+

WO1999044994A1 - Composes d'acide meta-azacyclique amino benzoique et derives antagonistes de l'integrine - Google Patents

Composes d'acide meta-azacyclique amino benzoique et derives antagonistes de l'integrine Download PDF

Info

Publication number
WO1999044994A1
WO1999044994A1 PCT/US1999/003281 US9903281W WO9944994A1 WO 1999044994 A1 WO1999044994 A1 WO 1999044994A1 US 9903281 W US9903281 W US 9903281W WO 9944994 A1 WO9944994 A1 WO 9944994A1
Authority
WO
WIPO (PCT)
Prior art keywords
added
condition treated
product
reaction mixture
nmr
Prior art date
Application number
PCT/US1999/003281
Other languages
English (en)
Inventor
Thomas E. Rogers
Peter G. Ruminski
Original Assignee
G.D. Searle & Co.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to UA2000095148A priority Critical patent/UA71906C2/uk
Priority to SK1300-2000A priority patent/SK13002000A3/sk
Priority to PL99342726A priority patent/PL342726A1/xx
Priority to BR9908470-8A priority patent/BR9908470A/pt
Priority to APAP/P/2000/001893A priority patent/AP1244A/en
Priority to EEP200000506A priority patent/EE200000506A/xx
Priority to OA1200000238A priority patent/OA11530A/en
Priority to IL13765399A priority patent/IL137653A0/xx
Priority to CA002322207A priority patent/CA2322207A1/fr
Priority to JP2000534538A priority patent/JP2002505323A/ja
Priority to EP99937927A priority patent/EP1060164A1/fr
Priority to KR1020007009774A priority patent/KR20010041584A/ko
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to EA200000804A priority patent/EA200000804A1/ru
Priority to HU0100865A priority patent/HUP0100865A3/hu
Priority to AU32947/99A priority patent/AU753230B2/en
Publication of WO1999044994A1 publication Critical patent/WO1999044994A1/fr
Priority to IS5582A priority patent/IS5582A/is
Priority to NO20004316A priority patent/NO315703B1/no
Priority to HR20000574A priority patent/HRP20000574A2/hr
Priority to BG104740A priority patent/BG104740A/xx

