MACROCYCLIC PEPTIDES USEFUL IN THE TREATMENT OF THROMBIN RELATED DISORDERS

Abstract: Compounds of Formula (I) and Formula (III) which are useful in the treatment of thrombin and trypsin related disorders.

Description: MACROCYCLIC PEPTIDES USEFUL IN THE TREATMENT OF THROMBIN RELATED DISORDERS This invention relates a series of macrocyclic peptides, intermediates used in their manufacture and pharmaceutical compositions containing them. The compounds are inhibitors of serine proteases, particularly α- thrombin and may be used in a variety of thrombin related disorders such as venous thrombosis and arterial thrombosis. BACKGROUND OF THE INVENTION With a rapidly aging population, diseases of the vascular system are of great concern to our society. Arterial thrombosis is the major cause of death in the form of heart attacks and strokes, while venous thrombosis is associated with pulmonary embolism which occurs after surgery or extended periods of inactivity. Thrombin is a multifunctional serine protease whose role in thrombosis and hemostasis has been documented by a number of sources (See generally. Tapparelli, et al. TiPS 1993, 14, 366-76). Thrombin acts as a procoagulant through proteolytic cleavage of fibrinogen to form fibrin and as an anticoagulant through activation of the protein C pathway (followed by inactivation of coagulation factors V and VIII. ) The concentration of active thrombin is limited by a number of feedback mechanisms involving endogenous factors and proteins. In addition to protein C, antithrombin III is another regulating protein which forms a complex with endogenous heparin. This complex binds to active thrombin, thus inactivating it. Current anticoagulant therapy consists of three classes of compounds: heparins, coumarins and low molecular weight heparins. These drugs act indirectly to limit the concentration of active thrombin. Heparins and low molecular weight heparins interact with antithrombin III and the coumarins inhibit a number of vitamin K dependent coagulation factors. Although these drugs are prescribed for diseases associated with venous thrombosis and arterial thrombosis, their use is limited. They have a number of side effects, a slow onset of action and only the coumarins are orally active (warfarin and dicumarol). Indirect thrombin inhibitors have been shown to be less effective at controlling associated diseases than direct thrombin inhibitors. Thus the search for orally active direct thrombin inhibitors is underway in a number of laboratories. These efforts have produced a number of acyclic peptidyl compounds which directly inhibit thrombin. PPACK, argatroban, (Q)- NAPAP, hirulog-1 and DUP 714 are examples of these inhibitors . Many of these compounds lack useful oral activity, and many have a poor selectivity for thrombin versus other serine proteases. Therefore, a need remains for new direct thrombin inhibitors. When compared to acyclic peptides, cyclic peptides have a number of structural features that have been linked to changes in the biological activity of simple peptides. Due to the absence of polar end groups and a relatively rigid structure, cyclic peptides are hypothesized to be more membrane permeable and less susceptible to peptidases. Potentially one could incorporate the structure of simple peptides, within rigid, non-polar macrocyclic framework, to produce active bioavailable compounds. Cyclotheonamide A (CtA) is a cyclic peptide which was isolated from Theonella.sp. a marine sponge. It inhibits a variety of serine proteases particularly thrombin and trypsin. cyclotheonamide A (CtA) Although this molecule inhibits thrombin (Ki# ca.1-2 nM), it is a scarce natural product which is difficult to extract from its natural source. In addition, CtA is not an optimal candidate for treating thrombin-related disorders as its selectivity for thrombin over trypsin does not favor thrombin. The invention described below claims a novel macrocyclic peptides that inhibit thrombin at nanomolar levels and exhibit reasonable selectivity for thrombin over trypsin. The invention relates to new compounds of the Formula I H 2 wherein: m is 2 to 12; A is where the amido carbonyl is bound to B and the α aminomethine is bound to the depicted ring carbonyl, R3 is hydrogen, hydroxy or d-salkoxy, n is 1 or 2 and a is 0 or 1 ; B is where the amido carbonyl of B is bound to the depicted ring methylenes and the methine is bound to A, R4 is selected from the group consisting of any of hydrogen, Cι-5alkyl, carboxyC-i-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Cι-5alkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine, bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Cι-5alkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylC-i-5alkyl, 4-pyridylCι-5alkyl, diphenylCι-2alkyl, naphthyl or substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), R5 and Rβ are each hydrogen or taken together with the carbon to which each is attached to form a carbonyl, and b is 0 or 1 G is where the amine of G is bound to the ring methylenes and the methine is bound to the depicted amide, Rγ is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-s alkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylCι-2alkyl, and naphthyl, substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon or C(CH2)q-, where q is 0 to 12, with the proviso that the sum of q and m cannot exceed 25, Rβ and Rg are hydrogen or taken together with the carbon of E to form a carbonyl, and g is 0 or 1 ; and pharmaceutically acceptable salts thereof. An additional aspect of the invention relates to novel compounds of the Formula π which are intermediates in the synthesis of compounds for the Formula I, II wherein: Ri is hydroxy; R2 is hydrogen; m is 2 to 12; A is where the amido carbonyl is bound to B and the α aminomethine is bound to the depicted ring carbonyl, R3 is hydrogen or Ci-salkoxy, n is 1 or 2, and a is 0 or 1 ; B is where the amido carbonyl of B is bound to the depicted ring methylenes and the methine is bound to A, R4 is selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι.salkyl, 4-pyridylCι-salkyl, diphenylC -2alkyl, naphthyl or substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine, bromine or chlorine), R5 and RQ are each hydrogen or taken together with the carbon to which each is attached to form a carbonyl, b is 0 or 1 G is where the amine of G is bound to the ring methylenes and the methine is bound to the depicted amide, R7 is selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Cι- 5alkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylCι-2alkyl, naphthyl or substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine, bromine or chlorine), E is carbon or C(CH2)q-, where q is 0 to 12, with the proviso that the sum of q and m cannot exceed 25, Rβ and Rg are each hydrogen or taken together with the carbon of E to form a carbonyl, g is 0 or 1 ; or pharmaceutically acceptable salts thereof. Yet another aspect of the invention relates to novel thrombin inhibitors of the Formula III. III wherein: m is 2 to 12; W is nitrogen, sulfur or oxygen; A is where the amido carbonyl is bound to B and the α aminomethine is bound to the depicted ring carbonyl, R3 is hydrogen, hydroxy or Ci-salkoxy, n is 1 or 2; a is 0 or 1 ; B is where the amido carbonyl of B is bound to the depicted ring methylenes and the methine is bound to A, R4 is selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, C1- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-5alkyl, 4-pyridylCι-salkyl, diphenylCι-2alkyl, naphthyl or substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), R5 and Re are each hydrogen or taken together with the carbon to which they are attached to form a carbonyl, b is 0 or 1 ; where the amine of G is bound to the ring methylenes and the methine is bound to the depicted amide, R7 is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylCι-2alkyl, naphthyl or substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon or C(CH2)q-, where q is 0 to 12, with the proviso that the sum of q and m cannot exceed 25, Rβ and Rg are each hydrogen or taken together with the carbon of E to form a carbonyl, g is 0 or 1 ; or pharmaceutically acceptable salts thereof. The terms used in describing the invention are commonly used and known to those skilled in the art. However, the terms that could have other meanings are defined. "Independently" means that when there are more than one substituent, the substitutents may be the same or different. The term "alkyl" refers to straight, cyclic and branched-chain alkyl groups and "alkoxy" refers to O-alkyl where alkyl is as defined supra. "CBZ" refers to benzyloxycarbonyl. "BOC" refers to t-butoxycarbonyl and "Ts" refers to toluenesulfonyl. "DCC" refers to 1 ,3-dicyclohexylcarbodiimide, "DMAP" refers to 4-N'N- dimethylaminopyridine and "HOBT refers to 1-hydroxybenzotriazole hydrate. "FMoc" refers to N-(9-fluorenylmethoxycarbonyl). Amino acid refers to compounds where the amino group and the carboxy group are on different carbon atoms. The term α-amino acid, refers to compounds where both the carboxy and the amino group are attached to the same carbon atom. The stereochemistry of this carbon is indicated by the terms "D and L" where D indicates right-handed chirality. DETAILED DESCRIPTION OF THE INVENTION The compounds of the invention may be prepared by a number of synthetic schemes, where the macrocyclic ring members A, B, and G dictate the appropriate synthesis. The starting protected mono and di-peptides are either known or readily synthesized by standard techniques known in the art. See Bodansky, M. Practice of Peptide Synthesis; Springer Verlag, 1984. All syntheses include a series of peptide coupling reactions, where the macrocycle is built, oxidized and deprotected. As illustrated, Scheme I may be used to prepare a compound of Formula I where m is 7; A is where R3 is hydrogen and n is 1 ; B is where R4 is 2-methyl-1 -propyl and R5 is taken together with Re to form a carbonyl. A known ^-protected α-amino acid la, is coupled at room temperature to a known ^-protected amino acid lb, using HOBT/DCC in an inert solvent, such as DMF, CH3CN or THF, over 5-24 h. Although HOBT/DCC is the preferred coupling agent other agents can be used and include: BOP, BOP-CI and PyBrOP. The protecting groups are chosen in order to permit selective removal, where the favored protecting groups are CBZ for nitrogen and t-butoxycarbonyl for carboxy. However, other well known protecting groups may be substituted and are described in Green, Theodora Protecting Groups in Organic Synthesis; John Wiley & Sons, New York, 1981. As illustrated the CBZ group is removed by hydrogenation at approximately 20 psig using Pd(OH)2/C as a catalyst. However, other conditions may be used such as catalytic transfer hydrogenation using Pd/C and formic acid. The resulting Q-protected di-peptide Iς, is coupled to an N- protected aliphatic amino acid, Id, followed by removal of the M-protecting group to give amine le. As illustrated, the CBZ serves as the JN-protecting group and Pd/(OH)2 is the hydrogenation catalyst. However either the protecting group or the reaction conditions may be modified as previously described. Intermediate le is coupled to 6-[[imino[4-methylbenzenesulfonyl)- amino]methyl]amino]-2-(R,S)-[[2-(trimethylsilyl)ethoxy]methoxy]-3(S)- [9-phenylmethoxycarbonyl)-amino]hexanoic acid, ( Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) using HOBT/DCC at room temperature for 4-24 h in an inert solvent and deprotected with Pd(OH)2 to give the arginine derivative If. The i-butoxycarbonyl and SEM protecting groups are removed with TFA and the resulting intermediate is coupled at room temperature with BOP-CI and DMAP in an inert solvent such as CH2CI2 to give the hydroxy macrocyclic derivative Ig. Compound Ig is oxidized using the Dess-Martin periodinane in an anhydrous aprotic solvent and deprotected using HF in the presence of a carbocation scavenger such as anisole, thioanisole, pentamethylbenzene, dimethylsulfide or cresol to give a compound of Formula I. This scheme may be used to form the compounds of the invention where m is 2-12, A is where n is 1 or 2 and R3 is hydrogen or C1-5 alkoxy, and B is 0^ N-H where R4 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Cι- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3- pyridylC -5alkyl, 4-pyridylC -salkyI, naphthyl, substituted naphthyl or diphenylCι-2alkyl. For example to prepare compounds where m is 2-12, the illustrated reactant . 