US 2013/0157960 A1Published application

Novel auristatin derivatives and use thereof

AssigneeSeattle Genetics, Inc.

InventorsHans-Georg Lerchen, Beatrix Stelte-Ludwig, Sven Golfier, Joachim Schuhmacher, Ursula Krenz

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Abstract

The present application relates to novel derivatives of monomethylauristatin F, to processes for preparing these derivatives, to the use of these derivatives for treating and/or preventing diseases, and also to the use of these derivatives for preparing medicaments for treating and/or preventing diseases, more particularly hyperproliferative and/or angiogenic disorders such as, for example, cancerous disorders. Such treatments may be practised as a monotherapy or else in combination with other medicaments or further therapeutic measures.

Claims10

Dependent claims

A compound of the formula (I)

or its salt, solvate, or solvate of the salt,
in which
R1 is hydrogen, (C1-C6)-alkyl or a group of the formula Q1L1-* or Q2L2-* in which
* denotes the point of attachment to the nitrogen atom,
Q1 is hydroxycarbonyl, (C1-C4)-alkoxycarbonyl or benzyloxycarbonyl,
L1 is a straight-chain (C1-C12)-alkanediyl which is optionally substituted up to four times by methyl and in which (a) two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
Q2 is hydroxyl, amino or mono-(C1-C4)-alkylamino,
and
L2 is a straight-chain (C2-C12)-alkanediyl which is optionally substituted up to four times by methyl and in which (a) two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
R2 is methyl or hydroxyl,
R3 is hydrogen or methyl,
R4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R3 and R4 together with the carbon atom to which both are attached form a 2-phenylcyclopropane-1,1-diyl group of the formula
in which
# denotes the points of attachment to the other parts of the molecule
and
ring A with the N—O grouping contained therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
** denotes the point of attachment to the carbonyl group,
R5 and R6 each represents is hydrogen, hydroxyl, (C1-C4)-alkoxy or benzyloxy,
and
R7 is hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl.

20 more elements

A process for preparing a compound of the formula (I)

or its salt, solvate, or solvate of the salt,
in which
R1 is hydrogen, (C1-C6)-alkyl or a group of the Q1-L1-* or Q2-L2-* in which
* denotes the point of attachment to the nitrogen atom,
Q1 is hydroxycarbonyl, (C1-C4)-alkoxycarbonyl or benzyloxycarbonyl,
L1 is a straight-chain (C1-C12)-alkanediyl which is optionally substituted up to four times by methyl and in which (a) two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
Q2 is hydroxyl, amino or mono-(C1-C4)-alkylamino,
and
L2 is a straight-chain (C2-C12)-alkanediyl which is optionally substituted up to four times by methyl and in which (a) two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
R2 is methyl or hydroxyl,
R3 is hydrogen or methyl,
R4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R3 and R4 together with the carbon atom to which both are attached form a 2-phenylcyclopropane-1,1-diyl group of the formula
in which
# denotes the points of attachment to the other parts of the molecule
and
ring A with the N—O grouping contained therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
** denotes the point of attachment to the carbonyl group,
R5 and R6 each is hydrogen, hydroxyl, (C1-C4)-alkoxy or benzyloxy,
and
R7 is hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl in which a compound of the formula (II)
in which R2 has the meaning given in the formula (I) and
PG is an amino protective group,
is coupled in an inert solvent with activation of the carboxyl function in (II) either
[A] first with the compound of the formula (III)
or a salt thereof to give a compound of the formula (IV)
in which R2 has the meaning given in the formula (I) and PG has the meaning given in the formula (II),
and this compound is then coupled in an inert solvent with activation of the carboxyl function with a compound of the formula (V)
in which R3, R4 and ring A each has the meaning given in the formula (I), or a salt of this compound, to give a compound of the formula (VI)
in which R2, R3, R4, ring A each has the meaning given in the formula (I) and PG has the meaning given in the formula (II),
Or
[B] with a compound of the formula (VII)
in which R3, R4 and ring A each has the meaning given in the formula (I), or a salt of this compound, to give the compound of the formula (VI)
in which R2, R3, R4, and ring A each has the meaning given in the formula (I) and PG has the meaning given in the formula (II),
and the respective resulting compound of the formula (VI) is deprotected to give a compound of the formula (I-B)
in which R2, R3, R4 and ring A each has the meaning given in the formula (I),
and this is optionally converted either (i) by base-induced alkylation with a compound of the formula (VIII)
R1A—X (VIII)
in which
R1A has the meaning of R1-given in the formula (I), but is not hydrogen,
and
X is a leaving group,
into a compound of the formula (I-C)
in which R1A has the meaning given in the formula (VIII), and R2, R3, R4 and ring A each has the meaning given in the formula (I) or (ii) by reaction with a compound of the formula (IX)
in which
R1B has the meaning of R1A given in the formula (VIII), but with the alkyl chain length reduced by one CH2 unit,
in the presence of a reducing agent into a compound of the formula (I-D)
in which R1B has the meaning of R1A given in the formula (VIII), but with the alkyl chain length reduced by one CH2 unit, and R2, R3, R4 and ring A each has the meaning given in the formula (I),
and the compounds of the formulae (I-B), (I-C) and (I-D) are optionally separated into their enantiomers and/or diastereomers and/or converted with the appropriate (i) solvents and/or (ii) bases or acids into their solvates, salts and/or solvates of the salts.

