US4680338A
Expired / Lapsed
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Bifunctional linker
Assignee: Immunomedics Inc
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Filing: 1985-10-17
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Granted: 1987-07-14
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Expires: 2005-10-17
Abstract
Abstract A selective bifunctional sequential linker has the formula Y═C═N--Q--A--C(O)--Z wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; Y is O or S; and Z is Cl, Br, I, N 3 , N-succinimidyloxy, imidazolyl, 1-benzotriazolyloxy, OAr where Ar is an electron-deficient activating aryl group, or OC(O)R where R is --A--Q--N═C═Y or C 4-20 tertiary-alkyl. A method for activating an amine function towards reaction with a second amine involves reacting the amine with the foregoing linker. The resultant isocyanate or isothiocyanate derivative can then be reacted with a second amine to form a urea or thiourea conjugate. The linker is useful for producing conjugates of ligands with amine-containing polymers and/or proteins, especially for forming antibody conjugates with chelators, drugs, enzymes, detectable labels and the like.
Inventors
- 👤 Boby M. Sundoro
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 03:39
CPC Classifications
G; G01; G01N; G01N33/00; G01N33/48; G01N33/50; G01N33/53; G01N33/543; G01N33/54353; Y; Y10; Y10S; Y10S530/00; Y10S530/807; Y10S930/00; Y10S930/01; Y10S930/29
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
69 words
A selective bifunctional sequential linker having the formula Y═C═N--Q--A--C(O)--Z wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; Y is O or S; and Z is Cl, Br, I, N 3 , N-succinimidyloxy, imidazolyl, 1-benzotriazolyloxy, OAr where Ar is an electron-deficient activating aryl group, or OC(O)R where R is --A--Q--N═C═Y or C 4-20 tertiary-alkyl.
Claim 2
Dependent Claim
69 words
A selective bifunctional sequential linker having the formula Y═C═N--Q--A--C(O)--Z wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; Y is O or S; and Z is Cl, Br, I, N 3 , N-succinimidyloxy, imidazolyl, 1-benzotriazolyloxy, OAr where Ar is an electron-deficient activating aryl group, or OC(O)R where R is --A--Q--N═C═Y or C 4-20 tertiary-alkyl.
Claim 3
Dependent Claim
11 words
The linker of claim 1, wherein A is a single bond.
Claim 4
Dependent Claim
23 words
The linker of claim 1, wherein A is a C n H 2n alkylene group, n being an integer from 1 to 6.
Claim 5
Dependent Claim
14 words
The linker of claim 1, wherein Z is Cl, Br or N 3 .
Claim 6
Dependent Claim
16 words
The linker of claim 1, wherein Z is OC(O)R; and R is --A--Q--N═C═Y, t-butyl or t-amyl.
Claim 7
Dependent Claim
23 words
The linker of claim 5, wherein Q is meta- or para-phenylene; and A is a single bond or a C 1-6 alkylene bridge.
Claim 8
Dependent Claim
12 words
The linker of claim 1, wherein Z is N-succinimidyloxy, imidazolyl or 1-benzotriazolyloxy.
Claim 9
Dependent Claim
15 words
The linker of claim 1, wherein Z is OAr; and Ar is nitrophenyl or dinitrophenyl.
Claim 10
Dependent Claim
11 words
The linker of claim 1, wherein Q is meta- or para-phenylene.
Claim 11
Dependent Claim
9 words
The linker of claim 1, wherein Y is S.
Claim 12
Dependent Claim
9 words
The linker of claim 10 which is p-isothiocyanatobenzoyl chloride.
Claim 13
Dependent Claim
9 words
The linker of claim 10 which is p,p'-diisothiocyanatobenzoic anhydride.
Claim 14
Independent Claim
151 words
A method for activating a first amine-containing compound having a primary or secondary amine function thereon towards reaction with a second amine-containing compound having a primary or secondary amine function thereon, comprising the step of contacting said first amine-containing compound with at least a stoichiometric equivalent of a selective bifunctional sequential linker having the formula Y═C═N--Q--A--C(O)--Z wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; Y is O or S; and Z is Cl, Br, I, N 3 , N-succinimidyloxy, imidazolyl, 1-benzotriazolyloxy, OAr where Ar is an electron-deficient activating aryl group, or OC(O)R where R is --A--Q--N═C═Y or C 4-20 tertiary-alkyl; thereby forming an amide bond to the acyl group of said linker and producing a resultant isocyanate or isothiocyanate derivative of said first amine-containing compound substantially without reaction with the N═C═Y group of said linker.
Claim 15
Independent Claim
151 words
A method for activating a first amine-containing compound having a primary or secondary amine function thereon towards reaction with a second amine-containing compound having a primary or secondary amine function thereon, comprising the step of contacting said first amine-containing compound with at least a stoichiometric equivalent of a selective bifunctional sequential linker having the formula Y═C═N--Q--A--C(O)--Z wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; Y is O or S; and Z is Cl, Br, I, N 3 , N-succinimidyloxy, imidazolyl, 1-benzotriazolyloxy, OAr where Ar is an electron-deficient activating aryl group, or OC(O)R where R is --A--Q--N═C═Y or C 4-20 tertiary-alkyl; thereby forming an amide bond to the acyl group of said linker and producing a resultant isocyanate or isothiocyanate derivative of said first amine-containing compound substantially without reaction with the N═C═Y group of said linker.
Claim 16
Dependent Claim
46 words
The method of claim 13, which further comprises the step of contacting said resultant isocyanate or isothiocyanate derivative with a second primary or secondary amine-containing compound; thereby forming a conjugate having at least one urea or thiourea linkage between said derivative and said second amine-containing compound.
Claim 17
Dependent Claim
19 words
The method of claim 14, wherein said second amine-containing compound is a protein containing a plurality of lysine residues.
Claim 18
Dependent Claim
15 words
The method of claim 15, wherein said protein is an immunoglobulin or a fragment thereof.
Claim 19
Dependent Claim
12 words
The method of claim 16, wherein said first amine-containing compound is deferoxamine.
Claim 20
Dependent Claim
15 words
The method of claim 17, wherein the isocyanate or isothiocyanate derivative of deferoxamine is isolated.
Claim 21
Dependent Claim
9 words
The method of claim 13, wherein Y is S.
Claim 22
Dependent Claim
49 words
A derivative of a primary or secondary amine-containing ligand, joined at the amine nitrogen, and having the formula Y═C═N--Q--A--C(O)-amine wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; and Y is O or S.
Claim 23
Dependent Claim
49 words
A derivative of a primary or secondary amine-containing ligand, joined at the amine nitrogen, and having the formula Y═C═N--Q--A--C(O)-amine wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; and Y is O or S.
Claim 24
Dependent Claim
59 words
A conjugate of a first primary or secondary amine-containing ligand and a second primary or secondary amine-containing ligand, each joined at the amine nitrogen, and having the formula amine-C(Y)NH--Q--A--C(O)-amine' wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; and Y is O or S.
Claim 25
Dependent Claim
59 words
A conjugate of a first primary or secondary amine-containing ligand and a second primary or secondary amine-containing ligand, each joined at the amine nitrogen, and having the formula amine-C(Y)NH--Q--A--C(O)-amine' wherein Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridging group; and Y is O or S.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1990-07-13 | 1991-01-12 | 1991-07-14 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1994-07-13 | 1995-01-12 | 1995-07-14 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1998-07-13 | 1999-01-12 | 1999-07-14 | $7700.00 | Window Closed / Lapsed |