8-(Λ/-benzyloxycarbonyl)aminooctanoic acid, is replaced with an analog of "m" methylenes such as 6-(N- benzyloxycarbonyl)aminohexanoic acid. To prepare a compound where A is R3 is hydrogen and n is 2, simply replace Ik, D-Pro-O-l-Bu, with D-pipecolinic acid -i-butyl ester To prepare a compound where B is 0^ N-H R 4 -^ and R 4 is 3-pyridylmethyl, replace la N-BOC-D-leucine with N-BOC-D-3- pyridyl-alanine. When active aromatic substituents are desired such as hydroxy, amino or carboxy, those compounds may be prepared as protected derivatives where the protecting groups well known in the art are described in Green, Theodora Protecting Groups in Organic Synthesis; John Wiley & Sons, New York, 1981. For example to prepare a compound where R4 is 4- hydroxybenzyl, a 1-butyldimethylsilyl group is used as protecting group and removed with HF in the last step of the scheme. SCHEME I Another method of synthesis, illustrated by Scheme II, may be used to prepare a compound of Formula I where m is 4; A is where R3 is hydrogen and n is 1 ; B is where R 4 is benzyl and R5 is taken together with RQ to form a carbonyl; and G is where E, Rβ and Rg are taken together to form a carbonyl and R7 is 4- chlorobenzyl. A known ^-protected -α-amino acid Ila, is coupled at room temperature to a known ^protected amino acid nb_, using HOBT/DCC in an inert solvent, such as DMF, CH3CN or THF, over 5-24 h. Although HOBT/DCC is the preferred coupling agent other agents may be used and include: BOP, BOP-CI and PyBrOP. The protecting groups are chosen in order to permit selective removal, where the favored protecting groups are CBZ for nitrogen and t-butoxycarbonyl for carboxy. However, other protecting groups well known in the art may be substituted and are described in Green, Theodora, Protecting Groups in Organic Synthesis; John Wiley & Sons, New York, 1981. As illustrated the t-butoxycarbonyl group is removed with TFA to give the ^-protected di-peptide Us.. This intermediate is coupled to an ^-protected di-peptide IM, followed by removal of the ^-protecting group to give amine He.. As illustrated the CBZ serves as the M-protecting group and Pd/(OH)2 is the hydrogenation catalyst. However either the protecting group or the reaction conditions may be modified as previously described. Intermediate Ik is coupled to 6-[[imino[4- methylbenzenesulfonyl)-amino]methyl]amino]-2-(R,S)-[[2- (trimethylsilyl)ethoxy]methoxy]-3(S)-[9-phenylmethoxycarbonyl)- amino]hexanoic acid, ( Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) using HOBT/DCC at room temperature for 4- 24 h in an inert solvent and deprotected with Pd(OH) 2 to give the arginine derivative ϋ - The i-butoxycarbonyl and SEM protecting groups are removed with TFA and the resulting intermediate is coupled at room temperature with BOP-CI and DMAP in an inert solvent such as CH2CI2 to give the hydroxy macrocyclic derivative Eg- Compound Eg is oxidized using the Dess-Martin periodinane in an anhydrous aprotic solvent and deprotected using HF in the presence of a carbocation scavenger to give a compound of Formula I. This scheme may be used to form the compounds of the invention where m is 2-12, A is where R3 is hydrogen or Ci-salkoxy, B is where R4 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3- pyridylCι-5alkyl, 4-pyridylCι-salkyl or diphenylCι-2alkyl, and G is where R7 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Cι- 5alkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3- pyridylCι-5alkyl, 4-pyridylCι-salkyl, naphthyl or diphenylCι-2alkyl. For example to prepare compounds where m is 2-12, the illustrated reactant Hh, 5-aminopentanoic acid -1-butyl ester is replaced with an analog of "m" methylenes such as 7-aminoheptanoic acid -t-butyl ester To prepare a compound where A is replace the illustrated reactant lid with 3-pyridylalanine-pipecolinic acid (O- IBu) A compound where G is O #\* R 7 H and R7 is butyl can be prepared by replacing Ua with N-BOC-D-norleucine. When the aromatic substituents hydroxy, amino or carboxy are desired, those compounds may be prepared as protected derivatives where the protecting groups well known in the art are described in Green, Theodora Protecting Groups in Organic Synthesis; John Wiley & Sons, New York, 1981. For example to prepare compound where R4 or R7 is 4-aminobenzyl, an allyloxycarbonyl group is used as protecting group and removed with tetrakis(triphenylphosphine)palladium(0) at the end of the scheme. SCHEME II Yet another method, illustrated by Scheme III, is used to prepare a compound of Formula I where m is 3; A is where R3 is hydrogen and n is 2; B is where R4 is benzyl and both R5 as well as RQ are hydrogen. A known f±- protected aldehyde Ula, is reductively aminated at room temperature to a known ^-protected amino acid IIIb_, using NaB(OAc)3H in an inert solvent, such as CH2CI2 or (CH2)2Cl2 . over 2-16 h. The protecting groups are chosen in order to permit selective removal, where the favored protecting groups are Fmoc for nitrogen and t-butoxycarbonyl for carboxy. However, other protecting groups may be substituted as previously discussed. The free amine of the resulting product inc. is protected as the CBZ and the Fmoc group of the other amine is cleaved with an anhydrous base such as piperidine to give IUd. Intermediate Ul . is coupled to 6-[[imino[4- methylbenzenesulfonyl)-amino]methyl]amino]-2-(R,S)-[[2- (trimethylsilyl)ethoxy]methoxy]-3(S)-[9-fluorenylmethoxycarbonyl)- amino]hexanoic acid, ( Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) using HOBT/DCC at room temperature for 4- 24 h in an inert solvent and deprotected with Pd(OH)2 to give the arginine derivative flle. The Fmoc group is removed with an organic base and the 1-butoxycarbonyl and SEM protecting groups are removed with TFA. The resulting intermediate is coupled at room temperature with BOP-CI and DMAP in an inert solvent such as CH2CI2 to give the hydroxy macrocyclic derivative fflf. Compound fflf is oxidized using the Dess-Martin periodinane in an anhydrous aprotic solvent and deprotected using HF in the presence of a carbocation scavenger to give a compound of Formula I. This Scheme III may be used to form the compounds of the invention where m is 2-12, A is where R3 hydrogen or Ci-salkoxy and n is 1 or 2, and B is where R4 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl or diphenylCι-2alkyl. For example to prepare compounds where m is 2-12, the illustrated reactant IHa. is replaced with an analog of "m" methylenes such as 5-(N-9- fluorenylmethoxycarbonyl)aminopentaldehyde To prepare a compound where A is and B is replace the illustrated reactant fflk with norleucine-proline-(O-t-Bu). When active aromatic substituents are desired such as hydroxy, amino or carboxy, those compounds may be prepared as protected derivatives where the protecting groups well known in the art are described in Green, Theodora Protecting Groups in Organic Synthesis; John Wiley & Sons, New York, 1981. For example to prepare compound where R4 is 4-carboxybenzyl, an methylester is used as protecting group and removed with aqueous LiOH prior to oxidation with Dess Martin periodiane. SCHEME III Another method of synthesis is illustrated by Scheme IV may be used to prepare a compound of Formula I where m is 5; A is where R3 is hydrogen and n is 1 ; and where E, Rβ and Rg are taken together to form a carbonyl and R7 is phenyl. A known M-protected amino acid IVa. is coupled at room temperature to a known ^-protected amino acid IVb. using HOBT/DCC in an inert solvent, such as DMF, CH3CN or THF, over 5-24 h. Although HOBT/DCC is the preferred coupling agent other agents be used and include: BOP, BOP-CI and PyBrOP. The preferred protecting groups are CBZ for nitrogen and 1-butoxycarbonyl for carboxy; however, other protecting groups may be substituted as discussed previously. As illustrated the t-butoxycarbonyl group is removed with TFA to give the -protected di-peptide e. This intermediate is coupled to an ^.-protected di-peptide d, followed by removal of the M-protecting group to give amine iy_£. As illustrated the CBZ serves as the N-protecting group and Pd/(OH) 2 is the hydrogenation catalyst. However either the protecting group or the reaction conditions may be modified as previously described. Intermediate IVe is coupled to 6- [[imino[4-methylbenzenesulfonyl)-amino]methyl]amino]-2-(R,S)-[[2- (trimethylsilyl)ethoxy]methoxy]-3(S)-[9-phenylmethoxycarbonyl)- amino]hexanoic acid, ( Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) using HOBT/DCC at room temperature for 4- 24 h in an inert solvent and deprotected with Pd(OH)2 to give the arginine derivative IY The t-butoxycarbonyl and SEM protecting groups are removed with TFA and the resulting intermediate is coupled at room temperature with BOP-CI and DMAP in an inert solvent such as CH2CI2 to give the hydroxy macrocyclic derivative IY_£. Compound iy_£ is oxidized using periodinane in an anhydrous aprotic solvent and deprotected using HF in the presence of a carbocation scavenger to give a compound of Formula I. This Scheme IV may be used to form the compounds of the invention where m is 2-12, A is and G is where R7 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, C - 5alkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3- pyridylCι-5alkyl, 4-pyridylCι-salkyl naphthyl or diphenylCι-2alkyl. For example to prepare compounds where m is 2-12, the illustrated reactant IVa. 6-(Λ/-CBZ)aminohexanoic acid is replaced with an analog of "m M methylenes such as 7-(Λ/-CBZ)aminoheptanoic acid. To prepare a compound where A is replace the illustrated reactant IYh with D-pipecolinic acid hbutyl ester. A compound where G is and R7 is butyl can be prepared by replacing iy_g with D-norleucine. When active aromatic substituents are desired such as hydroxy, amino or carboxy, those compounds may be prepared as protected derivatives where the protecting groups well known in the art are described in Green, Theodora Protecting Groups in Organic Synthesis; John Wiley & Sons, New York, 1981. For example to prepare compound where R7 is 4-hydroxybenzyl, a 1- butyldimethylsilyl group is used as protecting group and removed with HF in the last step of the scheme. SCHEME IV IVb IVd Another method of synthesis is illustrated by Scheme V and may be used to prepare a compound of Formula I where m is 5; A is where R3 is methoxy; n is 1 ; B is where R4 is 4-chlorobenzyl and R5 is taken together with RQ to form a carbonyl; and G is where E is carbon, Rβ and Rg are hydrogen and R7 is hydrogen. A known Fmoc-protected amino aldehyde a, is reductively aminated at room temperature to a known t-butoxy-protected amino acid Vb_, using NaB(θ2CCH 3 )H in an inert solvent, such as CH2CI2, over 5-24 h. The nitrogen of the resulting intermediate is protected with CBZ and the O- \- butoxy group is cleaved to give the acid Vc.. This intermediate is coupled to a C_-protected dipeptide Vgl using HOBT/DCC followed by the removal of the FMoc protection with an anhydrous base such as diethylamine to give Ve. Intermediate Ve. is coupled to 6-[[imino[4-methylbenzenesulfonyl)- amino]methyl]amino]-2-(R,S)-[[2-(trimethylsilyl)ethoxy]methoxy]-3(S)- [9-fluorenyllmethoxycarbonyl)-amino]hexanoic acid, ( Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) using HOBT/DCC at room temperature for 4-24 h in an inert solvent and deprotected with diethylamine to give the acyclic arginine derivative Yf. The t-butoxycarbonyl and SEM protecting groups are removed with TFA and the resulting intermediate is coupled at room temperature with BOP-CI and DMAP in an inert