MXPA01005395A - Benzimidazole compounds that are vitronectin receptor antagonists - Google Patents

Abstract

The present invention provides compounds having formula (I) wherein n, p, q and r are each independently selected from 0 or 1;a, b, c, and d each independently represents a carbon or nitrogen atom, with the proviso that no more than two of a, b, c, and d are nitrogen atoms;Y and Y'each independently represents 1-4 optional substituents selected from alkyl, alkoxy, halo, -CF3, and -C(O)OH;R1, R2, R3 and R4 are H or specified substituents;R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from H or C1-C3 alkyl;or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof. Also provided are methods of using these compounds for treating vitronectin-mediated disorders, e.g., cancer, retinopathy, artherosclerosis, vascular restenosis, and osteoporosis.

Description

BENZIMIDAZOLE COMPOUNDS THAT ARE VITRONECTIN RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This invention relates to compounds that are antagonists of vitronectin receptor and are useful for the treatment of cancer, retinopathy, cardiovascular disorders such as atherosclerosis and restenosis, and diseases wherein bone resorption constitutes a factor, such as osteoporosis.

BACKGROUND OF THE INVENTION Integrins constitute a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed in a variety of cells. These cell surface adhesion receptors include gpllb / lila, also known as the "fibrinogen receptor" and avß3, also known as the "vitronectin receptor". The fibrinogen receptor gpllb / IIla is expressed on the platelet surface, and acts as an intermediate in platelet aggregation and in the formation of a hemostatic clot at the site of a bleeding wound. Philips et al., Blood, 1988, 71, 831. The avr3 vitronectin receptor is expressed in a number of cells, including endothelial, smooth muscle, osteoclast and tumor cells, and thus, has a variety of functions. The avß3 receptor expressed in the membrane of osteoclast cells acts as an intermediary in the process of bone resorption, and contributes to the development of osteoporosis. Ross et al., J. Biol. Chem., 1987, 262, 7703. The avß3 receptor expressed in human aortic smooth muscle cells stimulates their migration to neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brow et al., Cardiovascular Res., 1994, 28, 1815. Additionally, a recent study has shown that an avß3 antagonist is capable of promoting tumor regression by inducing apoptosis of angiogenic blood vessels. Brooks et al., Cell, 1994, 79, 1157. Thus, agents that would block the vitronectin receptor would be useful in the treatment of diseases measured by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer. It is known that the vitronectin receptor binds to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton et al., Exp. Cell Res. 1991, 195, 368, disclose that peptides containing RGD and an anti-vitronectin receptor antibody (23C6) inhibit dentin resorption and cell dissemination by osteoclasts. Sato et al., J. Cell Biol. 1990, 111, 1713 further discloses that echistatin, a viper venom peptide containing the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits adhesion. from osteoclasts to bones. Fisher et al., Endocrinology 1993, 132, 1411, have also shown that echistatin inhibits bone resorption in vivo in the rat. Bertolini et al., J. Bone Min. Res., 6, Sup. 1, S146, 252 have shown that cyclo-S, S-Na-acetyl-cysteinyl-Na-methyl-arginyl-glycyl-aspartyl-penicillamine inhibits the adhesion of osteoclasts to bones. EP 0 528 587 and EP 0 528 586 disclose substituted phenyl derivatives that inhibit bone resorption mediated by osteoclates. Alig et al., EP 0 381 033, Hartman et al., EP 0 540 334, Blackburn et al., WO 93/08174, Bondineil et al., WO 93/00095, Blackburn et al., WO 95/04057 , Egbertson et al., EP 0 478 328, Sugihara et al., EP 0 529 858, Porter et al., EP 0 542 363 and Fisher et al., EP 0 635 492, describe certain compounds that are useful for inhibition. of the fibrinogen receptor. WO 96/00730 describes certain compounds that are vitronectin receptor antagonists.

BRIEF DESCRIPTION OF THE INVENTION New compounds which are antagonists in the vitronectin receptor have been invented, ie they possess a high affinity for the vitronectin receptor, thus making them useful for the treatment of disorders or diseases mediated by the vitronectin receptor, eg cancer, retinopathy , atherosclerosis, vascular restenosis and osteoporosis. The compounds of our invention have the formula: wherein n, p, q and r are each independently selected from 0 0 1; a, b, c and d each independently represent a carbon or nitrogen atom, with the proviso that not more than two of a, b, c and d are nitrogen atoms; Y and Y1 each independently represent 1-4 optional substituents selected from alkyl, alkoxy, halo, -CF3 and -C (O) OH; R1 is H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkyalkyl, heterocycloalkylalkyl, -NHRA, -NHC (O) RA, -NHSO2RA, NHC (O) NHRA or NHC (O) ORA; R1 is optionally substituted with 1-3 groups selected from halo, alkyl, -CF3, -CN, -ORB, -SRB, -CO2RB, -C (O) RB, -OC (O) RB, -OC (O) ORB , and -SO2RB, and RA and RB are independently selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R1 is alkyl, R1 is not substituted with halo , the condition that when R1 is -NHSO2RA or -NHC (O) ORA, RA is not H, and the condition that for -S02R ° or -OC (O) OR BB, R nBB is not H; R2 is H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; R2 is optionally substituted with 1-3 groups selected from halo, alkyl, -CF3, -CN, -ORc, -SRC, -CO2Rc, -C (O) Rc, -OC (O) Rc, OC (O) ORc and -SO2Rc, wherein Rc is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalicylic, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R2 is alkyl, R2 is not substituted with halo, and the condition that for -SO2Rc or -OC (O) ORc, Rc is not H; R3 is H, alkyl, aralkyl, arylcycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -C (O) RD, -C (0) ORD, -SO2RE, -C (O) NRFRG, -C (O) NRFSO2RE, or -C (= S) NR RG, wherein RD-RE, RF and RG are independently selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or RF and RG taken together complete a ring of 5-7 members containing 0 to 1 oxygen or sulfur atoms, and 1 to 2 nitrogen atoms; R3 is optionally substituted with 1-3 groups selected from halo, alkyl, aryl, -CF3, -CN, -ORH, -SRH, -CO2RH, -C (O) RH, -OC (O) RH, -OC (O ) ORH ', -SO2RH and -NRHRH, wherein RH is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R3 is alkyl, R3 is not substituted with halo, the condition that when R3 is -S02RE, -C (O) NR SO2RE, or -CO (O) RD, RD and Re are not H, and the condition that stops -SO2RH or -OC (O) ORH , RH is not H; R 4 is H, alkyl, aralkyl, arylcycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; R4 is optionally substituted with 1-3 groups selected from halo, alkyl, -CF3, -CN, -ORJ, SRJ, -CO2RJ, -C (O) RJ, -OC (O) RJ, -OC (O) ORJ Y -SO2RJ, wherein RJ is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R4 is alkyl R4 it is not substituted with halo, and the condition that for -SO2RJ or -OC (O) ORJ, RJ is not H; R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from H or CrC3 alkyl; and where they are located meta or para in relation to each other; or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION R1 is preferably H, -NHRA, NHC (O) RA, NHC (O) ORA, -NHC (O) NHRA; or NHSO2RA. R1 most preferably is -NHC (0) ORA. R1 with more preference is- (CH2) 3CH3 R is preferably H. R3 is preferably selected from H, alkyl, -C (O) RD, -C (O) ORD, -C (O) NRFRG, and -C (= S) NRFRG. RD is preferably selected from phenyl, alkyl, aralkyl, arylcycloalkyl, cycloalkyl and wherein RD is optionally substituted with 1-3 substituents selected from alkoxy, halo, cycloalkyl, -S-CH3, phenyloxy, -OC (O) CH3, -C (O) OC2H5 and -N (CH3) 2. RF and RG are preferably selected from H, alkyl, phenyl, cycloalkyl and aralkyl, wherein RF and RG are optionally substituted with alkoxy, halo or -CO2RH. R 4 is preferably H or alkyl, more preferably H. R 5, R 6, R 7, R 8, R 9, R 10, R 11 and R 12 are preferably each H. Preferably the sum of n + p is 1.

Preferably the sum of q + r is 1. Preferably, a, b, c and d are carbon atoms. Preferably; they are located in relation to each other. The following compounds, including biolabile esters or pharmaceutically acceptable salts thereof, are particularly preferred: xi r i o of the above, they are particularly preferred. Preferably, the compounds of the present invention are selected from those having affinities that are greater than 100 times more specific for avß3 than for a¡¡bβ3. As used herein, the following terms have the following meanings, unless defined otherwise: "Alkyl" refers to straight or branched chain hydrocarbon groups, having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms. "Alkoxy" refers to groups having the formula -OR, wherein R is alkyl.

