EP1668007A1 - Derives de dioxolane comme inhibiteurs de l'adhesion cellulaire - Google Patents

Derives de dioxolane comme inhibiteurs de l'adhesion cellulaire

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Publication number
EP1668007A1
EP1668007A1 EP04769418A EP04769418A EP1668007A1 EP 1668007 A1 EP1668007 A1 EP 1668007A1 EP 04769418 A EP04769418 A EP 04769418A EP 04769418 A EP04769418 A EP 04769418A EP 1668007 A1 EP1668007 A1 EP 1668007A1
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EP
European Patent Office
Prior art keywords
compound
carbonyl
amino
phenyl
dioxolane
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP04769418A
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German (de)
English (en)
Inventor
Venkata P. Palle
Viswajanani J. Sattigeri
Mohammad Salman
Ajay Soni
Abhijit Ray
Sunanda G. Dastidar
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of EP1668007A1 publication Critical patent/EP1668007A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to dioxolane derivatives as cell adhesion inhibitors. These compounds can be useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies, including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection or psoriasis.
  • This invention also relates to pharmacological compositions containing the compounds of the present invention, and the methods of treating bronchial asthma, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, and other inflammatory and/or autoimmune disorders, using the compounds.
  • CAMs cell adhesion molecules
  • CAMs can be classified into three groups - integrins, selectins and the immunoglobulin superfamily.
  • integrins are key mediators in the adhesive interactions between hemopoietic cells and their microenvironment. They are comprised of alpha-beta heterodimers that integrate signals from outside to the inside of cells and vice versa. Integrins can be classified on the basis of the beta subunits they contain. For example, the beta-1 subfamily contains beta-1 subunit noncovalently linked to one of the 10 different alpha subunits.
  • the alpha-4 beta-1 integrin also known as VLA-4 (very late activation antigen 4), is a member of the beta-1 integrin family, and comprises alpha-4 and beta-1 subunits.
  • VCAM-1 vascular cell adhesion molecule
  • CS1 region of the protein fibronectin Adhesion mediated by VLA-4 is central to the process of transendothelial migration of leukocytes. Ligation of VLA-4 is followed by gross rearrangement of the cytoskeleton, leading to flattening of cells along the blood vessel wall, followed by expression of specific molecules, which digest the endothelial cell wall and diapedesis. Once in the extraluminal region, the interactions of VLA-4 with extracellular fibronectin play a crucial role in migration to the site of inflammation, T cell proliferation, and the expression of cytokines and inflammatory mediators.
  • VLA-4 ligation provides co-stimulatory signals to the leukocytes, resulting in enhanced immunoreactivity. Therefore, it is expected that VLA-4 antagonists would ameliorate the immune response through twofold actions: inhibition of T cell recruitment at the site of inflammation; and inhibition of costimulatory activation of immune cells.
  • inhibitors of VLA-4 interactions have demonstrated beneficial therapeutic effects in several animal models of inflammatory, and allergic diseases including sheep allergic asthma.
  • the region of CS1 moiety of fibronectin involved in the interaction with VLA-4 has been identified as the tripeptide Leu-Asp-Val, also known as LDV.
  • U.S. Patent No. 6,329,344 Bl discloses several monosaccharide derivatives as cell adhesion inhibitors. It generally relates to substituted pentose and hexose monosaccharide derivatives, which exhibit potent anti-cell adhesion and anti-inflammatory activities.
  • Patent application WO 00/42054 discloses several monosaccharide derivatives as cell adhesion inhibitors.
  • Patent application WO 00/43369 provides compounds which bind to VLA-4, as well as triazine derivatives which inhibit leukocyte adhesion mediated by VLA-4.
  • WO 99/06434 discloses 4-aminophenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4.
  • WO 01/12186 discloses cell adhesion inhibitors which interact with VLA-4 molecules and inhibits VLA-4 dependent cell adhesion.
  • WO 98/58902 discloses molecules which are potent inhibitors of ⁇ ⁇ ,-mediated adhesion to either VCAM or CS-1 and which can be used for treating or preventing ⁇ ⁇ ,-mediated adhesion mediated conditions.
  • U.S. Patent No. 6,291,511 discloses several biarylalkanoic acids as cell adhesion inhibitors.
  • GB 2354440 discloses several aryl amides as cell adhesion inhibitors.
  • WO 98/53814 discloses heterocyclic amide compounds as cell adhesion inhibitors.
  • WO 01/12183 discloses heterocyclic amides as cell adhesion inhibitors.
  • WO 99/20272 and U.S. Patent No. 6,069,163 discloses several azapeptide acids as cell adhesion inhibitors.
  • U.S. Patent 6,020,347 discloses 4-substituted-4-piperidine carboxamide derivatives useful in the inhibition or prevention of cell adhesion and cell adhesion mediated pathologies.
  • U.S. Patent 6,191,171 discloses para-aminomethyl aryl carboxamide derivatives as cell adhesion inhibitors.
  • U.S. Patent 6,090,841 discloses substituted pyrrole derivatives as cell adhesion inhibitors.
  • Bioorg & Med. Chem., JO (2002), 1567-1580 discloses synthesis of potential thrombm inhibitors and incorporation of tartaric acid templates as P2 pro line mimetics.
  • the compounds of the present invention may be screened for inhibitory activity in VLA-4 mediated cell adhesion assay and the classical murine hypersensitivity assay in mice. These compounds could be used in treatment of chronic, cell adhesion mediated, allergic, autoimmune and inflammatory disorders, such as bronchial asthma, multiple sclerosis, rheumatoid arthritis etc.
  • Some of the prior art describes development of peptide derivatives as cell adhesion antagonists for treatment of these diseases.
  • substituted dioxolane derivatives which can be used as cell adhesion inhibitors.
  • a compound having the structure of Formula I having the structure of Formula I
  • Formula I its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides wherein m is an integer from 0-2;
  • Ri can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroarylalkyl, or heterocyclylalkyl;
  • R 2 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carboxy, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl;
  • Ri and R 2 may together join to form a cyclic ring (3-8 membered), which may be optionally benzofused, containing 0-4 heteroatoms such as O, S, or N, wherein the rings may be substituted with one or more of alkyl, alkenyl, alkynyl, amino, substituted amino, cycloalkyl, carboxy, alkoxy, aryloxy, halogen (F,C1, Br, I), aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl;
  • Rs and R$ may be independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, aryl, or aralkyl; or R 5 and R$ may together join to form a cycloalkyl ring.