solvent such as CH2CI2 to give the hydroxy macrocyclic derivative Yg. Compound Yg is oxidized using periodinane in an anhydrous aprotic solvent and deprotected using HF in the presence of a carbocation scavenger to give a compound of Formula I. This Scheme V may be used to form the compounds of the invention where m is 2-12, A is B is where R4 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Cι- 5aIkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3- pyridylCi-salkyl, 4-pyridylCι-salkyl naphthyl or diphenylCι-2alkyl, and G is H H R 7 H where R7 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkoxy, fluorine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkoxy, fluorine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl naphthyl or diphenylCι-2alkyl and E is C(CH2)q, where q is 0-12. For example to prepare compounds where m is 2-12, the illustrated reactant Yk, is replaced with an analog of "m" methylenes such as 8-aminooctanoic acid -i-butyl ester. To prepare a compound where A is and B is replace the illustrated reactant Vi with 3-pyridylalanine-D-pipecolinic acid -t-butyl ester. A compound where G is and R7 is hydrogen can be prepared by replacing Ya with 6-(N-9- fluorenylmethoxycarbonyl)aminobutylraldehyde. To prepare compounds where R7 is other than hydrogen, start with an N-protected α-amino acid, reduce the carboxy to an aldehyde. Any of the standard reagents and conditions may be used including 1 ,1 '-carbonyldiimidazole in THF at 0-10° C, followed by treatment with DIBAL/hexane at -42 °C. This α-substituted aldehyde is used in place of Ya and the remaining steps of the synthesis are carried through with only minor modifications. SCHEME V Yet another method of synthesis is illustrated by Scheme VI. This scheme is used to prepare a compound where m is 5 and G is *7 H and R7 is 4-chlorobenzyl. A known JfcJ-protected amino acid Via, is coupled at room temperature to a known C-protected amino acid γjb_, using HOBT/DCC in an inert solvent, such as DMF, CH3CN or THF, over 5-24 h to give YJς. . Although HOBT/DCC is the preferred coupling agent other agents be used and include: BOP, BOP-CI and PyBrOP. The preferred protecting groups are CBZ for nitrogen and t-butoxycarbonyl for carboxy; however, other protecting groups may be substituted as discussed previously. The protecting groups are removed by sequential treatment with TFA and P /(OH)2/H2 to give Jς Intermediate Ylc_ is coupled to 6-[[imino[4-methylbenzenesulfonyl)- amino]methyl]amino]-2-(R,S)-[[2-(trimethylsilyl)ethoxy]methoxy]-3(S)- [9-phenylmethoxycarbonyl)-amino]hexanoic acid, ( Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) using HOBT/DCC at room temperature for 4-24 h in an inert solvent to give Y - The CBZ, t-butoxycarbonyl and SEM protecting groups are removed by sequential treatment with TFA and Pd(OH)2/H2 to give YJe.. This intermediate is coupled at room temperature with BOP-CI and DMAP in an inert solvent such as CH2CI2 to give the hydroxy macrocyclic derivative Vlf. Compound Vlf is oxidized using periodinane in an anhydrous aprotic solvent and deprotected using HF in the presence of a carbocation scavenger such as anisole, thioanisole, pentamethylbenzene, dimethylsulfide or cresol to give a compound of Formula I. This Scheme VI may be used to form the compounds of the invention where m is 2-12, and G is where R7 is hydrogen, Ci-salkyl, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci- salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3- pyridylCι-5alkyl, 4-pyridylCι-salkyl naphthyl or diphenylCι-2alkyl. For example to prepare compounds where m is 2-12, the illustrated reactant Jh is replaced with an analog of "m" methylenes such as 8-aminoooctanoic acid 1-butyl ester. A compound where G is and R7 is butyl can be prepared by replacing YU2 with N-BOC-D- norleucine SCHEME VI Scheme VII may be used to prepare the compounds of Formula III where m is 4, W is sulfur, A is where R3 is hydrogen and n is 1 ; B is where R4 is benzyl and R5 is taken together with Re to form a carbonyl; and G is where E, Rβ and Rg are taken together to form a carbonyl and R7 is benzyl. M-α-Fmoc-H-γ-tosyl-L-arginine is treated with carbonyldiimidazole at 0 °C in THF and reduced with DIBAL at about -48 °C to give the corresponding aldehyde. The cyanohydrin Vllb is produced by treating the aldehyde with KCN and H2O at room temperature over several days in ethyl acetate. Treatment of Vllb with gaseous HCl in an alcohol such as MeOH at about -40 to -15 °C over several hours gives the imidate VIIc. Treatment of the imidate with Vlld (cysteine methyl ester hydrochloride) in an inert solvent such as CH2CI2 at room temperature for 1-5 h gives the Fmoc protected amino alcohol Vile. The hydroxy of Vile can be converted to the trisilylalkyi ether with standard silylating agents such as f butyldimethylsilyltriflate and an organic base such as 2,6- lutidine at 0 °C. The Fmoc group is removed by treatment with an organic base such as diethyl amine at room temperature over 2-5 h. The free amine can be protected as the N-Boc derivative by treatment with di-f-butyl dicarbonate in an inert solvent at 0 °C over 16 h to give the 4,5-dihydrothiazole intermediate Vllf. Intermediate VHf can be oxidized to the thiazole by treatment with with an oxidizing agent such as Mnθ2 in an inert solvent such as CH2CI2 at room temperature over several hours. The isolated 5-carboalkoxy thiazole intermediate is saponified at room temperature with LiOH in dioxane/water to give the 5-carboxy thiazole derivative Vllg. Derivative Vllg is coupled using HOBT/DCC to the ^-protected tripeptide Vllh. where the peptide is prepared using any of the methods discussed in the previous schemes. Treatment with TFA removes the Boc group to give the coupled intermediate jli. This intermediate is treated at room temperature with BOP-CI and DMAP in an inert solvent followed by removal of the silyl protecting group with BU 4 NF/THF at room temperature to give the macrocycle Vfl . This intermediate is oxidized using Dess-Martin periodinane in an anhydrous aprotic solvent and deprotected using HF in the presence of a carbocation scavenger to give a compound of Formula III. To produce compounds where W is nitrogen or oxygen, Vlld is replaced with 2,3-diamino propionic acid methyl ester or serine ethyl ester respectively. Intermediate VIIc is used to produce all of the compounds of Formula HI. This intermediate can be used in place of 6-[[imino[4-methylbenzenesulfonyl)- amino]methyl]amino]-2-(R,S)-[[2-(trimethylsilyl)ethoxy]methoxy]-3(S)- [9-phenylmethoxycarbonyl)-amino]hexanoic acid or 6-[[imino[4- methylbenzenesulfonyl)-amino]methyl]amino]-2-(R,S)-[[2- (trimethylsilyl)ethoxy]methoxy]-3(S)-[9-fluorenylmethoxycarbonyl)- amino]hexanoic acid in Schemes I through VIII with only minor modification to give the desired compounds. SCHEME VII vπf Yllg The compounds of the invention were tested for their ability to inhibit thrombin mediated hydrolysis. Two in vitro enzyme assays were performed to give both Michaelis-Menten kinetics or slow, tight-binding kinetics In addition, the compounds were tested in vitro for their ability to inhibit trypsin, as an indication of their selectivity Thrombin-catalyzed hydrolysis rates were measured spectrophotometrically using commercial human alpha-thrombin (American Diagnostica), a chromogenic substrate (Spectozyme® TH (H-D-HHT-Ala- Arg-pNA-2AcOH), American Diagnostica) in aqueous buffer (10 mM Tris, 10 mM Hepes, 150 mM NaCl, 0.1% PEG; pH 7.4), and a microplate reader (Molecular Devices). Changes in absorbance at 405 nm were monitored (Softmax, Molecular Devices), upon addition of enzyme, both with and without inhibitor present at 37°C over 30 minutes. Inhibition constants (Ki) were determined by fixing the enzyme and inhibitor concentrations and varying the substrate concentration (1 nM thrombin, 5-100 μM Spectozyme® TH). Michaelis-Menton kinetics were applied to the initial reaction slopes using the program K-Cat (Bio Metallics Inc.). Trypsin-catalyzed hydrolysis rates were measured using the same method as the thrombin procedure. Bovine type 1 trypsin (Sigma) and Spectrozyme ® TRY (Cbo-Gly-D-Ala-Arg-pNA « AcOH, American Diagnostics) replaced their thrombin equivalents in a concentration range of 3.2 U/ml trypsin and 0.1 -0.3 mM Spectrozyme. Compounds of the invention showed slow binding inhibition with thrombin which was demonstrated in the following assay. Serial dilutions of compounds and human alpha-thrombin (0.1 nM, American Diagnostica) were incubated at 25 °C for 4h. A chromogenic substrate was added (50 μM Spectozyme® TH (H-D-HHT-Ala-Arg-pNA 2AcOH), American Diagnostica) and the increase in absorbance at 405 nM was measured with a microplate reader (Molecular Devices) at 25 °C using an aqueous buffer (10 mM Tris, 10 mM Hepes, 150 mM NaCl, 0.1%PEG; pH 7.4). Data was collected over 4h and plotted (MOD v. Time). A compound was determined to be slow binding if the plot for any compound at any concentration was concave. Ki-slow was determined by measuring enzyme-catalyzed hydrolysis rates. A mixture of human alpha-thrombin (0.1 nM, American Diagnostica), substrate (50 μM Spectozyme® TH (H-D-HHT-Ala-Arg-pNA 2AcOH), American Diagnostica), compound and aqueous buffer (10 mM Tris, 10 mM Hepes, 150 mM NaCl, 0.1%PEG; pH 7.4) was monitored over 4h for changes in absorbance at 405 nM at 25 °C. A vehicle mixture was run under the same condition and inhibition constants were determined by applying the data to the following equation: P=vst-(1/k'(Vs-Vz)(1 -exp(" k, t)). Plotting k' Vs. I gives Ki from the equation k'=k6(1+S/Km)+k6/Ki(l). (Ref : Tight-Binding Inhibitors - 1. Sungman Cha, Biochemical Pharmacology 1995. Vol 24 pp2177-2185). The KjS and Kj-slow (μM) for representative compounds are listed in Table A. Cyclotheonamide, N-Me PPACK aldehyde ("GYKI-14766/LY-294468, Anticoagulant Thrombin Inhibitor", Drugs Future 1993, 18, 1159-1160) and argatroban ("Argaroban/Novastan/Slonnon, Anticoagulant Thrombin Inhibitor., Drugs Future 1990, 15, 1115-1116) were used as reference standards and their values are listed below. The compound numbers in the table correspond to the examples described hereinafter. Table A Gem Thr i Trø Ki Thr Ki-glow 491.9961268.809( 4.70511.509( N=2) 1.362± 0.7 (N=3) 4.0 ± 1.9 (N=4) N-Me-PPAC 0.010 0.0039 Argatroban 0.010 2.9 As indicated by Table A, the compounds of Formula I may be used in pharmaceutical compositions to treat patients (humans and other primates) with thrombotic disorders in a similar manner as known heparins and coumarins. The compounds can be administered by any parenteral route (intravenous, intraperitoneal, subcutaneous, dermal patch), where the preferred route is intravenous infusion. Infusion doses can range from about 0.1 -300 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques. Oral dosage forms may be elixers, syrups, capsules tablets and the like. Where the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl cellulose, magnesium sterate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known to those skilled in the art of preparing dosage forms. Parenteral dosage forms may be prepared using water or another sterile carrier. Typically the compounds of Formula I are isolated and used as their pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartatic, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2- naphthalenesulfonic, β-toluenesulfonic, cyclohexanesulfamic and saccharic. In addition to the treatment of thrombotic disorders, the compounds of Formula I may be used to prevent coagulation of stored blood samples and as coatings on medical devices such as stents and orthopedic devices. Generally they may be used in any circumstance where one seeks to inhibit coagulation by placing the compounds in contact with the medium containing thrombin. Those experienced in the use of anticoagulant agents, may find a variety of other uses for the thrombin inhibitors of this invention. These uses are considered to be within the scope of this invention, for this invention