"Aryl" refers to carbocyclic groups having at least one aromatic ring. "Aralkyl" refers to groups having the formula aryl-R-, wherein R is alkyl. "Arylcycloalkyl" refers to groups having the formula aryl-R-, wherein R is cycloalkyl. "Arylalkoxy" refers to groups having the formula aryl-R-O-, wherein R is alkyl. "Carboxi" refers to groups having the formula -C (O) OH. "Carboxyalkyl" refers to groups having the formula -R-C (O) OH, wherein R is alkyl. "Carbamoyl" refers to a group having the formula -C (O) NH2, "Cabamoylalkyl" refers to groups having the formula -R-C (O) NH2, wherein R is alkyl. "Cbz" refers to benzyloxycarbonyl. "Cycloalkyl" refers to a non-aromatic carbocyclic ring or multicarbocyclic ring system of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. "Cycloalkylalkyl" refers to groups having the formula cycloalkyl-R-, wherein R is alkyl. "Fmoc" refers to 9-fluorenylmethoxycarbonyl.

"Heteroaryl" refers to aromatic carbocyclic groups, wherein one or more of the carbon atoms of said groups are replaced with a heteroatom selected from O, S and N. "Heteroaralkyl" refers to groups having the formula heteroaryl-R -, where R is alkyl. "Heterocycloalkyl" refers to a cycloalkyl group, wherein one or more of the carbon atoms of said group is replaced with O, S, NH or N-alkyl. "Heterocycloalkylalkyl" refers to groups having the formula heterocycloalkyl-R-, wherein R is alkyl. "Halo" refers to a halogen substituent. The term "biolabile ester" means a pharmaceutically acceptable, biologically degradable ester derivative of a compound of formula (I), which is a prodrug which, upon administration to an animal or human being, is converted in the body into a compound of formula (I). The term "vitronectin mediated disorder" refers to a disease state or malignancy that is caused or exacerbated by a biological activity of vitronectin receptors. The disorders mediated by the vitronectin receptor include, without limitation, cancer, retinopathy, arteriosclerosis, vascular restenosis and osteoporosis. The term "effective amount" refers to an amount of vitronectin receptor antagonist compound sufficient to exhibit a detectable therapeutic effect. The therapeutic effect may include, for example, without limitation, the inhibition of the growth of unwanted tissue or malignant cells, or the increase of bone density. The precise effective amount for a subject will depend on the size and health of the subject, the nature and severity of the condition to be treated, and the like. The effective amount for a given situation can be determined by routine experimentation, based on the information provided herein. The following abbreviations are used for the solvents and reagents discussed here: ethanol ("EtOH"); methanol ("MeOH"); acetic acid ("AcOH"); ethyl acetate ("EtOAc"); 2- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate ("HBTU"); 1-hydroxybenzotriazole (HOBf); bromo-tris-pyrrolidino-phosphonium hexafluorophosphate ("PyBroP"); N, N-dimethylformamide ("DMF"); trifluoroacetic acid ("TFA"); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ("EDCI"); and diisopropylethylamine ("DI PEA"). In addition, "Ph" represents a phenyl group, "tBu" represents a group -C (CH3) 3; "OtBu" represents a group -OC (CH3) 3, "n-Bu" or "Bu-n" represents an n-butyl group, "Et" represents an ethyl group, "Me" represents a methyl group, "Ac" represents an acetyl group and "Boc" represents t-butoxycarbonyl. The compounds of the invention have asymmetric carbon atoms, and therefore, all isomers, including enantiomers and diastereomers are within the scope of this invention. The invention includes d and / isomers, both in pure form and as a mixture, including racemic mixtures. The isomers can be prepared using conventional techniques, either by reacting chiral starting materials, or by separating isomers of the compounds of formula (I). Certain compounds of the present invention will be acidic in nature (for example, those having a phenolic or carboxyl hydroxyl group). These compounds form pharmaceutically acceptable salts with organic and inorganic bases. The sai can be prepared by treating a solution of the compound with the appropriate base. Non-limiting examples of said salts are sodium, potassium, calcium, aluminum, gold and silver salts, and salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. Certain compounds of the invention will be basic in nature, and can form pharmaceutically acceptable salts with organic and inorganic acids. Non-limiting examples of acids suitable for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other carboxylic acids and minerals well known to the experts in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid, to produce a salt. When the compounds of the invention are provided for oral administration it may be convenient to use the compounds of formula (I) in the form of a biolabile ester. The suitability of any particular ester-forming group can be evaluated by in vitro enzymatic hydrolysis studies or conventional in vivo animals. Thus, conveniently, for optimum effect, the ester should only be hydrolyzed after absorption is complete. Accordingly, the ester should be resistant to premature hydrolysis by digestive enzymes prior to absorption, but should be productively hydrolyzed, for example, by enzymes from the intestinal wall, plasma or liver. In this way, the active acid is released into the bloodstream after oral absorption of the prodrug. Suitable biollabile esters may include esters of alkyl, alkanoyloxyalkyl, cycloalkanoyanoxyalkyl, aroyloxyalkyl, and alkoxycarbonyloxyalkyl, including derivatives thereof substituted with cycloalkyl and aryl, aryl esters and cycloalkyl esters, wherein said alkyl, alkanoyl or alkoxy groups may contain from 1 to 8 carbon atoms, and be branched chain or straight chain; said cycloalkyl groups may contain from 3-7 carbon atoms and said cycloalkanoyl groups from 4-8 carbon atoms, wherein both are optionally benzo-fused, and said aryl or aroyl groups include substituted indanyl, naphthyl or phenyl ring systems. Preferably, the biollabile esters of the invention are C C alkyl esters. More preferably, they are methyl, ethyl and pivaloyloxymethyl esters. Biolabile esters can be obtained from acids of formula (I) by standard reactions well known to those skilled in the art. For example, the aryl and alkyl esters can be synthesized by activating a carboxylic acid group of (I), in a variety of ways, such as by forming the acyl chloride, followed by the reaction with the alcohol or phenol required . Alternatively, the alkyl esters can be obtained by alkylation of a suitable metal, alkaline earth or alkaline carboxylate salt of a compound of formula (I). The compounds of the present invention can be prepared according to the following reaction scheme (Scheme I): SCHEME 1 decompose of resin In Scheme 1, which represents a solid phase preparation of compounds wherein at least one of qor is 1, compound 2 is adhered by conventional means to a polymeric resin 3 (for example, a polyethylene glycol copolymer). polystyrene or crosslinked polystyrene) through an acid labile connector capable of decomposition, L, having a -OH or -Cl group, for example, chlorotrityl resin, Wang and Sasrin, to form the resin compound 4. For example , adhesion to the resin can be carried out by reacting compound 2 with resin 3 (Cl form) in the presence of DIPEA in an organic solvent, for example, DMF or methylene chloride. The Fmoc group of compound 4 is removed by conventional means, for example, by treating with piperidine in DMF from 0 ° C to 80 ° C, and is acylated with benzoyl chloride 5, to form amide 6. The acylation is preferably carried out in an organic solvent (for example methylene chloride or DMF) from 0 ° C to 80 ° C, in the presence of a tertiary amine, preferably DIPEA. The amide 6 is reacted with benzimidazolamine 7 in a displacement reaction to produce compound 8. The displacement reaction is preferably carried out by shaking the reactants in DMF for a prolonged period, preferably 1-2 days. For compounds in which the R3 group is not H, said compounds can be made by subjecting compound 8 to conventional reactions to add the substituent R3 to form compound 9. For example, according to the desired substituent, compound 8 can be reacting with a carboxylic acid, an acyl chloride, acyl anhydride, socianate, carbamoyl chloride, isothiocyanate, alkyl halide, alkyl sulfonate, or epoxide, or alternatively, the compound 8 can be subjected to reductive alkylation with a aldehyde or ketone. Compound 1_O is formed by decomposition of the linker and the resin portion of compound 9 by conventional means, for example by treating with TFA diluted in methylene chloride at room temperature for 10 to 60 minutes. If desired, the compound 10 can be converted to a biolabile ester by standard esterification methods. The compounds wherein q and r are both 0 can be prepared according to the solid phase synthesis shown in scheme 2, below.

