ES2690993T3 - Composiciones que contienen y métodos que implican derivados de dolastatina enlazados con aminoácidos no naturales y usos de los mismos - Google Patents

Composiciones que contienen y métodos que implican derivados de dolastatina enlazados con aminoácidos no naturales y usos de los mismos Download PDF

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ES2690993T3
ES2690993T3 ES12793246.5T ES12793246T ES2690993T3 ES 2690993 T3 ES2690993 T3 ES 2690993T3 ES 12793246 T ES12793246 T ES 12793246T ES 2690993 T3 ES2690993 T3 ES 2690993T3
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alkylene
formula
nme
fifty
fifteen twenty
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Zhenwei Miao
Kyle C. ATKINSON
Sandra Biroc
Timothy BUSS
Melissa COOK
Vadim Kraynov
Robin MARSDEN
Jason Pinkstaff
Lillian SKIDMORE
Ying Sun
Angieszka SZYDLIK
Delia Ianina Lopez De Valenta
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Ambrx Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • A61K47/6861—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from kidney or bladder cancer cell
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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Abstract

Un compuesto que tiene: **Fórmula** en donde: Z tiene la estructura de: **Fórmula** R5 es H, COR8, C1-C6 alquilo o tiazol; R8 es OH o -NH-(alquileno-O)n-NH2; R6 es OH o H; Ar es fenilo o piridina; R7 es C1-C6 alquilo o hidrógeno; Y se selecciona del grupo que consiste en una hidroxilamina; L es un enlazador seleccionado del grupo que consiste en -alquileno-, -alquileno-C(O)-, -(alquileno-O)n-alquileno-, - (alquileno-O)n-alquileno-C(O)-, -(alquileno-O)n- (CH2)n'-NHC(O)-(CH2)n"-C(Me)2-S-S-(CH2)n'"-NHC(O)-(alquileno-O)n''''- alquileno-, -(alquileno-O)n-alquileno-W-, -alquileno-C(O)-W-, -(alquileno-O)n-alquileno-U-alquileno-C(O)- y - (alquileno-O)n-alquileno-U-alquileno-; W tiene la estructura de: **Fórmula** U tiene la estructura de: **Fórmula** o L está ausente, Y es metilo, R5 es COR8, y R8 es -NH-(alquileno-O)n-NH2; y cada n, n', n", n'" y n"" son independientemente enteros mayores que o iguales a uno; o una sal del mismo; (ii) Fórmula (III), (IV), (V) o (VI):**Fórmula** en donde: Z tiene la estructura de: **Fórmula** R5 es H, COR8, C1-C6 alquilo o tiazol; R8 es OH; R6 es OH o H; Ar es fenilo o piridina; R7 es C1-C6 alquilo o hidrógeno; Y y V se seleccionan cada uno del grupo que consiste en una hidroxilamina; L1, L2, L3 y L4 son cada uno de los enlazadores seleccionados independientemente del grupo que consiste en un enlace, -alquileno-, -(alquileno-O)n-alquileno-J-, -alquileno'-J-(alquileno-O)n-alquileno-, -J-(alquileno-O)n-alquileno-, - (alquileno-O)n-alquileno-J-(alquileno-O)n'-alquileno-J'-, -(alquileno-O)n-alquileno-J-alquileno'-, -W-, -alquileno-W-, alquileno'-J-(alquileno-NMe)n-alquileno-W-, -J-(alquileno-NMe)n-alquileno-W-, -J-alquileno-NMe-alquileno'-NMe- alquileno"-W-, y -alquileno-J-alquileno'-NMe-alquileno"-NMe-alquileno"'-W-; W tiene la estructura de: **Fórmula** cada J y J' tienen independientemente la estructura de: **Fórmula** y cada n y n' son independientemente enteros mayores que o iguales a uno; o una sal del mismo.