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms

Definitions

  • the present invention relates to pharmaceutical agents (compounds) which are useful as ⁇ v ⁇ 3 integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by a v p3 by inhibiting or antagonizing ⁇ v ⁇ s integrins.
  • Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked ⁇ and ⁇ polypeptide subunits. Currently eleven different ⁇ subunits have been identified and six different ⁇ subunits have been identified. The various ⁇ subunits can combine with various ⁇ subunits to form distinct integrins.
  • the integrin identified as ⁇ v ⁇ 3 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy, including macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis). Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials.
  • ⁇ v ⁇ 3 integrin and other ⁇ v containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules.
  • RGD Arg-Gly-Asp
  • Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors.
  • RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to ⁇ v ⁇ s also bind to ⁇ v ⁇ 5, ⁇ v ⁇ and ⁇ b ⁇ 3 .
  • Antagonism of platelet ⁇ H b ⁇ 3 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans.
  • fibrinogen receptor also known as the fibrinogen receptor
  • Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteoiytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
  • the adhesion receptor integrin ⁇ v ⁇ 3 was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization.
  • Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells.
  • Antagonists of ⁇ v ⁇ 3 inhibit this process by selectively promoting apoptosis of cells in neovasculature.
  • the growth of new blood vessels, or angiogenesis also contributes to pathological conditions such as diabetic retinopathy and macular degeneration (Adonis et al., Amer. J. Ophthal., Vol.
  • ⁇ v ⁇ 3 antagonists would be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571 ).
  • ⁇ v ⁇ 3 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (a loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of ⁇ v ⁇ 3 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413].
  • Antagonism of ⁇ v ⁇ 3 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resoround bottoming activity.
  • antagonists of osteoclast ⁇ v ⁇ 3 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
  • ⁇ v ⁇ 3 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vase. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
  • White Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses ⁇ v ⁇ 3 for entering host cells.
  • the integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit ⁇ v ⁇ 3 would find usefulness as antiviral agents.
  • the present invention relates to the following compounds:
  • R is H or alkyl; or pharmaceutically acceptable salts thereof.
  • the invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including diabetic retinopathy and macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials.
  • the present invention relates to a class of compounds represented by Formulae I-XVI, described above.
  • the invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds described above.
  • the invention also relates to a method of selectively inhibiting or antagonizing the ⁇ v ⁇ 3 integrin and more specifically relates to a method of inhibiting bone resorption, periodontal disease, osteoporosis, humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis, solid
  • tumor growth neoplasia
  • angiogenesis including tumor angiogenesis
  • retinopathy including diabetic retinopathy and macular degeneration
  • arthritis including rheumatoid arthritis
  • smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound described above to achieve such inhibition together with a pharmaceutically acceptable carrier.
  • alkyl or “lower alkyl” refer to a straight chain or branched chain hydrocarbon radicals having from about 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms.
  • alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
  • halo or halogen refers to bromo, chloro, or iodo.
  • haloalkyl refers to alkyl groups as defined above substituted with one or more of the same or different halo groups at one or more carbon atom.
  • haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like.
  • composition as used herein means a product which results from the mixing or combining of more than one element or ingredient.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.
  • terapéuticaally effective amount shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • CH 3 CN acetonitrile
  • CHN analysis carbon/hydrogen/nitrogen elemental analysis
  • CHNCI analysis carbon/hydrogen/nitrogen/chlorine elemental analysis
  • CHNS analysis carbon/hydrogen/nitrogen/sulfur elemental analysis
  • DI water deionized water
  • FAB MS fast atom bombardment mass spectroscopy
  • g gram(s)
  • HOBT 1-hydroxybenzotriazole hydrate
  • KSCN potassium thiocyanate
  • LiOH lithium hydroxide
  • Na 2 SO 4 sodium sulfate
  • NMM N-methylmorpholine
  • NMP N-methyl pyrrolidinone
  • P2O5 phosphorous pentoxide
  • a bond drawn across a bond of a ring can be to any available atom on the ring.
  • pharmaceutically acceptable salt refers to a salt prepared by contacting a compound described above with an acid whose anion is generally considered suitable for human consumption.
  • examples of pharmacologically acceptable salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate salts and the like. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Ber ⁇ e et al.. J Pharm. Sci.. 66(11. 1-19 (1977) for additional examples of pharmaceutically acceptable salts.)
  • compounds of the present invention may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intrape tonally.
  • the compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the ⁇ v ⁇ 3 cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds described above, wherein one or more compounds is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and if desired other active ingredients. More specifically, the present invention provides a method for inhibition of the ⁇ v ⁇ 3 cell surface receptor.
  • the present invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget's disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating diabetic retinopathy and macular degeneration, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis.
  • the compounds described above can be used in the treatment of patients suffering from the above pathological conditions.
  • selection of the most appropriate compound of the invention is within the ability of one with ordinary skill in the art and will depend on a variety of factors including assessment of results obtained in standard assay and animal models.
  • Treatment of a patient afflicted with one of the pathological conditions comprises administering to such a patient an amount of compound described above which is therapeutically effective in controlling the condition or in prolonging the survivability of the patient beyond that expected in the absence of such treatment.
  • inhibitory of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination
  • the compounds of the invention can be used in a variety of biological, prophylactic or therapeutic areas. It is contemplated that these compounds are useful in prevention or treatment of any disease state or condition wherein the ⁇ v ⁇ 3 integrin plays a role.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 1000 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions, and more preferably from about 0.01 mg to about 100 mg per kg of body weight per day.
  • the active ingredient administered by injection is formulated as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • a suitable daily dose would typically be about 0.01 to 10 mg kg body weight injected per day in multiple doses depending on the factors listed above.
  • the compounds in a therapeutically effective amount are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
  • compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
  • Scheme I illustrates methodology useful for preparing the tetrahydropyrimidinobenzoic acid portion of the present invention which can be coupled to a gly- ⁇ -amino acid ester.
  • 3,5- dihydroxybenzoic acid is converted to 3-amino-5-hydroxy-benzoic acid using the procedure described in Austr. J. Chem.. 34 (6), 1319-24 (1981 ).
  • the product is reacted with ammonium thiocyanate in hot dilute hydrochloric acid to give 3-thiourea-5-hydroxybenzoic acid after normal work-up.
  • This thiourea intermediate is converted to the S-methyl derivative by reaction with methyl iodide in ethanol at reflux.
  • the HCI salt may be obtained by lyophilizing from dilute hydrochloric acid.
  • the product may be isolated from the original reaction mixture by removing volatiles and concentrating.
  • the resulting product is taken up in water and pH adjusted to about 5-7 where zwitterionic product precipitates and is isolated by filtration.
