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Patent Application

App. No. 15/265,549

ASYMMETRIC SYNTHESES FOR SPIRO-OXINDOLE COMPOUNDS USEFUL AS THERAPEUTIC AGENTS

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Patent No.: US None
App. No.: 15/265,549

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Abstract

This invention is directed to asymmetric syntheses of certain spiro-oxindole derivatives, which are useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.

Claims (160)

1 .- 30 . (canceled)

31 . A compound of formula (11):

wherein:

p and r are each independently 1, 2, 3 or 4;

Pg 1 and Pg 2 are each independently an oxygen protecting group;

R 1 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 8 —C(O)R 5 , —R 8 —C(O)OR 5 , —R 8 —C(O)N(R 4 )R 5 , —S(O) 2 —R 5 , —R 9 —S(O) m —R 5 (where m is 0, 1 or 2), —R 8 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR) 2 , or —R 9 —O—R 9 —OR 5 ;

or R 1 is aralkyl substituted by —C(O)N(R 6 )R 7 where:

R 6 is hydrogen, alkyl, aryl or aralkyl; and

R 7 is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

or R 6 and R 7 , together with the nitrogen to which they are attached, form a N-heterocyclyl or a N-heteroaryl;

and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6 and R 7 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl;

or R 1 is independently aralkyl optionally substituted by one or more substituents selected from the group consisting of —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl;

or R 1 is independently —R 9 —N(R 1 )R 11 , —R 9 —N(R 12 )C(O)R 11 or —R 9 —N(R 10 )C(O)N(R 10 )R 11 where:

each R 10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

each R 11 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —N(R 4 )R 5 , —R 9 —OR 5 , or —R 9 —CN; and

R 12 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ;

and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 10 and R 11 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl;

or R 1 is independently heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , —R 8 —N(R 4 )R 5 , —R 8 —C(O)N(R 4 )R 5 , —R 8 —N(R 5 )C(O)R 4 , —R 8 —S(O) m R 4 (where m is 0, 1 or 2), —R 8 —CN, or —R 8 —NO 2 ;

each R 2 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —OS(O) 2 CF 3 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(═N—CN)N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;

and wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 2 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —S(O) m R 4 , —R 8 —S(O) n N(R 4 )R 5 , —R 8 —C(O)R 4 , —R 8 —C(O)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , and —N(R 5 )S(O) n R 4 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;

or any two adjacent R 2 's, together with the adjacent carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and the other R 2 's, if present, are as defined above;

each R 3 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —OS(O) 2 CF 3 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(N═C(R 4 )R 5 )N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;

or any two adjacent R 3 's, together with the adjacent carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the other R 3 's, if present, are as defined above;

each R 4 and R 5 is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;

or when R 4 and R 5 are each attached to the same nitrogen atom, then R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a N-heterocyclyl or a N-heteroaryl;

each R 8 is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

each R 9 is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;

as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.

32 .- 33 . (canceled)

34 . A compound of formula (12) or a compound of formula (13):

wherein:

each p and r are independently 1, 2, 3 or 4;

each Pg 1 and Pg 2 is independently an oxygen protecting group;

each R 1 is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 8 —C(O)R 5 , —R 8 —C(O)OR 5 , —R 8 —C(O)N(R 4 )R 5 , —S(O) 2 —R 5 , —R 9 —S(O) m —R 5 (where m is 0, 1 or 2), —R 8 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR) 2 , or —R 9 —O—R 9 —OR 5 ;

or each R 1 is independently aralkyl substituted by —C(O)N(R 6 )R 7 where:

R 6 is hydrogen, alkyl, aryl or aralkyl; and

R 7 is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

or R 6 and R 7 , together with the nitrogen to which they are attached, form a N-heterocyclyl or a N-heteroaryl;

or each R 1 is independently aralkyl optionally substituted by one or more substituents selected from the group consisting of —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl;

or each R 1 is independently —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11 or —R 9 —N(R 10 )C(O)N(R 10 )R 11

where:

each R 10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R 12 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ;

or each R 1 is independently heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R—OR 5 , —R 8 —C(O)OR 5 , —R 8 —N(R 4 )R 5 , —R 8 —C(O)N(R 4 )R 5 , —R 8 —N(R 5 )C(O)R 4 , —R 8 —S(O) m R 4 (where m is 0, 1 or 2), —R 8 —CN, or —R 8 —NO 2 ;

or when R 4 and R 5 are each attached to the same nitrogen atom, then R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a N-heterocyclyl or a N-heteroaryl;

each R 8 is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

each R 9 is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;

as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.

