US2018126000A1PendingUtilityA1
Glucocorticoid receptor agonist and immunoconjugates thereof
Est. expiryJun 2, 2036(~9.9 yrs left)· nominal 20-yr term from priority
Inventors:Michael McphersonAdrian D. HobsonMartin E. HayesChristopher C. MarvinDiana SchmidtWendy WaegellChristian GoessJason Z. OhAxel Hernandez, Jr.John T. Randolph
A61K 2039/505C07K 2317/21C07K 2317/569C07K 2318/20A61K 47/6849C07K 2317/55A61K 47/6889C07K 2319/30A61P 37/06C07J 71/0031C07K 2317/92C07K 16/18A61K 47/6845C07K 2317/24C07K 16/241C07K 2317/73C07K 2317/31A61K 31/58A61K 47/6803A61P 29/00A61P 37/02C07K 16/24A61P 37/00A61K 47/68
61
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Claims
Abstract
Provided herein are glucocorticoid receptor agonist immunoconjugates, glucocorticoid receptor agonists, and methods of using the same, e.g., to treat autoimmune or inflammatory diseases.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having Formula I-a:
(SM-L-Q) n -A 1 I-a
wherein:
A 1 is an anti-tumor necrosis factor (TNF) alpha protein;
L is a linker;
Q is a heterobifunctional group or heterotrifunctional group; or
Q is absent;
n is 1-10; and
SM is a monovalent radical of a glucocorticosteroid.
2 . A compound having Formula I-b:
(SM-L-Q) n -A 2 I-b
wherein:
A 2 is a protein;
L is a linker;
Q is a heterobifunctional group or heterotrifunctional group; or
Q is absent;
n is 1-10; and
SM is a radical of a glucocorticosteroid represented by Formula II-m or Formula II-p:
wherein:
R 1 is selected from the group consisting of hydrogen and halo;
R 2 is selected from the group consisting of hydrogen, halo, and hydroxy;
R 3 is selected from the group consisting of —CH 2 OH, —CH 2 SH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, —SCH 2 CF 3 , hydroxy, —OCH 2 CN, —OCH 2 Cl, —OCH 2 F, —OCH 3 , —OCH 2 CH 3 , —SCH 2 CN,
R 3a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 3b is selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
R 3c is selected from the group consisting of hydrogen, C 1-4 alkyl, —CH 2 OH, and C 1-4 alkoxy;
R 3d and R 3e are independently selected from hydrogen and C 1-4 alkyl;
R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy;
X is selected from the group consisting of —(CR 4a R 4b ) t —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 5 —, —CH 2 S—, —CH 2 O—, —N(H)C(R 8a )(R 8b )—, —CR 4c ═CR 4d —, and —C≡C—; or
X is absent;
Y 2 is selected from the group consisting of —O—, —S—, and —N(R 7a )—; or
Y 2 is absent;
t is 1 or 2;
Z is selected from the group consisting of ═CR 11a — and ═N—;
each R 4a and R 4b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 4a and R 4b taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 7a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 8a and R 8b are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 9f is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 11a and R 11b are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; and
represents a single or double bond.
3 . The compound of claim 1 or 2 , wherein SM is a radical of a glucocorticosteroid represented by Formula II-m:
R 1 is selected from the group consisting of hydrogen and halo;
R 2 is selected from the group consisting of hydrogen, halo, and hydroxy;
R 3 is selected from the group consisting of —CH 2 OH, —CH 2 SH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, —SCH 2 CF 3 , hydroxy, —OCH 2 CN, —OCH 2 Cl, —OCH 2 F, —OCH 3 , —OCH 2 CH 3 , —SCH 2 CN,
R 3a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 3b is selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
R 3c is selected from the group consisting of hydrogen, C 1-4 alkyl, —CH 2 OH, and C 1-4 alkoxy;
R 3d and R 3e are independently selected from hydrogen and C 1-4 alkyl;
R 6a , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy;
X is selected from the group consisting of —(CR 4a R 4b ) t —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 5 —, —CH 2 S—, —CH 2 O—, —N(H)C(R 8a )(R 8b )—, —CR 4c ═CR 4d —, and —C≡C—; or
X is absent;
Y 2 is selected from the group consisting of —O—, —S—, and —N(R 7a )—; or
Y 2 is absent;
t is 1 or 2;
Z is ═CH—;
each R 4a and R 4b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 4a and R 4b taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 7a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 8a and R 8b are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 9f is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 11b is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; and
represents a single or double bond.
