Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1019—Tetrapeptides with the first amino acid being basic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to compounds which are useful for treating pathological states which arise from or are exacerbated by angiogenesis, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting angiogenesis in a mammal
• Angiogenesis the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development and wound repair
• endothehal cells the primary cells of capillary blood vessels
• these molecules appear to maintain the microvasculature in a quiescent state (1 e one of no capillary growth) for prolonged periods which may last for as long as weeks or, in some cases, decades
• these same cells can undergo rapid proliferation and turnover within a 5 day period (Folkman, J and Shmg, Y , The Journal of Biological Chemistry, 267(16), 10931-10934, (1992) and Folkman. J and Klagsbrun, M . Science, 235, 442-447 (1987)
• angiogenesis is a highly regulated process unde * * normal conditions, manv diseases (characterized as angiogemc diseases) are driven bv persistent unregulated angiogenesis Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition
• unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition
• ocular neovascula ⁇ zation has been implicated as the most common cause of blindness and dominates approximately twenty eye diseases
• new capillaries formed in the retina invade the vitreous, bleed, and cause blindness
• Growth and metastasis of solid tumors are also dependent on angiogenesis (Folkman, J , Cancer Research, 46, 467-473 (1986), Folkman, J , Journal of the National Cancer Institute, 82, 4-6 (1989) It has been shown, for example, that tumors which enlarge to greater than 2 mm must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels Once these new blood vessels
• angiogenesis inhibitors are currently under development for use in treating angiogenic diseases (Gasparim, G. and Harris, A. L., J. Clin. Oncol., 13(3): 765-782, (1995), but there are disadvantages associated with these compounds.
• Suramin for example, is a potent angiogenesis inhibitor but causes severe systemic toxicity in humans at doses required for antitumor activity.
• Compounds such as retinoids, interferons and antiestrogens are relatively safe for human use but have weak antiangiogenic effects.
• Irsogladine an anti-tumor drug with low toxicity, has only weak anti-angiogemc effects. Thus there is still a need for compounds useful in treating angiogenic diseases in mammals
• W, X, Y, and Z are independently selected from (1) hydrogen and
• R2 and R3 are independently selected from
• alkyl of one to six carbons where the alkyl group is substituted with -NL--L-*-- where L-- and L- * - * are independently selected from (a) hydrogen,
• R4 and R-* 5 are independently selected from (1) hydrogen
• R*> and R ⁇ are independently selected from (1) hydrogen,
• R° and R" are independently selected from (1) hydrogen,
• L 4 is selected from (a) hydrogen and
• R ⁇ o is selected from
• L*- * is alkyl of one to six carbons, alkyl of one to six carbons, halogen, -N ⁇ 2, and
• Compounds of this invention include, but are not limited to, (45,75, 105, 135)-4-(4-am ⁇ nobutyl)- 13-(am ⁇ nocarbonyl)- 10-(4-hydroxybenzyl)-7- ⁇ sobutyl- 9-methyl-2,5,8,l l-tetraoxo-3,6,9,12-tetraazapentadecan-15-o ⁇ c acid, (25)-2-( ⁇ (25)-2-[((25)-2- ⁇ [(25)-2-(acetylam ⁇ no)-6-am ⁇ nohexanoyl]am ⁇ no ⁇ -4- methylpentanoyl)(methyl)am ⁇ no]-3-phenylpropanoyl ⁇ am ⁇ no)butaned ⁇ o ⁇ c acid, (25)-2- ⁇ [(25,55,85)-8-(4-am ⁇ nobutyl)-2-(4-hydroxybenzyl)-5- ⁇ sobutyl
• alkyl refers to a monovalent straight or branched chain group of one to twelve carbons derived from a saturated hydrocarbon by the removal of a hydrogen atom.
• the alkyl groups of this invention can be optionally substituted.
• aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings.
• the aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring.
• the aryl groups of this invention can be optionallty substituted.
• amino refers to -NH2-
• cycloalkyl refers to a monovalent group of three to twelve carbons derived from a saturated cyclic or bicyclic hydrocarbon by the removal of a hydrogen atom.
• the cycloalkyl groups of this invention can be optionally substituted.
• halogen refers to F, Cl, Br and I.
• hydroxy-protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures.
• hydroxy-protecting groups include, but are not limited to, ethers, for example, methyl, ethyl, t-butyl, benzyl and allyl; substituted methyl ethers, for example, methoxy methyl, benzyloxy methyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)- ethoxymethyl, and triphenylmethyl; substituted ethyl ethers, for example, 2,2,2- trichloroethyl and t-butyl; tetrahydropyranyl ethers; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; esters, for example, formate, acetate, trifluoroacetate, pival
• hydroxy- protecting groups are disclosed in Greene, T. W., & Wuts, P. G. M. (1991). Protectective Groups In Organic Synthesis (2nd ed.). New York: John Wiley & Sons.
