WO1997036862A1 - META-SUBSTITUTED PHENYLENE DERIVATIVES AND THEIR USE AS ALPHAvBETA3 INTEGRIN ANTAGONISTS OR INHIBITORS - Google Patents

META-SUBSTITUTED PHENYLENE DERIVATIVES AND THEIR USE AS ALPHAvBETA3 INTEGRIN ANTAGONISTS OR INHIBITORS Download PDF

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Publication number
WO1997036862A1
WO1997036862A1 PCT/US1997/004461 US9704461W WO9736862A1 WO 1997036862 A1 WO1997036862 A1 WO 1997036862A1 US 9704461 W US9704461 W US 9704461W WO 9736862 A1 WO9736862 A1 WO 9736862A1
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WIPO (PCT)
Prior art keywords
amino
phenyl
acid
carbonyl
methyl
Prior art date
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PCT/US1997/004461
Other languages
French (fr)
Inventor
Nizal Chandrakumar
Barbara B. Chen
Helen Chen
Michael Clare
Alan F. Gasiecki
Richard A. Haack
James W. Malecha
Peter G. Ruminski
Mark A. Russell
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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.)
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Publication date
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Priority to EP97916110A priority Critical patent/EP0889877B1/en
Priority to JP9535309A priority patent/JP2000506538A/en
Priority to DE69706407T priority patent/DE69706407T2/en
Priority to AT97916110T priority patent/ATE204857T1/en
Priority to DK97916110T priority patent/DK0889877T3/en
Priority to AU23370/97A priority patent/AU2337097A/en
Publication of WO1997036862A1 publication Critical patent/WO1997036862A1/en

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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
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Definitions

  • the present invention relates to pharmaceutical agents (compounds) which are useful as a v ⁇ 3 integrin antagonists or inhibitors and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by a v ⁇ 3 by inhibiting or antagonizing CL v ⁇ 3 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 o 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 a v ⁇ 2 (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, 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. Thus, compounds which selectively inhibit or ⁇ v ? 3 would be beneficial for treating such conditions.
  • a v ⁇ 2 integrin and other ⁇ v containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules.
  • RGD Arg-Gly-Asp
  • RGD peptides in general are non-selective for RGD dependent integrins.
  • most RGD peptides which bind to a v ⁇ 2 also bind to ⁇ v /J 5 , ot ⁇ ⁇ j ⁇ and ⁇ * llb ⁇ 3 .
  • Antagonism of platelet ⁇ IIb ⁇ 3 also known as the fibrinogen receptor
  • Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic 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 ot 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 a 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 (Adonis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med. , Vol. 175, (1992), 1135-1138).
  • ⁇ v /3 3 antagonists would be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571). It has been reported that the cell surface receptor ⁇ * v 3 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 3 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al. , J. Cell. Biol., Vol. Ill (1990) 1713-1723] and in vivo [Fisher et al. ,
  • Y 1 is selected from the group consisting of N-R 2 , 0, and S;
  • R 2 is selected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; aminocarbonyl; alkenyl; alkynyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylened
  • R 2 taken together with R 7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, oxo and phenyl;
  • R 2 taken together with R 7 forms a 5 membered heteroaromatic ring fused with a phenyl group optionally substituted with one or more substituent selected from the group consisting of alkoxycarbonyl and alkoxy;
  • R 7 (when not taken together with R 2 ) and R 8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, al
  • NR 7 and R 8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
  • R 5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl;
  • Y 2 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles; alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -S-R 9 and -0-R 9 wherein R 9 is selected from the group consisting of H ? alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R 9 taken together with R 7 forms a
  • R 5 and R 7 are as defined above;
  • R 7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or hydroxy;
  • Z 1 , Z 2 , Z 4 and Z 5 are independently selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A, wherein A is defined above; B is selected from the group consisting of
  • R 50 is selected from the group consisting of H and alkyl
  • Y is selected from the group consisting of
  • R 70 is selected from the group consisting of H, alkyl, aryl and aryl substituted with one or more substituent selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles;
  • t is an integer 0, 1 or 2;
  • R is X-R 3 wherein X is selected from the group consisting of O, S and NR 4 , wherein R 3 and R 4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof;
  • -XR 3 is -O- and Y is CH-Ph wherein the X-R 3 group is attached to the Ph of the Y group at the para position to form a lactone;
  • Y 3 and Z 3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl;
  • R 1 is selected from the group consisting of hydrogen; alkyl; aryl;
  • R 12 is selected from the group consisting of H, alkyl, cycloalkyl, aralkyl and aryl;
  • R 51 is selected from the group consisting of N- substituted pyrrolidinyl, piperidinyl and morpholinyl.
  • Such compounds and compositions are useful in selectively inhibiting or antagonizing the a v ⁇ 2 integrin and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the v/ 3 3 integrin.
  • 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, 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.
  • 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, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a
  • the present invention relates to a class of compounds represented by the Formula I, described above.
  • Another preferred embodiment of the present invention is a compound of the Formula III wherein B is selected from the group consisting of -CONR 50 CH 2 -; - S0 2 NR 50 ; -C0 2 CH 2 ; -CH 2 CH 2 -; alkenylene and alkynylene.
  • the invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formulas I-III.
  • 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, arthritis, including rheumatoid arthritis, smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound of the Formula I-III 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.
  • alkenyl or “lower alkenyl” refer to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
  • alkynyl or “lower alkynyl” refer to acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • cycloalkyl as used herein means saturated or partially unsaturated cyclic carbon radicals containing 3 to about 8 carbon atoms and more preferably 4 to about 6 carbon atoms.
  • examples of such cycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-l-yl, and the like.
  • aryl denotes aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three aromatic rings. The term embraces aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like. As used herein, the term “cyano" is represented by
  • hydroxy and "hydroxyl” as used herein are synonymous and are represented by a radical of the formula I—OH •
  • lower alkylene or “alkylene” as used herein refers to divalent linear or branched saturated hydrocarbon radicals of 1 to about 6 carbon atoms.
  • alkynylene or “lower alkynylene” refers to an alkylene radical wherein at least one bond between the carbon atoms is unsaturated and such unsaturation forms a triple bond.
  • alkenylene or “lower alkenylene” refers to an alkylene radical wherein at least one bond between the carbon atoms is unsaturated and such unsaturation produces a double bond in cis or transconformation.
  • alkoxy refers to straight or branched chain oxy containing radicals of the formula -OR 20 , wherein R 20 is an alkyl group as defined above. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like.
  • arylalkyl or “aralkyl” refer to a radical of the formula
  • R 21 is aryl as defined above and R 22 is an alkylene as defined above.
  • aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.
  • aralkoxy or "arylakoxy” refers to a radical of the formula —OR 53 wherein > 53
  • nitro is represented by a radical of the formula I—NO 2
  • halo or halogen refers to bromo, chloro, fluoro 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. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like.
  • carboxyl or “carboxy” refers to a radical of the formula -COOH.
  • aminoalkyl refers to a radical of the formula -R 54 -NH 2 wherein R 54 is lower alkylene as defined above.
  • carboxyl derivative refers to a radical of the formula -R 54 -NH 2 wherein R 54 is lower alkylene as defined above.
  • Y 6 and Y 7 are independently selected from the group consisting of 0, N or S and R 23 is selected from the group consisting of H, alkyl, aralkyl or aryl as defined above.
  • amino is represented by a radical of the formula -NH 2 .
  • alkylsulfonyl or “alkylsulfone” refers to a radical of the formula
  • R 24 is alkyl as def ined above .
  • alkylthio refers to a radical of the formula -SR 24 wherein R 24 is alkyl as defined above.
  • sulfonic acid refers to
  • N-substituted pyrrolidinyl refers to a radical of the formula
  • N-substituted piperidinyl refers to a radical of the formula
  • orpholinyl refers to a radical of the formula I—N o .
  • fused aryl refers to an aromatic ring such as the aryl groups defined above fused to one or more phenyl rings. Embraced by the term “fused aryl” is the radical naphthyl.
  • monocyclic heterocycle or “monocyclic heterocyclic” refer to a monocyclic ring containing from 4 to about 12 atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 of the atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur with the understanding that if two or more different heteroatoms are present at least one of the heteroatoms must be nitrogen. Representative of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole, and the like.
  • fused monocyclic heterocycle refers to a monocyclic heterocycle as defined above with a benzene fused thereto.
  • fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.
  • alkyl, aryl, or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline.
  • 5-membere ⁇ heteroaromatic ring includes for example a radical of the formula
  • phenyl refers to such a "5-membered heteroaromatic ring" with a phenyl fused thereto.
  • Representative of such 5-membered heteroaromatic rings fused with a phenyl is benzimidazole.
  • the term "bicycloalkyl” refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms which is saturated or partially unsaturated.
  • acyl refers to a radical
  • R 26 is alkyl, alkenyl.
  • alkynyl aryl or aralkyl as defined above.
  • aryl or aralkyl as defined above.
  • a radical is the groups acetyl, benzoyl and the like.
  • thio refers to a radical of the formula —SH
  • haloalkylthio refers to a radical of the formula -S-R 28 wherein R 28 is haloalkyl as defined above.
  • aryloxy refers to a radical of the formula I—OR29 wherein R 29 is aryl as
  • acylamino refers to a
  • alkylamino refers to a radical of the formula -NHR 32 wherein R 32 is alkyl as defined above.
  • dialkylamino refers to a radical of the formula -NR 33 R 34 wherein R 33 and R 34 are the same or different alkyl groups as defined above.
  • trifluoromethyl refers
  • trifluoroalkoxy refers to a radical of the formula F 3 C—R 35* —O— wherein R 35 is
  • alkyla inosulfonyl a bond or an alkylene as defined above.
  • R 36 is alkyl as defined above.
  • R 36 is alkyl as defined above.
  • trifluoromethylthio refers to a radical of the formula F 3 C—S—j .
  • trifluoromethylsulfonyl o refers to a radical of the formula F 3 c—S— .
  • 4-12 membered mono ⁇ nitrogen containing monocyclic or bicyclic ring refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4-12 atoms and more preferably a ring of 4-9 atoms wherein one atom is nitrogen. Such rings may optionally contain additional heteroatoms selected from nitrogen, oxygen or sulfur. Included within this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like.
  • the term "4-12 membered mono ⁇ nitrogen containing sulfur or oxygen containing heterocyclic ring” refers to a ring consisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein at least one atom is a nitrogen and at least one atom is oxygen or sulfur. Encompassed within this definition are rings such as thiazoline and the like. As used herein the term “arylsulfonyl” or
  • arylsulfone refers to a radical of the formula
  • R37 s "—*I wh._erei.n R3 J 7 i.s aryl as defined above.
  • alkylsulfoxide or arylsulfoxide refer to radicals of the formula
  • R 39 and R 40 are the same or different H, alkyl, aryl or aralkyl.
  • phosphinic acid derivatives refers to a radical of the formula O _ QD4 wherein R 41 is H , alkyl , aryl or aralkyl as
  • arylthio refers to a radical of the formula I—SR42 wherein R 42 is aryl as
  • thio refers to a radical of the formula —SR * "
  • R 43 is a monocyclic heterocycle radical as defined above.
  • R 43 is a monocyclic heterocycle radical as defined above.
  • the terms “monocyclic heterocycle sulfoxide” and “monocyclic heterocycle sulfone” refer,
  • R 43 is a monocyclic heterocycle
  • composition 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.
  • therapeutically 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. The following is a list of abbreviations and the corresponding meanings as used interchangeably herein:
  • CH analysis carbon/hydrogen/nitrogen elemental analysis
  • CHNC1 analysis carbon/hydrogen/nitrogen/chlorine elemental analysis
  • CHNS analysis carbon/hydrogen/nitrogen/sulfur elemental analysis
  • DCC 1,3-dicyclohexylcarbodiimide
  • DIEA diisopropylethylamine
  • DMAP 4-(N,N-dimethylamino)pyridine
  • DMF N,N-dimethylformamide
  • DSC disuccinyl carbonate
  • EDC1 l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • Et 2 0 diethyl ether Et 3
  • N triethylamine
  • GIHA HCI meta-guanidino-hippuric acid hydrochloride
  • GIHA meta-guanidino-hippuric acid
  • HPLC high performance liquid chromatography
  • MCPBA m-chloroperoxybenzoic acid or m-chloroperbenzoic acid
  • NaCNBH 3 sodium cyanoborohydride
  • Na 2 P0 4 sodium phosphate
  • Na 2 S0 4 sodium sulfate
  • NaHC0 3 sodium bicarbonate
  • NaOH sodium hydroxide
  • NMM N-methyl morpholine
  • NMR nuclear magnetic resonance
  • RPHPLC reverse phase high performance liquid chromatography
  • KSCN potassium thiocyanate
  • Ph phenyl
  • HPLC-Method 1 refers to reverse phase C-18 functionalized silica gel column (50 x 300 mm) using a linear gradient of 95% 0.6% TFA/water:5% CH 3 CN to 60% 0.6% TFA/water: 40% CH 3 CN with a flow rate of 80 ml/minute.
  • the compounds as shown in Formulas I-III can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
  • 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 of Formula I 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, alate, succinate, tartrate salts and the like. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Phar . Sci.. 66(1), 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 intraperitonally.
  • 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 a v ⁇ 2 cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in Formulas I-III, wherein one or more compounds of the Formulas I-III 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 ot v ⁇ 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, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis.
  • the compounds of Formula I can be used in the treatment of patients suffering from the above pathological conditions.
  • Treatment of a patient afflicted with one of the pathological conditions comprises administering to such a patient an amount of compound of the Formula I 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.
  • the term "inhibition" of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially controlled to some extent.
  • 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 a 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 of the order from about 0.01 mg to about 100 mg/kg of body weight.
  • 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 100 mg/kg body weight injected per day in multiple doses depending on the factors listed above and more preferably from about 0.01 to about 10 mg/kg body weight.
  • 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 chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • 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.
  • R 5 is H. If R 5 is other than H, alkylation of the amino functionality can be achieved by conventional methodology.
  • intermediate (A2) can also be accomplished as disclosed generally in US 3,202,660, starting with the appropriate amino benzoic acid.
  • intermediate (A2) and (A15) as well as further analogues of (A2) and (A15) such as substitutions on the heterocyclic ring, oxazolidines, thiazolidines, benzimidazoles and the like can also be accomplished as disclosed in
  • (A4) can be synthesized from Y 2 -CN and MeOH (1 equivalent) and HCI gas (1 equivalent) in heptane.
  • Aldehyde or ketone BI is condensed with (EtO) 2 P(0)CH 2 COR under standard conditions (NaH/THF 0° to room temperature) .
  • the resulting cinnamic acid derivative C_i is reduced (4% Pd/C, EtOH, 5 psi) to afford the desired phenylpropionic acids Dl.
  • Nitrophenylcinnamic acid Cl is partially reduced with magnesium in MeOH to afford nitrophenylpropionic acid Ei. Further reduction of the nitro moiety (SnCl 2 /H 2 0/HCl/EtOH) affords the desired phenylpropionic acid Dl.
  • Bromide B3. can be coupled with alkylacrylates E2. using a standard Heck coupling procedure (Pd(0Ac) 2 , P(PhMe) 3 , DMF, 130°) to afford cinnamic acid C3.
  • alkylacrylates E2. are readily prepared by condensing the requisite aldehyde (R 56 CHO) with (EtO) 2 P(0)CH 2 COR using standard and well known reaction conditions such as (NaH, THF, 0°).
  • Bromide B5 can be coupled with alkylacrylates E3_ using a standard Heck coupling procedure (Pd(OAc) 2 , P(PhMe) 3 , DMA, 130°) to afford phenylcinnamic acid C4.
  • Phenylcinnamic acid C ⁇ may be converted into D4 and D5 as described above in Scheme 11(E).
  • intermediates D1-D5 from Scheme II, (A-F) are coupled to 3-nitro phenylsulphonyl chloride FI (CH 2 C1 2 , NEt 3 0°).
  • the resulting coupled product T is reduced (SnCl 2 /EtOH H 2 0, 100°) to the corresponding aniline.
  • the resulting aniline may be converted into compounds of the present invention using the procedures described in Scheme I (A1-A16) followed by deprotection (TFA/CH 2 Cl 2 /0°) .
  • Method C is identical to that described in Method B except the 3-nitrophenylsulphonyl chloride PI is replaced with 3-nitrobenzoylchloride F2.
  • R 11 is not H
  • the appropriate nitrogen can be alkylated in an appropriate step by methodology known to those skilled in the art.
  • Alternate acid derivatives R are synthesized by methodologies known to those skilled in the art.
  • aldehyde Gl or bromide G2_ can be converted into phenylpropanoic acid HI (using well established and known chemistry to mask and unmask the hydroxy moiety) .
  • Phenylpropanoic acid HI is then readily coupled to benzoic acids A1-A15 using procedures previously described to afford the compounds of the present invention.
  • Scheme VII outlines methodologies for preparing the L3 type derivatives of the present invention.
  • 3- Hydroxybenzophenone was converted to LI using the methods described in Scheme 11(A).
  • LI was coupled with 3- nitrobenzyl bromide (LJ2) and reduced (H 2 , Pd/C) .
  • the resulting aniline L3. was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg 2 Cl 2 , DMF), followed by deprotection (TFA, CH 2 Cl 2 ) , or otherwise functionalized as described in Scheme I.
  • Scheme VIII outlines methodologies for preparing the thio derivatives of the present invention.
  • 3-Thioaniline (Ml) was reacted with 3-bromobenzophenone (NaH, DMF) to provide M..
  • Mg was converted to M3 using the methods described in Scheme 11(B).
  • M3 . was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg 2 Cl 2 , DMF) , or otherwise functionalized as described in Scheme I to give M.. M4.
  • was deprotected (TFA, CH 2 Cl 2 ) , followed by hydrolysis under standard basic conditions (NaOH/H 2 0/MeOH) to provide the corresponding carboxylic acid derivative.
  • M4 was oxidized (tetra-n-butyl ammonium oxone/CH 2 Cl 2 ) to give M5., which was deprotected (TFA, CH 2 C1 2 ) , followed by hydrolysis under standard basic conditions (NaOH/H 2 0/MeOH) to provide the corresponding carboxylic acid derivative.
  • M5 was oxidized (tetra-n-butyl ammonium oxone/CH 2 Cl 2 ) to give M6, which was deprotected (TFA, CH 2 C1 ) , followed by hydrolysis under standard basic conditions (NaOH/H 2 0/MeOH) to provide the corresponding carboxylic acid derivative.
  • Scheme IX outlines methodologies for preparing the alkene and alkyne derivatives of the present invention.
  • 3-Hydroxybenzophenone was converted to LI using the methods described in Scheme II(A) .
  • LI was reacted with trifluoromethane sulfonic anhydride (Et 3 N, CH 2 C1 2 ) to give NI.
  • NI was reacted with trimethylsilyl acetylene ((Ph 3 P) 2 PdCl 2 , Cul, Et 2 NH) , followed by hydrolysis (KOH/MeOH) , to provide NJ..
  • N2 was coupled with B_5 using the methods described in Scheme 11(F).
  • NI was coupled with 3-nitro styrene using the methods described in Scheme 11(F).
  • the resulting product N4 was reduced (SnCl 2 /EtOH) to the corresponding aniline.
  • the resulting aniline was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg 2 Cl 2 , DMF), followed by deprotection (TFA, CH 2 C1 2 ) , or otherwise functionalized as described in Scheme I.
  • N5 can be further reduced to its corresponding alkene (H 2 , Pd/C) which can be converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg 2 Cl 2 , DMF) , followed by deprotection (TFA, CH 2 C1 2 ) , or otherwise functionalized as described in Scheme I.
  • H 2 , Pd/C alkene
  • BOCNHCSNHBOC Hg 2 Cl 2 , DMF
  • Example B The title compound was synthesized according to the methodology of Example B, substituting an equivalent amount of 3-amino-5-trifluoromethyl benzoic acid [which was synthesized by reduction of 3-nitro-5- trifluoromethyl benzoic acid (Lancaster) in ethanol with 10% Pd/C under 50 psi H 2 for 4 hours] for 3-aminobenzoic acid.
  • Example G A solution of the product from Example E (8.9 g) in ethanol (80 mL) was hydrogenated under an atmosphere of 5 psi of hydrogen at room temperature for 2 hours using 4% palladium on carbon (1.5 g) as catalyst. The reaction mixture was concentrated and the crude product was purified on a silica gel column eluting with 1:1 ethyl acetate-hexane to afford 6.4 g of white solid. NMR was consistent with the proposed structure.
  • Example G A solution of the product from Example E (8.9 g) in ethanol (80 mL) was hydrogenated under an atmosphere of 5 psi of hydrogen at room temperature for 2 hours using 4% palladium on carbon (1.5 g) as catalyst. The reaction mixture was concentrated and the crude product was purified on a silica gel column eluting with 1:1 ethyl acetate-hexane to afford 6.4 g of white solid. NMR was consistent with the proposed structure.
  • Example G A solution of the product from Example E (8.
  • Example G The reaction was run as described in Example G using the product from Example F (1.5 g) , 3- nitrobenzoyl chloride (935 mg) (Aldrich) , triethylamine (510 mg) and methylene chloride (15 ml) .
  • the crude product was purified on a silica gel column eluting with 20% ethyl acetate -80% hexane to afford 1.6 g of white solid. NMR was consistent with the proposed structure.
  • Example F The reaction was run as described in Example F using the product from Example J (1.6 g) , ethanol (20 ml) and 4% Pd/C (100 mg) .
  • the crude product was purified on a silica gel column eluting with 1:1 ethyl acetate:hexane to afford 1.3 g of white solid.
  • Example II The reaction was run as described in Example I using the product from Example K (1.3 g) , bis-t- butoxycarbonyl thiourea (829 mg) , triethylamine (1.0 g) , mercuric chloride (896 mg) and DMF (10 ml) .
  • the crude product was purified on a silica gel column eluting with 25% ethyl acetate -75% hexane to afford 1.1 g of white solid.
  • Example 1 The reaction was run as described in Example 1 using the product from Example L (1.1 g) and a 1:1 TFA:CH 2 C1 2 solution (10 ml). The crude product was purified as previously described to afford 883 mg of white solid.
  • Example N The reaction was run as described in Example N using the product from Example P (450 mg) .
  • the crude product was purified in the same fashion to afford 240 mg of a colorless viscous oil. NMR was consistent with the proposed structure.
  • Example 6 The reaction was run as described in Example I using the product from Example Q (230 mg) , bis-t- butoxy-carbonyl thiourea (166 mg) , triethylamine (126 mg) , and mercuric chloride (163 mg) in DMF (10 ml) . The crude product was purified in similar fashion to afford 140 mg of white solid. NMR was consistent with the proposed structures.
  • Example 6
  • Example 4 The reaction was run as described in Example 4 using the product (229 mg) from Example H (640 mg) , potassium cyanate (229 mg) (Aldrich) , glacial acetic acid (3 ml) and water (10 ml) .
  • the crude product was purified on a silica gel column eluting with 5% methanol -95% methylene chloride to afford 435 mg of viscous golden oil. NMR was consistent with the proposed structure.
  • Example 11 The reaction was run as described in Example I using the product from Example U (320 mg) , bis-t-butoxy carbonyl thiourea (193 mg) , triethylamine (132 mg) , mercuric chloride (217 mg) and DMF (8 ml) .
  • the crude product was purified on a silica gel column eluting with 15% ethyl acetate -85% hexane to afford 303 mg of a colorless viscous oil. NMR was consistent with the proposed structure.
  • Example AN A solution of the product from Example AL (4.6 g) was stirred with IN methanolic potassium hydroxide solution (17 ml) at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified on a silica gel column eluting with 5% ethyl acetate - 95% hexane to afford 3.4 g of golden liquid. NMR was consistent with the proposed structure.
  • Example AN
  • Example 17 The reaction was run as described in Example I using the product from Example X (450 mg) , bis-t- butoxy-carbonylthiourea (346 mg) , triethylamine (253 mg) ; mercuric chloride (380 mg) and DMF (15 ml). The crude product was purified on a silica gel column eluting with 10% ethyl acetate -90% hexane to afford 460 mg of a colorless viscous oil. NMR was consistent with the proposed structure.
  • Example 17 The reaction was run as described in Example I using the product from Example X (450 mg) , bis-t- butoxy-carbonylthiourea (346 mg) , triethylamine (253 mg) ; mercuric chloride (380 mg) and DMF (15 ml). The crude product was purified on a silica gel column eluting with 10% ethyl acetate -90% hexane to afford 460 mg of a
  • 3-Aminophenylacetic acid (3 g, 19.8 mmol) was dissolved in dry ethanol (60 mL) at 0°C and a stream of hydrogen chloride gas was bubbled into the solution for 15 minutes. The solvent was removed under reduced pressure to give desired product.
  • Example AA The compound of Example AA was dissolved in a MeOH (15 mL) /NH 4 OH (7.5 mL) mixture and hydrogenated with W- 2 Raney Ni in a Parr Shaker (60 psi, 25°C) for 2.5 hours. The catalyst was filtered and the purple filtrate concentrated in vacuo . The green solid residue was dissolved in IM HCI and concentrated in vacuo to give a white/green solid. The solid was purified by slurrying with 9:1 CH 3 CN/MeOH mixture. The white undissolved solid was collected by vacuum filtration to give the desired product (0.664 g, 59% yield) . NMR was consistent with the proposed structure.
  • Example 19A The above compound was synthesized under conditions similar to Example 19A, replacing the compound of Example 19 with the compound of Example AD.
  • Example 19A The compound of Example 19A (0.42 g, 1.1 mmol) was dissolved in AcOH and hydrogenated with 4% Pd/C (53% wet, 0.050 g) in a Parr Shaker (60 psi, 60C) . The catalyst was filtered off and the filtrate concentrated in vacuo to give a white solid (pink tint) . The solid was slurried with acetonitrile and the resulting white solid was collected by vacuum filtration (0.347 g, 89% yield) .
  • Example 20 was reduced under conditions similar to conditions for Example 21, replacing the compound of Example 19A with the compound of Example 20.
  • Example AE The compound of Example AE was hydrogenated (4% Pd/C, EtOH, 5 psi, room temperature, 1.5 hours) and the filtrate concentrated in vacuo to give a yellow oil (2.095 g, 82% yield). NMR was consistent with the proposed structure.
  • Example 25 The compound of Example 25 (0.131 g, 0.34 mmol) was dissolved in MeOH (2 mL) and 1 M LiOH (0.68 mL) was added. The reaction was stirred at room temperature over 16 hours. The reaction was concentrated in vacuo to give a white solid. The solid was dissolved in a small amount of H 2 0 and acidified with 1 drop of TFA. The mixture was concentrated in vacuo and the residue was purified by HPLC - Method 1 to give a white solid (0.055 g, 45% yield) .
  • Example 28 The compound from Example 28 was hydrolyzed using the method described in Example 26. After acidifying with TFA, the resulting white precipitate was filtered off and washed with water (3X) and ether (IX). (0.261 g, 89% yield) .
  • Example 30 The compound of Example 30 was hydrolyzed using the method described in Example 26. After acidifying with TFA, the resulting white precipitate was filtered off and washed with water (3X) and ether (IX) . The desired product was collected as a cream-colored solid (0.115 g, 89% yield) .
  • Example 37, Step D The compound from Example 37, Step D, (0.8 g, 2.8 mmol) was coupled with 3-nitrobenzoic acid under similar conditions to the conditions described in Example AE using CH 2 C1 2 as the solvent.
  • the crude material was purified by column chromatography (100 g silica, 40% EtOAc/hexane) to give the desired product as a pale yellow oil (0.969 g) . NMR was consistent with the proposed structure.
  • Example 32 The compound of Example AG (0.969 g, 2.2 mmol) was dissolved in EtOH and hydrogenated with 4% Pd/C in a Parr Shaker (5 psi) at room temperature for 16 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the product as a brown oil (0.577 g) . NMR was consistent with the proposed structure.
  • Example 32
  • Example AH The compound of Example AH (0.25 g, 0.62 mmol) was treated with benzyl isocyanate under conditions described similar to the conditions described in Example 30. The desired product was collected as an off-white solid (0.314 g) .
  • Example 32 The compound of Example 32 (0.226 g, 0.4 mmol) was hydrolyzed under the same conditions as described in Example 26 to give the desired product as a white solid (0.118 g) .
  • Example AB The compound of Example AB (0.54 g, 2.2 mmol) was coupled with the compound of Example Al according to the procedure described in Example 34.
  • the crude material was purified by HPLC-Method 1 to give a yellow oil (0.212 g) .
  • Example AW The compound of Example AW (0.860 g, 4.45 mmol) was reduced under conditions similar to conditions for Example AF.
  • the product was isolated as a yellow oil (0.76 g) .
  • NMR was consistent with the proposed structure.
  • Step C The compound of Step C (l .931 g, 6.8 mmol) was dissolved in i-PrOH/HCl and hydrogenated with 10% Pd/C in a Parr Shaker (60 psi) for 6 hours at room temperature. The catalyst was removed and the filtrate was concentrated in vacuo. The residue was partitioned between saturated NaHC0 3 and ether. The aqueous layer was back-extracted with ether. The organic layers were combined, dried over MgS0 4 , and concentrated in vacuo to give a light brown oil (1.65 g, 86% yield). NMR was consistent with the proposed structure.
  • Step D The compound of Step D (0.45 g, 1.6 mmol) was coupled with the compound of Example Al according to similar procedures described in Example 34 and purified by HPLC-Method 1 to give white sticky solid (0.400 g) .
  • Example 37 The compound of Example 37 (0.32 g, 0.72 mmol) was hydrolyzed under the conditions described in Example 26 and purified by HPLC-Method 1 to give the desired product as a white sticky solid (0.327 g) .
  • Example AJ The compound of Example AJ was hydrogenated (i-PrOH+ l N HCI, 10% Pd/C, 60 psi, room temperature, 1.5 hours) and the filtrate concentrated in vacuo .
  • the solid residue was partitioned between saturated NaHC0 3 (25 mL) and ether (25 mL) .
  • the aqueous layer was back- extracted with ether (2X25 mL) .
  • the organic layers were combined, washed with brine, dried over K 2 C0 3 , and filtered through celite. Concentration of the filtrate in vacuo gave the desired product (free amine) as a yellow oil (0.401 g, 35% yield).
  • NMR was consistent with the proposed structure.
  • Example AK was coupled with the compound of Example Al under similar reaction conditions as described in Example 34.
  • the crude material was purified by HPLC-Method 1 to give the desired product (0.29 g, 62% yield).
  • Step A The ketone formed in Step A (0.959 g, 6.0 mmol) was treated with ethyl dimethylphosphonoacetate under conditions as described in Example 37, Step C. The product was isolated as a mixture of E and Z isomers in a 1:1 ratio (1.417 g) . NMR was consistent with the proposed structure.
  • Step C The product of Step C (1.087 g, 4.6 mmol) was coupled to the compound of Example Al according to conditions as described in Example 34. The residue was purified by HPLC-Method 1 to give the desired product as a yellow oil (1.571 g) .
  • Example 41 The product of Example 41 (1.4 g, 3.5 mmol) was hydrolyzed using the method described in Example 26.
  • the crude material was purified by HPLC-Method l to give the desired product as a colorless oil (1.10 g) ,
  • the reaction was cooled to -30°C (bath) and l.l equivalents of 1 M LiHMDS were added. The reaction was allowed to warm slowly to 10°C. Within 5 minutes, the TLC showed the isopropyl product to be the predominant product. After stirring for 40 minutes, the reaction was quenched with water (50 mL) and extracted with EtOAc (2X50 mL) . The organic layer was collected, dried over MgS0 4 , and dried under a stream of N 2 . The resulting orange residue was diluted with CH 2 Cl 2 and the undissolved white solid filtered off. The filtrate was collected and concentrated in vacuo to give an orange oil (1.229 g) .
  • Step C The mixture from Step C (0.521 g, 2.0 mmol) was hydrogenated under conditions similar to those described in Example AK to give a light tan oil (0.333 g) . NMR was consistent with the proposed structure.
  • Step D The product of Step D (0.28 g, l.l mmol) was coupled with the compound of Example Al using a method similar to that described in Example 34.
  • the crude material was purified by HPLC-Method 1 to give the desired product as a colorless oil (0.070 g) .
  • NMR was consistent with the proposed structure.
  • Step E The product of Step E (0.057, 0.14 mmol) was hydrolyzed under conditions similar to those described in Example 26. The residue was purified by HPLC-Method 1 to give a colorless oil (0.045 g) .
  • Step B The compound of Step B (1.04 g, 2.9 mmol) was hydrogenated (10% Pd/C, EtOH+THF, 60 psi, room temperature, 10 hours). The reaction was concentrated in vacuo to give a white solid (1.21 g) . The solid was purified by column chromatography [50 g silica gel, 20% EtOAc/hexane (500 mL) ] to give the desired product as a white solid (0.54 g, 52% yield). NMR was consistent with the proposed structure. Step D
  • Step D The compound of Step D (0.25 g, 1.1 mmol) was coupled with the compound of Example Al following the procedures described in Example 34.
  • the crude reaction mixture was purified by HPLC-Method 1 to give a sticky white/yellow solid (0.289 g) . NMR was consistent with the proposed structure.
  • Step E The compound of Step E (0.289 g) was hydrolyzed under conditions similar to those described in Example 40.
  • the crude material was purified by HPLC-Method 1 to give a colorless oil (0.144 g) .
  • Step B The product of Step B (0.307 g, 1.1 mmol) was coupled with the compound of Example Al under conditions similar to those described in Example 34.
  • the crude material was purified by HPLC-Method 1 to give the methyl ester of the desired product as a pale yellow oil (0.231 g) . NMR was consistent with the proposed structure.
  • Step D The compound of Step C (0.125 g, 0.30 mmol) was hydrolyzed with LiOH according to the procedures described in Example 26. The residue was purified by HPLC-Method 1 (2X) to give the desired product as a colorless oil (0.052 g) .
  • Example AX The compound of Example AX (0.3 g, 1.8 mmol) was coupled with the compound of Example AP under similar reaction conditions as described in Example 34.
  • the crude mixture was purified by HPLC-Method l (2X) to give the desired product as a sticky light yellow oil (0.057 g) .
  • Analysis Calculated for C 18 H 20 N 4 O 3 - 1.9 TFA: C, 47.01; H, 3.96; N, 10.06.
  • Example AQ The compound of Example AQ (3.1 g, 13.5 mmol) was dissolved in methanol (150 mL) at 0°C and a stream of hydrogen chloride gas was bubbled into the solution for 10 minutes. The mixture was then stirred for 2 hours at 0°C. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using EtOAc/Hexane (1:8) as eluant to give 1.3 g of the pure desired compound.
  • Example 47 The compound of Example AS (749 mg, 3.65 mmol) was dissolved in EtOH (30 mL) and transferred to a Parr Shaker with 4% Pd/C (200 mg) . The reaction was shaken for 24 hours at room temperature under 5 psi pressure of H 2 . The reaction mixture was filtered and concentrated and the residue was dissolved in 4 N HCI dioxane solution (4 mL) . The solvent was removed and the residue was recrystallized from ether to give 0.5 g of the pure desired compound as white solid.
  • Example 47 The compound of Example AS (749 mg, 3.65 mmol) was dissolved in EtOH (30 mL) and transferred to a Parr Shaker with 4% Pd/C (200 mg) . The reaction was shaken for 24 hours at room temperature under 5 psi pressure of H 2 . The reaction mixture was filtered and concentrated and the residue was dissolved in 4 N HCI dioxane solution (4 mL) . The solvent was removed and the residue was recrystallized
  • Example 47 The compound of Example 47 was hydrolyzed in the same manner as described in Example 26.
  • Example 48 The compound of Example 48 was hydrolyzed in the same manner as described in Example 26.
  • Step A The product of Step A (0.5 g, 1.8 mmol) in THF (20 mL) was cooled (-30°C) and treated with sodium hydride (50% dispersion in mineral oil, 0.1 g, 2 mmol) in small portions over 15 minutes. The solution was then warmed (0°C) and stirred 30 minutes and then cooled to -30°C. To this solution was added neat t-butyl bromoacetate (0.49 g, 2.5 mmol, Aldrich) and the mixture was stirred 1 hour at -30°C and then warmed to room temperature and stirred 1 hour. The volatile components were removed at reduced pressure on a rotary evaporator and the residue was taken up in ether (50 mL) . The ether was washed with water (25 mL) , 10% NaOH (25 mL) and brine (25 mL) . This produced 0.6 g (86%) of the above compound.
  • sodium hydride 50% dispersion in mineral oil, 0.1 g,
  • Step B The product of Step B (0.6 g, 1.6 mmol) in methylene chloride (25 mL) was cooled (0°C) and treated with trifluoroacetic acid (5 mL) . The solution was warmed to room temperature and stirred for 3 hours. The volatile components were removed at reduced pressure on a rotary evaporator. The residue was chromatographed on silica gel eluting with 1% acetic acid/ethyl acetate. This produced 0.39 g (76%) of the above compound.
  • Example 52C The product of Example 52C (0.3 g, 0.91 mmol) was subjected to the reaction conditions described for the preparation of Example 51B. This produced 0.08 g (90%) of the title compound.
  • Example 52D The product of Example 52D (0.08 g, 0.27 mmol) was subjected to the reaction conditions described for the preparation of Example 51C. This produced 0.04 g (32%) of the title compound.
  • Example AB The product from Example AB (0.09 g, 0.4 mmol) was subjected to the reaction conditions described for the preparation of Example 51A.
  • the crude product was chromatographed on silica gel gradient eluting with ethyl acetate (containing 1% acetic acid) and produced 0.06 g (42%) of the above compound.
  • Example 53A The product from Example 53A (0.06 g, 0.17 mmol) was subjected to the reaction conditions described for the preparation of Example 51B. This produced 0.06 g (100%) of the above compound.
  • Example 53B The product from Example 53B (0.06 g, 0.19 mmol) was subjected to the reaction conditions described for the preparation of Example 51C. This produced 0.05 g (56%) of the title compound.
  • Step D The compound of Step D was dissolved in EtOH and hydrogenated with 5% Pt/C at room temperature under 5 psi for 16 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give an oil (0.354 g) . NMR was consistent with proposed structure.
  • Step G The compound of Step G (0.101 g, 0.25 mmol) was dissolved in MeOH (3 mL) and 1 M LiOH (0.5 mL) was added at room temperature. The reaction was stirred for 23 hours. The reaction was concentrated in vacuo and the residue diluted with water (1 mL) . The solution was acidified dropwise to pH 1 with TFA. The reaction was reconcentrated and the residue purified by HPLC to give a white solid (0.053 g) .
  • Step D The compound of Step C (220 mg, 0.79 mmol) was coupled with the compound of Step D in Example 37 according to similar procedure described in Example 34 and purified by reverse phase HPLC (water/acetonitrile) to give a light yellow oil (194 mg) . NMR was consistent with the proposed structure.
  • Example AJ The product of Example AJ was hydrogenated (THF, 5% Pd/C, 5 psi, room temperature, 40 minutes) and the filtrate concentrated in vacuo. The two enantiomers were separated by chrial HPLC.
  • the R isomer from Step A was hydrogenated (EtOH, RaNi, 60 psi, room temperature, 1 hour) and the filtrate concentrated in vacuo .
  • Step B The compound of Step B (223 mg, 1 mmol) was coupled with the compound of Example Al (217 mg, l mmol) according to a similar procedure as described in Example 34 and purified by reverse phase HPLC (water/acetonitrile) to give a brown oil (134 mg) . NMR was consistent with the proposed structure.
  • Step E The compound of Step E (197 mg, 0.4 mmol) was hydrolyzed under the conditions described in Example 26 and purified by reverse phase HPLC (water/acetonitrile) to give a white solid (146 mg) . NMR was consistent with the proposed structure.
  • Example D The compound of Example D (88 mg, 0.31 mmol) was coupled with the compound of Step C in Example 41 (73 mg, 0.31 mmol) according to a similar procedure as described in Example 34 and purified by reverse phase HPLC (water/acetonitrile) to give a colorless oil (48 mg) .
  • NMR was consistent with the proposed structure.
  • Example 60 The product from Step C in Example 60 was deprotected as described in Step F of Example 54 and then coupled with the product from Step B using a method similar to that described in Example 54 (Step G to Step H) to afford the title compound. NMR was consistent with the proposed structure.
  • Step B The product of Step B (0.72 g, 1.7 mmol) was dissolved in EtOH and hydrogenated with 5% Pd/C in a Parr Shaker (5 psi) at room temperature for 2 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the desired product as a yellow oil (0.485 g) . NMR was consistent with the proposed structure.
  • Step D 330 mg, 1.05 mmol
  • the compound of Example Al 230 mg, 1.05 mmol
  • Step E The compound of Step E (360 mg, 0.76 mmol) was hydrolyzed under the conditions described in Example 26 and purified by reverse phase HPLC (water/acetonitrile) to give a colorless oil (300 mg) . NMR was consistent with the proposed structure.
  • Step A The product of Step A was hydrolysed in the same manner as described in Step C of Example 55. NMR was consistent with the proposed structure. Step C
  • the above compound was prepared under the same conditions as described in Example AJ, replacing t- butyl P,P-dimethylphosphonoacetate with ethyl P,P- dimethylphosphonoacetate.
  • Step C The product of Step C was hydrogenated under the same conditions as described in Example 37, Step D.
  • Step B was coupled with the compound of Step D according to similar procedure described in Example 34. NMR was consistent with the proposed structure. Step F
  • Example 64 The product from Step B of Example 64 was coupled with the compound of Example AK according to a similar procedure as described in Example 34. NMR was consistent with the proposed structure.
  • Step C To a mixture of the product from Step A (1.0 g, 3.8 mmol) in absolute ethanol (20 mL) was added ethyl 3-aminobenzoate (2.5 g, 15.3 mmol). The mixture was stirred at room temperature for 16 hours. The mixture - was concentrated in vacuo and the residue was purified by chromatography (85:14:1 CH 2 Cl 2 :MeOH:NH 4 OH) to give the desired product, 414 mg. NMR was consistent with the proposed structure. Step C
  • Step C The product from Step A (2.3 g, 6.7 mmol) was hydrogenated with Raney nickel catalyst to yield the desired product (606 mg) .
  • U NMR was consistent with the proposed structure.

