MXPA00012765A - INHIBITORS OF alpha4. - Google Patents

INHIBITORS OF alpha4.

Info

Publication number
MXPA00012765A
MXPA00012765A MXPA00012765A MXPA00012765A MXPA00012765A MX PA00012765 A MXPA00012765 A MX PA00012765A MX PA00012765 A MXPA00012765 A MX PA00012765A MX PA00012765 A MXPA00012765 A MX PA00012765A MX PA00012765 A MXPA00012765 A MX PA00012765A
Authority
MX
Mexico
Prior art keywords
carbon atoms
alkyl
hydrogen
carbon
equal
Prior art date
Application number
MXPA00012765A
Other languages
Spanish (es)
Inventor
Thomas J Lobl
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of MXPA00012765A publication Critical patent/MXPA00012765A/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
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    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
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    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
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    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom 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
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
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    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

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Abstract

The present invention relates to compound of formula (I), that are potent inhibitors of alpha4beta1 mediated adhesion to either VCAM or CS-1 and which could be useful for the treatment of inflammatory diseases. Specifically, the molecules of the present invention can be used for treating or preventing alpha4beta1 adhesion mediated conditions in a mammal such as a human. This method may comprise administering to a mammal or a human patient an effective amount of the compound or composition as explained in the present specification.

Description

INHIBITORS OF CELLULAR ADHESION MEDIATED BY o. "ß, BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to small molecules that are potential inhibitors of T jß-L mediated adhesion to either VCAM or CS-1 and which are useful for the treatment of inflammatory diseases. Description of the Prior Art The extracellular matrix (ECM) is the major component of the connective tissue that provides structural integrity, and promotes cell migration and differentiation. As part of these functions, it has been shown that extracellular matrix molecules such as fibronectin, collagen, laminin, von Willebrand factor, thrombospondin, fibrinogen, and tenascin support cell adhesion in vi tro. Adhesive interaction is critical for several biological processes including hemostasis, thrombosis, wound healing, tumor metastasis, immunity and inflammation. Fibronectin (FN) is the prototype extracellular matrix molecule. The largest cell binding site in the fibronectin molecule has been synthetically reproduced with the amino acid sequence of arginine-glycine-aspartic acid, or RGD using the single-letter nomenclature. The peptides containing the RGD sequence that either inhibits or promotes cell adhesion have been described (US Patent Nos. 4,589,881, 4,661,111, 4,517,686, 4,683,291, 4,578,079, 4,614,517, and 4,792,525). Changes in the peptide as small as the exchange of alanine for glycine or glutamic acid for aspartic acid, which constitute the addition of a single methyl or methylene group to the tripeptide, eliminate these activities (Pierschbacher et al., Proc. Nati. Acad. Sci. USA. 81: 5985 (1984)). Recently, a second fibronectin cell-binding domain has been identified within the region alternatively, i separated from the A chain of the molecule, known-as the connection segment 1 (CS-1). The most active cell binding site within this alternative separate region is composed of 25 amino acids where the term carboxy contains the sequence EILDVPST. The amino acid sequence EILDVPST forms a recognition motif of fibronectin for the superficial receptors of cells. (Wayner et al., J. Cell Biol. 109: 1321 (1989); Guan et al., Cell £ 0: 53 (1990)). a The receptors that recognize these fibronectin sites belong to the superfamily of genes called integrins that consist of heterodimeric complexes of non-covalently associated alpha and beta subunits. A common β subunit is combined with unique subunits I to form an adhesion receptor of defined specificity.
To date, eight ß subunits have been identified that can be dimerized with 16 different I subunits that form 22 different integrins. The ßl subfamily, also known as the VLA family (very late activation antigens), binds I to the extracellular matrix molecules such as fibrin, collagen, and laminin.The interaction of leukocytes with fibrin in the two spatially separated bonding domains are mediated by two distinct integrins.The RGD site is recognized by the CL5 $ X integrin, while EILDV is recognized by the integrin. (Pytela et al., Cell 40.:191 (1985 ), Wayner and collaborators, ".
Cell Biol. 109: 1321 (1989); Guan et al., Cell 60: 53 (1990) ) . Vascular endothelial cells form the interface between blood and tissues and control the passage of leukocytes as well as plasma fluid in tissues. A -. The variety of signals generated at the site of inflammation can activate both the endothelial cells and circulating leukocytes so that they become more adhesive with each other. Following this initial adhesion the leukocytes migrate to the tissues to perform host defense functions.
Several adhesion molecules have been identified that participate in the leukocyte-endothelium interactions. In the ßl t subfamily in addition to binding with fibronectin, a4β1 interacts with a cytokine-induced protein in endothelial cells called the vascular cell adhesion molecule (VCAM). Also involved in the leukocyte-endothelium adhesion process is the subfamily of β2 integrin. The β2 integrins include CDlla / CD18, CDllb / CD18, and CDllc / CD18. In addition, the β7 subunit associates with a4 to form a unique heterodimer oi4ß7 that binds with fibronectin, with VCAM, and with the cell adhesion molecule Adresina Mucosal-1 (MAdCAM) (Ruegg et al., "Cell.
Biol. 117: 179 (1992); Andrew and collaborators, J. Iixtmunol. 153: 3847 (1994); Briskin et al., Nature 363: 461 (1993); Shyjan et al., J. Immunol. 156: 2851 (1996).
C.4 integrins are widely expressed in different cell types including hematopoietic progenitors, lymphocytes, natural killer cells, monocytes, eosinophils, basophils, and mast cells (Helmer, ME, Annu, Rev. Immunol ._ __: 365 (1990) ). Other endothelial cell molecules that bind to leukocytes include ICAM-1, ICAM-2, E-selectin and P-selectin (Carlos and Harlan, Immunol Rev. 114: 1 (1990); Osborn, L., Cell 6J2 3 (1990), Springer T., Nature 346: 425 (1990), Geng et al., Nature 347: 757 (1990), Stoolman, Cell 56: 907 (1989)). Several in vi tro and live studies indicate that o.4ß_ 1 represents a critical role in the pathogenesis of a variety of diseases. Monoclonal antibodies directed against a4 have been tested in a variety of disease models.
Anti-a4 antibodies block the adhesion of lymphocytes with synovial endothelial cells; this adhesion represents a potential role in rheumatoid arthritis (van Dinther-Janssen et al, J. "Im unol. 142: 4207 (1991)) .4 a4 has also been implicated with respect to rheumatoid arthritis in separate studies (Laffon et al. , J. "Clin. Invest. 88.:546 (1991); Morales-Ducret et al.,". Immunol. 149: 1424 (1992).) A significant number of studies have evaluated the role of OI4 in allergy and asthma. For example, monoclonal antibodies to o4 block adhesion of basophils and eosinophils to endothelial cells activated with cytokine (Walsh et al., J. Immunol., 146: 3419 (1991), Bochner et al., J. Exp. Med. 173: 1553 (1991)). C44 monoclonal antibodies were also effective in several models of lung antigen stimuli (Abraham et al., J. Clin.Invest.J_3.:776 (1994); Weg et al., J. "Exp. Med. 177 : 561 (1993).) The cotton surface marmoset, which undergoes spontaneous chronic colitis, showed significant attenuation of its colitis when anti-c.4 antibody was administered (Podolsky et al., J., Clin. Invest. 92: 372 (1993), Bell et al., J ". Immunol., 151: 4790 (1993).) In a rat and mouse model, autoimmune encephalomyelitis was blocked by anti-4 antibody (Yednock et al., Nature 356: 63 (1992), Barón et al., J. Exp. Med. 177: 57 (1993).) Anti-or4 monoclonal antibodies also inhibit insulitis and delay the onset of diabetes in obese diabetic mice (Barón et al., J ". Clin. Invest. 93 .: 1700 (1994)). a4 is also involved in atherosclerosis due to its endothelial expression during atherogenesis (Cybulsky et al., Science 251: 788 (1991)). The migration of leukocytes to an inflammatory site can also be blocked by anti-a4 antibodies. In addition to blocking migration, leukocyte endothelial adhesion inhibitors can block integrin-mediated costimulatory signals and thereby inhibit the overproduction of inflammatory cytokines. In a separate set of experiments that do not use anti-c.4 antibodies, the GRDGSP or EILDV peptides were tested against the contact hypersensitivity response. The contact hypersensitivity response was found to be blocked by GRDGSP or EILDV suggesting that both o.4ß_ and o-sßi are participating in this inflammatory response. Other diseases that may involve conditions mediated by a4 x include the inflammatory disorders of rheumatoid arthritis, allergic disorders, asthma, chronic spontaneous colitis, insulitis, hypersensitivity response to contact, atherosclerosis and autoimmune encephalomyelitis. These studies illustrate that small molecules that are potent inhibitors of a4βx mediate adhesion to either VCA-1 or CS-1 can be used as a form of treatment in numerous inflammatory diseases. However, these inflammatory conditions could be extended to include adult respiratory distress syndrome, AIDS, cardiovascular disease, thrombosis or aggregation of harmful platelets, reocclusion following thrombolysis, allograft rejection, reperfusion injury, psoriasis, eczema, contact dermatitis and other inflammatory skin diseases, osteoporosis, osteoarthritis, atherosclerosis, neoplastic diseases including neoplastic or cancerous growth metastases, increased wound healing, treatment of certain diseases of the eyes such as retinal detachment, Type I diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), inflammatory and immunoinflammatory conditions including ophthalmic inflammatory conditions and inflammatory bowel diseases, ulcerative colitis, regional enteritis and other autoimmune diseases. In accordance with the foregoing, a compound which could inhibit these conditions is desired.
SUMMARY OF THE INVENTION The present invention particularly provides: A compound of the formula: displaying from one to four times and in each occurrence is independently hydrogen or alkyl having from 1 to 6 carbon atoms. Also in the above formula (I), R 2 is hydrogen, pyridyl, alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-R 11 (or -C0 2 -Ru. and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they can be attached to the same carbon atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached. In the above formula (I), R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-Rlx, (alkenyl having from 2 to 6 carbon atoms) -C02-Rllf (alkyl having from 1 to 6 carbon atoms) -CO-alkyl having from 1 to 6 carbon atoms (alkyl with 1 to 6 carbon atoms) -O-alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 carbon atoms) -OH, (alkyl with 1 to 6 atoms) carbon) -CN, adamantyl or one of the following: C,,) 2 In addition, R2 and R3- (Y) 0- may be combined together at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: In the above formula (I) R4 is -0-Ru, NH2, NHOH, -0- (arylalkyl with 7 to 10 carbon atoms), or is of the formula: -O-CH .- ^ ¿* t. In the previous formula (I), R5 is a formula of the following: - In the above, R6 is N or CH, R7 is hydrogen or halogen, R8 is -H-Yi-, -OCH2-, O -CONH-, R9 can occur from one to three times and is a halogen, alkoxy with from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl having from 1 to 6 carbon atoms, or (alkyl having from 1 to 6 carbon atoms) -OH, or hydrogen, RX1 is hydrogen or alkyl having from 1 to 6 carbon atoms, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: and R13 is N or CH. In the previous formula (I), W is (alkyl with 1 to 6 carbon atoms), X is S, O, or CH2, Y and Y. are independently -CO-, -C (= 0) 0-, -S02-, or -C (= 0) N (R10) - and Z is O, CH2, or N-RX1. In the above, l is l, 2 or 3, 21. is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3.