Description

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DESCRIPCIÓN
Composiciones que contienen y métodos que implican derivados de dolastatina enlazados con aminoácidos no naturales y usos de los mismos
ANTECEDENTES DE LA INVENCIÓN
[0001] La capacidad de incorporar aminoácidos no genéticamente codificados (es decir, "aminoácidos no naturales") en proteínas permite la introducción de grupos funcionales químicos que podrían proporcionar alternativas valiosas a los grupos funcionales naturales, tales como el épsilon -NH2 de lisina, el sulfhidrilo -SH de cisteína, el grupo imino de histidina, etc. Se sabe que ciertos grupos funcionales químicos son inertes a los grupos funcionales que se encuentran en los 20 aminoácidos codificados genéticamente, pero que reaccionan limpia y eficientemente para formar enlaces estables con grupos funcionales que pueden incorporarse a aminoácidos no naturales.
[0002] Los métodos ahora están disponibles para introducir selectivamente grupos funcionales químicos que no se encuentran en las proteínas, que son químicamente inertes a todos los grupos funcionales encontrados en los 20 aminoácidos genéticamente codificados, y que pueden usarse para reaccionar de manera eficiente y selectivamente con reactivos que comprenden ciertos grupos funcionales para formar enlaces covalentes estables.
Los documentos WO 03/043583 A2 y WO 2004/073656 A2 describen métodos para el tratamiento de trastornos inmunológicos usando anticuerpos anti-CD30. El documento WO 2004/073656 A2 describe conjugados de anticuerpo y fármaco de PSMA. El documento US 2009/047296 A1 describe conjugados de ligando de auristatina.
SUMARIO DE LA INVENCIÓN
[0003] En este documento, se describen restos tóxicos con uno o más engarce(s), grupos tóxicos unidos a aminoácidos no naturales y procedimientos para preparar tales aminoácidos y polipéptidos no naturales.
[0004] La presente invención describe un compuesto, o una sal del mismo, que comprende la Fórmula (I):
imagen1
en donde:
Z tiene la estructura de:
imagen2
R5 es H, CORa, C1-C6 alquilo o tiazol;
Re es OH o -NH-(alquileno-O)n-NH2;
R6 es OH o H;
Ar es fenilo o piridina;
R7 es C1-C6 alquilo o hidrógeno;
Y se selecciona del grupo que consiste en una hidroxilamina;
L es un engarce seleccionado del grupo que consiste en -alquileno-, -alquileno-C(O)-, -(alquileno-O)n-alquileno-, - (alquileno-O)n-alquileno-C(O)-, -(alquileno-O)n-(CH2)n'-NHC(O)-(CH2)n"-C(Me)2-S-S-(CH2)n'"-NHC(O)-(alquileno-
O)n""-alquileno-, -(alquileno-O)n-alquileno-W-, -alquileno-C(O)-W-, -(alquileno-O)n-alquileno-U-alquileno-C(O)-, y - (alquileno-O)n-alquileno-U-alquileno-;
W tiene la estructura de:
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imagen3
U tiene la estructura de:
imagen4
o L está ausente, Y es metilo, R5 es COR8, y R8 es -NH-(alquileno-O)n-NH2; y cada n, n', n”, n'" y n”” son independientemente enteros mayores que o iguales a uno.
[0005] En algunas realizaciones, R5 es tiazol. En otras realizaciones, R6 es H. En ciertas realizaciones, Ar es fenilo. En realizaciones adicionales o adicionales, R7 es metilo. En algunas realizaciones, n es un número entero de 0 a 20, de 0 a 10 o de 0 a 5.