contemplates the use of compounds of Formula I as antithrombotic agents. Yet another use for the compounds of the invention is as trypsin inhibitors. Inhibitors of trypsin have been used clinically in the treatment of pancreatic disorders, such as pancreatitis. The IC50 values for the compounds of the invention compare favorably with the pancreatic agents camostat mesilate and nafamostat (IC50 s, 1 x 10-8 and 1.3 x 10-8 respectively). The compounds of Formula I may be used in the same manner as those therapeutic agents. Although all of the claimed compounds are useful as thrombin or trypsin inhibitors, the preferred compounds of Formula I include With respect to compounds of Formulas I and II, the particularly preferred substituents are as follows. The particularly preferred "A"s are where n is 1 , R3 is hydrogen and the preferred stereochemistry of the starred carbon is S. The particularly preferred "B"s are where R5 and Re are taken with the carbon to which they are each attached to form a carbonyl; and R4 is naphthylmethyl, diphenylmethyl, phenylC-i-salkyl or substituted phenylC-i-salkyl where the phenyl substituents are chlorine or fluorine. The preferred stereochemistry of the starred ( * ) carbon is R. The particularly preferred M G"s are where Rβ and Rg are taken with the carbon to which each is attached to form a carbonyl; and R7 is naphthylmethyl, diphenylmethyl, phenylC-i-salkyl or substituted phenylC-i-salkyl where the phenyl substituents are chlorine or fluorine. The ring size of the macrocycle is determined by A, B, G and m, where a ring size of 15 to 25 is particularly preferred. With respect to the compounds of Formula III, the particularly preferred "W" is sulfur. All other particularly preferred substituents are as described for Formulas I and II. In order to illustrate the invention the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those skilled in the art may find other methods of practicing the invention, which are obvious to them. However, those methods are deemed to be within the scope of this invention. EXAMPLE 1 5R, 18S, 21S-N-[3-(4, 7, 16, 17, 20-PENTAOXO-5- PHENETHYLEICOSAHYDRO-3a, 6, 15, 19 - TETRAAZACYCLOPENTACYCLONONADECENE-18-YL) PROPYL] GUANIDINE Step 1 a la A solution of CBZ-D-homophenylalanine 5.6 g (18 mmol), ProO-J Bu (3.4 g, 19.8 mmol) and HOBT, (3.65 g, 27 mmol) in CH 3 CN (70 mL) was stirred for 20 min, treated with a solution of DCC (4 g, 19.8 mmol) in CH3CN (30 mL) and stirred overnight. This mixture was filtered, the filtrate was concentrated and dissolved in CHCI3 (400 mL). This solution was washed with successive portions of 2% Na2COs(aq) (100 mL) and brine (100 mL). The resulting organic layer was dried (Na2Sθ4), concentrated in vacuo and purified by flash column chromatography (silica, CHCI 3 ) to afford la as an oil: (8.4g). lh A mixture la (5.0 g) and Pd(OH) -C in MeOH (100 mL) was shaken under 20 psig for 1.5 h. The catalyst was filtered, and the filtrate concentrated to give the free amine JJ2, as an oil (61.6 g). Step 1c l£ A solution of DCC (3.8 g, 18.5 mmol) in CH3CN (40 mL) was added to a stirred mixture of lb (6.2 g, 18.5 mmol) 8-carbobenzoxyaminooctanoic acid ( 4.94 g, 16.8 mmol) and HOBT (3.4 g, 25.2 mmol) in CH3CN (300 mL). The resulting mixture was stirred for 16 h, filtered and concentrated in vacuo . The residue was dissolved in CHCI3, washed sequentially with 5% Na 2 C03(aq) and brine, dried (Na 2 S04), and concentrated in vacuo . The residue was purified by flash column chromatography (ether-MeOH; l00%->95:5) to give ester lc as an oil: (7.8 g, 70%); m/e « 607 (MH+). Id A mixture of l£, (7.8 g, 12.8 mmol), 20% Pd(OH) 2 /C (5.0 g) and 150 mLof MeOH was shaken under 20 psig of H 2 for 3 h. The mixture was filtered and concentrated to give the amine Id as an oil: (5.5 g, 91%), m/e = 474 (MH + ). Step 1 e la. A solution of DCC (0.91 , 4.4 mmol) in DMF (15 mL) was added to a solution of 6-[[imino[4-methylbenzenesulfonyl)amino]methyl]amino]-2-(R,S)-[[2- (trimethylsilyl)ethoxy]methoxy]-3(S)-[9-phenylmethoxycarbonyl)- amino]hexanoic acid, (2.5 g ,4.0 mmol: Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) , amine Id (2.0 g, 4.4 mmol) and HOBT (0.8 g) in DMF (150 mL). This mixture was stirred overnight, and filtered. The filter cake was washed with CH3CN , and the filtrate was concentrated in vacuo . The residue was purified by flash column chromatography (silica gel, 100% CHCI3, then 2% MeOH-CHCI 3 ) to give ester l£ as a foam: (3.4 g 78%); m/e = 1078 (MH+). If A solution of la (3.3 g) in MeOH (50 mL) was treated with 20% Pd(OH) 2 /C (2.0 g) and shaken under 20 psig of H 2 for 3 h. The mixture was filtered and concentrated to the ester Ji as a foam: (2.7 g); m/e = 944 (MH + ). lfl A solution f (2.6 g) in CH 2 CI 2 (10 mL) was added to a solution of 1 :1 CH 2 Cl 2 :trifluoroacetic acid (40 mL) at 0 °C and stirred for 2.5 h. Volatiles were removed under a stream of N 2 , and the resulting gum was triturated three times with ether to give the acid lfl as a white solid: (2.5 g); m/e = 758 (MH+). Step h lh A mixture of lg_(1.2 g, 1.38 mmol) in 1.4 L of CH2CI2 was treated with DMAP (0.93 g, 7.6 mmol), and stirred for 20 min. BOP-CI (0.1 , 2.76 mmol) was added and the mixture was stirred for another 2 h and concentrated in vacuo The residue was dissolved in CH 2 CI 2 (500 mL) and washed twice with 10% citric acid (aq)(2x250 mL). The organic layer was washed with brine, dried (Na2S04), filtered, and concentrated in vacuo . The residue was purified by flash column chromatography (CHCl3-MeOH; 100% -> 90%; silica gel) to give the coupled intermediate UQ. : (600 mg, 81 %); m/e = 740 (MH + ). Step i li Dess-Martin periodinane (499 mg, 1.2 mmol) was added to a stirred solution of lb. (580 mg, 0.78 mmol) in CH 2 CI 2 (50 mL) at room temperature. This mixture was stirred for 1.5 h, treated with an excess of 25% Na 2 S2θ (aq) in NaHCθ 3 (sat'd. aq) and stirred for another 5 min. The aqueous layer was extracted with several portions of CH 2 CI 2 and the combined organic extracts were washed twice with NaCl (sat'd, aq), dried (Na 2 Sθ4), filtered and concentrated to give the diketone li as a white solid: (495 mg); m/e = 738 (MH+). 5R, 18S, 21 S-N-[3-(4, 7, 16, 17, 20-PENTAOXO-5- PHENETHYLEICOSAHYDRO-3a, 6, 15, 19 - TETRAAZACYCLOPENTACYCLONONADECENE-18-YL) PROPYL] GUANIDINE COMPOUND 1 A suspension of li (480 mg, 0.65 mmol) in anisole (3 mL) was cooled to -78°C and treated with anhydrous HF ( ca. 10 mL) using a standard HF apparatus. This mixture was stirred at 0°C for 3.5 h, concentrated in vacuo and triturated twice with 25 mL portions of ether. A solid was collected , washed with ether, and purified by reverse-phase HPLC (MeCN-water-TFA, 35:65:0.2). The resulting solid was lyophilized to give the title compound as a white solid: 272 mg; mp 50 °C; FAB-MS m/e 584 (MH + ); Anal Calcd. for C 30 H 45 N 7 O 5 • 2.5 CF3CO 2 H • 1.25 H 0: Calcd.: C, 47.16; H, 5.65; N, 11.00; H 2 0, 2.53. Found: C, 46.90; H, 5.23; N, 11.12; H 2 0 2.60. EXAMPLE 2 5R, 16S, 19S-N-[3-(5-BENZYL-4, 7, 14, 15, 18- PENTAOXOOCTADECAHYDRO) -3a, 6, 13, 17- (TETRAAZACYCLOPENTACYCLOHEPTADECEN-16- YL)PROPYL]-GUANIDINE DI-TRIFLUOROACETIC ACID SESQUIHYDRATE. COMPOUND 2 Compound 2 was prepared using the general method of Example 1. CBZ-D-PheOH replaced CBZ-D-homophenylalanine in Step 1a and 5-carbobenzoxyaminopentanoic acid replaced 8-carbobenzoxyaminooctanoic acid in Step 1c to give the title compound as a solid. FAB-MS m/e 541 (MH + ); Anal. Calc'd for C2 7 H 39 N 7 θ 5 '2(C2HF 3 θ2)*1.5 H 2 0: Calc'd: C, 46.73; H, 5.57; N, 12.31 , H 2 0, 3.39. Found: C, 46.71 ; H, 5.73; N, 12.78; H 2 0, 3.52. H 2 N^ NH 2S, 5S, 18R-N-[3-(18-BENZYL)-3,6,7,16,19- (PENTAOXOEICOSAHYDRO)-IA, 4, 8, 17- (TETRAAZACYCLOPENTACYCLONONODECEN-δ-YL)PROPYL] GUANIDINE TRIFLUOROACETIC ACID HYDRATE. COMPOUND 3 Compound 3 was prepared following the method of Example 1 with only slight modifications. CBZ-D-PheOH replaced CBZ-D-homophenylalanine in Step 1a to give the title compound as a solid. FAB-MS m/z 570, (MH + ) Anal. Calc'd for C 29 H 43 N705*2.5C 2 HF 3 0 2 'H20; Calc'd: C, 46.79; H, 5.49; N,11.23; H 2 0, 2.06. Found: C, 47.05; H, 5.43; N, 11.29; H 2 0, 2.25. EXAMPLE 4 2S, 5R, 18S, 21 S-[3-(5-BENZYL-2METHOXY-4, 7, 16, 17, 20- PENTAOXOEICOSAHYDRO-3A, 6, 15, 19- TETRAAZACYCLOPENTACYCLONONADECEN-18-YL) PROPPYL] GUANIDINE TRIFLUOROACETIC ACID HYDRATE COMPOUND 4 Compound 4 was prepared following the method of Example 1 with only slight modifications. CBZ-D-PheOH replaced CBZ-D-homophenylalanine in Step 1a and cj≤- methoxyproline (prepared according to Barlos, K., et al. Tetrahedron Lett. 1983, 39, 475) replaced ProO-hBu in the same step to give the title compound as a solid: FAB-MS m/z 600 (MH+); Anal. Calc'd for C 3 oH45N7θ 6 *2.25 C 2 HF30 2 '1.5 H 2 0 Calc'd: C, 46.91 ; H, 5.73; N, 11.10; H 2 0, 3.05 Found: C, 46.90; H, 6.03; N, 11.44; H 2 0, 3.00. EXAMPLE 5 6R, 19S, 22S-N-[3-(6-BENZYL-5, 8, 17, 18, 21- PENTAOXODOCOSAHYDRO-4a, 7, 16, 20- TETRAAZABENCBZOCYCLONONADECEN-19-YL) PROPYL] GUANIDINE TRIFLUOROACETIC ACID HYDRATE COMPOUND 5 Compound 5 was prepared following the method of Example 1 with only slight modifications. CBZ-D-PheOH replaced CBZ-D-homophenylalanine in Step 1 a and L-pipecolinic acid replaced ProO-LBu in the same step to give the title compound as a solid: FAB-MS m/z 584 (MH + ); Anal. Calcd for C3θH45N7θ 5 -2.0 C 2 HF 3 O 2 *1.0 H 2 0: Calc'd: C, 49.21 ; H, 5.95; N, 11.82; H 2 0, 2.17 Found: C, 49.28; H, 5.66; N, 11.67, H 2 0, 2.56. EXAMPLE 6 5R, 2S, 18S-N-[3-(5-NAPTHALEN-2-YLMETHYL-4, 17, 16, 17, 20- PENTAOXOEICOSAHYDRO-3a, 6, 15, 19- TETRAAZACYCLOPENTACYCLONONADECEN-18-YL)PROPYL] GUANIDINE TRIFLUOROACETATE HYDRATE COMPOUND 6 Compound 6 was prepared following the method of Example 1 with only slight modifications. CBZ-D-2-napthylalanine replaced CBZ-D-homophenylalanine in Step 1 a to give the title compound as a solid: FAB-MS m/z: FAB-MS m/z 620 (MH+); Anal. Calc'd for 033^5^05* 1.5 C 2 HF 3 θ2 « 1.75 H2θ: Cacl'd: C, 51.80; H, 5.93; N, 11.59; H 2 0, 3.19 Found: C, 51.44; H, 5.95; N, 11.44; H 2 0, 3.23. EXAMPLE 7 3S, 16R, 19S-N-[3-(1 , 4, 5, 14, 17-PENTAOXO-16-PHENYL-2, 6, 15, 18-TETRAAZACYCLOPENTACYCLONONADECAN-3- YL)PROPYL] GUANIDINE TRIFLUOROACETIC ACID HYDRATE COMPOUND 7 Compound 7 was prepared following the method of Example 1 with only slight modifications. CBZ-D-phenylglycine replaced CBZ-D-homophenylalanine in Step 1 a to give the title compound as a solid: FAB-MS m/z 556 (MH + ); Anal. Calcd for C28H iN 7 0 5 *1.75 C 2 HF 3 0 2 '1.5 H 2 0: Calc'd: C, 48.37; H, 5.90; N, 12.53; H20 3.45 Found: C, 48.40; H, 5.95; N, 12.52; H20, 3.64. EXAMPLE 8 5R, 17S, 19AS-N-[3-(5-BENZYL-4, 7, 15, 16, 19- PENTAOXOOCTADECAHYDRO-3a, 6, 14, 18- TETRAAZACYCLOPENTACYCLOOCTADECEN-17-YL)PROPYL] GUANIDINE TRIFLUOROACETIC ACID HYDRATE COMPOUND 8 Compound 8 was prepared using the general method of Example 1. CBZ-D-PheOH replaced CBZ-D-homophenylalanine in Step 1a and 7- carbobenzyloxyaminoheptanoic acid replaced 8-carbobenzoxyaminooctanoic acid in Step 1c to give the title compound as a solid: FAB-MS m/z 556 (MH+); Anal. Calc'd for C 2 βH4iN θ5'1.5C 2 HF 3 O 2 » 2.0 H 2 0: Calc'd: C, 48.82; H, 6.15; N, 12.85, H 2 0, 4.72 Found: C, 48.68; H, 6.07; N, 12.74, H 2 0, 4.83. EXAMPLE 9 5R, 20S, 23S-[3-(5-BENZYL-4, 7, 18, 19, 22- PENTAOXOCYCLOEICOSAHYDRO-3A, 6, 17, 21 - TETRAAZACYLOPENTACYCLOHENEICOSEN-20- YL)PROPYL]GUANIDINE TRIFLUOROACETIC ACID HYDRATE COMPOUND 9 A slurry of 9-cyanopelargonic acid (8.6 g, 48 mmol), a catalytic amount 5%Rh/AI 2 0 3> and 200 mL of 2.0 N NH 3 -EtOH was shaken under 50 psig of H2 pressure for 6 h, then filtered through dicalite. The filter pad was washed with 100 L of hot 1 :1 MeOH-H 2 0, and the combined filtrates were concentrated to give 6.1 g of 10-aminodecanoic acid. The crude product (5.7 g) was dissolved in 15.5 mL of 2N NaOH and treated simultaneously with 23 mL of 2N NaOH and 5.8 g of carbobenzoxychloride at 0 °C with vigorous stirring over 0.5 h. Water and 2N NaOH were added as needed to maintain stirring and a pH between 10-14. After stirring for 2.5 h, the reaction was diluted with 400 mL of H2O and filtered through dicalite. The filtrate was acidined (pH 2) with H2SO4, then extracted with ether. The combined ether extracts were dried (Na2Sθ4), filtered and concentrated. The residue was dissolved in CH3CN, filtered, and the filtrate concentrated to afford 5.3 g of 10-(Λ/-carbobenzoxy)-aminodecanoic acid which was used without further purification: FAB-MS m/z 322 (MH + ). Compound 9 was prepared using the general method of Example 1. CBZ-D-PheOH replaced CBZ-D-homophenylalanine in Step 1a and 10-(Λ/- carbobenzoxy)-aminodecanoic acid replaced 8-carbobenzoxyaminooctanoic acid in Step 1c to give the title compound as a solid: FAB-MS m/z 598 (MH + ); Anal Calc'd for C 3 ιH 4 7N7θ5'1.75 C 2 HF 3 0 2 .1.75 H 2 0; Calc'd: C, 50.00; H, 6.35; N, 11.83; H 2 0, 3.80 Found: C, 49.62; H, 6.23; N, 11.93; H 2 0, 3.46. EXAMPLE 10 21 S, 24S, 27R-N-[3-(5-BENCBZYL-4, 7, 19, 20, 23- PENTAOXOTETRACOSAHYDRO-3a, 6, 18, 22- TETRAACBZACYCLOPENTACYCLODOCOSEN-21- YL)PROPYL]GUANIDINE COMPOUND 10 Compound 10 was prepared using the general method of Example 1. CBZ-D-PheOH replaced CBZ-D-homophenylalanine in Step 1 a and 11-carbobenzoxyaminoundecanoic acid replaced 8-carbobenzoxyaminooctanoic acid in Step 1c to give the title compound as a solid: FAB-MS m/z 612 (MH + ); Anal Calc'd for C 32 H 4 9N 7 θ5'1.75 H 2 0 « 1.5 C 2 HF 3 0 2 : Calc'd: C, 51.62; H, 6.68; N, 12.05; H 2 0, 3.93 Found: C, 51.83; H, 6.12; N, 11.98; H 0, 3.93 EXAMPLE 11 Preparation of Compound 11 Step 11 a H 2 N ^CO^i-Bu (CH 2 ) 4 Ila Carbobenzoxy chloride (271 mL, 1.9 mol) and 4N NaOH (475 mL) were added simultaneously to a solution of 6-aminopentanoic acid (100g, 0.76 mol) in 4 N NaOH (aq.) (190 mL) at such a rate as to maintain the temperature ≤. 