The above formula (I) has the conditions that: (1) when Y is -C (= 0) 0-, R3 can not be hydrogen; (2) when R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not the same as terbuyl; (3) in the pyrrolidine structures (2 is 1, m is 2, n is 0, or is 0, p is 1, X is CH2), W is equal to CH2; Y (4) The compound is not . * In another embodiment of the present invention, R5 is a formula of the following: wherein R is hydrogen or Cl. In another embodiment of the present invention, R 2 is hydrogen or alkyl having from 1 to 6 carbon atoms.
Additionally, Rx and R2 can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or attached to the same carbon atom and form a ring of carbon. 8 atoms of the formula: together with the carbon atom to which they are attached. Also, in this embodiment, n is 0, m is 2 and p is 0. In yet another embodiment of the invention, R x is hydrogen or alkyl having from 1 to 3 carbon atoms, and R 2 is hydrogen or alkyl having from 1 to 4 carbon atoms. Additionally, R-. and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or bound to the same atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached. Also in this embodiment, R3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl from 1 to 6) carbon atoms) -C02-Rlx, (alkyl having 1 to 6 carbon atoms) -CN, adamantyl, phenyl, or one of the following: ): Additionally, in this embodiment, R4 is -0-Rlx, NH2 NHOH, or R4 is of the formula: RX1 is hydrogen or CH3, and X is S or O. In another embodiment, Rx and R2 are hydrogen, and R3 is (alkenyl with 2 to 6 carbon atoms) -C02-R1: L, (alkyl with 1 to 6 carbon atoms) -O-alkyl with 1 to 3 carbon atoms, (alkyl with 1 to 6 atoms carbon) -COaR .., or one of the following: Also, in this embodiment, R4 is 0-Rn, R6 is CH, RX1 is hydrogen. Additionally, X is S, Y is -CO-, and 2 is 1. In another embodiment of the present invention, R? and R2 are hydrogen, and R3 is alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 carbon atoms) -C02-R11 # (alkenyl with 2 to 6 carbon atoms) -C02-Rllf ( alkyl having from 1 to 6 carbon atoms) -CO-alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -O-alkyl having from 1 to 3 carbon atoms, (alkyl) with 1 to 6 carbon atoms) -CN, or one of the following: Additionally, R4 is OH, R6 is CH, R1x is hydrogen, R7 is hydrogen, X is CH2 / and Y is CO- or -C (= 0) NH-. In another embodiment of the present invention, W is (alkyl having from 1 to 3 carbon atoms), X is CH2, Y is -C (= 0) 0-, Rx is hydrogen, R2 is hydrogen, (alkyl with 1 to 3 carbon atoms) -C02-Rn, or -C02-Rn, R3 is hydrogen, arylalkyl with 7 to 10 carbon atoms, alkyl with 1 to 6 carbon atoms, or (alkyl with 1 to 6 atoms carbon) -C02-Rxl, R4 is OH, R6 is CH, RX1 is hydrogen, R7 is hydrogen, 2 is 1 or 3, and n is O. In another embodiment of the present invention, W is alkyl with 1 to 3 carbon atoms, X is CH2, Rx is hydrogen, R2 is (alkyl having 1 to 4 carbon atoms) -C02-Rla, or C02-Ru, R3 is hydrogen, alkyl having from 1 to 3 carbon atoms, or alkenyl with 2 to 7 carbon atoms, R4 is OH, R6 is CH, RX1 is hydrogen, R7 is hydrogen, 2 is 1, m is 1, n is 1, or is 0 and p is 1. In another embodiment, the The compound of the present invention is represented by the following formula In another embodiment of the present invention, Rx and R2 are hydrogen, and R3 is alkyl with 1 to 6 carbon atoms, (alkyl having 1 to 6 carbon atoms) -C02R?: L, (alkenyl with 2 to 6 carbon atoms) -CO ^ n, (alkyl having 1 to 6 carbon atoms) -O-alkyl having from 1 to 3 carbon atoms, or one of the following: Additionally, in this embodiment, R4 is 0-Rn, R6 is CH, RL1 is hydrogen or alkyl with 1 to 6 carbon atoms, R7 is hydrogen, X is S, Y is -C (= 0) 0-, and 2 is 1. In another embodiment of the present invention, R. is hydrogen or alkyl having from 1 to 3 carbon atoms and R2 is hydrogen or alkyl having from 1 to 4 carbon atoms. Additionally, Rx and R2 can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms, or can be attached to the same atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached. In this embodiment, R 3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 atoms) carbon) -CO.-Rp, (alkyl having 1 to 6 carbon atoms) -CN, adamantyl, phenyl or one of the following: N (Alkyl C,,), Additionally / in this embodiment, R4 is -0-R, NH2, NHOH, or R4 is of the formula Also, RX1 is hydrogen or alkyl having from 1 to 6 carbon atoms, and X is S or O. In still another embodiment, the compound of the present invention is represented by the following formula (I-a): In the above formula (I -a), R_ can occur from one to four times and each occurrence is independently hydrogen or alkyl having from 1 to 6 carbon atoms, and R2 is hydrogen, pyridyl, alkyl having from 1 to 6 carbon atoms. carbon (alkyl having 1 to 6 carbon atoms) -C02-Rlx, or -C02-Rlx. Additionally, Rx and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they can be attached to the same carbon atom and form a ring of 8 atoms of the FORMULA: / (CH2) / C NR, together with the carbon atom to which they are attached. Additionally, in this embodiment, R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 atoms carbon) -C02-R__, (alkenyl with 2 to 6 carbon atoms) -C02-Rn, (alkyl with 1 to 6 carbon atoms) -CO-alkyl with 1 to 6 carbon atoms, (alkyl) with 1 to 6 carbon atoms) -O-alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 carbon atoms) -OH, (alkyl with 1 to 6 carbon atoms) -CN, adamantil and one of the following: In addition, R2 and R3- (Y) 0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: Additionally, R4 is -0-Ru, NH2, NHOH, -0- (arylalkyl with 7 to 10 carbon atoms) or is of the formula: Also, in this modality, R5 is a formula of the following: Additionally, in this embodiment, R6 is N or CH, R7 is hydrogen or halogen, R8 is -NH-YÍ-, -OCH2-, O -CONH-, R9 can occur from one to three times and is a halogen, alkoxy with from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl having from 1 to 6 carbon atoms, or (alkyl having from 1 to 6 carbon atoms) -OH, or hydrogen, R p is hydrogen or alkyl having from 1 to 6 carbon atoms, R 12 is alkyl having from 1 to 6 carbon atoms or the following formula: R13 is N or CH, W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Yx are independently -CO-, -C (= 0) 0-, -S02- , or -C (= O) N (R10) -, Z is O, CH2, or N-Rn, 2 is 1, 2 or 3, in is 1 or 2, n is 0 or 1, or is 0 or 1 , p is 0 or 1, q is 0 or 1 and r is 0, 1, 2 or 3. This particular embodiment of the present invention has the conditions that (1) when Y is -C (= 0) 0-, R3 it can not be hydrogen; (2) when R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to terbutyl; (3) in the pyrrolidine structures (2 is 1, m is 2, n is 0, or is 0, p is 1, X is CH2), W is equal to CH2; (4) the compound has an IC50 value of less than 5 μM in Jurkat CS-1 assay and / or an IC50 value of less than 50 μM in a Jurka EC assay; and (5) the compound is not In yet another embodiment of the formula compound (I), Rx can be presented one to four times and each occurrence is independently hydrogen or alkyl with 1 to 6 carbon atoms. Also, R2 is hydrogen, pyridyl, alkyl having 1 to 6 carbon atoms, (alkyl having 1 to 6 carbon atoms) -C02-R_ ?. or -C02-R__. Additionally, Rx and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or can be attached to the same carbon atom and form a ring of 8 atoms of the formula: together with the carbon atom to which they are attached. In this embodiment, R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) ) -C02-Rxl, (alkenyl with 2 to 6 carbon atoms) -COa-Rn, (alkyl with 1 to 6 carbon atoms) -CO- (alkyl with 1 to 6 carbon atoms), (alkyl) with 1 to 6 carbon atoms), (alkyl with 1 to 6 carbon atoms) -OH, (alkyl with 1 to 6 carbon atoms) -CN, adamantyl or one of the following: In addition, R2 and R3 - (Y) 0- can be combined with one another at the terminal thereof to form a ring of the following formula together with the carbon atom and the carbon atom. 15 nitrogen to which they are attached: In this embodiment, R4 is -0-Rn / NH2, NHOH, -0- (arylalkyl with 7 to 10 carbon atoms), or R4 is of the formula: -O-CH ^ - s 3 Also, in this embodiment, R5 is a formula of the following. In addition, in this embodiment, R6 is N or CH, R7 is hydrogen or halogen, R8 is -NHCO-, R9 may occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl with 1 to 6 carbon atoms, or (alkyl with 1 to 6 carbon atoms) -OH , or hydrogen, RX1 is hydrogen or alkyl having from 1 to 6 carbon atoms, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: R13 is N or CH; W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Yx are independently -CO-, -C (= 0) 0-, -S02-, or -C (= O) N (R10) -; Z is O, CH2, or N-R? A; 2 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3; with the conditions that: (1) When Y is -C (= 0) 0-, R3 can not be hydrogen; (2) When R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to terbutyl; (3) In the structures of pyrrolidine (2 is 1, m is 2, n is 0, or is 0, p is 1, X is CH2), W is equal to CH2. In yet another embodiment of the compound of the formula (I -a), Rx can occur from one to four times and each occurrence is independently hydrogen or alkyl having from 1 to 6 carbon atoms, and R2 is hydrogen, pyridyl, alkyl with from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-R1: L, or -C02-R?: 1. Additionally, Rx and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or can be attached to the same carbon atom and form a ring of 8 atoms of the formula: together with the carbon atom to which they are attached. In this embodiment, R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) ) -C02-Rll t (alkenyl with 2 to 6 carbon atoms) -C02-R_., (Alkyl with 1 to 6 carbon atoms) -CO- (alkyl with 1 to 6 carbon atoms), ( alkyl having from 1 to 6 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl or one of the following: N (? C, 3) 2 In addition, R2 and R3- (Y) 0- may be combined with one another at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: In this embodiment, R4 is -0-Rllf NH2, NHOH, -O- (arylalkyl with 7 to 10 carbon atoms), or is of the formula: -0-CH2-t Also, in this modality, R5 is a formula of the following Additionally, in this embodiment, R6 is N or CH, R7 is hydrogen or halogen, Ra is -NHCO, R9 can occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl with 1 to 6 carbon atoms, or (alkyl with 1 to 6 carbon atoms) -OH, or hydrogen, RX1 is hydrogen or alkyl with 1 to 6 atoms of carbon, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: R13 is N or CH; W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Yx are independently -CO-, -C (= 0) 0-, -S02-, or -C (= O) N (R10) -; Z is O, CH2, or N-Rn; 2 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, g is 0 or 1, and r is 0, 1, 2 or 3; with the conditions that: (1) When Y is -C (= 0) 0-, R3 can not be hydrogen; (2) When R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to terbutyl; (3) In pyrrolidine structures (1 is 1, m is 2, n is 0, or is 0, p is 1, X is CH2), W is equal to CH2, and (4) The compound has an IC50 value less than 5 μM in Jurkat CS-1 assay and / or an IC 50 value less than 50 μM in a Jurkat EC assay. In yet another embodiment of the compound of the formula (I), R-. it can occur from one to four times and each occurrence is independently hydrogen or alkyl with 1 to 6 carbon atoms, and R2 is hydrogen, pyridyl, alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 atoms carbon) -CO_-R11 # or -C02-Rn. Additionally, R x and R 2 can be attached to the same carbon atoms and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or can be attached to the same carbon atom and form a ring of 5- 8 atoms of the formula: together with the carbon atom to which they are attached. In this modality, R3 is hydrogen, phenyl, alkoyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) -C02 -Rxl, (alkenyl with 2 to 6 carbon atoms) -C02-R1: L, (alkyl with 1 to 6 carbon atoms) -CO- (alkyl with 1 to 6 carbon atoms), (alkyl with from 1 to 6 carbon atoms), (alkyl with 1 to 6 carbon atoms) -OH, (alkyl with 1 to 6 carbon atoms) -CN, adamantyl or one of the following C, 3) 2 In addition, R2 and R3- (Y) 0- may be combined with one another at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: In this embodiment, R4 is -0-R11 (NH2, NHOH, -0- (arylalkyl with 7 to 10 carbon atoms), or R4 is of the formula: -O-CH2-), N In this embodiment, R5 is a formula of the following: Also, in this particular embodiment, R6 is N or CH, R7 is hydrogen or halogen, R8 is -0CH2, R9 may occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl with 1 to 6 carbon atoms, or (alkyl with 1 to 6 carbon atoms) -OH, or hydrogen, R1X is hydrogen or alkyl having from 1 to 6 carbon atoms, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: R13 is N or CH; W is (alkyl having 1 to 6 carbon atoms), X is S, O or CH2, Y and x are independently -CO-, -C (= 0) 0-, -S02-, or -C (= O) N (R10) -; Z is O, CH2, or N-Rn; 2 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, g is 0 or 1, and r is 0, 1, 2 or 3; with the conditions that: (1) When Y is -C (= 0) 0-, R3 can not be hydrogen; (2) When R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to terbutyl; (3) In the structures of pyrrolidine (1 is 1, m is 2, n is 0, or is 0, p is 1, X is CH2), W is equal to CH2 (4) When R3 is phenyl, alkyl is 1 to 6 carbon atoms, arylalkyl of 7 to 17 carbon atoms, (alkyl of 1 to 6 carbon atoms) -C02-R?: L / (alkyl of 1 to 6 carbon atoms) -O-alkyl of 1 to 6 carbon atoms or (alkyl of 1 to 6 carbon atoms) -OH, or is 0; and (5) The compound is not In yet another embodiment of the compound of formula (Ia), Rx can occur from one to four times and each occurrence is independently hydrogen or alkyl having from 1 to 6 carbon atoms, and R2 is hydrogen, pyridyl, alkyl with 1 to 6 carbon atoms, (alkyl having 1 to 6 carbon atoms) -COa-Rii, or -C02-R- -. Additionally, R x and R 2 can be attached to the same carbon atoms and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or can be attached to the same carbon atom and form a ring of 5- 8 atoms of the formula: together with the carbon atom to which they are attached. In this embodiment, R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) ) -C02-R _. ?, (alkenyl with 2 to 6 carbon atoms) -COa-R ^, (alkyl with 1 to 6 carbon atoms) -CO- (alkyl with 1 to 6 carbon atoms) (alkyl having 1 to 6 carbon atoms), (alkyl having 1 to 6 carbon atoms) -OH, (alkyl having 1 to 6 carbon atoms) -CN, adamantyl or one of the following: In addition, R2 and R3- (Y) 0- may be combined with one another at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: Additionally, R4 is -0-Rlx, NH2, NHOH, -O- (arylalkyl with 7 to 10 carbon atoms), or is of the formula: Also, in this modality, R5 is a formula of the following: Additionally, in this embodiment, R6 is N or CH, R7 is hydrogen or halogen, R8 is -OCH2, R9 may occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl with 1 to 6 carbon atoms, or (alkyl with 1 to 6 carbon atoms) -OH, or hydrogen, Rlx is hydrogen or alkyl with 1 to 6 atoms of carbon, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: R13 is N or CH; W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Y * are independently -CO-, -C (= 0) 0-, -S02-, or -C ( = O) N (R10) -; Z is O, CH2, or N-Rx1; 2 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, g is 0 or 1, and r is 0, 1, 2 or 3; with the conditions that: (1) When Y is -C (= 0) 0-, R3 can not be hydrogen; (2) When R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to tert-butyl; (3) In pyrrolidine structures (2 is 1, m is 2, rz is 0, or is 0, p is 1, X is CH2), W is equal to CH2 (4) The compound has an IC50 value less than 5 μM in Jurkat CS-1 assay and / or an IC 50 value of less than 50 μM in a Jurkat EC assay, - (5) When R 3 is phenyl, alkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 17 carbon atoms, (alkyl of 1 to 6 carbon atoms) -C02-R11; (alkyl of 1 to 6 carbon atoms) -O-alkyl of 1 to 6 carbon atoms or (alkyl of 1 to 6 carbon atoms) -OH, or is 0; and (6) The compound is not In the above formula (I) the absolute stereochemistry of the bond leading to R5 is shown. However, absolute stereochemistry has not been shown for all the examples that follow. It is understood that all other formulas also follow this type of absolute stereochemistry unless otherwise stated. Additionally, it is understood by those skilled in the art that the present invention encompasses stereochemical configurations other than those shown. Specifically, the present invention encompasses all configurations that include the various stereoisomers. Compounds that do not satisfy the absolute stereochemistry in formula (1) should satisfy a threshold of activity in several tests, which will be explained below, that can ensure their effectiveness as useful molecules. The present invention includes mixtures, such as racemic mixtures, which contain molecules having the claimed stereochemistry. The desired compound of the present invention can be used clinically either in free form or in the form of pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include acid addition salts with inorganic acid or organic acid (for example, hydrochloride, sulfate, nitrate, hydrobromide, methanesulfonate, p-toluenesulfonate, acetate), a salt with an inorganic base, an organic base or an amino acid (e.g. , salt of triethylamine, a salt with lysine, and a salt with alkali metal, a salt with alkaline earth metal and the like). The compound can also be formulated as a pharmaceutical composition comprising a therapeutically effective amount of the compound as defined above and a pharmaceutically acceptable carrier or diluent. The compound can also be used to treat or prevent conditions mediated by the adhesion of 4ßx in a mammal such as a human. This method may comprise administering to an mammal or a human patient an effective amount of the compound or composition as explained above. This method can be used to treat inflammatory conditions such as rheumatoid arthritis, asthma, allergic conditions, adult respiratory distress syndrome, AIDS, cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, allograft rejection, damage by reperfusion, psoriasis, eczema, contact dermatitis and other inflammatory skin diseases, osteoporosis, osteoarthritis, atherosclerosis, neoplastic diseases including neoplastic or cancerous growth metastasis, improvement of wound healing, treatment of certain eye diseases such as retinal detachment, Type I diabetes, multiple sclerosis, systemic lupus erythematosus (SLE). Inflammatory and immunoinflammatory conditions including inflammatory ophthalmic conditions and inflammatory bowel diseases, ulcerative colitis, atherosclerosis, regional enteritis and other autoimmune diseases. As mentioned above, the compounds and compositions containing the compounds according to the present invention are particularly useful for treating or avoiding conditions mediated by the adhesion of o.sub.4.sub.x to a mammal such as a human. The present inventors have found that the compounds and compositions containing the compounds according to the present invention are more useful in the treatment of asthma. The desired compound of the present invention or the pharmaceutically acceptable salts thereof can be administered either orally or parenterally, and can be used as a convenient pharmaceutical preparation, for example, a tablet, a granule, a capsule, a powder, an injection , and an inhalation through a conventional process. The dose of the desired compound of the present invention or a pharmaceutically salt thereof varies depending on the method of administration, age, body weight, and condition of a patient, but, in general, the daily dose is preferably about 0.1. at 100 milligrams / kilogram / day, however, from 1 to 100 milligrams / kilogram / day may also be convenient.
Preferred administration routes for asthma: It is preferred that the compound of the present invention be administered in the form of an aerosol. However, other routes of administration include intravenous, oral, intramuscular, and subcutaneous. In the case of aerosol administration, compositions containing the compounds of the present invention can be prepared to provide an excellent means of administering in aerosol form for inhalation therapy. In accordance with the foregoing, the present invention will provide self-propelling compositions containing the compounds of the present invention. The injectors employed should be non-toxic and have a suitable vapor pressure for the conditions under which the administration is presented. These injectors may be fluorinated, saturated or fluorinated lower saturated aliphatic hydrocarbons. Preferred injectors of this type are halogenated alkanes that contain no more than two carbon atoms and at least one fluorine atom. Illustrative of these are trichloromonofluoromethane, dichlorodifluoromethane, monochlorotrifluoromethane, dichloromonofluoromethane and 1,2-dichloro-1,1,2,2-tetrafluoroethane. These compounds are available from E.l. duPont de Nemours & Company under the trade name "Freon". These injectors can be used singly or in a mixture.