SCHEME 2 R3- Cl (or analogous reagent) decompose resin In scheme 2, compound 4, prepared as described in scheme 1, is treated with piperidine in DMF at 0o to 80 ° C, and acylated with benzoyl chloride Ij. to form amide 12. Acylation is preferably carried out in an organic solvent (for example, methylene chloride or DMF) at 0o to 80 ° C in the presence of a tertiary amine, preferably DIPEA. Amide 12 is subsequently reacted with a benzimidazole 13 to form compound 14, and if desired is reacted with suitable reagent - to add the group R3 under the conditions described for scheme 1, to form compound 15. Compound 6 is formed by decomposition of the connector and the resin portion of compound 15, under the conditions described in scheme 1 If desired, the compound 16 can be converted to a biolabile ester by standard esterification methods. The compounds and initial reagents used in the above schemes can either be obtained commercially, or they can be prepared by methods well known to those skilled in the art. Those skilled in the art will recognize that the reactive groups in the preceding reaction schemes (eg, carboxyl, amino, hydroxy) can be protected if desired or necessary, with conventional protecting groups which can then be removed by standard procedures. See, for example, McOmie, Protecting Groups in Organic Chemistry, Plenum Press, N. Y., 1973, and Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, N. Y., 1991.

With an alternative to solid phase synthesis, the compounds of the present invention can be prepared by solution synthesis, employing suitable protecting groups for reactive groups. Particularly useful for the protection of carboxy are the t-butyl esters, although other groups such as allyl and benzyl are also suitable. The intermediate esters can be converted to the acids by appropriate deprotection methods. To prepare pharmaceutical compositions of the compounds of this invention, the inert pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, seals and suppositories. The powders and tablets may be composed of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, seals and capsules can be used as solid dosage forms suitable for oral administration. For the preparation of suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the active ingredient is dispersed homogeneously therein, as by agitation. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and thus solidify.

Liquid form preparations include solutions, suspensions and emulsions. As an example, there may be mentioned propylene glycol water solutions or water for parenteral injection. Liquid form preparations may also include solutions for intranasal administration. Ophthalmic preparations can be formulated using commercially available vehicles, such as Sorbi-care® (Allergan) or Neodecadron® (Merck, Sharp &Dohme). Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas. Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for either oral or parenteral administration. Such suitable liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be delivered transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions, and can be included in a transdermal patch of the matrix or reservoir type as are conventionally in the art for this purpose. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, for example, an effective amount to achieve the desired purpose. The amount of the active compound in a unit dose of preparation can be varied or adjusted from 0.01 mg to 1,000 mg, more preferably from 0.1 mg to 200 mg, more preferably from 5 mg to 100 mg, according to the particular application . The actual dosage used can be varied according to the patient's requirements and the severity of the condition being treated. The determination of the appropriate dosage for a particular situation is within the skill of the art. In general, treatment starts with lower dosages that are less than the optimum dose of the compound. Then, the dosage is increased by small increments until the optimum effect is achieved under the circumstances. For convenience purposes, the total daily dosage can be divided and administered in portions during the day, if desired. The amount and frequency of administration of the compounds of the invention will be regulated according to the judgment of the clinician in attention, considering factors such as the age, condition and size of the patient, as well as the severity of the symptoms that are being treated. A typical recommended dosage regimen is oral administration from 0.02 mg to 4,000 mg / day, preferably 0.2 mg to 800 mg / day, more preferably 10 mg to 400 mg / day in two to four divided doses, to block the tumor growth.

The following examples illustrate the preceding invention, although said examples should not be construed as limiting the scope of the invention. Alternative mechanistic pathways and analogous structures within the scope of the invention will be apparent to those skilled in the art.

EXAMPLES In the examples below, the "funnel apparatus" is a sintered glass funnel for stirring the contents with nitrogen and removing the solvent by filtration. When the resins are "washed" with solvent, for example, (20 ml x 5), the resin in solvent (20 ml) is stirred for 2 minutes in a funnel apparatus, and the solvent is removed by filtration (drainage), and this sequence is repeated 4 additional times. For the examples below, "AA" refers to according to the particular compounds used in the preparation examples "-U-" refers to -CH2-, -CH2-CH2-, or -CH (CH3) -, according to the particular compounds used in the preparation examples . "2-Chlorotrityl resin, chloride form" refers to where [P represents the resin portion (polymer). "CTR" refers to 2-chlorotryril resin. Thus, for example, N2-Cbz-L-2,3-diaminopropionic acid in 3-chlorotryl resin refers to PREPARATION 1 2- (Aminomethyl) benzimidazole H Add 2- (aminomethyl) benzimidazole, dihydrochloride, hydrate (18.50 g) to a solution of potassium hydroxide (9.50 g) in methanol (400 ml). Stir the resulting mixture at room temperature for 30 minutes, filter and concentrate the filtrate in vacuo. Extract the residue with EtOAc (5 x 500 ml) and filter. Concentrate the filtrate in vacuo to give the title compound as a white solid (9.60 g).

PREPARATION 2 Acid r3-r4-ben2imidazol-2-ylmethyl) aminomethylbenzoinamino1-3-phenylpropionic in 2-chlorotrityl resin Step 1. 3-Fmoc-amino-3-phenylpropionic acid H Combine 3-amino-3-phenylpropionic acid (3.70 g, 22.4 mmol) and NaHCO3 (8.42 g, 100 mmol) in acetone (50 ml) and water (50 ml). Cool in ice bath. Add Fmoc-O-hydroxysuccinimide (9.40 g, 28.0 mmol) and stir the resulting mixture for 3 hours while the ice melts. Concentrate the mixture in vacuo and extract the aqueous portion with EtOAc. Wash the EtOAc solution with 5% glacial acetic acid in water (3 x 300 ml), 5% NaHCO 3 solution (3 x 300 ml) and brine (3 x 300 ml). Concentrate the dried EtOAc solution (MgSO) in vacuo, to give the title compound (containing Fmoc-O-hydroxysuccinimide) as a white foam which is used in step 2. Reference: W.M. Kazmierski, Int. J. Prep. Prot. Res., 45, 242 (1995).

Step 2. 3-Amino-3-phenylpropionic acid in 2-chlorotrityl resin Step 2a. To a solution of DIPEA (1.6 ml) in DMF (10 ml), add the crude product (preparation 2, step 1) (0.64 g). Add 2-chlorotrityl resin, chloride form (2.00 g, 0.65 mmol / g). Shake the resulting mixture for 30 minutes. Add MeOH (0.44 mL), stir the mixture for 10 minutes and drain. Wash the resin with DMF (30 ml x 5) and then CH 2 Cl 2 (30 ml x 5), to give 3-Fmoc-amino-3-phenylpropionic acid in 2-cytotrityl resin.

Step 2b. Wash the resin (preparation 2, step 2a) with DMF (20 m! X 5). Add piperidine 20% in DMF (30 ml), stir for 15 minutes and collect the filtrate. Repeat twice. To determine the loading level, combine the filtrates in a 100 ml volumetric flask, and add DMF to 100 ml (solution A). Dilute solution A (0.2 ml) to 100 ml in a volumetric container. UV absorbance at 301 nM: 0.374. 0.374 x concentration / 7800 0.374 x 20,000 / 7800 = 0.959 mmoles / 2 g (0.479 mmoles / g) Step 3. 3- (4-Chloromethylbenzoii) amino-3-phenylpropionic acid in 2-chlorotrityl resin Place the resin (preparation 2, step 2b) (2.00 g, 0.959 mmol) in CH2CI2 (5 ml) in a container, and treat with DIPEA (1.84 ml, 10.6 mmol), followed by 4-chloromethylbenzoyl chloride (1.89 g, 9.6 mmoles). Seal the container and place in a shaker for 2.5 hours. Transfer the resin to a funnel apparatus. Wash the resin with CH 2 Cl 2 (20 ml x 3), DMF (20 ml x 3) and then CH 2 Cl 2 (20 ml x 3) to yield the title resin.

Acid Step 3-f4- (benzimidazol-2-ylmethyl) aminomethylbenzoylamino-3-phenyropropionic acid in 2-chlorotrityl resin Shake the resin (preparation 2, step 3) (2.00 g, 0.479 mmol) and 2- (aminomethyl) benzimidazole (9.6 g) (preparation 1) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 5), to give the title resin.

PREPARATION 3 N3-R3-benzimidazol-2-ylmethyl) amimethylbenzoin-N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 1. N3-Fmoc-N3-Cbz-L-2,3-diaminopropionic acid Combine N2-Cbz-L-2,3-diamnopropionic acid (2.66 g, 11.27 mmol) and NaHCO3 (4.21 g, 50 mmol) in acetone (25 ml) and water (25 ml). Cool in ice bath. Add Fmoc-O-hydroxysuccinimide (4.70 g, 14.0 mmol) and stir the resulting mixture for 3 hours while the ice melts. Concentrate the mixture in vacuo and extract the aqueous portion with EtOAc. Wash the EtOAc solution with 5% glacial acetic acid in water (3 x 125 ml), 5% NaHCO3 solution (3 x 100 ml) and brine (3 x 100 ml). Concentrate the dried EtOAc solution (MgSO) in vacuo, to give the title compound (contains Fmoc-O-hydroxysuccinimide) as a white foam (5.12 g) which is used in step 2.