  • alkyl unless and otherwise specified refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Alkyl groups may further be substituted with one or more substituents selected such as alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, aryl, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryloxy, aminosulfonyl, aminocarbonylamino, aminothiocarbonylamino, hydroxyamino, alkoxyamino, nitro, SH, S-alkyl, S-Salkyl, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 -alkyl, SO 2 -aryl and -SO 2 - heteroaryl, further alkyl may be substituted
  • substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, carboxy-alkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and - S(O) n R ⁇ 2 , where R ⁇ 2 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl and heterocyclyl and n is 0, 1 or 2; or or an alkyl group as defined above that is interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NR a - ⁇ where R a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl.
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R ⁇ 2 , where n and R ⁇ 2 are the same as defined earlier; or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry either in a acyclic or cyclic ring system wherein the cyclic may include mono- or multicyclic ring forms. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF , amino, substituted amino, cyano, and -S(O) n R ⁇ 2 , where R ⁇ 2 is the same as defined above and n is 0, 1 or 2.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms. In the event that alkynyl is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom.
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) n R ⁇ 2 , where R
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, for example cyclobutyl, cyclopentyl, adamantyl and the like.
  • Cycloalkyl groups may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO- heteroaryl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; further cycloalkyl may be substituted with a group represented by (CH 2 ) 0-3
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and -S(O) interceptR ⁇ , where R ⁇ 2 is the same as defined above and n is 0, 1 or 2.
  • R ⁇ 2 is the same as defined above and n is 0, 1 or 2.
  • Alkoxy denotes the group O-alkyl wherein alkyl is the same as defined above.
  • alkyl is the same as defined above.
  • alkyl is the same as defined above.
  • alkyl is the same as defined above.
  • alkyl is the same as defined above.
  • alkyl refers to (CH ) P aryl, wherein p is an integer in the range of 1-6 and aryl is as defined below.
  • aryl herein refers to phenyl or naphthyl ring and the like, which may optionally be fused to cycloalkyl or heterocyclyl.
  • R ⁇ 0 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl.
  • Aryloxy denotes the group O-Aryl wherein aryl is the same as defined above.
  • Alkoxy denotes the group O-aralkyl wherein aralkyl is the same as defined above.
  • substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF , amino, substituted amino, cyano, and -S(O) n Ri 2 , where R ⁇ 2 is the same as defined above and n is 0, 1 or 2.
  • heterocryl groups may optionally be fused to an aryl ring wherein aryl is the same as defined earlier.
  • the term 'heterocyclyl refers to a non aromatic cycloalkyl group having 5 to 10 atoms in which 1 to 3 carbon atoms in a ring are replaced by heteroatoms such as O, S or N, and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents can be halogen (F, CI, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO 2 - alkyl, -SO 2 -aryl and -SO 2 -heteroaryl, aryl, alkoxy, aralkyl, cyano, nitro, amino or substituted amino, cyano
  • Heteroarylalkyl refers to heteroaryl (wherein heteroaryl is same as defined earlier) linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6.
  • Heterocyclylalkyl refers to heterocyclyl (wherein heterocyclyl is same as defined earlier) linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides of these compounds are also provided.
  • compositions containing the compounds can be used for the treatment of cell adhesion mediated pathologies including inflammatory and autoimmune diseases such as . bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection or psoriasis.
  • the term "leaving group” generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, of being easily separated from synthetic products under defined conditions. Examples of such leaving groups include but are not limited to halogen (F, CI, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
  • Protecting groups is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also, protecting groups, unless otherwise specified, may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2 nd Ed, John Wiley and Sons, New York, N.Y., which is incorporated herein by reference.
  • the species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting group employed is not critical as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without distrupting the remainder of the molecule.
  • Compounds provided herein can contain one or more asymmetric carbon atoms and thus can occur as racemates, mixtures of enantiomers, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included herein.
  • Each stereogenic carbon may be of the R or S configuration.
  • a compound of Formula XI, XII and XVI can be prepared according to Scheme I.
  • R 2 is p-hydroxybenzyl.
  • the hydrolysis of a compound of Formula II to a compound of Formula III can be carried out in a solvent system, for example tetrahydrofuran, methanol, dioxane, ethanol or water or combinations thereof.
  • the hydrolysis of a compound of Formula II to compound of Formula III can be carried out in the presence of a base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the condensation of a compound of Formula III with compound of Formula IV to give a compound of Formula V can be carried out in an organic solvent, for example tetrahydrofuran, dichloromethane or dimethylformamide.
  • the condensation of a compound of Formula III with a compound of Formula IN can be carried out in the presence of an organic base, for example ⁇ -methylmorpholine, diisopropylethylamine or triethylamine.
  • the condensation of a compound of Formula III with a compound of Formula IV can be carried out in a condensing agent, for example 1- (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, dicyclohexylcarbodiimide or by a mixed anhydride reaction using chloroformates, for example ethyl chloroformate or isobutyl chloroformate.
  • the hydrolysis of a compound of Formula V to give a compound of Formula VI can be carried out in a solvent system, for example tetrahydrofuran, methanol, ethanol, dioxane or water or combinations thereof.
  • the hydrolysis of a compound of Formula V to give a compound of Formula VI can be carried out in the presence of a base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the condensation of a compound of Formula VI with a compound of Formula VII to give a compound of Formula VIII can be carried out in a organic solvent, for example tetrahydrofuran or dimethylformamide.
  • the condensation of a compound of Formula VI with a compound of Formula VII can be carried out in the presence of a condensing agent, for example l-(3-dimethylaminopropyl)-3-ethyl carbodiimide or dicyclohexylcarbodiimide.
  • a condensing agent for example l-(3-dimethylaminopropyl)-3-ethyl carbodiimide or dicyclohexylcarbodiimide.
  • the condensation of a compound of Formula VI with a compound of Formula VII can be carried out in the presence of a base, for example N-methylmorpholine, diisopropylethylamine or triethylamine.
