110078-44-9

Facile syntheses of bis-tetraazamacrocycles are reported starting from tripotection of tetraazamacrocycles. The triprotected macrocycle was mono N-alkylated and then this compound reacted with another macrocycle to give symmetrical or unsymmetrical bis-tetraazamacrocycles.

The fac-LCr(CO)3 tridentate complexes of 1,4,7,10-tetraazacyclododecane 1, 1,4,8,11-tetraazacyclotetradecane 2, 1,4,7,10-tetraazadecane 3 and 1,5,8,12-tetraazadodecane 4 have been shown selectively alkylated in high yield at the uncomplexed nitrogen atom, giving rise to mono N-functionalized tetraamines and bis-macrocyclic compounds.

Methods to elevate progenitor and stem cell counts in animal subjects using compounds which bind to the chemokine receptor CXCR4 are disclosed. Preferred embodiments of such compounds are of the formula [in-line-formulae]Z-linker-Z′??(1)[/in-line-formulae] or pharmaceutically acceptable salt thereof wherein Z is of the formula wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms, Z′ is of the formula [in-line-formulae]—Ar(Y)j;[/in-line-formulae] wherein Ar is an aromatic or heteroaromatic moiety, and each Y is independently a non-interfering substituent and j is 0-3; and “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.

Methods to elevate white blood cell counts in animal subjects using compounds of formula (1) are disclosed. These compounds have the formulaor pharmaceutically acceptable salt thereofwherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;Z' may be embodied in a form as defined by Z above, or alternatively may be of the formulawherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan;"linker" represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms;in an amount effective to elevate said WBC count in said subject.

Methods to elevate progenitor and stem cell counts in animal subjects using compounds which bind to the chemokine receptor CXCR4 are disclosed. Preferred embodiments of such compounds are of the formula Z-linker-Z′??(1) or pharmaceutically acceptable salt thereof wherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system; or Z is of the formula wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms, Z′ may be embodied in a form as defined by Z above, or alternatively may be of the formula —N(R)—(CR2)n—X wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan; “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.

Methods to elevate white blood cell counts in animal subjects using compounds of formula (1) are disclosed. These compounds have the formula Z-linker-Z′??(1) or pharmaceutically acceptable salt thereof wherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system; Z′ may be embodied in a form as defined by Z above, or alternatively may be of the formula —N(R)—(CR2)n—X wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan; “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms; in an amount effective to elevate said WBC count in said subject.

Tetraazamacrocyclic bis-aminals prove to be excellent tools for the synthesis of symmetrical, dissymmetrical or functionalized bis-tetraazamacrocycles. The key feature of the process is the separation of insoluble mono- or bis-quaternary ammonium salts from solution during the course of the alkylation reaction.

A new facile and convenient synthetic route has been designed for the preparation of bispolyazamacrocycles in high yields by direct condensation of the readily available intermediate //,W-diboctriazamacrocycle or N,N',N"triboctetraazamacrocycles with aromatic biselectrophiles, ie, o-, m-, p-xylyl and anthracenyl derivatives. The use of a versatile group, such as ferf-butyloxycarbonyl (Boc), which is easily removed within l h by treatment with 6 M HC1 or TFA, leads to polyazamacrocycles in which one nitrogen is discriminated from the others. The anthracenyl and o-xylyl dimers were synthesized by reacting diacyl chloride to give the corresponding diamides. Further reduction of the amide groups and elimination of the protecting Boc moieties were carried in a one-pot reaction with BHa-THF followed by acid treatment. In parallel, exclusive mono-JV-alkylation of the available secondary amine of the same protected macrocycle with the corresponding dibromoxylene gave the meta and para dimers; the protecting moieties were eliminated in a similar way. ESR measurements of spin-spin distances of the dicopper complexes were determined from the ratio of the intensity of the forbidden transition to the intensity of the allowed transitions. Molecular mechanics calculations were also undertaken in order to evaluate the Cu-Cu distance by using a new rule-based force field. Eisevier,.