  • the HCI salt may be obtained as previously stated or by simply dissolving in dilute hydrochloric acid and concentrating to a solid and drying.
  • Scheme IA illustrates methodology useful for preparing the tetrahydropyrimidinobenzoic acid portion of the present invention which can be coupled to a gly- ⁇ -amino acid ester.
  • Scheme IA 3- diamino-2-hydroxypropane is reacted with carbon disulfide in an appropriate solvent such as ethanol - water, refluxed, cooled, hydrochloric acid added, refluxed again, cooled and the product, 5- hydroxytetrahydropyrimidine-2-thione harvested by filtration and dried.
  • This cyclic thiourea intermediate is converted to the S-methyl derivative by reaction of thione and methyl iodide in ethanol at reflux.
  • 2-methylthioether-5-hydroxypyhmidine hydroiodide is readily isolated by removing volatiles at reduced pressure.
  • 2-methylthioether-5- hydroxypyrimidine hydroiodide in methylene chloride : DMA (about 10:1 ) and an equivalent of triethylamnine are cooled to about ice-bath temperature and an equivalent of di-tert-butyl dicarbonate (BOC anhydride) added.
  • BOC anhydride di-tert-butyl dicarbonate
  • 3-amino-5-hydroxy- benzoic acid is converted to 3-amino-5-hydroxy- benzoic acid using the procedure of Aust. J. Chem., 34 (6), 1319-24 (1981 ).
  • the final desired product, 3-hydroxy-5-[(5-hydroxy-1 ,4,5,6- tetrahydro-2-pyrimidinyl)amino]benzoic acid hydrochloride salt is prepared by reacting BOC-2-methylthioether-5-hydroxypyrimidine and 3-amino-5- hydroxy-benzoic acid in hot DMA. Upon cooling, a precipitate forms and zwitterionic product isolated by filtration.
  • the HCI salt can be obtained by lyophilizing from dilute hydrochloric acid, for example.
  • Ya ⁇ d X are halo groups
  • 3-iodo-5-chlorosalicylaldehyde may be prepared by reacting 5-chlorosalicylaldehyde with N-iodosuccinimide in DMF and subjecting the reaction mixture to usual work-up conditions.
  • 3-iodo-5- bromosalicylaldehyde may be prepared by reacting 5- bromosalicylaldehyde in acetonitrile with potassium iodide and chloramine T. Work-up gives a material that when treated with hexanes gives the desired 3-iodo-5-chlorosalicylaldehyde.
  • Coumarins are readily prepared from salicylaldehydes using a modified Perkin reaction (e.g., Vogel's Textbook of Practical Organic Chemistry, 5th Ed., 1989, p. 1040, ) .
  • the halo-substituted coumarins are converted to 3-aminohydrocoumarins (see J.G. Rico. Tett. Let.. 1994. 35, 6599-6602) which are readily opened in acidic alcohol to give 3-amino-3- (3,5-halo-2-hydroxy)phenyl propanoic acid esters.
  • 3-amino-3-(3,5-halo-2-hydroxy)phenyl propanoic acid esters are converted to N-gly-3-amino-3-(3,5-halo-2-hydroxy)phenyl propanoic acid esters by reaction of Boc-N-gly-N-hydroxysuccinimide to give Boc-N-gly- 3- amino-3-(3,5-halo-2-hydroxy)phenyl propanoic acid esters that are converted to HX salts of N-gly- 3-amino-3-(3,5-halo-2-hydroxy)phenyl propanoic acid esters (wherein X is a halo group) for example, by removal of the BOC-protecting group using HCI in ethanol.
  • amino acid compounds used in preparing the compounds of the present invention can be prepared according to the procedures set forth
  • Y and X are halo groups
  • the product is purified by prep hplc and the ester hydrolyzed to the acid by treating with a base, such as LiOH in a suitable solvent (dioxane/water or acetonitrile/water).
  • a suitable acid such as TFA can be used.
  • the product is isolated by prep hplc or by isolating the zwitterion at pH 5-7 and converting to the desired salt by standard procedures.
  • the temperature was maintained below 0°C overnight.
  • the reaction mixture was concentrated to about one-half its original volume and partitioned between EtOAc (3 L) and water (2L).
  • the organic layer was washed with aqueous HCI (3 x 1 L 0.5 N HCI).
  • the pH of the combined aqueous layers was adjusted to about 7 by addition of 10% aqueous NaOH and extracted with methylene chloride (3 x 2L).
  • the combined organic layers were dried (MgSO 4 ), filtered, and 4M HCI in dioxane (210 mL) added with stirring. Upon completion of precipitation the solid was removed by filtration.
  • the filtrate was concentrated to a small volume and methyl t-butyl ether added.
  • the solid obtained was combined with the initially formed solid and the combined product was washed with
  • N-t-Boc-glycine N-hydroxysuccinimide ester (Sigma, 15.0 g, 0.055 mol), dry DMF (Aldrich Sure Seal, 200 mL) and the product from Step 2 (21.67 g, 0.055 mol) under an inert atmosphere (Ar).
  • the reaction mixture was cooled to approximately 0°C (salt-ice bath) and N- methylmorpholine (5.58 g, 0.056 mole) and a catalytic amount of DMAP added and the reaction allowed to proceed overnight.
  • the reaction mixture was concentrated to a slush, and partitioned between EtOAc (0.4L) and aqueous base (2 x 0.2 L, aqueous saturated NaHCOs).
  • the organic layer was washed consecutively with aqueous citric acid (2 x 0.2 L, 10% w/v), again with aqueous sodium bicarbonate (2 x 0.2 L), brine and dried (Na 2 S0 4 ). Volatiles were removed under vacuum at 55°C to give an oil (22.5 g, 92% yield) that solidified on standing.
  • Step 3 The product obtained in Step 3 was de-protected to give the amine hydrochloride salt using the following procedure.
  • N-t-Boc-glycine N-hydroxysuccinimide ester (Sigma, 2.72 g, 0.010 mol)
  • dry THF Aldrich Sure Seal, 50 mL
  • the product from Step 3 (3.10 g, 0.01 mole, vacuum desiccated overnight over P 2 0 5 ) under an inert atmosphere (Ar).
  • the reaction mixture was cooled to approximately OX (salt-ice bath) and triethylamine (1.01 g, 0.010 mole) was added. The reaction was allowed to proceed overnight.
  • the reaction mixture was concentrated to a semi-solid and worked up in a fashion similar to Example A, Step 3. Volatiles were removed from the organic layer under vacuum at 55X to give an oil (4 g, 83% yield) that solidified on standing.
  • Step 4 The product obtained in Step 4 was de-protected to give the amine hydrochloride salt using the following procedure.
  • N-t-Boc-glycine N-hydroxysuccinimide ester (Sigma, 8.1 g, 0.030 mol)
  • dry DMF Aldrich Sure Seal, 50 mL
  • the product of Step 3 (12 g, 0.03 mole, vacuum desiccated overnight over P 2 O 5 ) under an inert atmosphere (Ar).
  • the reaction mixture was cooled to approximately OX (salt-ice bath) and N-methyl morpholine (3.03 g, 0.030 mole) and catalytic DMAP added. The reaction was allowed to proceed overnight warming to room temperature.
  • Step 4 The product obtained in Step 4 was deprotected to give the amine hydrochloride salt using the following procedure.
  • N-lodosuccinimide 144.0 g, 0.641 mole was added to a solution of 5-chlorosalicylaldehyde (100 g, 0.638 mole) in dimethylformamide (400 mL). The reaction mixture was stirred for 2 days at room temperature. Additional N-iodosuccinimide (20.0 g) was added and the stirring was continued for an additional 2 days.
  • reaction mixture was diluted with ethyl acetate (1 L), washed with hydrochloric acid (300 mL, 0.1 N), water (300 mL), sodium thiosulfate (5%, 300 mL), brine (300 mL), dried (MgSO 4 ) and was concentrated to dryness to afford the desired aldehyde (162 g, 90% yield) as a pale yellow solid.
  • Lithium hexamethyldisilazane (21.62 mL, 1M, 21.62 mmol) was added to a solution of 6-chloro-8-iodocoumarin (6.63 g, 21.62 mmol) in tetrahydrofuran (100 mL) at -78X.
  • the reaction mixture was stirred at this 5 temperature for 30 minutes, then at OX for 1 hour.
  • Acetic acid (1.3 g, 21.62 mmol) was added to the reaction mixture.
  • the reaction mixture was poured into ethyl acetate (300 mL) and saturated sodium carbonate (200 mL) solution.
  • Ethanol (375 mL) and deionized water (375 mL) were added to a 2L 3-neck round bottom flask fitted with a mechanical stirrer, Claisen adapter, addition funnel, reflux condenser and thermocouple.
  • 1 ,3- diamino-2- hydroxypropane (125.04 g, 1.39 mol) (Aldrich) was added to the reaction flask and stirred to dissolve.
  • Carbon disulfide (84 mL , 1.39 mol) was added in a drop-wise fashion via addition funnel at 25-33X over a 35 minute period to afford a milky-white mixture. The temperature was maintained with an ice bath.
  • the reaction mixture was refluxed at 73.4X for two hours to afford a yellow solution.
  • the reaction mixture was cooled with an ice bath to 25X and concentrated HCI (84 mL) was added in drop- wise fashion while maintaining the temperature at 25-26X.
  • the reaction mixture was refluxed for 21 hours at 78.4X.
  • the reaction solution was cooled to 2X and product collected via vacuum filtration.
  • the white solid was washed 3 times with ice bath chilled ethanol : water (1 :1 ) (50 mL) and dried in vacuo at 40X to afford 5-hydroxytetrahydropyrimidine-2-thione (63.75 g, 34.7% yield) as a white solid.
  • Step 1 absolute ethanol (570 mL), and methyl iodide (45 mL , 0.72 mol) were added to a 2 L round bottom flask fitted with a mechanical strirrer and thermocouple. The reaction mixture was refluxed at 78X for 5 hours and then cooled to room temperature. The reaction mixture was concentrated
