Synthesis of polycyclic alkaloids

Patent metadata

Field	Value
Publication number	US-9353112-B2
Application number	US-201414556659-A
Country	US
Kind code	B2
Filing date	Dec 1, 2014
Priority date	Mar 7, 2012
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

Disclosed embodiments concern polycyclic alkaloid compounds and methods for their use and synthesis. Particular embodiments concern polycyclic alkaloids having a fused, six-membered ring, while other embodiments concern polycyclic alkaloids having a fused, five-membered ring. Methods for making the polycyclic alkaloids are disclosed, as well as methods for their use as prophylactics or treatments for certain diseases. Also disclosed are pharmaceutical compositions comprising the polycyclic alkaloids and their use.

First claim

We claim:

1. A compound having a formula

wherein
R 1 is bound to either R 2 or R 3 to form a cyclopentyl ring and the other of R 2 and R 3 is selected from hydrogen, C 1-10 alkyl, aryl;
R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are selected from hydrogen, C 1-10 alkyl, aryl, halogen, a heteroatom-containing moiety, or any combination thereof;
R 10 , R 11 , R 12 , and R 13 independently are selected from C 1-10 alkyl, aryl, halogen, a heteroatom-containing moiety, hydrogen, and any combination thereof;
W is selected from oxygen, sulfur, and NR 17 wherein R 17 is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof;
Y is selected from —(CH 2 )—, —(CHR 17 )—, and —(CR 17 R 18 )—, oxygen, sulfur, any oxidized form of sulfur, and NR 17 wherein R 17 is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof; and
m is zero or one;

wherein each heteroatom-containing moiety independently is selected from —C(O)H; —C(O)X, where X is selected from fluorine, chlorine, bromine, and iodine; —OC(O)(OR b ); —C(O)OH; —OR b ; —C(O)OR b ; —OH; —C(O)R b ; —OSi(R b )(R c )R d ; —OOR b ; —OOH; —OP(O)(OH) 2 ; —P(O)(OH) 2 ; —OP(O)(OR b )OH; —PR b R c ; —SH; —SR b ; —SSR b ; —S(O)R b ; —SO 2 R b ; —C(S)R b ; —C(S)H; —S(O)OH; —SO 3 H; —SCN; —NCS; -5-oxazole; -4-oxazole; -2-oxazole; -5-1,2,3-oxadiazole; -2-1,3,4-oxadiazole; -4-1,2,3-oxadiazole; -2-1H-imidazole; -4-1H-imidazole; -5-1H-imidazole; -4-1H-1,2,3-triazole; -5-1H-1,2,3-triazole; -5-1H-tetrazole; -5-isoxazole; -4-isoxazole; -3-isoxazole; —C(O)N(R b ) 2 ; —N 3 ; —NNR b ; —OCN; —NCO; —C(O)NR b C(O)R b ; —CN; —N + C − ; —NO 2 ; —NO; —CH 2 NO 2 ; —NH 2 ; —NHR b ; —N(R b ) 2 ; or any combination thereof, and wherein each R b and R c independently is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof.

2. The compound according to claim 1 having a formula

wherein R 19 and R 20 independently are selected from C 1-10 alkyl, halogen, hydrogen, a Gi 10 heteroatom-containing moiety, or any combination thereof, n is 1, Y is CHR 17 , and wherein the heteroatom-containing moiety is selected from —C(O)H; —C(O)X, where X is selected from fluorine, chlorine, bromine, and iodine; —OC(O)(OR b ); —C(O)OH; —OR b ; —C(O)OR b ; —OH; —C(O)R b ; —OSi(R b )(R c )R d ; —OOR b ; —OOH; —OP(O)(OH) 2 ; —P(O)(OH) 2 ; —OP(O)(OR b )OH; —PR b R c ; —SH; —SR b ; —SSR b ; —S(O)R b ; —SO 2 R b ; —C(S)R b ; —C(S)H; —S(O)OH; —SO 3 H; —SCN; —NCS; -5-oxazole; -4-oxazole; -2-oxazole; -5-1,2,3-oxadiazole; -2-1,3,4-oxadiazole; -4-1,2,3-oxadiazole; -2-1H-imidazole; -4-1H-imidazole; -5-1H-imidazole; -4-1H-1,2,3-triazole; -5-1H-1,2,3-triazole; -5-1H-tetrazole; -5-isoxazole; -4-isoxazole; -3-isoxazole; —C(O)N(R b ) 2 ; —N 3 ; —NNR b ; —OCN; —NCO; —C(O)NR b C(O)R b ; —CN; —N + C − ; —NO 2 ; —NO; —CH 2 NO 2 ; —NH 2 ; —NHR b ; —N(R b ) 2 ; or any combination thereof, and wherein each R b and R c independently is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof.