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Abstract

The present invention relates to a class of compounds represented by Formula (I), or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula (I), and methods of selectively inhibiting or antagonizing the αvβ3 integrin.

Description

META-SUBSTTTUTED PHENYLENE DERIVATIVES ANDTHEIR USE AS ALPHA.BETA, INTE¬ GRINANTAGONISTSOR INHIBITORS
Field of the Invention The present invention relates to pharmaceutical agents (compounds) which are useful as avβ3 integrin antagonists or inhibitors and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by avβ3 by inhibiting or antagonizing CLvβ3 integrins.
Background of the Invention 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 o and β polypeptide subunits. Currently eleven different α subunits have been identified and six different β subunits have been identified. The various α subunits can combine with various β subunits to form distinct integrins.
The integrin identified as avβ2 (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, 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. Thus, compounds which selectively inhibit or αv?3 would be beneficial for treating such conditions. It has been shown that the avβ2 integrin and other αv containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors.
However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to avβ2 also bind to αv/J5, otγβj^ and <*llbβ3. Antagonism of platelet αIIbβ3 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin αv/33, it would be beneficial to develop compounds which are selective antagonists of αv/33 as opposed to α* IIb03.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic 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.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the avβ2 integrin has a biological function in melanoma cell invasion.
Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin αv/33 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the αv33 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of αv33 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of αv/33 antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin otvβ3 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 avβ3 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 (Adonis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med. , Vol. 175, (1992), 1135-1138).
Therefore, αv/33 antagonists would be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571). It has been reported that the cell surface receptor α* v33 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 αv33 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al. , J. Cell. Biol., Vol. Ill (1990) 1713-1723] and in vivo [Fisher et al. ,
Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of αv33 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast avβ3 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis. The role of the <xvβ2 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 <*vβ 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 α* v/33 would find usefulness as antiviral agents.
Summary of the Invention The present invention relates to a class of compounds represented by the Formula I
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000006_0002
wherein Y1 is selected from the group consisting of N-R2, 0, and S;
R2 is selected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; aminocarbonyl; alkenyl; alkynyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle; monocyclic heterocycles; and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or
R2 taken together with R7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, oxo and phenyl;
or R2 taken together with R7 forms a 5 membered heteroaromatic ring;
or R2 taken together with R7 forms a 5 membered heteroaromatic ring fused with a phenyl group optionally substituted with one or more substituent selected from the group consisting of alkoxycarbonyl and alkoxy;
R7 (when not taken together with R2) and R8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; monocyclic heterocycles; monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl; monocyclic and bicyclic heterocyclicalkyls; -S02R10 wherein R10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonyla ino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and
O II wherei . n Rx i nu i . s defined above ;
— C— Rio
NR7 and R8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl;
or
Figure imgf000009_0001
wherein Y2 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles; alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -S-R9 and -0-R9 wherein R9 is selected from the group consisting of H? alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R9 taken together with R7 forms a 4-12 membered mononitrogen containing sulfur or oxygen containing heterocyclic ring; and
R5 and R7 are as defined above;
or Y2 (when Y2 is carbon) taken together with R7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or hydroxy;
or A is selected from the group consisting of
Figure imgf000010_0001
Z1, Z2, Z4 and Z5 are independently selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A, wherein A is defined above; B is selected from the group consisting of
O
-CONR5o-(CH2)p- -SO2NR50—,-—N NH—(CH2)p-
H
— Cθ2 *-(CH2)p— - — CH2CH2— * alkenylene and alkynylene
Figure imgf000011_0001
wherein p is an integer selected from the group consisting of 0, 1 and 2; wherein n is an integer selected from the group consisting of 0, 1, 2 and 3 R50 is selected from the group consisting of H and alkyl;
Y is selected from the group consisting of
wherein q is an integer selected from the group consisting of 0 and 1; R70 is selected from the group consisting of H, alkyl, aryl and aryl substituted with one or more substituent selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles;
t is an integer 0, 1 or 2;
R is X-R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof;
or -XR3 is -O- and Y is CH-Ph wherein the X-R3 group is attached to the Ph of the Y group at the para position to form a lactone;
Y3 and Z3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl;
R1 is selected from the group consisting of hydrogen; alkyl; aryl;
Figure imgf000012_0001
O
-NHS02-R12, -NH—C-NHR12; R12 is selected from the group consisting of H, alkyl, cycloalkyl, aralkyl and aryl; and
R51 is selected from the group consisting of N- substituted pyrrolidinyl, piperidinyl and morpholinyl.
It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula I. Such compounds and compositions are useful in selectively inhibiting or antagonizing the avβ2 integrin and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the v/33 integrin. 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, 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.
Detailed Description The present invention relates to a class of compounds represented by the Formula I, described above.
A preferred embodiment of the present invention is a compound of the Formula II
Another preferred embodiment of the present invention is a compound of the Formula III
Figure imgf000013_0002
Another preferred embodiment of the present invention is a compound of the Formula III wherein B is selected from the group consisting of -CONR50CH2-; - S02NR50; -C02CH2; -CH2CH2-; alkenylene and alkynylene.
The invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formulas I-III.
The invention also relates to a method of selectively inhibiting or antagonizing the αv?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, arthritis, including rheumatoid arthritis, smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound of the Formula I-III to achieve such inhibition together with a pharmaceutically acceptable carrier.
The following is a list of definitions of various terms used herein:
As used herein, the terms "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. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like. As used herein the terms "alkenyl" or "lower alkenyl" refer to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
As used herein the terms "alkynyl" or "lower alkynyl" refer to acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term "cycloalkyl" as used herein means saturated or partially unsaturated cyclic carbon radicals containing 3 to about 8 carbon atoms and more preferably 4 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-l-yl, and the like.
The term "aryl" as used herein denotes aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three aromatic rings. The term embraces aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like. As used herein, the term "cyano" is represented by
a radical of the formula —CN .
The terms "hydroxy" and "hydroxyl" as used herein are synonymous and are represented by a radical of the formula I—OH • The term "lower alkylene" or "alkylene" as used herein refers to divalent linear or branched saturated hydrocarbon radicals of 1 to about 6 carbon atoms.
As used herein the term "alkynylene" or "lower alkynylene" refers to an alkylene radical wherein at least one bond between the carbon atoms is unsaturated and such unsaturation forms a triple bond.
As used herein the term "alkenylene" or "lower alkenylene" refers to an alkylene radical wherein at least one bond between the carbon atoms is unsaturated and such unsaturation produces a double bond in cis or transconformation.
As used herein the term "alkoxy" refers to straight or branched chain oxy containing radicals of the formula -OR20, wherein R20 is an alkyl group as defined above. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like. As used herein the terms "arylalkyl" or "aralkyl" refer to a radical of the formula |—R2 —R21 wherein
R21 is aryl as defined above and R22 is an alkylene as defined above. Examples of aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.
As used herein the term "aralkoxy" or "arylakoxy" refers to a radical of the formula —OR53 wherein >53
is aralkyl as defined above. As used herein the term "nitro" is represented by a radical of the formula I—NO2
As used herein the term "halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
As used herein the term "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. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like. As used herein the term "carboxyl" or "carboxy" refers to a radical of the formula -COOH.
As used herein the term "aminoalkyl" refers to a radical of the formula -R54-NH2 wherein R54 is lower alkylene as defined above. As used herein the term "carboxyl derivative"
refers to a radical of the formula || wherein
—C—Y7R23
Y6 and Y7 are independently selected from the group consisting of 0, N or S and R23 is selected from the group consisting of H, alkyl, aralkyl or aryl as defined above. As used herein the term "amino" is represented by a radical of the formula -NH2.
As used herein the term "alkylsulfonyl" or "alkylsulfone" refers to a radical of the formula
wherein R24 is alkyl as def ined above .
Figure imgf000017_0001
As used herein the term "alkylthio" refers to a radical of the formula -SR24 wherein R24 is alkyl as defined above. As used herein the term "sulfonic acid" refers to
0 a radical of the formula f—s—OR25 wherein R25 is H,
* II O alkyl or aryl as defined above.
As used herein the term "sulfonamide" refers to a
radical of the formula wherein R7 and R8 are as
Figure imgf000017_0002
defined above.
As used herein, the term "N-substituted pyrrolidinyl" refers to a radical of the formula
l-O
As used herein the term "N-substituted piperidinyl" refers to a radical of the formula
Figure imgf000017_0003
As used herein the term " orpholinyl" refers to a radical of the formula I—N o .
As used herein the term "fused aryl" refers to an aromatic ring such as the aryl groups defined above fused to one or more phenyl rings. Embraced by the term "fused aryl" is the radical naphthyl. As used herein the terms "monocyclic heterocycle" or "monocyclic heterocyclic" refer to a monocyclic ring containing from 4 to about 12 atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 of the atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur with the understanding that if two or more different heteroatoms are present at least one of the heteroatoms must be nitrogen. Representative of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole, and the like.
As used herein the term "fused monocyclic heterocycle" refers to a monocyclic heterocycle as defined above with a benzene fused thereto. Examples of such fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.
As used herein the term "methylenedioxy" refers to
the radical and the term "ethylenedioxy" refers
Figure imgf000018_0001
to the radical
Figure imgf000018_0002
As used herein the term "4-12 membered dinitrogen containing heterocycle refers to a radical of the
formula wherein m is 1 or 2 and R1 is H,
Figure imgf000018_0003
alkyl, aryl, or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline.
As used herein the term "5-membereά heteroaromatic ring" includes for example a radical of the formula
and "5-membered heteroaromatic ring fused
Figure imgf000019_0001
with a phenyl" refers to such a "5-membered heteroaromatic ring" with a phenyl fused thereto. Representative of such 5-membered heteroaromatic rings fused with a phenyl is benzimidazole. As used herein the term "bicycloalkyl" refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms which is saturated or partially unsaturated.
As used herein the term "acyl" refers to a radical
of the formula wherein R26 is alkyl, alkenyl.
Figure imgf000019_0002
alkynyl, aryl or aralkyl as defined above. Encompassed by such radical are the groups acetyl, benzoyl and the like.
As used herein the term "thio" refers to a radical of the formula —SH
As used herein the term "sulfonyl" refers to a
O radical of the formula j—S—R27 wherein R27 is alkyl,
II o
aryl or aralkyl as defined above. As used herein the term "haloalkylthio" refers to a radical of the formula -S-R28 wherein R28 is haloalkyl as defined above.
As used herein the term "aryloxy" refers to a radical of the formula I—OR29 wherein R29 is aryl as
defined above.
As used herein the term "acylamino" refers to a
O radical of the formula R30 ii NH wherein R30 is alkyl,
aralkyl or aryl as defined above. As used herein the term "amido" refers to a
radical of the formula wherein RJ-n1 is a bond
Figure imgf000020_0001
or alkylene as defined above.
As used herein the term "alkylamino" refers to a radical of the formula -NHR32 wherein R32 is alkyl as defined above.
As used herein the term "dialkylamino" refers to a radical of the formula -NR33R34 wherein R33 and R34 are the same or different alkyl groups as defined above. As used herein the term "trifluoromethyl" refers
to a radical of the formula f-CF3
As used herein the term "trifluoroalkoxy" refers to a radical of the formula F3C—R35*—O— wherein R35 is
a bond or an alkylene as defined above. As used herein the term "alkyla inosulfonyl"
refers to a radical of the formula wherein
Figure imgf000021_0001
R36 is alkyl as defined above.
As used herein the term "alkylsulfonyla ino"
refers to a radical of the formula
Figure imgf000021_0002
wherein R36 is alkyl as defined above.
As used herein the term "trifluoromethylthio" refers to a radical of the formula F3C—S—j .
As used herein the term "trifluoromethylsulfonyl" o refers to a radical of the formula F3c—S— .
As used herein the term "4-12 membered mono¬ nitrogen containing monocyclic or bicyclic ring" refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4-12 atoms and more preferably a ring of 4-9 atoms wherein one atom is nitrogen. Such rings may optionally contain additional heteroatoms selected from nitrogen, oxygen or sulfur. Included within this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like.
As used herein the term "benzyl" refers to the
radical j—CH2— fl As used herein the term "phenethyl" refers to the
radical j—CH2CH2— < .
As used herein the term "4-12 membered mono¬ nitrogen containing sulfur or oxygen containing heterocyclic ring" refers to a ring consisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein at least one atom is a nitrogen and at least one atom is oxygen or sulfur. Encompassed within this definition are rings such as thiazoline and the like. As used herein the term "arylsulfonyl" or
"arylsulfone" refers to a radical of the formula
O
R37—s "—*I wh._erei.n R3J7 i.s aryl as defined above.
As used herein the terms "alkylsulfoxide" or "arylsulfoxide" refer to radicals of the formula
wherein R3J8O i•s, respectively, alkyl or aryl as
Figure imgf000022_0001
defined above.
As used herein the term "phosphonic acid
derivative" refers to a radical of the formula
Figure imgf000022_0002
wherein R39 and R40 are the same or different H, alkyl, aryl or aralkyl.
As used herein the term "phosphinic acid derivatives" refers to a radical of the formula O _QD4 wherein R41 is H , alkyl , aryl or aralkyl as
H
defined above.
As used herein the term "arylthio" refers to a radical of the formula I—SR42 wherein R42 is aryl as
defined above.
As used herein the term "monocyclic heterocycle
thio" refers to a radical of the formula —SR*"
wherein R43 is a monocyclic heterocycle radical as defined above. As used herein the terms "monocyclic heterocycle sulfoxide" and "monocyclic heterocycle sulfone" refer,
respectively, to radicals of the formula and
Figure imgf000023_0001
wherein R43 is a monocyclic heterocycle
Figure imgf000023_0002
radical as defined above. As used herein the phrase "wherein the X-R3 group is attached to the phenyl of the Y group at the para position to form a lactone" refers to a radical of the
formula
Figure imgf000023_0003
The term "composition" as used herein means a product which results from the mixing or combining of more than one element or ingredient.
The term "pharmaceutically acceptable carrier", as used herein 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. The term "therapeutically 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. The following is a list of abbreviations and the corresponding meanings as used interchangeably herein:
1H-NMR = proton nuclear magnetic resonance AcOH = acetic acid BH3-THF = borane-tetrahydrofuran complex BOC = tert-butoxycarbonyl Cat. = catalytic amount CH2C12 = dichloromethane CH3CN = acetonitrile CH3I = iodomethane
CH analysis = carbon/hydrogen/nitrogen elemental analysis CHNC1 analysis = carbon/hydrogen/nitrogen/chlorine elemental analysis CHNS analysis = carbon/hydrogen/nitrogen/sulfur elemental analysis DCC = 1,3-dicyclohexylcarbodiimide DIEA = diisopropylethylamine DMA - H#N-dimethylacetamide DMAP = 4-(N,N-dimethylamino)pyridine DMF = N,N-dimethylformamide DSC = disuccinyl carbonate EDC1 = l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride Et20 = diethyl ether Et3N = triethylamine EtOAc = ethyl acetate EtOH = ethanol
FAB MS = fast atom bombardment mass spectroscopy g = gram(s)
GIHA HCI = meta-guanidino-hippuric acid hydrochloride GIHA = meta-guanidino-hippuric acid HPLC = high performance liquid chromatography
IBCF = isobutylchloroformate
K C03 = potassium carbonate
KOH = potassium hydroxide LiOH = lithium hydroxide
MCPBA = m-chloroperoxybenzoic acid or m-chloroperbenzoic acid
MeOH = methanol
MesCl = methanesulfonylchloride mg = milligram
MgS04 = magnesium sulfate ml = milliliter mL =* milliliter
MS = mass spectroscopy N2 = nitrogen
NaCNBH3 = sodium cyanoborohydride
Na2P04 = sodium phosphate
Na2S04 = sodium sulfate
NaHC03 = sodium bicarbonate NaOH = sodium hydroxide
NH4HC03 = ammonium bicarbonate
NH4 +HC02 ~ = ammonium formate
NMM = N-methyl morpholine
NMR = nuclear magnetic resonance RPHPLC = reverse phase high performance liquid chromatography
RT = room temperature
KSCN = potassium thiocyanate
Pd/C = palladium on carbon Bn = benzyl
Et - ethyl
Me = methyl
Ph = phenyl
NEt3 = triethylamine t-BOC = tert-butoxycarbonyl
TFA = trifluoroacetic acid
THF = tetrahydrofuran
Δ = heating the reaction mixture As used herein HPLC-Method 1 refers to reverse phase C-18 functionalized silica gel column (50 x 300 mm) using a linear gradient of 95% 0.6% TFA/water:5% CH3CN to 60% 0.6% TFA/water: 40% CH3CN with a flow rate of 80 ml/minute. The compounds as shown in Formulas I-III can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers. In the structures and formulas herein, a bond drawn across a bond of a ring can be to any available atom on the ring.
The term "pharmaceutically acceptable salt" refers to a salt prepared by contacting a compound of Formula I 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, alate, succinate, tartrate salts and the like. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Phar . Sci.. 66(1), 1-19 (1977) for additional examples of pharmaceutically acceptable salts.)
For the selective inhibition or antagonism of αv33 integrins, 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. The term parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitonally. 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. Accordingly, the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the avβ2 cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in Formulas I-III, wherein one or more compounds of the Formulas I-III 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 otvβ cell surface receptor. Most preferably 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, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis. Based upon standard laboratory experimental techniques and procedures well known and appreciated by those skilled in the art, as well as comparisons with compounds of known usefulness, the compounds of Formula I can be used in the treatment of patients suffering from the above pathological conditions. One skilled in the art will recognize that 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 of the Formula I 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. As used herein, the term "inhibition" of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially controlled to some extent.
As stated previously, 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 avβ3 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 of the order from about 0.01 mg to about 100 mg/kg of body weight.
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 100 mg/kg body weight injected per day in multiple doses depending on the factors listed above and more preferably from about 0.01 to about 10 mg/kg body weight. For administration to a mammal in need of such treatment, 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. Alternatively, the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The pharmaceutical 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.
The general synthetic sequences for preparing the compounds useful in the present invention are outlined in Schemes I-III. Both an explanation of, and the actual procedures for, the various aspects of the present invention are described where appropriate. The following Schemes and Examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those of skill in the art will readily understand that known variations of the conditions and processes described in the Schemes and Examples can be used to perform the process of the present invention.
Unless otherwise indicated all starting materials and equipment employed were commercially available.
Figure imgf000030_0001
SCHEME I (Cont'd)
Figure imgf000031_0001
SCHEME I (Cont'd)
Figure imgf000032_0001
Figure imgf000033_0001
in Scheme I is illustrative of methodology useful for preparing various compounds of the present invention. Such methodology is more specifically defined in the examples which follow. Such methodology can be modified by one skilled in the art, substituting known reagents and conditions from conventional methodology to produce the desired compounds.
Specifically, in Scheme I:
In the synthesis of intermediate benzoic acids (Al) through (A16) , the starting amino benzoic acids
are either commercially available
Figure imgf000034_0001
or can be converted to such amino benzoic acids via reduction of the corresponding nitro benzoic acid, which can be obtained commercially or syntheized by nitration of the appropriate benzoic acid, followed by reduction to the desired amino benzoic acid. These are all when R5 is H. If R5 is other than H, alkylation of the amino functionality can be achieved by conventional methodology.
Furthermore, synthesis of intermediate (A2) can also be accomplished as disclosed generally in US 3,202,660, starting with the appropriate amino benzoic acid. Furthermore, intermediate (A2) and (A15) as well as further analogues of (A2) and (A15) such as substitutions on the heterocyclic ring, oxazolidines, thiazolidines, benzimidazoles and the like can also be accomplished as disclosed in
1) Chem. Pharm. Bull. 41(1) 117-125 (1993) T 2) Chem. Pharm. Bull. 33(10) 4409-4421 (1985) 3) J. Med. Chem. 18 (1), 90-99 (1975).
Figure imgf000035_0001
used in the synthesis of intermediates <»3,,
can be synthesized from and (Me)3OBF4 in
Figure imgf000035_0002
dichloromethane.
\* /NH ~~ ' HCI used in the synthesis of intermediate
OMe
(A4), can be synthesized from Y2-CN and MeOH (1 equivalent) and HCI gas (1 equivalent) in heptane.
Furthermore, the procedures outlined in Scheme I are also applicable to the preparation of the corresponding sulphonic acids described herein.
All other reagents in Scheme I are either commercially available or readily synthesized by methodologies known by those skilled in the art.
SCHEME τi
(In all cases R ,5*"7 = alkyl, alkylaryl, t-Bu)
Figure imgf000036_0001
(A)
(B)
Cl
SCHEME II (Cont'd!
(C)
Figure imgf000037_0001
(D) (M = N02 or CN)
NaH/THF
SCHEME II (Cont'd)
(E) (M = N02 or CN)
Figure imgf000038_0001
SCHEME II (Cont'd)
(F) (M = N02 or CN)
Figure imgf000039_0001
DMF or i-Pr2NH2
In Scheme II(A) phenylpropionic acid Dl is readily prepared from aldehyde/or ketone BI in the following manner.
Aldehyde or ketone BI is condensed with (EtO)2P(0)CH2COR under standard conditions (NaH/THF 0° to room temperature) . The resulting cinnamic acid derivative C_i is reduced (4% Pd/C, EtOH, 5 psi) to afford the desired phenylpropionic acids Dl.
When substituents Z4 and Z5 are sensitive to the catalytic hydrogenation conditions described above, the following synthetic procedure may be utilized.
Nitrophenylcinnamic acid Cl is partially reduced with magnesium in MeOH to afford nitrophenylpropionic acid Ei. Further reduction of the nitro moiety (SnCl2/H20/HCl/EtOH) affords the desired phenylpropionic acid Dl.
In an identical manner to that described in Scheme 11(A) aldehyde/or ketone B2. is readily converted into phenylpropionic acid D2. In Scheme 11(D), phenylpropionic acids p_i and D2 may be prepared from bromide B3.
Bromide B3. can be coupled with alkylacrylates E2. using a standard Heck coupling procedure (Pd(0Ac)2, P(PhMe)3, DMF, 130°) to afford cinnamic acid C3.. Cinnamic acid C_3_ may be converted into phenylpropionic acid Dl (where M = N02) and phenylpropionic acid D2 (where M = CN) using the reductions described in Scheme 11(A) , (B) and (C) .
Furthermore, alkylacrylates E2., are readily prepared by condensing the requisite aldehyde (R56CHO) with (EtO)2P(0)CH2COR using standard and well known reaction conditions such as (NaH, THF, 0°).
In Scheme 11(E), phenylpropionic acids D4 and D5 may be prepared from aldehyde B4. as described below. Aldehyde B, is condensed with (EtO)2P(0)CH2COR using standard conditions (NaH, THF, 0°C) to afford substituted phenylcinnamic acid C . Phenylcinnamic acid C4. may be converted into phenylpropionic acid D4. (where M = N02) and phenylpropionic acid D5 (where M = CN) using the reductions described in Scheme 11(A), (B) and (C) . In Scheme 11(F), phenylpropionic acids D4_ and D£ may be prepared from bromide B5.
Bromide B5 can be coupled with alkylacrylates E3_ using a standard Heck coupling procedure (Pd(OAc)2, P(PhMe)3, DMA, 130°) to afford phenylcinnamic acid C4. Phenylcinnamic acid C± may be converted into D4 and D5 as described above in Scheme 11(E).
Coupling of the intermediates from Scheme I [ (Al) through (A16) ] with the intermediate (D1-D5) (from Scheme II Steps (A-F) ) can be accomplished using the following coupling methods and other coupling reagents known to those in the art to give the final desired products. All electrophilic intermediates containing R1 from Scheme I, Step (A) are either commercially available or are readily synthesized via methodology known to those skilled in the art.
Figure imgf000043_0001
in SCHEME III (Cont'd)
Method B
Figure imgf000044_0001
Method C
Figure imgf000045_0001
3) TFA
Method B
An alternative method to prepare compounds of the present invention is outlined below.
In this procedure, intermediates D1-D5 (from Scheme II, (A-F)) are coupled to 3-nitro phenylsulphonyl chloride FI (CH2C12, NEt3 0°). The resulting coupled product T is reduced (SnCl2/EtOH H20, 100°) to the corresponding aniline. The resulting aniline may be converted into compounds of the present invention using the procedures described in Scheme I (A1-A16) followed by deprotection (TFA/CH2Cl2/0°) .
This procedure is exemplified by converting the above aniline to its corresponding guanidine analog (BOCNHCSNHBOC, H2C12, DMF) followed by deprotection (TFA, CH2C12) . Method C
Method C is identical to that described in Method B except the 3-nitrophenylsulphonyl chloride PI is replaced with 3-nitrobenzoylchloride F2.
When R11 is not H, the appropriate nitrogen can be alkylated in an appropriate step by methodology known to those skilled in the art. Alternate acid derivatives R are synthesized by methodologies known to those skilled in the art.
To synthesize compounds wherein
where t = 1 and Y3 and 7? are both hydrogen:
Figure imgf000047_0001
Figure imgf000047_0002
which is then treated in the same manner of further derivatization as exemplified in the previous schemes for:
SCHEME IV
Figure imgf000048_0001
p = 0 and 1
In an analogous fashion to that described in Scheme IΙ(a-h) and as depicted in Scheme IV, aldehyde Gl or bromide G2_ can be converted into phenylpropanoic acid HI (using well established and known chemistry to mask and unmask the hydroxy moiety) .
Phenylpropanoic acid HI is then readily coupled to benzoic acids A1-A15 using procedures previously described to afford the compounds of the present invention.
Figure imgf000050_0001
in Scheme V outlines methodologies for preparing the chalcone derivatives (J3) of the present invention. 3- Hydroxyacetophenone was reacted with t-butyl bromoacetate (K2C03/DMF) to provide Jl, which was condensed with 3-nitrobenzaldehyde (J2) (KOH, EtOH). The resulting product J3 was reduced (SnCl2/EtOH) to the corresponding aniline. The resulting aniline was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg2Cl2, DMF), followed by deprotection (TFA, CH2C12) , or otherwise functionalized as described in Scheme I.
Figure imgf000052_0001
in Scheme VI outlines methodologies for preparing the K3 type derivatives of the present invention. 3- Hydroxycinnamate was reacted with 2-bromo-3'- nitroacetophenone (Kl) (K2C03/acetone) to provide K2. The resulting product was reduced (H2, Pd/C) to the corresponding aniline K3. The resulting aniline was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg2Cl2, DMF), followed by deprotection (TFA, CH2C12) , or otherwise functionalized as described in Scheme I, to give K4- Hydrolysis under standard basic conditions (NaOH/H20/MeOH) provided the carboxylic acid derivative.
SCHEME VII
Figure imgf000054_0001
Scheme VII outlines methodologies for preparing the L3 type derivatives of the present invention. 3- Hydroxybenzophenone was converted to LI using the methods described in Scheme 11(A). LI was coupled with 3- nitrobenzyl bromide (LJ2) and reduced (H2, Pd/C) . The resulting aniline L3. was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg2Cl2, DMF), followed by deprotection (TFA, CH2Cl2) , or otherwise functionalized as described in Scheme I.
SCHEME VIII
Figure imgf000056_0001
SCHEME VIII (Cont'd)
Figure imgf000057_0001
Scheme VIII outlines methodologies for preparing the thio derivatives of the present invention. 3-Thioaniline (Ml) was reacted with 3-bromobenzophenone (NaH, DMF) to provide M.. Mg: was converted to M3 using the methods described in Scheme 11(B). M3. was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg2Cl2, DMF) , or otherwise functionalized as described in Scheme I to give M.. M4. was deprotected (TFA, CH2Cl2) , followed by hydrolysis under standard basic conditions (NaOH/H20/MeOH) to provide the corresponding carboxylic acid derivative. M4 was oxidized (tetra-n-butyl ammonium oxone/CH2Cl2) to give M5., which was deprotected (TFA, CH2C12) , followed by hydrolysis under standard basic conditions (NaOH/H20/MeOH) to provide the corresponding carboxylic acid derivative.
M5 was oxidized (tetra-n-butyl ammonium oxone/CH2Cl2) to give M6, which was deprotected (TFA, CH2C1 ) , followed by hydrolysis under standard basic conditions (NaOH/H20/MeOH) to provide the corresponding carboxylic acid derivative.
SCHEME IX
Figure imgf000059_0001
SCHEME IX (Cont'd)
Figure imgf000060_0001
Scheme IX outlines methodologies for preparing the alkene and alkyne derivatives of the present invention. 3-Hydroxybenzophenone was converted to LI using the methods described in Scheme II(A) . LI was reacted with trifluoromethane sulfonic anhydride (Et3N, CH2C12) to give NI. NI was reacted with trimethylsilyl acetylene ((Ph3P)2PdCl2, Cul, Et2NH) , followed by hydrolysis (KOH/MeOH) , to provide NJ.. N2 was coupled with B_5 using the methods described in Scheme 11(F). The resulting product N3 was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg2Cl2, DMF), followed by deprotection (TFA, CH2C12) , or otherwise functionalized as described in Scheme I.
NI was coupled with 3-nitro styrene using the methods described in Scheme 11(F). The resulting product N4 was reduced (SnCl2/EtOH) to the corresponding aniline. The resulting aniline was converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg2Cl2, DMF), followed by deprotection (TFA, CH2C12) , or otherwise functionalized as described in Scheme I.
N3 was reduced (SnCl2/EtOH) to the corresponding aniline. The resulting aniline was further reduced (HC02H, Pd/C, Et3N) to its cis alkene N6- was converted to its corresponding guanidine analog
(BOCNHCSNHBOC, Hg2Cl2, DMF), followed by deprotection (TFA, CH2C12) , or otherwise functionalized as described in Scheme I.
N5 can be further reduced to its corresponding alkene (H2, Pd/C) which can be converted to its corresponding guanidine analog (BOCNHCSNHBOC, Hg2Cl2, DMF) , followed by deprotection (TFA, CH2C12) , or otherwise functionalized as described in Scheme I. Example A (3-Guanidinobenzoic acid hydrochloride)
Figure imgf000062_0001