• N-protected amino or "amino protecting group” refers to groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, T. W., & Wuts, P. G. M. (1991). Protectective Groups In Organic Synthesis (2nd ed.). New York: John Wiley & Sons. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t- butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
• pharmaceutically acceptable prodrugs represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
• pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit risk ratio. Pharmaceutically acceptable salts are well known in the art . For example, S. M.
• Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pe
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
• prodrug represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
• a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed.. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
• Stereoisomers include enantiomers and diastereomers, and equal mixtures of enantiomers are designated (— ).
• Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
• HMVEC Human Microvascular Endothelial Cells
• BSA bovine serum albumin
• the chamber was assembled and inverted, and cells were allowed to attach for 2 hours at 37 °C to polycarbonate chemotaxis membranes (5 ⁇ m pore size) that had been soaked in 0.1 % gelatin overnight and dried.
• the chamber was then reinverted and basic fibroblast growth factor (bFGF) and test substances were added to the wells of the upper chamber (to a total volume of 50 ⁇ L); the apparatus was then incubated for 4 hours at 37 °C.
• Membranes were recovered, fixed and stained (DiffQuick, Fisher Scientific, Pittsburgh, PA) and the number of cells that had migrated to the upper chamber per 10 high power fields were counted.
• bFGF basic fibroblast growth factor
• the compounds of the invention possess anti-angiogemc activity
• angiogenesis inhibitors such compounds are useful in the treatment of both primary and metastatic solid tumors and carcinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder, bile ducts, small intestine, urinary tract including kidney, bladder and urothelium female genital tract including cervix, uterus, ovaries choriocarcinoma and gestational trophoblastic disease, male genital tract including prostate, seminal vesicles, testes and germ cell tumors, endocrine glands including thyroid, adrenal, and pituitary, skin including hemangiomas, melanomas, sarcomas arising from bone or soft tissues and Kaposi's sarcoma, tumors of the brain, nerves, eyes, and menm
• chemotherapeutic agents include alkylating agents such as nitrogen mustards including mechloethamine, melphan, chlorambucil, cyclophosphamide and lfosfamide, mtrosoureas including carmustine, lomustine, semustine and streptozocin, alkyl sulfonates including busuitan t ⁇ azines including dacarbazine, ethyenimines including thiotepa and hexamethylmelamine, folic acid analogs including methotrexate, py ⁇ midine analogues including 5-fluorourac ⁇ l, cytosine arabinoside, purine analogs including 6-mercaptopu ⁇ ne and
• the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids
• pharmaceutically acceptable salt is meant those salts which are within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio
• Pharmaceutically acceptable salts are well-known in the art For example, S M Berge, et al describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 1977, 66 1 et seq
• the salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid
• Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate. benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hermsulfate, heptanoate, hexanoate, fumarate, hydrochlo ⁇ de, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, mcotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylprop ⁇ onate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecano
• the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
• long chain halides such as decyl
• acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydr ⁇ bromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
• Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
• Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
• Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
• Preferred salts of the compounds of the invention include phosphate, tris and acetate.
• sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids.
• a sustained-release matrix is desirably chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
• biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid) polyanhydr
• a preferred biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid).
• Compounds of this invention or combinations thereof may be combined with pharmaceutically acceptable excipients or carriers to form therapeutic compositions
• a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type
• the compositions may be administered parenterally, sub ngually, intracisternally, intra ⁇ aginally, lntrape ⁇ toneally, rectally, bucally or topically (as by powder, ointment, drops transdermal patch or iontophoresis device)
• compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use
• suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate
• Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfact
• Topical administration includes administration to the skin, mucosa and surfaces of the lung and eye
• Compositions for topical administration may be prepared as a dry powder which may be pressurized or non-pressurized
• the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter
• Suitable inert carriers include sugars such as lactose Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0 01 to 10 micrometers
• a compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, as, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea
• the composition may be pressurized and contain a compressed gas such as nitrogen or a liquified gas propellant
• a compressed gas such as nitrogen or a liquified gas propellant
• the liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent.
• the pressurized composition may also contain a surface active agent such as a liquid or solid non-ionic surface active agent or may be a solid aniomc surface active agent It is preferred to use the solid aniomc surface active agent in the form of a sodium salt
• compositions for rectal or vaginal administration are preferably supposito ⁇ es which may be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solids at room temperature but liquids at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound
• Liposomes are generally derived from phospho pids or other lipid substances Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used
• the present compositions in hposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like
• the preferred hpids are the phosphohpids and the phosphatidyl chohnes (lecithins), both natural and synthetic
• a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form and with or without a pharmaceutically acceptable excipient.
