Celltech Limited

Celltech Therapeutics Limited

Celltech R&d Limited

Thomas A Millican

Nigel Robert Beeley

David Parker

John R Morphy

John Robert Porter

Rikki Peter Alexander

Michael Anthony Eaton

Stephen Keith Rhind

Alison Turner

Richard C Titmas

Nigel Robert Arnold Beeley

Kenneth Millar

David John King

1,4,7,10-Tetrazacyclododecanes carrying a side chain terminating in a group capable of reacting with an antibody, and their complexes with a di- or tripositive metal having a coordination number of 6 or more can be used to prepare imaging agents. Typical metals are indium, copper, lead, bismuth, yttrium, terbium, gadolinium, and scandium. The compounds can be reacted with a monoclonal or polyclonal antibody or antibody fragment to target the metal to a specific type of tissue.

Tetra-aza macrocycles and metal complexes thereof

The invention provides a tri- or tetra-valent monospecific antigen-binding protein comprising three or four Fab fragments bound to each other covalently by a connecting structure, which protein is not a natural immunoglobuline. Further provided are novel connecting structures for use in assembling the proteins of the invention and means for attaching a labeling or effector group thereto. The proteins of the invention are useful, for example, in the treatment and diagnosis of cancer.

Tri- and tetra-valent monospecific antigen-binding proteins

##STR1## Compounds of formula (1) are described wherein Y represents a halogen atom or a group --OR.sup.1 where R.sup.1 represents an optionally substituted alkyl group; R.sup.2 represents an optionally substituted cycloalkyl, cycloalkenyl or polycycloalkyl group; R.sup.3 represents a hydrogen atom or an alkyl, aryl or aralkyl group; R.sup.4 represents an aryl or heteroaryl group; X represents --O--, --S--, --CH.sub.2 -- or --N(R.sup.5)--, where R.sup.5 is a hydrogen atom or an alkyl group; n is zero or an integer or value 1, 2 or 3; and the salts, solvates and hydrates thereof. The compounds are selective phosphodiesterase IV inhibitors and are useful for the prophylaxis or treatment of inflammatory diseases.

Phenylaminocarbonyl derivatives and processes for their preparation

Methods of use for compounds of formula (I) are described wherein R represent a --CONHOH, carboxyl (--CO.sub.2 H) or esterified carboxyl group; R.sup.1 represents a hydrogen atom or an optionally substituted alkyl, alkenyl, aryl, aralkyl, heteroaralkyl or heteroarylthioalkyl group; R.sup.2 represents an optionally substituted phenylethyl, phenylpropyl or phenylbutyl group; R.sup.3 represents a hydrogen atom or an alkyl group; R.sup.4 represents a hydrogen atom or an alkyl group; R.sup.5 represents an optionally substituted alkyl or alkenyl group optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)-- groups (where R.sup.7 is a hydrogen atom or a C.sub.1-6 alkyl group); X represents an amino (--NH.sub.2), or substituted amino, hydroxyl or substituted hydroxyl group; and the salts, solvates and hydrates thereof. The compounds are metalloproteinase inhibitors and in particular have a selective gelatinase action, and may be of use in the treatment of cancer to control the development of tumour metastases. ##STR1##

Peptidyl derivatives

Succinamide derivatives, processes for their preparation and their use

Cross-linked antibody conjugates are described which have at least one interchain bridge containing a reporter or effector molecule. The bridge may be the residue of a homo-or heterofunctional cross-linking reagent, and is located away from the antigen binding domains of the antibody. The antibody conjugates have an enhanced binding capacity and in vivo have good blood clearance and, in the presence of a tumour high tumour; blood and tumour; bone ratios. The conjugates are of use in the diagnosis and therapy of e.g. tumours and may be prepared by reaction of a cross-linking reagent with an antibody.