4 . The compound of claim 2 or 3 , wherein:
represents a double bond;
R 1 is selected from the group consisting of hydrogen and fluoro;
R 2 is selected from the group consisting of hydrogen and fluoro;
R 3 is selected from the group consisting of —CH 2 OH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, and
R 3d and R 3e are independently selected from the group consisting of hydrogen, methyl, and ethyl;
R 6a , R 6c , R 6d , and R 6e are hydrogen; X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —CH 2 S—, and —N(H)CH 2 —;
Y 2 is —N(H)—;
Z is ═CH—;
R 9f is hydrogen; and
R 11b is hydrogen.
5 . The compound of any one of claims 1 - 4 , wherein L is a linker comprising a dipeptide.
6 . The compound of any one of claims 1 - 5 , wherein Q is a heterobifunctional group selected from the group consisting of:
and
m is 1, 2, 3, or 4.
7 . The compound of any one of claims 1 - 6 , wherein -L-Q- is:
m is 2 or 3; and
R 10a and R 10b are independently selected from the group consisting of hydrogen and C 1-4 alkyl.
8 . The compound of any one of claims 1 - 7 , wherein n is 2-5.
9 . The compound of claim 1 or 2 , wherein SM is a monovalent radical of a glucocorticosteroid which is any one of the compounds of Table II.
10 . The compound of any one of claim 1 or 3 - 8 , wherein A 1 is (i) an antibody or antigen-binding fragment thereof that binds to human TNF alpha or (ii) a soluble TNF receptor.
11 . The compound of any one of claim 1 or 3 - 9 , wherein A 1 is selected from the group consisting of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placulumab, and golimumab.
12 . The compound of claim 1 , which is any one or more of the compounds of Table III, wherein:
n is 1-5; A is A 1 ; and A 1 is selected from the group consisting of adalimumab, infliximab, certolizumab pegol, afelimomab, nerelimomab, ozoralizumab, placulumab, and golimumab.
13 . The compound of claim 2 , which is any one or more of the compounds of Table III, wherein:
n is 1-5; A is A 2 ; and A 2 is an antibody or a soluble receptor protein.
14 . A compound selected from the group consisting of:
wherein n is 1-5 and A is an antibody comprising the heavy and light chain sequences of SEQ ID NO:66 and SEQ ID NO:73, respectively.
15 . The compound of claim 14 selected from the group consisting of:
Structure
n
4
2
4
2
4
2
16 . The compound of claim 15 , wherein the compound is
Structure
n
4
17 . The compound of claim 15 , wherein the compound is
Structure
n
2
18 . The compound of claim 15 , wherein the compound is
Structure
n
4
19 . The compound of claim 15 , wherein the compound is
Structure
n
2
20 . The compound of claim 15 , wherein the compound is
Structure
n
4
21 . The compound of claim 15 , wherein the compound is
Structure
n
2
22 . A pharmaceutical composition comprising the compound of any one of claims 1 - 21 , and a pharmaceutically acceptable carrier.
23 . A method for treating an autoimmune disease in a patient in need thereof comprising administering to said patient the compound of any one of claims 1 - 21 or the pharmaceutical composition of claim 22 , optionally wherein said autoimmune disease is rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcets disease, a spondyloarthropathy, or psoriasis.
24 . A compound having Formula VII:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 is selected from the group consisting of hydrogen and halo;
R 2 is selected from the group consisting of hydrogen, halo, and hydroxy;
R 3 is selected from the group consisting of —CH 2 OH, —CH 2 SH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, —SCH 2 CF 3 , —CH 2 OS(═O) 2 OH, hydroxy, —OCH 2 CN, —OCH 2 Cl, —OCH 2 F, —OCH 3 , —OCH 2 CH 3 , —SCH 2 CN,
R 3a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 3b is selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
R 3c is selected from the group consisting of hydrogen, C 1-4 alkyl, —CH 2 OH, C 1-4 alkoxy, —CH 2 (amino), and —CH 2 CH 2 C(═O)OR 3f ;
R 3d and R 3e are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 3f is selected from the group consisting of hydrogen and C 1-4 alkyl;
X is selected from the group consisting of —(CR 4a R 4b ) t —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 5 —, —CH 2 S—, —CH 2 O—, —N(H)C(R 8a )(R 8b )—, —CR 4c ═CR 4d —, —C≡C—, —N(R 5 )C(═O)—, and —OC(═O)—; or
X is absent;
t is 1 or 2;
Z is selected from the group consisting of ═CR 11a — and ═N—;
each R 4a and R 4b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 4a and R 4b taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 6a , R 6b , R 6c , and R 6d are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy;
R 7a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 7b is selected from the group consisting of hydrogen, -L-H, -L-PG,
R 7a and R 7b taken together with the nitrogen atom to which they are attached form:
R 7a and R 7b taken together with the nitrogen atom to which they are attached form a nitro group;
m is 1, 2, 3, 4, 5, or 6;
L is a linker;
PG is a protecting group;
R 9f is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 8a and R 8b are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 11a and R 11b are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; and
represents a single or double bond.