10°C. The reaction was stirred an additional 2 h at 0-5°C while the pH was maintained between 10 and 12. The mixture was then diluted with H 2 0 (250 mL) and extracted four portions of ether (250 mL). The aqueous extract was acidified with 3N H2SO4 (pH = 3), and extracted repeatedly with CH 2 CI 2 ■ The organic extracts were combined and washed with brine, dried (Na 2 Sθ4) , filtered, and concentrated in vacuo to yield 196 g of 6- carbobenzyloxyaminopentanoic acid as an oil which solidified upon standing: FAB-MS m/z 266 (MH+). A solution of 6-carbobenzyloxyaminopentanoic acid (50 g) in CH 2 CI 2 (500 mL) was treated with 2.2 mL of H Sθ4 (cone), saturated with isobutylene and stirred for 4 h. The resulting mixture was treated with 5% KOH (aq) (200 mL) and the layers were separated. The organic layer was washed twice with brine (2x100 mL), dried (Na 2 Sθ4) and concentrated, in vacuo. The residue was purified by flash column chromatography (silica gel, hexanes-ether) to afford 38 g of 6-carbobenzyloxyaminopentanoic acid f-butyl ester: MS m/z 322 (MH+). A mixture of 6-carbobenzyloxyaminohexanoic acid f-butyl ester (9 g, ?? mmol) , Pd(OH) 2 /C (4.5 g) and 50 mL of ethanol was shaken under 15 psig for 2 h, filtered and concentrated in vacuo to give the amine 11a. as an oil: MS m/z 188 (MH+). The material was used without further purification. A solution of HOBT (4.0 g, 30.2 mmol), DCC (4.6 g, 22.3 mmol) in DMF (35 mL) was added to a solution of amine Ha (4.2 g, 22.2 mmol) and CBZ-D- Phe (6.0 g,-20.0 mmol) in DMF (35 mL). This mixture was stirred overnight, filtered and concentrated in vacuo. The residue was dissolved in CHCI3, washed sequentially with 10% NaHCθ3 (aq) and brine, dried (Na 2 Sθ4) and concentrated in vacuo. A 2.0 g portion of the crude residue was purified by flash column chromatography (silica gel, CHCI3) to afford 1.8 g of the coupled ester IU2: MS m/z 469 (MH+). Step 11c ll£ A solution of lib (2.2 g, 4.7 mmol) in CH 2 CI 2 (5 mL) was added to a solution of 1 :1 TFA-CH 2 CI 2 (25 mL) at 0 °C. This solution was gradually warmed to RT and stirred for an additional 1.5 h. The volatiles were removed under a stream of N 2 , and the residue was triturated with ether to give the acid He. as a white solid: (1.8 g); MS m/z 413 (MH+). Hd A solution of DCC (1.1 g, 5.5 mmol) in CH3CN (5 mL) was added to a stirred solution of He (2.0 g, 5.0 mmol), D-Phe-Pro-O-l-Bu (1.8 g, 5.5 mmol) and HOBT (1.07 g, 7.5 mmol ) in CH3CN (35 mL). This mixture was stirred for 16 h, filtered and concentrated in vacuo . The residue was dissolved in CHCI3 , washed sequentially with 10% NaHC03 and brine, dried (Na 2 Sθ4) and concentrated in vacuo . This residue was purified by flash column chromatography (silica gel, CHCl3->CHCl3-MeOH) to give the coupled product as a foam: MS m/z 542 (M - Pro-0-f-Bu)+. This material was combined with MeOH (50 mL) and Pd(OH) 2 (1.2 g) and shaken under H2 (20 psig) for 2.5 h. The reaction was filtererd through dicalite and the filter pad thoroughly washed with MeOH. The filtrate was concentrated to give intermediate Hd as a foam: (1.8 g,); MS 579 (MH+). Ha A solution of 6-[[imino[4-methylbenzenesulfonyl) amino]methyl]amino]-2- (R,S)-[[2-(trimethylsilyl)ethoxy]methoxy]-3(S)-[9-phenylmethoxycarbonyl)- amino]hexanoic acid, (1.0 g, 1.6 mmol) of Hd (1.0 g, 1.8 mmol) and HOBT (0.3 g, 2.2 mmol) in CH3CN (35 mL) was treated with a solution of DCC (0.4 g, 1.8 mmol) in CH3CN (5 mL) and stirred overnight. The mixture was filtered and the filtrate was concentrated in vacuo . The residue was dissolved in CHCI3, washed successively with 10% Na 2 Cθ3 and H 2 0, dried (Na 2 Sθ4) and concentrated in vacuo . The residue was purified by flash chromatography (siica gel, CHCI3 ->CHCl3-MeOH) to give the arginine derivative Ha as a solid: (1.5 g); MS m/z 1184 (MH+). A mixture of Ha (1.5 g, 1.26 mmol), Pd(OH) 2 , (0.8 g) and MeOH (50 mL)was shaken under of H 2 at 20 psig for 2.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the deprotected intermediate Hi 1.2 g as an off white solid: MS m/z 1049 (MH+). Hfl To a solution of 1 :1 TFA-CH 2 CI 2 (15 mL) was added to a solution of HJti (1.24 g, 1.2 mmol) in CH 2 CI 2 (5 mL) at 0 °C. This mixture was stirred for 2.5 h at room temperature, and the volatiles were removed under a stream of N 2 . The residue was triturated with ether and collected to afford Hg, 1.1 g as a white solid: MS 863 (MH+). Hll A mixture of 11 g (1.1 g, 1.1 mmol) in CH 2 CI 2 (1.1 L) was treated with DMAP (0.7 g, 5.7 mmol) followed by BOP-CI (0.6 g, 2.3 mmol). This mixture was stirred for 24 h, then concentrated in vacuo. The residue was dissolved in CH 2 CI 2 , washed with 10% citric acid (aq), dried (Na2S04) and concentrated. in vacuo The residue was purified by flash column chromatography (silica gel, CH 2 CI 2 -> 95% CH 2 CI 2 -MeOH to yield HJl (0.3 g )as a solid: MS 845 (MH+). Hi Intermediate Hh (0.3 g, 0.3 mmol) was added to a mixture of of Dess- Martin periodinane (2.0 g, 0.5 mmol) in CH 2 CI 2 (10 mL). The mixture was stirred for 1.5 h, and treated with an excess of 10% Na 2 S 2 θ3 (aq) in NaHC03 (satd. aq.). The layers were separated, and the aqueous layer was extracted three times with CHCI3. The combined organic extracts were washed with H 2 0, dried (Na 2 S04) , and concentrated in vacuo to give Hi (0.3 g) as a white solid which was used without purification. 5R, 15R, 19S, 21AS-N-[3-(5, 15-DIBENZYL-4, 7, 14, 17, 18, 21 , HEXAOXOEICOSAHYDRO-3a, 6, 16, 20- PENTAAZACYCLOPENTACYCLOEICOSEN-19- YL)PROPYL]GUANIDINE TRIFLUOROACETATE COMPOUND 11 A mixture of intermediate Hi (0.3 g) and anisole (6 mL) was treated with HF (ca. 10 mL) at -78°C, and warmed to 0°C. This mixture was stirred for 4.5 h and the HF was removed in vacuo. The residue was triturated with ether and the resulting solid was purified by reverse phase HPLC (1 :1 0.2 CH3CN-H2O- TFA) to afford the title compound (0.1 g ) as a white powder: MS 620 (MH+); Anal. Calc'd for C23H45N7θ5»1.75 C2HF3θ2'1.5 H2O: Calc'd: C, 51.14; H, 5.63; N, 11.93; H 2 0, 2.40. Found: C, 51.19; H, 5.70; N, 12.08; H 2 0, 2.59. EXAMPLE 12 5R, 15S, 19S, 21a-S-N-[3-(5, 15-DIBENZYL-4, 7, 14, 17, 18, 21- HEXAOXODOCOSAHYDRO-3a, 6, 13, 16, 20- PENTAAZACYCLOPENTACYCLOEICOSEN-19- YL)PROPYL)GUANIDINE TRIFLUOROACETATE COMPOUND 12 Compound 12 was prepared following the method of Example 1 1. N-α-CBZ-L- Phe was used in place of Λ/-α-CBZ-D-Phe in Step 11 b and all other steps were carried out with only minor modifications: Anal calc'd for C36H48Nβθ6 # 1.35 C2HF 3 O 2 » 2.0 H 2 0: Calc'd: C, 52.89; H, 6.12; N, 12.75; H 2 0, 4.10 Found: C, 53.02; H, 5.92; N, 12.82; H 2 0, 3.97 EXAMPLE 13 5R, 18S, 20a-S - N - [3-(5-BENZYL-4, 16, 17, 20- TETRAOXOEICOSAHYDRO-3a, 6, 15, 19- TETRAAZACYCLOPENTACYCLONONADECEN-18-YL) PROPYL] GUANIDINE TRIFLUOROACETATE Step 13a C < CH 2)7 FM0C' N CHO H 13a Fluorenylmethoxycarbonyl chloride (4.87 g, 0.02 mol) to a mixture of aminooctanoic acid (3.0 g ,0.02 mol) in 200 mL of 10% Na 2 Cθ3 (aq) and dioxane (150 mL) at 0°C. The mixture was stirred for 2.5 h at 0°C, acidified to pH 5 with acetic acid and extracted three times withCHC . The combined organic extracts were washed with H 2 0, dried (Na 2 S04) and concentrated in vacuo . The residue was purified by flash chromatography (silica gel, CHCI 3 -> 95:5 CHCI 3 -MeOH) to afford 8- fluorenylmethoxycarbonylaminooctanoic acid (6.4 g) as a solid: MS 382 (MH+). The product was dissolved in CH 2 CI 2 (40 mL), cooled to 0°C, and treated with methoxymethyl amine hydrochloride (2.05 g, 21.1 mmol), triethylamine (8.1 mL) and BOP reagent (8.0 g). This mixture was stirred for 12 h at 0°C, washed sequentially with 3N HCl, NaHC03 (saf'd. aq.) and brine. The organic phase was dried (Na 2 Sθ4) and concentrated, in vacuo. The residue was purified by flash column chromatography (silica gel; CHCl3->98:2 CHCl3-MeOH) to afford 8-fluorenylmethoxycarbonyl-aminooctanoic acid N,N-methoxymethyl amide (7.1 g): MS m/z 425 (MH+). A solution of the product (6.8 g) in THF (80 mL) was cooled to -40°C and treated dropwise with 1.0 M DIBAL THF (48.5 mL). The mixture was stirred an additional 15 min, quenched with 3N HCl (50 mL) and warmed to room temperature. The resulting aqueous layer was extracted repeatedly with CHCI3 and the combined organic extracts were washed with brine, dried (Na 2 S04) and concentrated in vacuo. The residue was purified by chromatography (silica gel; CH2CI2->2% MeOH-CH2CI2) to afford aldehyde 13a as a solid: 5.2 g; MS m/z 366 (MH+). 13b A solution of 13a (4.2 g, 11.6 mmol) and D-Phe-Pro-O-f-Bu (4.1 g, 12.7 mmol) in CH 2 CI 2 (100 mL) was treated with sodium triacetoxy borohydride (3.7 g, 17.4 mmol), followed by glacial acetic acid (0.7 g). This mixture was stirred for 3.5 h, treated with excess NaHCOβ (sat'd) and the resulting aqueous layer was extracted repeatedly with CH 2 CI 2 . The combined organic layers were washed with brine, dried (Na 2 Sθ4), and concentrated in vacuo to give the coupled product 13b as a semi-solid: 7.8 g; MS m/z 668 (MH+). 13c A mixture of 13_b_{7.8 g, in 1 :1 CH 2 CI 2 -H 2 0 (30 mL) was cooled to 0 °C and treated with NaHCOβ (1.1 g, 12.7 mmol) of followed by dropwise addition of benzylchloroformate (1.8 mL, 12.7 mmol). This mixture was stirred for 2h at 0 °C, and the aqueous phase was extracted repeatedly with CH 2 CI 2 . The combined organic layers were washed sequentially with H 2 0 and brine, dried (Na 2 S04) and concentrated in vacuo. The residue was purfied by flash chromatography (silica gel, CHCI3) to give 12c. as a semi-solid: 7.3 g; MS m/z 802 (MH+). Step 13d (CH 2 ) 8 H 2 N-^ \ 13d A solution of 12ς (2.4 g) in DMF (20 mL) was treated with piperidine 4 mL and stirred for 25 min. The resulting mixture was concentrated in vacuo and triturated with hexane to give 13d as an oil: 1.5 g; MS m/z 580 (MH+). i o 12a A solution of 6-[[imino[4-methylbenzenesulfonyl) amino]methyl]amino]-2-(R,S)- [[2-(trimethylsilyl)ethoxy]methoxy]-3(S)-[9-fluorenylmethoxycarbonyl)- amino]hexanoic acid (1.6 g, 2.3 mmol), 12d (1.4 g, 2.5 mmol), and HOBT (0.46 g, 3.4 mmol) in CH3CN (35 mL) was treated with a solution of DCC 15 (0.51 g, 2.5 mmol) in CH3CN (5 mL). This mixture was stirred for 12 h, filtered, and the filtrate was concentrated in vacuo . The residue was purified by flash column chromatography (silica gel, CHCl3->5% MeOH-CHCl3) to afford 12a as a semi solid: 1.8 g; MS m/z 1273 (MH+) 121 Piperidine (4 mL) was added to a solution of 12a (1.7 g) in DMF (20 mL) and stirred for 30 min. This mixture was concentrated in vacuo and the residue was washed with hexanes to yield 13f as an oil: 1.4 g; MS m/z 1050 (MH+) 12a A solution of TFA (15 mL) and CH 2 CI 2 (10 mL) was added a solution of 121 (1.4 g) in CH 2 CI 2 (5 mL) at 0 °C. This mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under a stream of N 2 . and the residue was triturated with ether to afford ^3. as a solid: 1.1 g; MS m/z 864 (MH+). 