In addition to the injector, an organic solvent may also be used. The organic solvent must be non-toxic and without undesirable effects on inhalation in the amount present in the aerosol produced. In addition, the solvent should be substantially anhydrous, completely miscible in the injector or mixture of injectors employed and have a suitable boiling point. Examples of these solvents include non-toxic aliphatic alcohols such as ethanol; ethers such as ethyl ether and vinyl ether; ketones such as acetone; and convenient halogenated lower alkanes. In addition to the organic solvent, the composition also optionally may contain a non-toxic hygroscopic glycol. The glycol must be substantially miscible with the organic solvent and the injector employed. Satisfactory glycols include propylene glycol, triethylene glycol, glycerol, butylene glycol and hexylene glycol. The methods indicated above for administration and formulation of aerosol compositions should not be seen as limiting. The compounds of the present invention can be formulated in any manner deemed convenient by a person skilled in the art to obtain the desired effects. Pharmaceutical compositions As indicated above, the compounds of formula (1) can be formulated into pharmaceutical compositions.
To determine when a compound of formula (1) is indicated for the treatment of a given disease, the particular disease in question, its severity, as well as the age, sex, weight, and condition of the subject to be treated, must be Take into consideration and this examination will be determined by the responsible physician. For medical use, the amount of a compound of formula (1) required to achieve the therapeutic effect will, of course, vary both with the particular compound, the route of administration, the patient under treatment, and with the particular disorder or disease that is is trying. A convenient daily dose of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, for a mammalian subject suffering from, or likely to suffer from, any condition described hereinabove is 0.1 milligram to 100 milligrams of the compound of formula I, per kilogram of body weight of the mammalian subject. In the case of routine administration, the dose should be in the range of 0.5 to 500 milligrams of the compound per kilogram of body weight, the most preferred dose being 0.5 to 50 milligrams / kilogram of the body weight of the administered mammal of two to three times a day. In the case of topical administration, for example, to the skin or to the eye, a suitable dose may be in the range of 0.1 microgram to 100 microgram of the compound per kilogram, typically about 0.1 microgram / kilogram. In the case of oral dosing, a convenient dose of a compound of Formula (1), or a physiologically acceptable salt thereof, may be as specified in the preceding paragraph, but more preferably is from 1 milligram to 10 milligrams of the compound per kilogram, the most preferred dosage being 1 milligram to 5 milligrams / kilogram of the mammal's body weight, for example, 1 to 2 milligrams / kilogram. More preferably, a unit dose of an orally administrable composition encompassed by the present invention contains less than about 1 gram of a compound of formula (I). It is understood that the formulation, both for human and veterinary use, of the present invention can be presented to the mammal by inhalation. To achieve the therapeutic effect, the dose may be in the range of 0.5 to 500 milligrams of the compound, per kilogram of body weight. The most preferred dose being 0.5 to 50 milligrams / kilogram of body weight of the mammal administered two to three times a day. It is understood that the ordinarily experienced physician or veterinarian will readily determine and prescribe the effective amount of a compound of formula (I) to prevent or arrest the progression of the disease for which the treatment is administered. In doing so, the doctor or veterinarian could use relatively low doses at the beginning, subsequently increasing the dose until a maximum response is obtained. The compounds and compositions of the present invention can be administered to patients suffering from a condition listed herein in an amount that is effective to completely or partially alleviate the undesirable symptoms of the disease. Symptoms may be caused by inadequate cellular adhesion mediated by integrins o-4ß- .. This inadequate cell adhesion typically It would be expected to occur as a result of an increased expression of VCAM-1 and / or CS-1 on the surface of endothelial cells. The increased expression of VCAM-1 and / or CS-1 may be due to the normal inflammation response or may be due to abnormal inflammatory conditions. In any case, An effective dose of a compound of the invention can reduce increased cell adhesion due to increased expression of VCAM-1 by endothelial cells. Reducing the adherence observed in the disease state by 50 percent can be considered an effective reduction in the 20 adhesion. More preferably, a reduction in adhesion of 90 percent is achieved. More preferably, adhesion mediated by the interaction of VCAM-1 / o 4 4: L and / or CS-1 is suppressed by an effective dose. Clinically, in some cases, the effect of the compound can be observed or a decrease in 25 the infiltration of white blood cells into the tissues or a site of injury. To achieve a therapeutic effect, then, the compounds or compositions of the present invention are administered to provide an effective dose to reduce or eliminate inappropriate cell adhesion or to alleviate unwanted symptoms. Although it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising a compound of formula (I) and a pharmaceutically acceptable carrier thereof. These formulations constitute another feature of the present invention. The formulations, both for human and veterinary medical use, of the present invention comprise an active ingredient of formula (I), in association with a pharmaceutically acceptable carrier thereof and optionally other or other therapeutic ingredients, which are generally known to be effective for treat the disease or condition found. The vehicle or vehicles must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not harmful to the recipient thereof. The formulations include those in convenient form for oral, pulmonary, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), intra-articular, topical, nasal inhalation (e.g., with an aerosol) or buccal administration administration. This formulation is understood to include long acting formulations known in the art. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods may include the step of placing the active ingredient in association with the vehicle which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired form. Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, lozenges, tablets, or troches, each containing a predetermined amount of active ingredient in the form of a powder or granules; in the form of a solution or suspension in an aqueous liquid. Formulations for other uses could include a non-aqueous liquid; in the form of an oil-in-water emulsion or a water-in-oil emulsion; in the form of an aerosol; or in the form of a cream or ointment or impregnated in a transdermal patch for use to administer the active ingredient transdermally, to a patient in need thereof. The active ingredient of the present inventive compositions may also be administered to a patient in need thereof in the form of a bolus, electuary, or paste. The professional can consult "Remington: The Science and Practice of Pharmacy", 19th Edition, c. 1995, by the Philadelphia College of Pharmacy and Science, as a comprehensive volume on pharmaceutical preparations. Abbreviations Ac20: Acetic anhydride EtOAc: Ethyl acetate BCECF-AM: 2 ', 7' -bis- (2-carboxyethyl) -5- (and 6-) carboxyfluorescein acetoxy-methyl ester BOP-CI: Chloride bis (2-oxo-3-oxazolidinil) fosfínico Reagent Benzotriazol-1-yloxy-tris (dimethylamino) BOP: phosphonium hexafluoro-phosphate DMEM Minimum Medium of Dulbecco's Eagle DMF: Dimethyl formamide DIEA: Di-isopropylethylamine EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodi-imide hydrochloride Et: Ethyl EtOH: Ethanol HATU: N- [(Dimethylamino) -1H-1, 2, 3-triazol [4, 5-b] pyridin-1-ylmethylene] -N-methylmetanaminium hexafluorophosphate N-oxide HBSS: Hank's balanced salt solution HBTU: O-Benzotriazol-1-yl-?,?,?, Hexafluorophosphate ,? ' -tetramethyluronium HOBT (HOBt) 1-Hydroxybenzotriazole HSA: Human serum albumin LDA: Lithium di-isopropylamide Me: Methyl meq: miliequivalent MeOH: Methanol n-Bu: n-Butyl ? MP: 1-Methyl-2-pyrrolidinone PBS: Regulated phosphate solution Pd-C: Palladium in carbon Ph: Phenyl SPDP: 3- (2-pyridyldithio) propionic acid N-hydroxysuccinimide ester T-Bu: t-butyl THF: Tetrahydrofuran TFA: Trifluoroacetic acid DMSO: dimethyl sulfoxide HOAt 1-hydroxy-7-azabenzotriazole DMAP: 4-dimethylaminopyridine FMOC: 9-fluorenylmethoxycarbonyl Bn: benzyl PyBOP: (benzotriazol-1-yloxy) tripyrrolidinephosphonium hexafluoro-phosphate BOC: tert-butoxycarbonyl Representative compounds according to the present invention are prepared as described below. The compounds of the present invention are prepared in a similar manner.
Scheme A RA-I and A-2 are independently defined as Rx. Scheme A describes a general method for the preparation of the examples of the formula A-5, 1-6, 1-7, 1-8, 1-9 and A-10. A commercially available or readily prepared sulfur containing amino acid of Al structure (for the synthesis of amino acids of β, β-disubstituted cysteine see: Stanfield, GT.F .; Hruby, VJ Synth Commun. 1988, 18, 531 and references therein) are condensed with formaldehyde to provide the thiazolidine-4-carboxylic acid of general formula A-2 (for the condensation of aldehydes with cyst or similar sulfur-containing amino acids see for example: (a) Ratner, S.; Clark, HTJ Am. Chem. Soc. 1937, 59, 200, (b) Lewis, NJ, Inloes, RL; Hes, J.; Matthews, RH; Milo, G. J. "Med. Chem. 1978, 21, 1070, ® Oya, M.; Baba, T .; Kato, E .; Kawashima, Y.; Watanbe, T. Chem. Pharm. Bull., 1982, 30, 440.) The standard protection gives carbamate A-3 which easily is condensed with amino acid derivative A-4 under standard peptide synthesis conditions to provide the pseudopeptide A-5 (for a review of the procedures of the Peptide synthesis see: Bodansky, M.; Bodansky, A. The Practice of Peptide Synthesis, - Springer-Verlag: Berlin, 1984). Deprotection of the carbamate from A-5 provides the useful intermediate A-6. The amine group can be reacted with a variety of electrophilic reagents such as: (1) commercially available or readily prepared sulfonyl chlorides (for the synthesis of sulfonyl chlorides see for example: (a) Robin, RO; Clapp, JW J Am. Chem. Soc. 1950, 72, 4890, (b) Gilbert, EE in Sulfonation and Related Reactions Olah, GA, Ed. John Wiley and Sons, New York, 1965, ® Park, YJ; Shin, HH; Kin, YH Chem Lett, 1992, 1483, (d) Kim, D .; Ko, YK; Kim, SH Synthesis, 1992, 1203) to give sulfonamides of general structure A-7 wherein Y is S02- (preparation 5) (2) carbonates or chloroformates to give carbamates of general structure A-7 wherein Y is C02- (preparations 2, 7, 8), (3) isocyanates to give urea of general structure A-7 where Y is CONHR3 ( preparation 9); (4) fosgene or a suitable equivalent and an amine to give ureas of general structure A-7 where Y is CON (alkyl with 1 to 6 carbon atoms) R3- (preparation 10, see also for example: Nowick, JS; Homes, DL; Noronha, G.; Smith, EM; Tram, MN; Huang, S.J. "Org. Chem. 1996, 61, 3929); (5) Acid chlorides and carboxylic anhydrides to provide amides of structure A-7 wherein Y is CO- (preparation 11). The light base hydrolysis of monoesters of general structure A-7 (preparation 6) or diesters of general structure A-7 (preparation 12) presents the acids of general structure A-8. The hydrolysis of light base of the ester of general structure A -5 provides the acid A-9 (preparation 6 or 13) which can be further deprotected to give the amino acid A-10 (preparation 14).
