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Compositions Comprising Enzyme-Cleavable Ketone

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Compositions Comprising Enzyme-Cleavable Ketone (19) TZZ _T (11) EP 2 475 429 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 489/02 (2006.01) C07D 489/08 (2006.01) 29.07.2015 Bulletin 2015/31 A61K 31/485 (2006.01) A61P 25/00 (2006.01) (21) Application number: 10815769.4 (86) International application number: PCT/US2010/031956 (22) Date of filing: 21.04.2010 (87) International publication number: WO 2011/031350 (17.03.2011 Gazette 2011/11) (54) COMPOSITIONS COMPRISING ENZYME- CLEAVABLE KETONE-MODIFIED OPIOID PRODRUGS AND OPTIONAL INHIBITORS THEREOF ZUSAMMENSETZUNGEN AUS ENZYMSPALTBAREN KETONMODIFIZIERTEN OPIOID- PRODRUGS UND OPTIONALEN HEMMERN DAFÜR COMPOSITIONS COMPORTANT DES PROMÉDICAMENTS OPIOÏDES MODIFIÉS PAR CÉTONE, CLIVABLES PAR ENZYME ET INHIBITEURS FACULTATIFS DE CEUX- CI (84) Designated Contracting States: • HUSFELD, Craig O. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR California 94070 (US) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • SEROOGY, Julie D. PT RO SE SI SK SM TR CA 94070 (US) Designated Extension States: • WRAY, Jonathan W. AL BA ME RS 94070 (US) (30) Priority: 08.09.2009 US 240611 P (74) Representative: Wytenburg, Wilhelmus Johannes 18.12.2009 US 288148 P et al Mewburn Ellis LLP (43) Date of publication of application: City Tower 18.07.2012 Bulletin 2012/29 40 Basinghall Street London EC2V 5DE (GB) (73) Proprietor: Signature Therapeutics, Inc. Palo Alto, CA 94303 (US) (56) References cited: US-A1- 2005 176 644 US-A1- 2009 136 980 (72) Inventors: US-A1- 2009 137 618 US-A1- 2009 209 569 • JENKINS, Thomas E. US-B1- 7 060 290 CA 94070 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 475 429 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 475 429 B1 Description Introduction 5 [0001] Ketone-containing opioids are susceptible to misuse, abuse, or overdose. Use of and access to these drugs therefore needs to be controlled. The control of access to the drugs is expensive to administer and can result in denial of treatment for patients that are not able to present themselves for dosing. For example, patients suffering from acute pain may be denied treatment with an opioid unless they have been admitted to a hospital. Furthermore, control of use is often ineffective, leading to substantial morbidity and deleterious social consequences. 10 Summary of the Invention [0002] A first aspect of the invention is a compound of the formula: 15 20 wherein: X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group 5 1 2 3 4 of the ketone is replaced by a covalent bond to -C(O)-NR -(C(R )(R ))n-NR R ; 25 R5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or R1 and R2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 30 or two R1 and R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; n is an integer from 2 to 4; R3 is hydrogen; R4 is 35 40 each R6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R6 and R7 together with the atoms to which they are bonded form a cycloheteroalkyl 45 or substituted cycloheteroalkyl ring; each W is independently -NR8-, -O- or -S-; each R8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 50 p is an integer from one to 100; and R7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycar- bonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof. 55 [0003] In one embodiment, the compound is a compound of the formula: 2 EP 2 475 429 B1 5 10 wherein: Ra is hydrogen or hydroxyl; 15 R5 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl; each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or R1 and R2 together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; 20 or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl group; n is an integer from 2 to 4; R3 is hydrogen; R4 is 25 30 each R6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, 35 or optionally, R6 and R7 together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each W is independently -NR8-, -O- or -S-; each R8 is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or optionally, each R 6 and R 8 independently together with the atoms to which they are bonded form a cycloheteroalkyl 40 or substituted cycloheteroalkyl ring; p is an integer from one to 100; and R7 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycar- bonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof. 45 [0004] In one embodiment, the compound is a compound of the formula: 50 wherein: 55 X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding enolic group 5 1 2 3 4 of the ketone is replaced by a covalent bond to -C(O)-NR -(C(R )(R ))n-NR R ; 5 R is selected from (1-6C)alkyl, (1-6C) substituted alkyl, -(CH2)q(C6H4)-COOH, -(CH2)q(C6H4)-COOCH3, and 3 EP 2 475 429 B1 -(CH2)q(C6H4)-COOCH2CH3, where q is an integer from one to 10; each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or R1 and R2 together with the carbon to which they are attached form a cycloalkyl or substituted cycloalkyl group; 5 or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; n is 2 or 3; R3 is hydrogen; R4 is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, 10 glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, pheny- lalanine, proline, serine, threonine, tryptophan, tyrosine and valine or a residue of an N-acyl derivative thereof; 15 or a salt, hydrate or solvate thereof. [0005] In one embodiment, the compound is a compound of the formula: 20 25 30 wherein: Ra is hydrogen or hydroxyl; 5 R is selected from (1-6C)alkyl, (1-6C) substituted alkyl, -(CH2)q(C6H4)-COOH, -(CH2)q(C6H4)-COOCH3, and -(CH2)q(C6H4)-COOCH2CH3, where q is an integer from one to 10; 35 each R1 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl; or R1 and R2 together with the carbon to which they are attached form a cycloalkyl and substituted cycloalkyl group; or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a cycloalkyl or substituted cycloalkyl group; 40 n is 2 or 3; R3 is hydrogen; R4 is a residue of an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, or a residue of an N-acyl derivative of any of said amino acids; or a residue of a 45 peptide composed of at least two L-amino acid residues selected independently from alanine, arginine, asparagine, aspartic
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