[0006] En algunas realizaciones, se describe un compuesto que comprende la Fórmula (II):
imagen5
En ciertas realizaciones, L es -(alquileno-O)n-alquileno-. En realizaciones específicas, cada alquileno es -CH2CH2-, n es igual a 3, y R7 es metilo. En otras realizaciones, L es -alquileno-. En realizaciones específicas, cada alquileno es - CH2CH2- y R7 es metilo o hidrógeno. En ciertas realizaciones, L es -(alquileno-O)n-alquileno-C(O)-. En ciertas realizaciones específicas, cada alquileno es -CH2CH2-, n es igual a 4, y R7 es metilo. En realizaciones adicionales o alternativas, L es -(alquileno-O)n-(CH2)n'-NHC(O)-(CH2)n”-C(Me)2-S-S-(CH2)n”-NHC(O)-(alquileno-O)n'-alquileno-. En realizaciones específicas, cada alquileno es -CH2CH2-, n es igual a 1, n' es igual a 2, n” es igual a 1, n"' es igual a 2, n”” es igual a 4, y R7 es metilo. La presente invención también describe un compuesto, o una sal del mismo, que comprende la Fórmula (III), (IV), (V) o (VI):

Claims (8)

  1. 5
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    1. Un compuesto que tiene: (i) Fórmula (I):
    imagen1
    en donde:
    Z tiene la estructura de:
    imagen2
    R5 es H, COR8, C1-C6 alquilo o tiazol;
    R8 es OH o -NH-(alquileno-O)n-NH2;
    R6 es OH o H;
    Ar es fenilo o piridina;
    R7 es C1-C6 alquilo o hidrógeno;
    Y se selecciona del grupo que consiste en una hidroxilamina;
    L es un enlazador seleccionado del grupo que consiste en -alquileno-, -alquileno-C(O)-, -(alquileno-O)n-alquileno-, - (alquileno-O)n-alquileno-C(O)-, -(alquileno-O)n- (CH2)n'-NHC(O)-(CH2)n"-C(Me)2-S-S-(CH2)n'"-NHC(O)-(alquileno-O)n— alquileno-, -(alquileno-O)n-alquileno-W-, -alquileno-C(O)-W-, -(alquileno-O)n-alquileno-U-alquileno-C(O)- y -
    (alquileno-O)n-alquileno-U-alquileno-;
    W tiene la estructura de:
    imagen3
    U tiene la estructura de:
    imagen4
    o L está ausente, Y es metilo, R5 es COR8, y R8 es -NH-(alquileno-O)n-NH2; y cada n, n', n”, n'" y n”” son independientemente enteros mayores que o iguales a uno;
    5
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    o una sal del mismo;
    (ii) Fórmula (III), (IV), (V) o (VI):
    imagen5
    imagen6
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    imagen7
    imagen8
    en donde:
    Z tiene la estructura de:
    imagen9
    R5 es H, COR8, C1-C6 alquilo o tiazol;
    R8 es OH;
    R6 es OH o H;
    Ar es fenilo o piridina;
    R7 es C1-C6 alquilo o hidrógeno;
    Y y V se seleccionan cada uno del grupo que consiste en una hidroxilamina;
    L1, L2, L3 y L4 son cada uno de los enlazadores seleccionados independientemente del grupo que consiste en un enlace, -alquileno-, -(alquileno-O)n-alquileno-J-, -alquileno'-J-(alquileno-O)n-alquileno-, -J-(alquileno-O)n-alquileno-, - (alquileno-O)n-alquileno-J-(alquileno-O)n-alquileno-J'-, -(alquileno-O)n-alquileno-J-alquileno'-, -W-, -alquileno-W-, alquileno'-J-(alquileno-NMe)n-alquileno-W-, -J-(alquileno-NMe)n-alquileno-W-, -J-alquileno-NMe-alquileno'-NMe-
    5
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    alquileno”-W-, y -alquileno-J-alquileno-NMe-alquileno”-NMe-alquileno”'-W-; W tiene la estructura de:
    imagen10
    cada J y J' tienen independientemente la estructura de:
    imagen11
    o
    imagen12
    y
    cada n y n' son independientemente enteros mayores que o iguales a uno; o una sal del mismo
  2. 2. El compuesto de la reivindicación 1 que tiene la Fórmula (I), o una sal del mismo.
  3. 3. El compuesto de cualquier reivindicación precedente que tiene la Fórmula (I), (III) o (V), donde R5 es tiazol o ácido carboxílico.
  4. 4. El compuesto de cualquier reivindicación precedente que tiene la Fórmula (I), (III) o (V), en donde Ar es fenilo.
  5. 5. El compuesto de cualquier reivindicación precedente en el que cada alquileno, alquileno', alquileno'' y alquileno''
    es independientemente -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -
    CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2-, -
    CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, -
    CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-, o -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-.