48 more elements

A medicament comprising a compound of the formula (I)

or its salt, solvate, or solvate of the salt,
in which
R1 is hydrogen, (C1-C6)-alkyl or a group of the formula Q1-L1-* or Q2-L2-* in which
* denotes the point of attachment to the nitrogen atom,
Q1 is hydroxycarbonyl, (C1-C4)-alkoxycarbonyl or benzyloxycarbonyl,
L1 is a straight-chain (C1-C12)-alkanediyl which is optionally substituted up to four times by methyl and in which a two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
Q2 is hydroxyl, amino or mono-(C1-C4)-alkylamino,
and
L2 is a straight-chain (C2-C12-alkanediyl which is optionally substituted up to four times by methyl and in which (a) two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
R2 is methyl or hydroxyl,
R3 is hydrogen or methyl,
R4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 4-hydroxybenzyl 4-hydroxy-3-nitrobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R3 and R4 together with the carbon atom to which both are attached form a 2-phenylcyclopropane-1,1-diyl group of the formula
in which
# denotes the points of attachment to the other parts of the molecule
and
ring A with the N—O grouping contained therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
** denotes the point of attachment to the carbonyl group,
R5 and R6 each is hydrogen, hydroxyl, (C1-C4)-alkoxy or benzyloxy,
and
R7 is hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl,
and pharmaceutically suitable auxiliaries.

21 more elements

A method for the treatment of cancerous and tumour disorders in humans and animals comprising the administration of an effective amount of a compound of the formula (I):

or its salt, solvate, or solvate of the salt,
in which
R1 is hydrogen, (C1-C6)-alkyl or a group of the formula Q1-L1-* or Q2-L2-* in which
* denotes the point of attachment to the nitrogen atom,
Q1 is hydroxycarbonyl, (C1-C4)-alkoxycarbonyl or benzyloxycarbonyl,
L1 is a straight-chain (C1-C12-alkanediyl which is optionally substituted unto four times by methyl and in which (a) two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
Q2 is hydroxyl, amino or mono-(C1-C4)-alkylamino,
and
L2 is a straight-chain (C2-C12)-alkanediyl which is optionally substituted up to four times by methyl and in which (a) two carbon atoms are optionally bridged in 1,2-, 1,3- or 1,4-relation to one another including any carbon atoms located between them to form a (C3-C6)-cycloalkyl ring or a phenyl ring or (b) up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
R2 is methyl or hydroxyl,
R3 is hydrogen or methyl,
R4 is isopropyl, isobutyl, sec-butyl, tart-butyl, phenyl, benzyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl,
or
R3 and R4 together with the carbon atom to which both are attached form a 2-phenylcyclopropane-1,1-diyl group of the formula
in which
# denotes the points of attachment to the other parts of the molecule
and
ring A with the N—O grouping contained therein is a mono- or bicyclic, optionally substituted heterocycle of the formula
in which
** denotes the point of attachment to the carbonyl group,
R5 and R6 each is hydrogen, hydroxyl, (C1-C4)-alkoxy or benzyloxy,
and
R7 is hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/702,881Filed 6 Jun 2011
Priority: EP 10165550.410 Jun 2010
Published: 20 Jun 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07K 7/02
Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof: linear peptides containing at least one abnormal peptide link
A61K 38/08
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides having 5 to 11 amino acids
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents

Family

US 8,722,629 B2Related patent
US 2013/0157960 A1This patent

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

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