25 . A compound having Formula VII-A or Formula VII-B:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 is selected from the group consisting of hydrogen and halo;
R 2 is selected from the group consisting of hydrogen, halo, and hydroxy;
R 3 is selected from the group consisting of —CH 2 OH, —CH 2 SH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, —SCH 2 CF 3 , —CH 2 OS(═O) 2 OH, hydroxy, —OCH 2 CN, —OCH 2 Cl, —OCH 2 F, —OCH 3 , —OCH 2 CH 3 , —SCH 2 CN,
R 3a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 3b is selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
R 3c is selected from the group consisting of hydrogen, C 1-4 alkyl, —CH 2 OH, C 1-4 alkoxy, —CH 2 (amino), and —CH 2 CH 2 C(═O)OR 3f ;
R 3d and R 3e are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 3f is selected from the group consisting of hydrogen and C 1-4 alkyl; X is selected from the group consisting of —(CR 4a R 4b ) t —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NR 5 —, —CH 2 S—, —CH 2 O—, —N(H)C(R 8a )(R 8b )—, —CR 4c ═CR 4d —, —C≡C—, —N(R 5 )C(═O)—, and —OC(═O)—; or
X is absent;
t is 1 or 2;
Z is selected from the group consisting of ═CR 11a — and ═N—;
each R 4a and R 4b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; or
R 4a and R 4b taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
R 4c and R 4d are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 6a , R 6b , and R 6c are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy;
R 7a is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 7b is selected from the group consisting of hydrogen, -L-H, -L-PG,
or
R 7a and R 7b taken together with the nitrogen atom to which they are attached form:
or
R 7a and R 7b taken together with the nitrogen atom to which they are attached form a nitro group;
m is 1, 2, 3, 4, 5, or 6;
L is a linker;
PG is a protecting group;
R 9f is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 8a and R 8b are independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 11a and R 11b are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 haloalkyl, cyano, hydroxy, thiol, amino, alkylthio, and alkoxy; and
represents a single or double bond.
26 . The compound of claim 24 or 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 7b is selected from the group consisting of:
m is 1, 2, 3, 4, 5, or 6; and
R 10a and R 10b are each independently selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl.
27 . The compound of claim 24 or 26 , or a pharmaceutically acceptable salt or solvate thereof, having Formula VIII-a:
28 . The compound of any one of claims 24 - 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
represents a double bond; R 1 is selected from the group consisting of hydrogen and fluoro; R 2 is selected from the group consisting of hydrogen and fluoro; R 3 is selected from the group consisting of —CH 2 OH, —CH 2 Cl, —SCH 2 Cl, —SCH 2 F, and
R 3d and R 3e are independently selected from the group consisting of hydrogen, methyl, and ethyl;
Z is ═CH—;
R 6a , R 6b , R 6c , and R 6d are hydrogen;
R 7a is hydrogen;
X is selected from the group consisting of —CH 2 —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —CH 2 S—, and —N(H)CH 2 —;
R 9f is hydrogen; and
R 11b is hydrogen.
29 . The compound of any one of claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b is hydrogen.
30 . The compound of any one of claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b is R 7b -1.
31 . The compound of any one of claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b is R 7b -2, and PG is BOC.
32 . The compound of any one of claims 24 - 28 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 7b is R 7b -3.
33 . The compound of claim 29 , or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds of Table VI.
34 . The compound of claim 29 , or a pharmaceutically acceptable salt or solvate thereof, which is any one of the compounds of Table VII.
35 . The compound of claim 33 , or a pharmaceutically acceptable salt or solvate thereof, which is:
36 . The compound of claim 24 , or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds of Table VIII,
wherein R 7b is selected from the group consisting of:
37 . The compound of claim 24 , or a pharmaceutically acceptable salt or solvate thereof, which is any one or more of the compounds of Table X.
38 . The compound of claim 37 , or a pharmaceutically acceptable salt or solvate thereof, which is:
39 . A method of making a compound having Formula I-e:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is A 1 or A 2 ;
A 1 is an anti-tumor necrosis factor (TNF) alpha protein;
A 2 is a protein;
L is a linker;
R 7a is selected from the group consisting of hydrogen and C 1-4 alkyl;
n is 1-10;
m is 1, 2, 3, 4, 5, or 6; and
SM is a radical of a glucocorticosteroid,
the method comprising:
a) conjugating a compound having Formula XI:
with an anti-tumor necrosis factor (TNF) alpha protein or a protein; and
b) isolating the compound having Formula I-e, or a pharmaceutically acceptable salt or solvate thereof.
40 . The method of claim 38 further comprising hydrolyzing the compound having Formula I-e to give a compound having Formula I-f:
or a pharmaceutically acceptable salt or solvate thereof.Cited by (0)
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