Spliceostatin analogs and methods for their preparation

Patent metadata

Field	Value
Publication number	US-9764040-B2
Application number	US-201615280563-A
Country	US
Kind code	B2
Filing date	Sep 29, 2016
Priority date	Nov 5, 2012
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention is directed to novel cytotoxic spliceostatin analogs and derivatives, to antibody drug conjugates thereof, and to methods for using the same to treat medical conditions including cancer.

First claim

We claim:

1. A compound of formula (II):
L-P  (II)

or a pharmaceutically acceptable salt thereof, wherein:
L is the linker moiety L 1 -L 2 -L 3 , where L 3 is bound to P;
P is a radical of formula (I):

wherein:
a dashed line represents an optional bond;
each X 1 is independently selected from the group consisting of: —O—, —S— and —NR—;
each X 2 is independently selected from the group consisting of: —O—, —S— and —NR—;
each X′ is CR or N;
each X″ is CH—, CR—(C(R) 2 ) m —NR—, CR—(C(R) 2 ) m —O—; CR—(C(R) 2 ) m —C(O)NR—, CR—(C(R) 2 ) m —C(O)NR—NR—, CR—(C(R) 2 ) m —SO 2 NR—, CR—(C(R) 2 ) m —NR—NR—, CR—(C(R) 2 ) m —NR—C(O)— or N— if X″ binds to L 2 or an additional L 3 , or otherwise is O, S, CRR, CR—(C(R) 2 ) m —NRR or NRR;
each X″′ is —(C(R) 2 ) m —NR— or CR—(C(R) 2 ) m —O— if X″′ binds to L 2 , or otherwise is R;
Y is —C(R) 2 —, —O—, —NR— or —S—;
R 1 is selected from the group consisting of: —R, —OR, —OCOR 13 , —OCONR 14 R 15 , —OCON(R 14 )NR(R 15 ), ═O (double bond to oxygen) and —NR 14 R 15 ;
R 2 and R 3 are independently selected from the group consisting of: hydrogen and C 1-6 alkyl;
R 4 and R 5 are independently selected from the group consisting of: hydrogen, —OR, —NR 14 R 15 and oxo;
R 6 and R 7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen,
R 6 and R 7 , together with the carbon atom to which they are bound, form a C 2-5 alkylidene optionally substituted with 1-3 substituents independently selected from R,
R 6 and R 7 together are oxo, or
R 6 and R 7 , together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R;
R 8 is hydrogen, C 1-6 alkyl or —OR;
R 9 is —(C(R) 2 ) m —C(O)— or —(C(R) 2 ) m —;
L 1 is selected from: -acid, —NR-acid and

L 2 is L 2A -L 2B -L 2C or L 2C -L 2B -L 2A where:
L 2A comprises one or more components selected from:

—O—, —C(O)—, —C(O)NR—, —C(O)—C 1-6 alkyl-, —C(O)NRC 1-6 alkyl-, —C 1-6 alkyl(OCH 2 CH 2 ) 1-6 —, —C(O)—C 1-6 alkyl-NRC(O)—, —C(O)—C 1-6 alkyl(OCH 2 CH 2 ) 1-6 —, —C 1-6 alkyl(OCH 2 CH 2 ) 1-6 —C(O)—, —C 1-6 alkyl-S—S—C 1-6 alkyl-NRC(O)CH 2 —, —C 1-6 alkyl-(OCH 2 CH 2 ) 1-6 —NRC(O)CH 2 —, —C(O)—C 1-6 alkyl-NRC(O)C 1-6 alkyl-, —N═CR-phenyl-O—C 1-6 alkyl-, —N═CR-phenyl-O—C 1-6 alkyl-C(O)—, —C(O)—C 1-6 alkyl(OCH 2 CH 2 ) 1-6 —NRC(O)—, —C(O)—C 1-6 alkyl-phenyl-(NR—C(O)—C 1-6 alkyl) 1-4 -, —C(O)—C 1-6 alkyl-(OCH 2 CH 2 ) 1-6 —NRC(O)C 1-6 alkyl-, —C 1-6 alkyl-, —S—, —C(O)—C 1-6 alkyl-phenyl-NR—, —O—C 1-6 alkyl-S—, —C(O)—O—C 1-6 alkyl-S— and (—CH 2 —CH 2 —O—) 1-20 , or L 2A is absent;
L 2B is selected from AA 0-aa , where AA is a natural or non-natural amino acid and aa is 12; and
L 2C comprises one or more components selected from: —PABA- and —PABC—, or L 2C is absent;