Crosslinked antibodies and processes for their preparation

Peptidyl derivatives as metalloproteinase inhibitors

##STR1## Conjugate compounds are described comprising a compound of formula (1), wherein A is a group --Alk.sup.3 -- or --Alk.sup.3 N(R.sup.4)Alk.sup.1 --, Alk.sup.2, Alk.sup.3 and Alk.sup.4 which may be the same or different is each a C.sub.1-4 alkylene chain optionally substituted by one or more C.sub.1-6 alkyl groups; and R.sup.1, R.sup.2, R.sup.3 and R.sup.4, which may be the same or different, is each a hydrogen atom or a group--AlkR.sup.5 where Alk is an optionally substituted straight or branched C.sub.1-6 alkyl group and R.sup.5 is a hydrogen atom or a --CO.sub.2 H, --CONR.sup.6 R.sup.7 (where R.sup.6 and R.sup.7, which may be the same or different is each a hydrogen atom or an alkyl group) or --P(X.sup.1)(X.sup.2 R.sup.8)L group where X.sup.1 and X.sup.2 is each an oxygen or sulphur atom. R.sup.8 is a hydrogen atom or an alkyl group and L is an aliphatic, aromatic, or heteroaromatic group or a linker group with the proviso that at least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is a group AlkP(X.sup.1)(X.sup.2 R.sup.8)L where L is a linker group; and a metal complexes and/or salts thereof, coupled to a protein, peptide or carbohydrate. The conjugates are useful for imaging and in the treatment of abnormal cell disorders, such as in the treatment of tumours.

Conjugate compounds containing aza-macro-cycles and processes for their

Peptidyl derivatives and their use as metalloproteinases inhibitors

Triaza macrocycles carrying a -CH.sub.2 COOH, -CH.sub.2 CONR.sup.6 R.sup.7, --CH.sub.2 P(R.sup.5)O.sub.2 H, or --CH.sub.2 PO.sub.3 H.sub.2 group on two of the three ring nitrogen atoms and a --CH(L--Z)COOH, --CH(L--Z)CONR.sup.6 R.sup.7, --CH(L--Z)P(R.sup.5)O.sub.2 H, or --CH(L--Z)PO.sub.3 H.sub.2 group on the third ring nitrogen atom, in which L is an organic linking radical and Z is any group capable of reacting with a thiol, amino, carboxy, hydroxyl, aldehyde, aromatic, or heteroaromatic group, and metal complexes thereof, are useful for imaging, diagnosis, and therapy. A typical embodiment is N-[5-carboxy-5-{4,7-bis-(carboxymethyl)-1,4,7-triazacyclonon-1-yl}pentyl] 3-maleimidopropionamide.

Triaza macrocycles

Phenylaminocarbonyl derivatives

N-sulphonylamino derivatives of dipetide compounds as metalloproteinase

Ti-aza macrocycles of formula (1), wherein m and n, which may be the same or different, is each zero or an integer 1, 2, or 3; p is zero or an integer 1 or 2; q is zero or an integer from 1 to 6 inclusive; R.sup.1, R.sup.2 and R.sup.3, which may be the same or different, is each a hydrogen atom or an alkyl, alkoxyalkyl, --CO.sub.2 H, --SO.sub.3 H, PO.sub.3 H.sub.2 or aryl group; L is a covalent bond or linker group; Z is a hydrogen atom or a reactive functional group, with the proviso that when L is a covalent bond Z is a reactive functional group; and metal complexes and/or salts thereof are described together with processes for their preparation and compositions containing them. The compounds are useful for imaging and in the treatment of abnormal cell disorders, such as in the treatment of tumours, and are particularly suitable for coupling to other molecules such as proteins for use in diagnosis and therapy.

Tri-aza macrocycles and metal complexes thereof

##STR1## Compounds of formula (1) are described wherein Y represents a halogen atom or a group --OR.sup.1 where R.sup.1 represents an optionally substituted alkyl group; R.sup.2 represents an optionally substituted cycloalkylcycloalkenyl or polycycloalkyl group; R.sup.3 represents a hydrogen atom or an alkyl, aryl or aralkyl group; R.sup.4 represents an aryl or heteroaryl group; X represents --O--, --S--, --CH.sub.2 -- or --N(R.sup.5)--, where R.sup.5 is a hydrogen atom or an alkyl group; n is zero or an integer or value 1, 2 or 3; and the salts, solvates and hydrates thereof. The compounds are selective phosphodiesterase IV inhibitors and are useful for the prophylaxis or treatment of inflammatory diseases.

Growing community of inventors

Maidenhead, United Kingdom

Thomas A Millican