Preparation 1 (Scheme A, A-2, where RA.X and RA_2 are the same and are also equal to H and the stereochemistry is (S)) The D-cysteine hydrochloride monohydrate (Al, where RA.X and RA-2 are equal and also equal to H and the stereochemistry is (S)) (35.04 grams, 0.19 mol) was dissolved in formaldehyde (40 percent by weight of solution in water, 38 milliliters) and the reaction mixture was allowed to stir for 18 hours at room temperature. The mixture was cooled (0-5 ° C) and absolute ethanol (93 milliliters) and pyridine (57 milliliters) were added. After one hour, the precipitate was collected by filtration, washed with cold absolute ethanol followed by diethyl ether and dried under vacuum to give the title compound (.24.6 grams) as a white crystalline solid: mp 181-184 ° - C (Lit. 194-196 ° C; Lewis, NJ; Inoles, RL; Hes, J. J., Med. Chem. 1978, 21, 1070);: H NMR (DMS0-d6) d 4.22 (1 H) , 4.04 (1 H), 3.86 (1 H), 3.09 (1 H), 2.24 (1 H), MS (ESI +) for C4H7N02S m / z 134.0 (M + H) * Preparation 2 (Scheme A, A- 3, where RA.X and RA_2 are equal and equal to H, R3 is t-butyl and the stereochemistry is (S)) A solution of A-2 (Scheme A where RA.X and RA_2 are equal and equal to H and the stereochemistry is. {S)) (24.6 grams, 0.185 mol) and di-t-butyl bicarbonate (44.4 grams, 0.2 mol) in THF (1 liter) was heated under reflux for 18 hours. The aqueous layer was washed with ethyl acetate, and the residue was partitioned between ethyl acetate and 0.1 N NaOH. made acid with 1.0 N HCl (pH 3-4) and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Crystallization of white solid from hexane / methylene chloride gave the title compound (31.8 grams) as white crystals: mp 132-134 ° C [a] 25D = 117 ° (c 0.66, ethanol); IR (Mull) 3002, 1747, 1635, 1421, 1404, 1393, 1310, 1215, 1198, 1166, 1144, 1122, 894, 862, 774 cm "1; XH NMR (DMS0-d6) d 4.57 (2 H) , 4.28 (1 H), 3.09 (1 H), 1.35 (9 H), 13 C NMR (DMS0-d6) d 171.8, 152.5, 79.8, 60.9, 48.4, 47.7, 33.8, 32.6, 27.7, MS (ESI + ) for C, H15N04S m / z 234.2 (M + H) S MS (Is f? for C9H15N04S / z 232.1 (MH) \ - Anal.Called for C9H15N04S: C, 46.34; H, 6.48; N, 6.00. C, 46.27; H, 6.48; N, 6.03, Preparation 3, Example 1 3- (1, 1-dimethylethyl) ester of acid [S- (R *, R *)] -4- [- [l - [[ 4 - [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-5: where RA., RA_2 are the same and equal to H, R3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [S, S)).
To a cooled suspension (0.5 ° C) of A-3 (Scheme A where RA.X and RA.2 are equal to and equal to H, R3 is t-butyl and the stereochemistry is {S)) (8.67 grams , 37.2 mmol) and HOBT (5.69 grams, 37.2 mmol) in CH2C12 (60 milliliters) was added an EDC solution (7.12 grams, 37.2 mmol) in CH2C12 (140 milliliters). After 30 minutes at 0-5 ° C, A-4 (where R5 is 4 - [(2,6-dichlorobenzoyl) -amino] phenyl, and the stereochemistry is (_?)) (10 grams, 24.8 mmol) was added followed by 4-methylmorpholine (2.72 milliliters, 24.8 mmol). The reaction mixture was gradually warmed to room temperature, stirred for an additional 18 hours and diluted with CH2C12 and 0.1 N HCl. The organic layer was separated and washed with 0.1 N HCl, saturated aqueous HaHC03, brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography of the residue using hexane / ethyl acetate (50 percent) as eluent afforded the title compound (13.9 grams) as a white solid. Recrystallization of acetone / hexane showed a crystalline solid: mp 222-224 ° C; IR (Mull) 3282, 3254, 1738, 1714, 1707, 1678, 1662, 1610, 1562, 1545, 1431, 1414, 1287, 1256, 784 was "1; * H NMR (CDC13) d 7.57 (2 H), 7.34 (5 H), 7.14 (2 H), 4.74 (3 H), 4.30 (1 H), 3.74 (3 H), 3.37 (1 H), 3.15 (3 H), 1.45 (9 H), 13 C NMR (DMSO-dg) d 172.1, 162.3, 153.2, 137.6, 136.9, 133.2, 131.8, 131.7, 130.1, 128.7, 119.8, 80.4, 62.2, 53.7, 52.4, 36.7, 28.3; MS (ESI +) for C26H29Cl2N3OgS m / z 604.3 (M + Na) *; Anal Caled for C26H29Cl3N3OfiS: C, 53.61; H, 5.02; N, 7.21, Found: C, 53.82; H, 4.81; N, 7.22, Preparation 4 (Scheme A, A-6: wherein RA.1 (RA_2 are equal and equal to H, R5 is 4 - [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is {S, S)).
To a cooled solution (5-10 ° C) of A-5 (Scheme A where RA-X and RA.2 are equal to and equal to H, R3 is t-butyl, R5 is 4 - [(2, 6 - dichlorobenzoyl) amino] phenyl, and the stereochemistry is (& , &) (3.3 grams, 5.67 mmol) in dioxane (34 milliliters) was added a solution of HCl in dioxane (4 M, 140 milliliters) by drip for 30 minutes. After an additional 30 minutes at 0-5 ° C, the ice bath was stirred and the reaction mixture was stirred one hour at room temperature. The volatiles were removed in vacuo to yield the title compound (2.94 grams) as a yellow solid: * H NMR (DMSO-d6) d 10.70 (1 H), 9.1 (1 H), 7.52 (5 H), 7.18 ( 2 H), 4.64 (1 H), 4.37 (1 H), 4.21 (2 H), 3.67 (3 H), 3.10 (1 H), 2.89 (1 H), 2.70 (1 H); 13 C NMR (DMSO-dg) d 172.1, 162.3, 153.2, 137.6, 136.9 * 133.2, 131.8, 131.7, 130.1, 128.7, 119.8, 80.4, 62.2, 53.7, 52.4, 36.7, 28.3; MS (ESI +) for C21H21C12N304S m / z 482.1 (M + H) *. Preparation 5 and Example 2 4 - [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- (methylsulfonyl) -4-iazolidinyl] carbonyl] -L-phenylalanine methyl ester (Scheme A, A -7: where RA-! RA_2 are equal and equal to H, R3 is methyl, Y is S02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _? )).
To a cooled solution (0-5 ° C) of A-6 (Scheme A where RA-i and RA.2 are equal and equal to H, R5 is 4- [(2,6-dichlorobenzoyl) -amino] phenyl , and the stereochemistry is (S, S)) (2 grams, 3.86 mmol) in anhydrous THF (50 milliliters) was added methanesulfonyl chloride (2.99 milliliters, 38.6 mmol) followed by pyridine (6.24 milliliters, 77.2 mmol). After 1 hour at 0-5 ° C, the ice bath was stirred and the solution was stirred at room temperature for 2 hours then diluted with ethyl acetate and 0.25 N HCl. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate / methylene chloride / hexane (1: 1: 1) and isopropanol (0.1 percent) as eluent afforded the title compound (1.99 grams) as an amorphous powder: IR (Mull). ) 1742, 1666, 1605, 1562, 1534, 1515, 1432, 1413, 1344, 1327, 1269, 1218, 1195, 1156, 780 cm "1; XH NMR (300 MHz, CDCl3) d 7.55 (3 H), 7.33 (3 H), 7.12 (3 H), 4.84 (1 H), 4.69 (1 H), 4.61 (1 H), 4.29 (1 H), 3.74 (3 H), 3.50 (1 H), 329 (1 H), 3.14 (2 H), 2.92 (3 H), 13 C NMR (75 MHz, CDCl 3) d 171.2, 168.1, 162.4, 136.5, 135.9, 132.3, 132.2, 130.8, 130.0, 128.1, 120.6, 64.9, 53.2, 52.5, 51.8, 37.2, 34.1; MS (ESI +) for C22H23Cl2 30gS2 m / z 559.8 (M + H) +; HRMS (FAB) caled for C22H23Cl2N3OgS2 + Hx 560.0483, found 560.0504; Anal.Called for C22H23Cl2N3OsS2: C, 47.15; 4.14, N, 7.50, Found: C, 46.88, H, 4.32, N, 7.16, Preparation 6 and Example 3 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(S) -3- ( methylsulfonyl) -4-thiazolidin il] carbonyl] -L-phenylalanine (Scheme A, A-8 where RA-_, RA.2 are equal and equal to H, R3 is methyl, Y is S02, R5 is 4- [(2,6-dichlorobenzoyl ) amino] phenyl, and stereochemistry is (_ ?, £?)).