  6. 6. El compuesto de cualquiera de las reivindicaciones precedentes en el que la Fórmula (I) es:
    5
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    imagen13
    imagen14
    imagen15
    imagen16
    imagen17
    imagen18
    imagen19
    imagen20
    5
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    imagen21
    5
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    imagen22
    5
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    imagen23
    ; o
    imagen24
  7. 7. El compuesto de cualquiera de las reivindicaciones anteriores en el que la Fórmula (I) es:
    imagen25
    imagen26
    a
    o □ a a
    2 a. 1 |
    Z-
    CN
    □
    □
    m ■
    imagen27
    o_
    LV205
    LK145
    HS163
    HE272
    HK329
    HN289
    HH288
    HK217
    HK213
    HN211
    HT200
    HS122
    HA121
    wt
    FIG. 2
    147
    C
    ~9
    a
    K
    c
    ra
    T.
    EZE5? Z
    imagen28
    HS163
    HE272
    HK329
    HN289
    HK288
    HK217
    HK213
    HN211
    HT200
    HS122
    HA121
    wt
    en
    E
    Q.
    FIG. 3
    148
    % de control de medio
    Ensayo de proliferación HCC1953 enlazador de dolastatina 100810, IV
    imagen29
    1e-5 1e-4 1e-3 1e-2 1e-1 1e+0 1e*1 1e*2 1e+3
    log[nM]
    • Dolastatina (fármaco libre) CI50=0,04nM R2=0,9951 Q WT hier vs Her ▼ NCL-D1 Ci50<0.01nM v NCL D-2 Ci5O<0,0lnM ■ PHC-D-2 Ci50=2nM R2=0.9981
    imagen30
    Ensayo de proliferación HCC1954
    Conjugados de Herx-tox, 100810, IV
    imagen31
    100 -
    60
    40
    20
    1000
    0,0001
  8. 0.001
    logfnM]
    Doas;a:na ífarmaco libre} CI5Q=0.07nM RZ-Q.9S59
    WT Her vs WT Herceplm
    4D5-A121 NCL D-1 CiSO-0 15nM R2=0,9990
    4D5-A121-l\ICL-D-2 Cl5ü=0 n.nM R2=0.9937
    V
    4D&-A121-PHC-D-2Ci50=0.12nM R2=O.9980
    F G. 5
    % de corirgl ce medio
    Ensayo de proliferación SKOV3
    imagen32
    logfnMJ
    • Dolastaüna [fármaco libre)CI5C=Ü. 15nM R2=0,9954 o WT Herceptin IC50=>300nM ▼ NC-D-1 ci5D<o inM v NL O'2Ci5C=0.08nM R2=0-9830'
    ■ PHC-D-2Ci50=8nM R2=0 9970
    FIG.6
    %■ de control cíe medio
    Ensayo de proliferación SKOV3 Conjugados Her-tox 101210 IV
    imagen33
    0,0001 0 001 0,01 0,1 1 10 100 1000
    log[rM]
    • Dolasiatina (fármaco libre] CI5Q-Q.2pM R2=Q,993& O WT Herceptin IC50=>30ÜnM ▼ 4D5-A121-NCL-D-1 Ci50=1 3nM R2=0.9987
    v 4D5-A121-NCL-D 2 CI50=1,3,nM R2=0.9287*
    ■ 4D5-A121 -PHC-D-2 C i5ü=Q,3nM R2=0.9992
    FIG. 7
    % de control de medio
    Ensayo de proliferación MDA-MB-468 Enlazador de dolastatina 100810, IV
    imagen34
    1e-5 1e4 1e-3 1e-2 1e-1 1e+0 1e+1 1e+2 1e+3
    log[nM]
    • Dolasiatinú (fármaco libro) *0,01 nM o WTHercept¡nci5O=>300nM v NCL-D-1 ciso <Q.1nM ▼ NCL-D2 ciso=0r3nM R2=0.9438