1311 BOP-CI (0.5 g, 2.0 mmol) was added to a solution of 12g. (1.1 g, 1.0 mmol) and DMAP (0.63 g, 5.2 mmol) in CH2CI 2 (1.0 L). This mixture was stirred for 6 h and concentrated jn vacuo. The residue was purified by flash column chromatography (silca gel; 5%MeOH-CH2Cl2 ) to afford 12il as a white foam: 0.31 g; MS m/z 846 (MH+). 5R, 18S, 20a-S - N - [3-(5-BENZYL-4, 16, 17, 20- TETRAOXOEICOSAHYDRO-3a, 6, 15, 19- TETRAAZACYCLOPENTACYCLONONADECEN-18-YL) PROPYL] GUANIDINE TRIFLUOROACETATE COMPOUND 13 A suspension of 12a (0.2 g, 0.4 mmol) in CH 2 CI 2 (10 mL) was treated with (0.3 g, 0.6 mmol) of the Dess-Martin periodinane and stirred for 2 h. The mixture was treated with excess solution of 25% NaS 2 θ3 in NaHC03 (sat'd aq.) and the the aqueous layer was extracted repeatedly with CH 2 Cl 2 . The combined organic extracts were washed with water, dried (Na 2 S04) and concentrated jn vacuo to yield the keto-amide product (0.3 g)which was used in the next step without purification: MS m/z 844 (MH+). A stirred mixture of the keto-amide and anisole (3 mL) was treated with HF (ca. 15 mL) at -78°C. This mixture was stirred an additional 3.5 h at 0 °C, and the HF was removed in vacuo at 0 °C. The residue was triturated with ether, and the residue was purified by reverse- phase HPLC (30:70:0.2 CH3CN-H 2 0-TFA). The desired fractions were lyophilized to give the title compound as a white solid : 0.1 g; MS m/z 556.5 (MH+); Anal. Calcd for C 2 9H 4 5N7θ4*2.75 C 2 HF 3 0 2 -1.25 H 2 0 Calc'd: C, 46.46; H, 5.68; N, 10.99; H 2 0, 2.47 Found: C, 46.53; H, 5.72; N, 11.15; H 2 0, 2.77. EXAMPLE 14 2S, 5S, 9R-N[3-(9-BENZYL-3, 6, 7, 10, 19- (PENTAOXOEICOSAHYDRO)-la, 4, 8, 11 - (TETRAAZACYCLOPENTACYCLONONADECEN-5- YL)PROPYL] GUANIDINE TRIFLUOROACETIC ACID. Step 14a 14a A solution of £Lα-Cbz-aminooctanoic acid (2.5 g, 8.5 mmol), Pro-O-l-Bu (1.6 g, 9.4 mmol) and HOBT (1.7 g, 12.8 mmol) in CH3CN (80 mL) was added a solution of DCC (1.4 g, 9.4 mmol) in CH3CN. (15 mL). The reaction was stirred overnight, filtered and the resulting filtrate concentrated in vacuo. The residue was purified by flash column chromatography CH 2 CI 2 -> 2% MeOH-CH 2 CI 2 ) to afford 14a :3.8 g; MS m/z 447 (MH+). 14b A mixture of 14 (3.6 g), Pd(OH) 2 (1.8 g) in MeOH (75 mL) was shaken under H 2 (20 psig) for 2.5 h. This mixture was filtered, and the filtrate was concentrated in vacuo to give the free amine 14b (2.5 g) which was used without further purification. Step 14c 14c A solution of N-α-Cbz-D-Phe (2.2 g, 7.3 mmol) of, 14c. (2.5 g, 8.1 mmol) and HOBT (1.4 g, 11.0 mmol) in CH3CN (10 mL) was treated with DCC (1.7 g, 8.1 mmol)in CH3CN (10 L). The mixture was stirred overnight, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in CHCI3, washed with NaHCθ3 (sat'd. aq), dried (Na 2 Sθ 4 ) and concentrated in vacuo This residue was purified by flash column chromatography (silica gel, 97:3 CHCl 3 -MeOH) to afford 14c.: 3.7 g; MS m/z 594 (MH+). 14d A mixture of 14£ (3.7 g), MeOH ( 75 mL) and PdOH 2 (1.4 g)was shaken under H (20 psig) for 2.5 h and filtered. The filtrate was concentrated in vacuo to afford 14d (2.5 g) which was used in the next step without purification. Step 14e 14e A mixture of 6-[[imino[4-methylbenzenesulfonyl) amino]methyl]amino]-2-(R,S)- [[2-(trimethylsilyl)ethoxy]methoxy]-3(S)-[9-phenylmethoxycarbonyl)- amino]hexanoic acid (1.0 g, 1.6 mmol) , 14d (0.81 g, 1.8 mmol) and HOBT (0.32 g, 2.4 mmol) of HOBT in CH3CN (60 mL) was treated with DCC (0.36 g, 1.8 mmol) in CH3CN (60 mL). This mixture was stirred overnight, filtered and the resulting filtrate was concentrated in vacuo . The residue was dissolved in CHCI3, washed with 10% aqueous Na 2 Cθ3, dried (Na 2 S04) and concentrated in vacuo. This residue was purified by flash column chromatography (silica gel, CHCI 3 ->98% CHCl3-MeOH) to afford ϋa (1 -42 g) as a white solid: MS m/z 1064 (MH+). IM A mixture of 14 (1 -42 g) Pd(OH) 2 (0.8 g) and MeOH (50 mL) under H (20 psig) for 2.5 h. This mixture was filtered, and the filtrate concentrated in vacuo to yield amine 141 (1 -18 g) : MS m/z 930 (MH+). Step 14g A solution of 14g (1.18 g) in CH2CI2 (5 mL) was added to a solution of 1 :1 TFA- CH2CI2 (20 mL) at 0 °C. This mixture was stirred for 2 h at room temperature and the solvent was removed under a stream, of N2. The residue was triturated with ether to afford 14g (1.02 g) which wasd used without additional purification. Step 14h 14h A solution of 1_4h. (1.01 g, 1.18 mmol) in CH 2 CI 2 was treated with DMAP (0.73 g, 6.0 mmol) of DMAP followed by BOP-CI (0.60 g, 2.35 mmol). This mixture was stirred for 24 h and the total volume was reduced to 100 mL in vacuo. This solution was washed with 10% aqueous citric acid, dried (Na 2 S04) and concentrated in vaci|Q. The residue was purified by flash column chromatography (silica gel, CH 2 CI 2 ->10% MeOH-CH 2 CI 2 ) to yield 14h (0.30 g) Step 14i 14i A solution of 14i (0.30 g, 0.42 mmol) in CH 2 CI 2 (10 mL) was added to a suspension of Dess-Martin periodinane (0.26 g, 0.62 mmol) in CH 2 CI 2 (10 mL) After 2.5 h, the mi\xture was treated with an excess of 25% Na 2 S 2 θ4 (aq) in NaHC03 (sat'd. aq) and stirred for 5 min. The aqueous layer was extracted with CH 2 CI 2 and the combined organic extracts were washed with H 2 0, dried (Na 2 Sθ4) and concentrated under in vacuo to afford 14i (0.30 g) which was used in the next step without purification: MS m/z 724 (MH+). (PENTAOXOEICOSAHYDRO)-l a, 4, 8, 11 - (TETRAAZACYCLOPENTACYCLONONADECEN-5- YL)PROPYL] GUANIDINE TRIFLUOROACETIC ACID COMPOUND 14 A suspension of 1_4i (0.30 g) in anisole (2 mL) was cooled to -78°C and treated with anhydrous HF (ca. 10 mL) using a standard HF apparatus. This mixture was stirred for 4h at 0 °C and the HF was removed in vacuo at 0°C. This residue was triturated twice with ether (2 X 25 mL) and the resulting solid was purified by reverse-phase HPLC (MeCN-water-TFA, 40:60:0.2). Lyophillization of the eluate provided the title compound (0.44 g) as a white solid : FAB-MS m/z 570 (MH+) Anal. Calc'd for C 2 9H 3N 7 θ5'1.25 C 2 HF 3 O 2 » 2.0 H 2 0 Calc'd: C, 50.56; H, 6.50; N, 13.10; H 2 0, 4.82. Found: C, 50.31 , H, 6.25; N, 12.70; H 2 0; 4.33. EXAMPLE 15 12R,16S,19S-N-[3-(12-BENZYL-4,1 1 ,14,15,18-PENTAOXOOCTADECAHYDRO)- 3A, 10.13,17-(TETRAAZACYCLOPENTACYCLOHEPTADECEN-16-YL)PROPYL]- GUANIDINE TRIFLUOROACETIC ACID COMPOUND 15 The preparation of compound 15 is analogous to Example 14. The hexanoyl analog of 14d. namely 1 (S)-[6-(2(R)-amino-3- phenylpropionylamino)hexanoyl]pyrrolidine-2-carboxyiic acid t-butyl ester, was prepared by coupling CBZ-D-Phe with 6-aminohexanoic acid -1-butyl ester, saponifying the ester and coupling the resulting acid with Pro-O-l-Bu. The remaining steps of Example 14 were carried out to give the title compound as a solid: FAB-MS m/z 542 (MH+); Anal Calc'd. for C 2 7H 3 9N7θs-1.75 CF 3 C0 2 H » 1.5 H 2 0: Calc'd: C, 47.69; H, 5.74; N, 12.76; H 2 0, 3.53 Found: C, 47.81 ; H, 5.74; N, 13.04; H 2 0, 3.57. EXAMPLE 16 12S,16S,19S-3-[16-(3-GUANIDINOPROPYL)-4,11 ,14, 15,18- PENTAOXOOCTADECAHYDRO-3,10,13,17- TETRAAZACYCLOPENTACYCLOHEPTADECEN-1 ,2-YL]PROPIONIC ACID TRIFLUOROACETATE COMPOUND 16 The preparation of compound 16 is analogous to Example 14. The hexanoyl analog of 14d, namely 1 (S)-[6-(2(R)-amino-3- (carboxymethyl)propionylamino)hexanoyl]pyrrolidine-2-carboxylic acid 1-butyl ester, was prepared by coupling L-N-α-Fmoc-Glu(OBzl)-OH with 6- aminohexanoic acid -1-butyl ester, saponifying the ester and coupling the resulting acid with Pro-O- -Bu. The remaining steps of Example 14 were carried out to give the title compound as a solid: FAB-MS m/z 523 (MH+); Anal Calc'd. for C 23 H 3 7N7θ7*2.0CF 3 CO 2 H « 1.5 H 2 0: Calc'd: C, 41.65; H, 5.44; N, 12.59; H 2 0, 3.47 Found: C, 41.83; H, 5.30; N, 12.64; H 2 0, 3.57. EXAMPLE 17 5R,18S,21 S-N-[3-(4,7,16,17,20-PENTAOXO-5-PHENETHYLEICOSAHYDRO- 3a, 6, 15, 19-TETRAACBZACYCLOPENTACYCLONONADECEN-18- YL)PROPYL]GUANINDINE TRIFLUOROACETIC ACID Step 17a Fm oc'^ N^^- Cθ2tBU H lZa Sodium Trriacetoxyborohydride (6.1 g, 29 mmol) and acetic acid (1 mL) were added to a solution of N-α-(fluorenylmethyloxycarbonyl)glycinal (5.4 g, 19 mmol: prepared by the method of Ho, et al. Journal Of Organic Chemistry 1983, 58, 2313-16) and 5-aminopentanoic acid 1-butyl ester (3.6 g, 20 mmol) in CH 2 CI 2 (30 mL). This mixture was stirred overnight and concentrated in vacuo to give 17a which was used without purification Step 17b Fmoc-^ N^^~ Cθ2lBu CBZ 12b To a solution of 11 g of intermediate 3 and 5.6 L of triethylamine in 150 mL of CH2CI 2 at 0 °C Carbobenzoxychloride (3.1 mL) was added to a stirred solution of 14a (11g) and triethylamine (5.6 mL) in CH 2 CI 2 (150 mL). After 2 h, the reaction was quenched with H 2 0, and the resulting organic layer was extracted twice with CH 2 CI 2 . The combined organic layers were dried (Na 2 Sθ4) and concentrated. The residue was purified by flash chromatography (silica gel; 3:1 hexanes-ether-> 3:2 hexanes-ether) to afford 2.6 g of 17b as a white solid: MS m z 573 (MH+). Step 17c H 2 N^^ N ^ v ^^ ^C0 2 tBu CBZ 12fi A solution of intermediate 12h (2.42 g) in CH 2 CI 2 (5 mL) was added to a 1 :1 solution of TFA-CH 2 CI 2 (20 mL) at 0 °C. The reaction was stirred for 1 h at room temperature, then volatiles were removed under a stream of N 2 at room temperaature. The residue was purified by chromatography (flash column, silica gel; 9:1 CHCI 3 -MeOH) to afford 1.8 g of 12a : MS m/z 517 (MH+). Step 17d IZd A solution of 12a (1.72 g, 3.33 mmol) and D-Phe-Pro-O-l-Bu (1.58 g, 4.99 mmol) and HOBT (0.67 g, 4.99 mmol) was treated with a solution of DCC (1.03 g, 5.00 mmol) in CH3CN (3 mL) and stirred overnight. The mixture was filtered and concentrated, and the residue was purified by flash chromatography (silica gel, 100 % CHCI 3 -> 98% CHCb-MeOH) to give 2.28 g of intermediate 17_d: MS m/z 817 (MH+). H 2 N Ha A solution of 12d (2.24 g) in CH3CN (25 mL) was treated with diethylamine (6 mL) and the mixture was stirred for 2.5 h. The solution was concentrated in vacuo , and the residue was purified by flash chromatography (silica gel, 100 % CHCb -> 90% CHCb-MeOH) to give 1.27 g of intermediate H :MS m/z 595 (MH+). 121 To a stirred solution of [[imino[4-methylbenzenesulfonyl)amino]methyl]amino]-2- (R,S)-[[2-(trimethylsilyl)ethoxy]methoxy]-3(S)-[9-fluorenylmethoxycarbonyl)- amino]hexanoic acid, (2.5 g ,4.0 mmol: prepared analogous to the CBZ derivative in Maryanoff et al. Journal of the American Chemical Society 1995, 117, 1225-39) and intermediate 12L(1.27 g, 2.13 mmol) and HOBT (0.39 g, 2.91 mmol) in CH3CN (45 mL) was added DCC (0.44 g, 2.13 mmol) and this mixture was stirred overnight. The reaction was filtered, the filtrate was concentrated, and the residue was purified by flash chromatography (silica gel, 100 % CHCb -> 95% CHCb-MeOH) to yield 1.96 g of intermediate 17f_: MS m z 1 87 (MH+). 12a A solution of intermediate 12fl (1.93 g) in CH3CN (20 mL) was treated with diethylamine (5 mL) and stirred for 2h. The solution was concentrated, and the residue was triturated repeatedly with ether to afford 1.31 g of intermediate 12fl MS m/z 1065 (MH+). 