To a cooled solution (0-5 ° C) of A-7 (Scheme A, where RA._, RA.2 are equal to and equal to H, R3 is methyl, Y is S02, R5 is 4- [(2 , 6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (S, S)) (1.75 grams, 3.12 mmol) in THF (100 milliliters) and water (10 milliliters) was added an aqueous solution of 0.1 N NaOH (34.3 milliliters, 3.43 mmol) via a syringe pump for one hour. After an additional 45 minutes at 0-5 ° C the reaction mixture was diluted with ethyl acetate and acidified with 0.25 N HCl to a pH of about 3. The organic layer was separated, washed with water and concentrated to vacuum. Purification of the residue by flash chromatography using methylene chloride and methanol (0-5 percent) as eluent provided a solid that was lyophilized from glacial acetic acid to provide the title compound (1.42 grams) as an amorphous powder: [α] 25 D = 103 ° (c 0.97 ethanol); IR (Mull) 3291, 1736, 1666, 1605, 1562, 1534, 1516, 1432, 1414, 1339, 1270, 1195, 1154, 799, 780 cm'1; XH NMR (300 MHz, CD30D) d 7.58 (2 H), 7.45 (3 H), 7.25 (2 H), 4.72 (2 H), 4.37 (1 H), 3.17 (5 H), 2.99 (3 H); 13 C NMR (75 MHz, CD30D) d 174.1, 171.6, 165.2, 138.3, 137.7, 134.8, 133.4, 132.4, 131.2, 129.4, 121.6, 66.2, 55.0, 52.9, 37.9, 37.5, 35.7; MS (ESI +) for 546.0327, found 546.0358. Anal. Caled for C21H21C12N306S2 C, 46.16; H, 3.87; n, 7.69. Found: C, 46.24; H, 4.04; N, 7.33. Preparation 7 and Example 4 3-Ethyl acid ester [S-, (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] - 2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA._, RA.2 are equal to and equal to H, R3 is ethyl, Y is C02-, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
To a cooled solution (0-5 ° C) of A-6 (where RA._, RA.2 are equal and equal to H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (£?, £?)) (1.25 grams, 2.40 mmol) in anhydrous THF (30). milliliters) was added ethyl chloroformate (340 microliters, 3.60 mmol), followed by triethylamine (810 microliters, 5.79 mmol). After 1 hour at 0-5 ° C, the ice bath was stirred and the solution was stirred at room temperature for 2 hours then diluted with ethyl acetate and 0.25 N HCl. . The layers were separated and the organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate / methylene chloride / hexane (1; 1; 1) and isopropanol (0.1 percent) as eluent afforded the title compound (1.10 grams) as an amorphous powder: H NMR ( 300 MHz, CDC13) d 7.59 (2 H), 7.30 (3 H), 7.10 (2 H), 4.81 (1 H), 4.72 (2 H), 4.38 (1 H), 4.11 (2 H), 3.19 ( 4 H), 1.25 (3 H); 13 C NMR (75 MHz, CDCl 3) d 171.6, 163.0, 136.9, 136.2, 132.3, 132.1, 130.7, 129.8, 128.0, 120.3, 63.0, 62.8, 57.1, 53.2, 52.5, 37.0, 14.4; MS (ESI +) for C 24 H 25 C 12 N 306 S 2 m / z 554.2 (M + H) +; MS (FAB) m / z (relative intensity) 554 (MH \ 99), 557 (29), 556 (76), 555 (45), 554 (99), 349 (35), 245 (27), 175 ( 35), 173 (52), 160 (93), 88 (38); HRMS (FAB) caled for C24H25C12N306S + H_ 554.0919, found 554.0908. Anal. Caled for C24H25C12N306S: C, 51.99; H, 4.55; N, 7.58. Found: C, 52.05; H, 4.67; N, 7.44. Preparation 8 and Example 5 Ester 3- [2- (1-piperidinyl) ethyl] acid [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorophenyl)] methoxy] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA.!, and RA_2 are equal and equal to H, R3 2- ( 1-piperidinyl) ethyl, Y is C02-, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry is [S, S)).
The title compound was prepared by modifying the literature method of Ghosh, A.K .; Duong, T.T .; McKee, S.P .; Thompson, W.J. Tetrahedron Lett. 1992, 33, 2781. To a solution of 1- (2-hydroxyethyl) piperidine (5.11 grams, 39.6 mmol) in CH 3 CN (220 milliliters) at room temperature was added N, N-disuccinimidyl carbonate (10.13 grams, 39.6 mmol). and triethylamine (16.6 milliliters, 118.8 mmol). The solution was stirred at room temperature for 4 hours and concentrated in vacuo to give a viscous oil. The oil was dissolved in a minimum amount of methylene chloride (50 milliliters) and added to a solution of A-6 (Scheme A, where RA_ ?, and RA_2 are equal and equal to H, R5 is 4- [( 2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry is (S, S)) (2.0 grams, 3.96 mmol) triethylamine (0.60 milliliters) and DMAP (5 milligrams) in CH2C12 (10 milliliters). The solution was stirred overnight and five equivalents of carbonate in methylene chloride (10 milliliters) [prepared as described above for N, N-disuccinimidyl carbonate (5.6 grams, 19.8 mmol), triethylamine (8.3 milliliters) were added., 59.4 mmol), and 1- (2-hydroxyethyl) piperidine (2.56 grams, 19.8 mmol)]. After 3 hours at room temperature, propylamine (30 milliliters, 0.71 mol) was slowly added. { exothermic) and the solution was diluted with CH2C12. The resulting solution was stirred vigorously for 15 minutes and diluted with water. The organic layer was separated and washed with 0.1 M HCl, saturated aqueous NaHCO 3, dried (MgSO 4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate / methylene chloride (3: 1) as eluent followed by trituration in hexanes afforded the title compound (1.54 grams, 62 percent) as a white powder: IR (Mull). ) 1745, 1704, 1660, 1553, 1512, 1435, 1426, 1397, 1303, 1245, 1227, 1212, 1173, 1019, 765 cm "1; X H NMR (300 MHz, DMS0-d 6) d 8.42 (1 H), 7.54 (2 H), 7.44 (1 H), 7.13 (2 H), 6.94 (2 H), 5.17 (2 H), 4.59 (2 H), H), 4.48 (1 H), 4.26 (1 H), 4.02 (2 H), 3.63 (3 H), 3.19 (2 H), 3.19 (1 H), 2.82 (3 H), 2.35 (4 H), 1.36 (6 H); 13 C NMR (75 MHz, DMSO-dg) d 172.2, 170.0, 157.7, 153.9, 136.5, 132.2, 132.0, 130.8, 130.1, 129.2, 114.8, 65.3, 63.6, 57.3, 54.6, 53.9, 52.4, 36.4, 26.0, 24.3; MS (ESI +) for C29H35C12N306S m / z 623.9 (M + H) +; Anal. Caled for C29H3SCl2N3OgS: C, 55.77; H, 5.65; N, 6.73. Found: C, 55.48; H, 5.73; N, 6.91. Preparation 9 and Example 6 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4 S) -3 - [((1,1-dimethylethyl) amino) carbonyl] -4-thiazolidinyl] methyl ester] carbonyl] -L-phenylalanine (Scheme A, A-7: where RA- ?, and RA_2 are equal and equal to H, R3 is t-butyl, Y is CONH-, R5 is 4- [(2,6- dichlorobenzoyl) amino] phenyl, and the stereochemistry is (S, S)).
To a cooled solution (0-5 ° C) of A-6 (Scheme A, where RA_ ?, and RA.2 are equal and equal to H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl , and the stereochemistry is (S, S)) (140 milligrams, 0.27 mmol) in anhydrous THF (6 milliliters) was added tert-butyl isocyanate (0.62 milliliters, 5.4 mmol) followed by 4-dimethylaminopyridine (5 milligrams, 0.04 mmol ). After 0.5 hours at 0-5 ° C, the ice bath was stirred and the solution was stirred at room temperature for 16 hours. Additional tert-butyl isocyanate (0.62 milliliters, 5.4 mmol) was added and the solution was heated at 50 ° C for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and 0.25 N HCl. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate / methylene chloride (1: 1: 1) and isopropanol (0.1 percent) as eluent afforded the title compound (150 milligrams) as a white powder: XH NMR (300 MHz , CDC13) d 7.93 (1 H), 7.54 (2 H), 7.26 (4 H), 7.09 (2 H) \ 4.74 (2 H), 4.66 (1 H), 4.41 (1 H), 4.23 (1 H) ), 3.70 (3 H), 3.28 (1 H), 3.09 (3 H), 1.31 (9 H); 13C NMR (75 MHz, CDC13) d 171.4, 170.6, 162.4, 155.5, 136.3, 135.9, 132.5, 132.3, 130.8, 129.9, 128.1, 120.6, 62.7, 53.2, 52.4, 51.5, 49.0, 37.0, 32.9, 29.2; MS (ESI +) for C 26 H 30 Cl 2 N 4 O s S m / z 581.0 (M + H) 603.0 (M + Na) -; MS (FAB) m / z (relative intensity) 581 (MH +, 23), 482 (50), 97 (36), 88 (36), 83 (45) _ 69 (99), 57 (81), 55 ( 79), 43 (50), 43 (69), 41 (50). HRMS (FAB) caled for C 26 H 30 Cl 2 N 4 O 5 S + H 1 581.1392, found 581.1376. Preparation 10 and Example 7 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- [(diethylamino) carbonyl] -4-thiazolidinyl] carbonyl] -L-phenylalanine methyl ester (Scheme A, A-7: where RA _ .., and RA.2 are equal and equal to H, R3 is ethyl, Y is CON (CH2CH3) -, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl , and the stereochemistry is [S, S)).
The title compound was prepared by a literature process modification of Majer, P .; Randad, R.S. J. Org. Chem. 1994, 59, 1937. To a cooled solution (0-5 ° C) of A-6 (Scheme A, where R1 -.X and RA_2 are equal and equal to H, R5 is 4- [(2 , 6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is { S, S)) (200 milligrams, 0.39 mmol) and triethylamine (56 microliters, 0.40 mmol) in anhydrous methylene chloride (10 milliliters) was added to triphosgene. (47 milligrams, 0.16 mmol) followed by additional triethylamine (56 microliters, 0.40 mmol). After 0.5 hours at 0-5 ° C, the ice bath was stirred and the solution was stirred at room temperature for 2 hours. The solution was re-cooled (0-5 ° C) and diethylamine (1.20 milliliters, 11.70 mmol) and 4-dimethylaminopyridine (5 milligrams, 0.04 mmol) were added. After 0.5 hours at 0-5 ° C, the ice bath was stirred and the solution was stirred at room temperature for 16 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and 0.25 N HCl. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using ethyl acetate / methylene chloride / hexane (1: 1: 1) and isopropanol (0.1 percent) as eluent afforded the title compound (200 milligrams) as an amorphous solid: R NMR ( 300 MHz, CDC13) d 7.86 (1 H), 7.55 (2 H), 7.30 (3 H), 7.03 (2 H), 6.90 (1 H), 5.09 (1 H), 4.83 (1 H), 4.33 ( 2 H), 3.76 (3 H), 3.34 (3 H), 3.11 (5 H), 1.08 (6 H); 13C NMR (CDC13) d 171.1, 169.6, 162.3, 162.2, 136.5, 135.9, 132.3, 132.1, 130.9, 129.9, 128.1, 120.3, 64.7, 53.4, 52.7, 52.5, 42.0, 37.0, 32.4, 13.1; MS (ESI +) for C26H30N4O5S m / z 580.9 (M + H) S HRMS (El) caled for C2gH30Cl2N4O5S 580.1314, found 580.1297. Anal. Caled for C 26 H 30 Cl 2 N 4 O 5 S: C, 53.70; H, 5.20; N, 9.63. Found: C, 53.63; H, 5.33; N, 9.36. Preparation 11 and Example 8 3-methyl ester of acid [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2 -methoxy-2-oxoethyl] amino] carbonyl] -? - 3-thiazolidinobutanoic (Scheme A, A-7: where RA.lt and RA-2 are equal and equal to H, R3 is CH2CH2C02CH3, Y is CO, Rb is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (_?, _?)).