Reference: W. M. Kazmierski, Int. J. Prep. Prot. Res., 45, 242 (nineteen ninety five).

Step 2. N-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 2a To a solution of DIPEA (1.47 ml) in DMF (30 ml), add the crude product of preparation 3, step 1 (1.5 g). Add 2-chlorotryril resin, form chloride (2.0 g, 0.65 mmol / g). Stir the resulting mixture for 30 minutes. Add MeOH (0.86 ml) and stir the mixture for 10 minutes and drain. Wash the resin with DMF (30 ml x 5) and then CH 2 Cl 2 (20 ml x 5), to give N 3 -Fmoc-N 2-Cbz-L-2,3-diaminoproponic acid in 2-chlorotrityl resin.

Step 2b Wash the resin (preparation 3, step 2a) with DMF (20 ml x 5).

Add piperidine 20% in DMF (30 ml), stir for 15 minutes and collect the filtrate. Repeat twice. Determine the charge as in the preparation 2. Measure the UV absorbance at 301 nM: 0.391. 0. 391 x concentration / 7800 0.391 x 20,000 / 7800 = 1.0026 mmoles / 2 g (0.501 mmol / g) Acid Step N3- (3-chloromethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Place the resin (preparation 3, step 2b) (1.00 g, 0.50 mmol) in CH2CI2 (5 ml) in container, and treat with DIPEA (0.96 g, 5.5 mmol), followed by 3-chloromethylbenzoyl chloride (0.95 g, 5 g). mmoles). Seal the container and place in a shaker for 2.5 hours. Transfer the resin to a funnel apparatus. Wash the resin with CH 2 Cl 2 (20 ml x 3), DMF (20 ml x 3) and then CH 2 Cl 2 (20 ml x 3) to yield the title resin.

Step 4. N -r3- (Benzimidazol-2-ylmethyl) aminomethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Shake the resin from preparation 3, step 3 (1.00 g, 0.5 mmol) and 2- (aminomethyl) benzimidazole (5 g) (preparation 1) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 3), to give the title resin.

PREPARATION 4 N3-f4- (Benzimidazol-2-ylmTtil) aminomethylbenzoin-N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step N3- (4-chloromethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Place the resin (preparation 3, step 2b) (1.00 g, 0.50 mmol) in CH2Cl2 (5 ml) in a container, and treat with DIPEA (0.96 g, 5.5 mmol), followed by 4-chloromethylbenzoyl chloride (0.95 g, 5 mmoles). Seal the container and place in a shaker for 2.5 hours. Transfer the resin to a funnel apparatus. Wash the resin with CH 2 Cl 2 (20 ml x 3), DMF (20 ml x 3) and then CH 2 Cl 2 (20 ml x 3) to yield the title resin.

Step 2. N3-r4-benzimidazol-2-ylmethyl-aminomethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Shake the resin from preparation 1 (1.0 g, 0.5 mmol) and 2- (aminomethyl) benzimidazole (5.00 g) (preparation 1) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 5), to give the title resin.

PREPARATION 5 N3-r4- (Benzimidazol-2-ylmethyl) aminomethylbenzoin-N2-Cbz-D-2,3-diaminopropionic acid in 2-cytotrityl resin Step 1. N3-Fmoc-N2-Cbz-D-2,3-diaminopropionic acid , C02H Fmoc - N 'H HÑ ^ Cbz Combine N2-Cbz-D-2,3-diaminopropionic acid (1.3 g, 5.6 mmoles) and NaCHO3 (2.10 g, 25 mmoles) in acetone (15 ml) and water (15 ml) ). Cool in ice bath. Add Fmoc-O-hydroxysuccinimide (2.35 g, 7.0 mmol) and stir the resulting mixture for 3 hours while the ice melts. Concentrate the resulting mixture in vacuo and extract the aqueous portion with EtOAc. Wash the EtOAc solution with 5% glacial acetic acid in water (3 x 60 ml), 5% NaHCO3 solution (3 x 50 ml) and brine (3 x 50 ml). Concentrate the dried EtOAc solution (MgSO) in vacuo, to give the title compound (containing Fmoc-O-hydroxysuccinimide) as a white foam that is used in step 2. Reference: W. M. Kazmierski, Int. J. Prep. Prot. Res., 45, 242 (1995).

Step 2. N2-Cbz-D-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 2a To a solution of DIPEA (0.8 ml) in DMF (10 ml), add the crude product of preparation 5, step 1 (0.81 g). Add 2-chlorotryril resin, form chloride (1.00 g) (0.65 mmol / g). Stir the resulting mixture for 30 minutes. Add MeOH (0.4 ml) and stir the mixture for 10 minutes and drain. Wash the resin with DMF (30 ml x 5) and then CH2CI (20 ml x 5), to give N3-Fmoc-N2-Cbz-D-2,3-diaminopropionic acid in 2-chlorotrityl resin.

Step 2b Wash the resin of preparation 5, step 2a, with DMF (20 ml x 5). Add piperidine 20% in DMF (30 ml), stir for 15 minutes and collect the filtrate. Repeat twice. Determine the load as in the preparation 2. Measure the UV absorbance at 301 nM: 0.154. 0.154 x concentration / 7800 0.154 x 20.000 / 7800 = 0.394 mmoles / g Step 3. N3- (4-chloromethylbenzoyl) -N2-Cbz-D-2,3-diaminopropionic acid in 2-chlorotrityl resin Place the resin (preparation 5, step 2b) (1.00 g, 0.394 mmol) in CH2CI2 (5 ml) in a container, and treat with DIPEA (0.75 ml, 4.33 mmol), followed by 4-chlorometiIbenzoii chloride (0.75 g, 3.94 mmoles). Seal the container and place in a shaker for 2.5 hours. Transfer the resin to a funnel apparatus. Wash the resin with CH 2 Cl 2 (20 ml x 3), DMF (20 ml x 3) and then CH 2 Cl 2 (20 ml x 3) to yield the title resin.

Step 4. N3-f4- (Benzimidazol-2-ylmethyl) aminomethylbenzoyl) -N2-Cbz-D-2,3-diaminopropionic acid in 2-chlorotrityl resin Shake the resin (preparation 5, step 3) (1.00 g, 0.394 mmol) and 2- (aminomethyl) benzimidazole (5.00 g) (preparation 1) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI (20 ml x 5), to give the title resin.

PREPARATION 6 N3-r4- (Benzimidazol-2-ylmethyl) aminomethylbenzoin-N2-Boc-L-2,3-diaminopropionic acid in 2-cytotrityl resin Step 1. N -Boc-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 1a To a solution of DIPEA (1.60 ml) in DMF (10 ml), add (N3-Fmoc-N2-Boc-L-2,3-diaminopropionic acid) (0.72 g). Add 2-chlorotryril resin, form chloride (2.0 g) (0.65 mmol / g). Stir the resulting mixture for 30 minutes. Add MeOH (0.8 mL), stir the mixture for 10 minutes and drain. Wash the resin with DMF (30 ml x 5) and then CH 2 Cl 2 (20 ml x 5), to give N 3 -Fmoc-N 2 -Boc-L-2,3-diaminopropionic acid in 2-chlorotrityl resin.

Step 1 b Wash the resin (preparation 6, step 1) with DMF (20 ml x 5). Add piperidine 20% in DMF (30 ml), stir for 15 minutes and collect the filtrate. Repeat twice. Determine the charge as in the preparation 2. Measure the UV absorbance at 301 nM; 0.216. 0.216 x concentration / 7800 0.216 x 20,000 / 7800 = 0.276 mmole / g Step N3- (4-Chloromethylbenzoyl) -N2-Boc-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Place the resin (preparation 6, step 1b) (2.00 g, 0.55 mmole) in CH2CI2 (5 ml) in a container, and treat with DIPEA (1.05 g, 6.08 mmol), followed by 4-chloromethylbenzoll chloride (1.04 g, 5.52 mmoles). Seal the container and place in a shaker for 2.5 hours. Transfer the resin to a funnel apparatus. Wash the resin with CH 2 Cl 2 (20 ml x 3), DMF (2 O ml x 3) and then CH 2 Cl 2 (20 ml x 3) to yield the title resin.