12 To a solution of 1 :1 TFA -CH 2 CI 2 (20 mL) at 0 °C was added a solution of intermediate 12g . (1.31 g, 1.23 mmol) in CH 2 CI 2 (5 mL). After stirring at room temperature for 1 h, the solution was concentrated under a stream of N2, and the residue was triturated with ether to afford 1.1 g of intermediate 17h as a white solid: MS m/z 879 (MH+). Step 17i CBZ 12i A mixture of intermediate 12h (1.1 g, 1.0 mmol) and DMAP (0.63 g, 5.1 mmol) in CH 2 CI 2 (1 L) was treated with BOP-CI (0.5 1 g, 2.0 mmol) and stirred for 4 h. The mixture was reduced ca. 75%, washed twice with 10% aqueous citric acid, dried (Na2S04) and concentrated. The residue was purified by flash column chromatography (silica gel, CH2CI2-> 10% MeOH-CH2CI2) to give 0.53 g of intermediate 12i : MS m/z 861 (MH+). H 5R,18S,21 S-N-[3-(4,7,16,17,20-PENTAOXO-5-PHENETHYLEICOSAHYDRO- 3a, 6, 15, 19-TETRAAZACYCLOPENTACYCLONONADECEN-18- YL)PROPYL]GUANINDINE TRIFLUOROACETIC ACID COMPOUND 17 To a mixture of Dess-Martin periodinane (0.39 g, 0.89 mmol) in CH 2 CI 2 (10 mL) was added to a solution of intermediated (0.51 g) in CH 2 CI 2 (10 mL). After stirring for 1 h, the reaction was treated with excess 25% Na 2 S 2 θ 3 (aq) in NaHCθ3 (sat'd., aq.) and the layers were separated. The aqueous layer was extracted three times with CHCI3, and the combined organic layers were washed with water, dried (Na 2 Sθ4), and concentrated in vacuo to afford 0.46 g of the corresponding keto-amide: MS m/z 859 (MH+). A mixture of the keto- amide (0.44 g) in anisole (3 mL) was treated with ca. 10 mL of HF at -78 °C and stirred at 0 °C for 3.5 h. Excess HF was removed under in vacuo at 0 °C, and the residue was triturated twice with ether. The residue was purified by reverse-phase HPLC (80:20:0.2 H 2 0-CH 3 CN-TFA) to afford 0.052 g of the title compound as a white solid: MS m/z 571.5 (MH+); mp 102-106 °C; Anal. Calcd. for C 28 H 42 N 8 0 5 *2.5 C 2 HF 3 0 2 '3.5 H 2 0: Calculated C, 43.14; H, 5.65; N, 12.20; H 2 0, 6.86; Found: C, 42.91 ; H, 5.38; N, 12.42; H 2 0, 6.44. EXAMPLE 18 N-[3-(3-BENZYL-2,5,6,9-TETRAOXO-1 ,4,8-TRIAZACYCLOTETRADEC- 7-YL)PROPYL]GUANIDINE TRIFLUOROACETIC ACID Step 18a Intermediate 12a was prepared following steps 11 a and 11 b of example by using 6-aminohexanoic acid instead of aminopentanoic acid in step 11a. Step 18b 18b A mixture of 18a (0.72 g, 2.15 mmol), 6-[[imino[4-methylbenzenesulfonyl) amino]methyl]amino]-2-(R,S)-[[2-(trimethylsilyl)ethoxy]methoxy]-3(S)-[9- phenylmethoxycarbonyl)-amino]hexanoic acid (1.47 g, 2.36 mmol) and HOBT (0.44 g, 3.22 mmol) dissolved in CH3CN (30 mL) was treated with a solution of DCC (0.49 g, 2.36 mmol) in CH3CN (30 mL)and stirred overnight. The mixture was filtered, concentrated in vacuo and the residue was dissolved in mL ethyl acetate (50 mL) and washed with saturated aqueous NaHC03 (5 mL). The organic extract was dried (Na 2 S04) and concentrated. The residue was purified via flash column chromatography (9:1 CH CI 2 -MeOH) to yield 1.72 g of intermediate 18b. 12a A solution of intermediate I8J2 (1.71 g, 1.82 mmol) in CH 2 CI 2 (5 mL) was added to 1 :1 TFA-CH 2 CI 2 (28 mL) solution at 0 °C. The mixture was stirred for 1 h at room temperature and concentrated under a stream of N 2 . The residue was triturated with ether to afford 1.6 g of intermediate ISc as a white solid. Step 18d 13 A mixture of intermediate lfia (500 mg, 0.5 mmol), Pd(OH) 2 (600 mg) and methanol (30 mL) was shaken under H 2 at 21 psig for 5 h. The mixture was filtered, and the filtrate was concentrated to afford 390 mg of intermediate 18d as a white solid: m/z 619 (MH+). 18e A solution of intermediate 5 (340 mg, 0.464mmol) and DMAP (283 mg, 2.32 mmol) in 450 mL of CH 2 CI 2 was treated with BOP-CI (236 mg, 0.928 mmol) and stirred for 5 h. Solvent was removed under reduced pressure, and the residue was purified via flash column chromatography (silica gel, 95:5 CH 2 CI 2 -MeOH-> 90:10 CH 2 CI 2 -MeOH) to yield 78 mg of intermediate 12a: m/z 601 (MH+). 121 A solution of intermediate 18e (78 mg, 0.13 mmol) in CH 2 CI 2 (15 mL) was treated with (82 mg, 0.19 mmol) of the Dess-Martin periodinane. The mixture was stirred for 3.5 h, treated with of aqueous 4:1 NaHCθ 3 -Na 2 S 2 θ 3 (20mL). This mixture was extracted four times with 25 mL portions of CH 2 CI 2 . The combined CH 2 CI 2 extracts were washed with brine, dried (Na 2 Sθ4), and concentrated to provide 49 mg of intermediate 121 which was used in the following step without further purification: m/z 599 (MH+). N-[3-(3-BENZYL-2,5,6,9-TETRAOXO-1 ,4,8-TRIAZACYCLOTETRADEC- 7-YL)PROPYL]GUANIDINE TRIFLUOROACETIC ACID COMPOUND 18 A suspension of intermediate 121 (49 mg) in anisole (1 mL) was treated with ca. 5 mL of anhydrous HF at -78 °C. The mixture was stirred at 0 °C for 3.5 h and the excess HF was removed under vacuum. The residue was triturated with ether and purified by reverse-phase HPLC (MeCN-water-TFA, 30:70:0.2) to give 10.4 mg of the title compound as a white solid: m/z 445 (MH+); Anal. Calcd for C22H 3 2N 6 θ * 1.75C 2 H F 3 0 2 « 1.18H 2 0: Calculated: C, 46.03; H, 5.47; N, 12.63; H 2 0, 3.19 Found: C, 46.03; H, 4.95; N, 12.99; H 2 0, 3.49. EXAMPLE 19 5R,15R,19S,21AS-N-[3-(15-BENZHYDRYL-5-BENZYL-4,7,14,17,18,21 - HEXAOXODOCOSAHYDRO-3a,6, 13,16,20- PENTAAZACYCLOPENTACYCLOEICOSEN-19-YL)PROPYL]GUANIDINE TRIFLUOROACETIC ACID COMPOUND 19 Compound 19 was prepared using the method of Example 11 with the following modifications. 6-Aminohexanoic acid is used in place of 5-aminoheptanoic acid In step 11a and CBZ-D-Phe is replaced with CBZ-D-diPhe (prepared via the method of US Pat 5,198,548) in step 11 b to give the title compound as a solid: FAB-MS m/z 766 (MH+); Anal. Calc'd for C42H52Nδθ6'1.75 C2HF3θ2*2.25 H2O: Calc'd: C, 54.38; H, 5.84; N, 11.15; H 2 0, 4.03. Found: C, 54.57; H, 5.71 ; N, 11.29; H 2 0, 4.09. EXAMPLE 20 5R, 15S, 19S.21 aS-N-[3-(5, 15-DIBENZYL-4.7, 14,17,18,21- HEXAOXODOCOSAHYDRO-3a,6, 13, 16,20- PENTAAZACYCLOPENTACYCLOEICOSEN- 19-YL)PROPYL]GUANIDINE TRIFLUOROACETIC ACID COMPOUND 20 Compound 20 was prepared using the method of Example 11 with the following modifications. 6-Aminohexanoic acid is used in place of 5-aminoheptanoic acid in step 11a and CBZ-D-diPhe-ProO-1-Bu replaced with D-Phe-ProO-1-Bu in step 11d to give the title compound as a solid: FAB-MS m/z 766 (MH+); Anal. Calc'd for C42H52Nδθ6'2.0 C2HF3θ2 » 2.75 H2O: Calc'd: C, 53.00; H, 5.75; N, 10.75; H 2 0, 4.75. Found: C, 53.30; H, 5.51 ; N, 10.70; H 2 0, 4.96. EXAMPLE 21 5R,14R, 18S,20aS-N-[3-(5-BENZYL- 14-METH YL-4,7, 13,16,17,20- HEXAOXOEICOSAH YDRO-3a,6, 12, 15, 19-PENTAAZAC YCLOPENTA- CYCLONONADECEN-18-YL)PROPYL]GUANIDINE TRIFLUOROACETIC ACID COMPOUND 21 Compound 21 was prepared using the method of Example 11 with the following modifications. 6-Aminohexanoic acid is used in place of 5-aminoheptanoic acid in step 11a and CBZ-D-Phe is replaced with CBZ-D-Ala in step 11b to give the title compound as a solid: FAB-MS m/z 600 (MH+); Anal. Calc'd for C29H42Nδθ6-2.15 C2HF3θ2*2.50 H2O: Calc'd: C, 45.00; H, 5.57; N, 12.16; H 2 0, 5.07. Found: C, 45.01 ; H, 5.46; N, 12.82; H 2 0, 5.31. EXAMPLE 22 [20aR-(20aR, 5R. 18S)]-N-[3-(5-PHENYLETHYL-17-HYDROXY- 4, 7, 16, 20-TETRAOXOEICOSAHYDRO-3a, 6, 15, 19-TETRA- AZACYCLONONADECANE-18-YL) PROPYL] GUANIDINE COMPOUND 22 A suspension of intermediate lh. (0.245 g, 0.372 mmol) anisole (2 mL) was cooled to -78°C and treated anhydrous HF (ca. 10mL) using a standard HF apparatus. After stirring for 4 h, HF was removed under reduced pressure at 0°C, and the residue was triturated twice with 25 mL portions of ether. The solid was collected, washed with ether, then purified by reverse-phase HPLC (MeCN-water-TFA, 30:70:0.2). Lyophillization of the eluate provided the title compound as a white solid : FAB-MS m/z 586 (MH + ); Anal. Calcd for C 3 θH47N 7 θ5 » 2C 2 HF30 0.75 H 2 0: Calc'd: C, 49.36; H, 6.15; N, 11.85; H20, 1.63. Found: C, 49.10, H, 6.07; N, 12.15; H20; 1.42. EXAMPLE 23 23a 1 ,1 -Carbonyldiimidazole (1.8 g, 11.0 mmol) was added to a solution of N-α-Fmoc-ϋG-tosyl-L-arginine (6.0 g, 10.0 mmol) in anhydrous THF (30 mL) at 0 °C under argon and stirred at 0 °C for 1.5 h. The reaction mixture was cooled to -48 °C and 1 M DIBAL (28 mL, 28 mmol) was added dropwise over 20 min. The resulting mixture was stirred for another 1.5 h and 1.2 N HCL (67 mL) was added with stirring. The mixture was allowed to warm up to room temperature and partitioned between 0.6N HCl (65 mL) and chloroform. The resulting aqueous layer was washed with several portions of chloroform. The combined organic extracts were washed withsuccessive portions of water and brine, dried (Na2S04) and concentrated in vacuo to affordthe aldehyde 23a as a white flakey solid. 23b A solution of KCN (1.44 g, 22 mmol) and H2O (125 mL) was added to a solution of aldehyde 22a (5.9 g, 11.0 mmol) in ethyl acetate (250 mL) and the resulting mixture was stirred for 40 h at room temperature under argon. The organic layer was separated and the aqueous layer was washed with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried (Na2S04), concentrated in vaςuo and stored in the refrigerator under argon. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous NaHCθ3 (200 mL) and the pH was maintained at 7.0 by the addition of solid NaHCθ3. The solid NaHCθ3 was removed by filtration and the resulting aqueous layer was washed with several portions of ethyl acetate. The combined organic layer was washed twice with brine, dried (MgSθ4) and concentrated in vacuo to give the cyanohydrin 23b as a white solid; FAB-MS m/z 562 (MH)+. 22a HCl (21 g) was bubbled into a solution of nitrile 22d (3.0 g, 5.34 mmol) and methanol (53 mL) under argon at a temperature of less than -40 °C over 20 min. The reaction vessel was closed under nitrogen and placed in a freezer at -15 °C for 46 h and concentrated in vacuo at room temperature. The residue was partitioned between saturated aqueous NaHCθ3 solution (250 mL) and ethyl acetate. The organic layer was washed with two portions of brine, dried (MgS04) and concentrated in vacuo to give the imidate 22a as a solid. Step d 22d Cysteine methyl ester hydrochloride (2.7 g, 15.9 mmol) was added to a solution of imidate 22£ (5.0 g, 7.9 mmol) and CH2CI2 (100 mL) and the resulting mixture was stirred under argon at room temperature for 2 d. The mixture was washed sequentially with brine and water, then dried (Na2Sθ4) and concentrated. The residue was purified by flash chromatography (silica gel, 95:5 CH2Cl2-MeOH) to give 3.8 g of 22d as a white foam: MS m/z 680 (MH+). 22a f-Butyldimethylsilyitriflate (3.3 g, 12.6 mmol) was added dropwise to a solution of 22d (1.9 g, 2.8 mmol) and 2,6-lutidine and cooled to 0 °C. The mixture was stirred for 1 h at 0 °C, then quenched with ice. The CH2CI2 layer was washed with water, dried (Na2S04) and concentrated to give the corresponding silyl ether which was used without purification: m z 794 (MH+). The silyl ether was dissolved in 50 mL of 20 % diethylamine -CH3CN and stirred for 2.5 h. The solution was concentrated, and the residue was purified via flash chromatography (silica gel, CH2Cl2->10% MeOH-CH2Cl2) to yield 1 g (1.85 mmol) of the corresponding α-amino derivative as an oil. This material (1.0 g, 1.85 mmol) was dissolved in CH 2 CI 2 (25 mL) and treated with ό\-t-butyl dicarbonate (0.49 g, 2.25 mmol) at 0 °C. After stirring overnight at room temperature the reaction was washed with water and the CH CI 2 layer was dried (Na2S04) and concentrated. The residue was purified by flash chromatography (silica gel, 95:5 CH 2 CI 2 -MeOH) to afford 1.1 g of 22a as a semi-solid: m/z 558 (MH+). Step f 221 Activated Mn0 2 (3.5 g) was added to a solution of 22a (1 1 g, 1 -7 mmol) in CH 2 CI 2 (100 mL). The mixture was stirred for 6.5 h and filtered through dicalite. The filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel; 95:5 CH 2 CI 2 -MeOH) to afford 800 mg (1.3 mmol) of the corresponding thiazole derivative as a white foam. The material was combined with LiOH (94 mg, 3.9 mmol) and 9:1 dioxane-water solution (12 mL). The mixture was stirred for 4 h, diluted with water and acidified to pH 5 with acetic acid. The mixture was extracted three times with ethyl acetate, dried (Na 2 S04) and concentrated to give 221 as a white semi-solid: m/z 656 (MH+). Step g 22fl Intermediate 23g was prepared from D-Phe, ProO-1-Bu and 4-(Λ -carbobenzoxy)aminobutanoic acid, using steps a-d of Example 1 23h A solution of intermediate 221 (0.4 g, 0.60 mmol), intermediate 22a (0-26 g, 0.63 mmol), and HOBt (121 mg, 0.90 mmol) in CH3CN (10 mL) was treated with DCC (130 mg, 0.63 mmol) in CH3CN (2 mL). The mixture was stirred overnight, filtered and concentrated. The residue was dissolved in CH 2 CI 2l washed sequentially with saturated aqueous NaHC03, dried (Na 2 S04) and concentrated. The residue was purified via flash column chromatography (silica gel, 95:5 CH 2 CI 2 -MeOH) to afford 350 mg of the coupled product as a white foam: m/z 1055 (MH+). The material was dissolved in CH 2 CI 2 (10 mL) and treated with a solution of 1 :1 TFA-CH 2 CI 2 (10 mL) at 0 °C. The mixture was stirred for 1 h at room temperature and concentrated under a stream of N2 at room temperature. The residue was triturated with ether to give 413 mg of intermediate 22tl as a white solid: MS m/z 899 (MH+). 