To a cooled solution (0-5 ° C) of A-6 (Scheme A, where RA- !, and RA.2 are equal and equal to H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is { S, S)) (1.03 grams, 1.72 mmol) in anhydrous CH2C12 (25 milliliters) was added triethylamine (460 microliters, 3.27 mmol) followed by methyl succinyl chloride (320 microliters, 2.58 mmol).
After 1 hour at 0-5 ° C, the ice bath was stirred and the solution was stirred at room temperature for 2 hours then diluted with 1 N HCl. The organic layer was separated, washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. Crystallization of the yellow solid from ethanol / water gave the title compound (824 mg) as a light yellow solid: mp 221-223 ° C; IR (Mull) 3275, 1748, 1731, 1687, 1626, 1610, 1561, 1542, 1517, 1430, 1416, 1326, 1268, 1224, 1193 cm "1; XH NMR (DMS0-d6) d 10.64 (1 H) , 8.59 (1 H), 8.24 (1 H), 7.50 (5 H), 7.16 (2 H), 4.75 (2 H), 4.51 (2 H), 4.23 (1 H), 3.63 (3 H), 3.56 (3 H), 2.87 (5 H), 13 C NMR (DMSO-dg) d 172.9, 171.6, 169.9, 169.5, 161.9, 137.2, 136.5, 133.0, 132.8, 131.3, 129.8, 128.3, 119.4, 61.6, 53.6, 52.1 , 51.4, 48.6, 36.4, 35.7, 35.2, 33.1, 29.0, 28.9, 28.5; MS (ESI +) for C26H27C12N307S m / z 596.0 (M + H) +; MS (ESI-) for C26H27C12N307S m / z 593.9 (MH ) - Anal Caled for C26H27C12N307S: C, 52.35; H, 4.56; N, 7.04 Found: C, 52.11; H, 4.47; N, 6.96, Preparation 12 and Example 9 Acid [S- (R *, R * )] -4- [[[l-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -? - oxo-3- iazole idinocarbutanoic (Scheme A, A- 8: where RA._, and RA-2 are equal and equal to H, R3 is CH2CH2C02C02H, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (_? , _?)).
'To a cooled solution (0-5 ° C) of A-7 (Scheme A, where RA-_, and RA.2 are equal and equal to H, R3 is CH2CH_C02CH3, Y is CO, R5 is 4- [ (2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (S, S)) (130 milligrams, 0.22 mmol) in anhydrous THF (5 milliliters) and MeOH (1 milliliter) was added an aqueous solution (2). milliliters) of lithium hydroxide monohydrate (23 milligrams, 0.55 mmol) via a syringe pump for 1 hour. After an additional 1 hour at 0-5 ° C, the ice bath was stirred and the solution was stirred 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and 0.1 N HCl and the organic layer was separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. Lyophilization of the residue from glacial acetic acid yielded the title compound (101 milligrams) as a white amorphous powder: * H NMR (CD3CN) d 8.87 (1 H), 7.55 (2 H), 7.42 (3 H), 7.22 (2H), 7.16 (1H), 4.95 (1H), 4.52 (3H), 3.12 (5H), 2.55 (5H); 13C NMR (CD3CN) d 173.8, 171.7, 171.1, 169.8, 162.5, 136.7, 136.0, 133.5, 131.7, 131.3, 130.1, 129.2, 128.2, 119.7, 62.4, 53.6, 48.8, 36.2, 32.4, 29.1, 28.6; MS (ESI-) for C24H23C12N307S m / z 566.1 (MH) "; Anal Caled for C24H23C12N307S: C, 50.31; H, 4.13; N, 7.33. Found: C, 50.13; H, 4.37; N, 6.93. and Example 10 3- (1, 1-dimethylethyl) acid ester [S- (R *, R *)] -4- [[[1-Carboxi-2 - [4 - [(2,6-dichlorobenzoyl) amino] ] phenyl] ethyl]] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-9: where RA., RA-2 are equal to and equal to H, R3 is t-butyl, Y is C02-, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
To a cooled (0-5 ° C) of A-5 (Scheme A wherein RA._, and RA-2 solution are equal and equal to H, R3 t-butyl, Y is C02-, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)) (150 milligrams, 0.26 mmol) in anhydrous THF (5 milliliters) and MeOH (1 milliliter) ) an aqueous solution (2 milliliters) of lithium hydroxide monohydrate (14 milligrams, 0.325 mmol) was added via a syringe pump for 1 hour. After an additional 1 hour at 0-5 ° C, the ice bath was stirred and the solution was stirred 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and 0.1 N HCl, the organic layer was separated and washed with water, dried (Na2SO4), filtered and concentrated in vacuo. Lyophilization of the residue from glacial acetic acid yielded the title compound (142 milligrams) as an amorphous powder: IR (Mull) 3285, 1735, 1666, 1606, 1562, 1539, 1516, 1432, 1413, 1394, 1326, 1259, 1219, 1195, 1161 cm.?; ? NMR (DMF-d7) d 10.71 (1 H), 8.36 (1 H), 7.91 (2 H), 7.72 (3 H), 7.47 (2 H), 4.88 (3 H), 4.51 (1 H), 3.40 (3 H), 3.22 (2 H). 1.57 (9 H); 13C NMR (DMF-d7) d 173.3, 163.1, 162.9, 162.7, 162.3, 154.0, 138.3, 137.5, 134.2, 132.3, 131.9, 130.6, 128.9, 120.0, 80.9, 63.1, 54.5, 49.9, 37.4, 28.3; MS (FAB) m / z (relative intensity) 568 (MH +, 23), 570 (14), 568 (23), 471 (13), 470 (65), 469 (23), 468 (99), 466 (23), 175 (19) , 88 (17), 57 (42); HRMS (FAB) caled for C25H27C12N306S + H? 568.1075, found 568.1071; MS (ESI-) for C2SH27C12N306S + H? m / z 565.8 (M-H) -; Anal. Caled for C25H27C12N306S. 0.26 H20: C, 52.38; H, 4. 84; N, 7.33. Found: C, 52.07; H, 5.12; N, 7.46; Water (KF): 0.83 Preparation 14 and Example 11 Salt of 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -4-thiazolidinyl] carbonyl] -L-phenylalanine monohydrochloride (Scheme A, A-10: where RA.?, And RA_2 are equal and equal to H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [S, S)).
To a cooled solution (5-10 ° C) of A-9 (Scheme A, where RA.?, And RA.2 are equal and equal to H, R3 t-butyl, Y is C02-, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is. {S, S)) (193 milligrams, 0.34 mmol) in dioxane (2 milliliters) was added a solution of HCl (4M, 8 mL) of way by dripping for 30 minutes. After an additional 3.5 hours at 0-5 ° C, the reaction mixture was concentrated in vacuo. Lyophilization of the water residue afforded the title compound (158 milligrams) as an amorphous powder: IR (Mull) 3248, 3191, 3048, 1731, 1664, 1605, 1577, 1562, 1541, 1516, 1431, 1414, 1327, 1195, 799 was "1; * H NMR (DMF-d7) d 9.11 (1 H), 7.76 (2 H), 7.60 (3 H), 7.35 (2 H), 4.66 (2 H), 4.46 (2 H), 3.55 (3 H), 3.24 (2 H), 3.10 (2 H); 13C NMR (DMF-d7) d 172.8, 167.6, 163. 1, 162.9, 162.7, 162.3, 138.5, 137.5, 133.8, 132.3, 131.9, 130. 6, 128.9, 120.0, 63.8, 54.8, 50.0, 37.3; MS (FAB) m / z (relative intensity) 468 (MH +, 99), 544 (18), 528 (15), 472 (13), 471 (16), 470 (70), 469 (24), 468 (99), 175 (14), 173 (16), 88 (18); HRMS (FAB) caled for C20H? 9Cl2N3O4S + H? 468.0551, found 468.0556. EXAMPLE 12 3-Ethyl Ester of [S- (R *, R *)] -4- [[[1-Carboxy-2- [4 - [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is ethyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (S, S)).
Example 12 was prepared from Example 4 by the procedure described in Preparation 6. The physical properties are as follows: Mp 118-121 °; [] 25D = 106 ° (c 0.88, ethanol); IR (Mull) 3283, 3196, 1665, 1606, 1561, 1539, 1516, 1431, 1414, 1345, 1327, 1271, 1219, 1195, 799 crn "1; XH NMR (300 MHz, CD3OD) d 7.59 (2 H ), 7.44 (3 H), 7.22 (2 H), 4.69 (1 H), 4.64 (1 H), 4.41 (1 H), 3.24 (3 H), 2.95 (2 H), 1.26 (3 H); 13C NMR (75MHz, CDC13) d 172.4, 171.5, 163.0, 154.8, 136.7, 136.6, 132.4, 132.1, 130.6, 129.9, 127.9, 120.3, 63.0, 62.7, 53.1, 36.7, 14.3, MS (FAB) m / z ( relative intensity) 540 (MH *, 59), 544 (12), 543 (17), 542 (53), 540 (59), 160 (32), 123 (15), 118 (20), 107 (99) , 95 (11), 23 (21); HRMS (FAB) caled for C23H23C12N306S + H540.0762, found 540.0730, Anal.Called for C23H23C1_N306S: C, 51.12; H, 4.29; N, 7.78. Found: C, 50.77; H, 4.43; N, 7.68.Example 13 3- (1, 1-dimethylethyl) acid ester [R- (R *, S *)] -4- [[[1- [[4 - [(2, 6 -Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA._, RA.2 are equal to and equal to H, R3 is t-butyl, Y is C02, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (R, S)).
Example 13 was prepared as described in Scheme A from L-cysteine using di-t-butyl dicarbonate to form the required carbamate. The physical data are as follows: IR (Mull) 1746, 1666, 1606, 1562, 1538, 1516, 1432, 1413, 1324, 1267, 1260, .1216, 1195, 1162, 799 cm "1; XH NMR (CDC13) d 7.56 (2 H), 7.46 (1 H), 7.33 (3 H), 7.13 (2 H), 6.94 (1 H), 4.75 (3 H), 4.25 (1 H), 3.75 (3 H), 3.39 (1 H), 3.14 (3 H), 1.43 (9 H), 13 C NMR (DMSO-d6 d 171.6, 171.5, 170.7, 170.1, 161.7, 152.6, 137.0, 136.9, 136.2, '132.6, 132.6, 131.2, 131.0 , 129.3, 128.1, 119.1, 79.7, 78.2, 61.5, 53.4, 53.3, 51.8, 49.3, 49.1, 35.8, 27.6; MS (ESI +) for C 26 H 29 C 12 N 306 S m / z 604 (M + Na) +; MS (ESI-) for C2gH29Cl2N30gS m / z 580 (MH) "; Anal Caled for C26H29C12N306S .0.17 H20: C, 53.34; H, 5.05; N, 7.18 Found: C, 53.47; H, 5.14; N, 7.15 percent Water (KF): 0.51 Example 14 3- (1, 1-dimethylethyl) ester of acid [R- (R *, S *)] -4- [[[1- Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-8: wherein RA.?, RA_2 are equal to and equal to H, R3 is t-butyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (R, S)).