  • the reaction of a compound of Formula VIII (Path a) with a compound Formula IX to give compound of Formula X can be carried out in an organic solvent, for example acetone, dichloromethane, carbon tetrachloride, dimethylformamide or chloroform.
  • the reaction of a compound of Formula VIII with a compound Formula IX can be carried out in the presence of a base, for example, sodium hydride, sodium carbonate or potassium carbonate.
  • the hydrolysis of a compound of Formula X to give a compound of Formula XI can be carried out in a solvent system, for example ethanol, dimethylformamide, dimethylsulphoxide, dioxane, tetrahydrofuran, methanol or water or combination thereof.
  • the hydrolysis of a compound of Formula X (when P is methyl, ethyl or benzyl) to give a compound of Formula XI can be carried out in the presence of a base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • a base for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the hydrolysis of a compound of Formula X (when P is tert-butyl) to give a compound of Formula XI can be carried out in the presence of an acid, for example trifluoroacetic acid or hydrochloric acid, in a solvent, for example tetrahydrofuran in water or dichloromethane.
  • Morpholine-4-carboxylic acid 4-((S)-2- ⁇ [(4R,5R)-5-(biphenyl-2-yl-carbamoyl)- [l,3]dioxolane-4-carbonyl]-amino ⁇ -2-carboxy-ethyl)-phenyl ester (Compound No. 15)
  • the hydrolysis of compound of Formula VIII (when P is a protecting group such as methyl, ethyl or benzyl) to give a compound of Formula XII can be carried out in the presence of an organic base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the hydrolysis of a compound of Formula VIII (when P is tert-butyl) to give a compound of Formula XI can be carried out in the presence of an acid, for example trifluoroacetic acid or hydrochloric acid.
  • the reduction of a compound of Formula VIII to give a compound of Formula XIII can be carried out in the presence of hydrogen using a catalyst, for example palladium on carbon or platinum on carbon.
  • a catalyst for example palladium on carbon or platinum on carbon.
  • the condensation of a compound of Formula XIII with a compound of Formula XIN to give a compound of Formula XV can be carried out in an organic solvent, for example dimethylformamide, tetrahydrofuran or dimethylsulphoxide.
  • the condensation of a compound of Formula XIII with a compound of Formula XIV can be carried out in the presence of an organic base, for example N-methylmorpholine ⁇ triethylamine or diisopropylethylamine.
  • the condensation of a compound of Formula XIII (when X is OH) with a compound of Formula XIV can be carried out in the presence of a condensing agent, for example l-(3-dimethylaminopropyl)-3-carbodiimide or dicyclohexyl carbodiimide or by a mixed anhydride reaction using chloroformates, for example ethyl chloroformate or isobutyl chloroformate.
  • a condensing agent for example l-(3-dimethylaminopropyl)-3-carbodiimide or dicyclohexyl carbodiimide or by a mixed anhydride reaction using chloroformates, for example ethyl chloroformate or isobutyl chloroformate.
  • the condensation of a compound of Formula XIII (when X is CI or Br) with a compound of Formula XIV can be carried out in the presence of an organic base, for example N-methyl
  • the hydrolysis of a compound of Formula XV to give a compound of Formula XVI can be carried out in a solvent or solvent system, for example ethanol, tetrahydrofuran, dimethylformamide, dimethylsulphoxide, dioxane, methanol or water or combinations thereof.
  • a solvent or solvent system for example ethanol, tetrahydrofuran, dimethylformamide, dimethylsulphoxide, dioxane, methanol or water or combinations thereof.
  • the hydrolysis of a compound of Formula XV (when P is a protecting group such as methyl, ethyl or benzyl) to give a compound of Formula XVI can be carried out in the presence of a base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • a compound of Formula XXI can be prepared according to Scheme II.
  • the condensation of a compound of Formula III with compound of Formula XVII to give a compound of Formula XVIII can be carried out in an organic solvent, for example tetrahydrofuran, dimethylformamide or dimethylsulphoxide.
  • the condensation of a compound of Formula III with a compound of Formula XVII can be carried out in the presence of an organic base, for example N-methylmorpholine, diisopropylethylamine or triethylamine.
  • the condensation of a compound of Formula III with a compound of Formula XVII can be carried out in the presence of a condensing agent, for example l-(3- dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride or dicyclohexylcarbodiimide or by a mixed anhydride reaction using chloroformates, for example ethyl chloroformate or isobutyl chloroformate.
  • a condensing agent for example l-(3- dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride or dicyclohexylcarbodiimide
  • chloroformates for example ethyl chloroformate or isobutyl chloroformate.
  • the hydrolysis of a compound of Formula XVIII (when P is ethyl) to give a compound of Formula XIX can be carried out in a solvent system, for example ethanol, dimethylformamide, tetrahydrofuran, dimethylsulphoxide, dioxane, methanol or water or combinations thereof.
  • a solvent system for example ethanol, dimethylformamide, tetrahydrofuran, dimethylsulphoxide, dioxane, methanol or water or combinations thereof.
  • the hydrolysis of a compound of Formula XVIII (when P is ethyl) to give a compound of Formula XIX can be carried out in a presence of a base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the condensation of a compound of Formula XIX with a compound of Formula IV to give a compound of Formula XX can be carried out in an organic solvent, for example tetrahydrofuran, dimethylformamide or dimethylsulphoxide.
  • the condensation of a compound of Formula XIX with a compound of Formula IV can be carried out in the presence of an organic base, for example N-methylmorpholine, diisopropylethylamine or triethylamine.
  • the condensation of a compound of Formula XIX with a compound of Formula IV to give a compound of Formula XX can be carried out with condensing agent for example l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride or dicyclohexylcarbodiimide or by a mixed anhydride reaction using chloroformates, for example ethyl chloroformate or isobutyl chloroformate.
  • the condensation of a compound of Formula XIX with a compound of Formula IV can also be carried out by mixed anhydride reaction using chloroformates for example, ethyl chloroformate or isobutyl chloroformate.
  • the hydrolysis of a compound of Formula XX (when P is t-butyl) to give a compound of Formula XXI can be carried out in a solvent, for example tetrahydrofuran in water or dichloromethane.