  • 2-Methyl thioether-5-hydroxypyrimidine hydroiodide 150.81 g, 0.55 mol
  • methylene chloride 530 mL
  • dimethylacetamide 53 mL
  • triethylamine 76.7 mL, 0.55 mol
  • the mixture was cooled with an ice bath and di- tert -butyl dicarbonate (120.12 g, 0.55 mol) was added at 4X.
  • the reaction mixture was heated at 42.5X for 18 hours to afford a light yellow solution.
  • reaction solution was transferred to a 2L separatory funnel and washed 3 times with DI water (200 mL), dried with MgS0 4 , filtered and concentrated in vacuo to afford Boc-2-methylthioether-5-hydroxypyrimidine (134.6 g, 99.35% yield) as a light yellow viscous oil. MS and H NMR were consistent with the desired structure.
  • Boc-2-methylthioether-5-hydroxypyrimidine (50.3 g, 0.204 mol), 3- amino-5-hydroxybenzoic acid (Aust. J. Chem. (1981 ) 34(6), 1319-24) (25.0 g, 0.1625 mole) and 50 mL anhydrous DMA were heated at 100X with stirring for 2 days. A slurry precipitate resulted. The reaction was cooled to room temperature and the precipitate was filtered, washed with CH 3 CN, then ethyl ether and dried. This solid was slurried in H 2 O and acidified with concentrated HCI resulting in a solution. This was frozen and lyophilized to yield the desired product as a white solid (14.4 g). MS and 1 H NMR were consistent with the desired structure.
  • the mixture was cooled to 50X before charging tert-butyl bromoacetate (488 g, 369 mL, 2.5 mol) via 50 mL syringe and syringe pump (delivery set to 4.1 mlJminutes) over 1.5 hours. Reaction temperature of 50° +/- 5X was maintained throughout the addition. The reaction mixture was allowed to stir at 50X for one hour after the addition was complete. Subsequently, the mixture was allowed to cool to 25X and the precipitated product allowed to settle. The THF mother liquor was decanted into a 2-L round bottom flask using a coarse fritted filter stick and partial vacuum transfer (20 mm Hg). This removed about 65% of the THF from the mixture. 1- Methyl-2-pyrrolidinone (NMP, 800 mL) was added and agitation resumed for 5 minutes. The reaction mixture can be filtered to remove any remaining zinc. Analysis indicated a titer of desired Reformatsky reagent
  • the solid reagent can be isolated by filtration from the original reaction mixture.
  • the cake can be washed with THF until a white solid is obtained and dried under N 2 to obtain the desired product as a mono THF solvate that may be stored at - 20X (desiccated) for extended periods. Typical recoveries are 85-90%.
  • Potassium carbonate (powder, oven dried at 100X under vacuum, 8.82 g, 60 mmoles) was added to a solution of 3,5-dichlorosalicylaldehyde (11.46 g, 60 moles) in DMF (40 mL) at room temperature to give a bright yellow slurry.
  • MEMCI (neat, 7.64 g, 61 mmoles) was then added while maintaining the bath temperature at 20X. The mixture was then stirred at 22X for 6 hours and MEMCI (0.3 g, 2.4 mmoles) was added. The mixture was stirred for another 0.5 hour and the reaction mixture poured into cold water (200 mL) to precipitate the product.
  • the Boc-protected glycine amide prepared in Step 4 (27.0 g, 0.062 mole) was dried overnight over P 2 O 5 and NaOH pellets. The solid was dissolved in dioxane (40 mL) and the solution cooled to OX. An equivalent volume of 4N HCI/dioxane (0.062 mole) was added and the reaction was run for 2 hours. At this point the conversion was 80% by RPHPLC. The reaction mixture was allowed to warm to room temperature
  • Potassium carbonate (powder, oven dried at 100X under vacuum, 22.1g, 0.16 moles) was added to a solution of 3-chloro-5- bromosalicylaldehyde (35.0 g, 0.15 moles) in DMF (175 ml) at room temperature to give a bright yellow slurry.
  • MEMCI (neat, 25.0 g, 0.2 moles) was then added while maintaining the bath temperature at 20X. The mixture was then stirred at 22X for 6 hours and was poured into DI water (1200mL) to precipitate the product. The slurry was filtered on a pressure filter and the cake was washed with DI water (2 x 400 mL) and was dried under N 2 /vacuum to afford the product (46.
  • Example I The above compound was prepared according to the procedures outlined in Example I, Step 4 and Step 5 where an equivalent quantity of the intermediate prepared in Step 5 as the free base is substituted fin Example I, Step 4.
  • N-lodosuccinimide 144.0 g, 0.641 mole was added to a solution of 5-chlorosalicylaldehyde (100 g, 0.638 mole) in dimethylformamide (400 mL). The reaction mixture was stirred for 2 days at room temperature. Additional N-iodosuccinimide (20.0 g) was added and stirring was continued for additional 2 days.
  • reaction mixture was diluted with ethyl acetate (1L), washed with hydrochloric acid (300 mL, 0.1 N), water (300 mL), sodium thiosulfate (5%, 300 mL), brine (300 mL), dried (MgSO 4 ) and was concentrated to dryness to afford the desired aldehyde as a pale yellow solid (162 g, 90% yield).
  • Example I The above compound is prepared according to the procedure of Example I by substituting an equivalent amount of 3-iodo-5- bromosalicylaldehyde prepared in Example F, Step 1 for 3,5- dichlorosalicylaldehyde in Example I, Step 2 A.
  • Example B (0.58 g, 0.0014 mole), triethylamine (0.142 g, 0.0014 mole), DMAP (17 mg), and anhydrous DMA (4 ml) was added EDCI (0.268 g, 0.0014 mole) at ice bath temperature. The reaction was stirred overnight at room temperature. The resulting ester intermediate was isolated by reverse phase preparatory HPLC. To this ester in H 2 O (10 ml) and CH 3 CN (5 ml) was added LiOH (580 mg, 0.0138 mole). After stirring at room temperature for 1 hour, the pH was lowered to 2 with TFA and the product was purified by reverse phase preparatory HPLC to yield (after lyophilization) the desired product as a white solid (230 mg). MS and 1 H NMR were consistent with the desired structure.
  • Example 2 The above compound was prepared according to the methodology of Example 1 , substituting an equivalent amount of the product from Example A for the product from Example B. The yield, after lyophiiization was 320 mg of as a white solid. MS and 1 H NMR were consistent with the desired structure.
  • Example 1 The above compound was prepared according to the methodology of Example 1 , substituting an equivalent amount of the product from Example F for the product from Example B. The yield (after lyophiiization) was 180 mg as a white solid. MS and 1 H NMR were consistent with the desired structure.
  • Example 2 The above compound was prepared according to the methodology of Example 1 , substituting an equivalent amount of the product of Example D for the product of Example B. The yield (after lyophiiization) was 180 mg as a white solid. MS and 1 H NMR were consistent with the desired structure.
  • Example 2 The above compound was prepared according to the methodology of Example 1, substituting an equivalent amount of the product from Example E for the product from Example B. The yield (after lyophiiization) was 250 mg as a white solid. MS and 1 H NMR were consistent with the desired structure.
  • Example 2 The above compound was prepared according to the methodology of Example 1 , substituting an equivalent amount of the product from Example C for the product from Example B. The yield (after lyophiiization) was 220 mg as a white solid. MS and ⁇ NMR were consistent with the desired product.
  • Example H To the product from Example H (7.8 g, 0.027 mole) dissolved in anhydrous DMA (50 mL) in a flame dried flask under N 2 and at ice bath temperature was slowly added isobutylchloroformate (3.7 g, 0.027 mole) followed by N-methylmorphoiine (2.73 g, 0.027 mole). The solution was stirred at ice bath temperature for 15 minutes. To the reaction mixture was then added the product from Example L (10.0 g, 0.024 mole) at ice bath temperature followed by N-methylmorpholine (2.43 g, 0.024 mole). The reaction was then stirred at room temperature overnight. The resulting ester intermediate was isolated by reverse phase prep HPLC.
  • Step A To the product from Example H (9.92 g, 0.0345 mole) dissolved in anhydrous DME (200 mL) is added N-methylmorpholine (4.0 mL, 0.0362 mole). The reaction mixture was cooled to -5X (salt-ice bath). Isobutylchloroformate, IBCF (4.48 mL, 4.713 g, 0.0345 mole) was added over one minute and the reaction mixture stirred at ice bath temperature for 12 minutes. To the reaction mixture was then added the product from Example I (11.15 g, 0.030 mole) at ice bath temperature followed by N- methylmorpholine (4.0 mL, 0.0362 mole).
  • the product produced in Step A (about 11 g) was dissolved in dioxane : water and the pH of the solution adjusted to approximately 11.5 (pH meter) by the addition of 2.5 N NaOH.
  • the reaction mixture was stirred at room temperature. Periodically, the pH was re-adjusted to > 11 by further addition of base. After 2-3 hours the conversion of ester to acid was deemed complete by RPHPLC.