35 .- 38 . (canceled)

39 . A method of preparing a compound of formula (I):

as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;

wherein:

p and r are each independently 1, 2, 3 or 4;

or R 1 is aralkyl substituted by —C(O)N(R 6 )R 7 where:

R 6 is hydrogen, alkyl, aryl or aralkyl; and

R 7 is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

or R 6 and R 7 , together with the nitrogen to which they are attached, form a N-heterocyclyl or a N-heteroaryl;

or R 1 is aralkyl optionally substituted by one or more substituents selected from the group consisting of —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl;

or R 1 is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11 or —R 9 —N(R 10 )C(O)N(R 10 )R 11 where:

each R 10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R 12 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ;

or R 1 is heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , —R 8 —N(R 4 )R 5 , —R 8 —C(O)N(R 4 )R 5 , —R 8 —N(R 5 )C(O)R 4 , —R 8 —S(O) m R 4 (where m is 0, 1 or 2), —R 8 —CN, or —R 8 —NO 2 ;

or when R 4 and R 5 are each attached to the same nitrogen atom, then R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a N-heterocyclyl or a N-heteroaryl;

each R 8 is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

each R 9 is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;

wherein the method comprises treating a compound of formula (22):

where p, r, R 2 and R 3 are each as described above for the compound of formula (I), as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof, with a compound of formula (2):

X—R 1 (2);

40 .- 79 . (canceled)

80 . A method of preparing a compound of formula (I):

as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;

wherein:

p and r are each independently 1, 2, 3 or 4;

or R 1 is aralkyl substituted by —C(O)N(R 6 )R 7 where:

R 6 is hydrogen, alkyl, aryl or aralkyl; and

R 7 is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

or R 6 and R 7 , together with the nitrogen to which they are attached, form a N-heterocyclyl or a N-heteroaryl;

or R 1 is —R 9 —N(R 1 )R 11 , —R 9 —N(R 12 )C(O)R 11 or —R 9 —N(R 10 )C(O)N(R 10 )R 11 where:

each R 10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R 12 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ;

or when R 4 and R 5 are each attached to the same nitrogen atom, then R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a N-heterocyclyl or a N-heteroaryl;

each R 8 is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and

each R 9 is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;

wherein the method comprises the following steps:

(a) treating a compound of formula (1):

where p and R 2 are each as defined above for the compound of formula (I), or a pharmaceutically acceptable salt thereof, with a compound of formula (14):

X-Pg 3 (14);

where X is halo and Pg 3 is a nitrogen protecting group, under suitable nitrogen protecting conditions to provide a compound of formula (15):

where p and R 2 are each as described above for the compound of formula (I), and Pg 3 is a nitrogen protecting group, or a pharmaceutically acceptable salt thereof;

(b) treating a compound of formula (15) under suitable Grignard reaction conditions with an intermediate Grignard addition product formed from the treatment of a compound of formula (4):

where r and R 3 are each as defined above for the compound of formula (I), with a Grignard reagent of formula (5):

RMgX (5);

where R is alkyl and X is iodo, bromo or chloro, under suitable conditions to provide a compound of formula (16):

where p, r, R 2 and R 3 are each as described above for the compound of formula (I) and Pg 3 is a nitrogen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof;

Pg 1 X (7)

where X is halo and Pg 1 is an oxygen protecting group under suitable protecting conditions to provide a compound of formula (17):

where p, r, R 2 and R 3 are each as described above for the compound of formula (I), Pg 1 is an oxygen protecting group and Pg 3 is a nitrogen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof;

(d) treating a compound of formula (17) under suitable dehydroxylation conditions to provide a compound of formula (18):

(e) treating a compound of formula (18) with a compound of formula (10):

Pg 2 OCH 2 X (10);

where Pg 2 is an oxygen protecting group and X is halo, under suitable C-alkylation conditions comprising the presence of a phase transfer catalyst to provide a compound of formula (19):

where p, r, R 2 and R 3 are each as described above for the compound of formula (I), Pg 1 and Pg 2 are each independently an oxygen protecting group and Pg 3 is a nitrogen protecting group, as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;

(f) treating a compound of formula (19) under suitable deprotection conditions to provide a compound of formula (20):

where p, r, R 2 and R 3 are each as described above for the compound of formula (I), and Pg 3 is a nitrogen protecting group, as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;

(g) treating a compound of formula (20) under suitable Mitsunobu reaction conditions to provide the compound of formula (21):

(h) treating a compound of formula (21) under suitable nitrogen deprotecting conditions to provide a compound of formula (22):

(i) treating a compound of formula (22) with a compound of formula (2):

X—R 1 (2);

where X is halo and R 1 is as described above for the compound of formula (I), or a pharmaceutically acceptable salt thereof, under suitable N-alkylation conditions to provide a compound of formula (I), as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.

81 . A compound of formula (19), a compound of formula (20), a compound of formula (21) or a compound of formula (22):

wherein:

each p and r is independently 1, 2, 3 or 4;

each Pg 1 and Pg 2 is independently an oxygen protecting group;

each Pg 3 is a nitrogen protecting group;

or when R 4 and R 5 are each attached to the same nitrogen atom, then R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a N-heterocyclyl or a N-heteroaryl; and

each R 8 is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;

as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.

82 .- 86 . (canceled)

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 21, 2016

From: SUN, SHAOYI; FU, JIANMIN; CHOWDHURY, SULTAN; HEMEON, IVAN WILLIAM; GRIMWOOD, MICHAEL EDWARD; MANSOUR, TAREK SUHAYL

To: XENON PHARMACEUTICALS INC.

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