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Hydrazine-Based and Carbonyl-Based Bifunctional Crosslinking Reagents

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Hydrazine-Based and Carbonyl-Based Bifunctional Crosslinking Reagents (19) TZZ_¥_5699B_T (11) EP 1 315 699 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 207/46 (2006.01) C07D 401/12 (2006.01) 02.01.2013 Bulletin 2013/01 C08G 65/329 (2006.01) C07F 7/18 (2006.01) C07D 213/82 (2006.01) A61K 47/48 (2006.01) (2006.01) (2006.01) (21) Application number: 01920666.3 C07K 17/06 C07K 17/14 C12N 11/06 (2006.01) C12N 11/14 (2006.01) (22) Date of filing: 22.03.2001 (86) International application number: PCT/US2001/009252 (87) International publication number: WO 2001/070685 (27.09.2001 Gazette 2001/39) (54) HYDRAZINE-BASED AND CARBONYL-BASED BIFUNCTIONAL CROSSLINKING REAGENTS HYDRAZIN- UND CARBONYL-BASIERTE BIFUNKTIONELLE VERNETZUNGSMITTEL AGENTS DE RETICULATION BIFONCTIONNELS A BASE D’HYDRAZINE ET DE CARBONYLE (84) Designated Contracting States: • W.L. SCOTT ET AL: BIOORG. MED. CHEM. LETT., AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU vol. 6, no. 13, 1996, pages 1491-1496, MC NL PT SE TR XP002202926 • G.SZOKAN ETAL: J. CHIN. CHEM. SOC. (TAIPEI), (30) Priority: 22.03.2000 US 191186 P vol. 44, no. 5, 1997, pages 519-526, XP000925994 • T. CURTIUS ET AL: CHEM. BER., vol. 43, 1910, (43) Date of publication of application: pages 2457-2467, XP002202927 04.06.2003 Bulletin 2003/23 • D. GILLESSEN ET AL: DEV. ENDOCRINOL., vol. 13, 1981, pages 37-47, XP000926737 (60) Divisional application: • DATABASECA [Online] CHEMICAL ABSTRACTS 10184127.8 / 2 295 407 SERVICE, COLUMBUS, OHIO, US; STN, CAPLUS 10184203.7 / 2 298 736 accession no. 1986:573000, XP002223793 & JP 61 057595 A (YUKI GOSEI KOGYO CO LTD) 24 (73) Proprietor: Solulink, Incorporated March 1986 (1986-03-24) San Diego, CA 92121 (US) • E. LUKEVITS ET AL: J. GEN. CHEM. USSR, vol. 47, 1977, pages 101-104, XP001041813 (72) Inventor: SCHWARTZ, David, A. • B. BLANK ET AL: J. MED. CHEM. , vol. 17, no. 10, Encinitas, CA 92024 (US) 1974, pages 1065-1071, XP002158204 • DATABASE CAPLUS [Online] CHEMICAL (74) Representative: Ritter, Thomas Kurt et al ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Jones Day retrieved from STN Database accession no. 1980: Prinzregentenstraße 11 180407 XP002223794 & S.M. SHEVCHENKO ET 80538 München (DE) AL: KHIM. GETEROTSIKL. SOEDIN., no. 12, 1979, pages 1637-1647, (56) References cited: • J.R. NULU ET AL: TETRAHEDRON LETT., vol. 10, EP-A- 0 326 863 EP-A- 0 384 769 no. 17, 1969, pages 1321-1324, XP001109223 EP-A- 0 665 020 WO-A-01/09385 • O.P. SHVAIKA ET AL: SOV. PROG. CHEM., vol. WO-A-86/06073 WO-A-90/03401 37, no. 2, 1971, pages 55-61, XP001040695 WO-A-90/10621 WO-A-94/10149 • L. KATZ ET AL: J. ORG. CHEM., vol. 18, no. 10, WO-A-95/15769 WO-A-99/52861 1953, pages 1380-1402, XP002223788 GB-A- 782 420 US-A- 3 180 875 • D.L. KLAYMAN ET AL: J. ORG. CHEM., vol. 33, US-A- 4 797 491 US-A- 4 882 399 no. 2, 1968, pages 884-887, XP002223789 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 1 315 699 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 315 699 B1 • R.R. WEBB II ET AL: BIOCONJUGATE CHEM, vol. • DATABASE CAPLUS [Online] CHEMICAL 1, no. 2, 1990, pages 96-99, XP002223790 ABSTRACTS SERVICE, COLUMBUS, OHIO, US; • DATABASE CAPLUS [Online] CHEMICAL retrieved from STN Database accession no. 1975: ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 478986 XP002223796 -& CHEMICAL retrieved from STN Database accession no. 1988: ABSTRACTS, vol. 83, no. 9, 1 September 1975 38245 XP002223795 -& CHEMICAL ABSTRACTS, (1975-09-01) Columbus, Ohio, US; abstract no. vol. 108, no. 5, 1 February 1988 (1988-02-01) 78986, XP002223792 & S.I. SADYKH- ZADE ET AL: Columbus, Ohio, US; abstract no. 38245, UCH. ZAP. AZERB. GOS. UNIV., SER. KHIM. XP002223791 & A.R. KHOMUTOV ET AL: NAUK, no. 2, 1972, pages 33-37, BIOORGANICHESKAYA KHIMIYA, vol. 12, no. 12, • M.A.BAKER ET AL:JOURNAL OF CONTROLLED 1986, pages 1662-1674, RELEASE, vol. 40, no. 1-2, 1996, pages 89-100, • L. BAUER ET AL: J. ORG. CHEM., vol. 30, 1965, XP000589917 pages 949-951, XP002128002 • T. KANEKO ET AL: BIOCONJUGATE CHEMISTRY, vol. 2, no. 3, 1991, pages 133-141, XP000215610 cited in the application 2 EP 1 315 699 B1 Description [0001] The present disclosure may be applied in general to the field of chemistry, more particularly in the area of crosslinking reagents. 