  • the pH of the reaction mixture was adjusted to about 6 and a viscous oil precipitated from solution. The oil was isolated by decantation and washed with hot water (200 mL). The resulting aqueous mixture was allowed to cool and the solid was collected by filtration to yield The above compound (2.6 g after lyophiiization from HCI solution). The residue, which was a dark viscous oil was treated with hot water to give on cooling a tan powder (4.12 g after lyophiiization from HCI solution). MS and 1 H NMR were consistent with the desired structure.
  • Step 2 The product of Step 2 was dissolved in a suitable solvent
  • Example 8 The above compound was prepared using the procedure of Example 8 substituting the product of Example N for the product of Example I in Example 8, Step A.
  • the product was isolated by prep RPHPLC and lyophilized to give the desired product as a TFA salt.
  • Example 8 The above compound was prepared using essentially the procedures of Example 8 and substituting the product of Example M for the product of Example I in Example 8, Step A.
  • the product was isolated by preparatory RPHPLC and lyophilized to give the desired product as a TFA salt.
  • Example 8 The above compound was prepared using the procedures of Example 8 and substituting the product of Example P for the product of Example I in Example 8, Step A.
  • the product is isolated by prep RPHPLC and lyophilized to give the desired product as a TFA salt.
  • Step 6 A solution of m-(5-hydroxypyrimidino)hippuric acid (3.74 g, 12.98 mmol) in dimethylacetamide (25 mL) was heated until all the material had dissolved. This was then cooled to OX and isobutylchloroformate (1.68 mL) was added in one portion followed by N-methylmorpholine (1.45 mL). After 10 minutes, ethyl 3-(N-gly)-amino-3-(3,5-diiodo-2-hydroxyphenyl)- propionate hydrochloride (6.0 g, 10.82 mmol) was added in one portion followed by N-methylmorpholine (1.45 mL). The reaction mixture was stirred for 18 hours at room temperature.
  • reaction mixture was concentrated, the residue dissolved in tetrahydrofuran/water (1 :1 , 20mL), and was chromatographed (reverse phase, 95:5 water: acetonitrile over 60 minutes to 30:70 water: acetonitrile containing 0.1 % TFA). The combined fractions were concentrated. The residue was dissolved in acetonitrile water and lithium hydroxide was added until basic. The solution was stirred for 2 hours. The reaction mixture was concentrated and was
  • Human vitronectin receptor ( ⁇ v ⁇ s) was purified from human placenta as previously described [Pytela et al., Methods in Enzvmolo ⁇ v. 1 4:475- 489 (1987)]. Human vitronectin was purified from fresh frozen plasma as previously described [Yatohgo et al., Cell Structure and Function. 13:281 - 292 (1988)]. Biotinylated human vitronectin was prepared by coupling NHS-biotin from Pierce Chemical Company (Rockford, IL) to purified vitronectin as previously described [Charo et al., J. Biol. Chem., 266(3):1415-1421 (1991 )].
  • Assay buffer, OPD substrate tablets, and RIA grade BSA were obtained from Sigma (St. Louis, MO).
  • Anti-biotin antibody was obtained from Calbiochem (La Jolla, CA). Linbro microtiter plates were obtained from Flow Labs (McLean, VA).
  • ADP reagent was obtained from Sigma (St. Louis, MO).
  • TBS +++ /BSA as the diluent.
  • This premixing of labeled ligand with test (or control) ligand, and subsequent transfer of 50 L aiiquots to the assay plate was carried out with a CETUS Propette robot; the final concentration of the labeled ligand was 1 nM and the highest concentration of test compound was 1.0 x 10 " M.
  • the competition occurred for two hours after which all wells were washed with a plate washer as before.
  • Affinity purified horseradish peroxidase labeled goat anti-biotin antibody was diluted 1 :3000 in TBS +++ /BSA and 125 L were added to each well.
  • the plates were washed and incubated with OPD/H 2 O substrate in 100 mM/L Citrate buffer, pH 5.0.
  • the plate was read with a microtiter plate reader at a wavelength of 450 nm and when the maximum-binding control wells reached an absoround bottomance of about 1.0, the final A 450 were recorded for analysis.
  • the data were analyzed using a macro written for use with the EXCEL spreadsheet program.
  • the mean, standard deviation, and %CV were determined for duplicate concentrations.
  • the mean A 450 values were normalized to the mean of four maximum-binding controls (no competitor added)(B-MAX).
  • Example 1 which is a potent ⁇ v ⁇ 3 antagonist (IC 50 in the range 3-10 nM) was included on each plate as a positive control.
  • Human fibrinogen receptor ( ⁇ n b ⁇ 3) was purified from outdated platelets. (Pytela, R., Pierschbacher, M.D., Argraves, S., Suzuki, S., and Rouslahti, E. "Arginine-Glycine-Aspartic acid adhesion receptors", Methods in Enzvmology 144(1987):475-489.) Human vitronectin was purified from fresh frozen plasma as described in Yatohgo, T., Izumi, M., Kashiwagi, H., and Hayashi, M., "Novel purification of vitronectin from human plasma by heparin affinity chromatography," Cell Structure and Function 13(1988):281-292.
  • Biotinylated human vitronectin was prepared by coupling NHS-biotin from Pierce Chemical Company (Rockford, IL) to purified vitronectin as previously described.
  • NHS-biotin from Pierce Chemical Company (Rockford, IL)
  • purified vitronectin as previously described.
  • Assay buffer, OPD substrate tablets, and RIA grade BSA were obtained from Sigma (St. Louis, MO).
  • Anti-biotin antibody was obtained from Calbiochem (La Jolla, CA). Linbro microtiter plates were obtained from Flow Labs (McLean, VA).
  • ADP reagent was obtained from Sigma (St. Louis, MO).
  • the diluted receptor was immediately transferred to Linbro microtiter plates at 100 ⁇ Uwell (100 ng receptor/well). The plates were sealed and incubated overnight at 4X to allow the receptor to bind to the wells. All remaining steps were at room temperature. The assay plates were emptied and 200 ⁇ L of 1 % RIA grade BSA in TBS +++ (TBS +++ /BSA) were added to block exposed plastic surfaces. Following a 2 hour incubation, the assay plates were washed with TBS +++ using a 96 well plate washer.
  • Affinity purified horseradish peroxidase labeled goat anti-biotin antibody was diluted 1 :3000 in TBS +++ /BSA and 125 ⁇ L were added to each well. After 30 minutes, the plates were washed and incubated with ODD/H 2 O 2 substrate in 100 mM/L citrate buffer, pH 5.0. The plate was read with a microtiter plate reader at a wavelength of 450 nm and when the maximum-binding control wells reached an absoround bottomance of about 1.0, the final A450 were recorded for analysis. The data were analyzed using a macro written for use with the EXCELTM spreadsheet program. The mean, standard deviation, and %CV were determined for duplicate concentrations.
  • the mean A 450 values were normalized to the mean of four maximum-binding controls (no competitor added)(B-MAX).
  • the normalized values were subjected to a four parameter curve fit algorithm, [Robard et al., Int. Atomic Energy Agency. Vienna, pp 469 (1977)], plotted on a semi-log scale, and the computed concentration corresponding to inhibition of 50% of the maximum binding of biotinylated vitronectin (IC50) and corresponding R 2 was reported for
  • Healthy aspirin free donors were selected from a pool of volunteers.
  • the harvesting of platelet rich plasma and subsequent ADP induced platelet aggregation assays were performed as described in Zucker, M.B., "Platelet Aggregation Measured by the Photometric Method", Methods in Enzvmoloov 169(1989):117-133.
  • Standard venipuncture techniques using a butterfly allowed the withdrawal of 45 mL of whole blood into a 60 mL syringe containing 5 mL of 3.8% trisodium citrate.
  • the anti-coagulated whole blood was transferred to a 50 mL conical polyethylene tube.
  • the blood was centrifuged at room temperature for 12 minutes at 200 mg to sediment non-platelet cells.
  • Platelet rich plasma was removed to a polyethylene tube and stored at room temperature until used. Platelet poor plasma was obtained from a second centrifugation of the remaining blood at 2000 xg for 15 minutes. Platelet counts are typically 300,000 to 500,000 per microtiter. Platelet rich plasma (0.45 mL) was aliquoted into siliconized cuvettes and stirred (1100 rpm) at 37X for 1 minute prior to adding 50 uL of pre-diluted test compound. After 1 minute of mixing, aggregation was initiated by the addition of 50 uL of 200 uM ADP. Aggregation was recorded for 3 minutes in a Payton dual channel aggregometer (Payton Scientific, Buffalo, NY).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Oncology (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)
  • Indole Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule (1) ainsi que des sels pharmaceutiquement acceptables et des isomères de ces composés convenant comme antagonistes de la αvβ3.
PCT/US1999/003281 1998-03-04 1999-02-22 Composes d'acide meta-azacyclique amino benzoique et derives antagonistes de l'integrine WO1999044994A1 (fr)