To 3,5-dimethylpyrazole-l-carboxamidine nitrate (6 g, 0.03 mole) (Aldrich) and diisopropylamine (3.8 g, 0.03 mole) in dioxane (20 ml) and H20 (10 ml) was added 3-aminobenzoic acid (2.7 g, 0.02 mole). The reaction was stirred at reflux for 2.5 hours then overnight at room temperature. The resulting precipitate was filtered, washed with dioxane/H20 and dried. The precipitate was then slurried in H20 and acidified with concentrated HCI until a solution formed. The solvent was removed under vacuum and the residue was slurried twice in ether (ether decanted off) . The product was dried under vacuum to yield 3-guanidinobenzoic acid hydrochloride (1.77 g) as a white solid. MS and NMR were consistent with the desired structure.
Example B 3-(l-Aza-2-amino-l-cycloheptyl) enzoic acid hydrochloride
Figure imgf000062_0002
To l-aza-2-methoxy-l-cycloheptene (3.67 g, 0.0288 mole) (Aldrich) in absolute ethanol (20 ml) was added 3-aminobenzoic acid hydrochloride (5 g, 0.0288 mole). A solution quickly formed. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered, washed with ether and dried under vacuum to yield 3-(l-aza-2-amino-l-cycloheptene)- benzoic acid (4.9 g) .
Example C
3-(l-aza-2-amino-l-cycloheptene)-5- trifluoromethylbenzoic acid hydrochloride
Figure imgf000063_0001
The title compound was synthesized according to the methodology of Example B, substituting an equivalent amount of 3-amino-5-trifluoromethyl benzoic acid [which was synthesized by reduction of 3-nitro-5- trifluoromethyl benzoic acid (Lancaster) in ethanol with 10% Pd/C under 50 psi H2 for 4 hours] for 3-aminobenzoic acid.
Example D
3-guanidino-5-trifluoromethylbenzoic acid, hydrochloride
Figure imgf000063_0002
The title compound was synthesized according to the methodology of Example A, substituting an equivalent amount of 3-amino-5-trifluoromethylbenzoic acid (see Example C) for 3-aminobenzoic acid.
Figure imgf000064_0001
In a flask under nitrogen was placed 1.8 g of sodium hydride (60% mineral oil dispersion; Aldrich) which was washed three times with hexane. The hydride was then suspended in 50 mL of dry tetrahydrofuran (THF) and chilled in an ice bath. A solution of t-butyl P,P-dimethyl phosphonacetate (10.1 g) (Fluka) in THF (25 ml) was added dropwise and the reaction mixture was stirred for 1 hour at 0°. In another flask was dissolved 3-nitrobenzaldehyde (6.8 g) in THF (50 ml) . The flask was chilled in an ice bath and the contents of the first flask was added dropwise over 15 minutes at 0-5°C. The ice bath was then removed and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous portion was extracted several times with ethyl acetate and the combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and purified on a silica gel column eluting with 10% ethyl acetate - 90% hexane to afford 8.9 g of a yellow oil. NMR was consistent with the proposed structure as a mixture of cis and trans isomers. Example F
Figure imgf000065_0001
A solution of the product from Example E (8.9 g) in ethanol (80 mL) was hydrogenated under an atmosphere of 5 psi of hydrogen at room temperature for 2 hours using 4% palladium on carbon (1.5 g) as catalyst. The reaction mixture was concentrated and the crude product was purified on a silica gel column eluting with 1:1 ethyl acetate-hexane to afford 6.4 g of white solid. NMR was consistent with the proposed structure. Example G
Figure imgf000065_0002
A solution of the product from Example F (1.5 g) and 3-nitro-benzenesulfonylchloride (1.2 g) (Aldrich) in methylene chloride (15 mL) (CH2C12) was chilled to 0° under nitrogen. A solution of triethylaraine (510 mg) in CH2C12 (2 mL) was added in one portion and the reaction mixture was then allowed to stir while warming to room temperature for 12 hours. The reaction mixture was then partitioned between chloroform and water and the aqueous portion extracted several times with chloroform. The combined organic extracts were washed with saturated sodium chloride solution (2X) , dried (Na2S04) , and purified on a silica gel column eluting with 40% ethylacetate -60% hexane to afford 900 mg of white solid. NMR was consistent with the proposed structure. Example H
Figure imgf000066_0001
A solution of the product from Example G (3.0 g) in a 1:1 mixture of ethanol and THF (50 ml) was hydrogenated using Raney nickel at warm temperature and 5 psi of hydrogen for 16 hours. The reaction mixture was concentrated and purified on a silica gel column eluting with 70% ethyl acetate -30% hexane to afford 1.8 g of white solid.
NMR was consistent with the proposed structure.
Example I
Figure imgf000066_0002
To a solut on of the product from Example H (625 mg) , bis-t-butoxycarbonyl thiourea, (Ivanowicz et al., Synthetic Communications, 1993, 2., 1443) and triethylamine (461 mg) (Et3N) in DMF (10 ml) at 0° under nitrogen was added mercuric chloride (416 mg) in one portion. The reaction mixture was stirred for 30 minutes at 0° and then 30 minutes at room temperature. The reaction was quenched with ethyl acetate (15 L) , stirred for 30 minutes, and then filtered and concentrated. The crude product was purified on a silica gel column eluting with 25% ethyl acetate -75% hexane to afford 393 mg of white solid.
NMR was consistent with the proposed structure. Example 1 Synthesis of 3-[ [ [3-[ (aminoiminomethyl)amino]phenyl] sulfonyl]amino]-/9-phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000067_0001
A solution of trifluoroacetate acid (5 ml) , methylene chloride (5 ml) and the product from Example I (380 mg) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified via reverse phase HPLC using a water (0.5% TFA) and acetonitrile gradient as eluant to afford 191 mg of white solid. NMR was consistent with the proposed structure. Analysis Calculated for C22H22N404S- 1.4 CF3C02H:
C, 49.80; H, 3.94; N, 9.37; S, 5.36 Found: C, 49.81; H, 3.72; N, 9.35; S, 5.17.
Example J
Figure imgf000068_0001
The reaction was run as described in Example G using the product from Example F (1.5 g) , 3- nitrobenzoyl chloride (935 mg) (Aldrich) , triethylamine (510 mg) and methylene chloride (15 ml) . The crude product was purified on a silica gel column eluting with 20% ethyl acetate -80% hexane to afford 1.6 g of white solid. NMR was consistent with the proposed structure.
Example K
Figure imgf000068_0002
The reaction was run as described in Example F using the product from Example J (1.6 g) , ethanol (20 ml) and 4% Pd/C (100 mg) . The crude product was purified on a silica gel column eluting with 1:1 ethyl acetate:hexane to afford 1.3 g of white solid.
NMR was consistent with the proposed structure. Example L
Figure imgf000069_0001
The reaction was run as described in Example I using the product from Example K (1.3 g) , bis-t- butoxycarbonyl thiourea (829 mg) , triethylamine (1.0 g) , mercuric chloride (896 mg) and DMF (10 ml) . The crude product was purified on a silica gel column eluting with 25% ethyl acetate -75% hexane to afford 1.1 g of white solid.
NMR was consistent with the proposed structure.
Example 2 Synthesis of 3-[ [ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]-/3-phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000070_0001
The reaction was run as described in Example 1 using the product from Example L (1.1 g) and a 1:1 TFA:CH2C12 solution (10 ml). The crude product was purified as previously described to afford 883 mg of white solid.
NMR was consistent with the proposed structure.
Analysis Calculated for C23H22N403* CF3COzH -0.75 H20:
C, 56.66; H, 4.66; N, 10.57. Found: C, 56.60; H, 4.38; N, 10.57.
Example 4
Synthesis of l,l-dimethylethyl 3-[ [ [3- [ (aminocarbonyl)amino]phenyl]carbonyl]amino] 3-phenylbenzenepropanoate
Figure imgf000071_0001
A solution of the product from Example K (750 mg) , glacial acetic acid (15 ml) and water (2.5 ml) was heated to 38°. A solution of potassium cyanate (406 mg) (Aldrich) in water (2.5 ml) was added dropwise with stirring. A gummy precipitate resulted. After stirring at room temperature overnight, the solvent was removed in vacuo and the residue was purified on a silica gel column eluting with 1% methanol -99% methylene chloride to afford 452 mg of white solid. NMR was consistent with the proposed structure.
Example 5 Synthesis of 3-[ [ [3-[ (aminocarbonyl)amino]phenyl]' carbonyl]amino]-/3-phenylbenzenepropanoic acid
Figure imgf000072_0001
The reaction was run as described in Example 1 using the product from Example 4 (425 mg) to afford 285 mg of white solid. NMR was consistent with the proposed structure.
Analysis Calculated for C23H21N304 -1.25 H20:
C, 64.85; H, 5.56; N, 9.86. Found: C, 64.69; H, 5.27; N, 9.63.
Example P
Figure imgf000073_0001
To a solution of potassium carbonate (175 mg)
(Aldrich) in DMF (9 ml) at room temperature was added a solution of the product from Example G (500 mg) in DMF (3 ml) dropwise. The reaction mixture was stirred for 30 minutes and then a solution of iodomethane (426 mg) (Aldrich) in DMF (3 ml) was added dropwise. The reaction mixture was stirred for 30 minutes and then partitioned between ethyl acetate and water. The aqueous portion was extracted several times with ethyl acetate and the combined organic extracts were washed with water (2X) , saturated sodium chloride solution
(IX) , and dried (Na2S04) . The solvent was removed in vacuo and the residue was purified on a silica gel column eluting with 25% ethyl acetate -75% hexane to afford 311 mg of a light yellow glass. NMR was consistent with the proposed structure.
Example 0
Figure imgf000074_0001
The reaction was run as described in Example N using the product from Example P (450 mg) . The crude product was purified in the same fashion to afford 240 mg of a colorless viscous oil. NMR was consistent with the proposed structure.
Example R
Figure imgf000074_0002
The reaction was run as described in Example I using the product from Example Q (230 mg) , bis-t- butoxy-carbonyl thiourea (166 mg) , triethylamine (126 mg) , and mercuric chloride (163 mg) in DMF (10 ml) . The crude product was purified in similar fashion to afford 140 mg of white solid. NMR was consistent with the proposed structures. Example 6
Synthesis of 3-[[[4-[ (aminoiminomethyl)amino]phenyl] sulfonyl]methylamino]-β-phenylbenzenepropanoic aci , trifluoroacetate salt
Figure imgf000075_0001
The reaction was run as described in Example 1 using the product from Example R (130 mg) to afford 58 mg of white solid. NMR was consistent with the proposed structure.
Analysis Calculated for C23H24N404S -1.5 TFA: C, 50.08; H, 4.12; N, 8.98; S, 5.14.
Found: C, 49.74; H, 4.00; N, 8.87; S, 5.26.
Example 7
Synthesis of 1,1-dimethylethyl 3-[ [ [3-[ (aminocarbonyl)- amino]phenyl]sulfonyl]amino]-/9-phenylbenzenepropanoate
Figure imgf000076_0001
The reaction was run as described in Example 4 using the product (229 mg) from Example H (640 mg) , potassium cyanate (229 mg) (Aldrich) , glacial acetic acid (3 ml) and water (10 ml) . The crude product was purified on a silica gel column eluting with 5% methanol -95% methylene chloride to afford 435 mg of viscous golden oil. NMR was consistent with the proposed structure.
Example 8 Synthesis of 3-[ [ [3-[ (aminocarbonyl)amino]phenyl] sulfonyl]amino]-3-phenylbenzenepropanoic acid
Figure imgf000077_0001
The reaction was run as described in Example 1 using of the product from Example 7 (400 mg) to afford 195 mg of white solid. NMR was consistent with the proposed structure.
Analysis Calculated for C22H21N305S -0.4TFA- 0.4 H20.
C, 55.63; H, 4.55; N, 8.54; S, 6.51. Found: C, 55.66; H, 4.38; N, 8.46; S, 6.76.
Example 9
Synthesis of 1 , 1-dimethylethyl 3 - [ [ [ 3 - [ ( aminothioxomethyl ) amino ] phenyl ] sulfonyl ] amino ] -<5-phenylbenzenepropanoate
Figure imgf000078_0001
To a solution of thiophosgene (92 mg) (Aldrich) in methylene chloride (1 ml) at 0° was added a solution of the product from Example H (350 mg) , triethylamine (162 mg) and methylene chloride (1.5 ml) dropwise. The reaction mixture was stirred for 15 minutes and then concentrated. The residue was dissolved in THF (5 ml) and treated with concentrated ammonium hydroxide solution (5 ml) for 5 minutes at room temperature. The reaction mixture was concentrated and purified on a silica gel column eluting with 3% methanol -97% methylene chloride to afford 236 mg of white solid. NMR was consistent with the proposed structure.
Example 10
Synthesis of 3-[ [ [3-[ (ammothioxomethyl) amino ] phenyl] sulfonyl] amino] -β- phenylbenzenepropanoic acid
Figure imgf000079_0001
The reaction was run as described in Example 1 using the product from Example 9 (225 mg) to afford 150 mg of white solid. NMR was consistent with the proposed structure.
Analysis Calculated for C22H21N304S2 -0.5 H20-o.25 CH3CN C, 56.91; H, 4.83; N, 9.59; S, 13.51.
Found: C, 56.91; H, 4.55; N, 9.48; S, 13.20.
Example S
Figure imgf000080_0001
A solution of the product from Example F (1.5 g), 3-nitrobenzyl bromide (1.1 g) (Fluka) , potassium carbonate (1.4 g) and DMF (25 ml) was stirred at room temperature under nitrogen for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted several times with ethyl acetate and then the combined organic extracts were washed with saturated sodium chloride solution (2X) , dried (Na2S04) and concentrated. The residue was purified on a silica gel column eluting with 25% ethyl acetate -75% hexane to afford 1.5 g of a viscous orange oil. NMR was consistent with the proposed structure.
Example T
Figure imgf000081_0001
A solution of the product from Example S (1.5 g) , triethylamine (7.5 ml), and DMF (20 ml) was treated with di-t-butyldicarbonate (3.0 g) (Aldrich) and 4- dimethyla inopyridine (50 mg) (Aldrich) at 55° for 24 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous portion was extracted with additional ethyl acetate and then the combined organic extracts were washed with saturated sodium chloride solution (2X) , dried (Na2S04) and concentrated. The residue was purified on a silica gel column eluting with 20% ethyl acetate -80% hexane to afford 580 mg of viscous golden oil. The NMR structure was consistent with the proposed structure.
Example U
Figure imgf000082_0001
A solution of 560 mg of the product from Example T (560 mg) in ethanol (10 ml) was reduced under an atmosphere of 5 psi hydrogen at room temperature for 4 hours with 5% platinum on carbon catalyst. The reaction mixture was concentrated and purified on a silica gel column eluting with 25% ethyl acetate -75% hexane to afford 340 mg of a viscous colorless oil. NMR was consistent with the proposed structure.
Example V
Figure imgf000082_0002
The reaction was run as described in Example I using the product from Example U (320 mg) , bis-t-butoxy carbonyl thiourea (193 mg) , triethylamine (132 mg) , mercuric chloride (217 mg) and DMF (8 ml) . The crude product was purified on a silica gel column eluting with 15% ethyl acetate -85% hexane to afford 303 mg of a colorless viscous oil. NMR was consistent with the proposed structure. Example 11
3~[[ .3~[ (aminoiminomethyl)amino]phenyl]methyl]amino]-/?■ phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000083_0001
The reaction was run as described in Example 1 using the product from Example V (280 mg) and a 1:1 TFA:methylene chloride solution (15 ml) . The crude product was purified as previously described to afford 205 mg of white solid. NMR was consistent with the proposed structure.
Analysis Calculated for C23H2 N402* 2.5TFA- 1.2H20
C, 48.38; H, 4.19; N, 8.06. Found: C, 48.18; H, 4.03; N, 8.06.
Example 12
Synthesis of 1, 1-dimethylethyl 3-[[[3- [ [ [ (phenylmethyl) amino]carbonyl]amino]phenyl]- sulfonyl]amino]-3-phenylbenzenepropanoate, monohydrate
Figure imgf000084_0001
A solution of the product from Example H (400 mg) , benzyl isocyanate (600 mg) (Aldrich) and toluene (5 ml) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo . The residue was purified on a silica gel column eluting with 40% ethyl acetate -60% hexane to afford 208 mg of white solid. NMR was consistent with the proposed structure.
Example 13
Synthesis of 3-[ [ [3-[ [[ (phenylmethyl)amino]carbonyl] amino]phenyl]sulfonyl]amino]-3-phenylbenzenepropanoic acid, monohydrate
Figure imgf000085_0001
The reaction was run as described in Example 1 using the product from Example 12 (190 mg) to afford 150 mg of white solid. NMR was consistent with the proposed structure.
Analysis Calculated for C29H27N305S- 1.0 H20:
C, 63.60; H, 5.34; N, 7.67; S, 5.85. Found: C, 63.64; H, 5.17; N, 7.48; S, 5.76.
Example 14 1,1-Dimethylethyl 3—[ [ [3—[ [ (cyanoimino)- ( ethylthio)methyl]amino]phenyl]sulfonyl]amino] 3-phenylbenzenepropanoate
Figure imgf000086_0001
A mixture of the product from Example H (395 mg) , N-cyano-S,S dimethyldithio iminocarbonate (266 mg) (Aldrich) and pyridine (2.5 ml) was refluxed for 3.5 hours in a hood. The reaction mixture was cooled to room temperature and the solvent removed under a stream of nitrogen. The residue was purified on a silica gel column eluting with 1:1 ethyl acetate-hexane to afford 336 mg of white solid. NMR was consistent with the proposed structure.
Example 15
1,1-dimethylethyl 3-[ [ [3-[ [amino(cyanoimino)methyl]' amino]phenyl]sulfonyl]amino]-/9-phenylpropanoate
Figure imgf000087_0001
A solution of the product from Example 14 (315 mg) , ethanol (8 ml) and concentrated ammonium hydroxide solution (5 ml) was heated at 80° for 16 hours. The reaction mixture was cooled to room temperature and the solvent removed under a stream of nitrogen. The crude product was purified on a silica gel column eluting with 100% ethyl acetate to afford 257 mg of white solid. NMR was consistent with the proposed structure.
Example 16
Synthesis of 3-[ [ [3-[ [amino[ (aminocarbonyl) imino] methyl]amino]phenyl]sulfonyl]amino]- 3-phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000088_0001
The reaction was run as described in Example 1 using the product from Example 15 (225 rag) to afford 195 mg of white solid. NMR was consistent with the proposed structure.
Analysis Calculated for C23H23N505S* 1.25TFA.
C, 49.08; H, 3.92; N, 11.22; S, 5.14. Found: C, 49.23; H, 4.23; N, 11.08; S, 5.23.
Example AV
Figure imgf000089_0001
A solution of trifluoromethane sulfonic anhydride (12.1 g) (Aldrich) in methylene chloride (20 ml) was prepared in a dry flask under nitrogen. The reaction mixture was cooled to -70° and a solution of of 3- hydroxy benzophenone (8.5 g) (Aldrich) in methylene chloride (30 ml) was rapidly added, followed by the immediate addition of triethylamine (4.3 g) . The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was then partitioned between ethyl acetate and saturated sodium chloride solution. The aqueous portion was extracted with additional ethyl acetate and the combined organic extracts were dried (Na2S04) and concentrated. The crude product was purified on a silica gel column eluting with 20% ethyl acetate -80% hexane to afford 10.7 g of yellow viscous liquid. NMR was consistent with the proposed structure.
Example AL
Figure imgf000090_0001
A mixture of the product from Example AV (10.6 g) , tri ethylsilyl acetylene (3.9 g) (Aldrich), diethylamine (130 ml) (Aldrich), bis(triphenylphosphine)-palladium(II) dichloride (450 mg) (Aldrich) and copper(I)iodide (32 mg) (Aldrich) was placed in a dry flask under argon. The reaction mixture was stirred at room temperature for 16 hours and then the solvent was removed under a stream of nitrogen. The residue was purified on a silica gel column eluting with 5% ethyl acetate - 95% hexane to afford 4.6 g of viscous golden oil. NMR was consistent with the proposed structure.
Example AM
Figure imgf000090_0002
A solution of the product from Example AL (4.6 g) was stirred with IN methanolic potassium hydroxide solution (17 ml) at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified on a silica gel column eluting with 5% ethyl acetate - 95% hexane to afford 3.4 g of golden liquid. NMR was consistent with the proposed structure. Example AN
Figure imgf000091_0001
A mixture of the product from Example AM (3.2 g) , 3-bromonitrobenzene (2.5 g) (Fluka) , bis(triphenylphosphine)-palladium(II)acetate (187 mg) (Aldrich) and triethylamine (15 ml) was placed in a Parr bottle and degassed with argon. The bottle was stoppered and heated in an oil bath at 80° for 16 hours. The reaction mixture was cooled and the solvent removed under a stream of nitrogen. The black residue was partitioned between ethyl acetate and water and the aqueous portion was extracted with additional ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution (2X) , dried (Na2S04) and concentrated. The crude product was purified on a silica gel column eluting with 20% ethyl acetate - 80% hexane to afford 2.2 g of yellow solid. NMR was consistent with the proposed structure.
Example W
Figure imgf000092_0001
In a dried flask under nitrogen was placed a 60% oil dispersion of sodium hydride (290 mg) . The dispersion was washed (3X) with hexane and decanted and then the hydride was suspended in dry THF (10 ml) and chilled to 0°. A solution of triethylphosphonate (1.6 g) (Aldrich) in dry THF (15 ml) was added dropwise and the reaction stirred at 0° for 30 minutes. A solution of the product from Example AN (2.2 g) in dry THF (10 ml) was added dropwise at 0° and then the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate and 0.5 N hydrochloric acid. The aqueous portion was extracted with additional ethyl acetate and the combined organic extracts were washed with saturated sodium chloride solution, dried (Na2S0 ) , and concentrated. The crude product was purified on a silica gel column eluting with 15% ethyl acetate -85% hexane to afford 2,.3 g of viscous golden oil. NMR was consistent with the proposed structure. Example X
Figure imgf000093_0001
A solution of the product from Example (810 mg) in ethanol (5 ml) and THF (5 ml) was hydrogenated under a 5 psi atmosphere of hydrogen at room temperature for 23.1 hours using 4% palladium on carbon catalyst. The reaction mixture was concentrated and the residue was purified on a silica gel column eluting with 40% ethyl acetate -60% hexane to afford 615 mg of oil. NMR was consistent with the proposed structure.
Example Y
Figure imgf000093_0002
The reaction was run as described in Example I using the product from Example X (450 mg) , bis-t- butoxy-carbonylthiourea (346 mg) , triethylamine (253 mg) ; mercuric chloride (380 mg) and DMF (15 ml). The crude product was purified on a silica gel column eluting with 10% ethyl acetate -90% hexane to afford 460 mg of a colorless viscous oil. NMR was consistent with the proposed structure. Example 17
ethyl 3-[2-[3-[ (aminoiminomethyl)amino]phenyl] ethyl]-0-phenylbenzenepropanoate
Figure imgf000094_0001
The reaction was run and the crude product purified as described in Example 1 using the product from Example Y (440 mg) to afford 270 mg of colorless glass. NMR was consistent with the proposed structure.
Example 18
3 - [ 2 - [ 3- [ ( aminoiminomethyl ) amino ] phenyl ] ' ethyl ] -/3-phenylbenzenepropanoic acid
Figure imgf000095_0001
A solution of 250 mg of the product from Example 17 (250 mg) , methanol (6 ml) and IN lithium hydroxide (3 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue was treated with a solution of methylene chloride (7 ml) and TFA (3 ml) at room temperature for 5 minutes. The solvent was removed in vacuo and the crude product was purified via reverse phase HPLC using a water (0.5% TFA) and acetonitrile gradient as eluant to afford 210 mg of white powder. NMR was consistent with the proposed structure.
Analysis Calculated for C24H25N302- 1.25TFA.
C, 60.05; H, 4.99; N, 7.93. Found: C, 59.68; H, 5.07; N, 7.97.
Example Z
Figure imgf000096_0001
3-Aminophenylacetic acid (3 g, 19.8 mmol) was dissolved in dry ethanol (60 mL) at 0°C and a stream of hydrogen chloride gas was bubbled into the solution for 15 minutes. The solvent was removed under reduced pressure to give desired product.
Example AA
Figure imgf000097_0001
A mixture of 3-cyanobenzaldehyde (1.004 g, 7.6 mmol), raalonic acid (0.880 g, 8.4 mmol), and pyridine (0.10 mL, 1.3 mmol) in absolute ethanol (2 mL) was heated to 100°C (bath) under argon. Upon heating, the mixture became a solution; after 20-30 minutes, a white precipitate formed. The reaction was monitored by TLC (10% MeOH/CH2Cl2) . After 21.5 hours, the reaction mixture was allowed to cool to room temperature and the white precipitate was collected by vacuum filtration. The solid was slurried with hot EtOH and collected by filtration to give the product as a white solid, (0.903 g, 69% yield) . NMR was consistent with the proposed structure.
Example AB
Figure imgf000098_0001
The compound of Example AA was dissolved in a MeOH (15 mL) /NH4OH (7.5 mL) mixture and hydrogenated with W- 2 Raney Ni in a Parr Shaker (60 psi, 25°C) for 2.5 hours. The catalyst was filtered and the purple filtrate concentrated in vacuo . The green solid residue was dissolved in IM HCI and concentrated in vacuo to give a white/green solid. The solid was purified by slurrying with 9:1 CH3CN/MeOH mixture. The white undissolved solid was collected by vacuum filtration to give the desired product (0.664 g, 59% yield) . NMR was consistent with the proposed structure.
Example AC
Figure imgf000098_0002
A mixture of the compound of Example AB in absolute EtOH (50 mL) was cooled to 0°C and HCI gas was bubbled into the mixture for 20 minutes. The resulting green/blue solution was allowed to stir for 2 hours. An aliquot was removed and concentrated in vacuo . HNMR showed the reaction to be complete. The reaction was concentrated in vacuo to give a slightly green-tinted white solid (0.710 g, quantitative.) NMR was consistent with the proposed structure. Example 19
Synthesis of ethyl 3-[ [[[3-(cyano)phenyl]carbonyl]' amino]methyl]benzenepropanoate, diacetate salt
Figure imgf000099_0001
A solution of 3-cyanobenzoic acid (0.447 g, 3.0 mmol) and 1-methyl piperidine (0.37 mL, 3.0 mmol) in CH2C12 (15 mL) was cooled to 9°C. Isobutylchloroformate (0.39 mL, 3.0 mmol) was added slowly under argon and the reaction stirred for another 5 minutes. A solution of the compound of Example AC (0.710 g, 2.9 mmol) and 1-methyl piperidine (0.37 mL, 3.0 mmol) in CH2C12 (3 mL) was then added and the ice bath immediately removed. The reaction was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo to give a green solid residue. The residue was partitioned between EtOAc (25 mL) and water (25 mL) . The organic layer was collected, washed with IM HCI (1X25 mL) , saturated NaHC03 (1X25 mL) , and brine (1X25 mL) , and then dried over MgS04. Concentration in vacuo gave the crude product as a pale yellow oil (1.17 g) . The product was purified by column chromatography (75 g silica gel, 3% MeOH/CH2Cl2) to give a yellow\white solid (0.491 g, 43% yield). NMR was consistent with the proposed structure. Example AD
Figure imgf000100_0001
The above compound was synthesized under conditions similar to Example 19, replacing the compound of Example AC with the compound of Example Z.
Analysis Calculated for C18H16N203:
C, 69.31; H, 5.30; N, 8.98, Found: C, 69.15; H, 5.36; N, 8.86,
Example 19A
ethyl 3-[[[ [3-[amino(hydroxyimino)methyl]- phenyl]carbonyl]amino]methyl] enzenepropanoate
Figure imgf000101_0001
A solution of the compound of Example 19 (0.491 g, 1.3 mmol), hydroxylamine hydrochloride (0.092 g, 1.3 mmol), and triethylamine (0.18 mL, 1.3 mmol) in absolute EtOH (10 mL) was heated to reflux (86-90°C) . After 5 hours, TLC [1:1 EtOAc/hexane (10 mL) and 5 drops of AcOH] showed that starting material was still present. Additional hydroxylamine hydrochloride (0.038 g, 0.5 eq) and triethylamine (0.09 mL) was added. After 40 minutes, the TLC showed no difference. The reaction was concentrated in vacuo to give a pale yellow oil (0.53 g) . The oil was purified by column chromatography [50 g silica gel, 3% MeOH/CH2Cl2 (500 mL) followed by 10% MeOH/CH2Cl2 (150 mL) ] and the desired product was collected in 85% yield (0.42 g) . NMR was consistent with proposed structure.
Example 20 ethyl 3-[ [ [3-[amino(hydroxyimino)methyl]phenyl]- carbonyl]amino]benzeneacetate
Figure imgf000102_0001
The above compound was synthesized under conditions similar to Example 19A, replacing the compound of Example 19 with the compound of Example AD.
Analysis Calculated for C18H19N304:
C, 63.33; H, 5.61; N, 12.31, Found: C, 63.08; H, 5.90; N, 12.02
Example 21
ethyl 3-[ [ [ [3-(aminoiminomethyl)phenyl]- carbonyl]amino]methyl]benzenepropanoate
Figure imgf000103_0001
The compound of Example 19A (0.42 g, 1.1 mmol) was dissolved in AcOH and hydrogenated with 4% Pd/C (53% wet, 0.050 g) in a Parr Shaker (60 psi, 60C) . The catalyst was filtered off and the filtrate concentrated in vacuo to give a white solid (pink tint) . The solid was slurried with acetonitrile and the resulting white solid was collected by vacuum filtration (0.347 g, 89% yield) .
Analysis Calculated for C20H23N3O3* 2.0 AcOH:
C, 60.80; H, 6.60; N, 8.87. Found: C, 60.17; H, 6.47; N, 8.89. M+ = 353.
Example 22 ethyl 3-[ [ [3-[aminoiminomethyl]phenyl]- carbonyl]amino]benzeneacetate
Figure imgf000104_0001
The compound of Example 20 was reduced under conditions similar to conditions for Example 21, replacing the compound of Example 19A with the compound of Example 20.
Analysis Calculated for C18H19N303* 1.3 AcOH:
C, 61.33; H, 6.05; N, 10.42. Found: C, 61.09; H, 6.23; N, 10.29.
Example 23
Synthesis of 3-[[[ [3-(aminoiminomethyl)phenyl]carbonyl] amino]methyl]benzenepropanoic acid, trifluoroacetate salt
Figure imgf000105_0001
To a mixture of the compound of Example 21 (0.200 g, 0.57 mmol) in IM phosphate buffer was added esterase from porcine liver (Sigma, 0.5 mL) at room temperature. The reaction was stirred for 18 hours and then concentrated in vacuo. A solution of IM HCI (2-4 L)/CH3CN (4 mL) was added to the resulting residue and the undissolved solid filtered. The filtrate was collected, concentrated in vacuo, and purified by HPLC - Method 1 to give the desired product as a white solid (0.09 g, 36% yield) .
Analysis Calculated for C18H19N303- 1.0 TFA+0.2 H20:
C, 54.23; H, 4.64; N, 9.49. Found: C, 54.06; H, 4.60; N, 9.46.
MH+=326.
Example 24 3~[ [ [3-(aminoiminomethyl)phenyl]carbonyl]' amino]benzeneacetic acid
Figure imgf000106_0001
The above compound was synthesized under conditions similar to the conditions described in Example 23, replacing the compound of Example 21 with the compound of Example 22.
Analysis Calculated for C16H15N3o3* ITFA- 1H20:
C, 50.34; H, 4.23; N, 9.79. Found: C, 50.21; H, 4.07; N, 9.50.
Example AE
Figure imgf000107_0001
A solution of 3-nitrobenzoic acid (2.42 g, 9.95 mmol) and 1-methyl piperidine (1.2 mL, 9.95 mmol) in CH2C12 (55 mL) was cooled to 0°C and isobutyl chloroformate (1.3 mL, 9.95 mmol) was added under argon. The reaction was allowed to stir for 5 minutes before adding a solution of the compound of Example AC (2.42 g, 9.95 mmol) and 1-methyl piperidine (1.2 mL, 9.95 mmol) in CH2C12 (10 mL) . The flask containing the compound of Example AC was rinsed with CH2C12 (1 mL) and the rinse added to the reaction. The ice bath was removed after addition and the reaction was allowed to stir at room temperature over 24 hours. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic layer was washed with 1 M HCI, followed by NaHC03 and brine. The organic layer was collected, dried over MgS04, and concentrated in vacuo to give a pale yellow oil. The crude reaction mixture was purified by column chromatography [300 g silica gel, 2:1 hexane/EtOAc (1:1)] to give the desired product as a white solid (2.87 g, 81% yield). NMR was consistent with the proposed structure. Example AF
Figure imgf000108_0001
The compound of Example AE was hydrogenated (4% Pd/C, EtOH, 5 psi, room temperature, 1.5 hours) and the filtrate concentrated in vacuo to give a yellow oil (2.095 g, 82% yield). NMR was consistent with the proposed structure.
Example 25 Synthesis of 3-[ [ [ [3-[ (aminothioxomethyl)amino]phenyl] carbonyl]amino]methyl]benzenepropanoic acid
Figure imgf000109_0001
A solution of the compound of Example AF (0.49 g, 1.5 mmol) in CH3CN (10 mL) was cooled to 0°C and DMAP (0.021 g, 0.15 mmol) was added under argon followed by benzoyl isothiocyanate (0.25 g, 1.5 mmol). After 30 minutes, the reaction solidified and stirring became difficult. The reaction was allowed to warm to room temperature After 2 hours, additional benzoyl isothiocyanate (0.05 mL) was added. Within 15 minutes, the reaction appeared complete as monitored by TLC (5% MeOH/CH2Cl ) . The reaction was concentrated in vacuo and the residue was diluted with MeOH (7 mL)/water (7 mL) . Potassium carbonate (0.21, 1.5 mmol) was added at room temperature and the reaction stirred over 17 hours. The reaction mixture was worked-up with water and extracted with EtOAc. The reaction appeared by TLC to be incomplete. The residue was submitted to heating (84°C) with potassium carbonate (2 equivalents) for 1.5 hours. The reaction was cooled to room temperature and concentrated in vacuo . The residue was suspended in water and extracted with EtOAc (2X50 mL) . The organic layers were washed with brine and dried over MgS04. Concentration in vacuo gave the desired product as a yellow oil. The oil was purified by column chromatography [50-75 g silica gel, 2% MeOH/CH2Cl2 (1.5 1) ] to give the desired product as a white solid (0.131 g, 23% yield) . The HNMR showed the solid to be a mixture of the ethyl ester and the methyl ester. Example 26
3-[ [ [ [3-[ (aminothioxomethyl) amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid
Figure imgf000110_0001
The compound of Example 25 (0.131 g, 0.34 mmol) was dissolved in MeOH (2 mL) and 1 M LiOH (0.68 mL) was added. The reaction was stirred at room temperature over 16 hours. The reaction was concentrated in vacuo to give a white solid. The solid was dissolved in a small amount of H20 and acidified with 1 drop of TFA. The mixture was concentrated in vacuo and the residue was purified by HPLC - Method 1 to give a white solid (0.055 g, 45% yield) .
Analysis Calculated for C18H19N303- 0.45 H20:
C, 59.15; H, 5.49; N, 11.50. Found: C, 58.85; H, 5.10; N, 11.75. M+=357.
Example 28
Synthesis of ethyl 3-[ [[ [3-[ (aminocarbonyl)amino] phenyl]carbonyl]amino]methyl]benzenepropanoate
Figure imgf000111_0001
A mixture of the compound of Example AF (0.447 g, 2.2 mmol) and acetic acid (1 mL) in water (2 mL) was heated to 38°C (bath) . A solution of potassium cyanate (0.343 g, 4.4 mmol) in water (2 mL) was then added slowly. The reaction became cloudy and a white precipitate resulted. The reaction was allowed to cool to room temperature and stirred for l.5 hours. The reaction was monitored by TLC (10% MeOH/CH2Cl2) . The white solid was collected by vacuum filtration and washed with water (0.469 g, 58% yield).
Analysis Calculated for C20H23N303* 0.1 H20 TFA:
C, 64.71; H, 6.30; N, 11.32. Found: C, 64.52; H, 6.37; N, 11.11.
M+=369.
Example 29
Synthesis of 3-[ [[ [3-[ (aminocarbonyl)amino]phenyl] carbonyl]amino]methyl]benzenepropanoic acid
Figure imgf000112_0001
The compound from Example 28 was hydrolyzed using the method described in Example 26. After acidifying with TFA, the resulting white precipitate was filtered off and washed with water (3X) and ether (IX). (0.261 g, 89% yield) .
Analysis Calculated for C18H19N304- 0.3 H20:
C, 62.35; H, 5.70; N, 12.12. Found: C, 62.32; H, 5.45; N, 12.23.
M+=341.
- Ill - Example 30
Synthesis of ethyl 3-[ [[ [3-[ [[ (phenylmethyl)amino] carbonyl]amino]phenyl]carbonyl]amino]methyl]benzene- propanoate
Figure imgf000113_0001
To a solution of benzyl isocyanate (0.12 g, 0.88 mmol) in CH2C12 (6 mL) was added a solution of the compound of Example AF (0.30 g, 0.92 mmol) in CH2C12 (2 mL) under argon. The flask containing the compound of Example AF was rinsed with CH2Cl2 (1 mL) and added to the reaction. The reaction was stirred at room temperature for 17 hours. The reaction was concentrated in vacuo and ether added to the yellow oil. Upon addition, the oil solidified. The resulting white solid was collected by vacuum filtration and washed with a small amount of ether (0.303 g, 75% yield) .
Analysis Calculated for C27H29N304:
C, 70.57; H, 6.36; N, 9.14, Found: C, 70.59; H, 6.74; N, 9.13 M+=459. Example 31
Synthesis of 3-[ [[ [3-[ [[ (phenylmethyl)amino]carbonyl] amino]phenyl]carbonyl]amino]methyl]benzenepropanoic acid
Figure imgf000114_0001
The compound of Example 30 was hydrolyzed using the method described in Example 26. After acidifying with TFA, the resulting white precipitate was filtered off and washed with water (3X) and ether (IX) . The desired product was collected as a cream-colored solid (0.115 g, 89% yield) .
Analysis Calculated for C25H25N304- 0.1 H20:
C, 69.30; H, 5.86; N, 9.70.
Found: C , 69.17; H, 5.81; N, 9.63. MH+=432.
Example AG
Synthesis of
Figure imgf000115_0001
The compound from Example 37, Step D, (0.8 g, 2.8 mmol) was coupled with 3-nitrobenzoic acid under similar conditions to the conditions described in Example AE using CH2C12 as the solvent. The crude material was purified by column chromatography (100 g silica, 40% EtOAc/hexane) to give the desired product as a pale yellow oil (0.969 g) . NMR was consistent with the proposed structure.
Example AH
Figure imgf000115_0002
The compound of Example AG (0.969 g, 2.2 mmol) was dissolved in EtOH and hydrogenated with 4% Pd/C in a Parr Shaker (5 psi) at room temperature for 16 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the product as a brown oil (0.577 g) . NMR was consistent with the proposed structure. Example 32
ethyl 3-[ [ [ [3-[ [ [ (phenylmethyl)amino]carbonyl] amino]phenyl]carbonyl]amino]methyl ]-β- phenylbenzenepropanoate
Figure imgf000116_0001
The compound of Example AH (0.25 g, 0.62 mmol) was treated with benzyl isocyanate under conditions described similar to the conditions described in Example 30. The desired product was collected as an off-white solid (0.314 g) .
Analysis Calculated for C33H33N304- 0.5 H20:
C, 72.77; H, 6.29; N, 7.71,
Found: C, 72.66; H, 6.26; N, 7.68,
MH+=536.
Example 33
3-[ [ [ [3-[ [ [ (phenylmethyl)amino]carbonyl] amino]phenyl]carbonyl]amino]methyl] -β- phenylbenzenepropanoic acid
Figure imgf000117_0001
The compound of Example 32 (0.226 g, 0.4 mmol) was hydrolyzed under the same conditions as described in Example 26 to give the desired product as a white solid (0.118 g) .
Analysis Calculated for C31H 9N304* 0.4 H20:
C, 72.33; H, 5.83; N, 8.16, Found: C, 72.23; H, 5.59; N, 7.96,
MH+=508.
Figure imgf000118_0001
A solution of 3-aminobenzoic acid (40.47 g, 0.29 mol), 3,5-dimethylpyrazole carboxamidine nitrate (88.24 g, 0.44 mol) , and diisopropylethylamine (76 mL, 0.44 mol) in dioxane(300 mL)/water (150 mL) was heated to reflux for 1 hour, 15 minutes. A brown precipitate resulted. The reaction was stirred at room temperature for over 48 hours. The reaction mixture was filtered and the resulting lavender solid rinsed with dioxane (150 mL) followed by 1:1 dioxane/water (100 mL) . The solid was dried in vacuo and then treated with a mixture of ether(400 mL)/acetonitrile(100 mL)/4N HCl/Dioxane (100 mL) . To this slurry was added 20% HCI (1 mL) . The mixture was stirred at room temperature over 18 hours. The undissolved solid was filtered off and washed with ether (2X) . The desired product was collected as a pale purple solid (28.15 g, 45% yield). NMR was consistent with the proposed structure.
Example 34
Synthesis of ethyl 3-[ [[ [3-[ (aminoiminomethyl)amino] phenyl]carbonyl]amino]methyl]benzenepropanoate, trifluoroacetate salt
Figure imgf000119_0001
A solution of the compound of Example Al (0.494 g, 2.3 mmol) and 1-methyl piperidine (0.28 mL, 2.3 mmol) in DMF (5 mL) was cooled to 0°C and isobutyl chloroformate (0.30 mL, 2.3 mmol) was added under argon. The reaction was allowed to stir for 5 minutes before adding a mixture of the compound of Example AC (0.499 g, 2.3 mmol) and l-methyl piperidine (0.28 mL, 2.3 mmol) in DMF (2 mL) . The flask containing the compound of Example AC was rinsed with DMF (2 mL) and the rinse added to the reaction. The ice bath was removed and the reaction was allowed to stir at room temperature over 24 hours. The reaction time varied from 16-24 hours. The reaction was concentrated in vacuo and the residue purified by HPLC-Method 1 to give the desired product as a colorless oil. Upon azeotroping with CH3CN, the oil solidified and the white solid was collected by vacuum filtration (0.149 g, 14% yield) .
Analysis Calculated for C20H24N403- 1. 4 TFA:
C , 51. 86 ; H, 4 . 85 ; N , 10. 61. Found: C , 51.57 ; H , 4 . 99 ; N , 11. 01. MH+=368 . Example 35
Synthesis of 3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]benzenepropanoic acid, trifluoroacetate salt
Figure imgf000120_0001
The compound of Example AB (0.54 g, 2.2 mmol) was coupled with the compound of Example Al according to the procedure described in Example 34. The crude material was purified by HPLC-Method 1 to give a yellow oil (0.212 g) .
Analysis Calculated for C18H20N403* 1.0 TFA:
C, 52.86; H, 4.66; N, 12.33.
Found: C, 52.61; H, 4.44; N, 12.35. M+=340.
Example AW
Figure imgf000121_0001
3-Nitrobenzaldehyde (2.98 g, 20 mmol) was treated with malonic acid (2.376 g, 22 mmol) under the same reaction conditions described in Example AA. Recrystallization from EtOH (10 mL) gave the product as tan needles (0.873 g) . NMR was consistent with the proposed structure.
Example AX
Figure imgf000121_0002
The compound of Example AW (0.860 g, 4.45 mmol) was reduced under conditions similar to conditions for Example AF. The product was isolated as a yellow oil (0.76 g) . NMR was consistent with the proposed structure.
Example 36 3-[ [ [3-[ (aminoiminomethyl) amino]phenyl]carbonyl] amino]benzenepropanoic acid, trifluoroacetate salt
Figure imgf000122_0001
The above compound was synthesized following the same synthetic method as described in Example 34 replacing the compound of Example AC with the compound of Example AX.
Analysis Calculated for C17H18N403- 1.0 TFA:
C, 51.82; H, 4.35; H, 12.72.
Found: C, 51.52; H, 4.37; N, 12.83. M+=326.
Example 37
Synthesis of ethyl 3-[[[ [3-[ (aminoiminomethyl)amino] phenyl]carbonyl]amino]methyl]-/3-phenylbenzene- propanoate, trifluoroacetate salt
Step A
Figure imgf000123_0001
A solution of 3-cyanobenzaldehyde (3.00 g, 22.9 mmol) in distilled THF (30 mL) was cooled to -78°C and a 1 M solution of phenylmagnesium bromide in THF (45 mL) was added slowly over 10 minutes under argon. The resulting light brown reaction mixture was allowed to warm slowly to room temperature in the dry ice bath over 2 hours. The purple reaction was stirred at room temperature for an additional 2 hours, then quenched with saturated NH C1 (40 mL) . The mixture was extracted with ether (50 mL) and dried over MgS04. Concentration in vacuo gave an orange oil (5.52 g, quantitative yield) . NMR was consistent with the proposed structure.
Step B
Figure imgf000123_0002
To a mixture of the compound of Step A (3.250 g, 15.5 mmol) and activated 4A molecular sieves in CH2Cl2 (60 mL) was added pyridinium dichromate (6.007 g, 15.5 mmol) at room temperature The mixture was stirred under argon for 21.5 hours. The reaction was diluted with ether and filtered (2X) through florisil (60-100 mesh) . The filtrate was collected and concentrated in vacuo to give a white/yellow solid. The solid was purified by column chromatography [150 g silica gel, 20% EtOAc/hexane (l L) ] to give the desired product as a white solid (2.40 g, 77% yield). NMR was consistent with the proposed structure.
Step C
Figure imgf000124_0001
A suspension of 60% NaH in mineral oil (washed with hexane before use, 0.535 g, 12 mmol) in distilled THF (25 mL) was cooled to 0°C and ethyl dimethylphosphonoacetate (1.9 mL, 12 mmol) was added very slowly under argon. Vigorous bubbling was observed and the reaction eventually became a white slurry. The reaction was allowed to stir at 0°C for 1.5 hours before adding a solution of the compound of Step B (2.40 g, 12 mmol) in THF (10 mL) . The flask containing the compound of Step B was rinsed with THF (5 mL) and added to the reaction. The reaction was allowed to warm to room temperature. After 4 hours, the reaction was quenched with water (50 mL) and extracted with EtOAc (2X60 mL) . The organic layers were collected, dried over MgS04, and concentrated under a stream of N2 to give the crude product (2.843 g, 83% yield) . NMR was consistent with the proposed structure. Step D
Figure imgf000125_0001
The compound of Step C (l .931 g, 6.8 mmol) was dissolved in i-PrOH/HCl and hydrogenated with 10% Pd/C in a Parr Shaker (60 psi) for 6 hours at room temperature. The catalyst was removed and the filtrate was concentrated in vacuo. The residue was partitioned between saturated NaHC03 and ether. The aqueous layer was back-extracted with ether. The organic layers were combined, dried over MgS04, and concentrated in vacuo to give a light brown oil (1.65 g, 86% yield). NMR was consistent with the proposed structure.
Figure imgf000125_0002
The compound of Step D (0.45 g, 1.6 mmol) was coupled with the compound of Example Al according to similar procedures described in Example 34 and purified by HPLC-Method 1 to give white sticky solid (0.400 g) .
Analysis Calculated for C26H28N403' 1.3 TFA+0.3 H 0: C, 57.43; H, 5.04; N, 9.37.
Found: C, 57.33; H, 4.74; N, 9.37. MH+=445. Example 38
Synthesis of 3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]-,9-phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000126_0001
The compound of Example 37 (0.32 g, 0.72 mmol) was hydrolyzed under the conditions described in Example 26 and purified by HPLC-Method 1 to give the desired product as a white sticky solid (0.327 g) .
Analysis Calculated for C24H24N403* 1.6 TFA+0.6 H20: C, 53.58; H, 4.43; N, 9.19,
Found: C, 53.41; H, 4.15; N, 9.22, MH+=417.
Example AJ
Figure imgf000127_0001
3-acetylbenzonitrile was treated with t-butyl P,P- dimethylphosphonoacetate under the same conditions as described in Example 37, Step C. The crude material was purified by column chromatography to give one pure isomer as a yellow oil (1.401 g, 42% yield) . NMR was consistent with the proposed structure.
Example AK
Figure imgf000127_0002
The compound of Example AJ was hydrogenated (i-PrOH+ l N HCI, 10% Pd/C, 60 psi, room temperature, 1.5 hours) and the filtrate concentrated in vacuo . The solid residue was partitioned between saturated NaHC03 (25 mL) and ether (25 mL) . The aqueous layer was back- extracted with ether (2X25 mL) . The organic layers were combined, washed with brine, dried over K2C03, and filtered through celite. Concentration of the filtrate in vacuo gave the desired product (free amine) as a yellow oil (0.401 g, 35% yield). NMR was consistent with the proposed structure. Example 39
Synthesis of 1,1-dimethylethyl 3-[ [[ [3-[ (aminoimino¬ methyl)amino]phenyl]carbonyl]amino]methyl]-,9-methyl- benzenepropanoate, trifluoroacetate salt
Figure imgf000128_0001
The compound of Example AK was coupled with the compound of Example Al under similar reaction conditions as described in Example 34. The crude material was purified by HPLC-Method 1 to give the desired product (0.29 g, 62% yield).
Analysis Calculated for C23H30N403* 1.0 TFA+ 0.7 H20: C, 55.90; H, 6.08; N, 10.43,
Found: C, 55.73; H, 5.68; N, 10.27 M+=410.
Example 40
Synthesis of 3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]-3-methylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000129_0001
To a solution of the compound of Example 39 (0.163 g) in CH2C12 (4 mL) was added TFA (2 mL) at room temperature. The reaction was stirred for 8 hours, then concentrated in vacuo to give an orange oil. The crude product was purified by HPLC-Method 1 to give a white sticky solid (0.112 g) .
Analysis Calculated for C19H22H403- 1.4 TFA+ 0.1 H20:
C, 50.76; H, 4.61; N, 10.86. Found: C, 50.49; H, 4.52; N, 10.93.
Example 41
Synthesis of ethyl 3-[ [[ [3-[ (aminoiminomethyl)amino] phenyl]carbonyl)amino]methyl]-3-ethylbenzenepropanoate, trifluoroacetate salt
Figure imgf000130_0001
Step A
A solution of 3-acetylbenzonitrile (1.018 g, 7.0 mmol) in distilled THF (15 mL) was cooled to 0°C. A 1 M LiHMDS solution in THF (7.6 mL) was added slowly under argon to give a red/brown solution. The ice bath was removed and the reaction allowed to stir at room temperature for 30 minutes. The solution was then transferred into a flask containing iodomethane (15 mL, 241 mmol) under an argon atmosphere. The reaction was monitored by TLC (20% EtOAc/hexane) and quenched with water after 1 hour at room temperature. The reaction was concentrated in vacuo and the residue partitioned between EtOAc (40 mL) and water (40 mL) . The organic layer was collected, dried over MgS04 and concentrated in vacuo to give an orange/red oil (1.02 g) . The crude mixture was purified by column chromatography [50 g silica gel, 10% EtOAc/hexane (700 mL) ] to give the desired product as a yellow/white solid (0.372 g) . The impure fractions were collected and repurified by plate chromatography to give the pure product as a pale yellow solid (0.585 g) . [yield=86%. ] NMR was consistent with the proposed structure.
Step B
Figure imgf000131_0001
The ketone formed in Step A (0.959 g, 6.0 mmol) was treated with ethyl dimethylphosphonoacetate under conditions as described in Example 37, Step C. The product was isolated as a mixture of E and Z isomers in a 1:1 ratio (1.417 g) . NMR was consistent with the proposed structure.
Step C
Figure imgf000131_0002
The compound from Step B (1.42 g, 6.2 mmol) was hydrogenated under conditions similar to those described in Example AK to give the desired product as a pale yellow oil (1.087g, 75% yield). NMR was consistent with the proposed structure.
Figure imgf000131_0003
The product of Step C (1.087 g, 4.6 mmol) was coupled to the compound of Example Al according to conditions as described in Example 34. The residue was purified by HPLC-Method 1 to give the desired product as a yellow oil (1.571 g) .
Analysis Calculated for C22H28N403- 1.1 TFA:
C, 55.69; H, 5.62; N, 10.73.
Found: C, 55.43; H, 5.33; N, 10.60. MH+=397.
Example 42
Synthesis of 3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]-/3-ethylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000133_0001
The product of Example 41 (1.4 g, 3.5 mmol) was hydrolyzed using the method described in Example 26. The crude material was purified by HPLC-Method l to give the desired product as a colorless oil (1.10 g) ,
Analysis Calculated for C20H24N403- 1.1 TFA+ 0.7 H20:
C, 52.65; H, 5.27; N, 11.06,
Found: C, 52.41; H, 4.93; N, 11.27,
M+=368.
Example 4 3
Synthesis of 3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl] -β-(1-methylethy1) benzenepropanoic acid, trifluoroacetate salt
Figure imgf000134_0001
Step A
A solution of 3-acetylbenzonitrile (1.0 g, 6.9 mmol) in distilled THF (15 mL) was cooled to 0°C. A IM solution of LiHMDS in THF (7.6 mL) was added slowly under argon. The resulting brown/red solution was allowed to warm to room temperature over 30 minutes. This solution was then added to a flask containing iodomethane (15 mL, 241 mmol) at room temperature The reaction was monitored by TLC (20% EtOAc/hexane) . At the end of 1 hour, the TLC showed mostly the ethyl product and a minor amount of both the starting benzonitrile and the desired isopropyl product. The reaction was cooled to -30°C (bath) and l.l equivalents of 1 M LiHMDS were added. The reaction was allowed to warm slowly to 10°C. Within 5 minutes, the TLC showed the isopropyl product to be the predominant product. After stirring for 40 minutes, the reaction was quenched with water (50 mL) and extracted with EtOAc (2X50 mL) . The organic layer was collected, dried over MgS04, and dried under a stream of N2. The resulting orange residue was diluted with CH2Cl2 and the undissolved white solid filtered off. The filtrate was collected and concentrated in vacuo to give an orange oil (1.229 g) . The oil was purified by column chromatography [50 g silica gel, 20% EtOAc/hexane (500 mL) ] to give the desired product as a yellow oil (0.45 g) . The impure fractions from the chromatography were combined and repurified by plate TLC (10% EtOAc/hexane) to give the product as a yellow oil (0.37 g) . The pure samples from the column and plate chromatographies were combined to give the clean product (0.82 g, 69% yield). NMR was consistent with the proposed structure. Step B
Figure imgf000135_0001
A solution of potassium tert-butoxide (0.37 g, 3.0 mmol) in distilled THF (20 mL) was cooled to 0°C and ethyl dimethylphosphonoacetate (0.49 mL, 3.0 mmol) was added slowly under argon. The solution eventually became a white slurry. The reaction was stirred at 0°C for 30 minutes before adding a solution of the compound of Step A (0.510 g, 2.9 mmol) in THF (3 mL) . The reaction was heated to 50°C (bath) for 7.5 hours, then stirred at room temperature over 15 hours. The reaction was quenched with water and extracted with EtOAc (2X) . The organic layers were collected and dried over MgS04. Concentration in vacuo gave the crude product as a yellow oil (0.594 g) . The crude product was combined with crude products from two other runs and purified by column chromatography to give two major fractions containing the desired compound as a yellow oil (0.256 g) contaminated with starting material (0.85 g) . NMR was consistent with the proposed structure. Step C
Figure imgf000136_0001
The mixture from Step B (0.85 g, 1.2 mmol) was dissolved in absolute ethanol (10 mL) and NaBH4 (0.053 g, 1.4 mmol) was added at 0°C under argon. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched with H20 (30 mL) and extracted with EtOAc (2X) . The organic layers were collected, dried over MgS04, and concentrated in vacuo to give a yellow oil (1.15 g) . The crude product was purified by column chromatography [100 g silica gel, 10% EtOAc/hexane (500 mL) ] to afford the desired compound as an impure mixture (0.47 g) . NMR was consistent with the proposed structure.
Step D
Figure imgf000136_0002
The mixture from Step C (0.521 g, 2.0 mmol) was hydrogenated under conditions similar to those described in Example AK to give a light tan oil (0.333 g) . NMR was consistent with the proposed structure. Step E
Figure imgf000137_0001
The product of Step D (0.28 g, l.l mmol) was coupled with the compound of Example Al using a method similar to that described in Example 34. The crude material was purified by HPLC-Method 1 to give the desired product as a colorless oil (0.070 g) . NMR was consistent with the proposed structure.
Step F
Figure imgf000137_0002
The product of Step E (0.057, 0.14 mmol) was hydrolyzed under conditions similar to those described in Example 26. The residue was purified by HPLC-Method 1 to give a colorless oil (0.045 g) .
Analysis Calculated for C21H26N403* 1.5 TFA+ 0.7 H20:
C, 50.92; H, 5.15; N, 9.90.
Found: C, 50.82; H, 4.99; H, 10.23. MH+=383. Example 44
3-[2-[ [ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]ethyl]benzeneacetic acid, monohydrate trifluoroacetate salt
Figure imgf000138_0001
Step A
Figure imgf000138_0002
To a solution of 3-bromophenylacetic acid (2.980 g, 13.9 mmol) and condensed isobutylene (15 mL) in CH2C12 was added a catalytic amount of H2S04. The mixture was sealed in a Parr Shaker and allowed to shake at room temperature for 18 hours. The bilayered reaction mixture was quenched with saturated NaHC03 (20 mL) and extracted with CH2C12 (2X30 mL) . The organic layers were combined, washed with brine, dried over MgS04, and concentrated in vacuo to give a pale yellow oil (2.78 g, 74% yield)). NMR was consistent with the proposed structure. Step B
To a solution of the product of Step A (2.032 g, 7.4 mmol) in CH3CN (4 mL) was added diisopropylamine (2 mL, 14.8 mmol), N-vinylphthalamide (1.285 g, 7.4 mmol), palladium acetate (0.059 g, 0.22 mmol), and tri-o- tolylphosphine (0.226 g, 0.7 mmol). The resulting yellow solution was heated to reflux for 18.5 hours. The reaction was allowed to cool to room temperature, at which point the reaction mixture solidified into a yellow/brown mass. The solid was dissolved in CH2C12 (50 mL) and the undissolved grey solid filtered off. The filtrate was treated with activated charcoal and filtered through celite. Concentration of the filtrate gave a yellow/brown solid. The material was recrystallized from CH3CN2 (5 mL) /MeOH (50 mL) . A yellow needle-like solid was collected (1.435 g, 41% yield) . NMR was consistent with the proposed structure.
Analysis Calculated for C22H21N04- 0.4 H20: C, 71.30; H, 5.93; N, 3.78,
Found: C, 71.08; H, 5.63; H, 3.46,
Step C
Figure imgf000139_0001
The compound of Step B (1.04 g, 2.9 mmol) was hydrogenated (10% Pd/C, EtOH+THF, 60 psi, room temperature, 10 hours). The reaction was concentrated in vacuo to give a white solid (1.21 g) . The solid was purified by column chromatography [50 g silica gel, 20% EtOAc/hexane (500 mL) ] to give the desired product as a white solid (0.54 g, 52% yield). NMR was consistent with the proposed structure. Step D
Figure imgf000140_0001
A mixture of the compound of Step C (0.54 g, 1.5 mmol) and hydrazine hydrate (0.33 g, 10.4 mmol) in absolute EtOH (6 mL) was heated to 75-80°C (bath) . The solution solidified into a white mass after 20 minutes of heating. The reaction was stirred at 80°C for 2 hours. The reaction was allowed to cool to room temperature and then slurried with EtOH. A white solid was collected by vacuum filtration and then slurried with CH2C12 (2X) . The undissolved solid was filtered and the filtrate concentrated in vacuo to give a white sticky solid. Column chromatography [50 g silica gel, 84:15:1 CHCl3/EtOH/NH4OH (700 mL) ] gave the desired product as a pale yellow oil (0.25 g, 7% yield). NMR was consistent with the proposed structure.
Step E
Figure imgf000140_0002
The compound of Step D (0.25 g, 1.1 mmol) was coupled with the compound of Example Al following the procedures described in Example 34. The crude reaction mixture was purified by HPLC-Method 1 to give a sticky white/yellow solid (0.289 g) . NMR was consistent with the proposed structure.
M+=396 Step F
Figure imgf000141_0001
The compound of Step E (0.289 g) was hydrolyzed under conditions similar to those described in Example 40. The crude material was purified by HPLC-Method 1 to give a colorless oil (0.144 g) .
Analysis Calculated for C18H20N4O1- 1.2 TFA+ 1.0 H20:
C, 49.48; H, 4.72; N, 11.31. Found: C, 49.32; H, 4.47; N, 11.68.
MH+=341.
Example AQ
Figure imgf000142_0001
The above compound was prepared according to (Bernatowicz, JOC, Vol. 57, No. 8, (1992), p. 2497- 2502. NMR was consistent with the proposed structure.
Example 45
Synthesis of N-acetyl-3-[ [[ [3-[ (aminoiminomethyl)amino] phenyl]carbonyl]amino]methyl]phenylalanine, bis(trifluoroacetate) salt
Figure imgf000143_0001
Step A
A mixture of N-acetylglycine (0.608 g, 5.1 mmol), sodium acetate (0.318 g, 3.8 mniol) , 3- cyanobenzaldehyde (1.005 g, 7.6 mmol), and acetic anhydride (1.2 mL, 12.9 mmol) was heated to 88-90°C (bath) under argon for 7 hours. The reaction was allowed to cool to room temperature and stored in the refrigerator over the weekend. The resulting yellow solid was slurried in an ice bath and collected by vacuum filtration. The solid was dissolved in an acetone (36 mL) /water (14 mL) mixture and heated to reflux for 6-7 hours. The reaction was allowed to cool to room temperature and the acetone removed in vacuo. Additional water (40 mL) was added to the residue and the reaction mixture heated to reflux for 1 hour. The hot solution was filtered and the filter paper washed with hot water. The filtrate was collected and allowed to cool slowly to room temperature. Yellow crystals precipitated out of solution and the mixture was cooled for 5 hours. The crystals were collected by vacuum filtration, washed with cold water, and then rinsed with hexane to remove excess water. The desired product was collected as a yellow solid (0.427 g, 49! yield) . NMR was consistent with the proposed structure.
Step B
Figure imgf000144_0001
The product from Step A (0.201 g, 0.87 mmol) was hydrogenated at room temperature with Raney Nickel in MeOH/NH40H over 16 hours at 60 psi. The catalyst was filtered and the filtrate concentrated in vacuo to give a green-tinted solid. 1 M HCI (10 mL) was added slowly until the solid dissolved. The solution was concentrated in vacuo to give the desired product as a yellow oil (0.314 g, quantitative yield). NMR was consistent with the proposed structure.
Step C
Figure imgf000144_0002
The product of Step B (0.307 g, 1.1 mmol) was coupled with the compound of Example Al under conditions similar to those described in Example 34. The crude material was purified by HPLC-Method 1 to give the methyl ester of the desired product as a pale yellow oil (0.231 g) . NMR was consistent with the proposed structure.
Step D The compound of Step C (0.125 g, 0.30 mmol) was hydrolyzed with LiOH according to the procedures described in Example 26. The residue was purified by HPLC-Method 1 (2X) to give the desired product as a colorless oil (0.052 g) .
Analysis calculated for C20H23N504* 2.0 TFA+ 0.6 H20:
C, 45.30; H, 4.15; N, 11.01. Found: C, 45.47; H, 4.19; N, 10.73. MH+=398.
Example AP
Figure imgf000146_0001
A solution of 3-aminophenylacetic acid (2.712 g, 17.9 mmol), the compound of Example AO (3.023 g, 20.6 mmol), and Hunig's base (3.6 mL, 20.6 mmol) in dioxane (30 mL)/water (15 mL) was refluxed for 16 hours under argon. Upon heating, a white precipitate formed. The reaction was cooled to room temperature and the white solid filtered. The solid was washed with 1:1 dioxane/water (3 X 5 mL) . The solid was suspended in 15 mL of water and acidified with concentrated HCI until the solid dissolved. The solution was concentrated in vacuo and the resulting yellow residue slurried with ether. The yellow solid was collected by vacuum filtration (3.025 g, 74% yield). NMR was consistent with the proposed structure.
Example 46
Synthesis of 3-[ [ [3-[ (aminoiminomethyl)amino]phenyl] acetyl]amino]benzenepropanoic acid, trifluoroacetate salt
Figure imgf000147_0001
The compound of Example AX (0.3 g, 1.8 mmol) was coupled with the compound of Example AP under similar reaction conditions as described in Example 34. The crude mixture was purified by HPLC-Method l (2X) to give the desired product as a sticky light yellow oil (0.057 g) . Analysis Calculated for C18H20N4O3- 1.9 TFA: C, 47.01; H, 3.96; N, 10.06.
Found: C, 47.21; H, 4.14; N, 9.86. MH+=341.
Example AQ
Figure imgf000148_0001
To a stirred solution of m-tolylacetic acid (3 g, 20 mmol) in carbon tetrachloride (60 mL) was added N- bromosuccinamide (3.6 g, 20 mmol). The mixture was refluxed for 3 hours then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to yield 3.1 g of the desired compound.
Example AR
Figure imgf000148_0002
The compound of Example AQ (3.1 g, 13.5 mmol) was dissolved in methanol (150 mL) at 0°C and a stream of hydrogen chloride gas was bubbled into the solution for 10 minutes. The mixture was then stirred for 2 hours at 0°C. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using EtOAc/Hexane (1:8) as eluant to give 1.3 g of the pure desired compound.
Example AS
Figure imgf000149_0001
To a stirred solution of the compound of Example AR (1.3 g, 5.5 mmol) in dimethyl formamide (15 mL) was added sodium azide (377 mg, 5.8 mmol), and the mixture was stirred for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The combined organic phases were washed with water and brine, dried over MgS04 and evaporated. The residue was chromatographed on silica gel using EtOAc/Hexane (1:8) as eluant to give 0.8 g of the pure desired compound as a colorless oil.
Example AT
Figure imgf000149_0002
The compound of Example AS (749 mg, 3.65 mmol) was dissolved in EtOH (30 mL) and transferred to a Parr Shaker with 4% Pd/C (200 mg) . The reaction was shaken for 24 hours at room temperature under 5 psi pressure of H2. The reaction mixture was filtered and concentrated and the residue was dissolved in 4 N HCI dioxane solution (4 mL) . The solvent was removed and the residue was recrystallized from ether to give 0.5 g of the pure desired compound as white solid. Example 47
Synthesis of methyl 3-[ [[ [3-[ (aminoiminomethyl)amino] phenyl]carbonyl]amino]methyl]benzeneacetate, trifluoroacetate salt
Figure imgf000150_0001
The title compound was prepared in the same manner as described in Example 34, replacing the compound of Example AC with the compound of Example AT.
Analysis Calculated for C18H2oN403* 1 TFA* 0.8 H20:
C," 51.24; H, 4.86; N, 11.95. Found: C, 51.32; H, 4.66; N, 11.91.
Example 48
Synthesis of ethyl 3-[ [ [3-(aminoiminomethyl)phenyl] carbonyl]amino]benzeneacetate, trifluoroacetate salt monohydrate
Figure imgf000151_0001
The above compound was prepared in the same manner as described in Example 34, replacing the compound of Example AC with the compound of Example Z.
Analysis Calculated for C18H20N403- 1 TFA- 1 H20:
C, 50.85; H, 4.91; N, 11.86. Found: C, 50.69; H, 4.54; N, 11.81.
Example 49
Synthesis of 3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]benzeneacetic acid, trifluoroacetate salt
Figure imgf000152_0001
The compound of Example 47 was hydrolyzed in the same manner as described in Example 26.
Analysis Calculated for C17H18N403- 1.3 TFA* 0.4 H20:
C, 48.86; H, 4.20; N, 11.63. Found: C, 48.95; H, 3.90; N, 11.49.
Example 50
Synthesis of 3-[ [ [3-[ (aminoiminomethyl) amino]phenyl] carbonyl]amino]benzeneacetic acid, trifluoroacetate salt
Figure imgf000153_0001
The compound of Example 48 was hydrolyzed in the same manner as described in Example 26.
Analysis Calculated for C16H16N403' 1 TFA- 0.5 H20:
C, 49.66; H, 4.17; N, 12.87. Found: C, 49.34; H, 4.03; N, 13.50.
Example 51
Synthesis of 3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] amino]carbonyl]amino]benzenepropanoic acid, trifluoroacetate salt
Figure imgf000154_0001
To a stirred solution of 3-nitrophenylisocyanate (0.5 g, 3.1 mmol, Aldrich) in methylene chloride (20 mL) was added 3-aminohydrocinnamic acid (0.45 g, 2.7 mmol, Example AX) in small portions over 5 minutes.
The mixture was stirred 18 hours at room temperature. The mixture was then poured into 10% aqueous sodium hydroxide (50 mL) and washed with ethyl acetate (2 x 25 mL) . The basic solution was acidified with 10% HCI and the resulting precipitate was filtered and dried. This produced 0.63 g (70%) of the title compound.
HRMS (M+) for C16H15N305 calculated : 329 . 1012 found : 329. 1003
Step B
Figure imgf000154_0002
A stirred solution of the product of Example 51A (0.3 g, 0.91 mmol) in ethyl alcohol (25 mL) and THF (50 mL) was hydrogenated over 4% palladium on carbon under an atmosphere of hydrogen at 5 psi. The solvent was removed at reduced pressure to produce 0.29 g (100%) of the title compound.
APCI MS (M+) for C16H17N303 Calculated: 299
Found: 299
Step C
Figure imgf000155_0001
A stirred solution of the product of Example 5IB (0.29 g, 0.97 mmol), diisopropylethylamine (0.27 mL) and pyrazole-l-carboxamidine hydrochloride (219 mg, l.ϊ mmol) in dioxane (9 mL) and water (1.5 mL) was heated at reflux for 3 hours. After cooling to room temperature, the solvents were removed at reduced pressure and the residue was chromatographed (reverse phase HPLC, gradient elution with water/acetonitrile/ trifluoroacetic acid). This produced 0.02 g (4.5%) of the title compound.
ESI MS (free base MH+) for C17H20N5O3 Calculated: 342
Found: 342 Example 52
Synthesis of [3-[ [[ [3-[ (aminoiminomethyl)amino]phenyl] amino]carbonyl]amino]phenoxy]acetic acid, trifluoroacetate salt
Figure imgf000156_0001
Step A
Figure imgf000156_0002
3-Aminophenol (1.0 g, 9.2 mmol, Aldrich) was subjected to the reaction conditions described for the preparation of Example 51A. This produced 0.5 g (20%) of the title compound.
HRMS (M+) for C13H11N304 Calculated: 273 . 0749 Found : 273 . 0732
Step B
The product of Step A (0.5 g, 1.8 mmol) in THF (20 mL) was cooled (-30°C) and treated with sodium hydride (50% dispersion in mineral oil, 0.1 g, 2 mmol) in small portions over 15 minutes. The solution was then warmed (0°C) and stirred 30 minutes and then cooled to -30°C. To this solution was added neat t-butyl bromoacetate (0.49 g, 2.5 mmol, Aldrich) and the mixture was stirred 1 hour at -30°C and then warmed to room temperature and stirred 1 hour. The volatile components were removed at reduced pressure on a rotary evaporator and the residue was taken up in ether (50 mL) . The ether was washed with water (25 mL) , 10% NaOH (25 mL) and brine (25 mL) . This produced 0.6 g (86%) of the above compound.
HRMS (M+) for C19H21N306 Calculated: 387.1430 Found: 387.1427
Step C
Figure imgf000157_0001
The product of Step B (0.6 g, 1.6 mmol) in methylene chloride (25 mL) was cooled (0°C) and treated with trifluoroacetic acid (5 mL) . The solution was warmed to room temperature and stirred for 3 hours. The volatile components were removed at reduced pressure on a rotary evaporator. The residue was chromatographed on silica gel eluting with 1% acetic acid/ethyl acetate. This produced 0.39 g (76%) of the above compound.
HRMS (M+) for C15H13N306 Calculated: 331.0804 Found: 331.0790 Step D
Figure imgf000158_0001
The product of Example 52C (0.3 g, 0.91 mmol) was subjected to the reaction conditions described for the preparation of Example 51B. This produced 0.08 g (90%) of the title compound.
ESI MS (MH+) for C16H17N303 Calculated: 302 Found: 302
Step E
Figure imgf000158_0002
The product of Example 52D (0.08 g, 0.27 mmol) was subjected to the reaction conditions described for the preparation of Example 51C. This produced 0.04 g (32%) of the title compound.
ESI MS ( free base MH+) for C16H18N504
Calculated: 344
Found : 344 Example 53