• a "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat an angiogenic disease (for example, to limit tumor growth or to slow or block tumor metastasis) at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
• Total daily dose of compounds of this invention to be administered locally or systemically to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.01 to 200 mg/kg body weight daily and more usually 1 to 300 mg/kg body weight. If desired, the effective daily dose may be divided into multiple doses for purposes of administration Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
• agents which can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of angiogenic diseases are not limited to those listed above, but include, in principle, any agents useful for the treatment or prophylaxis of angiogenic diseases.
• NMM for 4-methylmorphol ⁇ ne
• EDCI for l-ethyl-3-[3- (d ⁇ methylammo)propyl]-carbod ⁇ m ⁇ de hydrochlo ⁇ de
• HOBT for hydroxybenztriazole
• TFA tor t ⁇ fluoroacetic acid THF for tetrahydrofuran
• DMF dimethylformamide
• R 6 , R 7 , R 8 , R 9 , and Rl° are defined previously unless indicated otherwise Depending on the nature of W, X, Y, Z, R A , R B , R , RD RE RF RG RH R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and Rl°, protection and subsequent deprotection of other reactive groups can be required to successfully complete the described synthetic sequences.
• N-methyl tyrosine was converted into an ester.
• the amino protecting group on tyrosine was removed and the free amine was coupled to leucine.
• the amino protecting group on leucine was removed and the free amine was coupled to lysine.
• the ester on tyrosine was saponified and the carboxylic acid coupled to aspartic acid amide.
• the amino protecting group on lysine was removed and the free amine was acetylated with acetic anhydride.
• the oxygen protecting group on tyrosine was removed by hydrogen gas in the presence of palladium on carbon.
• leucine was converted to leucinal and then was allowed to undergo a reductive amination with phenylalanine
• the amino protecting group was removed with trifluoroacetic acid and the free amine was coupled to lysine.
• the ester was saponified with sodium hydroxide and the carboxylic acid was coupled to aspartic acid.
• the benzyl esters on aspartic acid were removed with hydrogen gas in the presence of palladium on carbon.
• Example IB methyl (25)-3-r4-(benzyloxy)phenvn-2-(methylamino)propanoate
• a solution of the product of example 1A (4.01 g, 10 mmol), in 1,4-dioxane saturated with hydrogen chloride (30 mL) was stirred at ambient temperature for 1 hour, evaporated to dryness, suspended in ethyl ether then concentrated and vacuum dried to give a white solid (3.35 g).
• Example 1C methyl (25)-3-[4-(benzyloxy)phenyll-2-[ ⁇ (25)-2- (tgrt-butoxycarbonyl)aminol-4- methylpentanoyl ⁇ (methyl)aminolpropanoate
• a solution of the product of example IB (3.35 g, 10 mmol), N-(tert- butoxycarbonyl)-L-leucine (2.99 g, 12 mmol), EDCI (2.11 g, 11 mmol), HOBT (1.69 g, 11 mmol) and NMM (1.21 mL, 11 mmol) in CH2CI2 (50 mL) was stirred at 0 °C for 90 minutes, then at ambient temperature for 16 hours, evaporated to dryness, redissolved in ethyl acetate (70 mL) then washed sequentially with brine, 10% aqueous KHSO4, brine, aqueous NaHC03, and brine, dried (
• Example 1C was processed as in example IB to provide the dipeptide.
• Example IE methyl (95, 125, 155)- 15-r4-(benzyloxy)benzyl1-9-r(tgrt-butoxycarbonyl)aminol- 12- lsob ⁇ tyl- 14-methyl-3 , 10,13-trioxo- 1 -phenyl-2-oxa-4, 11,14-triazahexadecan- 16-oate
• Example 1H tgrr-butyl (95.125.155, 185)-9-amino- 18-(aminocarbonyl)- 15-r4-(benzyloxy)benzyl1- 12- isobutyl- 14-methyl-3 ,10,13,16-tetraoxo- 1 -phenyl-2-oxa-4, 11,14,17-tetraazaicosan-20-oate
• the product of example 1G was processed as in example IB to provide the tetrapeptide.