  • the hydrolysis of a compound of Formula XX (when P is t-butyl) to give a compound of Formula XXI can be carried out in the presence of an acid, for example trifluoroacetic acid or hydrochloric acid.
  • the hydrolysis of a compound of Formula XX (when P is ethyl, methyl or benzyl) to give a compound of Formula XXI can be carried out in an organic solvent for example, ethanol, dimethylformamide, tetrahydrofuran, dimethylsulphoxide, dioxane, methanol or water or combinations thereof.
  • an organic solvent for example, ethanol, dimethylformamide, tetrahydrofuran, dimethylsulphoxide, dioxane, methanol or water or combinations thereof.
  • the hydrolysis of a compound of Formula XVIII to give a compound of Formula XXII can be carried out in a solvent system, for example tetrahydrofuran in water or dichloromethane.
  • the hydrolysis of a compound of Formula XVIII to give a compound of Formula XXII can be carried out in the presence of an acid, trifluoroacetic acid or hydrochloric acid.
  • the compound of Formula XXII is condensed with a compound of Formula IV to give a compound of Formula XXI in an organic solvent, for example methanol, ethanol, dimethylformamide or tetrahydrofuran.
  • Compounds(s) prepared following Scheme II, path b are:
  • a compound of Formula XXIV can be prepared according to Scheme II thus a compound of Formula XVIII (Path c) is reacted with a compound of Formula IX to give a compound of Formula XXIII, which undergoes hydrolysis to give a compound of Formula XX1N.
  • the reaction of a compound of Formula XVIII with a compound of Formula IX to give a compound of Formula XXIII can be carried out in a organic solvent, for example acetone, dichloromethane, tetrahydrofuran, dimethylformamide or acetonitrile.
  • the reaction of a compound of Formula XVIII with a compound of Formula IX can be carried out in the presence of a base, for example sodium hydride, sodium carbonate or potassium carbonate.
  • a base for example sodium hydride, sodium carbonate or potassium carbonate.
  • the hydrolysis of a compound of Formula XXIII (when P is ethyl, methyl or benzyl) to give a compound of Formula XXIV is carried out in a solvent system, for example ethanol, dimethylformamide, dimethylsulphoxide, dioxane, tetrahydrofuran, methanol or water or combinations thereof.
  • a solvent system for example ethanol, dimethylformamide, dimethylsulphoxide, dioxane, tetrahydrofuran, methanol or water or combinations thereof.
  • XXIII (when P is ethyl, methyl or benzyl) to give a compound of Formula XXIV can be carried out in the presence of base, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • base for example, lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • P is t-butyl
  • XXVI can be carried out in an organic solvent, for example tetrahydrofuran, dimethoxyethane, diethoxyethane, methanol, dioxane or water or combination thereof.
  • the reduction of a compound of Formula XXV to give a compound of Formula XXVI through an intermediacy of a mixed anhydride can be carried out in the present of a base, for example N-methylmorpholine, pyridine, triethylamine or diisopropylethylamine with chloroformates, for example ethyl chloroformate or isobutyl chloroformate.
  • the reduction of a compound of Formula XXV to give a compound of Formula XXVI can be carried out with a reducing agent, for example sodium borohydride or sodium cyanoborohydride.
  • a reducing agent for example sodium borohydride or sodium cyanoborohydride.
  • the hydrolysis a compound of Formula XXVI (when Pi is ethyl) to give a compound of Formula XXVII can be carried out in a solvent system, for example tetrahydrofuran, methanol, dioxane, ethanol or water or combinations thereof.
  • the hydrolysis of a compound of Formula XXVI (when Pi is ethyl) to give a compound of Formula XXVII can be carried out in the presence of a base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the hydrolysis of a compound of Formula XXVI (when Pi is t-butyl) to give a compound of Formula XXVII can be carried out in an organic solvent, for example, tetrahydrofuran in water or dichloromethane.
  • the hydrolysis of a compound of Formula XXVI (when Pi is t-butyl) to give a compound of Formula XXVII can be carried out in the presence of an acid, for example, trifluoroacetic acid or hydrochloric acid.
  • Compound(s) prepared following the procedure described in Scheme III (Path a) include:
  • a compound of Formula XXVI (Path b) is reacted with a compound Rm- hal [wherein Rm is alkyl and hal is halogen (CI, Br, I)] to give a compound of Formula XXVIII and XXIX, which are further hydrolyzed to give a compound of Formula XXXIII and XXXrV.
  • the reaction of a compound of Formula XXVI with a compound Rm-hal to give a compound of Formula XXVIII and XXIX can be carried out in an organic solvent, for example tetrahydrofuran, dimethylformamide, di ethyl ether or dioxane.
  • the reaction of a compound of Formula XXVI with a compound Rm-hal to give a compound of Formula XXVIII and XXIX can be carried out in the presence of a base, for example sodium hydride or potassium tert-butoxide.
  • a base for example sodium hydride or potassium tert-butoxide.
  • a compound of Formula XXVIII and XXIX (Pi is t- butyl) can be hydrolyzed to give a compound of Formula XXXIII and XXXIV in the presence of an acid for example trifluoroacetic acid or hydrochloric acid in a solvent system, for example tetrahydrofuran in water or dichloromethane.
  • a compound of Formula XXVIII and XIX (when Pi is ethyl) can be hydrolyzed to give a compound of
  • a compound of Formula XXVI (Path c) is reacted with a compound L-hal [wherein OL is mesyl or tosyl and hal is halogen (CI, Br, I)] to give a compound of Formula XXX, which is reacted with a compound IV (wherein R 7 and R 8 are the same as defined earlier) to give a compound of Formula XXXI, which undergoes hydrolysis to give a compound of Formula XXXII.
  • a compound of Formula XXVI is reacted with a compound L-hal to give a compound of Formula XXX in an organic solvent, for example dichloromethane, dichloroethane, chloroform or carbon tetrachloride.
  • reaction of a compound of Formula XXVI with a compound L-hal to give a compound of Formula XXX can be carried out in the presence of a base, for example triethylamine, pyridine, sodium carbonate, sodium bicarbonate or diisopropylethylamine.
  • a base for example triethylamine, pyridine, sodium carbonate, sodium bicarbonate or diisopropylethylamine.