Priority Applications (19)

Application Number Priority Date Filing Date Title
EP99937927A EP1060164A1 (fr) 1998-03-04 1999-02-22 Composes d'acide meta-azacyclique amino benzoique et derives antagonistes de l'integrine
PL99342726A PL342726A1 (en) 1998-03-04 1999-02-22 Metha-azacyclic compounds of aminobenzoic acid and their derivatives constituting antagonists of integrins
BR9908470-8A BR9908470A (pt) 1998-03-04 1999-02-22 Composto, composição farmacêutica, e, processo para tratar condições mediadas pela inegrina avb3 em um mamìfero em necessidade de tal tratamento
APAP/P/2000/001893A AP1244A (en) 1998-03-04 1999-02-22 Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists.
EEP200000506A EE200000506A (et) 1998-03-04 1999-02-22 Meta-asatsüklilised aminobensoehappeühendid ja nende derivaadid integriini antagonistidena
OA1200000238A OA11530A (en) 1998-03-04 1999-02-22 Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists.
IL13765399A IL137653A0 (en) 1998-03-04 1999-02-22 Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists
CA002322207A CA2322207A1 (fr) 1998-03-04 1999-02-22 Composes d'acide meta-azacyclique amino benzoique et derives antagonistes de l'integrine
JP2000534538A JP2002505323A (ja) 1998-03-04 1999-02-22 インテグリンアンタゴニストであるメタ‐アザサイクリックアミノ安息香酸化合物類及びその誘導体
UA2000095148A UA71906C2 (en) 1998-03-04 1999-02-22 Meta-azacyclic compounds of aminobenzoic acid and derivatives thereof being integrin inhibitors
SK1300-2000A SK13002000A3 (sk) 1998-03-04 1999-02-22 Deriváty meta-azacyklickej aminobenzoovej kyseliny a ich deriváty, ktoré sú antagonisty integrínu
KR1020007009774A KR20010041584A (ko) 1998-03-04 1999-02-22 인티그린 길항제로 사용되는 메타-질소치환고리형 벤조산화합물 및 이의 유도체
EA200000804A EA200000804A1 (ru) 1998-03-04 1999-02-22 Мета-азациклические соединения аминобензойной кислоты и их производные, являющиеся ингибиторами интегрина
HU0100865A HUP0100865A3 (en) 1998-03-04 1999-02-22 Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists, pharmaceutical compositions comprising thereof and their use
AU32947/99A AU753230B2 (en) 1998-03-04 1999-02-22 Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists
IS5582A IS5582A (is) 1998-03-04 2000-08-04 Meta-asahringamínóbensósýrusambönd og afleiður þeirra reynast mótlyf við integríni.
NO20004316A NO315703B1 (no) 1998-03-04 2000-08-30 Meta azasykliske aminobenzosyreforbindelser og derivater derav som er integrinatantagonister
HR20000574A HRP20000574A2 (en) 1998-03-04 2000-09-01 Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists
BG104740A BG104740A (en) 1998-03-04 2000-09-01 Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3427098A 1998-03-04 1998-03-04
US09/034,270 1998-03-04