3. The compound according to claim 1 having a formula

wherein R 20 and R 21 independently are selected from C 1-10 alkyl, halogen, hydrogen, a heteroatom-containing moiety, or any combination thereof; wherein the heteroatom-containing moiety is selected from C(O)H; —C(O)X, where X is selected from fluorine, chlorine, bromine, and iodine; —OC(O)(OR b ); —C(O)OH; —OR b ; —C(O)OR b ; —OH; —C(O)R b ; —OSi(R b )(R c )R d ; —OOR b ; —OOH; —OP(O)(OH) 2 ; —P(O)(OH) 2 ; —OP(O)(OR b )OH; —PR b R c ; —SH; —SR b ; —SSR b ; —S(O)R b ; —SO 2 R b ; —C(S)R b ; —C(S)H; —S(O)OH; —SO 3 H; —SCN; —NCS; -5-oxazole; -4-oxazole; -2-oxazole; -5-1,2,3-oxadiazole; -2-1,3,4-oxadiazole; -4-1,2,3-oxadiazole; -2-1H-imidazole; -4-1H-imidazole; -5-1H-imidazole; -4-1H-1,2,3-triazole; -5-1H-1,2,3-triazole; -5-1H-tetrazole; -5-isoxazole; -4-isoxazole; -3-isoxazole; —C(O)N(R b ) 2 ; —N3; —NNR b ; —OCN; —NCO; —C(O)NR b C(O)R b ; —CN; —N + C − ; —NO 2 ; —NO; —CH 2 NO 2 ; —NH 2 ; —NHR b ; —N(R b ) 2 ; or any combination thereof, and wherein each R b and R c independently is selected from hydrogen, C 1-10 alkyl, aryl, C 1-10 heteroaliphatic having 1-3 heteroatoms independently selected from S, O, or NH, or a combination thereof, or a 5- or 6-membered heteroaromatic ring having 1-3 heteroatoms independently selected from S, O, or N, or a combination thereof.

4. The compound according to claim 1 wherein the compound is selected from

5. A method for making a polycyclic alkaloid, comprising:
providing an aromatic amine compound having a formula

 and a carboxylic acid intermediate having a formula

exposing the aromatic amine compound and the carboxylic acid compound to reaction conditions sufficient to form a hemiaminal intermediate having a formula

exposing the hemiaminal intermediate to an acid to form a polycyclic alkaloid having a formula

wherein
R 1 is bound to either R 2 or R 3 to form a cyclopentyl ring and the other of R 2 and R 3 is selected from hydrogen, C 1-10 alkyl, or aryl;
R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are selected from C 1-10 alkyl, aryl, hydrogen, halogen, a heteroatom-containing moiety, or any combination thereof;
R 10 , R 11 , R 12 , and R 13 independently are selected from C 1-10 alkyl, aryl, hydrogen, halogen, a heteroatom-containing moiety, and any combination thereof;
W is selected from oxygen, sulfur, and NR 17 wherein R 17 is selected from

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Goff Dane
• Payan Donald G
• Braselmann Sylvia

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D513/14

  Ortho-condensed systems · CPC title