  • the reaction of a compound of Formula XXX with a compound of Formula IV to give a compound of Formula XXI can be earned out in an organic solvent, for example tetrahydrofuran, dimethylformamide, dioxane or di ethyl ether.
  • the reaction of a compound of Formula XXX with a compound of Formula IV to give a compound of Formula XXXI can be carried out in the presence of an organic base, for example diisopropylethylamine, pyridine, N-methylmorpholine or triethylamine.
  • an organic base for example diisopropylethylamine, pyridine, N-methylmorpholine or triethylamine.
  • the hydrolysis of a compound of Formula XXXI (when Pi is t-butyl) to give a compound of Formula XXXII can be carried out in a solvent, for example dichloromethane or tetrahydrofuran in water with an acid, for example trifluoroacetic acid or hydrochloric acid.
  • Formula XXXVIII A compound of Formula XXXVIII can be prepared according to Scheme IV.
  • a compound of Formula XXXV (wherein R 5 and R ⁇ are the same as defined earlier R t is H or CH 3 ) undergoes hydrolysis to give a compound of Formula XXXVI, which is reacted with a compound of Formula VII to give a compound of Formula XXXVII, which is hydrolyzed to give a compound of Formula XXXVIII.
  • a compound of Formula XXXV undergoes hydrolysis to give a compound of
  • Formula XXXVI in a solvent system for example tetrahydrofuran, methanol, dioxane, ethanol or water or combinations thereof in the presence of base, for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • base for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the reaction of a compound of Formula XXXVI with a compound of Formula VII to give a compound of Formula XXXVII can be carried out in an organic solvent for example, dimethylformamide, tetrahydrofuran, dioxane or di ethyl ether.
  • reaction of a compound of Formula XXXVI with a compound of Formula VII to give a compound of Formula XXXVII can be carried out in the presence of an organic base for example, in the presence of an organic base for example, N-methylmorpholine, triethylamine, pyridine or diisopropylethylamine.
  • the reaction of a compound of Formula XXXVI with a compound of Formula VII to give a compound of Formula XXXVII can be carried out with a condensing agent for example, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide.
  • hydrolysis of a compound of Formula XXXVII to a compound of Formula XXXVIII can be carried out in a solvent system for example, tetrahydrofuran, tetrahydrofuran, methanol, dioxane, ethanol or water or combinations thereof.
  • a solvent system for example, tetrahydrofuran, tetrahydrofuran, methanol, dioxane, ethanol or water or combinations thereof.
  • Formula XXXVII to a compound of Formula XXXVIII can be carried out in the presence of a base for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • a base for example lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • a compound of Formula XL can be prepared according to Scheme V.
  • a compound of Formula VI is condensed with a compound of Formula XXXIX to give a compound of Formula XL.
  • XXXIX to give a compound of Formula XL can be carried out in an organic solvent for example, tetrahydrofuran, dimethylformamide, dioxane or diethyl ether.
  • the condensation of a compound of Formula VI with a compound of Formula XXXIX to give a compound of Formula XL can be carried out in the presence of a base for example, N- methylmorpholine, triethylamine, pyridine or diisopropylethylamine.
  • a base for example, N- methylmorpholine, triethylamine, pyridine or diisopropylethylamine.
  • Formula XL can be carried out with condensing agents for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide.
  • condensing agents for example, l-(3- dimethylaminopropyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide.
  • Formula XL can also be carried out by a mixed anhydride reaction using chloroformates for example, ethyl chloroformate or isobutyl chloroformate.
  • chloroformates for example, ethyl chloroformate or isobutyl chloroformate.
  • the compounds(s) prepared following the procedure described in Scheme V include:
  • the reaction mixture was concentrated and the crude oil was taken in water and extracted with ethyl acetate (2x50 ml). The aqueous layer was then acidified (cone. HC1) and extracted with ethyl acetate (2x200 ml). The combined organic extracts were then washed with water and brine (100 ml) and dried over sodium sulphate. Evaporation of the solvent under vacuo furnished the title compound (8.7g crude) as a sticky solid.
  • Step 1 Synthesis of (4R, 5R)-5-(Biphenyl-2-yl-carbamoyl)-[l,3]dioxolane-4- carboxylic acid ethyl ester.
  • N-methyl-morpholine (NMM) (265 mg, 2.63 mmol) was added to the compound of Formula III (0.5 g, 2.63 mmol) in dry tetrahydrofuran (10 ml) at -15°C followed by the addition of ethyl chloroformate (285 mg, 2.63 mmol).
  • the reaction mixture was stirred at the same temperature for 30 min. and then 2-aminobiphenyl (444 mg, 2.63 mmol) and p- toluenesulfonic acid (49 mg, 0.263 mmol) were added.
  • the reaction mixture was stirred at -10°C for 30 min. followed by stirring at 0°C for 2 hour and then at room temperature overnight.
  • the reaction was quenched with water and extracted the compound with ethyl acetate (2x25 ml).
  • the combined organic extract was washed with brine and dried over sodium sulphate and concentrated to obtain the crude residue.
  • the residue was then purified over a silica gel column using 30% ethyl acetate hexane as eluent to obtain the title compound (0.6 gm, 67%) as a light yellow solid.
  • Step 2 Synthesis of (4R, 5R)-5-(Biphenyl-2-ylcarbamoyl)-[l,3]dioxolane-4-carboxylic acid.
  • Step 3 Synthesis of Methyl (S)-2- ⁇ [(4R, 5R)-5-(Biphenyl-2-yl-carbamoyl)- [l,3]dioxolane-4-carbonyI]-amino ⁇ -3-(4-nitro phenyl)-propionate.
  • reaction mixture was taken into water (50 ml) and organic compound was extracted with ethyl acetate (2x50 ml). The combined organic layer was washed with water and brine and dried over sodium sulphate (anhydrous). Evaporation of the solvent followed by purification of the residue over a silica gel column using 2.5% methanol dichloromethane as eluent furnished the title compound (1.78 g, 73%) as a solid.
  • Step 4 Synthesis of Methyl (S)-3-(4-amino-phenyl)-2- ⁇ [(4R, 5R)-5-(biphenyI-2- ylcarbamoyl)-[l,3]dioxolane-4-carbonyl]-amino ⁇ -propionate.