Publications (1)

Publication Number Publication Date
WO1999044994A1 true WO1999044994A1 (fr) 1999-09-10

Family

ID=21875345

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/003281 WO1999044994A1 (fr) 1998-03-04 1999-02-22 Composes d'acide meta-azacyclique amino benzoique et derives antagonistes de l'integrine

Country Status (29)

Country Link
EP (1) EP1060164A1 (fr)
JP (1) JP2002505323A (fr)
KR (1) KR20010041584A (fr)
CN (1) CN1214011C (fr)
AP (1) AP1244A (fr)
AR (1) AR018139A1 (fr)
AU (1) AU753230B2 (fr)
BG (1) BG104740A (fr)
BR (1) BR9908470A (fr)
CA (1) CA2322207A1 (fr)
EA (1) EA200000804A1 (fr)
EE (1) EE200000506A (fr)
GE (1) GEP20033118B (fr)
HR (1) HRP20000574A2 (fr)
HU (1) HUP0100865A3 (fr)
ID (1) ID25591A (fr)
IL (1) IL137653A0 (fr)
IS (1) IS5582A (fr)
MY (1) MY123908A (fr)
NO (1) NO315703B1 (fr)
NZ (1) NZ506598A (fr)
OA (1) OA11530A (fr)
PL (1) PL342726A1 (fr)
SK (1) SK13002000A3 (fr)
TR (1) TR200002542T2 (fr)
UA (1) UA71906C2 (fr)
WO (1) WO1999044994A1 (fr)
YU (1) YU52000A (fr)
ZA (1) ZA994406B (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
WO2004060376A1 (fr) * 2002-12-20 2004-07-22 Pharmacia Corpration Isomere r de composes d'acides amines beta en tant que derives antagonistes du recepteur des integrines
US6921767B2 (en) * 2000-06-15 2005-07-26 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
EP1904468A2 (fr) * 2005-06-10 2008-04-02 Bipar Sciences, Inc. Modulateurs de parp et traitement du cancer
US8313729B2 (en) 2007-03-01 2012-11-20 Medibeacon, LLC Integrated photoactive small molecules and uses thereof
US8716226B2 (en) 2012-07-18 2014-05-06 Saint Louis University 3,5 phenyl-substituted beta amino acid derivatives as integrin antagonists
US9085606B2 (en) 2012-07-18 2015-07-21 Saint Louis University Beta amino acid derivatives as integrin antagonists
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
US10035778B2 (en) 2015-12-30 2018-07-31 Saint Louis University Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
WO2021230325A1 (fr) 2020-05-14 2021-11-18 宇部興産株式会社 Dérivé de 1,4,5,6-tétrahydropyrimidine-2-amine
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes
WO2023085396A1 (fr) 2021-11-12 2023-05-19 Ｕｂｅ株式会社 Composition pharmaceutique pour le traitement ou la prévention du syndrome de l'alport