• Example II (95, 125, 155, 185)-9-(acetylamino)- 18-(aminocarbonyl)- 15-r4-(benzyloxy)benzyll- 12- isobutyl- 14-methyl-3 ,10,13.16-tetraoxo- 1 -phenyl-2-oxa-4, 11,14.17-tetraazaicosan-20-oic acid
• a solution of example 1H (0.37 g, 0.43 mmol), acetic anhydride (101 mL, 1.08 mmol) and triethylamine (210mL, 1.5 mmol) in CH2CI2 (6 mL) was stirred at ambient temperature for 48 hours, evaporated to dryness, redissolved in ethyl acetate then washed sequentially with aqueous NaHC ⁇ 3, brine, 10% aqueous KHSO4 and brine, dried (MgS04), and concentrated. The residue was purified by flash chromatography on silica
• N-(tert-Butoxycarbonyl)-N-methyl-L-phenylalanine and L-aspartic acid dibenzyl ester were processed as in examples 1C and IB to provide the dipeptide.
• Example 2B dibenzyl (2S)-2-( f (25)-2-[ ( (25)-2-r(tgrt-butoxycarbonyl)aminol-4- methylpentanoyl ⁇ (methyl)aminol-3-phenylpropanoyl ⁇ amino)butanedioate
• the product of example 2A and N-(tgrt-butoxycarbonyl)-L-leucine were processed s in examples 1C and IB to provide the tripeptide.
• Example 2D dibenzyl (25 -2-(( (2S)-2- ⁇ ((2S)-2-i r(25)-2-(acetylamino)-6-aminohexanoyllamino)-4- methylpentanoyl)(methyl)aminol-3-phenylpropanoyl ) amino)butanedioate
• the product of example 2C was processed as in examples 1C and II to provide the acetylated tetrapeptide.
• Example 2E (2S)-2-(((25 -2-r((25)-2- ⁇ r(2S)-2-(acetylamino)-6-aminohexanoyl]amino)-4- methylpentanoyl)(methyl)amino1-3-phenylpropanoyl 1 amino)butanedioic acid
• the product of example 2D was processed as in Example 1J to provide the title compound.
• Example 3 A methyl (95,125,155)-15-r4-(benzyloxy)benzyll-9-r(tgrt-butoxycarbonyl)aminol-12- isobutyl- 11,14-dimethyl-3 ,10,13-trioxo- 1 -phenyl-2-oxa-4, 11,14-triazahexadecan- 16-oate N-(tert-Butoxycarbonyl)-N-methyl-L-leucine and O-benzyl-L-tyrosine methyl ester are processed as in examples 1C and IB to provide the dipeptide.
• Example 3B (95.125,155)-15-r4-(benzyloxy)benzvn-9-r(tgrt-butoxycarbonyl)aminol-12-isobutyl- 11.14-dimethyl-3,10,13-trioxo-l-phenyl-2-oxa-4,l 1,14-triazahexadecan- 16-oic acid
• the product of example 3A and N-alpha-(tert-butoxycarbonyl)-N-epsilon- (carbonylbenzyloxy)-L-lysine are processed as in examples IC and IF to provide the tripeptide.
• Example 3C dibenzyl (25)-2-( ( (25,55,85)-2-r4-(benzyloxy)benzyl1-8-r(tgrt-butoxycarbonyl)aminol-5- isobutyl-3,6-dimethyl-4,7,14-trioxo-16-phenyl-15-oxa-3,6,13-triazahexadec-l- anoyl ⁇ amino)butanedioate
• the product of example 3B and L-aspartic acid dibenzyl ester are processed as in examples IC and IF to provide the tetrapeptide.
• Example 5A methyl (95.125, 1 5)- 15-benzyl-9-r(tgrt-butoxycarbonyl)amino1- 12-isobutyl-3 , 10-dioxo- 1 - phenyl-2-oxa-4, 11 , 14-triazahexadecan- 16-oate H-Leuy(CH2NH)Phe-OMe prepared as described in Bravo et al. J. Chem. Soc.
• Example 5B (2S)-2- 1 r(25.55.85)-8-(4-aminobutvi)-2-benzyl-5-isobutyl- 12.12-dimethyl-7.10-dioxo- 11 - oxa-3, 6,9-triazatridec- 1-anoyll amino ⁇ butanedioic acid
• the product from example 5 A and L-aspartic acid dibenzyl ester are processed as in examples IC and 1J to provide the title compound.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Ophthalmology & Optometry (AREA)
• Immunology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Rheumatology (AREA)
• Physical Education & Sports Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=22179061

Family Applications (1)

Country Status (4)

Families Citing this family (2)

Family Cites Families (3)

• 1999
  • 1999-05-21 EP EP99925742A patent/EP1077995A1/en not_active Withdrawn
  • 1999-05-21 WO PCT/US1999/011308 patent/WO1999061466A1/en not_active Application Discontinuation
  • 1999-05-21 JP JP2000550870A patent/JP2002516337A/ja not_active Withdrawn
  • 1999-05-21 CA CA002332772A patent/CA2332772A1/en not_active Abandoned

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events