  • Step 5 Synthesis of Methyl (S)-2- ⁇ [((4R, 5R)-5-biphenyl-2-ylcarbamoyl)- [l,3]dioxolane-4-carbonyl]-amino ⁇ -3- ⁇ 4-[(pyridine-4-carbonyl)-amino]-phenyl ⁇ - propionate.
  • the aniline obtained from step 4 above (150 mg, 0.31 mmol) in dry dimethyl formamide (2.5 ml) was coupled to isonicotinic acid (37 mg, 0.31 mmol) following the conditions as used for step 3 above, using hydroxybenzotriazole (45 mg, 0.33 mmol), N- methylmorpholine (35 mg, 0.35 mmol) and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC. ⁇ C1)(60 mg, 0.32 mmol) to furnish the title compound (110 mg, 61%) as a solid after column purification over silica gel.
  • hydroxybenzotriazole 45 mg, 0.33 mmol
  • N- methylmorpholine 35 mg, 0.35 mmol
  • l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC. ⁇ C1)(60 mg, 0.32 mmol)
  • Step 6 Synthesis of (S)-2- ⁇ [(4R, 5R)-5-(Biphenyl-2-yl-carbamoyl)-[l,3]dioxolane-4- carbonyl]-amino ⁇ -3- ⁇ 4-[(pyridine-4-carbonyl)-amino]-phenyl ⁇ -propionic acid.
  • step 5 above The compound obtained from step 5 above (104 mg, 0.1 mmol) was subjected to basic hydrolysis using lithium hydroxide monohydrate (7.6 mg, 0.18 mmol) following the procedure as described in step 2 above furnished after acidic workup the title compound
  • Step 1 Synthesis of Benzyl (S)-2- ⁇ [(4R, 5R)-5-(biphenyl-2-yl-carbamoyl)- [l,3]dioxoIane-4-carbonyl]-amino ⁇ -3-(4-hydroxy-phenyl)-propionate.
  • Step 2 Synthesis of Benzyl (S)-2- ⁇ [(4R,5R)-5-(biphenyl-2-yl-carbamoyl)- [l,3]dioxolane-4-carbonyl]-amino ⁇ -3-[4-(2,6-dichloro-benzyloxy)-phenyl]-propionate Potassium carbonate (98 mg, 0.71 mmol) and 2,6-dichlorobenzyl bromide (93 mg, 0.39 mmol) was added to the phenol obtained from step 1 above (200 mg, 0.35 mmol) in dry acetone (5 ml) and the mixture was refluxed for 5.6 hour.
  • Step 3 Synthesis of (S)-2- ⁇ [(4R, 5R)-5-(Biphenyl-2-yl-carbamoyl)-[l,3]dioxolane-4- carbonyl]-amino ⁇ -3-[4-(2,6-dichloro-benzyloxy)-phenyl]-propionic acid
  • Lithium hydroxide monohydrate (25 mg, 0.59 mmol) was added to the ester obtained from step 2 above (210 mg, 9.29 mmol) and following the general procedure as outlined in
  • Example 2 the title compound was obtained (140 mg, 76%) as a yellow sticky solid.
  • Morpholine-4-carboxylic acid 4-((S)-2- ⁇ [(4R,5R)-5-(biphenyl-2-yl-carbamoy ⁇ )- [1 ,3]dioxolane-4-carbonyl]-amino ⁇ -2-carboxy-ethyl)-phenyl ester (Compound No. 15)
  • Step a Synthesis of (4R,5R)-5-(bis-thiophen-2-ylmethyl-carbamoyl)-[l,3]dioxolane-4- carboxylic acid ethyl ester.
  • N-methyl morpholine (1.06 g) and stirred the reaction mixture for 10 minutes at the same temperature.
  • ethyl chloroformate (0.57 g) and stirred the reaction mixture for 20 minutes followed by the addition of p-toluene sulphonic acid (95 mg) and bis-thiophene-2-ylmethyl amine (1.29 g).
  • the reaction mixture was stirred for 30 minutes at -20°C for 30 minutes followed by stirring at 0°C for 3 hours and subsequently overnight at room temperature.
  • the reaction mixture was diluted with ethyl acetate and water.
  • the organic layer was washed with water & brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (22.5 g).
  • Step b Synthesis of (4R,5R)-5-(bis-thiophen-2-ylmethyl-carbamoyl)-[l,3]dioxolane- 4-carboxylic acid
  • lithium hydroxide monohydrate 124 mg
  • the reaction mixture was concentrated under reduced pressure.
  • the residue thus obtained was taken in water and acidified with concentrated hydrochloric acid.
  • the organic layer was extracted with ethyl acetate, washed with water and brine. The organic layer was concentrated under reduced pressure to furnish the title compound (440 mg).
  • Step c Synthesis of (S)-2- ⁇ [(4R,5R)-5-(bis-thiophen-2-ylmethyl-carbamoyl)-[l,3] dioxolane-4-carbonyl]-amino ⁇ -3-[4-(2,6-dichIoro-benzyloxy)-phenyl]propionic acid methyl ester.
  • the reaction mixture was warmed to room temperature, diluted with water and ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure to furnish the title compound (145 mg).
  • Step d Synthesis of (S)-2- ⁇ [(4R,5R)-5-(Bis-thiophen-2-ylmethyl-carbamoyl)- [l,3]dioxolane-4-carbonyI]-amino ⁇ -3-[4-(2,6-dichloro-benzyloxy)-phenyl]-propionic acid (Compound No. 88)
  • Step a Synthesis of (4R,5R)-5-(2,6-diethyl-phenylcarbamoyl)-[l,3]dioxolane-4- carboxylic acid ethyl ester.
  • the solution of the compound (4R,5R)-[l,3]dioxolane-4,5-dicarboxylic acid monoethyl ester (1 g) (Formula III) in thionyl chloride (10 ml) was refluxed at 80°C for 1 hour. The excess of thionyl chloride was removed under reduced pressure and the residue thus obtained was taken into xylene (10ml).
  • Step b Synthesis of (4R,5R)-5-(2,6-diethyl-phenyIcarbamoyI)-[l,3]-dioxolane-4- carboxylic acid.