221 A solution of intermediate 22h (1 -0 g, 0.90 mmol) in CH 2 CI 2 (900 mL) was treated with DMAP (560 mg. 4.6 mmol) followed by BOP-CI (450 mg, 1.8 mmol). The mixture was stirred for 2 h and concentrated in vacuo. The residue was purified via flash column chromatography (silica gel, 95:5 CH 2 CI 2 -MeOH) to give 500 mg of an off-white solid: m/z 882 (MH+). This solid was stirred for 1 h in 1 M BU4NF/THF and concentrated under reduced pressure. The residue dissolved in CH 2 CI 2 and washed repeatedly with H 2 0. The organic layer was dried (Na 2 S04) and concentrated under reduced pressure to yield 275 mg of the corresponding alcohol 23i which was used in the following step without further purification: m/z 767 (MH+). 3S,6S,12R-M-[3-(12-BENZYL-2, 5,11 ,14,20-PENTAOXO-23-THIA- 4.10,13, 19.24-PENTAAZATRICYCLO[19.2.1.3]- 6, 10-TETRACOSA-1 (2H), 21-DIEN-3-YL)PROPYL]GUANIDINE COMPOUND 23 The alcohol (275 mg) was suspended in 30 mL of CH 2 CI 2 and added to a suspension of the Dess-Martin periodinane (228 mg, 0.54 mmol) in 1 mL of CH2CI2. The mixture was stirred for 3h, quenched with 25% Na2S2θ3 (aq) in NaHCθ3 (sat'd., aq.) and stirred for 0.5 h. The layers were separated, and the CH2CI2 layer was washed twice with water, dried (Na2Sθ4) and concentrated under reduced pressure to yield 273 mg of the corresponding keto-amide derivative as a foam: m/z 611 (MH+). A mixture of 270 mg of the keto-amide derivative was suspended in 2 mL of anisole and treated with excess (ca. 10 mL) anhydrous HF at -78 °C. The mixture was stirred at 0 °C for 4.5 h, then HF was removed at 0 °C under reduced pressure. The residue was triturated with ether and purified by reverse-phase HPLC (70:30:0.2 H2O-CH3CN-TFA). Lyophillization of the eluate provided 120 mg of the title compound as a white solid: FAB-MS m/z 556 (MH+); Anal. Calc'd for C29H 38 N8θ5S'1.75C2HF 3 θ2*1.5 H2O: Calc'd: C. 46.62; H, 5.15; N, 13.38, H 2 0, 3.23. Found: C, 46.40; H, 5.03; N, 13.57; H 2 0; 3.33.

Claims: What is claimed is: 1. A compound of the Formula I wherein: m is 2 to 12; where the amido carbonyl is bound to B and the α aminomethine is bound to the depicted ring carbonyl, R3 is hydrogen, hydroxy or Ci-salkoxy, n is 1 or 2, and a is 0 or 1 ; B is where the amido carbonyl of B is bound to the depicted ring methylene and the methine is bound to A, R4 is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenyICι- 2 alkyl, and naphthyl, substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), Rs and Rβ are hydrogen or taken together with the carbon of attachment to form a carbonyl, and b is 0 or 1 ; where the amine of G is bound to the ring methylene and the methine is bound to the depicted amide, R7 is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylCι- 2 alkyl, and naphthyl, substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon or C(CH2)q-, where q is 0 to 12, with the proviso that the sum of q and m cannot exceed 25, Rβ and Rg are hydrogen or taken together with the carbon of E to form a carbonyl, and g is 0 or 1 ; or the pharmaceutically acceptable salt thereof. 2. The compound of Claim 1 where a is 1 , b is 0 and g is 0. 3. The compound of Claim 2 where n is 1. 4. The compound of Claim 1 where a is 0, b is 1 and g is 0. 5. The compound of Claim 4 where R5 and RQ are taken together with the carbon to which each is attached to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 6. The compound of Claim 1 where a is 0, b is 0 and g is 1. 7. The compound of Claim 6 where E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 8. The compound of Claim 6 where Rβ and Rg are hydrogen, E is C(CH 2 ) q and q is 0-6. 9. The compound of Claim 1 where a is 1 , b is 1 and g is 0. 10. The compound of Claim 9 where n is 1 , R5 and & are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 11. The compound of Claim 1 where a is 1 , b is 1 and g is 1. 12. The compound of Claim 11 where n is 1 , Rs and RQ are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 13. The compound of Claim 11 where n is 1 , R5 and Re are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), Rβ and Rg are hydrogen, E is C(CH 2 ) and q is 0-6. 14. The compound of Claim 1 where a is 1 , b is 0 and g is 1. 15. The compound of Claim 14 where n is 1 , E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 16. The compound of Claim 14 where n is 1 , Rβ and Rg are hydrogen, E is C(CH 2 )q and q is 0-6. 17. The compound of Claim 1 where a is 0, b is 1 and g is 1. 18. The compound of Claim 17 where R5 and Re are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 aIkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine); E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 19. The compound of Claim 11 where R5 and Re are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylC -2alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine) Rβ and Rg are hydrogen, E is C(CH 2 ) qι and q is 0-6 20. The compounds of Claim 1 selected from the group consisting of 21. The compounds of Claim 1 selected from the group consisting of 22. The compounds of Claim 1 selected from the group consisting of 23. The compounds of Claim 1 selected from the group consisting of H and 25. A compound of the Formula II H 2 II wherein: Ri is hydroxy; R 2 is hydrogen; A is where the amido carbonyl is bound to B and the α aminomethine is bound to the depicted ring carbonyl, R3 is hydrogen or Ci-salkoxy, n is 1 or 2, and a is 0 or 1 ; B is where the amido carbonyl of B is bound to the depicted ring methylenes and the methine is bound to A, R4 is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylC - 2 alkyl, and naphthyl, substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), R5 and Re are hydrogen or taken together with the carbon of attachment to form a carbonyl, and b is O or 1 ; where the amine of G is bound to the ring methylenes and the methine is bound to the depicted amide, R7 is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylCι- 2 alkyl, and naphthyl, substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon or C(CH 2 ) q -, where q is 0 to 12, with the proviso that the sum of q and m cannot exceed 25, Rβ and Rg are hydrogen or taken together with the carbon of E to form a carbonyl, and g is 0 or 1 ; and pharmaceutically acceptable salts thereof. 26. A compound of the Formula III. wherein: m is 2 to 12; W is nitrogen, sulfur or oxygen; where the amido carbonyl is bound to B and the α aminomethine is bound to the depicted ring carbonyl, R3 is hydrogen, hydroxy or Ci-salkoxy, n is 1 or 2, and a is 0 or 1 B is where the amido carbonyl of B is bound to the depicted ring methylene and the methine is bound to A, R4 is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylCι-2alkyl, and naphthyl, substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine); R5 and Re are hydrogen or taken together with the carbon of attachment to form a carbonyl, and b is 0 or 1 ; G is where the amine of G is bound to the ring methylene and the methine is bound to the depicted amide, R7 is independently selected from the group consisting of hydrogen, Ci-salkyl, carboxyCi-salkyI, phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), 3-pyridylCι-salkyl, 4-pyridylCι-salkyl, diphenylCι- 2 alkyl, and naphthyl, substituted naphthyl (where the naphthyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon or C(CH 2 ) q -, where q is 0 to 12, with the proviso that the sum of q and m cannot exceed 25, Rβ and Rg are hydrogen or taken together with the carbon of E to form a carbonyl, and g is 0 or 1 ; and pharmaceutically acceptable salts thereof. 27. The compound of Claim 26 where a is 1 , b is 0 and g is 0. 28. The compound of Claim 27 where n is 1. 29. The compound of Claim 26 where a is 0, b is 1 and g is 0. 30. The compound of Claim 29 where R5 and Rβ are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 31. The compound of Claim 26 where a is 0, b is 0 and g is 1. 32. The compound of Claim 31 where E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 33. The compound of Claim 31 where Rβ and Rg are hydrogen, E is C(CH 2 ) q and q is 0-6. 34. The compound of Claim 26 where a is 1 , b is 1 and g is 0. 35. The compound of Claim 34 where n is 1 , R5 and Re are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 36. The compound of Claim 26 where a is 1 , b is 1 and g is 1. 37. The compound of Claim 36 where n is 1 , R5 and Rβ are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 38. The compound of Claim 36 where n is 1 , R5 and Re are taken together with the carbon of attachment to form a carbonyl; and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), Rβ and Rg are hydrogen, E is C(CH 2 ) q , and q is 0-6. 39. The compound of Claim 26 where a is 1 , b is 0 and g is 1. 40. The compound of Claim 39 where n is 1 , E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 41. The compound of Claim 39 where n is 1 , Rβ and Rg are hydrogen, E is C(CH 2 ) q and q is 0-6. 42. The compound of Claim 26 where a is 0, b is 1 and g is 1. 43. The compound of Claim 42 where R5 and Rβ are taken together with the carbon of attachment to form a carbonyl, and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), E is carbon, Rβ and Rg are taken with the carbon of attachment for form a carbonyl, and R7 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine). 44. The compound of Claim 42 where R5 and Re are taken together with the carbon of attachment to form a carbonyl and R4 is selected form the group consisting of phenyl, substituted phenyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), phenylCi-salkyl, substituted phenylCi-salkyl (where the phenyl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine), diphenylCι- 2 alkyl, naphthyl and substituted naphthyl (where the aryl substituents are Ci-salkyl, carboxy Ci-salkoxycarbonyl, carboxamido, amino, Ci-salkylamino, hydroxy, Ci-salkylcarbonylamino, Ci-salkoxy, fluorine bromine or chlorine); Rβ and Rg are hydrogen, E is C(CH 2 ) q and q is 0-6 45. The compounds of Claim 26 selected from the group consisting of 46. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 1 or of Claim 26 for treating thrombin mediated diseases in a mammal. 47. A method for inhibiting thrombin comprising contacting a compound of Claim 1 or of Claim 26 with a medium containing thrombin. 48. The method of Claim 47 where the compound contacts the medium via an orthopedic or a surgical device. 49. The method of claim 47 where the medium is mammailian blood. 50. A method of claim 49 where the mammal is a human. 51. A method treating a thrombin mediated disease in a mammal comprising administering an effective amount of a compound of Claim 1 or of Claim 26. 52. A method for inhibiting trypsin comprising contacting a compound of Claim 1 or of Claim 26 with a medium containing trypsin. 53. A method of treating a trypsin related disorder in a mammal comprising administering an effective amount of a compound of Claim 1 or of Claim 26.

Inventors: GRECO MICHAEL N, MARYANOFF BRUCE E, GRECO, MICHAEL, N., MARYANOFF, BRUCE, E.
Applicants: ORTHO PHARMA CORP, ORTHO PHARMACEUTICAL CORPORATION
Application year: 1997
Main classification: C07K7
IPC codes: A61K38, C07D255, C07D487, C07K5, C07K7