L 3 is selected from one or more of: —C 1-6 alkyl-, —NR—C 3 -C 8 heterocyclyl-NR—, —NR—C 3 -C 8 carbocyclyl-NR—, —NR—C 1-6 alkyl-NR—, —NR—C 1-6 alkyl-, —S—, —NR—, —NR—NR— and —NR—C(O)—NR— where the two R groups optionally join to form a 4-10 membered ring, —NR—C 1-6 alkyl-phenyl-NR—, —NR—C 1-6 alkyl-phenyl-SO 2 —NR—, —SO 2 —, —NR—C 1-6 alkyl-phenyl-C(O)—,

or L 3 is absent;
R 13 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 carbocyclyl, C 3-8 heterocyclyl, C 1-6 alkyl-C 6-14 aryl, C 1-6 alkyl-C 5-14 heteroaryl, wherein R 13 is optionally substituted with —NRR or —SO 2 NRR;
each R 14 and R 15 is independently selected from the group consisting of: hydrogen, hydroxyl, —NRR, —NRNR 2 , —C 3-10 carbocyclyl, —C 1-6 alkylene-C 3-10 carbocyclyl, —C 3-10 heterocyclyl, —C 1-6 alkylene-C 3-10 heterocyclyl, —(CH 2 CH 2 O) 1-6 CH 2 CH 2 C(O)OR, —(CH 2 CH 2 O) 1-6 CH 2 CH 2 NRR, —C 1-6 alkyl, C 6-14 aryl, —C 1-6 alkylene-C 6-14 aryl and —C 5-14 heteroaryl;
or R 14 and R 15 , together with the atom or atoms to which they are joined, form a C 3-10 heterocyclyl ring,
wherein R 14 , R 15 , or both, or a ring formed with R 14 and R 15 , are optionally substituted with —(C(R) 2 ) m —R 18 where each R 18 is independently selected from (i) —NRR, (ii) —C(NRR)(C(O)OR), (iii) —S—R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, —CF 3 , —(C(R) 2 ) m —NRR or —(C(R) 2 ) m —SO 2 NRR, (v) —SO 2 R, (vi) —S—S—C 1-6 alkyl-C(O)OR, (vii) —SO 2 NRR, (viii) —C(O)NRR, (ix) —C(O)OR, (x) —C 4-6 cycloalkyl optionally substituted with —NRR, —SO 2 NRR or —NR—C(O)(CH 2 ) 0-6 NRR, (xi) —R, (xii) —OR, (xiii) —N(R)NRR, (xiv) —C(O)N(R)NRR, (xv) —(C(R) 2 ) m —O—NRR and (xiv) —S—S—C 1-6 alkyl-NRR;
acid is an amino acid residue selected from —SCH 2 CH(COOH)(NH 2 ), —NH(CH 2 ) 4 CH(COOH)(NH 2 ) and —C(O)(CH 2 ) 2 CH(COOH)(NH 2 );
each R is independently selected from the group consisting of: hydrogen and —C 1-6 alkyl; and
each m is independently 0, 1, 2 or 3.

2. Additionally, a compound or compounds of formula (II′):
L-P′  (II′)

or a pharmaceutically acceptable salt thereof, wherein:
L is the linker moiety L 1 -L 2 -L 3 , where L 3 is bound to P′;
P′ is a radical of formula (I′):

wherein:
a dashed line represents an optional bond;
each X 1 is independently selected from the group consisting of: —O—, —S— and —NR—;
each X 2 is independently selected from the group consisting of: —O—, —S— and —NR—;
each X′ is CR or N;
each X″ is CH—, CR—(C(R) 2 ) m —NR—, CR—(C(R) 2 ) m —O—; CR—(C(R) 2 ) m —C(O)NR—, CR—(C(R) 2 ) m —C(O)NR—NR—, CR—(C(R) 2 ) m —SO 2 NR—, CR—(C(R) 2 ) m —NR—NR—, CR—(C(R) 2 ) m —NR—C(O)— or N— if X″ binds to L 2 or an additional L 3 , or otherwise is O, S, CRR, CR—(C(R) 2 ) m —NRR or NRR;
each X″′ is —(C(R) 2 ) m —NR— or CR—(C(R) 2 ) m —O— if X″′ binds to L 2 , or otherwise is R;
Y is —C(R) 2 —, —O—, —NR— or —S—;
R 1 is selected from the group consisting of: —(C(R) 2 ) m —, —OR″, —OCOR 13′ , —OC(O)NRR 4′ , —OCON(R)N(R)—, and —NR—
R 2 and R 3 are independently selected from the group consisting of: hydrogen and C 1-6 alkyl;
R 4 and R 5 are independently selected from the group consisting of: hydrogen, —OR, —NR 14 R 15 and oxo;
R 6 and R 7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C 1-6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen,
R 6 and R 7 , together with the carbon atom to which they are bound, form a C 2-5 alkylidene optionally substituted with 1-3 substituents independently selected from R,
R 6 and R 7 together are oxo, or
R 6 and R 7 , together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R;
R 8 is hydrogen, C 1-6 alkyl or —OR;

Assignees

• Pfizer

Inventors

• Subramanyam Chakrapani
• Koehn Frank Erich
• Dirico Kenneth John
• Eustaquio Alessandra S
• Green Michael Eric
• He Haiyin
• He Min
• O'Donnell Christopher John
• Puthenveetil Sujiet
• Ratnayake Anokha
• Teske Jesse Alexander
• Yang Hui Yu

Classifications

• A61K31/351

  not condensed with another ring · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K47/6855 Primary

  the tumour determinant being from breast cancer cell · CPC title

• C07D493/20

  Spiro-condensed systems · CPC title