  • Step c Synthesis of (S)-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2- ⁇ [(4R,5R)-5-(2,6- diethyI-phenylcarbamoyl)-[l,3]-dioxolane-4-carbonyl]-amino ⁇ -propionic acid ethyl ester.
  • reaction mixture was stirred at 0°C for 30 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (162 mg) and stirred the reaction mixture it room temperature for overnight.
  • the reaction mixture was quenched with water and extracted with ethyl acetate.
  • the organic layer was separated, dried over anhydrous sodium sulphate and concentrated.
  • the residue thus obtained was purified by column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound (210 mg).
  • Step d Synthesis of (S)-3-[4-(2,6-DichIoro-benzyloxy)-phenyl]-2- ⁇ [(4R,5R)-5-(2,6- diethyl-phenylcarbamoyl)-[l,3]dioxoIane-4-carbonyl]-amino ⁇ -propionic acid (Compound No. 90)
  • Stepl Synthesis of (4R,5R)- ⁇ lS-tert-butoxycarbonyl-2-[4-(2,6-dichloro-benzyloxy)- phenyl]-ethyl-carbamoyl ⁇ -[l,3]dioxolane-4-carboxylic acid ethyl ester
  • O-(2,6-dichloro-benzyl)-L-tyrosine-t-butyl ester (430 mg, 1.08 mmol) was added to the compound of Formula III (20.6 mg, 1.08 mmol) in dry dimethylformamide (5 ml) under stirring.
  • the reaction mixture was cooled to 0°C and then N-methylmorpholine (109 mg, 1.08 mmol) and hydroxybenzotriazole (146 mg, 1.08 mmol) were added and the mixture was stirred for 20 minutes.
  • To the mixture was then added l-(3-dimethylaminopropyl)-3- ethyl carbodiimide hydrochloride (EDC.HCl) (206 mg, 1.08 mmol) under stirring.
  • Step 2 Synthesis of S-(4R,5R)-5- ⁇ lS-tert-butoxy-carbamoyl-2-[4-(2,6-di-chloro- benzyIoxy)-phenyl]-ethylcarbamoyl]-[l,3]dioxolane-4-carboxylic acid
  • Lithium hydroxide monohydrate (26 mg, 0.62 mmol) was added to the ethyl ester obtained from Step 1 above (350 mg, 0.62 mmol) in tetrahydrofuran: water: methanol (3:1:1 ml), was added and the reaction mixture was stirred at room temperature for 2 hours. The solvents were evaporated; the residue was taken into water and extracted the organic layer with ethyl acetate. The aqueous layer was then acidified with saturated aqueous sodium bisulphate solution and then extracted with ethyl acetate (3x20 ml). The combined organic extract was washed with brine and dried over sodium sulphate and concentrated to obtain the title compound as a white solid (330 mg).
  • Step 3 Synthesis of (S)-3-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2- ⁇ [(4R,5R)-5-(4- methyl-piperazine-l-carbonyl)-[l,3]dioxolane-4-carbonyl]-amino ⁇ -propionic acid tert-butyl ester N-methylpiperazine (57 mg, 0.57 mmol), N-methylmorpholine (58 mg, 0.58 mmol) and hydroxybenzotriazole (78 mg, 0.58 mmol) was added to the acid obtained from Step 2 above (310 mg, 0.57 mmol) in dry dimethyl formamide (5 ml) at 0°C.
  • Step 4 Synthesis of (S)-3- ⁇ 4-(2,6-Dichloro-benzyloxy)-phenyl-2- ⁇ [(4R,5R)-5-(4- methyl-piperazine-l-carbamoyl)-[l,3]dioxolane-4-cabonyl]-amino ⁇ -propionic acid trifluoroacetic acid salt
  • Step a Synthesis of (4R,5R)-5-[(S)-l-benzyloxycarbonyl-2-(4-hydroxy-phenyl)- ethylcarbamoyl]-[l,3]dioxolane-4-carboxy!ic acid ethyl ester
  • Step b Synthesis of (4R,5R)-5- ⁇ (S)-l-benzyloxy carbonyl-2-[4-(2,6-dichloro- benzyloxy)-phenyl]-ethylcarbamoyl-[l,3]dioxolane-4-carboxylic acid ethyl ester
  • Step c Synthesis of (4R,5R)-5- ⁇ (S)-l-carboxy-2-[4-(2,6-dichlorobenzyloxy)-phenyl]- ethylcarbamoyl ⁇ -[l,3]dioxolane-4-carboxylic acid (Compound No. 35)
  • Step a Synthesis of (4R,5R)-5- ⁇ (S)-l-tert-butoxycarbenyl-2-[4-(2,6-dichloro- benzyloxy)-phenyl]-ethylcarbamoyl ⁇ -[l,3]dioxolane-4-carboxylic acid ethyl ester
  • Step b Synthesis of (4R,5R)-5- ⁇ (S)-l-carboxy-2-[4-(2,6-dichloro-benzyloxy)- phenyl)ethylcarbamoyl]-[l,3]dioxolane-4-carboxylic acid ethyl ester (Compound No. 46)
  • Step a Synthesis of (S)-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-[((4R,5S)-5-hydroxy methyl-[l,3]dioxolane-4-carbonyl)-amino]-propionic acid tert butyl ester
  • N-methylmorpholine hydrochloride salt 51 mg
  • isobutyl chloroformate 70 mg
  • N-methylmorpholine was removed by filtration, washed with 1,2-dimethoxyethane (10 ml) and the filtrate was cooled to -10°C.
  • a solution of sodium borohydride in water (2 ml) followed by the addition of water and extracted with ethyl acetate.
  • the organic layer was concentrated under reduced pressure and the residue thus obtained was purified by column chromatography using 50% ethyl acetate in hexane to furnish the title compound (180 mg).
