US 11,998,611 B2Granted

Cryptophycin antibody conjugates for the treatment of cancer

AssigneeSanofi

InventorsHervé Bouchard, Marie-Priscille Brun, Philippe Hubert

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Abstract

The present disclosure relates, inter alia, to cryptophycin conjugates of formula (V): The disclosure also relates to precursors of these conjugates, compositions containing these conjugates, and to their therapeutic use, especially as anticancer agents. The disclosure also relates to the process for preparing these conjugates.

Claims17

Dependent claims

A compound of formula (V):

wherein:
R1 is (C1-C6)alkyl;
R2 is hydrogen or (C1-C6)alkyl;
R3 is hydrogen or (C1-C6)alkyl;
R4 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, (C1-C6)alkylene-NHR12, (C1-C6)alkylene-OH, or (C1-C6)alkylene-SH;
R5 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, (C1-C6)alkylene-NHR12, (C1-C6)alkylene-OH, or (C1-C6)alkylene-SH;
X is —NR6— or —O—;
R6 is hydrogen or (C1-C6)alkyl;
R7 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, or (C1-C6)alkylene-N[(C1-C6)alkyl]2;
R8 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, or (C1-C6)alkylene-N[(C1-C6)alkyl]2;
each R9 is independently hydrogen, halogen, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH(C3-C6)cycloalkyl, OH, O(C1-C4)alkyl, or (C3-C6)heterocycloalkyl;
each R10 is independently hydrogen or (C1-C4)alkyl;
each R12 is independently hydrogen or (C1-C6)alkyl;
Y is —NR11—(C1-C6)alkylene-, —O—(C1-C6)alkylene-, or —S—(C1-C6)alkylene-, wherein the (C1-C6)alkylene of Y is bonded to the phenyl ring and the —NR11—, —O—, or —S— of Y is either (a) bonded directly to the —C(O)— of L1 in formula (II) or (b) bonded directly to the —C(O)— of an (AA)w of L1 in formula (II);
R11 is hydrogen or (C1-C6)alkyl;
and
L is formula (II):
wherein:
L1 is formula (III):
wherein:
(i) x is 0;
y is 0;
and
z is 0;
or
(ii) x is 1;
y is 0;
and
z is 0;
or
(iii) x is 1;
y is 1;
and
z is 1;
A5 is hydrogen or (C1-C6)alkyl;
ALK is (C1-C12)alkylene;
A6 is hydrogen or (C1-C6)alkyl;
A2 is hydrogen or (C1-C6)alkyl;
A3 is hydrogen or (C1-C6)alkyl;
J1 is CA1 or N;
J2 is CA1 or N;
J3 is CA1 or N;
J4 is CA1 or N;
each A1 is independently hydrogen or (C1-C6)alkyl;
and
A4 is hydrogen or (C1-C6)alkyl;
wherein L1 is bonded directly to —O—, or —S— of Y;
(AA)w is a sequence of w amino acids connected together via peptide bonds, wherein each amino acid, (AA) W, is independently a natural or non-natural amino acid, (AAns);
w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
each (AA n O is independently selected from the group consisting of alanine (Ala), γ-aminobutyric acid (GABA), arginine (Arg), asparagine (Asn), aspartic acid (Asp), citrulline (Cit), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), ε-(acetyl)-lysine ((ε-Ac)Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val);
and
L2 is:
(a) —(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(b) —C(O)—(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(c) —NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(d) —C(O)—NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(e) —NA7-(C1-C6)alkylene-;
(f) —(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(g) —C(O)—(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(h) —NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(i) —C(O)—NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(j) —C(O)—NA7-(C1-C6)alkylene-;