Synthesis of 3-[ [[[ [3-[ (aminoiminomethyl)amino]phenyl] amino]carbonyl]amino]methyl]benzenepropanoic acid, trifluoroacetate salt
Figure imgf000159_0001
Step A
Figure imgf000159_0002
The product from Example AB (0.09 g, 0.4 mmol) was subjected to the reaction conditions described for the preparation of Example 51A. The crude product was chromatographed on silica gel gradient eluting with ethyl acetate (containing 1% acetic acid) and produced 0.06 g (42%) of the above compound.
HRMS (M+) for C17H17N305 Calculated: 343 . 1168
Found : 343 . 1158
Step B
The product from Example 53A (0.06 g, 0.17 mmol) was subjected to the reaction conditions described for the preparation of Example 51B. This produced 0.06 g (100%) of the above compound.
APCI MS (MH+) for C17H20N3O3 Calculated: 314.15 Found: 314.12
Step c
Figure imgf000160_0001
The product from Example 53B (0.06 g, 0.19 mmol) was subjected to the reaction conditions described for the preparation of Example 51C. This produced 0.05 g (56%) of the title compound.
APCI MS (free base MH+) for C18H22N503 Calculated: 356 Found: 356
Example 54 β~[3-[ [ [ [3-(aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]phenyl]-3,5-dichloro- benzenepropanoic acid
Figure imgf000161_0001
A solution of 3-bromobenzylamine hydrochloride (2.93 g, 13 mmol), di-tert-butyldicarbonate (2.874 g, 13 mmol), and triethylamine (3.7 mL, 26 mmol) in 80:20 dioxane/water (40 mL) was stirred for 23 hours. The reaction was concentrated in vacuo and the residue dissolved in EtOAc. The solution was washed with water and brine. Concentration in vacuo gave a light yellow solid (4.59 g) . NMR was consistent with proposed structure.
Step B
Figure imgf000161_0002
A mixture of 3,5-dichlorobenzaldehyde (2.00 g, 11.4 mmol), malonic acid (1.451 g, 12.6 mmol), and pyridine (0.16 mL, 1.9 mmol) in absolute ethanol (20 mL) was heated to 105°C (bath) under argon. After 24 hours, the reaction was allowed to cool to room temperature and then concentrated in vacuo to give a white solid slurry. The solid was redissolved in Et20 (50 mL) and washed with l M HCI followed by water. The organic layer was collected, dried over MgS04, and concentrated in vacuo to give a white sticky solid. The solid was purified by slurrying with hexane. The undissolved white solid was collected by vacuum filtration (0.65 g) . NMR was consistent with proposed structure.
Step C
Figure imgf000162_0001
A solution of the compound of Step B (0.65 g, 3.0 mmol) in absolute EtOH (60 mL) was cooled to 0°C and HCI (g) was bubbled into it for 15 minutes. The solution was allowed to stir for 5 hours. An aliquot was removed and concentrated in vacuo . H NMR showed the reaction to be complete. The reaction was concentrated in vacuo to give a white solid (0.74 g) . NMR was consistent with proposed structure.
Step D
Figure imgf000162_0002
A solution of the compound of Step A (0.44 g, 1.5 mmol) and the compound of Step C (0.36 g, 1.5 mmol) in diisopropylamine (4 mL) was purged for 5 minutes with argon before adding tri-o-tolylphosphine (0.024 g, 0.05 mmol) and palladium acetate (0.010 g, 0.03 mmol). The resulting solution was purged with argon for 2 minutes and sealed. The reaction vessel was heated to 135- 140°C (bath) for 5 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL) . The organic layer was collected and washed a second time with water. The organic layer was dried over MgS04 and filtered through celite. Concentration in vacuo gave the crude product as a yellow solid (0.69 g) . The solid was purified by column chromatography [100 g silica gel, 20% EtOAc/hexane (500 mL) ] to give a white solid (0.31 g) . NMR was consistent with proposed structure.
Step E
Figure imgf000163_0001
The compound of Step D was dissolved in EtOH and hydrogenated with 5% Pt/C at room temperature under 5 psi for 16 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give an oil (0.354 g) . NMR was consistent with proposed structure. Step F
Figure imgf000164_0001
To a solution of the compound of Step E (0.354 g, 0.7 mmol) in CH2C12 (5 mL) was added TFA (1 mL) at 0°C. The ice bath was removed after the addition and the reaction was stirred at room temperature for 1.5 hours, The reaction was concentrated in vacuo to give a green/brown oil (0.493 g) . NMR was consistent with proposed structure.
Step G
Figure imgf000164_0002
A solution of Al (0.153 g, 0.7 mmol) and 1-methyl piperidine (0.09 mL, 0.7 mmol) in DMF (3 mL) was cooled to 0°C and isobutyl chloroformate (0.09 L, 0.7 mmol) was added under argon. The reaction was allowed to stir for 5 minutes before adding a solution of the compound of Step F (0.7 mmol) and 1-methyl piperidine (0.09 mL, 0.7 mmol) in DMF (2 mL) . The flask - containing the compound of Step F was rinsed with DMF (1 mL) and the rinse was added to the reaction. The reaction was allowed to warm slowly to room temperature over 16 hours. The reaction was concentrated in vacuo and the residue purified by HPLC to give the desired product as a yellow oil (0.101 g) . NMR was consistent with proposed structure.
Step H
Figure imgf000165_0001
The compound of Step G (0.101 g, 0.25 mmol) was dissolved in MeOH (3 mL) and 1 M LiOH (0.5 mL) was added at room temperature. The reaction was stirred for 23 hours. The reaction was concentrated in vacuo and the residue diluted with water (1 mL) . The solution was acidified dropwise to pH 1 with TFA. The reaction was reconcentrated and the residue purified by HPLC to give a white solid (0.053 g) .
Analysis Calculated for C24H22N403C12- 1.0 TFA+1.0 H20:
C, 50.58; H, 4.08; N, 9.07. Found: C, 50.41; H, 3.86; N, 9.29.
M+ = 485.
Example 55 3-[ [ [[3-[ [ (cyanoimino) (methylamino)- methyl]amino]phenyl]carbonyl]amino]methyl] 9-phenylbenzenepropanoic acid
Figure imgf000166_0001
Step A
Figure imgf000166_0002
A stirred mixture of 3-amino methyl benzoate (6.04 g, 40 mmol) and dimethyl N-cyanodithioiminocarbonate (11.96 g, 80 mmol) in pyridine (70 mL) was heated at reflux under a nitrogen atmosphere for 2.5 hours. The reaction mixture was cooled to room temperature. On standing overnight at room temperature the above compound crystallized from the reaction mixture affording 6.2 g (two crops). The above compound was used without further purification in the proceeding examples. NMR was consistent with the proposed structure.
A stirred mixture of the compound produced in Step A (0.56 g, 2.2 mmol) and methylamine (40%, 1.21 g, 15.4 mmol) in ethanol (20 mL) was heated in a sealed pressure vessel to 90°C for 3.5 hours. The reaction mixture was cooled to room temperature. After standing overnight at room temperature a white solid was obtained, which was isolated by filtration and washed with methanol. This afforded the above compound as a white solid (510 mg) . NMR was consistent with the proposed structure.
Step C
Figure imgf000167_0001
To a stirred solution of the product from Step B (0.51 g, 2.2 mmol) in THF (3 mL) and methanol (3mL) , 1 NaOH (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to afford a white solid. The residue was acidified by suspension in water followed by addition of 1 N HCI. The resultant solid was filtered, washed with diethyl ether, and dried to afford the above compound (259 mg) . NMR was consistent with the proposed structure.
Step D The compound of Step C (220 mg, 0.79 mmol) was coupled with the compound of Step D in Example 37 according to similar procedure described in Example 34 and purified by reverse phase HPLC (water/acetonitrile) to give a light yellow oil (194 mg) . NMR was consistent with the proposed structure. Step E
The compound of Step D (111 mg, 0.23 mmol) was hydrolyzed under the conditions described in Example 26 and purified by reverse phase HPLC (water/acetonitrile) to give the title compound as a white solid (100 mg) . NMR was consistent with the proposed structure. Analysis Calculated for c20H24N4O3»l.4 TFA:
C, 51.86; H, 4.85; N, 10.61 Found: C, 51.57; H, 4.99; N, 11.01.
Example 56 3-[ [ [ [3-[ (aminoiminomethyl)amino]phenyl]carbonyl] amino]methyl]-?R-methylbenzenepropanoic acid, trifluoroacetate salt hydrate
Figure imgf000169_0001
Step A
Figure imgf000169_0002
The product of Example AJ was hydrogenated (THF, 5% Pd/C, 5 psi, room temperature, 40 minutes) and the filtrate concentrated in vacuo. The two enantiomers were separated by chrial HPLC.
Step B
The R isomer from Step A was hydrogenated (EtOH, RaNi, 60 psi, room temperature, 1 hour) and the filtrate concentrated in vacuo .
S e C
The compound of Step B (223 mg, 1 mmol) was coupled with the compound of Example Al (217 mg, l mmol) according to a similar procedure as described in Example 34 and purified by reverse phase HPLC (water/acetonitrile) to give a brown oil (134 mg) . NMR was consistent with the proposed structure. Step D
The compound of Step C (134 mg, 0.35 mmol) was hydrolyzed under the conditions described in Example 26 and purified by reverse phase HPLC (water/acetonitrile) to give the title compound (130 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C19H22N403«1.2 TFA + 1.5 H 0:
C, 49.60; H, 5.10; N, 10.81 Found: C, 49.39; H, 4.72; N, 10.45.
Example 57 3-[ [ [ [3-[ (aminoiminomethyl)amino]phenyl]carbonyl] amino]methyl]-,9S-methylbenzenepropanoic acid
Figure imgf000171_0001
The title compound was prepared in the same manner as described in Example 56, replacing the R isomer with the S isomer. NMR was consistent with the proposed structure. MH+ = 355.
Example 58
(±) 3-[[[[3-[ (aminoiminomethyl)amino]-4-chlorophenyl]' carbonyl]amino]methyl]-/3-ethylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000172_0001
To a stirred suspension of 3-amino-4-chlorobenzoic acid (25.0 g, 157 mmol) in MeOH (300 mL) at 0°C, hydrogen chloride gas was added until the methanolic solution was saturated. The reaction mixture was stirred at 0-5°C for 30 minutes, allowed to attain room temperature, and then stirred for a further 4 days. The reaction mixture was concentrated in vacuo and the resulting white solid triturated with diethyl ether to afford the above compound as a white solid (26.2 g) .
Step B
BocHN
Figure imgf000172_0002
To a solution of N,N'-£>is-tert-butoxycarbonyl thiourea (24.8 g, 90 mmol) and methyl-3-amino-4- chlorobenzoate (20 g, 90 mmol) in dimethylformamide (120 mL) and triethylamine (45 ml) at 0°C mercury II chloride (30.1 g, 111 mmol) was added. The reaction mixture was stirred for 15 minutes at 0°C, allowed to attain room temperature, and then stirred for a further 2 hours. The reaction mixture was diluted with ethyl acetate (600 mL) and the resulting slurry filtered under reduced pressure. The filtrate was concentrated, to afford an oily gum which was purified by chromatography on silica gel (eluent:ethyl acetate/heptane 20:80) to afford the above compound as a white solid (8.6 g) .
Step C
BocHN
Figure imgf000173_0001
The product of Step B (2 g, 4.7 mmol) was dissolved in MeOH (3 mL) and 1 M NaOH (14 mL) was added at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and the residue dissolved in water and washed with ether. The aqueous layer was acidified to pH=3 with IN HCI. A white precipitate formed, was filtered and washed with water and ether and dried to give 1.2 g of a white solid. NMR was consistent with the proposed structure.
Step D
Figure imgf000173_0002
To a solution of the product of Step C (550 mg, 1.33 mmol) in CH2C12 (4 ml) was added TFA (1 mL) at 0°C, The ice bath was removed after the addition and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give a colorless oil. To this was added 4N HCI solution in dioxane (2 mL) and white precipitate formed. The solution was concentrated in vacuo to afford 280 mg of a white solid. NMR was consistent with the proposed structure.
Step E
The compound of Step D (245 mg, 0.98 mmol) was coupled with the compound of Step C in Example 41 (238 mg, 0.98 mmol) according to a similar procedure as described in Example 34 and purified by reverse phase HPLC (water/acetonitrile) to give a yellow oil (200 mg) . NMR was consistent with the proposed structure.
Step F
The compound of Step E (197 mg, 0.4 mmol) was hydrolyzed under the conditions described in Example 26 and purified by reverse phase HPLC (water/acetonitrile) to give a white solid (146 mg) . NMR was consistent with the proposed structure.
Analysis Calculated for C20H23N4O3Cl«l.4 TFA + 0.8 H20: C, 47.47; H, 4.54; N, 9.71
Found: C, 47.38; H, 4.28 N, 9.67.
Example 59
(±) 3-[ [ [ [3-[ (aminoiminomethyl)amino]-5-
(trifluoromethyl)phenyl]carbonyl]amino]methyl]-3- ethylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000175_0001
Step A
The compound of Example D (88 mg, 0.31 mmol) was coupled with the compound of Step C in Example 41 (73 mg, 0.31 mmol) according to a similar procedure as described in Example 34 and purified by reverse phase HPLC (water/acetonitrile) to give a colorless oil (48 mg) . NMR was consistent with the proposed structure.
Step B
The compound of Step A (48 mg, 0.1 mmol) was hydrolyzed under the conditions described in Example 26 and purified by reverse phase HPLC (water/acetonitrile) to give a colorless oil (38 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C21H23N403F3»1.4 TFA + 0.,4 H20:
C, 47.39; H, 4.21; N, 9.29 Found: C, 47.33; H, 3.97; N, 9.29 Example 60 (±) /3-[3-[[[[3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]phenyl]-3,5-difluoro- benzenepropanoic acid, trifluoroacetate salt
Figure imgf000176_0001
A solution of potassium tert-butoxide (0.9 g, 7.2 mmol) in THF (20 mL) was cooled to 0°C and ethyl dimethyl phosphonoacetate (1.4 g, 7.2 mmol) was added slowly under argon. The reaction was stirred for 20 minutes. A solution of benzaldehyde in THF (5 mL) was added to the reaction dropwise. The ice bath was taken off immediately and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with ethyl acetate (2X) . The organic layers were combined and washed with brine, dried over MgS04 and concentrated in vacuo . The residue was purified by chromatography on silica gel (eluent:ethyl acetate/Hexane 20%) to afford the above compound as colorless oil (1.5 g) . NMR was consistent with the proposed structure. Step B
Figure imgf000177_0001
The above compound was prepared in the same manner described in Step D of Example 54, replacing the compound of Step C in Example 54 with the product of Step A. NMR was consistent with the proposed structure.
Step C
Figure imgf000177_0002
The product from Step B was reduced in the same manner described in Step C, Example 77.
Step D
The title compound was prepared in the same manner as described in Example 54 (Step F to Step H) , replacing the compound of Step E in Example 54 with the product of Step C. NMR was consistent with the proposed structure.
Analysis Calculated for C24H22N403F2»l.6 TFA + 0.3 H20: C, 51.02; H, 3.81; N, 8.75
Found: C, 50.82; H, 3.54; N, 9.02 Example 61 (±) 3-[3-[[[[3-[ (aminoiminomethyl)amino]-5- (trifluoromethyl)phenyl]carbonyl]amino]methyl] phenyl]-3,5-di luorobenzenepropanoic acid, trifluoroacetate salt hydrate
Figure imgf000178_0001
The product from Step C in Example 60 was deprotected as described in Step F, Example 54, and then coupled with the compound of Example D using a method similar to that described in Example 54 (Step G to Step H) to afford the title compound. NMR was consistent with the proposed structure. Analysis Calculated for C25H21N403F5«»1.8 TFA«1.1 H20:
C, 46.08; H, 3.38; N, 7.52 Found: C, 45.70; H, 3.12; N, 7.64
Example 62
(±) 3,5-difluoro-3-[3-[ [ [ [3-[ (l,4,5, 6-tetrahydro- pyrimidin-2-yl)amino]phenyl]carbonyl]amino]- methyl]phenyl]benzenepropanoic acid, trifluoroacetate salt monohydrate
Figure imgf000179_0001
1-(3-Carboxyphenyl)-2-thiourea (5 g, 0.025 mole) (Trans World Chemicals) in THF (75 mL) and iodomethane (3.62 g, 0.025 mole) were stirred at reflux for 2 hours. The solvent was removed under vacuum and the residue was slurried in ether (3X) , to yield, after drying under vacuum, N-(3-carboxyphenyl)-S- methylisothiouronium hydriodide (7.8 g) as a yellow solid.
Step B
Figure imgf000179_0002
To the product of Step A (10.1 g, 0.03 mole) in DMF (15 mL) was added 1,3-diaminopropane (2.22 g, 0.03 mole), triethylamine (3.9 g, 0.03 mole), and DMAP (420 g) . The reaction mixture was heated at 140-150°C for 4.5 hours. After cooling to room temperature, H20 (30 mL) was added and, after stirring for 15 minutes, the precipitate was filtered and washed with H20. The precipitate was slurried in H20 and made acidic with concentrated HCI. A solution formed. After lyophilizing off the solvent, the residue was slurried 2X with isopropyl ether. After drying under vacuum 3- (2-amino-l,4,5, 6-tetrahydropyrimidine) -benzoic acid hydrochloride was produced (4.0 g) as a white solid. MS and NMR were consistent with the desired structure.
Step C
The product from Step C in Example 60 was deprotected as described in Step F of Example 54 and then coupled with the product from Step B using a method similar to that described in Example 54 (Step G to Step H) to afford the title compound. NMR was consistent with the proposed structure.
Analysis Calculated for C27H26N403F2»1.4 TFA«1.0 H20: C, 53.41; H, 4.42; N, 8.36 Found: C, 43.12; H, 4.14; N, 8.25
Example 63 (±) 3-[3-[[[[3-[ (aminoiminomethyl)amino]phenyl] carbonyl]amino]methyl]phenyl]-2-methoxybenzene- propanoic acid, trifluoroacetate salt hydrate
Figure imgf000181_0001
Step A
A solution of potassium tert-butoxide (1.06 g, 8.8 mmol) in THF (40 mL) was cooled to 0°C and ethyl dimethyl phosphonoacetate (1.7 g, 8.8 mmol) was added slowly under argon. The reaction was stirred for 30 minutes. A solution of o-anisaldehyde (1.02 g, 7.3 mmol) in THF (3 mL) was added to the reaction dropwise. The ice bath was taken off immediately and the reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with water and extracted with ethyl acetate (2X) . The organic layers were combined and washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:ethyl acetate/hexane 30%) to afford the above compound as colorless oil (1.58 g) . Step B
Figure imgf000182_0001
The above compound was prepared in the same manner described in Step D of Example 54, replacing the compound of Step C in Example 54 with the product of Step A. NMR was consistent with the proposed structure.
Figure imgf000182_0002
The product of Step B (0.72 g, 1.7 mmol) was dissolved in EtOH and hydrogenated with 5% Pd/C in a Parr Shaker (5 psi) at room temperature for 2 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the desired product as a yellow oil (0.485 g) . NMR was consistent with the proposed structure. Step D
Figure imgf000183_0001
The product of Step C was deprotected in the same manner described in Step F of Example 54. NMR was consistent with the proposed structure.
Step E
The product of Step D (330 mg, 1.05 mmol) was coupled with the compound of Example Al (230 mg, 1.05 mmol) according to a similar procedure as described in
Example 34 and purified by reverse phase HPLC
(water/acetonitrile) to give a yellow solid (360 mg) .
NMR was consistent with the proposed structure.
Step F
The compound of Step E (360 mg, 0.76 mmol) was hydrolyzed under the conditions described in Example 26 and purified by reverse phase HPLC (water/acetonitrile) to give a colorless oil (300 mg) . NMR was consistent with the proposed structure.
Analysis Calculated for C25H26N404»1.8 TFA + 1.3 H20: C, 50.88; H, 4.54; N, 8.30
Found: C, 50.54; H, 4.26; N, 8.51 Example 64 (±) [ [ [ [3-[ [amino(cyanoimino)methyl]amino] phenyl]carbonyl]amino]methyl]-/3-methyl- benzenepropanoic acid
Figure imgf000184_0001
Step A
Figure imgf000184_0002
A stirred mixture of the compound from Step A in Example 55 (1 g) and ammonium hydroxide (2 mL) in ethanol (20 mL) was heated at 70°C in a sealed tube for 3.5 hours. The reaction mixture was cooled to room temperature and reduced to half its volume. After standing overnight at room temperature a white solid was obtained, which was isolated by filtration and washed with methanol. This afforded the above compound as a white solid. NMR was consistent with the proposed structure.
Step B
The product of Step A was hydrolysed in the same manner as described in Step C of Example 55. NMR was consistent with the proposed structure. Step C
Figure imgf000185_0001
The above compound was prepared under the same conditions as described in Example AJ, replacing t- butyl P,P-dimethylphosphonoacetate with ethyl P,P- dimethylphosphonoacetate.
Figure imgf000185_0002
The product of Step C was hydrogenated under the same conditions as described in Example 37, Step D.
Step E
Figure imgf000185_0003
The compound of Step B was coupled with the compound of Step D according to similar procedure described in Example 34. NMR was consistent with the proposed structure. Step F
The compound of Step E was hydrolyzed under the conditions described in Example 26. NMR was consistent with the proposed structure. Analysis Calculated for C20H21N5O3 + 0.5 H20:
C, 61.84; H, 5.71; N, 18.03 Found: C, 61.84; H, 5.63; N, 17.70
Example 65 (±) 3[[ [ [3-[ [amino[ (aminocarbonyl) imino]methyl]amino] phenyl]carbonyl]amino]methyl]-?-methylbenzene- propanoic acid, trifluoroacetate salt
Figure imgf000187_0001
Step A
The product from Step B of Example 64 was coupled with the compound of Example AK according to a similar procedure as described in Example 34. NMR was consistent with the proposed structure.
Step B
A solution of the product from Step A (100 mg, 0.23 mmol) in a 1:1 CH2C12:TFA solution (1 mL) was kept at room temperature for 2 hours. The reaction solution was evaporated under a stream of N2. The residue was purified by reverse phase HPLC (H20/TFA:MeCN) to give the title compound, 77 mg. 1H NMR and MS were consistent with the proposed structure. Example 67
(±) 3-[[[ [3-[ (4,5-dihydro-4-oxo-lH-imidazol-2- y1)amino]phenyl]carbonyl]amino]methyl] -β- methylbenzenepropanoic acid
Figure imgf000188_0001
Step A
Figure imgf000188_0002
To a mixture of 2-thiohydantoin (5.5 g, 47.4 mmol) in absolute ethanol (60 mL) was added methyl iodide (3.5 mL, 56.6 mmol). The mixture was heated at reflux for 5 hours. The mixture was cooled to room temperature and concentrated in vacuo . 1H NMR was consistent with the proposed structure.
Step B
To a mixture of the product from Step A (1.0 g, 3.8 mmol) in absolute ethanol (20 mL) was added ethyl 3-aminobenzoate (2.5 g, 15.3 mmol). The mixture was stirred at room temperature for 16 hours. The mixture - was concentrated in vacuo and the residue was purified by chromatography (85:14:1 CH2Cl2:MeOH:NH4OH) to give the desired product, 414 mg. NMR was consistent with the proposed structure. Step C
Figure imgf000189_0001
To a mixture of the product from Step B (250 mg, 1.0 mmol) in THF (2 mL) and methanol (2 mL) was added 1 N NaOH solution (2 mL) . The reaction was stirred at room temperature for 2 hours and concentrated in vacuo . The residue was suspended in water and carefully acidified to pH 4 with 1 N HCI. The solid was collected by filtration and washed with water and ether to give the desired product, 190 mg. 1H NMR was consistent with the proposed structure.
Step D
Figure imgf000189_0002
The product of Step C and the product from Step D in Example 64 were coupled according to a similar procedure as described in Example 34. -*Η NMR was consistent with the proposed structure.
Figure imgf000190_0001
The product of Step D was hydrolyzed using the procedure in Step C. 1H NMR was consistent with the proposed structure.
Exact mass calculated for C21H22N404: 394.3519
Found: 394.3520
Example 69
(±) 3-[ [ [ [3-[ (lH-benzimidazol-2-yl)amino]- phenyl]carbonyl]amino]methyl]-0-methyl- benzenepropanoic acid
Figure imgf000191_0001
Step A
Figure imgf000191_0002
To a solution of 2-nitrophenylisothiocyanate (3.0 g, 16.6 mmol) in ethanol (45 mL) was added ethyl 3- aminobenzoate (2.75 g, 16.6 mmol) and triethylamine (2.6 mL, 18.6 mmol). The reaction solution was kept at room temperature for 17 hours. The reaction solution was concentrated in vacuo . The solid was washed with ether and water to give the desired product (3.3 g) . NMR was consistent with the proposed structure.
Step B
The product from Step A (2.3 g, 6.7 mmol) was hydrogenated with Raney nickel catalyst to yield the desired product (606 mg) . U NMR was consistent with the proposed structure. Step C
Figure imgf000192_0001
To a solution of the product from Step B (600 mg, 1.9 mmol) in ethanol (15 mL) was added mercury oxide (784 mg, 3.6 mmol) and sulfur (12 mg, 0.36 mmol). The mixture was heated at reflux for 3 hours. The mixture was cooled and filtered. The filtrate was concentrated in vacuo to afford the desired product (410 mg) . 1H NMR was consistent with the proposed structure.
Step D
Figure imgf000192_0002
To a solution of the product from Step C (410 mg, 1.5 mmol) in methanol (18 mL) was added IN NaOH solution (7 mL) . The reaction solution was kept at room temperature for 5 hours. Volatiles were removed in vacuo and the residue acidified with IM KHS04 solution. A solid precipitate was collected and dried in vacuo to give the desired product (425 mg) . 1H NMR was consistent with the proposed structure. 191 -
Step E
Figure imgf000193_0001
To a solution of the product from Step D (190 mg, 0.75 mmol) in DMF (5 mL) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (158 mg, 0.82 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (112 mg, 0.82 mmol) and N- methylmorpholine (0.25 mL, 2.25 mmol). The compound of Example AK (206 mg, 0.82 mmol) in DMF (1 mL) was added via canula. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (94:5:1 CH2C12:MeOH:NH4OH) to afford the desired product (105 mg) .
Step F
Figure imgf000193_0002
A solution of the product from Step E (105 mg) in a 1:1 CH2C12:TFA solution (4 mL) was kept at room temperature for 1 hour. The solution was concentrated with a stream of N2. The residue was purified by chromatography on silica gel (85:14:1 CH2Cl2:MeOH:NH4OH) to give the desired product. _ Anal, calcd for C25H24N403 + 1.1 TFA: C, 58.98; H, 4.56; N, 10.11.
Found: C, 59.08; H, 4.80; N, 10.04. Example 70
(±) 3-[ [ [ [3-[ (5-methoxy-lH-benzimidazol-2-yl)- amino]phenyl]carbonyl]amino]methyl]-/3-methyl- benzenepropanoic acid, trifluoroacetate salt
Figure imgf000194_0001
The title compound was prepared as in Example 69, starting from 5-methoxy-2-nitrophenylisothiocyanate. Anal, calcd for C26H26N 04 + 1.6 TFA:
C, 54.71; H, 4.34; N, 8.73. Found: C, 54.71; H, 4.00; N, 8.70.
Example 71 3-[2-[3-[ (4,5-dihydro-lH-imidazol-2-yl)amino] phenyl]-2-hydroxyethoxy]benzenepropanoic acid, trifluoroacetate salt
Figure imgf000195_0001
Step A
Figure imgf000195_0002
To a solution of methyl 3-hydroxycinnamate (14.3 g, 80 mmol) in acetone (400 mL) was added powdered potassium carbonate (12.16 g, 88 mmol) and 2-bromo-3'- nitroacetophenone. The reaction mixture was heated at reflux for 3.5 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo to give a dark brown gum. The solid was triturated with methanol to give a light brown powder, 12.6 g. LH NMR was consistent with the proposed structure.
A solution of the product from Step A (3.0 g, 8.8 mmol) in methanol (100 mL) was hydrogenated with 5% Pd/C catalyst for 2 hours. The catalyst was removed by filtration and the filtrate concentrated to give the desired product, 2.9 g. 1H NMR was consistent with the proposed structure. Step C
Figure imgf000196_0001
The product from Step B (345 mg, l.l mmol) was treated with N,N'-bis-(tert-butoxycarbonyl)-2- i idazolidinethione as described in Example 72, Step D to give the desired product (428 mg) . **Η NMR was consistent with the proposed structure.
Step D
Figure imgf000196_0002
The product from Step C (420 mg) was deprotected in the same manner as described in Example l to give the desired product (160 mg) . 1H NMR was consistent with the proposed structure.
Step E
Figure imgf000196_0003
The product from Step D (150 mg, 0.4 mmol) was saponified with NaOH to give the desired product (91 mg) . Anal, calcd for C20H23N3O4 + 1.6 TFA:
C, 50.52; H, 4.50; N, 7.61.
Found: C, 50.91; H, 4.72; N, 7.22. Example 72 2-[3-[3-[3-[ (4,5-dihydro-lH-imidazol-2-yl)amino]' phenyl]-l-oxo-2-propenyl]phenoxy]acetic acid, trifluoroacetate salt hydrate
Figure imgf000197_0001
Step A
Figure imgf000197_0002
To a solution of 10.Og (73.5 mmoles) of 3- hydroxyacetophenone and 13.0ml (15.8g, 80.9 mmoles) of t-butyl bromoacetate in of dimethylformamide (75 ml) was added 15.2g (110 mmoles) of anhydrous potassium carbonate. The mixture was stirred in an 95°C oil bath for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the above compound (17.0g) as a water white oil. The structure was confirmed by 1H NMR.
Step B
To a solution of 10.Og (40.0 mmoles) of the product of Step A and 6.04g (4.10 mmoles) of 3- nitrobenzaldehyde in absolute ethanol (40 ml) was added a solution of 513mg (9.14 mmoles) of potassium hydroxide in ethanol (5 ml) , and the mixture stirred overnight at room temperature. The resulting solid was recovered by filtration, washed with ethanol, and air dried to give the above compound (7.92g), as a nearly white solid. Anal. Calcd. for C21H21FN05 -»H20 (MW 401.42):
C, 62.84, H, 5.27, N, 3.49. Found: C, 63.13, H, 5.08, N, 3.57.
Step C
Figure imgf000198_0001
To a warm (60°C) suspension of 7.57g (19.8 mmoles) of the product of Step B in ethanol (200 ml) was added 17.9g (79.2 mmoles) of stannous chloride dihydrate as a solid. The mixture was stirred in an oil bath at 75°C for 2 hours eventually forming a homogeneous solution. After cooling, the solvent was evaporated, and the residue partitioned between ethyl acetate and IN aqueous sodium hydroxide. Following removal of precipitated salts by filtration, the organic layer was separated, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 35% ethyl acetate - hexane as eluent gave the above compound (1.87g) as a yellow oil. The structure was confirmed by ***H NMR. Step D
Figure imgf000199_0001
A mixture of 750mg (2.12 mmoles) of the product of Step C (896mg, 2.97 mmoles) of N,N'-bis-(tert- butoxycarbonyl)-2-imidazolidinethione (808mg, 2.97 mmoles) of mercuric chloride, and (832μl, 604mg, 5.98 mmoles) triethylamine was stirred in an 85°C oil bath for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and water, filtered, and the organic layer separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using a gradient of 25-35% ethyl acetate - hexane as eluent gave the above compound (850mg) as a yellowish foam. The structure was confirmed by ^Η NMR.
Step E
A solution of 880mg (1.37 mmoles) of the product of Step D in dichloromethane-trifluoroacetic acid (20 ml, 1:1) was stirred overnight at room temperature, and then concentrated. Reverse phase preparative HPLC of the residue using a gradient of 95:5 to 50:50 dilute aqueous trifluoroacetic acid and acetonitrile gave, after concentration of the appropriate fractions, the title compound (75mg) as a nearly pure white solid.
Anal. Calcd. for C20H19N3O4«CF3COOH«2.5H20 (MW 486.45):
C, 54.32, H, 4.14, N, 8.64. Found: C, 54.26, H, 4.39, N, 8.25. Example 73
2-[3-[3-[3-[ (aminoiminomethyl)amino]phenyl]-1- oxopropenyl]phenoxy]acetic acid, monohydrochloride
Figure imgf000200_0001
Figure imgf000200_0002
To a solution of 1.61g (4.56 mmoles) of the product from Step C of Example 72 and (1.57g, 5.70 mmoles) of bis-Boc thiourea in (48ml) dimethylformamide was added (1.55g, 5.70 mmoles) mercuric chloride, and then (1.8ml, 1.3g, 13 mmoles) triethylamine. The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate and filtered. The filtrate was washed with water, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 15% ethyl acetate- hexane as eluent gave the above compound (1.13g) as a very pale yellow solid. The structure was confirmed by 1H NMR.
Step B
The above product of Step A (1.13g, 1.99 mmoles) was dissolved in 1:1 dichloromethane-trifluoroacetic acid (30 ml) and after 2 hours was concentrated. Reverse phase preparative HPLC of the residue using a gradient of 80:20 to 50:50 dilute aqueous trifluoroacetic acid and acetonitrile gave, after concentration of the appropriate fractions, the above compound (as the zwitterion) (340mg) as a nearly pure white solid. Anal. Calcd. for C18H17N3O4»0.5H20 (MW 348.36): C, 62.06, H, 4.92, N, 12.06. Found: C, 62.21, H, 4.99, N, 12.00.
Step C A suspension of 120mg of the product from Step B in water (20 ml), 3N aqueous hydrochloric acid (2 ml), and methanol (10 ml) was kept at room temperature for 1 hour and then evaporated to give the title compound (130mg) as a nearly white solid. Anal. Calcd. for C18H18C1N304»0.375H20 (MW 375.81): C, 56.51, H, 4.74, N, 10.98. Found: C, 57.53, H, 4.83, N, 11.18.
Example 74 3-[2-[3-[ (aminoiminomethyl)amino]phenyl]ethyny1] -β- phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000202_0001
Step A
In a flame dried flask under N2 at 0°C was suspended sodium hydride (2.08 g, 60% dispersion) in dry THF (100 ml) . This suspension was treated with a solution of 3- hydroxybenzophenone (10.0 g) in THF (50 ml) dropwise at 0°. After stirring for 30 minutes at 0°, a solution of trimethylsilyl chloride (5.86 g) in THF (25 ml) was added dropwise at 0°.
In another flame dried flask under N2 at 0° was prepared a suspension of sodium hydride (2.40 g, 60% dispersion) in THF (50 ml) . A solution of tert-butyl P,P-dimethyl phosphonoacetate (13.50 g) was added dropwise and the reaction allowed to stir and warm to room temperature over 1 hour. The contents of this flask was then added dropwise to the first flask at 0° and the reaction was allowed to stir and warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (500 ml) and 2N HCI (500 ml) . The aqueous portion was extracted with additional ethyl acetate and the combined organic extracts were washed with water, saturated sodium chloride solution, dried over Na2S04, concentrated, and purified on a flask column eluting with 20% ethyl acetate-80% hexane to afford a white solid (12.5 g) . NMR was consistent with the proposed structure.
Step B
Figure imgf000203_0001
A solution of the product from Step A (12.4 g) , ethanol (50 ml) , and THF (50 ml) was hydrogenated at 5 psi for 5 hours at room temperature with Raney nickel. The reaction mixture was filtered, concentrated and purified on a flash column eluting with 20% ethyl acetate-80% hexane to afford the product (11.6 g) as a viscous oil. NMR was consistent with the proposed structure.
Figure imgf000203_0002
The reaction was run as described in Example AV using the product from Step B (11.6 g) . The crude product was purified on a flash column eluting with 20% ethyl acetate- 80% hexane to afford the product (15.4 g) as a viscous liquid. NMR was consistent with the proposed structure.
Step D
Figure imgf000204_0001
The above compound was prepared as described in Example AL from the compound produced in Step C (15.4 g) . The crude product was purified on a flash column eluting with 10% ethyl acetate - 90% hexane to afford the product (3.2 g) as a tan solid. NMR was consistent with the proposed structure.