Step 3. N -r4- (Benzimidazol-2-ylmethyl) aminomethylbenzoyl) -N2-Boc-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Shake the resin (preparation 6, step 2) (2.00 g, 0.55 mmol) and 2- (aminomethyl) benzimidazole (5.00 g) (preparation 1) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 5), to give the title resin.

PREPARATION 7 N3-f4-r2- (Benzimidazol-2-yl) etinaminomethiibenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 1 a. 2-f2- (aminoethyl-l-benzimidazole) hydrochloride H Combine o-phenylenediamine (10.8 g, 100 mmol) and ß-alanine (13.4 g, 150 mmol) in 6 N HCl (100 mL). Heat at reflux for 25 hours, allow to cool and freeze at -15 ° C. Filter the solid and wash with 6 N cold HCl, then cold EtOH. Dissolve the solid in 80% EtOH (125 ml), treat with decolorizing charcoal and concentrate in vacuo at 40 g. Warm while EtOH (80 ml) is added. Allow to cool, filter and wash with EtOH to obtain the product as plates.

Step 1b. 2- [2- (Aminoetiiyibenzimidazole H Add the product (preparation 7, step 1a) (7.18 g) to a solution of potassium hydroxide (3.45 g) in methanol (120 ml). Stir the resulting mixture at room temperature for 30 minutes, filter and concentrate the filtrate in vacuo. Extract with EtOAc (3 x 500 ml) and filter. Concentrate the filtrate in vacuo to give the title compound as a white solid (3.33 g).

Step 2. N3-44-22- (Benzimidazol-2-yl) etipaminomethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Shake the resin (preparation 4, step 1) (0.8 g, 0.4 mmol) and 2- [2- (aminoethyl)] benzimidazole (3.25 g) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 5), to give the title resin.

PREPARATION 8 N3-r4-Ri-F-benzimidazol-2-yl) etipaminomethylbenzoyl-N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 1a. 2- (1-aminoethyl) benzimidazole dichlorohydrate hydrate Combine o-phenylenediamine (10.8 g, 100 mmol) and d, 1-alanine (13.4 g, 150 mmol) in 6N HCl (100 mL). Heat at reflux for 75 hours, allow to cool and freeze at -15 ° C. Filter to remove 2.4 g of solid. Bleach the filtrate with charcoal, concentrate in vacuo at 30 g and dilute with 95% EtOH (90 ml). Cool to -15 ° C, filter and wash with 90% EtOH to obtain the title compound as a white powder.

Step 1 b. 2- (1-aminoethyl) benzimidazole Add the product (preparation 8, step 1a) (6.99 g) to a solution of potassium hydroxide (3.36 g) in methanol (120 ml). Stir the resulting mixture at room temperature for 30 minutes, filter and concentrate the filtrate in vacuo. Extract the residue with EtOAc (3 x 500 ml). Concentrate the filtrate in vacuo as a white solid (4.23 g).

Step 2, N3- [4- [1- (Benzamidazol-2-yl) ethyl-1-aminomethylbenzoyl-N2-Cbz-L-2,3-diaminoproponic acid in 2-chlorotrityl resin Shake the resin (preparation 4, step 1) (1.0 g, 0.5 mmol) and 2- (l-aminoethyl) benzimidazole (4.20 g) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 5), to give the title resin.

PREPARATION 9 N3-r4-r (Benzimidazol-2-yl) metinmethylaminomethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 1a. (Methylaminomethyl-benzimidazole dichlorohydrate) H Combine o-phenylenediamine (10.8 g, 100 mmol) and sarcosine (13.4 g, 150 mmol) in 6 N HCl (100 mL). Heat at reflux for 90 hours, allow to cool and concentrate in vacuo at 45 g. Add EtOH (50 mL) and cool to -15 ° C. Filter the solid and wash with 90% cold EtOH. Dissolve in 80% EtOH (150 ml) and decolorize with charcoal. Concentrate in vacuo at 28 g, warm with 95% EtOH (160 ml), allow to cool and filter to give colorless rods.

Step 1 b. 2- (methylaminomethyl) benzimidazole H Add the product (preparation 9, step 1a) (2.33 g) to a solution of potassium hydroxide (1.21 g) in methanol (50 ml). Stir the resulting mixture at room temperature for 30 minutes, filter and concentrate the filtrate in vacuo. Extract with EtOAc (400 mL) and filter. Concentrate the filtrate in vacuo to give the title compound as a white solid (1.28g).

Acid Step N3-r4-r (benzimidazol-2-yl) methynilaminomethylbenzoyl) -N-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Shake the resin (preparation 4, step 1) (0.30 g, 0.15 mmol) and 2- (methylaminomethyl) benzimidazole (1.25 g) in DMF (20 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH CI2 (20 ml x 5), to give the title resin.

PREPARATION 10 N3-R4- (Benzimidazole-2-limethyl) aminomethylbenzoin-N2-benzenesulfonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 1a. N2-benzenesulfonyl-L-asparaqine To L-asparagine (10 g), add sodium hydroxide (3.4 g) and dioxane / water (50 ml / 50 ml). Cool the remaining solution in an ice bath and add benzenesulfonyl chloride (10.6 ml), sodium hydroxide (3.4 g) and water (80 ml). Stir for 3 hours. Add water (200 ml) and extract with EtOAc. Acidify the aqueous solution to pH 3 with concentrated HCl and cool, to give a precipitate. After 1 hour collect the solid and dry it in vacuo at 40 ° C, to give the title compound.

Step 1 b. N-benzenesulfonyl-L-diaminopropionic acid Prepare a solution of sodium hydroxide (10.5 g) in water (50 g), cool and add bromide (2.5 ml). Add product from step 1a (10 g) and sodium hydroxide (2.9 g) in water (35 ml) and stir for 30 minutes. Heat at 90 ° C for 30 minutes and cool in an ice bath. Adjust to pH 7 with concentrated HCl. Collect the title compound as a white solid, m.p. 203-206 ° C.

Step 1c. N-Fmoc-N-benzenesulfonyl-L-2,3-diaminopropionic acid Combine N2-benzenesulfonyl-L-2,3-dlaminopropionic acid (2.92 g, 12.0 mmol) and NaHCO3 (4.57 g) in acetone (40 ml) and water (40 ml). Cool in ice bath. Add Fmoc-O-hydroxysuccinimide (4.97 g, 19.2 mmol) and stir the resulting mixture for 3 hours while the ice melts. Add additional NaHCO3 (1.5 g), acetone (40 ml) and water (40 ml), and dioxane (80 ml) and stir for 20 hours. Concentrate the mixture in vacuo and extract the aqueous portion with EtOAc. Wash the solution with EtOAc with 5% glacial acetic acid in water (3 x 300 ml), 5% NaHCO 3 solution (3 x 300 ml) and brine (3 x 300 ml). Concentrate the dried EtOAc solution (MgSO4) in vacuo, to give the title compound (containing Fmoc-O-hydroxysuccinimide) as a light yellow solid which is used in step 2. Reference: W. M. Kazmierski, Int. J. Prep. Res., 45, 242 (1995).

Step 2. N2-Benzenesulfonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 2a. To a solution of DIPEA (1.60 ml) in DMF (10 ml), add (N3-Fmoc-N2-benzenesulfonyl-L-2,3-diaminopropionic acid) (0.787 g). Add 2-chlorotryril resin, form chloride (2.00 g) (0.65 mmol / g). Stir the resulting mixture for 30 minutes. Add MeOH (0.8 mL), stir the mixture for 10 minutes and drain. Wash the resin with DMF (30 ml x 5) and then CH 2 Cl 2 (20 ml x 5), to give N 3 -benzenesulfonyl-L-2,3-diaminopropionic acid in 2-chlorotrity resin.

Step 2b. Wash the resin (preparation 10, step 2a) with DMF (20 ml x 5). Add piperidine 20% in DMF (30 ml), stir for 15 minutes and collect the filtrate. Repeat twice. Determine the load as in the preparation 1. Measure the UV absorbance at 301 nM: 0.389. 0.389 x concentration / 7800 0.389 x 20.000 / 7800 = 0.9958 / 2 g (0.498 mmoles / g) Step 3. N3- (4-Chloromethylbenzoyl) -N2-benzenesulfonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin.

Place the resin (preparation 10, step 2b) (1.00 g, 0.498 mmol) in CH2Cl2 (5 ml) in a container, and treat with DIPEA (0.95 ml, 5.48 mmol), followed by 4-chloromethylbenzoyl chloride (0.94 g, 4.98 mmoles). Seal the container and place in a shaker for 2.5 hours. Transfer the resin to a funnel apparatus. Wash the resin with CH 2 Cl 2 (20 ml x 3), DMF (20 ml x 3) and then CH 2 Cl 2 (20 ml x 3) to yield the title resin.