(k) —(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(l) —NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(m) —C(O)—NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(n) —C(O)—(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(o) —(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(p) —C(O)—(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(q) —NA8-(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(r) —C(O)—NA8-(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(s) —C(O)—NA7-(OCH2CH2)i—(C1-C6)alkylene-;
(t) —NA7-(CH2CH2O)i—(C1-C6)alkylene-;
(u) —(C1-C6)alkylene-NA7-;
(v) —C(O)—(C1-C6)alkylene-NA7-;
(w) —NA8-(C1-C6)alkylene-NA7-;
(x) —C(O)—NA8-(C1-C6)alkylene-NA7-;
(y) —(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(z) —C(O)—(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(aa) —NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(bb) —C(O)—NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(cc) —(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(dd) —C(O)—(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(ee) —NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(ff) —C(O)—NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(gg) —(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(hh) —C(O)—(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(ii) —NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(jj) —C(O)—NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(kk) —NA7-arylene-;
(ll) —C(O)—NA7-arylene-;
(mm) —NA7-heteroarylene-;
or
(nn) —C(O)—NA7-heteroarylene-;
A7 is a straight, branched, saturated, or unsaturated C1-C160 hydrocarbon;
wherein one or more —CH2— units of the C1-C160 hydrocarbon are optionally and independently replaced by one or more atoms or groups independently selected from the group consisting of —CH(OH)—, —CH(SO3H)—, —CH(SO3−M+)—, —C(O)—, —C(O)NH—, —C(O)N(alkyl)-, —C(O)O—, —NHC(O)—, —N(alkyl)C(O)—, —NHS(O)2—, —N(alkyl)S(O)2—, —P(O)(OH)—, —P(O)(OH)O—, —O—, —OC(O)—, —OC(O)O—, —OP(O)(OH)—, —OP(O)(OH)O—, —S(O)—, —S(O)2—, —S(O)2NH—, —S(O)2N(alkyl)-, and heterocycloalkyl;
wherein each heterocycloalkyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, NH2, NH(alkyl), N(alkyl)2, OH, and O(alkyl);
and
wherein the C1-C160 hydrocarbon is optionally substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, NH2, NH(alkyl), N(alkyl)2, OH, and O(alkyl);
A8 is hydrogen or (C1-C6)alkyl;
M+ is an alkali metal;
and
i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50;
wherein the right end of L2 is bonded to —C(O)— and the left end of L2 is bonded to RCG1 of G;
G is the product of a reaction between RCG1, a reactive chemical group present at the end of L of formula (II), and RCG2, an orthogonal reactive chemical group present on an antibody, Ab;
(i) RCG1 is:
Cl,C≡CH,NH2,N3,OH,O(alkyl)-NHOH,SH,
wherein:
R21 is hydrogen or (C1-C6) alkyl;
and
the —CO—, —NH—, —NR21—, —N═, —O—, or S is bonded to L2;
or
(ii) RCG1 is:
C(O)ZaRa,
wherein:
Za is a single bond, —NH—, or —O—;
and
Ra is hydrogen, (C1-C6)alkyl, alkenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C7)heterocycloalkyl, aryl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, OH, O(alkyl), and =0;
wherein —C(O)— is bonded to L2;
RCG2 is:
C≡CH,C(O)H,C(O)C1-C6alkyl,C(O)NH2,C(O)OH,NH2,N3,SH,
wherein:
R21 is hydrogen or (C1-C6) alkyl;
and
Ab is the antibody.