5 [0002] Methods to crosslink biomolecules such as proteins, oligonucleotides and carbohydrates to each other, to radioactive and nonradioactive metal chelates, to drugs and to surfaces have allowed development of both in vitro and in vivo diagnostic assays as well as in vivo therapies. A wide variety of methods have been developed and reviewed (Greg T. Hermanson, Bioconjugate Techniques, Academic Press). [0003] There are a limited number of crosslinking couples,i.e., maleimide/thiol and bromoacetamide/thiol, that are 10 routinely used to prepare conjugates for diagnostic and therapeutic uses. These reagents have limitations in that at high protein concentrations (i.e., >5 mg/mL) protein/protein crosslinking may occur. Also, the maleimido-modified moieties have a limited half-life due to hydrolysis at neutral and basic pH. Incorporation of thiol moieties on biomolecules requires both a coupling and a subsequent activation step. The resultant thiol- modified proteins can readily oxidize to form disulfide polymerized proteins. Also macromolecules containing disulfide bonds,i.e., antibodies, are readily cleaved following 15 activation of the thiol moiety by a reductant. Also, quantitation of the maleimido moiety is somewhat difficult and there is no means to quantify directly the level of conjugation. Therefore, it is advantageous to have a crosslinking couple that does not have these limitations. [0004] Consequently there is a need for crosslinking couples that: bind more efficiently to surfaces; may be controlled to achieve desired crosslinking; do not lead to homobifunctional crosslinking following modification of aggregated proteins; 20 are stable to biological conditions of varying pH and temperature; are stable in solution or when lyophilized; are one step modifications unlike those reagents currently used in the art, e.g., SATA, SPDP type reagents; can be indirectly quantified by a spectrophotometric assay; and can be used to quantify the level of conjugation by spectrophotometric means utilizing the bond formed following conjugation. [0005] Therefore, it is an object herein to provide reagents and methods for crosslinking biomolecules to other bio- 25 molecules, polymers, metals or drugs that meet the above needs and have improved properties over known crosslinking reagents and methods. [0006] The present invention relates to the compounds, conjugates and methods of the appended claims. [0007] Reagents and methods for crosslinking biomolecules to other biomolecules, polymers, metals or drugs are provided. The reagents are heterobifunctional compounds, all as defined herein. The reagents are used in the methods 30 provided herein to afford improved crosslinking for both in vitro and in vivo diagnostic assays as well as in vivo therapies. [0008] Provided herein are bifunctional compounds containing amine reactive moieties and a hydrazino moiety that may be utilized to modify small molecules, macromolecules, biomolecules and solid surfaces. A number of hydrazino moieties may be utilized including aliphatic and aromatic hydrazine derivatives, including hydrazines, semicarbazides, carbazides, thiosemicarbazides and thiocarbazides (see, e.g., FIGURE 1). 35 [0009] Also described herein are reagents that have the formula: B-R-Y or a derivative thereof, where B is an amino or thiol reactive moiety; Y is a hydrazino group, as defined herein, an 40 oxyamino group or a carbonyl group; and R is a divalent group having any combination of the following groups, which 10 10 10 12 13 12 are combined in any order: arylene, heteroarylene, cycloalkylene, C (R )2, -C(R )=C(R )-, >C=C(R )(R ), >C(R ) 13 10 10 10 + 12 13 (R ), -C≡C-, O, S(G)a, P(J)b(R ), P(J)b(LR ), N(R ), >N (R )(R ) and C(L); where a is 0, 1 or 2; b is 0, 1, 2 or 3; G is O or NR 10; J is S or O; and L is S, O or NR 10; each R 10 is a monovalent group independently selected from hydrogen and M1-R14; each M1 is a divalent group independently having any combination of the following groups, which groups 45 15 15 15 12 are combined in any order: a direct link, arylene, heteroarylene, cycloalkylene, C(R )2, -C(R )=C(R )-, >C=C(R ) 13 12 13 1 15 15 15 15 + 12 13 (R ), >C(R )(R ), -C≡C-, O, S(G )a, P(J)b(R ), P(J)b(LR ), N(R ), N(COR ), >N (R )(R ) and C(L); where a is 0, 1 or 2; b is 0, 1, 2 or 3; G’ is O or NR15; J is S or O; and L is S, O or NR15; R14 and R15 are each independently selected from the group among hydrogen, halo, pseudohalo, cyano, azido, nitro, SiR16R17R18, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, het- 50 erocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, hydroxy, alkoxy, aryloxy, aralkoxy, heteroaralkoxy and NR 19R20; R19 and R 20 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and heterocyclyl; R12 and R13 are selected from (i) or (ii) as follows: (i) 12R and R13 are
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