Figure imgf000204_0002
The above compound was prepared as described in Example AM from the product produced in Step D (3.2 g) . The crude product was purified on a flash column eluting with 10% ethyl acetate - 90% hexane to afford the product (2.0 g) as a viscous brown oil. NMR was consistent with the proposed structure. Step F
Figure imgf000205_0001
The above compound was prepared as described in Example AN from the compound produced in Step E (1.9 g) . The crude product was purified on a flash column eluting with 20% ethyl acetate - 80% hexane to afford the product as a brown oil. NMR was consistent with the proposed structure.
Step G
Figure imgf000205_0002
A mixture of the product from Step F (1.0 g) , SnCl2 (1.33 g) , water (250 ml) and ethanol (25 ml) was refluxed for 90 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and 10% potassium carbonate solution. The aqueous portion was extracted several times with ethyl acetate and the combined organic extracts were washed with saturated sodium chloride solution, dried over Na2S04, concentrated, and purified on a flash column eluting with 30% ethyl acetate - 70% hexane to afford the product (580 mg) as a viscous orange oil. NMR was consistent with the proposed structure. Step H
Figure imgf000206_0001
The reaction was run as described in Example Y using the product from Step G (220 mg) . The crude product was purified on a flash column eluting with 10% ethyl acetate - 90% hexane to afford the product (220 mg) as a light yellow powder. NMR was consistent with the proposed structure.
A solution of the product from Step H (220 mg) was stirred with methylene chloride (5 ml) and trifluoroacetic acid (5 ml) at room temperature for l hour. The solvent was removed in vacuo and the crude product was purified via reverse phase HPLC using a water (0.5%TFA) and acetonitrile gradient as eluant to afford a white powder (175 mg) . NMR was consistent with the proposed structure. Analysis: Calculated for C24H21N302»1.5 TFA
C, 58.49; H, 4.09; N, 7.58 Found: C, 58.78; H, 4.20; N, 7.75.
Example 75 3-[2E-[3-[ (aminoiminomethyl)amino]phenyl] etheny1]-/3-phenylbenzenepropanoic acid, bis(trifluoroacetate) salt
Figure imgf000207_0001
A mixture of the compound described in Step C, Example 74 (3.34 g) , 3-nitro styrene (1.56 g) , triethylamine (1.06 g) , palladium acetate (19 mg) and triphenylphosphine (45 mg) were mixed in a thick walled tube and sealed with a screw cap. The tube was heated at 100°C for 12 hours and then cooled. The reaction mixture was placed directly on a flash column and eluted with 10% ethyl acetate - 90% hexane to afford the product (191 mg) as a light yellow solid. NMR was consistent with the proposed structure.
Step B
Figure imgf000207_0002
The above compound was prepared as described in Step G, Example 74 from the product produced in Step A (180 mg) . The crude product was purified via flash chromatography eluting with 50% ethyl acetate - 50% hexane to afford the compound (114 mg) as a golden oil. NMR was consistent with the proposed structure.
Step C
Figure imgf000208_0001
The above compound was prepared as described in Example Y using the compound (104 mg) prepared in Step B. The crude product was purified on a flash column eluting with 10% ethyl acetate - 90% hexane to afford the desired product (157 mg) as a light brown solid. NMR was consistent with the proposed structure.
Step D
The title compound was prepared as described in Example 74, Step I from the product (153 mg) produced in Step C. The crude product was purified via reverse phase HPLC using a water (0.5% TFA) and acetonitrile gradient as eluant to afford white powder (92 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C24H23N302 • 2.0 TFA C, 54.82; H, 4.11; N, 6.85. Found: C, 54.70; H, 4.04; N, 7.08. Example 76
3-[2Z-[3-[ (aminoiminomethyl)amino]phenyl]' ethenyl]-/3-phenylbenzenepropanoic acid, bis(trifluoroacetate) salt
Figure imgf000209_0001
A mixture of the product produced in Step G, Example 74 (316 g) , triethylamine (236 mg) , formic acid (40 mg) and 10% palladium on carbon (9 mg) was placed in a tube and sealed with a screw cap. The reaction was heated at 80°C for 24 hours, cooled, filtered, and concentrated. The crude product was purified on a flash column eluting with 30% ethyl acetate - 70% hexane to afford the product as a golden oil (113 mg) . NMR was consistent with the proposed structure.
Step B
Figure imgf000209_0002
The reaction was run as described in Example Y using the product from Step A (113 mg) . The crude product was purified on a flash column eluting with 10% ethyl acetate - 90% hexane to afford an off white solid (140 mg) . NMR was consistent with the proposed structure.
The title compound was prepared as described in Step I, Example 74 using the product produced in Step B (132 mg) . The product was purified to yield a white solid (94 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C24H23N302 • 2.0 TFA.
C, 54.82; H, 4.11; N, 6.85. Found C, 54.26; H, 3.96; N, 7.16.
Example 77
0-[3-[ [ [3-[ (aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-dichlorobenzene- propanoic acid, trifluoroacetate salt
Figure imgf000211_0001
In a flame dried flask under N2 was dissolved 3,5- dichlorobenzoylchloride (10.o g) in dry THF (100 ml). The stirred reaction mixture was chilled to 50°C and treated dropwise with a 1.0M solution of 3-[bis(trimethylsilyl)- amino]-phenylmagnesium chloride (40 ml) (Aldrich) in THF. After the addition was completed, the reaction was allowed to warm to room temperature and then partitioned between ethyl acetate and IN HCI. The mixture was adjusted to pH - 10 with IN KOH and shook well in a separatory funnel. The layers were separated and the aqueous portion was extracted with additional ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and purified on a flash column eluting with 25% ethyl acetate - 75% hexane to afford a yellow solid (7.2 g) . NMR was consistent with the proposed structure. Step B
Figure imgf000212_0001
The reaction was run as described in Example E using the product produced in Step A (7.1 g) . The crude product was purified on a flash column eluting with 30% ethyl acetate - 70% hexane to afford viscous golden oil (5.1 g) . NMR was consistent with the proposed structure.
Step C
Figure imgf000212_0002
In a flame dried flask under N2 was stirred a mixture of magnesium turnings (3.6 g) , dry methanol (150 ml) and the compound produced in Step B (5.1 g) . The reaction was stirred at room temperature (mildly exothermal) until all of the metal had dissolved. The reaction was then concentrated and partitioned between ethyl acetate and 2N HCI. The mixture was then adjusted to pH~ll with 2N KOH and shaken well in a separatory funnel. The layers were separated and the aqueous portion was extracted with additional ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over Na2S04 and concentrated. The crude product was purified on a flash column eluting with 25% ethyl acetate- 75% hexane to yield a golden oil (5.3 g) . NMR was consistent with the proposed structure.
Step D
Figure imgf000213_0001
The reaction was run as described in Example G using the product produced in Step C (3.2 g) . The crude product was purified on a flash column eluting with 30% ethyl acetate - 70% hexane to afford a yellow gum (2.8 g) . NMR was consistent with the proposed structure.
Step E
Figure imgf000213_0002
The reaction was run as described in Example 74, Step G, using the compound produced in Step D (2.7 g) . The crude product was purified on a flash column eluting with 50% ethyl acetate - 50% hexane to afford a white solid (2.1 g) . NMR was consistent with the proposed structure.
Figure imgf000214_0001
The reaction was run as described in Example Y using the product produced in Step E (340 mg) . The crude product was purified on a flash column eluting with 20% ethyl acetate - 80% hexane to yield a white solid (200 mg) . NMR was consistent with the proposed structure.
Step G
The title compound was prepared as described in Example 74, Step I, using the product from Step F (180 mg) . The crude material was purified in a similar fashion to afford a white solid (96 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C22H 0N404C12S • 1.5 TFA
C, 44.26; H, 3.19; N, 8.26; Cl, 10.45; S, 4.73. Found: C, 44.02; H, 3.27; N, 8.28; Cl, 10.29; S, 5.05.
Example 78
0~[3-[ [ [3-[ (aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-difluorobenzene- propanoic acid, trifluoroacetate salt
Figure imgf000215_0001
The above compound was prepared from 3,5-difluoro benzoyl chloride in a sequence of reactions as described in Example 77. NMR was consistent with the proposed structure.
Analysis Calculated for C22H20N4O4F2S • 1.65 TFA C, 45.86; H, 3.29; N, 8.46; S, 4.84 Found: C, 45.56; H, 3.07; N, 8.61; S, 5.26.
Example 79 β-[3-[ [ [3-[ (aminoiminomethyl)amino]phenyl] sulfonyl]amino]phenyl]-4-fluorobenzene- propanoic acid, trifluoroacetate salt
Figure imgf000216_0001
The above compound was prepared from 4-fluoro benzoyl chloride in a sequence of reactions as described in Example 77. NMR was consistent with the proposed structure.
Analysis Calculated for C22H21N404FS • 1.5 TFA C, 47.85; H, 3.61; N, 8.93; S, 5.11. Found: C, 47.69; H, 3.74; N, 9.14; S, 5.53.
Example 80
,β—[3—[ [ [3—[ (aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,4,5-trifluorobenzene- propanoic acid, trifluoroacetate salt
Figure imgf000217_0001
The above compound was prepared from 3,4,5-trifluoro benzoyl chloride in a sequence of reactions as described in Example 77. NMR was consistent with the proposed structure.
Analysis Calculated for C22H19N404F3S • 1.25 TFA. C, 46.34; H, 3.21; N, 8.82; S, 5.05. Found: C, 46.54; H, 3.15; N, 8.86; S, 5.29.
Example 81 0-[3-[ [ [3-[ (aminoiminomethyl)amino]phenyl] sulfonyl]amino]phenyl]perfluorobenzene- propanoic acid, trifluoroacetate salt
Figure imgf000218_0001
The above compound was prepared by hydrogenation of the precursor, which was prepared similarly as described in Example 77, Step B, with 5% platinum on carbon in ethanol at 60 psi for 16 hours at 50°C. The crude product was purified on a flash column eluting with 30% ethyl acetate - 70% hexane. NMR was consistent with the proposed structure.
Step B
The title compound was prepared from the product produced in Step A through a series of similar reactions as described in Example 77, (Steps D through G) . NMR was consistent with the proposed structure. Analysis Calculated for C22H17N404F5S • 1.5 TFA C, 42.93; H, 2.67; N, 8.01; S, 4.58. Found: C, 42.98; H, 2.56; N, 8.19; S, 5.02. Example 82 β~ [ 3 - [ [ [3-[ (aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-2,3,5,6-tetrafluoro- benzenepropanoic acid, trifluoroacetate salt
Figure imgf000219_0001
The above compound was prepared from a similar reaction as described in Example 77, Step C using the tetrafluoro analog which was prepared in an analogous fashion as described in Example 77, Step B. NMR was consistent with the proposed structure.
Step B
The title compound was prepared from the product produced in Step A by a series of similar reactions as described in Example 77, (Steps D through G) . NMR was consistent with the proposed structure. Analysis Calculated for C22H18N404F4S • 1.8 TFA
C, 42.96; H, 2.79; N, 7.83; S, 4.48 Found: C, 42.70; H, 2.84; N, 7.89; S, 4.89. Example 83
3,5-difluoro-?-[3-[ [ [3-[ [ [ (phenylmethyl)amino]- thiocarbony1]amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid
Figure imgf000220_0001
Step A
A mixture of the 3,5-difluoro precursor (648 mg) , which was prepared in an analogous manner as described in Example 77, Step E, benzyl isothiocyanate (373 mg) , and toluene (8 ml) was refluxed for 20 hours. The reaction was cooled and concentrated. The residue was dissolved in acetonitrile at room temperature and treated with several equivalents of benzyl amine for 1 hour. The reaction was concentrated and purified on a flash column eluting with 30% ethyl acetate - 70% hexane to afford a white solid (330 mg) . NMR was consistent with the proposed structure. Step B
The title compound was prepared using the product prepared in Step A (115 mg) in a similar procedure as described in Example 74, Step I. The crude product was purified in similar style to yield a white solid (82 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C2gH25N304F2S2 • 0.25 H20 C, 59.42; H, 4.38; N, 7.17; S, 10.94. Found: C, 59.34; H, 4.34; N, 7.20; S, 11.22.
Example 84
3,5-difluoro-/3-[3-[ [ [3-[ [ [ (phenylmethyl) imino]- methy1]amino]phenyl]sulfonyl]amino]phenyl]- benzenepropanoic acid, trifluoroacetate salt
Figure imgf000222_0001
A solution of the product from Example 83, Step A (550 mg) in methanol (15 ml) was treated with several equivalents of Raney nickel and refluxed for 3 hours under N2. The reaction mixture was cooled, filtered, concentrated and purified on a flash column eluting with 60% ethyl acetate - 40% hexane to afford a white solid (233 mg) . NMR was consistent with the proposed structure.
Step B
The title compound was prepared as described in Example 74, Step I using the product produced in Step A (233 g) . The crude product was purified in a similar fashion to yield a white solid (160 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C29H25N304F2S • 1.25 TFA C, 54.66; H, 3.82; N, 6.07; S, 4.63. Found: C, 54.37; H, 3.74; N, 6.00; S, 5.05. Example 87
3 - [ [ 3 - [ (aminoiminomethyl ) amino ] phenylthio ] ethyl ] -β- phenylbenzenepropanoic acid , trif luoroacetate salt
Figure imgf000223_0001
Step A
To a suspension of sodium hydride (1.0 g, 60% dispersion) in DMF (30 ml) at room temperature under N2 was added dropwise a solution of 3-thioaniline in DMF (20 ml) . After the addition was completed, the reaction mixture was stirred for 30 minutes and then a solution of 3-bromobenzophenone (Lancaster) in DMF (20 ml) was added dropwise at room temperature. After stirring for 1 hour, the solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted several times with ethyl acetate and the combined organic extracts were washed with water, saturated sodium chloride solution, dried over sodium sulfate, concentrated, and purified on a flash column eluting with 30% ethyl acetate - 70% hexane to afford a yellow oil (5.9 g) . NMR was consistent with the proposed structure.
Figure imgf000224_0001
The reaction was run as described in Example E using the product produced in Step A (3.9 g) and triethyl phosphonoacetate (2.7 g) . The crude product was purified on a flash column eluting with 25% ethyl acetate - 75% hexane to yield viscous golden oil (3.5 g) . NMR was consistent with the proposed structure.
Step C
Figure imgf000224_0002
The reaction was run as described in Example 77, Step C using the product produced in Step B (3.4 g) . The crude product was purified on a flash column eluting with 30% ethyl acetate - 70% hexane to afford a viscous golden oil (3.0 g) . NMR was consistent with the proposed structure. Step D
Figure imgf000225_0001
The above compound was prepared as described in Example Y using the compound produced in Step C (2.5 g). The crude product was purified on a flash column eluting with 15% ethyl acetate - 85% hexane to afford a viscous oil (3.2 g) . NMR was consistent with the proposed structure.
Figure imgf000225_0002
The above compound was prepared in a similar manner as described in Example 74, Step I using the prqduct from Step D (900 mg) . The crude product was purified in similar fashion to yield a clear glass (570 mg) . NMR was consistent with the proposed structure. Analysis Calculated for C24H25N302S • 1.5 TFA
C, 54.91; H, 4.52; N, 7.12; S, 5.43.
Found: C, 54.96; H, 4.56; N, 7.24; S, 5.49. Step F
A solution of the product from Step E (350 mg) with IN NaOH solution (5 ml), methanol (5 ml) and THF (10 ml) was stirred at room temperature for 18 hours. The reaction was then concentrated to dryness and the residue treated with a 1:1 solution of TFA and methylene chloride (10 ml) at room temperature for 1 hour. The solvents were then removed and the residue purified via reverse phase HPLC using a water (0.5% TFA) and acetonitrile gradient as eluant to afford a white solid (293 mg) . NMR was consistent with the proposed structure.
Analysis Calculated for C23H23N302S • l.l TFA.
C, 57.01; H, 4.58; N, 7.91; S, 6.04.
Found: C, 56.82; H, 4.77; N, 8.13; S, 6.31.
Example 88
3-[ [[3-[ (aminoiminomethy1)amino]pheny1]sulfinyl]methyl]-/3- phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000227_0001
Step A
A solution of the product from Example 87, Step D (2.0 g) in methylene chloride (20 ml) was treated with tetra-n-butyl ammonium oxone (3.6 g) at room temperature for 30 minutes. The reaction mixture was then partitioned between water and methylene chloride. The aqueous phase was extracted with additional methylene chloride and the combined organic extracts were washed with water and saturated sodium chloride solution, dried over Na2S04, concentrated and purified on a flash column eluting with 1:1 ethyl acetate - hexane to yield a white solid (1.4 g) . NMR was consistent with the proposed structure. Step B
Figure imgf000228_0001
The title compound was prepared as described in Example 87, Step E using material from Step A (465 mg) . The crude product was purified in similar manner to afford a white solid (372 mg) . NMR was consistent with the proposed structure.
Analysis Calculated for C24H25N303S • 2.1 TFA.
C, 50.18; H, 4.05; N, 6.23; S, 4.75.
Found: C, 49.97; H, 4.35; N, 6.35; S, 5.31.
Step C
The title compound was prepared as described in Example 87, Step F from the compound obtained from Step B (350 mg) . The crude material was purified in similar style to afford a white powder (182 mg) . NMR was consistent with the proposed structure.
Analysis Calculated for C23H23N303S • 1.6 TFA
C, 52.10; H, 4.11; N, 6.96; S, 5.31.
Found: C, 52.13; H, 4.25; N, 7.02; S, 5.49. Example 89
3-[ [ [3-[ (aminoiminomethyl)amino]phenyl]sulfonyl]methyl] 3-phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000229_0001
A solution of the product from Example 88, Step A (850 mg) in methylene chloride (10 ml) was treated with tetra-n-butyl ammonium oxone (3.0 g) at room temperature for 24 hours. The reaction mixture was worked up and purified as described in Example 88, Step A to yield a white solid (830 mg) . NMR was consistent with the proposed structure.
Step B
Figure imgf000229_0002
The above compound was prepared as described in Example 88, Step B from the compound prepared from Step A (500 mg) . The crude product was purified in a similar fashion to afford a white solid (494 mg) . NMR was consistent with the proposed structure.
Analysis Calculated for c24H25N304S • 1.75 TFA.
C, 50.73; H, 4.14; N, 6.45; S, 4.92.
Found: C, 50.62; H, 4.09; N, 6.75; S, 4.82.
The title compound was prepared as described in Example 87, Step F using the product produced in Step B (500 mg) . The crude material was purified in similar fashion to afford a white solid (250 mg) . NMR was consistent with the proposed structure.
Analysis Calculated for C23H23N304S • 1.2 TFA.
C, 53.12; H, 4.25; N, 7.32; S, 5.58.
Found: C, 53.34; H, 4.50; N. 7.46; S, 5.90.
Example 90
,9—[3—[ [ [3—[ [amino[ (aminocarbonyl) imino]methyl]- amino]phenyl]sulfonyl]amino]phenyl]-3,5-dichloro- benzenepropanoic acid, trifluoroacetate salt
Figure imgf000231_0001
The above compound was prepared as described in
Example 14, from the compound prepared from Example 77, Step E (1.0 g) . The reaction was worked up and purified in a similar manner to afford a white solid (725 mg) . NMR was consistent with the proposed structure.
The title compound was prepared from the product obtained in Step A utilizing the reactions described in Examples 15 and 16. The crude product was purified in similar fashion. NMR was consistent with the proposed structure. Analysis Calculated for C23H21N505SC12 • 1.5 TFA
C, 43.29; H, 3.14; N, 9.71; Cl, 9.83; S, 4.44. Found C, 43.24; H, 3.05; N, 9.53; Cl, 9.97; S, 4.80. Example 91
0-*[3-[ [ [3-[ [amino[ (aminocarbonyl) imino]methyl]- amino]phenyl]sulfonyl]amino]phenyl]-3,5-difluoro- benzenepropanoic acid, trifluoroacetate salt
Figure imgf000232_0001
The above compound was prepared via the same sequence of reactions as described in Example 90 from the corresponding 3,5-difluoro intermediate. The crude material was purified in a similar manner. NMR was consistent with the proposed structure.
Analysis Calculated for C23H21N505SF2 • 1.4 TFA
C, 45.76; H, 3.33; N, 10.34; S, 4.74.
Found: C, 45.80; H, 3.36; N, 10.41; S, 5.18.
Example 94 3-[[[3-[ (aminoiminomethyl)amino]phenyl]sulfonyl]amino] /3-ethylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000233_0001
The above compound was prepared in an analogous manner as described in Example 77, Step A using propionyl chloride (5.0 g) . The crude product was purified in a similar style to afford a viscous oil (2.4 g) . NMR was consistent with the proposed structure.
Step B
Figure imgf000233_0002
The above compound was prepared from the compound produced in Step A (2.4 g) utilizing similar reaction conditions as described in Example G. NMR was consistent with the proposed structure. Step C
Figure imgf000234_0001
The above compound was prepared from the compound produced in Step B utilizing the reactions described in Examples E and F. NMR was consistent with the proposed structure.
Step D
The title compound was prepared from the compound produced in Step C using the methodologies described in Examples I and 74, Step I. NMR was consistent with the proposed structure.
Analysis Calculated for C18H22N404S • 1.7 TFA
C, 43.99; H, 4.09; N, 9.59; S, 5.49
Found: C, 44.03; H, 4.11; N, 9.85; S, 5.73.
Example 95 3-[ [ [3-[ [amino[ (aminocarbonyl) imino] ethyl]amino]' phenyl]sulfonyl]amino]-/3-ethylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000235_0001
The above compound was prepared from the product produced in Example 94, Step C utilizing the reaction conditions described in Example 14 through 16. NMR was consistent with the proposed structure.
Analysis Calculated for. C19H23N505S • 1.4 TFA. C, 44.15; H, 4.15; N, 11.81; S, 5.41
Found: C, 44.14; H, 4.08; N, 11.65; S, 5.65.
Example 96
3-[ [3-[ (aminoiminomethyl)amino]phenyl]methoxy] -β- phenylbenzenepropanoic acid, trifluoroacetate salt
Figure imgf000236_0001
A solution of the product produced in Example 74, Step B (1.0 g) , 3-nitrobenzyl bromide (735 mg) , potassium carbonate (967 mg) and DMF (20 ml) was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and water and the aqueous portion was extracted with additional ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over Na2S04, concentrated and purified on a flash column eluting with 20% ethyl acetate -80% hexane to afford a viscous oil (1.3 g) . NMR was consistent with the proposed structure.
Step B
Figure imgf000237_0001
A solution of the product produced in Step A (1.3 g) in ethanol (40 ml) was hydrogenated under an atmosphere of 5 psi of hydrogen at room temperature for 3 hours using 3% platinum on carbon poisoned with sulfur. The crude product was purified on a flash column eluting with 20% ethyl acetate-80% hexane to afford a golden oil (1.1 g) . NMR was consistent with the proposed structure.
Step C
The title compound was prepared from the product produced in Step B using the procedures described in Examples I and 74, Step I. The product was purified as previously described. NMR was consistent with the proposed structure.
Analysis Calculated for C23H23N303 • 1.15 TFA • 0.5H20
C, 57.38; H, 4.79; N, 7.93.
Found: C, 57.28; H, 4.63; N, 8.19. Example 97
3,5-difluoro-/3-[3-[ [ [3-[ (1,4,5,6-tetrahydropyrimidin-2- y1)amino]phenyl]sulfonyl]amino]phenyl]benzene- propanoic acid, bis(trifluoroacetate) salt
Figure imgf000238_0001
The above compound was prepared using the 3,5 difluoro precursor similarly as described in Example 77, Step E and coupling with N,N'-bis-(tert-butoxycarbonyl)-2- (1H)-tetrahydropyrimidinethione (using the same conditions described in Example I) followed by deprotection as described in Example 74", Step I. NMR was consistent with the proposed structure.
Analysis Calculated for C25H24N404F2S • 2TFA.
C, 46.91; H, 3.53; N, 7.54; S, 4.32.
Found: C, 47.11; H, 3.67; N, 7.78; S, 4.50,
Example 98
0-[3-[ [ [3-[ (4,5-dihydro-lH-imidazol-2-yl)amino]- phenyl]sulfonyl]amino]phenyl]-3,5-difluorobenzene- propanoic acid, trifluoroacetate salt
Figure imgf000239_0001
The above compound was prepared using the 3,5- difluoro precursor substantially as described in Example 77, Step E and coupling with, N,N'-bis-( tert- butoxycarbonyl)-2 imidazolidinethione (using the same conditions described in Example I) followed by deprotection as described in Example 74, Step I. NMR was consistent with the proposed structure.
Analysis Calculated for C25H25N303F2S • 1.8 TFA.
C, 46.97; H, 3.40; N, 7.94; S, 4.54.
Found: C, 46.84; H, 3.50; N, 8.08; S, 4.90.
Example 99 3- [ [ 3- [ (4 , 5-dihydro-lH-imidazol-2-yl) amino] phenyl ] methoxy] - 3-phenylbenzenepropanoic acid , trif luoroacetate salt
Figure imgf000240_0001
The above compound was prepared from the product produced in Example 96, Step B utilizing the methodology described in Example 98. NMR was consistent with the proposed structure.
Analysis Calculated for C25H25N303S • 1.5 TFA. C, 57.34; N, 4.55; N, 7.16.
Found: C, 57.65; H, 4.48; N, 7.30.
Example 100
3-[ (aminoiminomethyl)amino]-N-[3-(3,4-dihydro-2-oxo-
2H-benzopyran-4-yl)phenyl]benzenesulfonamide, trifluoroacetate salt
Step A
Figure imgf000241_0001
A solution of 2-bromophenol (10.0 g) , dimethyl-t- butyl silyl chloride (9.8 g) , imidazole (6.8 g) and DMF (100 ml) was stirred at room temperature for 18 hours. The reaction was partitioned between ethyl acetate and water and the aqueous portion was extracted with additional ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over sodium sulfate, concentrated and purified on a flash column eluting with 5% ethyl acetate- 95% hexane to afford a colorless liquid (15.5 g) . NMR was consistent with the proposed structure.
Step B
Figure imgf000241_0002
A Grignard reagent was prepared from the product produced in Step A (15.5 g) and magnesium turnings (1.3 g) in THF (150 ml) . The Grignard reagent was added dropwise to a solution of 3-nitrobenzaldehyde in THF (50 ml) at room temperature. The reaction was stirred for 1 hour and then quenched with IN HCI. The mixture was then partitioned between water and ethyl acetate. The aqueous portion was extracted several times with ethyl acetate and then the combined organic extracts were washed with water, saturated sodium chloride, dried over Na2S04, concentrated and purified on a flash column eluting 20% EA -80% hexane to yield a yellow solid (9.2 g) . NMR was consistent with the proposed structure.
Step C
Figure imgf000242_0001
A solution of the product produced in Step B (3.9 g) was stirred at room temperature with a 1:1 solution of TFA and methylene chloride (50 ml) for 18 hours. The solvent was removed and the residue dried under high vacuum at 60° for 1 hour to afford a yellow solid (2.9 g) . This material was used without further purification. NMR was consistent with the proposed structure. Step D
Figure imgf000243_0001
The above compound was prepared from the product produced in Step C (2.8 g) using the procedure described in Step A to yield a colorless oil (3.7 g) after purification via flash column eluting with 10% ethyl acetate-90% hexane. NMR was consistent with the proposed structure.
Step E
Figure imgf000243_0002
The above compound was prepared from the product produced in Step D using the methodologies described in Examples E and 74, Step G. The crude product was purified on a flash column eluting with 25% ethyl acetate-75% hexane. NMR was consistent with the proposed structure. Step F
Figure imgf000244_0001
The above compound was prepared from the product produced in Step E using the procedures described in Example 77, Step C and Example G. The crude product was purified on a flash column eluting with 40% ethyl acetate- 60% hexane. NMR was consistent with the proposed structure.
Step G
Figure imgf000244_0002
The above compound was prepared from the product produced in Step F utilizing the procedure described in Example 74, Step G. The crude product was purified on a flash column eluting with 1:1 ethyl acetate-hexane. NMR was consistent with the proposed structure. Step H
The title compound was prepared from the product produced in Step G using the procedures described in Examples I and 74, Step I. NMR was consistent with the proposed structure.
Analysis Calculated for C22H20N404S • 1.75 TFA
C, 48.00; H, 3.79; N, 8.96; S. 5.13.
Found: C, 47.96; H, 3.48; N, 8.64; S, 5.44.
Example 101 3-[ (4,5-dihydro-lH-imidazol-2-yl)amino]-N-[3- (3,4-dihydro-2-oxo-2H-benzopyran-4-yl)phenyl] benzenesulfonamide, trifluoroacetate salt
Figure imgf000246_0001
The above compound was prepared from the product produced in Example 100, Step G utilizing the methodology described in Example 98. NMR was consistent with the proposed structure.
Analysis Calculated for C24H22N404S • 1.75 TFA. C, 49.89; H, 3.62; N, 8.46; S, 4.84.
Found: C, 50.10; H, 3.46; N, 8.48; S, 5.18.
Example 102 sodium β- [ 2- [ [ [3[ (aminoiminomethyl)amino]- phenyl]-sulfonyl] mino]phenyl]-2-hydroxy- benzenepropanoate, trifluoroacetate salt
Figure imgf000247_0001
A mixture of the product produced in Example 100 ,
Step H (113 mg) , acetonitrile (2 ml) , ethanol (2 ml) and IN sodium hydroxide solution (0.5 ml) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue taken up in ethanol and filtered through glass wool and reconcentrated. The residue was dried at 50°C under high vacuum for 4 hours to afford a white solid (110 mg) . NMR was consistent with the proposed structure.
The activity of the compounds of the present invention was tested in the following assays. The results of testing in the assays are tabulated in Table 1.
VITRONECTIN ADHESION ASSAY MATERIALS
Human vitronectin receptor(αv/33) was purified from human placenta as previously described [Pytela et al., Methods in Enzymoloαy, 144:475-489 (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) .
METHODS
Solid Phase Receptor Assays
This assay was essentially the same as previously reported [Niiya et al., Blood, 70:475-483 (1987)]. The purified human vitronectin receptor (αv/33) was diluted from stock solutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca++, Mg++, and Mn++, pH 7.4 (TBS+++) . The diluted receptor was immediately transferred to Linbro microtiter plates at 100 μL/well (100 ng receptor/well) . The plates were sealed and incubated overnight at 4°C to allow the receptor to bind to the wells. All remaining steps were at room temperature. The assay plates were emptied and 200 μL 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. Logarithmic serial dilution of the test compound and controls were made starting at a stock concentration of 2 mM and using 2 nM biotinylated vitronectin in TBS+++/BSA as the diluent. This premixing of labeled ligand with test (or control) ligand, and subsequent transfer of 50 μL aliquots 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 10~4 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 μL were added to each well. After 30 minutes, the plates were washed and incubated with OPD/H202 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 absorbance of about 1.0, the final A450 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 A450 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 [Rodbard 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 R2 was reported for those compounds exhibiting greater than 50% inhibition at the highest concentration tested; otherwise the IC50 is reported as being greater than the highest concentration tested. β-[[2-[[5- [ (aminoiminomethyl) amino]-l-oxopentyl]amino]-1- oxoethyl]amino]-3-pyridinepropanoic acid [USSN
08/375,338, Example 1] which is a potent αv/33 antagonist (IC50 in the range 3-10 nM) was included on each plate as a positive control.
PURIFIED Ilb/IIIa RECEPTOR ASSAY
MATERIALS
Human fibrinogen receptor (αIIb/33) 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 Enzy ology 144 (1987) :475-489. ) Human vitronectin was purified from fresh frozen plasma as described in Yatohgo, T. , Izumi, M. , Kashiwagi, H. , and Hayaεhi, 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.
(Charo, I.F., Nannizzi, L. , Phillips, D.R., Hsu, M.A. , Scarborough, R.M. , "Inhibition of fibrinogen binding to GP lib/Ilia by a GP Ilia peptide" , J. Biol. Chem. 266(3) (1991) : 1415-1421.) 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) . METHODS
Solid Phase Receptor Assays
This assay is essentially the same reported in Niiya, K. , Hodson, E. , Bader, R. , Byers-Ward, V.
Koziol, J.A., Plow, E.F. and Ruggeri, Z.M. , "Increased surface expression of the membrane glycoprotein Ilb/IIIa complex induced by platelet activation: Relationships to the binding of fibrinogen and platelet aggregation", Blood 70(1987) :475-483. The purified human fibrinogen receptor (αI1J:>,33) was diluted from stock solutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca++, Mg++, and Mn++, pH 7.4 (TBS+"t'+) . The diluted receptor was immediately transferred to Linbro microtiter plates at 100 μL/well (100 ng receptor/well) . The plates were sealed and incubated overnight at 4°C to allow the receptor to bind to the wells. All remaining steps were at room temperature. The assay plates were emptied and 200 μL 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. Logarithmic serial dilution of the test compound and controls were made starting at a stock concentration of 2 mM and using 2 nM biotinylated vitronectin in TBS+++/BSA as the diluent. This premixing of labeled ligand with test (or control) ligand, and subsequent transfer of 50 μL aliquots 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"4 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 μL were added to each well. After 30 minutes, the plates were washed and incubated with ODD/H202 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 absorbance of about 1.0, the final A450 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 A450 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 R2 was reported for those compounds exhibiting greater than 50% inhibition at the highest concentration tested; otherwise the IC50 is reported as being greater than the highest concentration tested. 0-[[2-[[5- [ (aminoiminomethyl) amino]-l-oxopentyl]amino]-1- oxoethyl]amino]-3-pyridinepropanoic acid [USSN 08/375,338, Example 1] which is a potent αv/33 antagonist (IC 5o -*-n tne ran9e 3-10 nM) was included on each plate as a positive control.
TABLE 1
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001