    ■ PHC-D2 CI&0=1.6nM R2=Ü,9984
    FIG. 8
    % de control de medio
    Ensayo de proliferación MDA-MB-468 Conjugados de Her-tox, 100810, IV
    imagen35
    1e-5 1M 1e-3 1e-2 1e-1 1e+0 ie+1 1e+2 ie+3
    log[nM]
    • Doiasiatina (fármaco I ib reí
    o WT Herceplin >3ÜGnM
    v 4D5-A121-NC-D1 ci5Cs >10GnM
    t 405-A121-NC D2 Ci50= >1 OOnM
    ■ 4D5-A121-PHC-D2 ci5t=5.SnM R2=Ü,9882'
    FIG. 9
    imagen36
    vahííütc IV un* íti
    trastuiumab 3 3 nrtg.'kg trasUizumab 10 mg/ng * trastuzuroab20 mgkg
    Her-HS123-MC1D3.3 miyKj -o- hef-HS1?MJClDl0nts/k5 her-HS12MClD2Dmc/kg Her-HS122/LK WS HC ‘ 0 3 3 mg/kg her-HS12^LK‘4GHC1D10mgjVg ^ h er-HS122/LK145- H C ‘ D 20 mg.kg -*■ pací laxe 25 mgfcg V qo<Jx5
    —l
    35
    imagen37
    Formatos do ensayo utilizados para medirla concentración do dorivado do dolastatina ligada a HER2 on suero do ratón dolastatina do molócula pequera (SM)
    imagen38
    Aplicación:
    •Perfil PK para HER2 SM •Ab na conjugado •Ab conjugado
    imagen39
    Conc. do su oro {ng/mL) Conc. do suero {ngJmL]
    imagen40
    imagen41
    imagen42
    hora* Ir» InyéítiÓrt IV únk*
    ♦ HER-HS122-NC10
    * HER-HS122-HC1D
    HER-HS122-PHC?D
    HER-HA121-NC1D
    HER-HA121-HC1D
    imagen43
    158
    100000 10000
    Conc. do guaro <
    (ng/mL) 1000 100
    10 t 1 t 1 T 1
    0 100 200 300 400 600
    horas tras Inyección IV única
    imagen44
    HER-HS122-NC1D HER-HS122-HC1D HER-HS122-PHC2D ■W- HER-HS122ÍLK145-NC1D HER-H$122fl_K145-HC1D ^ HER-HA121-NC1D -B- HER-HA121-NC1D
    FIG. 13
    Cnnc. ¡Ir sunrn (ng.'rrl.)
    imagen45
    Pma mrpnrtl (g)
    Datos de resumen medios de grupo HCC1954-e202 (TV = 1.000 mm3 o Día 60)
    imagen46
    imagen47
    Vorucuio IV una ve2
    trastuzumab 3.3 mgkg
    trastuzumab 10 mg/kg
    trastuzumab 20 mg/kg
    HS122-NC1D 3 3 mg/kg
    Volumen 400 -
    HS122-NCID 10 mg/kg
    tumora
    (mm’l
    HS122-NC1D 20 mg/kg
    HS122/LK145-HC1D 3 3 mg/kg
    HS122/LK145-HC1D 10 mg/kg
    200 -
    HS122/LK145-HC1D 20 mg/kg
    paclitaxel 25 mg/kg IV qodx5
    Días iras dosis iv única en el día i
    FIG. 16
    Ve lumen
    Mama MDA361DYT2 (2+)
    imagen48
    Da
    Ver (culo
    -o- AmbotAI NC Di lOng/kg Ambot A1-NC*D*1 3 rngrttg -4- AubncAl-NC'tM 1 mgAg Al mcMWAD 10 nig/kg _cv A1 mcMWAD 3 mg^g Al mcMMAF 1 mgAg A1 mcMMAF 10 mg/kg
    imagen49
    imagen50
    '500
    Vehículo
    121NCMJ1 lümgrt.g
    1000
    121NC-D1 3 mufla
    121NC-D1 1 oiQKQ
    AlncMMAJ 10 mg/kg
    AlmcMMA j 3 rng/M
    AlntiMMAj 1 mqíkg
    500
    A1ndMMAr lOngflig
    AlncMMA- 3 mgAc
    □ j
    FG. 18
    Modelo de xenoinjerto de Mama MDA361DYT2 (2+)
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