# US 2013/0157960 A1 · Novel auristatin derivatives and use thereof

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- Number: US 2013/0157960 A1
- Document ID: US20130157960A1
- Status: Published application
- Kind: A1
- Application number: 13/702,881
- Filed: 2011-06-06
- Published: 2013-06-20
- Earliest claimed: 2010-06-10
- Assignees: Seattle Genetics, Inc.
- Inventors: Hans-Georg Lerchen; Beatrix Stelte-Ludwig; Sven Golfier; Joachim Schuhmacher; Ursula Krenz
- Web page: https://patentgrep.com/patent/US20130157960A1

## CPC

- C07K 7/02: Linear peptides containing at least one abnormal peptide link
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07K 5/0205: {containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of the formula (I) according to claim 1, or its salt, solvate, or solvate of the salt, in which
R1 is hydrogen, (C1-C4)-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 or (C1-C4)-alkoxycarbonyl,
L1 is a straight-chain (C1-C12)-alkanediyl in which (a) two carbon atoms are optionally bridged in 1,3- or 1,4-relation to one another including the one or the two carbon atom(s) located between them to form 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 methylamino
and
L2 is a straight-chain (C2-C12)alkanediyl which is optionally mono- or disubstituted by methyl and in which up to three CH2 groups not adjacent to one another are optionally replaced by —O—,
R2 is methyl or hydroxyl,
R3 is hydrogen,
R4 is benzyl, 4-hydroxybenzyl, 1-phenylethyl 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,
and
R5 is hydrogen, hydroxyl or benzyloxy.

### Claim 3 (depends on 1)

The compound of the formula (I) according to claim 1, or its salt, solvate, or solvate of the salt, in which
R1 is hydrogen, methyl 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, methoxycarbonyl or ethoxycarbonyl,
L1 is a straight-chain (C1-C6)-alkanediyl in which two carbon atoms are optionally bridged in 1,4-relation to one another including the two carbon atoms located between them to form a phenyl ring,
Q2 is hydroxyl or amino,
and
L2 is a straight-chain (C2-C6)-alkanediyl,
R2 is methyl,
R3 is hydrogen,
R4 is benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl,
or
R3 and R4 together with the carbon atom to which both are attached form a (1S,2R)-2-phenylcyclopropane-1,1-diyl group of the formula
in which
#1 denotes the point of attachment to the adjacent nitrogen atom
and
#2 denotes the point of attachment to the carbonyl group
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,
and
R5 is hydrogen, hydroxyl or benzyloxy.

### Claim 4 (depends on 1)

The compound of claim 1 having the formula (I-A)
or its salt, solvate, or solvate of the salt., in which R1, R2, R3, R4 and ring A have the meanings defined in claim 1 and the CX carbon atom carrying the radicals R3 and R4 has the S configuration as shown.

### Claim 5

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.

### Claim at position 6

-8. (canceled)

### Claim 9

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.

### Claim 10 (depends on 9)

The medicament of claim 9 in combination with one or more further active compounds.

### Claim 11

(canceled)

### Claim 12

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.