Claims

What is claimed is: 1. A compound of the formula
Figure imgf000256_0001
or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000256_0002
wherein Y1 is selected from the group consisting of N-R2, O, and S;
R2 is selected from the group consisting of H;
alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; aminocarbonyl; alkenyl; alkynyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy,
methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid. sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle; monocyclic heterocycles; and monocyclic heterocycles optionally substituted with one or more substituent selected from
halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid,
sulfonamide, aryl or fused aryl; or
R2 taken together with R7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, oxo and phenyl; or R2 taken together with R7 forms a 5 membered
heteroaromatic ring; or R2 taken together with R7 forms a 5 membered
heteroaromatic ring fused with a phenyl group optionally substituted with one or more
substituent selected from the group consisting of alkoxycarbonyl and alkoxy;
R7 (when not taken together with R2) and R8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl;
cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl
derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally
substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,
haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles; aryl optionally
substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio,
haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; monocyclic heterocycles; monocyclic heterocycles optionally substituted with one or more
substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl; monocyclic and bicyclic heterocyclicalkyls; -SO2R10 wherein R10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio,
trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic
heterocycles; and —
Figure imgf000258_0001
wherein R10 is defined above; or NR7 and R8 taken together form a 4-12 membered
mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl; or
Figure imgf000259_0001
wherein Y2 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; bicycloalkyl;
aryl; monocyclic heterocycles; alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryl
optionally substituted with one or more
substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -S-R9 and -O-R9 wherein R9 is selected from the group consisting of H; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R9 taken together with R7 forms a 4-12 membered mononitrogen
containing sulfur or oxygen containing
heterocyclic ring; and R5 and R7 are as defined above; or Y2 (when Y2 is carbon) taken together with R7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or
hydroxy; or A is selected from the group consisting of
Figure imgf000260_0001
Z1, Z2, Z4 and Z5 are independently selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino;
dialkylamino; cyano; alkylthio; alkylsulfonyl;
carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A, wherein A is defined above;
B is selected from the group consisting of
Figure imgf000260_0002
wherein p is an integer selected from the group consisting of 0, 1 and 2; wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; R50 is selected from the group consisting of H and alkyl;
Y is selected from the group consisting of
-(CHR70)g- and -O-;
wherein q is an integer selected from the group consisting of 0 and 1; R70 is selected from the group consisting of H, alkyl, aryl and aryl substituted with one or more substituent selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl;
haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl;
carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; t is an integer 0, 1 or 2 ;
R is X-R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof;
or
Figure imgf000261_0001
wherein the X-R3 group is attached to the phenyl of the Y group at the para position to form a lactone; Y3 and Z3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl;
R1 is selected from the group consisting of hydrogen; alkyl; aryl;
O
Figure imgf000262_0002
R12 is selected from the group consisting of H, alkyl, cycloalkyl, aralkyl and aryl; and
R51 is selected from the group consisting of N- substituted pyrrolidinyl, piperidinyl and
morpholinyl.
2. A compound according to Claim 1 wherein Y is
-(CHR70)q-.
3. A compound according to Claim 2 wherein q is 1,
4. A compound according to Claim 3 of the formula
Figure imgf000262_0001
5. A compound according to Claim 4 wherein the
compound is selected from the group consisting of β-[3-[[[[3-(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]phenyl]-3,5- dichlorobenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl] sulfonyl]amino]-β-phenylbenzeneprooanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl] carbonyl]amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminocarbonyl)- amino]phenyl]carbonyl]amino]- β-phenylbenzenepropanoate;
3-[[[3-[(aminocarbonyl)amino]phenyl]carbonyl]- amino]-β-phenylbenzenepropanoic acid;
3-[[[4-[(aminoiminomethyl)amino]phenyl]sulfonyl]- methylamino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminocarbonyl)amino]- phenyl]sulfonyl]amino]-β-phenylbenzenepropanoate;
3-[[[3-[(aminocarbonyl)amino]phenyl]sulfonyl]- amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminothioxomethyl)- amino]phenyl]sulfonyl]amino]-β- phenylbenzenepropanoate; 3-[[[3-[(ammothioxomethyl)amino]phenyl]sulfonyl]- amino]-β-phenylbenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]methyl]- amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[[[(phenylmethyl)- amino]carbonyl]amino]phenyl]sulfonyl]amino]- β-phenylbenzenepropanoate;
3-[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]sulfonyl]amino]-β- phenylbenzenepropanoic acid; 1,1-dimethylethyl 3-[[[3-[[(cyanoimino)-
(methylthio)methyl]amino]phenyl]sulfonyl]amino]- β-phenylbenzenepropanoate; 1,1-dimethylethyl 3-[[[3-[[amino(cyanoimino)methyl]- amino]phenyl]sulfonyl]amino]-β-phenyIpropanoate;
3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]-β- phenylbenzenepropanoic acid; ethyl 3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethyl]-β-phenylbenzenepropanoate;
3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethyl]-β-phenylbenzenepropanoic acid; ethyl 3-[[[[3-(aminoiminomethyl)phenyl]- carbonyl]amino]methyl]benzenepropanoate; ethyl 3-[[[[3-[aminoiminomethyl]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-(aminoiminomethyl)phenyl]carbonyl]- amino]methyl]benzenepropanoic acid;
3-[[[[3-[(aminothioxomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[[3-[(aminothioxomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[(aminocarbonyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[(aminocarbonyl)amino]phenyl]carbonyl]- amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[[[(phenylmethyl)amino]carbonyl]amino]- phenyl]carbonyl]amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenylbenzenepropanoate;
3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenylbenzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]benzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-phenylbenzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[[3-[(aminoiminomethyl)- amino]phenyl]carbonyl]amino]methyl]-β-methyl- benzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-methylbenzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-ethyIbenzenepropanoate; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-ethylbenzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-(1-methylethyl)
benzenepropanoic acid;
N-acetyl-3-[[[[3-[(aminoiminomethyl)amino]- phenyl]carbonyl]amino]methyl]phenylalanine;
3-[[[3-[(aminoiminomethyl)amino]phenyl]- acetyl]amino]benzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- amino]carbonyl]amino]benzenepropanoic acid;
3-[[[[[3-[(aminoiminomethyl)amino]phenyl]amino]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[[3-[[(cyanoimino)(methylamino)methyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenylbenzenepropanoic acid; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-βR-methylbenzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-βS-methylbenzene- propanoic acid;
(±) 3-[[[[3-[(aminoiminomethyl)amino]-4- chlorophenyl]carbonyl]amino]methyl]-β- ethylbenzenepropanoic acid; (i) 3-[[[[3-[(aminoiminomethyl)amino]-5-
(trifluoromethyl)phenyl]carbonyl]amino]- methyl]-β-ethylbenzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]- phenyl]carbonyl]amino]methyl]phenyl]-3,5- difluorobenzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]-5- (trifluoromethyl)phenyl]carbonyl]amino]methyl]- phenyl]-3,5-difluorobenzenepropanoic acid;
(±) 3,5-difluoro-β-[3-[[[[3-[(1,4,5,6- tetrahydropyrimidin-2-yl)amino]phenyl]carbonyl]- amino]methyl]phenyl]benzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]phenyl]-2- methoxybenzenepropanoic acid;
(±) 3[[[[3-[[amino(cyanoimino)methyl]amino]- phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
(±) 3[[[[3-[[amino[(aminocarbonyl)imino]- methyl]amino]phenyl]carbonyl]amino]methyl]- β-methylbenzenepropanoic acid;
(±) 3-[[[[3-[(4,5-dihydro-4-oxo-1H-imidazol-2- yl)amino]phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
(±) 3-[[[[3-[(1H-benzimidazol-2-yl)amino]- phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid; ( ± ) 3 - [ [ [ [ 3 - [ ( 5-methoxy-1H-benz imidazol-2- yl)amino]phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
3-[2-[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]- phenyl]-2-hydroxyethoxy]benzenepropanoic acid;
3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethynyl]-β-phenylbenzenepropanoic acid;
3-[2E-[3-[(aminoiminomethyl)amino]phenyl]- ethenyl]-β-phenylbenzenepropanoic acid;
3-[2Z-[3-[(aminoiminomethyl)amino]phenyl]- ethenyl]-β-phenylbenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-dichloro- benzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-difluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-4-fluoro- benzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]- phenyl]sulfonyl]amino]phenyl]-3,4,5- trifluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]perfluoro- benzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-2,3,5,6-tetra- fluorobenzenepropanoic acid;
3,5-difluoro-β-[3-[[[3-[[[(phenylmethyl)amino]- carbonyl]amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid;
3,5-difluoro-β-[3-[[[3-[[[(phenylmethyl)- imino]methyl]amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid;
3-[[3-[(aminoiminomethyl)amino]phenylthio]- methyl]-β-phenylbenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfinyl]- methyl]-β-phenylbenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfonyl]- methyl]-β-phenylbenzenepropanoic acid; β-[3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]phenyl]-3,5- dichlorobenzenepropanoic acid; β-[3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]phenyl]-3,5- difluorobenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfonyl]- amino]-β-ethylbenzenepropanoic acid;
3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]-β- ethylbenzenepropanoic acid; 3-[[3-[(aminoiminomethyl)amino]phenyl]- methoxy]-β-phenylbenzenepropanoic acid;
3,5-difluoro-β-[3-[[[3-[(1,4,5,6-tetrahydro- pyrimidin-2-yl)amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid; β-[3-[[[3-[(4,5-dihydro-1H-imidazol-2-yl)- amino]phenyl]sulfonyl]amino]phenyl]-3,5- difluorobenzenepropanoic acid;
3-[[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]phenyl]- methoxy]-β-phenylbenzenepropanoic acid; and sodium β-[3-[[[3-[(aminoiminomethyl)amino]- phenyl]sulfonyl]amino]phenyl]-2- hydroxybenzenepropanoate.
6. A compound according to Claim 1 wherein Y is
(CHR70)q and q is 0 or Y is -O-
7. A compound according to Claim 6 wherein the
compound is selected from the group consisting of ethyl 3-[[[3-[amino(hydroxyimino)methyl]phenyl]- carbonyl]amino]benzeneacetate;
3-[[[3-(aminoiminomethyl)phenyl]carbonyl]- amino]benzeneacetic acid;
3-[2-[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]ethyl]benzeneacetic acid; methyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzeneacetate; ethyl 3-[[[3-(aminoiminomethyl)phenyl] carbonyl]amino]benzeneacetate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzeneacetic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]
carbonyl]amino]benzeneacetic acid;
2-[3-[3-[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]- phenyl]-1-oxo-2-propenyl]phenoxy]acetic acid;
2-[3-[3-[3-[(aminoiminomethyl)amino]phenyl]-1- oxopropenyl]phenoxy]acetic acid; and
[3-[[[[3-[(aminoiminomethyl)amino]phenyl]- amino]carbonyl]amino]phenoxy]acetic acid.
8. A compound according to Claim 1 selected from the group consisting of 3-[(aminoiminomethyl)amino]-N-[3-(3,4-dihydro-2-oxo- 2H-benzopyran-4-yl)phenyl]benzenesulfonamide; and
3-[(4,5-dihydro-1H-imidazol-2-yl)amino]-N-[3-
(3,4-dihydro-2-oxo-2H-benzopyran-4-yl)- phenyl]benzenesulfonamide.
9. A pharmaceutical composition comprising a
therapeutically effective amount of a compound of the formula
Figure imgf000271_0001
or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000272_0001
wherein Y1 is selected from the group consisting of N-R2, O, and S;
R2 is selected from the group consisting of H;
alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; aminocarbonyl; alkenyl; alkynyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy,
methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid,
sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle; monocyclic heterocycles; and monocyclic heterocycles optionally substituted with one or more substituent selected from
halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid,
sulfonamide, aryl or fused aryl; or R2 taken together with R7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, oxo and phenyl; or R2 taken together with R7 forms a 5 membered
heteroaromatic ring; or R2 taken together with R7 forms a 5 membered
heteroaromatic ring fused with a phenyl group optionally substituted with one or more
substituent selected from the group consisting of alkoxy and alkoxycarbonyl;
R7 (when not taken together with R2) and R8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl,- cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl
derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally
substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio,
haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,
haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles; aryl optionally
substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio. haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; monocyclic heterocycles; monocyclic heterocycles optionally substituted with one or more
substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl; monocyclic and bicyclic heterocyclicalkyls; -SO2R10 wherein R10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl,
alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio,
trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic
heterocycles; and
wherein R10 is defined above;
Figure imgf000274_0001
or NR7 and R8 taken together form a 4-12 membered
mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S; R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl; or
Figure imgf000275_0001
wherein Y2 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; bicycloalkyl;
aryl; monocyclic heterocycles; alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryl
optionally substituted with one or more
substituent selected from halo, haloalkyl,
hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -S-R9 and -O-R9 wherein R9 is selected from the group consisting of H; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R9 taken together with R7 forms a 4-12 membered mononitrogen
containing sulfur or oxygen containing
heterocyclic ring; and
R5 and R7 are as defined above; or Y2 (when Y2 is carbon) taken together with R7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or
hydroxx; or A is selected from the group consisting of
Figure imgf000276_0001
Z1, Z2, Z4 and Z5 are independently selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino;
dialkylamino; cyano; alkylthio; alkylsulfonyl;
carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A, wherein A is defined above;
B is selected from the group consisting of
—
Figure imgf000276_0002
wherein p is an integer selected from the group consisting of 0, 1 and 2; wherein n is an integer selected from the group consisting of 0, 1, 2 and 3 ; R50 is selected from the group consisting of H and alkyl;
Y is selected from the group consisting of
-(CHR70)q- and -O- ; wherein q is an integer selected from the group consisting of 0 and 1; R70 is seleeted from the group consisting of H, alkyl, aryl and aryl substituted with one or more substituent selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl;
haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl;
carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; t is an integer 0, 1 or 2 ;
R is X-R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof; or
Figure imgf000277_0001
wherein the X-R3 group is attached to the phenyl of the Y group at the para position to form a lactone;
Y3 and Z3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl;
R1 is selected from the group consisting of hydrogen; alkyl; aryl;
Figure imgf000277_0002
R12 is selected from the group consisting of H, alkyl, cycloalkyl, aralkyl and aryl;
R51 is selected from the group consisting of N- substituted pyrrolidinyl, piperidinyl and
morpholinyl; and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition according to Claim 9 wherein Y is (CHR70)q or -O-.
11. A pharmaceutical composition according to Claim 10 wherein when Y is (CHR70)q, q is 0 or 1.
12. A pharmaceutical composition according to Claim 11 of the formula
Figure imgf000278_0001
13. A pharmaceutical composition according to Claim 12 wherein the compound is selected from the group consisting of β-[3-[[[[3-(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]phenyl]-3,5- dichlorobenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl] sulfonyl]amino]-β-phenylbenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl] carbonyl]amino]-β-phenylbenzenepropanoic acid; 1,1-dimethylethyl 3-[[[3-[(aminocarbonyl)- amino]phenyl]carbonyl]amino]- β-phenyIbenzenepropanoate;
3-[[[3-[(aminocarbonyl)amino]phenyl]carbonyl]- amino]-β-phenylbenzenepropanoic acid;
3-[[[4-[(aminoiminomethyl)amino]phenyl]sulfonyl]- methylamino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminocarbonyl)amino]- phenyl]sulfonyl]amino]-β-phenylbenzenepropanoate;
3-[[[3-[(aminocarbonyl)amino]phenyl]sulfonyl]- amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminothioxomethyl)- amino]phenyl]sulfonyl]amino]-β- phenyIbenzenepropanoate; 3-[[[3-[(aminothioxomethyl)amino]phenyl]sulfonyl]- amino]-β-phenylbenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]methyl]- amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[[[(phenylmethyl)- amino]carbonyl]amino]phenyl]sulfonyl]amino]- β-phenylbenzenepropanoate;
3-[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]sulfonyl]amino]-β- phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[[(cyanoimino)-
(methylthio)methyl]amino]phenyl]sulfonyl]amino]- β-phenylbenzenepropanoate; 1,1-dimethylethyl 3-[[[3-[[amino(cyanoimino)methyl]- amino]phenyl]sulfonyl]amino]-β-phenyIpropanoate;
3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]-β- phenylbenzenepropanoic acid; ethyl 3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethyl]-β-phenylbenzenepropanoate;
3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethyl]-β-phenylbenzenepropanoic acid; ethyl 3-[[[[3-(aminoiminomethyl)phenyl]- carbonyl]amino]methyl]benzenepropanoate; ethyl 3-[[[[3-[aminoiminomethyl]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-(aminoiminomethyl)phenyl]carbonyl]- amino]methyl]benzenepropanoic acid;
3-[[[[3-[(aminothioxomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[[3-[(aminothioxomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[(aminocarbonyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[(aminocarbonyl)amino]phenyl]carbonyl]- amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]benzenepropanoate; 3-[[[[3-[[[(phenylmethyl)amino]carbonyl]amino]- phenyl]carbonyl]amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenylbenzenepropanoate;
3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenylbenzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]benzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-phenylbenzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[[3-[(aminoiminomethyl)- amino]phenyl]carbonyl]amino]methyl]-β-methyl- benzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-methylbenzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-ethyIbenzenepropanoate; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-ethylbenzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-(1-methylethyl)
benzenepropanoic acid;
N-acetyl-3-[[[[3-[(aminoiminomethyl)amino]- phenyl]carbonyl]amino]methyl]phenylalanine;
3-[[[3-[(aminoiminomethyl)amino]phenyl]- acetyl]amino]benzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- amino]carbonyl]amino]benzenepropanoic acid;
3-[[[[[3-[(aminoiminomethyl)amino]phenyl]amino]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[[3-[[(cyanoimino)(methylamino)methyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenylbenzenepropanoic acid; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-βR-methylbenzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-βS-methylbenzenepropanoic acid;
(±) 3-[[[[3-[(aminoiminomethyl)amino]-4- chlorophenyl]carbonyl]amino]methyl]-β- ethylbenzenepropanoic acid;
(±) 3-[[[[3-[(aminoiminomethyl)amino]-5-
(trifluoromethyl)phenyl]carbonyl]amino]- methyl]-β-ethylbenzenepropanoic acid; (±) β-[3-[[[[3-[(aminoiminomethyl)amino]- phenyl]carbonyl]amino]methyl]phenyl]-3,5- difluorobenzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]-5- (trifluoromethyl)phenyl]carbonyl]amino]methyl]- phenyl]-3,5-difluorobenzenepropanoic acid;
(±) 3,5-difluoro-β-[3-[[[[3-[(1,4,5,6- tetrahydropyrimidin-2-yl)amino]phenyl]carbonyl]- amino]methyl]phenyl]benzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]phenyl]-2- methoxybenzenepropanoic acid;
(±) 3[[[[3-[[amino(cyanoimino)methyl]amino]- phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
(±) 3[[[[3-[[amino[(aminocarbonyl)imino]- methyl]amino]phenyl]carbonyl]amino]methyl]- β-methylbenzenepropanoic acid;
(±) 3-[[[[3-[(4,5-dihydro-4-oxo-1H-imidazol-2- yl)amino]phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
(±) 3-[[[[3-[(1H-benzimidazol-2-yl)amino]- phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
(±) 3-[[[[3-[(5-methoxy-1H-benzimidazol-2- yl) amino]phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
3-[2-[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]- phenyl]-2-hydroxyethoxy]benzenepropanoic acid; 3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethynyl]-β-phenylbenzenepropanoic acid;
3-[2E-[3-[(aminoiminomethyl)amino]phenyl]- ethenyl]-β-phenylbenzenepropanoic acid;
3-[2Z-[3-[(aminoiminomethyl)amino]phenyl]- ethenyl]-β-phenylbenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-dichloro- benzenepropanoeic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-difluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-4-fluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]- phenyl]sulfonyl]amino]phenyl]-3,4,5- trifluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]perfluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-2,3,5,6-tetrafluorobenzenepropanoic acid; 3,5-difluoro-β-[3-[[[3-[[[(phenylmethyl)amino]- carbonyl]amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid; 3, 5-difluoro-β-[3-[[[3-[[[(phenylmethyl)- imino]methyl]amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid;
3-[[3-[(aminoiminomethyl)amino]phenylthio]- methyl]-β-phenylbenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfinyl]- methyl]-β-phenylbenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfonyl]- methyl]-β-phenylbenzenepropanoic acid; β-[3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]phenyl]-3,5- dichlorobenzenepropanoic acid; β-[3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]phenyl]-3,5- difluorobenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfonyl]- amino]-β-ethylbenzenepropanoic acid;
3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]-β- ethylbenzenepropanoic acid;
3-[[3-[(aminoiminomethyl)amino]phenyl]- methoxy]-β-phenylbenzenepropanoic acid;
3,5-difluoro-β-[3-[[[3-[(1,4,5,6-tetrahydro- pyrimidin-2-yl)amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid; β- [ 3 - [ [ [ 3- [ ( 4 , 5-dihydro-1H-imidazol-2-yl ) - amino]phenyl]sulfonyl]amino]phenyl]-3,5- difluorobenzenepropanoic acid; 3-[[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]phenyl]- methoxy] -β-phenylbenzenepropanoic acid; sodium β- [ 3- [[[3-[(aminoiminomethyl)amino]- phenyl]sulfonyl]amino]phenyl]-2- hydroxybenzenepropanoate; ethyl 3-[[[3-[amino(hydroxyimino)methyl]phenyl]- carbonyl]amino]benzeneacetate;
3-[[[3-(aminoiminomethyl)phenyl]carbonyl]- amino]benzeneacetic acid;
3-[2-[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]ethyl]benzeneacetic acid; methyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzeneacetate; ethyl 3-[[[3-(aminoiminomethyl)phenyl]
carbonyl]amino]benzeneacetate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzeneacetic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]
carbonyl]amino]benzeneacetic acid;
2-[3-[3-[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]- phenyl]-l-oxo-2-propenyl]phenoxy] acetic acid;
2-[3-[3-[3-[(aminoiminomethyl)amino]phenyl]-1- oxopropenyl]phenoxy]acetic acid; and [3-[[[[3-[(aminoiminomethyl)amino]phenyl]- amino]carbonyl]amino]phenoxy] acetic acid.
14. A pharmaceutical composition according to Claim 9 wherein the compound is selected from the group consisting of
3-[(aminoiminomethyl)amino]-N-[3-(3,4-dihydro-2-oxo- 2H-benzopyran-4-yl)phenyl]benzenesulfonamide; and
3-[(4,5-dihydro-1H-imidazol-2-yl)amino]-N-[3-
(3,4-dihydro-2-oxo-2H-benzopyran-4-yl)- phenyl]benzenesulfonamide.
15. A method for treating conditions mediated by the αvβ3 integrin in a mammal in need of such treatment comprising administering an effective α vβ3
inhibiting amount of a compound of the formula
Figure imgf000287_0001
or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000287_0002
wherein Y1 is selected from the group consisting of N-R2, O, and S; R2 is selected from the group consisting of H;
alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; aminocarbonyl; alkenyl; alkynyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen,
haloalkyl, hydroxy, lower alkyl, alkoxy,
methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid,
sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle; monocyclic heterocycles; and monocyclic heterocycles optionally substituted with one or more substituent selected from
halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid,
sulfonamide, aryl or fused aryl; or
R2 taken together with R7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, oxo and phenyl; or R2 taken together with R7 forms a 5 membered
heteroaromatic ring; or R2 taken together with R7 forms a 5 membered
heteroaromatic ring fused with a phenyl group optionally substituted with one or more
substituent selected from the group consisting of alkoxy and alkoxycarbonyl;
R7 (when not taken together with R2) and R8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl;
cycloalkyl; biσycloalkyl; aryl; acyl; benzoyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally
substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio,
haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,
haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles; aryl optionally
substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio,
haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; monocyclic heterocycles; monocyclic heterocycles optionally substituted with one or more
substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl; monocyclic and bicyclic heterocyclicalkyls; -SO2R10 wherein R10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl,
alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio,
trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic
heterocycles; and
wherei.n R10 is defined above;
Figure imgf000290_0001
or NR7 and R8 taken together form a 4-12 membered
mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl; or
Figure imgf000290_0002
wherein Y2 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; bicycloalkyl;
aryl; monocyclic heterocycles; alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryl
optionally substituted with one or more
substituent selected from halo, haloalkyl,
hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; -S-R9 and -O-R9 wherein R9 is selected from the group consisting of H; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R9 taken together with R7 forms a 4-12 membered mononitrogen
containing sulfur or oxygen containing
heterocyclic ring; and
R5 and R7 are as defined above; or Y2 (when Y2 is carbon) taken together with R7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or
hydroxy; or A is selected from the group consisting of
Figure imgf000291_0001
Z1, Z2, Z4 and Z5 are independently selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino;
dialkylamino; cyano; alkylthio; alkylsulfonyl;
carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A, wherein A is defined above;
B is selected from the group consisting of
Figure imgf000292_0001
O wherein p is an integer selected from the group consisting of 0, 1 and 2; wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; R50 is selected from the group consisting of H and alkyl;
Y is selected from the group consisting of
-(CHR70)q- and -O-; wherein q is an integer selected from the group consisting of 0 and 1; R70 is selected from the group consisting of H, alkyl, aryl and aryl substituted with one or more substituent selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl;
haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl;
carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; t is an integer 0, 1 or 2 ; R is X-R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof;
or
Figure imgf000293_0001
wherein the X-R3 group is attached to the phenyl of the Y group at the para position to form a lactone;
Y3 and Z3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl;
R1 is selected from the group consisting of hydrogen; alkyl; aryl;
Figure imgf000293_0002
R12 is selected from the group consisting of H, alkyl, cycloalkyl, aralkyl and aryl; and
R51 is selected from the group consisting of N- substituted pyrrolidinyl, piperidinyl and
morpholinyl.
16. A method according to Claim 15 wherein the
compound is selected from the group consisting of β-[3-[[[[3-(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]phenyl]-3,5- dichlorobenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl] sulfonyl]amino]-β-phenylbenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl] carbonyl]amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminocarbonyl)amino]phenyl]- carbonyl]amino]-β-phenylbenzenepropanoate;
3-[[[3-[(aminocarbonyl)amino]phenyl]carbonyl]- amino]-β-phenylbenzenepropanoic acid;
3-[[[4-[(aminoiminomethyl)amino]phenyl]sulfonyl]- methylamino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminocarbonyl)amino]- phenyl]sulfonyl]amino]-β-phenylbenzenepropanoate;
3-[[[3-[(aminocarbonyl)amino]phenyl]sulfonyl]- amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[(aminothioxomethyl)amino]- phenyl]sulfonyl]amino]-β-phenylbenzenepropanoate;
3-[[[3-[(aminothioxomethyl)amino]phenyl]sulfonyl]- amino]-β-phenylbenzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]methyl]- amino]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[[[(phenylmethyl)- amino]carbonyl]amino]phenyl]sulfonyl]amino]- β-phenyIbenzenepropanoate; 3-[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]sulfonyl]amino]-β- phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[3-[[(cyanoimino)-
(methylthio)methyl]amino]phenyl]sulfonyl] amino]- β-phenylbenzenepropanoate; 1,1-dimethylethyl 3-[[[3-[[amino(cyanoimino)methyl]- amino]phenyl]sulfonyl]amino]-β-phenyIpropanoate;
3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]-β- phenylbenzenepropanoic acid; ethyl 3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethyl]-β-phenylbenzenepropanoate;
3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethyl]-β-phenylbenzenepropanoic acid; ethyl 3-[[[[3-(aminoiminomethyl)phenyl]- carbonyl]amino]methyl]benzenepropanoate; ethyl 3-[[[[3-[aminoiminomethyl]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-(aminoiminomethyl)phenyl]carbonyl]- amino]methyl]benzenepropanoic acid;
3-[[[[3-[(aminothioxomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[[3-[(aminothioxomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[(aminocarbonyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[(aminocarbonyl)amino]phenyl]carbonyl]- amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[[[(phenylmethyl)amino]carbonyl]amino]- phenyl]carbonyl]amino]methyl]benzenepropanoic acid; ethyl 3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenyIbenzenepropanoate;
3-[[[[3-[[[(phenylmethyl)amino]carbonyl]- amino]phenyl]carbonyl]amino]methyl]-β- phenylbenzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]benzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-phenyIbenzenepropanoate;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-phenylbenzenepropanoic acid;
1,1-dimethylethyl 3-[[[[3-[(aminoiminomethyl)- amino]phenyl]carbonyl]amino]methyl]-β-methyl- benzenepropanoate; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-methylbenzenepropanoic acid; ethyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-ethyIbenzenepropanoate; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-β-ethylbenzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-β-(1-methylethyl)
benzenepropanoic acid;
N-acetyl-3-[[[[3-[(aminoiminomethyl)amino]- phenyl]carbonyl]amino]methyl]phenylalanine;
3-[[[3-[(aminoiminomethyl)amino]phenyl]- acetyl]amino]benzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- amino]carbonyl]amino]benzenepropanoic acid;
3-[[[[[3-[(aminoiminomethyl)amino]phenyl]amino]- carbonyl]amino]methyl]benzenepropanoic acid;
3-[[[[3-[[(cyanoimino)(methylamino)methyl]- amino]phenyl]carbonyl]amino]methyl ] -β- phenylbenzenepropanoic acid; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]carbonyl]- amino]methyl]-βR-methylbenzenepropanoic acid;
3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]-βS-methylbenzenepropanoic acid; (±) 3-[[[[3-[(aminoiminomethyl)amino]-4- chlorophenyl]carbonyl]amino]methyl]-β- ethylbenzenepropanoic acid;
(±) 3-[[[[3-[(aminoiminomethyl)amino]-5-
(trifluoromethyl)phenyl]carbonyl]amino]- methyl]-β-ethylbenzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]- phenyl]carbonyl]amino]methyl]phenyl]-3,5- difluorobenzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]-5- (trifluoromethyl)phenyl]carbonyl]amino]methyl]- phenyl]-3,5-difluorobenzenepropanoic acid;
(±) 3,5-difluoro-β-[3-[[[[3-[(1,4,5,6- tetrahydropyrimidin-2-yl)amino]phenyl]carbonyl]- amino]methyl]phenyl]benzenepropanoic acid;
(±) β-[3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]phenyl]-2- methoxybenzenepropanoic acid;
(±) 3[[[[3-[[amino(cyanoimino)methyl]amino]- phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
(±) 3[[[[3-[[amino[(aminocarbonyl)imino]- methyl]amino]phenyl]carbonyl]amino]methyl]- β-methylbenzenepropanoic acid;
(±) 3-[[[[3-[(4,5-dihydro-4-oxo-1H-imidazol-2- yl)amino]phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid; ( ± ) 3 - [ [ [ [ 3 - [ ( 1H-benzimidazol-2 -yl) amino ] - phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
(±) 3-[[[[3-[(5-methoxy-1H-benzimidazol-2- yl)amino]phenyl]carbonyl]amino]methyl]-β- methylbenzenepropanoic acid;
3-[2-[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]- phenyl]-2-hydroxyethoxy]benzenepropanoic acid;
3-[2-[3-[(aminoiminomethyl)amino]phenyl]- ethynyl]-β-phenylbenzenepropanoic acid;
3-[2E-[3-[(aminoiminomethyl)amino]phenyl]- ethenyl]-β-phenylbenzenepropanoic acid;
3-[2Z-[3-[(aminoiminomethyl)amino]phenyl]- ethenyl]-β-phenylbenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-dichloro- benzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-3,5-difluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-4-fluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]- phenyl]sulfonyl]amino]phenyl]-3,4,5- trifluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]perfluorobenzenepropanoic acid; β-[3-[[[3-[(aminoiminomethyl)amino]phenyl]- sulfonyl]amino]phenyl]-2,3,5,6-tetra- fluorobenzenepropanoic acid;
3,5-difluoro-β-[3-[[[3-[[[(phenylmethyl)amino]- carbonyl]amino]phenyl]sulfonyl]amino]- phenyllbenzenepropanoic acid;
3,5-difluoro-β-[3-[[[3-[[[(phenylmethyl)- imino]methyl]amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid;
3-[[3-[(aminoiminomethyl)amino]phenylthio]- methyl]-β-phenylbenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfinyl]- methyl] -β-phenylbenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfonyl]- methyl]-β-phenylbenzenepropanoic acid; β-[3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl ] sulfonyl] amino]phenyl] -3,5- dichlorobenzenepropanoic acid; β-[3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]phenyl]-3,5- difluorobenzenepropanoic acid; 3-[[[3-[(aminoiminomethyl)amino]phenyl]sulfonyl]- amino] -β-ethylbenzenepropanoic acid; 3-[[[3-[[amino[(aminocarbonyl)imino]methyl]- amino]phenyl]sulfonyl]amino]-β- ethylbenzenepropanoic acid;
3-[[3-[(aminoiminomethyl)amino]phenyl]- methoxy]-β-phenylbenzenepropanoic acid;
3,5-difluoro-β-[3-[[[3-[(1,4,5,6-tetrahydro- pyrimidin-2-yl)amino]phenyl]sulfonyl]amino]- phenyl]benzenepropanoic acid; β-[3-[[[3-[(4,5-dihydro-1H-imidazol-2-yl)- amino]phenyl]sulfonyl]amino]phenyl]-3,5- difluorobenzenepropanoic acid; 3-[[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]phenyl]- methoxy]-β-phenylbenzenepropanoic acid; sodium β-[3-[[[3-[(aminoiminomethyl)amino]- phenyl]sulfonyl]amino]phenyl]-2- hydroxybenzenepropanoate; ethyl 3-[[[3-[amino(hydroxyimino)methyl]phenyl]- carbonyl]amino]benzeneacetate;
3-[[[3-(aminoiminomethyl)phenyl]carbonyl]- amino]benzeneacetic acid;
3-[2-[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]ethyl]benzeneacetic acid; methyl 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzeneacetate; ethyl 3-[[[3-(aminoiminomethyl)phenyl]
carbonyl]amino]benzeneacetate; 3-[[[[3-[(aminoiminomethyl)amino]phenyl]- carbonyl]amino]methyl]benzeneacetic acid;
3-[[[3-[(aminoiminomethyl)amino]phenyl]
carbonyl]amino]benzeneacetic acid;
2-[3-[3-[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]- phenyl]-1-oxo-2-propenyl]phenoxy] acetic acid;
2-[3-[3-[3-[(aminoiminomethyl)amino]phenyl]-1- oxopropenyl]phenoxy]acetic acid;
[3-[[[[3-[(aminoiminomethyl)amino]phenyl]- amino]carbonyl]amino]phenoxy] acetic acid;
3-[(aminoiminomethyl)amino]-N-[3-(3,4-dihydro-2-oxo- 2H-benzopyran-4-yl)phenyl]benzenesulfonamide; and
3-[(4,5-dihydro-1H-imidazol-2-yl)amino]-N-[3-
(3,4-dihydro-2-oxo-2H-benzopyran-4-yl)- phenyl]benzenesulfonamide.
17. The method according to Claim 15 wherein the
condition treated is tumor metastasis.
18. The method according to Claim 16 wherein the
condition treated is tumor metastasis.
19. The method according to Claim 15 wherein the
condition treated is solid tumor growth.
20. The method according to Claim 16 wherein the
condition treated is solid tumor growth.
21. The method according to Claim 15 wherein the
condition treated is angiogenesis.
22. The method according to Claim 16 wherein the condition treated is angiogenesis.
23. The method according to Claim 15 wherein the
condition treated is osteoporosis.
24. The method according to Claim 16 wherein the
condition treated is osteoporosis.
25. The method according to Claim 15 wherein the
condition treated is humoral hypercalcemia of malignancy.
26. The method according to Claim 16 wherein the
condition treated is humoral hypercalcemia of malignancy.
27. The method according to Claim 15 wherein the
condition treated is smooth muscle cell migration.
28. The method according to Claim 16 wherein the
condition treated is smooth muscle cell migration.
29. The method according to Claim 15 wherein
restenosis is inhibited.
30. The method according to Claim 16 wherein
restenosis is inhibited.
PCT/US1997/004461 1996-03-29 1997-03-26 META-SUBSTITUTED PHENYLENE DERIVATIVES AND THEIR USE AS ALPHAvBETA3 INTEGRIN ANTAGONISTS OR INHIBITORS WO1997036862A1 (en)