121 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/210,072Filed 23 Mar 2021 · division
Priority: EP 1730553110 May 2017
Published: US 2021/0228726 A129 Jul 2021
Granted: 4 Jun 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

A61K 47/65
The modifying agent being a protein, peptide or polyamino acid: peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
A61K 38/15
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: depsipeptides; Derivatives thereof
A61K 47/10
Containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides: alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene…
A61K 47/22
Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite: heterocyclic compounds, e.g.…

Family

Application15/975,423Parent of this division · filed 9 May 2018
Application16/673,367Parent of this division · filed 4 Nov 2019
US 2021/0228726 A1Pre-grant publication · published 29 Jul 2021
US 11,007,275 B2Parent of this division
US 2018/0369401 A1Published application
US 2020/0054760 A1Published application
US 11,998,611 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (V):

wherein:
R1 is (C1-C6)alkyl;
R2 is hydrogen or (C1-C6)alkyl;
R3 is hydrogen or (C1-C6)alkyl;
R4 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, (C1-C6)alkylene-NHR12, (C1-C6)alkylene-OH, or (C1-C6)alkylene-SH;
R5 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, (C1-C6)alkylene-NHR12, (C1-C6)alkylene-OH, or (C1-C6)alkylene-SH;
X is —NR6— or —O—;
R6 is hydrogen or (C1-C6)alkyl;
R7 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, or (C1-C6)alkylene-N[(C1-C6)alkyl]2;
R8 is hydrogen, (C1-C6)alkyl, (C1-C6)alkylene-C(O)OH, or (C1-C6)alkylene-N[(C1-C6)alkyl]2;
each R9 is independently hydrogen, halogen, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH(C3-C6)cycloalkyl, OH, O(C1-C4)alkyl, or (C3-C6)heterocycloalkyl;
each R10 is independently hydrogen or (C1-C4)alkyl;
each R12 is independently hydrogen or (C1-C6)alkyl;
Y is —NR11—(C1-C6)alkylene-, —O—(C1-C6)alkylene-, or —S—(C1-C6)alkylene-, wherein the (C1-C6)alkylene of Y is bonded to the phenyl ring and the —NR11—, —O—, or —S— of Y is either (a) bonded directly to the —C(O)— of L1 in formula (II) or (b) bonded directly to the —C(O)— of an (AA)w of L1 in formula (II);
R11 is hydrogen or (C1-C6)alkyl;
and
L is formula (II):
wherein:
L1 is formula (III):
wherein:
(i) x is 0;
y is 0;
and
z is 0;
or
(ii) x is 1;
y is 0;
and
z is 0;
or
(iii) x is 1;
y is 1;
and
z is 1;
A5 is hydrogen or (C1-C6)alkyl;
ALK is (C1-C12)alkylene;
A6 is hydrogen or (C1-C6)alkyl;
A2 is hydrogen or (C1-C6)alkyl;
A3 is hydrogen or (C1-C6)alkyl;
J1 is CA1 or N;
J2 is CA1 or N;
J3 is CA1 or N;
J4 is CA1 or N;
each A1 is independently hydrogen or (C1-C6)alkyl;
and
A4 is hydrogen or (C1-C6)alkyl;
wherein L1 is bonded directly to —O—, or —S— of Y;
(AA)w is a sequence of w amino acids connected together via peptide bonds, wherein each amino acid, (AA) W, is independently a natural or non-natural amino acid, (AAns);
w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
each (AA n O is independently selected from the group consisting of alanine (Ala), γ-aminobutyric acid (GABA), arginine (Arg), asparagine (Asn), aspartic acid (Asp), citrulline (Cit), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), ε-(acetyl)-lysine ((ε-Ac)Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val);
and
L2 is:
(a) —(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(b) —C(O)—(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(c) —NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(d) —C(O)—NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-;
(e) —NA7-(C1-C6)alkylene-;
(f) —(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(g) —C(O)—(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(h) —NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(i) —C(O)—NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-;
(j) —C(O)—NA7-(C1-C6)alkylene-;
(k) —(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(l) —NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(m) —C(O)—NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(n) —C(O)—(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-;
