as defined above;
ii) producing a compound of Formula IIb, wherein R2, R3 and R4 are as defined above, and BComp is a borylated complex, by contacting the compound of Formula IIa with a borylating agent;
iii) replacing BComp with R1 to produce a compound of Formula I:,