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Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042329A1 (en) * 1997-03-21 1998-10-01 Mitsubishi Chemical Corporation Preventives and/or remedies for diseases caused by abnormal neovascularization
WO1999010313A1 (en) * 1997-08-22 1999-03-04 F.Hoffmann-La Roche Ag N-aroylphenylalanine derivatives
WO1999033789A1 (en) * 1997-12-23 1999-07-08 Aventis Pharma Limited SUBSTITUTED β-ALANINES
WO1999052872A1 (en) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. AMINOPIPERIDINE DERIVATIVES AS INTEGRIN αvβ3 ANTAGONISTS
WO1999054321A1 (en) * 1998-04-21 1999-10-28 Aventis Pharma Limited Substituted diamines and their use as cell adhesion inhibitors
WO2000005223A2 (en) * 1998-07-23 2000-02-03 Astrazeneca Ab Heterocyclic derivatives and their use as integrin inhibitors
WO2000005224A2 (en) * 1998-07-23 2000-02-03 Astrazeneca Ab Heterocyclic derivatives and their use as integrin inhibitor
WO2000039103A1 (en) * 1998-12-23 2000-07-06 Aventis Pharma Limited Dihydro-benzo(1,4)oxazines and tetrahydroquinoxalines
WO2000041469A2 (en) * 1999-01-15 2000-07-20 Bayer Aktiengesellschaft β-PHENYLALANINE DERIVATIVES AS INTEGRIN ANTAGONISTS
WO2000049005A1 (en) * 1999-02-16 2000-08-24 Aventis Pharma Limited Bicyclic compounds and their use as integrin receptor ligands
WO2000068213A1 (en) * 1999-05-05 2000-11-16 Aventis Pharma Limited Substituted bicyclic compounds
WO2001010841A2 (en) * 1999-08-07 2001-02-15 Merck Patent Gmbh Fluorene derivatives as integrin inhibitors
WO2001014337A1 (en) * 1999-08-24 2001-03-01 Merck Patent Gmbh αvβ3 INTEGRIN INHIBITORS
WO2001025181A1 (en) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same
US6229011B1 (en) 1997-08-22 2001-05-08 Hoffman-La Roche Inc. N-aroylphenylalanine derivative VCAM-1 inhibitors
WO2001056607A1 (en) * 2000-02-03 2001-08-09 Eisai Co., Ltd. Integrin expression inhibitors
US6288267B1 (en) 1999-02-18 2001-09-11 Hoffmann-La Roche Inc. Thioamide derivatives
WO2001087840A1 (en) * 2000-05-16 2001-11-22 Pharmacia Italia S.P.A. Propanoic acid derivatives as integrin receptor antagonists
WO2001092201A1 (en) * 2000-05-29 2001-12-06 Kyorin Pharmaceutical Co., Ltd. Substituted phenylpropionic acid derivatives
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6352977B1 (en) 1998-07-13 2002-03-05 Aventis Pharma Limited Substituted β-alanines
US6362204B1 (en) * 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
WO2002051810A2 (en) * 2000-12-22 2002-07-04 Abbott Gmbh & Co. Kg Integrin receptor ligands
US6420600B1 (en) 1999-02-18 2002-07-16 Hoffman-La Roche Inc. Phenylalaninol derivatives
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
WO2002070468A2 (en) * 2001-02-08 2002-09-12 Rotta Research Laboratorium S.P.A. Novel benzamidine derivatives having anti-inflammatory and immunosuppressive activity
US6455550B1 (en) 1997-08-22 2002-09-24 Hoffmann-La Roche Inc. N-alkanoylphenylalanine 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
US6479519B1 (en) 1997-10-31 2002-11-12 Aventis Pharma Limited Substituted anilides
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic 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
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US7049342B2 (en) 2000-05-29 2006-05-23 Kyorin Pharmaceutical Co., Ltd. Substituted phenylpropionic acid derivatives
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
WO2017139414A1 (en) * 2016-02-09 2017-08-17 Inventisbio Inc. Inhibitor of indoleamine-2,3-dioxygenase (ido)
US10035778B2 (en) 2015-12-30 2018-07-31 Saint Louis University Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
CN115232027A (en) * 2022-08-03 2022-10-25 中国农业大学 Preparation method of N-tert-butyl-N' - (2, 6-diisopropyl-4-phenoxyphenyl) formamidine

Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL186370B1 (en) * 1995-08-30 2003-12-31 Searle & Co Methaguanidine, urea, thiourea or azacyclic derivatives of aminobenzoic acid as antagonists of integrin
AU2420897A (en) * 1996-03-29 1997-10-22 G.D. Searle & Co. Meta-substituted phenylene sulphonamide derivatives
US6245809B1 (en) * 1996-12-09 2001-06-12 Cor Therapeutics Inc. Integrin antagonists
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
CA2319465C (en) * 1998-01-29 2013-03-19 Viropharma Incorporated Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
US6495580B1 (en) 1998-01-29 2002-12-17 Viropharma Incorporated Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
AU3260399A (en) * 1998-02-26 1999-09-15 Celltech Therapeutics Limited Phenylalanine derivatives as inhibitors of alpha4 integrins
GB9811969D0 (en) 1998-06-03 1998-07-29 Celltech Therapeutics Ltd Chemical compounds
GB9821222D0 (en) 1998-09-30 1998-11-25 Celltech Therapeutics Ltd Chemical compounds
US6420403B1 (en) * 1998-10-29 2002-07-16 Edwin J. Iwanowicz Inhibitors of IMPDH enzyme
GB9825652D0 (en) * 1998-11-23 1999-01-13 Celltech Therapeutics Ltd Chemical compounds
US6677360B2 (en) * 1998-12-16 2004-01-13 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
US6420396B1 (en) 1998-12-16 2002-07-16 Beiersdorf Ag Biphenyl and biphenyl-analogous compounds as integrin antagonists
AU2713500A (en) 1998-12-23 2000-07-31 G.D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
GB9929988D0 (en) * 1999-12-17 2000-02-09 Celltech Therapeutics Ltd Chemical compounds
EP1242352A2 (en) * 1999-12-23 2002-09-25 University Of Georgia Research Foundation, Inc. Chalcone and its analogs as agents for the inhibition of angiogenesis and related disease states
JP2004525069A (en) * 2000-06-15 2004-08-19 ファルマシア・コーポレーション Cycloalkylalkanoic acids as integrin receptor antagonists
EP1289983A2 (en) * 2000-06-15 2003-03-12 Pharmacia Corporation Heteroarylalkanoic acids as integrin receptor antagonists
CA2419580A1 (en) 2000-08-18 2002-02-28 Genentech, Inc. Integrin receptor inhibitors
WO2002036554A2 (en) * 2000-10-30 2002-05-10 Warner-Lambert Company Llc Amidino-urea serotonin receptor ligands and compositions, their pharmaceutical uses, and methods for their snythesis
FR2817749A1 (en) * 2000-12-13 2002-06-14 Aventis Pharma Sa NEW USE OF CHALCON CLASS COMPOUNDS
US20040043988A1 (en) * 2001-06-15 2004-03-04 Khanna Ish Kurmar Cycloalkyl alkanoic acids as intergrin receptor antagonists
WO2003042190A1 (en) * 2001-11-12 2003-05-22 Pfizer Products Inc. N-alkyl-adamantyl derivatives as p2x7-receptor antagonists
PA8557501A1 (en) 2001-11-12 2003-06-30 Pfizer Prod Inc BENZAMIDA, HETEROARILAMIDA AND INVESTED AMIDAS
AU2003217930A1 (en) * 2002-03-04 2003-09-22 Medimmune, Llc The prevention or treatment of cancer using integrin alphavbeta3 antagonists in combination with other agents
JP2005525368A (en) * 2002-03-04 2005-08-25 メディミューン，インコーポレーテッド Method for preventing or treating disorders in which an integrin αvβ3 antagonist is administered in combination with an HMG-CoA reductase inhibitor or bisphosphonate
CA2495245A1 (en) 2002-08-09 2004-02-19 Viropharma Incorporated Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
EP1545513A2 (en) 2002-08-09 2005-06-29 Viropharma Incorporated Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
EP1572690A1 (en) * 2002-12-20 2005-09-14 Pharmacia Corporation Thiazole compounds as integrin receptor antagonists derivatives
CA2507699A1 (en) * 2002-12-20 2004-07-15 Pharmacia Corporation Heteroarylalkanoic acids as integrin receptor antagonists
US20050004200A1 (en) * 2002-12-20 2005-01-06 Pharmacia Corporation Pyrazole compounds as integrin receptor antagonists derivatives
US7071223B1 (en) * 2002-12-31 2006-07-04 Pfizer, Inc. Benzamide inhibitors of the P2X7 receptor
PA8591801A1 (en) * 2002-12-31 2004-07-26 Pfizer Prod Inc BENZAMID INHIBITORS OF THE P2X7 RECEIVER.
CA2514653A1 (en) * 2003-01-30 2004-08-12 Medimmune, Inc. Uses of integrin alphavbeta3 antagonists
ATE355273T1 (en) * 2003-05-12 2006-03-15 Pfizer Prod Inc BENZAMIDINE INHIBITORS OF THE P2X7 RECEPTOR
GB0401334D0 (en) * 2004-01-21 2004-02-25 Novartis Ag Organic compounds
UA87854C2 (en) 2004-06-07 2009-08-25 Мерк Энд Ко., Инк. N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
CN1980902A (en) * 2004-06-29 2007-06-13 辉瑞产品有限公司 Method for preparing 5-'4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h'1,2,4!triazin-2-yl!-benzamide derivatives by deprotecting the hydroxyl-protected precursers
BRPI0512915A (en) * 2004-06-29 2008-04-15 Warner Lambert Co combination therapies using p2x7 receptor benzamide inhibitors
EP1768965A1 (en) * 2004-06-29 2007-04-04 Pfizer Products Incorporated Method for preparing 5-¬4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3h-¬1,2,4|-triazin-2-yl|benzamide derivatives with p2x7 inhibiting activity by reaction of the derivative unsubstituted in 4-position of the triazine with an oxiran in the presence of a lewis acid
WO2006043930A1 (en) * 2004-10-14 2006-04-27 Pharmacia Corporation Biphenyl integrin antagonists
FR2896245B1 (en) * 2006-01-17 2010-09-17 Univ Claude Bernard Lyon NEW CHALCONE DERIVATIVES WITH ANTIMITOTIC ACTIVITY
DK2222636T3 (en) 2007-12-21 2013-06-03 Ligand Pharm Inc Selective androgen receptor modulators (SARMS) and applications thereof
IE20070935A1 (en) * 2007-12-21 2009-06-24 Trinity College Dublin Guanidine based compounds and their use in the treatment of mental and neurological disorders.
JP6433001B2 (en) 2013-08-07 2018-12-05 アローヘッド ファーマシューティカルズ インコーポレイテッド Polyconjugates for in vivo delivery of RNAi triggers to tumor cells
SG11201609050UA (en) 2014-05-30 2016-12-29 Pfizer Carbonitrile derivatives as selective androgen receptor modulators
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CN107652210B (en) * 2017-09-30 2021-01-01 瑞阳（上海）新药研发有限公司 Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof
WO2023275715A1 (en) 2021-06-30 2023-01-05 Pfizer Inc. Metabolites of selective androgen receptor modulators
CN113717133B (en) * 2021-09-14 2023-11-17 浙江大学 3-amido-N-aryl benzamide compound and application thereof
CN114394946A (en) * 2022-02-21 2022-04-26 艾美科健（中国）生物医药有限公司 Synthesis method of flurarana

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0381033A1 (en) * 1989-01-31 1990-08-08 F. Hoffmann-La Roche Ag Carboxylic-acid and sulphonic-acid amides
EP0656348A2 (en) * 1993-12-03 1995-06-07 F. Hoffmann-La Roche Ag Aceric acid derivatives as medicaments
WO1996000574A1 (en) * 1994-06-29 1996-01-11 Smithkline Beecham Corporation Vitronectin receptor antagonists

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL99537A (en) * 1990-09-27 1995-11-27 Merck & Co Inc Fibrinogen receptor antagonists and pharmaceutical compositions containing them
NZ239846A (en) * 1990-09-27 1994-11-25 Merck & Co Inc Sulphonamide derivatives and pharmaceutical compositions thereof
US5523302A (en) * 1993-11-24 1996-06-04 The Du Pont Merck Pharmaceutical Company Aromatic compounds containing basic and acidic termini useful as fibrinogen receptor antagonists
DE69528829T2 (en) * 1994-05-27 2003-08-07 Merck & Co., Inc. PREPARATIONS FOR INHIBITING BONE RESORPTION BROUGHT BY OSTEOCLASTIC

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0381033A1 (en) * 1989-01-31 1990-08-08 F. Hoffmann-La Roche Ag Carboxylic-acid and sulphonic-acid amides
EP0656348A2 (en) * 1993-12-03 1995-06-07 F. Hoffmann-La Roche Ag Aceric acid derivatives as medicaments
WO1996000574A1 (en) * 1994-06-29 1996-01-11 Smithkline Beecham Corporation Vitronectin receptor antagonists

Cited By (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042329A1 (en) * 1997-03-21 1998-10-01 Mitsubishi Chemical Corporation Preventives and/or remedies for diseases caused by abnormal neovascularization
US6806365B2 (en) 1997-08-22 2004-10-19 Hoffmann-La Rocher Inc. N-alkanoylphenylalamine derivatives
US6229011B1 (en) 1997-08-22 2001-05-08 Hoffman-La Roche Inc. N-aroylphenylalanine derivative VCAM-1 inhibitors
WO1999010313A1 (en) * 1997-08-22 1999-03-04 F.Hoffmann-La Roche Ag N-aroylphenylalanine derivatives
US6455550B1 (en) 1997-08-22 2002-09-24 Hoffmann-La Roche Inc. N-alkanoylphenylalanine derivatives
US6479519B1 (en) 1997-10-31 2002-11-12 Aventis Pharma Limited Substituted anilides
JP2001527061A (en) * 1997-12-23 2001-12-25 アベンテイス・フアルマ・リミテツド Substituted β-alanine
WO1999033789A1 (en) * 1997-12-23 1999-07-08 Aventis Pharma Limited SUBSTITUTED β-ALANINES
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
WO1999052872A1 (en) 1998-04-09 1999-10-21 Meiji Seika Kaisha, Ltd. AMINOPIPERIDINE DERIVATIVES AS INTEGRIN αvβ3 ANTAGONISTS
US6420558B1 (en) 1998-04-09 2002-07-16 Meiji Seika Kaisha, Ltd. Aminopiperidine derivates as integrin αvβ3 antagonists
WO1999054321A1 (en) * 1998-04-21 1999-10-28 Aventis Pharma Limited Substituted diamines and their use as cell adhesion inhibitors
US6362204B1 (en) * 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6352977B1 (en) 1998-07-13 2002-03-05 Aventis Pharma Limited Substituted β-alanines
WO2000005223A2 (en) * 1998-07-23 2000-02-03 Astrazeneca Ab Heterocyclic derivatives and their use as integrin inhibitors
WO2000005223A3 (en) * 1998-07-23 2001-07-12 Astrazeneca Ab Heterocyclic derivatives and their use as integrin inhibitors
WO2000005224A3 (en) * 1998-07-23 2001-08-09 Astrazeneca Ab Heterocyclic derivatives and their use as integrin inhibitor
US6441012B1 (en) 1998-07-23 2002-08-27 Astrazeneca Ab Chemical compounds
WO2000005224A2 (en) * 1998-07-23 2000-02-03 Astrazeneca Ab Heterocyclic derivatives and their use as integrin inhibitor
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
US6632814B1 (en) 1998-12-23 2003-10-14 Aventis Pharma Ltd. Dihydro-benzo(1,4)oxazines
WO2000039103A1 (en) * 1998-12-23 2000-07-06 Aventis Pharma Limited Dihydro-benzo(1,4)oxazines and tetrahydroquinoxalines
US6291503B1 (en) 1999-01-15 2001-09-18 Bayer Aktiengesellschaft β-phenylalanine derivatives as integrin antagonists
US6589972B2 (en) 1999-01-15 2003-07-08 Bayer Aktiengesellschaft β-phenylalanine derivatives as integrin antagonists
WO2000041469A3 (en) * 1999-01-15 2000-11-16 Bayer Ag β-PHENYLALANINE DERIVATIVES AS INTEGRIN ANTAGONISTS
WO2000041469A2 (en) * 1999-01-15 2000-07-20 Bayer Aktiengesellschaft β-PHENYLALANINE DERIVATIVES AS INTEGRIN ANTAGONISTS
US6593354B2 (en) 1999-02-16 2003-07-15 Aventis Pharma Limited Substituted benzoxazole compounds
WO2000049005A1 (en) * 1999-02-16 2000-08-24 Aventis Pharma Limited Bicyclic compounds and their use as integrin receptor ligands
US6458844B2 (en) 1999-02-18 2002-10-01 Hoffmann-La Roche Inc. Diphenyl carbocyclic thioamide derivatives
US6423728B1 (en) 1999-02-18 2002-07-23 Hoffman-La Roche Inc. Heterocyclic thioamide derivatives
US6426348B1 (en) 1999-02-18 2002-07-30 Hoffmann-La Roche Inc. Diphenyl heterocyclic thioamide derivatives
US6420600B1 (en) 1999-02-18 2002-07-16 Hoffman-La Roche Inc. Phenylalaninol derivatives
US6288267B1 (en) 1999-02-18 2001-09-11 Hoffmann-La Roche Inc. Thioamide derivatives
US6562851B2 (en) 1999-05-05 2003-05-13 Aventis Pharma Limited Substituted bicyclic compounds
WO2000068213A1 (en) * 1999-05-05 2000-11-16 Aventis Pharma Limited Substituted bicyclic compounds
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6429214B1 (en) 1999-07-21 2002-08-06 Wyeth Bicyclic antagonists selective for the αvβ3 integrin
US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
WO2001010841A2 (en) * 1999-08-07 2001-02-15 Merck Patent Gmbh Fluorene derivatives as integrin inhibitors
WO2001010841A3 (en) * 1999-08-07 2001-09-07 Merck Patent Gmbh Fluorene derivatives as integrin inhibitors
WO2001014337A1 (en) * 1999-08-24 2001-03-01 Merck Patent Gmbh αvβ3 INTEGRIN INHIBITORS
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
EP1216980A4 (en) * 1999-10-01 2010-12-08 Eisai R&D Man Co Ltd Carboxylic acid derivatives and drugs containing the same
WO2001025181A1 (en) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same
US6884821B1 (en) 1999-10-01 2005-04-26 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same
EP1216980A1 (en) * 1999-10-01 2002-06-26 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same
US6849639B2 (en) 1999-12-14 2005-02-01 Amgen Inc. Integrin inhibitors and their methods of use
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US7834049B2 (en) 2000-02-03 2010-11-16 Eisai R&D Management Co., Ltd. Integrin expression inhibitor
WO2001056607A1 (en) * 2000-02-03 2001-08-09 Eisai Co., Ltd. Integrin expression inhibitors
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
WO2001087840A1 (en) * 2000-05-16 2001-11-22 Pharmacia Italia S.P.A. Propanoic acid derivatives as integrin receptor antagonists
US6974828B2 (en) 2000-05-16 2005-12-13 Pharmacia Italia S.P.A. Propanoic acid derivatives as intergrin receptor antagonists
WO2001092201A1 (en) * 2000-05-29 2001-12-06 Kyorin Pharmaceutical Co., Ltd. Substituted phenylpropionic acid derivatives
US7049342B2 (en) 2000-05-29 2006-05-23 Kyorin Pharmaceutical Co., Ltd. Substituted phenylpropionic acid derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
WO2002051810A2 (en) * 2000-12-22 2002-07-04 Abbott Gmbh & Co. Kg Integrin receptor ligands
WO2002051810A3 (en) * 2000-12-22 2003-03-20 Abbott Gmbh & Co Kg Integrin receptor ligands
WO2002070468A2 (en) * 2001-02-08 2002-09-12 Rotta Research Laboratorium S.P.A. Novel benzamidine derivatives having anti-inflammatory and immunosuppressive activity
US7560591B2 (en) 2001-02-08 2009-07-14 Rotta Research Laboratorium S.P.A. Benzamidine derivatives having anti-inflammatory and immunosuppressive activity
US7202277B2 (en) 2001-02-08 2007-04-10 Rotta Research Laboratorium S.P.A. Benzamidine derivatives having anti-inflammatory and immunosuppressive activity
WO2002070468A3 (en) * 2001-02-08 2003-09-04 Rotta Research Lab Novel benzamidine derivatives having anti-inflammatory and immunosuppressive activity
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
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
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US10980807B2 (en) 2016-02-09 2021-04-20 Inventisbio Llc Inhibitor of indoleamine-2,3-dioxygenase (IDO)
CN113896685A (en) * 2016-02-09 2022-01-07 益方生物科技(上海)股份有限公司 Indoleamine-2, 3-dioxygenase (IDO) inhibitors
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US11969425B2 (en) 2016-02-09 2024-04-30 Inventisbio Llc Inhibitor of indoleamine-2,3-dioxygenase (IDO)
CN115232027A (en) * 2022-08-03 2022-10-25 中国农业大学 Preparation method of N-tert-butyl-N' - (2, 6-diisopropyl-4-phenoxyphenyl) formamidine
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