(o) —(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(p) —C(O)—(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(q) —NA8-(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(r) —C(O)—NA8-(C1-C6)alkylene-(OCH2CH2)i—NA7-(C1-C6)alkylene-;
(s) —C(O)—NA7-(OCH2CH2)i—(C1-C6)alkylene-;
(t) —NA7-(CH2CH2O)i—(C1-C6)alkylene-;
(u) —(C1-C6)alkylene-NA7-;
(v) —C(O)—(C1-C6)alkylene-NA7-;
(w) —NA8-(C1-C6)alkylene-NA7-;
(x) —C(O)—NA8-(C1-C6)alkylene-NA7-;
(y) —(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(z) —C(O)—(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(aa) —NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(bb) —C(O)—NA8-(C1-C6)alkylene-NA7-C(O)—(C1-C6)alkylene-(OCH2CH2)i—;
(cc) —(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(dd) —C(O)—(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(ee) —NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(ff) —C(O)—NA8-(C1-C6)alkylene-NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(gg) —(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(hh) —C(O)—(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(ii) —NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(jj) —C(O)—NA8-(C1-C6)alkylene-C(O)—NA7-(C1-C6)alkylene-(OCH2CH2)i—;
(kk) —NA7-arylene-;
(ll) —C(O)—NA7-arylene-;
(mm) —NA7-heteroarylene-;
or
(nn) —C(O)—NA7-heteroarylene-;
A7 is a straight, branched, saturated, or unsaturated C1-C160 hydrocarbon;
wherein one or more —CH2— units of the C1-C160 hydrocarbon are optionally and independently replaced by one or more atoms or groups independently selected from the group consisting of —CH(OH)—, —CH(SO3H)—, —CH(SO3−M+)—, —C(O)—, —C(O)NH—, —C(O)N(alkyl)-, —C(O)O—, —NHC(O)—, —N(alkyl)C(O)—, —NHS(O)2—, —N(alkyl)S(O)2—, —P(O)(OH)—, —P(O)(OH)O—, —O—, —OC(O)—, —OC(O)O—, —OP(O)(OH)—, —OP(O)(OH)O—, —S(O)—, —S(O)2—, —S(O)2NH—, —S(O)2N(alkyl)-, and heterocycloalkyl;
wherein each heterocycloalkyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, NH2, NH(alkyl), N(alkyl)2, OH, and O(alkyl);
and
wherein the C1-C160 hydrocarbon is optionally substituted by one or more substituents independently selected from the group consisting of halogen, alkyl, NH2, NH(alkyl), N(alkyl)2, OH, and O(alkyl);
A8 is hydrogen or (C1-C6)alkyl;
M+ is an alkali metal;
and
i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50;
wherein the right end of L2 is bonded to —C(O)— and the left end of L2 is bonded to RCG1 of G;
G is the product of a reaction between RCG1, a reactive chemical group present at the end of L of formula (II), and RCG2, an orthogonal reactive chemical group present on an antibody, Ab;
(i) RCG1 is:
Cl,C≡CH,NH2,N3,OH,O(alkyl)-NHOH,SH,
wherein:
R21 is hydrogen or (C1-C6) alkyl;
and
the —CO—, —NH—, —NR21—, —N═, —O—, or S is bonded to L2;
or
(ii) RCG1 is:
C(O)ZaRa,
wherein:
Za is a single bond, —NH—, or —O—;
and
Ra is hydrogen, (C1-C6)alkyl, alkenyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C7)heterocycloalkyl, aryl, or heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, CN, NO2, alkyl, OH, O(alkyl), and =0;
wherein —C(O)— is bonded to L2;
RCG2 is:
C≡CH,C(O)H,C(O)C1-C6alkyl,C(O)NH2,C(O)OH,NH2,N3,SH,
wherein:
R21 is hydrogen or (C1-C6) alkyl;
and
Ab is the antibody.

121 more elements

Facts

Application

17/210,072Filed 23 Mar 2021 · division

Priority

EP 1730553110 May 2017

Published

US 2021/0228726 A129 Jul 2021

Granted

4 Jun 2024

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

A61K 47/65
The modifying agent being a protein, peptide or polyamino acid: peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
A61K 38/15
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: depsipeptides; Derivatives thereof
A61K 47/10
Containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides: alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene…
A61K 47/22
Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite: heterocyclic compounds, e.g.…

Family

Application15/975,423Parent of this division · filed 9 May 2018

Application16/673,367Parent of this division · filed 4 Nov 2019

US 2021/0228726 A1Pre-grant publication · published 29 Jul 2021

US 11,007,275 B2Parent of this division

US 2018/0369401 A1Published application

US 2020/0054760 A1Published application

US 11,998,611 B2This patent

From the US filing history. Foreign family members aren’t listed.