  • Step b Synthesis of (S)-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-[((4R,5S)-5- hydroxymethyl-[l,3]dioxolane-4-carbonyl)-amino]-propionic acid
  • Step a Synthesis of (S)-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-[((4R,5S)-5-methoxy methyI-[l,3]dioxolane-4-carbonyl)-amino]-propionic acid tert butyl ester and (S)-3- [4-(2,6-dichloro-benzyloxy)-phenyl]-2-[((4R,5S)-5-methoxymethyl-[l,3]dioxoIane-4- carbonyl)-methyI-amino]-propionic acid tert-butyl ester
  • Step b Synthesis of (S)-3-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2-[((4R,5S)-5- methoxymethyl-[l,3]dioxolane-4-carbonyl)-methyI-amino]-propionic acid (Compound No. 126)
  • dichloromethane 1 ml
  • trifluoro acetic acid 1 ml
  • Step a (S)-3-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2-[((4R,5S)-5-methoxymethyl- [1, 3] dioxolane-4-carbonyl)-amino] -propionic acid (Compound No.
  • Example 12 Trifluoroacetate salt of (S)-3-[4-(2,6-Dichlorobezyloxy)-phenyl]-2- r((4R,5S)-5-pyrrolidin- 1 -ylmethyl-[ 1 ,3]Dioxolane-4-carbonyl)-amino]-propionic acid (Compound No. 146)
  • Step a Synthesis of (S)-3-[4-(2,6-dichloro-benzyIoxy)-phenyl]-2-[((4R,5S)-5-methane sulphonyloxymethyI-[l,3]-dioxolane-4-carbonyl amino]-propionic acid tert-butyl ester
  • step a Example 9
  • methanesulphonyl chloride 43.6 mg, 0.06 ml
  • triethylamine 0.051 ml
  • Step b Synthesis of (S)-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-[((4R,5S)-5- pyrrolidin-l-yloxymethyl)-[l,3]-dioxolane-4-carbonyl]-amino ⁇ -propionic acid tert- butyl ester.
  • Step c Synthesis of triflate salt of l-((4S,5R)- ⁇ (S)-l-Carboxy-2-[4-(2,6-dichloro- benzyloxy)-phenyI]-ethylcarbomoyl ⁇ -[l,3]dioxolane-4-ylmethyl)-pyrrolidinum
  • Example 13 (SV3-r4-(2.6-Dichloro-benzyloxy -phenyll-2-r((S)-2,2-dimethyl- ⁇ .31 dioxolane-4-carbonyl)-amino]-propionic acid (Compound No. 122)
  • Step a Synthesis of lithium salt (S)-2,2-dmethyl-[l,3]dioxoIane-4-carboxylic acid To a solution of (S)-2,2-dimethyl-[l,3]dioxolane-4-carboxylic acid methyl ester
  • Step b Synthesis of (S)-3-[4-(2,6-Dichloro-benzyIoxy)-phenyl]-2-[((S)-2,2-dimethyl- [l,3]dioxo!ane-4-carbonyI)-amino]-propionic acid ethyl ester
  • Step c Synthesis of (S)-3-[4-(2,6-Dichloro-benzyloxy)-phenyl]-2-[((S)-2,2-dimethyl- [l,3]dioxolane-4-carbonyl)-amino]-propionic acid ethyl ester (Compound No.
  • Example 14 (4R,5R)-[l,3]Dioxolane-4,5-dicarboxylic acid 4-(((S)-l-carbamoyl-2-[4- (2,6-dichloro-benzyloxy)-phenyl1-ethyl)-amino)-5-[(2-chloro-phenyl)-amide (Compound No. 118)
  • VCAM-1 (lOOng/well) was coated in Maxisorp microtitre modules at 4°C overnight. Non-specific blocking was carried out with 3% BSA for two hours and the wells washed with TBS (50mM) Tris, 0.15M NaCI pH 7.4, O.lmM CaCl , O.lmM MgCl 2 ). U937 cells were suspended in fresh medium and incubated at 37°C for two hours before the assay. Cells were then washed in TBS solution and 180 ⁇ l of cell suspension (lxl 0 6 cells/ml in TBS buffer) was added per well in VCAM-1 coated wells.
  • Compounds of this invention tested for activity have shown activities following this assay in the range of from about 100 nM to about 100 ⁇ M, for example, from about 100 nM to 10 ⁇ M, or from about 100 nM to about 3 ⁇ M, or from about 100 nM to about 1 ⁇ M.
  • the compounds disclosed herein for utility for the treatment of asthma and the symptoms of asthma, as well as for the treatment of multiple sclerosis, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease, and other cell adhesion - associated diseases and conditions and relief from the symptoms thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Dérivés de dioxolane comme inhibiteurs de l'adhésion cellulaire. Ces composés sont utiles pour inhiber et prévenir l'adhésion cellulaire et les états pathologiques induits par l'adhésion cellulaire, y compris des maladies inflammatoires et auto-immunes telles que l'asthme bronchique, la polyarthrite rhumatoïde, le diabète de type I, la sclérose en plaques, le rejet d'allogreffes ou le psoriasis. L'invention concerne également des compositions pharmacologiques qui contiennent les composés décrits et des méthodes de traitement de l'asthme bronchique, de la polyarthrite rhumatoïde, de la sclérose en plaques, du diabète de type I, du psoriasis, du rejet d'allogreffes et d'autres maladies inflammatoires et/ou auto-immunes au moyen de ces composés.
EP04769418A 2003-09-17 2004-09-17 Derives de dioxolane comme inhibiteurs de l'adhesion cellulaire Withdrawn EP1668007A1 (fr)

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DE3813416A1 (de) * 1988-04-21 1989-11-02 Hoechst Ag 3,4-dihydroxypyrrolidin-2-on-derivate, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung sowie die bei der herstellung anfallenden neuen zwischenprodukte
WO1991009851A1 (fr) * 1989-12-27 1991-07-11 Japan Tobacco Inc. Derive d'oxyde de 1,3,2-dioxathiolane
US5827868A (en) * 1991-10-07 1998-10-27 E. R. Squibb & Sons, Inc. Prostaglandin analogs
JPH06199831A (ja) * 1992-12-28 1994-07-19 Japan Tobacco Inc 血小板凝集抑制活性を有する新規１，３，２−ジオキサチオラン オキシド誘導体及びその中間体化合物
JPH07228549A (ja) * 1994-02-17 1995-08-29 Japan Tobacco Inc 新規な４−アリール−２，３−ジヒドロキシ酪酸誘導体及びその製造方法
WO2001012183A1 (fr) * 1999-08-16 2001-02-22 Merck & Co., Inc. Amides heterocycles comme inhibiteurs de l'adhesion cellulaire

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