Step 4. N3- [4-Benzimidazol-2-ylmethyl) aminomethylbenzoyl) -N2-benzenesulfonyl-L-2,3-diamotropionic acid in 2-ciorotryl resin.

Shake the resin (preparation 10, step 3) (1.00 g, 0.55 mmole) and 2- (aminomethyl) benzimidazole (5.00 g) (preparation 1) in DMF (25 ml) in a sealed container for 44 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 5), to give the title resin.

PREPARATION 11 N3-r4.benzimidazol-2-ylmethylaminomethylbenzoin-N2-n-butoxycarbonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Acid Step N3-Fmoc-N2-n-butoxycarbonyl-L-2,3-diaminopropionic acid Combine N2-n-butoxycarbonyl-L-2,3-diaminopropionic acid (18.0 g, 88.2 mmol) and NaHCO3 (38.2 g) in acetone (400 mL) and water (400 mL). Cool in ice bath. Add Fmoc-O-hydroxysuccinimide (42.7 g, 126.6 mmol) and stir the resulting mixture for 3 hours while the ice melts. Continue stirring for 20 hours. Concentrate the mixture in vacuo and extract the aqueous portion EtOAc. Wash the EtOAc solution with 5% glacial acetic acid in water (3 x 100 ml), 5% NaHCO3 solution (8 x 100 ml) and brine (3 x 100 ml). Concentrate the dried EtOAc solution (MgSO) in vacuo. Pursue with heptane, dry in vacuum oven overnight and then transfer to a large disc and air dry (to remove AcOH), to give the title compound (contains Fmoc-O-hydroxysuccinimide) as a yellow solid clear that is used in step 2. Reference: WM Kazmierski, Int. J. Prep. Prot. Res., 45 242 (1995).

Step 2. N-n-butoxycarbonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Step 2a. Add (N3-Fmoc-N2-n-butoxycarbonyl-L-2,3-diaminopropionic acid) (16.7 g) dissolved in DMF (100 ml), warm, add DMF (50 ml) and filter. Add DIPEA (14 ml) and then add 2-chlorotryril resin, form chloride (15.00 g) (0.65 mmol / g). Stir the resulting mixture for 45 minutes. Add MeOH, stir the mixture for 10 minutes and drain. Wash the resin with DMF (100 ml x 5) and then CH 2 Cl 2 (100 ml x 5), to give N 3 -Fmoc-N 2-n-butoxycarbonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin.

Step 2b Wash the resin (preparation 11, step 2a) with DMF (100 ml x 5). Add piperidine 20% in DMF (100 ml), stir for 15 minutes and collect the filtrate. Repeat twice and then DMF (2 x 100 ml). Determine the loading as in preparation 1 (dilute the filtrate to 1,000 ml (solution A), take 1 ml and dilute to 100 ml). Measure the UV absorbance at 301 nM; 0.794. 0.794 x concentration / 7800 0.794 x 10,000 / 7800 = 18.18 mmoles / 15 g (0.67 mmoles / g) Step 3. N3- (4-Chloromethyl-benzoyl) -N2-n-butoxycarbonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Place the resin (preparation 11, Step 2b) (15.00 g, 10 mmol), in CH2CI2 (50 ml) in a container and treat with DIPEA (12.3 ml, 70 mmol), followed by 4-c! Orometi! Benzole chloride ( 11.5 g, 60 mmol). Splash moderately for 4 hours. Wash the resin with CH 2 Cl 2 (100 ml x 3), NMP (100 ml x 3) and then CH 2 Cl 2 (100 x 5) to yield the title resin.

Step 4. N3- [4- (Benzimidazol-2-ylmethyl) aminomethylbenzoyl) -N2-n-butoxycarbonyl-L-2,3-diaminopropionic acid in 2-chlorotrityl resin Shake the resin (preparation 11, step 3) (15.00 g, 10 mmol) and 2- (aminomethyl) benzimidazole (80.85 g) (preparation 1) in NMP (500 ml) in a sealed container for 24 hours. Transfer the resin to the funnel apparatus, and wash the resin with NMP (100 ml x 3) and then CH2CI2 (100 ml x 5), to give the title resin.

PREPARATION 12 N-r4-rp-methylbenzyl-midazol-2-yl) methylaminomethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chlorotrityl resin 1-Methyl-2- (aminomethyl) benzimidazole dihydrochloride passed Me .2HCI Combine? / -methyl-o-phenylenediamine (12.2 g, 100 mmol) and glycine (11.3 g, 150 mmol) in 6 N HCi (100 mL). Heat at reflux for 90 hours, allow to cool and concentrate in vacuo at 60 g. Add EtOH (50 mL) and cool to -15 ° C. Filter the solid and wash with 90% cold EtOH. Dissolve the blue solid in water (30 ml), add EtOH (100 ml) and treat with decolorizing carbon. Wash the solid with 2: 1 EtOH-water and concentrate filtrates in vacuo at 33 g. Add water (15 ml) and warm while adding EtOH (150 ml). Allow to cool, filter and wash with 90% EtOH, to obtain the product as blue flakes. Process the filtrate to obtain a second crop.

Pasolb. 1-Methyl-2- (aminomethyl) benzimidazole Add the product (preparation 12, step 1 a) (10.3 g) to a solution of potassium hydroxide (5.20 g) in methanol (200 ml). Stir the resulting mixture at room temperature for 30 minutes, filter and concentrate the filtrate in vacuo. Extract with EtOAc (400 mL) and filter. Concentrate the filtrate in vacuo to give the title compound as a white solid (5.60 g).

Step 2. N3- [4 - [(1-Methylbenzimidazol-2-yl) methyl] aminomethylbenzoyl) -N2-Cbz-L-2,3-diaminoproponic acid in 2-chlorotrityl resin Shake the resin (preparation 4, step 1) (1.50 g, 0.60 mmol) and 1-methyl-2- (aminomethyl) benzimidazole (5.00 g) in DMF (25 ml) in a sealed container for 18 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH2CI2 (20 ml x 5), to give the title resin.

PREPARATION 13 N3-r4-r (5-chlorobenzimidazol-2-yl) metinaminomet »lbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-chloro-trityl resin Step 1a. 2- (aminomethyl) -5-chlorobenzimidazole dihydrochloride Combine 4-chloro-o-phenylenediamine (14.3 g, 100 mmol) and glycine (11.3 g, 150 mmol) in 6 N HCl (100 mL). Heat at reflux for 72 hours, allow to cool, add EtOH (30 ml) and cool to -15 ° C. Filter and wash with 3: 1 EtOH-water, then water. Combine the filtrates, concentrate in vacuo at 50 g and dilute with EtOH (75 ml). Cool to -15 ° C, filter and wash with 90% cold EtOH. Dry to obtain solid (18.8 g). Absorb in 2: 1 EtOH-water (120 ml), treat with decolorizing charcoal, concentrate in vacuo to 29 g, add water (6 ml) and heat while adding EtOH (120 ml). Boil up to 100 ml, add EtOH (50 ml), boil until 125 ml and let cool. Collect the solid and wash with 95% EtOH. Dry to obtain the title compound as a light orange powder.

Step 1 b. 2- (Aminomethyl) -5-chlorobenzimidazole Add the product (preparation 12, step 1a) (10.3 g) to a solution of potassium hydroxide (5.20 g) in methanol (200 ml). Stir the resulting mixture at room temperature for 30 minutes, filter and concentrate the filtrate in vacuo. Extract with EtOAc (400 mL) and filter. Concentrate the filtrate in vacuo to give the title compound as a white solid (7.62 g).

Step 2. N3- [4 - [(5-Chlorbezimidazol-2-yl) methyl] aminomethylbenzoyl) -N2-Cbz-L-2,3-diaminopropionic acid in 2-cytotrityl resin Shake the resin (preparation 4, step 1) (1.50 g, 0.60 mmol) and 1-methyI-2- (aminomethyl) benzimidazole (5.00 g) in DMF (25 ml) in a sealed container for 18 hours. Transfer the resin to the funnel apparatus, and wash the resin with DMF (25 ml x 5) and then CH 2 Cl 2 (20 ml, x 5) to give the title resin.