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4792124B1 (ja) * 2010-11-15 2011-10-12 エフイートレード株式会社 車両用保護フィルムの型取り方法、及び、車両用保護フィルムの製造方法
US9856201B2 (en) * 2014-06-04 2018-01-02 Monsanto Technology Llc 3,6-dichlorosalicylic acid compounds and related synthetic processes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FIELDS,G.B.: "Integrins: cell adhesion molecules in cancer", EXP.OPIN.THER.PATENTS, vol. 8, no. 6, August 1998 (1998-08-01), LONDON, pages 633 - 644, XP002105988 *
HONG,H. ET AL.: "Discovery of HIV-1 Integrase Inhibitors by Pharmacophore Searching", J.MED.CHEM., vol. 40, no. 6, 1997, WASHINGTON, pages 930 - 936, XP002105987 *
NICKLAUS,M.C. ET AL.: "HIV-1 Integrase Pharmacophore: Discovery of Inhibitors through Three-Dimensional Database Searching", J.MED.CHEM., vol. 40, no. 6, 1997, WASHINGTON, pages 920 - 929, XP002105986 *
POMMIER,Y. ET AL.: "HIV-1 Integrase as a target for antiviral drugs", ANTIVIRAL CHEM.CHEMOTHER., vol. 8, no. 6, 1997, AMSTERDAM, pages 463 - 483, XP002105985 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6780874B2 (en) 2000-04-17 2004-08-24 Celltech R & D Limited Enamine derivatives
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6921767B2 (en) * 2000-06-15 2005-07-26 Pharmacia Corporation Cycloalkyl alkanoic acids as integrin receptor antagonists derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
WO2004060376A1 (fr) * 2002-12-20 2004-07-22 Pharmacia Corpration Isomere r de composes d'acides amines beta en tant que derives antagonistes du recepteur des integrines
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
EP1904468A2 (fr) * 2005-06-10 2008-04-02 Bipar Sciences, Inc. Modulateurs de parp et traitement du cancer
EP1904468A4 (fr) * 2005-06-10 2009-04-22 Bipar Sciences Inc Modulateurs de parp et traitement du cancer
US8313729B2 (en) 2007-03-01 2012-11-20 Medibeacon, LLC Integrated photoactive small molecules and uses thereof
US8716226B2 (en) 2012-07-18 2014-05-06 Saint Louis University 3,5 phenyl-substituted beta amino acid derivatives as integrin antagonists
US9085606B2 (en) 2012-07-18 2015-07-21 Saint Louis University Beta amino acid derivatives as integrin antagonists
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
US10328082B2 (en) 2014-05-30 2019-06-25 Pfizer Inc. Methods of use and combinations
US10035778B2 (en) 2015-12-30 2018-07-31 Saint Louis University Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
US10577330B2 (en) 2015-12-30 2020-03-03 Saint Louis University Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
WO2021230325A1 (fr) 2020-05-14 2021-11-18 宇部興産株式会社 Dérivé de 1,4,5,6-tétrahydropyrimidine-2-amine
KR20230011967A (ko) 2020-05-14 2023-01-25 유비이 가부시키가이샤 1,4,5,6-테트라하이드로피리미딘-2-아민 유도체
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes
WO2023085396A1 (fr) 2021-11-12 2023-05-19 Ｕｂｅ株式会社 Composition pharmaceutique pour le traitement ou la prévention du syndrome de l'alport

Also Published As

Publication number Publication date
AP2000001893A0 (en) 2000-09-30
CN1291978A (zh) 2001-04-18
AU753230B2 (en) 2002-10-10
BR9908470A (pt) 2000-12-05
HRP20000574A2 (en) 2001-08-31
IS5582A (is) 2000-08-04
IL137653A0 (en) 2001-10-31
ID25591A (id) 2000-10-19
HUP0100865A3 (en) 2001-11-28
KR20010041584A (ko) 2001-05-25
EA200000804A1 (ru) 2001-04-23
NO315703B1 (no) 2003-10-13
JP2002505323A (ja) 2002-02-19
CA2322207A1 (fr) 1999-09-10
BG104740A (en) 2001-02-28
NO20004316L (no) 2000-11-06
AU3294799A (en) 1999-09-20
UA71906C2 (en) 2005-01-17
AR018139A1 (es) 2001-10-31
NO20004316D0 (no) 2000-08-30
GEP20033118B (en) 2003-11-25
PL342726A1 (en) 2001-07-02
AP1244A (en) 2004-02-04
HUP0100865A2 (hu) 2001-08-28
NZ506598A (en) 2003-07-25
SK13002000A3 (sk) 2001-07-10
OA11530A (en) 2004-05-17
EP1060164A1 (fr) 2000-12-20
TR200002542T2 (tr) 2001-05-21
YU52000A (sh) 2003-02-28
ZA994406B (en) 2000-02-11
EE200000506A (et) 2002-04-15
CN1214011C (zh) 2005-08-10
MY123908A (en) 2006-06-30

Similar Documents

Publication Publication Date Title
AU753230B2 (en) Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists
AU765294B2 (en) Heterocyclic glycyl beta-alanine derivatives as vitronectin antagonists
US6677308B1 (en) Meta-substituted phenylene sulphonamide derivatives
US5773644A (en) Cyclopropyl alkanoic acid derivatives
US6372719B1 (en) ανβ3 integrin antagonists in combination with chemotherapeutic agents
US6013651A (en) Meta-azacyclic amino benzoic acid compounds and derivatives thereof
US6689754B1 (en) Heterocyclic glycyl β-alanine derivatives
JP2004509950A (ja) ヒドロキシ酸系インテグリンアンタゴニスト
US6172256B1 (en) Chiral-β-amino acid compounds and derivatives thereof
US6720327B2 (en) Lactone integrin antagonists
US20040019206A1 (en) Lactone integrin antagonists
MXPA00008427A (en) Meta-azacyclic amino benzoic acid compounds and derivatives thereof being integrin antagonists
CZ20003218A3 (cs) Deriváty meta-azacyklické aminobenzoové kyseliny a jejich deriváty, které jsou antagonisty integrinu
MXPA00009967A (en) Heterocyclic glycyl beta-alanine derivatives as vitronectin antagonists

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: P-520/00

Country of ref document: YU

Ref document number: 99803581.5

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 137653

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 1200000690

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 1999937927

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: IN/PCT/2000/248/KOL

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 13002000

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/008427

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2322207

Country of ref document: CA

Ref document number: 2322207

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 506598

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2000 534538

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 32947/99

Country of ref document: AU

Ref document number: 200000804

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: P20000574A

Country of ref document: HR

Ref document number: 2000/02542

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: PV2000-3218

Country of ref document: CZ

Ref document number: 1020007009774

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1999937927

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2000-3218

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1020007009774

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 32947/99

Country of ref document: AU

WWR Wipo information: refused in national office

Ref document number: 1020007009774

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV2000-3218

Country of ref document: CZ

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载