EXAMPLE 1 Acetylation of pcts of preparations 2-4 and 6-7 H Place the resin (0.16 g, -0.07 mmol) in CH2CI2 (4 ml) in a container, and treat with DIPEA (0.77 mmol), followed by acetic anhydride. (0.70 mmoles). Seal the container and place it in a shaker for 2 hours at room temperature. Place the resin in a funnel apparatus, and wash the resin with CH CI2 (15 ml x 3), DMF (15 ml x 5) and then CH2CI2 (20 ml x 5), to give a diacylated pct. Wash the resin with DMF (15 ml x 5), and then treat the resin with 20% piperidine in DMF (30 ml) with stirring for 1.5 hours. Wash the resin with DMF (15 ml x 5) and then CH 2 Cl 2 (20 ml x 5), to pce monoacetylated resin. Using the same method, prepare the following compound EXAMPLE 2 Acylation of pcts of preparations 2-8 with acid chlorides and chloroformates H Place the resin (0.16 g, -0.07 mmol) in CH2CI2 (4 ml) in a container, and treat with DI PEA (0.77 mmol), followed by acid chloride or chloroformate (0.70 mmol). Seal the container and place it in a shaker for 2 hours at room temperature. Place the resin in a funnel apparatus, and wash the resin with CH 2 Cl (15 ml x 3), DMF (15 ml x 5) and then CH 2 Cl 2 (20 ml x 5), to give a diacylated pct. Wash the resin with DMF (15 ml x 5), and then treat the resin with 20% piperidine in DMF (30 ml) with stirring for 1.5 hours. Wash the resin with DMF (15 ml x 5) and then CH2CI2 (20 ml x 5), to pce monoacylated resin. Acid chlorides and chloroformates used: CBJCKJO- CH3o ^ oi EXAMPLE 3 Acylation of pcts of preparation 4 with acids Place the resin (0.16 g, -0.07 mmol) in CH2CI2 (4 mL) in a container, and treat with DIPEA (0.70 mmol), followed by carboxylic acid (0.35 mmol) and PyBroP (0.35 mmol) Seal the container and place it in a shaker for 1.5 hours at room temperature. Place the resin in a funnel apparatus, and wash the resin with CH 2 Cl 2 (15 ml x 3), DMF (15 ml x 5) and then CH 2 Cl 2 (20 ml x 5), to give a diacylated pct. Wash the resin with DMF (15 ml x 5), and then treat the resin with 20% piperidine in DMF (30 ml) with stirring for 1.5 hours. Wash the resin with DMF (15 ml x 5) and then CH2CI2 (20 ml x 5), to pce monoacylated resin. Acids used: o o O CH3SCH2-Me2NCH2- CH3OCH2CH2- CHgCHgOChk- EXAMPLE 4 Preparation of ureas: Reaction of isocyanates or isothiocyanates with pcts of preparation 4 H Place the resin (0.16 g, -0.107 mmol) in DMF (5 ml) in a container, and add isocyanate (0.22 mmol). Seal the container and place it in a shaker for 2-2.5 hours at room temperature. Place the resin in a funnel apparatus, and wash the resin with CH2CI2 (15 ml x 3), DMF (15 ml x 5) and then CH 2 Cl 2 (20 ml x 5), to give the title resin. Isocyanates used: Et02CH2CH2C- Isothiocyanates used: MeO- EXAMPLE 5 Decomposition of resin pcts Treat the resins of preparations 2-13 or examples 1-4 (-0.16 g) with CH2Cl2: TFA: H2O (99: 0.95: 0.05) (10 ml) at room temperature for 15 minutes and filter. Repeat this once. Combine the filtrates and concentrate on a Speed Vac. Add heptane (1 ml) and concentrate in Speed Vac. Dry the pcts in a vacuum oven at 40 ° C for 20 hours, to pce the following pcts which are listed in Tables 1 to 8, below (CALR condition: Vydac column (218TP5405): gradient 5-95% MeCN - H2O (0.1% TFA) for 10 minutes at 1 ml / min UV detection 254 nM): TABLE 1 TABLE 2 "Purified by preparative TLC" Purified by preparative TLC TABLE 3 TABLE 4 TABLE 5 TABLE 6 TABLE 7 TABLE 8"Purified by preparative TLC TABLE 8-1 "Purified by preparative TLC TABLE 8-2 "Purified by preparative TLC TABLE 8-3" Purified by preparative TLC EXAMPLE 6 Acid N3-r4-r (benzimidazole-2-inmetinrr (carboxymethinamino1carbonyllamine-n-methylbenzo-p-N2-Cbz-L-2,3-diamidopropionic acid) Dissolve N3- [4 - [(benzimidazoi-2-yl) methyl] [[(ethoxycarbonylmethyl) amino] carbonyl] aminomethylbenzoyl] -N2-Cbz-L-2,3-diaminopropionic acid (5-45) (2.60 g, 4.1 mmoles) in MeOH (12 ml) and slowly add 1 N NaOH (40 ml). After 3 hours slowly add 1 N HCl (40 ml) and then add 1 N HCl at pH 6.5, to give a white precipitate. Decant water and wash with water (2 x 10 ml). Dry the title compound (Table 8-4) in a vacuum oven.

EXAMPLE 7 Acid N3-r4-r (Benzimidazole-2-inmetiprr (carboxymethyl) amino-1-carbonaminomethyl-benzoyl-N2-fn-butoxycarbonyl) -L-2,3-diaminopropionic acid Dissolve N - [4 - [(benzimidazol-2-yl) methyl] [[ethoxycarbonylmethyl) amino] carbonyl] aminomethylbenzoyl] -N2- (n-butoxycarbonyl) -L-2,3-diaminopropionic acid (5-86) (0.432) g, 0.72 mmol) in MeOH (5 mL) and slowly add 1 N NaOH (4 mL). After 3 hours evaporate the MeOH under a stream of nitrogen. Slowly add 1 N HCl (4 mL) and then add 1 N HCl at pH 6.5, to give a white gum. Decant water and dry the title compound (Table 8-4) in a vacuum oven.

TABLE 8-4 EXAMPLE 8 Methyl N3-r4-r (Benzimidazol-2-yl) metinfr (cyclohexyl) amino1carboninaminomethylbenzoin-N2- (n-butoxycarbonyl) -L-2,3-d-aminopropionate Add 3 M HCl in MeOH (5 mL) to N3- [4 - [(benzimidazol-2-yl) methyl] [[(cyclohexyl) amino] carbonyl] amine-methylbenzoyl] -N2- (n- butoxycarbonyl) -L-2,3-diaminopropionic acid (0.155 g) in MeOH (20 ml) and heating under reflux for 7 hours. The reaction mixture was concentrated in vacuo. MeOH was added and concentrated in vacuo to give the title compound as a white solid. MS m / e [M + H] 641: reaction time HPLC: 6.77 min. The following test procedure, which is a competition radioligand binding assay, was carried out to determine the activity of the preceding compounds as vß3 antagonists. The competitive assay procedure described in Kumar et al., "Biochemical Characterization of the Binding of Echistatin to Integrin avß3 Receptor", Journal of Pharmacology and Experimental Therapeutics, Vol. 283, No. 2, pages 843-853 (1997) was employed. . Thus, the binding of 125l-echistatin (radio-labeled by the chloramine-T method at a specific activity of 2,000 Ci / mmole (Amersham, Chicago, II.)) To avß3 receptor (purified from human placenta), both prepared as described in Kumar et al., was made to compete for the compounds prepared in the previous examples. With the purified avß3 receptor, Microlite-2 plates were coated at a concentration of 50 ng / container. L125-echistatin was added to the containers at a final concentration of 0.05 nM in binding buffer (50 μl / vessel) in the presence of the competitor evaluation compound. The competing evaluation compounds were used at diluted concentrations in serial form, ranging from 1 pM to 100 nM. After 3 hours of incubation at room temperature, the vessels were washed, and radioactivity was determined which reflected the binding by 125 I -equistatin to avß3 receptors with Top Count (Packard). Each information point is an average of tripled container values. The specific binding of 125l-echistatin was calculated as the difference between the amount of 125 I-linked echistatin in absence (total binding), and the amount of 125 I-linked echistatin in the presence of a 200-fold molar excess of unlabeled echistatin (link Not specific). The efficacy of the evaluation compounds for the inhibition of the specific binding of 125i-echistatin to avß3 receptors was determined by plotting a specific binding plot (y-axis) as a function of the concentration of evaluation compound (x-axis). The concentration of the evaluation compound necessary to inhibit 50% of the specific binding (1C50) was determined from the diagram. The IC 0 can be converted directly into mathematical form in Ki, which is a measure of the receptor binding affinity of the compounds under the defined test conditions. To measure the relative affinity of the evaluation compounds for avß3 receptors, against affinity for anbβ3 receptors, similar competitive assays were carried out using purified anbβ3 receptor and 125 μl-equistatin (iodinated using the lactoperoxidase method). The specificity index, which is a measure of the relative binding affinity for av3 against anb3, can be determined by dividing the IC50 value for anb3 by the value IC0 for av3.

The IC50 values of avß3 determined by the preceding assay for the compounds identified in the preceding examples, and the specificity index (IC50 ?? bß3 / IC5o ctvßβ) are summarized in the tables below.

TABLE 9 TABLE 10 -21 4.4 41 5-22 6.4 26 5-23 5.5 22 5-24 5.3 14 5-25 4.5 52 5-26 3.5 91 5-27 1.56 481 5-28 0.65 1136 5-29 4.3 144 5-30 2.3 296 5-31 6.0 80 5-32 6.5 151 5-33 17 128 5-34 2.3 421 5-35 8.1 240 5-36 11.7 129 5-37 5.3 10 203 5-38 13.6 49 5-139 3.1 223 5-40 5.7 288 5-41 2.8 19 5-42 1.8 39 5-43 2.2 585 5-44 19.6 66.3 5-45 2.2 1333 5-46 2.7 1065 5-47 15 2.2 1252 5-48 1.0 2028 5-49 4.2 504 5-50 3.0 805 5-51 1.1 1210 5-52 4.0 448 5-53 3.8 483 5-54 2.0 413 5-55 2.5 620 5-56 1.6 514 TABLE 11 TABLE 12 TABLE 13 TABLE 14 TABLE 15 TABLE 16 Examples of pharmaceutical dosage forms The following are examples of pharmaceutical dosage forms containing a compound (ie, "active compound") of the invention. The scope of the invention in its pharmaceutical composition aspect should not be limited by the examples provided.

EXAMPLE 9 Tablets Manufacturing method Mix items nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with item no. 3. Grind the wet granules through a coarse screen (eg, "0.63 cm), if necessary, dry the wet granules, sieve the dried granules if necessary, and mix with item No. 4 and mix for 10-15 minutes Add item No. 5 and mix for 1-3 minutes Compress the mixture to an appropriate size and weigh in a suitable tablet machine.

EXAMPLE 10 Capsules Manufacturing method Mix items nos. 1, 2 and 3 in a suitable mixer for 10-15 minutes. Add item no. 4 and mix for 1-3 minutes.

Fill the mixture with suitable two-piece hard gelatin capsules in a suitable encapsulating machine. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those skilled in the art. All such alternatives, modifications and variations are intended to be within the spirit and scope of the present invention.

Claims (22)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula: ( wherein n, p, q and r are each independently selected from 0 or 1; a, b, c and d each independently represent a carbon or nitrogen atom, with the proviso that not more than two of a, b, c and d are nitrogen atoms; Y and Y1 each independently represent 1-4 optional substituents selected from alkyl, alkoxy, halo, -CF3 and -C (0) OH; R1 is H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl, NHRA, -NHC (O) RA, -NHSO2RA, NHC (O) NHRA- or -NHC (O) ORA; R1 is optionally substituted with 1-3 groups selected from halo, alkyl, -CF3, -CN, -ORB, -SRB, -C02RB, -C (O) RB, -OC (0) RB, -OC (0) ORB and -SO2RB, and RA and RB are independently selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R1 is alkyl, R1 is not substituted with halo, the condition that when R1 is -NHSO2RA or -NHC (O) ORA, RA is not H, and the condition that for -SO2RB or -OC (O) ORB, RB is not H; R2 is H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl, or heterocycloalkylalkyl; R2 is optionally substituted with 1-3 groups selected from halo, alkyl, -CF3, -CN, -ORc, -SRC, -CO2Rc, -C (O) Rc, -OC (O) Rc, -OC (O) ORc and -SO2Rc, wherein Rc is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyo, cycloalkylaikyl or heterocycloalkylalkyl, with the proviso that when R2 is alkyl, R2 is not substituted with halo, and condition that for -S02Rc or -OC (O) ORc, Rc is not H; R3 is H, alkyl, aralkyl, arylcycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkyl, -C (O) RD, -C (0) ORD, -SO2Re, -C (0) NRFRG, -C (O) NRFSO2RE, or -C (= S) NRFRG, wherein RD, RE, RF and RG are independently selected from H, alkyl, aryl, aralkyl, arylcyanoalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or RF and RG taken together complete a 5-7 member ring containing 0 to 1 oxygen or sulfur atom, and 1 to 2 nitrogen atoms; R3 is optionally substituted with 1-3 groups selected from halo, alkyl, aryl, CF3, -CN, -ORH, -SRH, -CO2RH, -C (O) RH, -0C (O) RH, -OC (0) ORH, -S02RH and -NRHRH, wherein RH is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R3 is alkyl, R3 is not substituted with halo, the condition that when R3 is -S0 RE, -C (0) NRFSO2RE, or -CO (0) RD, RD and RE are not H, and the condition that stops -SO2RH or -OC (O) ORH, RH It is not H; R 4 is H, alkyl, aralkyl, arylcycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroaralkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, R 4 is optionally substituted with 1-3 groups selected from halo, alkyl, CF 3, -CN, -ORJ, -SRJ, -C02RJ, -C (O) RJ, -OC (O) RJ, -OC (O) ORJ, and -SO2RJ, wherein RJ is selected from H, alkyl, aryl, aralkyl, arylcycloalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroaralkyl, cycloalkylalkyl or heterocycloalkylalkyl, with the proviso that when R4 is alkyl, R4 is not substituted with halo, and the condition that for -SO2RJ or -OC (0) ORJ, RJ is not H; R5, R6, R7, R8, R9, R10, R11 and R12 are independently selected from H or C? -C3 alkyl; and where they are located meta or para in relation to each other; or a biolvalent ester thereof, or a pharmaceutically acceptable salt thereof.

2.- The compound of claim 1 where they are located for relation to each other.

3. The compound of claim 2, wherein R4 is H.

4. The compound of claim 3, wherein R5, R6, R7, R8, R9, R10, R11, and R12, are each H.

5 The compound of claim 4, wherein the sum of n + p is 1, the sum of g + r is 1.

6. The compound of claim 5, wherein a, b, c and d are each atoms of carbon, R2 is H.

The compound of claim 6, wherein R3 is selected from H, alkyl, -C (O) RD, -C (O) ORD, -C (O) NRFRG and -C ( = S) NRFRG; wherein RD is selected from phenyl, alkyl, aralkyl, cycloalkyl, arylcycloalkyl, and wherein RD is optionally substituted with 1-3 substituents selected from alkoxy, halo, cycloalkyl, -S-CH 3, phenyioxy, -OC (0) CH 3, -C (0) OC2H5 and -N (CH3) 2; wherein RF and RG are selected from H, alkyl, phenyl, cycloalkyl, and aralkyl, and wherein RF and RG are optionally substituted with alkoxy, halo or CO2RH.

8. The compound of claim 7, wherein R1 is H, -NHRA, -NHC (O) RA, -NHC (O) ORA, -NHC (O) NHRA or NHSO2RA.

9. The compound of claim 1, wherein said compound is selected from the group consisting of or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

10. - The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

12. - The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

14. - The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 9, wherein said compound is or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.

18. The use of the compound as claimed in claim 1, for the manufacture of a medicament for the treatment of a mammal affected with a vitronectin-mediated disorder.

19. - The use of a. compound as claimed in claim 18, wherein the vitronectin mediated disorder is cancer, retinopathy, atherosclerosis, vascular restenosis, or osteoporosis.

20. The use of a compound as claimed in claim 19, wherein a, b, c and d are each carbon atoms; they are located for in relation to each other; R2, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are each H; the sum of n + p is 1, and the sum of q + r is 1; R1 is H, -NHRA, -NHC (0) RA, NHC (0) ORA, -NHC (0) NHRA or -NHS02RA; R3 is selected from H, alkyl, -C (O) RD, -C (0) ORD, -C (0) NRFRG and -C (= S) NRFRG; wherein RD is selected from phenyl, alkyl, aralkyl, cycloalkyl, arylcycloalkyl, and wherein RD is optionally substituted with 1-3 substituents selected from alkoxy, halo, cycloalkyl, -S-CH3 > phenyloxy, -OC (O) CH 3, -C (O) OC 2 H 5 and -N (CH 3) 2; wherein RF and RG are selected from H, alkyl, phenyl, cycloalkyl and aralkyl, and wherein RF and RG are optionally substituted with alkoxy, halo or CO2RH.

21. The use of a compound as claimed in claim 20, wherein the disorder is cancer.

22. - The use of a compound as claimed in claim 18, wherein the disorder is cancer and the compound is selected from the group consisting of: or a biolabile ester thereof, or a pharmaceutically acceptable salt thereof.