Example 14 was prepared from Example 13 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 32.85 1665, 1607, 1562, 1538, 1516, 1432, 1413, 1394, 1327, 1259 , 1217, 1195, 1162, 799 cm "1; XH NMR (DMS0-d6) d 12.70 (1 H), 10.67 (1 H), 8.14 (1 H), 7.51 (5 H), 7.20 (2 H), 4.56 (1 H), 4.35 (3 H), 2.98 (3 H), 1.22 (9 H), 13 C NMR (DMSO-d6 d 172.5, 170.1, 169.9, 161.6, 152.6, 136.9, 136.3, 133.0, 131.2, 131.0 , 129.4, 128.1, 119.1, 79.8, 79.7, 61.6, 53.4, 49.2, 48.3, 35.9, 27.6, 20.9; HRMS (FAB) caled for C25H27C12N306S + H? 568.1075, found 568.1058; MS (ESI +) for C25H27C12N306S m / z 567.8 (M + H) +; MS (ESI-) for C25H27C12N306S m / z 565.8 (MH) "; Anal.Called for C25H27C12N306S .0.24 H20: C, 52.43; H, 4.84; N, 7.34.
Found: C, 52.23; H, 4.76; N, 7.24. percent Water (KF): 0.75. EXAMPLE 15 3-Ethyl acid ester [R- (R *, S *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy- 2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA.?, RA_2 are equal to and equal to H, R3 is ethyl, Y is C02, Rs is 4- [(2, 6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (R, S)).
Example 15 was prepared as described in Scheme A from L-cysteine using ethyl chloroformate to form the required carbamate. The physical data are the following: IR (Mull) 1744, 1666, 1606, 1561, 1538, 1515, 1445, 1431, 1414, 1345, 1325, 1270, 1216, 1194, 1184 cm "1; H NMR (CDC13) d 7.55 (2 H), 7.36 (4 H), 7.13 (2 H), 6.95 (1 H), 4.74 (3 H), 4.21 (3 H), 3.75 (3 H), 3.40 (1 H), 3.13 (3 H). 1.26 (3 H); 13 C NMR (CDCl 3 d 7.55 (2 H), 7.36 (4 H), 7.13 (2 H), 6.95 (1 H), 4.74 (3 H), 4.21 (3 H), 3.75 (3 H), 3.40 (1 H), 3.13 (3 H), 1.26 (3 H); 13 C NMR (CDC13) d 171.2, 169.4, 162.3, 136.2, 135. 8, 132.4, 132.2, 131.0, 130.3, 130.1, 129.9, 128.2, 128.0, 127. 9, 120.2, 62.9, 62.7, 53.2, 52.5, 37.1, 14.5, 14.3; MS (ESI +) for C 24 H 25 Cl 2 N 30 g S m / z 553.8 (M + H) +; MS (ESI-) for C24H25C12N306S m / z 551.8 (MH) "; Anal Caled for C24H25C12N306S .0.24 H20: C, 51.59; H, 4.60; N, 7.52, Found: C, 51.89; H, 4.62; N, 7.51. Percent Water (KF) ): 0.77 Example 16 3-Ethyl acid ester [R- (R *, S *)] -4- [[[1-Carboxi-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is ethyl, Y is C02, R5 is 4- [(2, 6- dichlorobenzoyl) amino] phenyl, and stereochemistry is (R, S)).
Example 16 was prepared from Example 15 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3287, 1664, 1606, 1561, 1539, 1516, 1445, 1431, 1414, 1346, 1327, 1271, 1217, 1195, 799 cm-1; XH NMR (DMS0-d6) d 12.80 (1 H), 10.69 (1 H), 8.26 (1 H), 7.51 (5 H), 7.19 (2 H), 4.62 (2 H), 4.37 (2 H), 3.94 (2 H), 2.96 (3 H), 1.11 (3 H); 13C NMR (DMSO-d6 d 172.5, 169.6, 161.7, 153.5, 136.9, 136.3, 133.0, 131.2, 131.0, 129.5, 128.1, 119.1, 61.2, 53.4, 52.5, 35.9, 22.3, 14.3; MS (ESI +) for C23H23C12N306S m / z 540.0 (M + H) *; MS (ESI-) for C23H23C12N306S m / z 538.0 (MH) '; HRMS (FAB) caled for C23H23Cl2N3OßS + H? 540.0762, found 540.0775; Anal.Called for C23H23C12N306S .0.34 H20 : C, 50.54; H, 4.37; N, 7.69, Found: C, 50.53; H, 4.48; N, 7.59. percent Water (KF): 1.13 Example 17 Ester 3- (1,1-dimethylethyl) acid [R- (R *, S *)] -4 - [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -5,5-dimethyl-3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA.?, RA_2 are equal and equal to CH3, R3 is t-butyl, Y is C02, R5 is 4- [(2, 6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (R, S)) Example 17 was prepared as described in Scheme A from L-penicillamine using di-t-butyl dicarbonate to form the required carbamate. data s musicians are: IR (Mull) 1747, 1666, 1606, 1562, 1537, 1516, 1432, 1413, 1324, 1268, 1259, 1213, 1195, 1161, 1142 crn "1; aH NMR (CDC13) d 7.56 (2 H), 7.34 (4 H), 7.21 (2 H), 6.44 (1 H), 4.94 (1 H), 4.60 (2 H), 4.08 (1 H), 3.70 ( 3 H), 3.10 (2 H). 1.53 (3 H), 1.42 (9 H), 1.25 (3 H); 13C NMR (CDC13) d 171.4, 162.3, 136.3, 135.8, 132.6, 132.4, 131.0, 130.2, 130.0, 128.2, 120.5, 120.2, 72.7, 63.9, 60.4, 52.9, 52.3, 48.3, 38.0, 30.3, 28.1, 23.9, 21.0, 14.2; MS (ESI +) for C28H33Cl2N3OgS m / z 630.7 (M + Na) *; Anal. Caled for .0.13 H20: C, 54.87; H, 5.47; N, 6.86. Found: C, 54.54; H, 5.55; N, 6.54. percent Water (KF): 0.38. Example 18 Ester 3 - [9H-fluoren-1-yl] methyl] acid [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] ] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA__, RA.2 are equal to and equal to H, R3 is 9-fluoronylmethyl, Y is C02, R5 is 4 - [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
Example 18 was prepared as described in Scheme A from D-cysteine using 9-f-luorenylmethyl chloroformate to form the required carbamate. The physical data are as follows: IR (Mull) 3280, 1750, 1692, 1671, 16O4, 1560, 1538, 1515, 1441, 1430, 1422, 1346, 1320, 1222, 1118 cm "1; H NMR (DMS0-d6 ) d 8.59 (1 H), 7.87 (2 H), 7.49 (12 H), 4.65 (3 H), 4.26 (4 H), 3.52 (3 H), 2.96 (3 H), 13 C NMR (DMSO-dg) ) d 171.4, 161.8, 143.5, 140.6, 137.0, 136.3, 132.5, 131.2, 131.1, 129.5, 128.1, 127.6, 127.1, 125.2, 125.1, 120.0, 119.2, 70.6, 70.0, 63.8, 63.2, 53.3, 53.1, 46.4, 36.2, 25.4; MS (ESI +) for C36H3? Cl2N30gS m / z 703.9 (M + H) *; Anal Caled for C36H3? Cl2N30gS .0.1 H20: C, 61.23; H, 4.45; N, 5.95. Found: C 61.18; H, 4.56; N, 5.89 percent Water (KF): 0.22 Example 19 Ester 3- [9H-Fluoren-1-yl] methyl] acid [S- (R *, R *)] - 4 - [[[1 -Carboxi -2- [4- [(2,6 -Dichlorobenzoyl) amino] phenyl] ethyl] amino] carbsnyl] -3-thiazolidinocarboxylic (Scheme A, A-8: wherein RA.?, RA_2 are equal and equal to H, R3 is 9-fluoronylmethyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)). U- Example 19 was prepared from Example 18 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1672, 1606, 1561, 1533, 1517, 1431, 1413, 1347, 1324, 1269, 1218, 1195, 1116, 760, 742 cm "1; ? NMR (DMS0-d6) d 10.71 (1 H), 8.32 (1 H), 7.87 (2 H), 7.47 (13 H), 7.16 (2 H), 4.62 (2 H), 4.15 (5 H), 2.90 (4 H), 8.32 (1 H), 7.87 (2 H), 7.47 (13 H), 7.16 (2 H), 4.62 (2 H), 4.15 (5 H), 2.90 (4 H); 13 C NMR (DMSO-d d 172.4, 169.2, 161.8, 143.6, 140.6, 137.0, 136.3, 133.0, 131.3, 131.1, 129.7, 129.6, 128.9, 128.2, 127.7, 127.1, 126.8, 125.2, 121.3, 120.1, 120.0, 119.2 , 53.4, 48.4, 46.4, 36.4, 29.5, 20.0, MS (ESI +) for C35H29Cl2N30gS m / z 690.1 (M + H) *, Anal.
C35H29C12N306S .0.4 H20: C, 60.25; H, 4.30; N, 6.02. Found: C, 59.88; H, 4.47; N, 5.75. percent Water (KF): 1.02. EXAMPLE 20 3-Phenylmethyl Ester of [S- (R *, R *)] -4- [[[1- [[2,6- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy- ester 2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA.?, RA_2 are equal to and equal to H, R3 is phenylmethyl, Y is C02, R5 is 4- [(2, 6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 20 was prepared as described in Scheme A from D-cysteine using benzyl chloroformate to form the required carbamate. The physical data are as follows: IR (Mull) 1748, 1694, 1690, 1673, 1610, 1561, 1542, 1517, 1441, 1430, 1408, 1355, 1324, 1269, 1217 crn "1; XH NMR (CDC13) d 7.50 (2 H), 7.33 (9 H), 7.09 (2 H), 6.75 (1 H), 5.19 (2 H), 4.78 (3 H), 4.38 (3 H), 3.73 (3 H), 3.20 ( 3 H); 13C NMR (DMSO-d6) d 171.4, 162.3, 136.3, 135.9, 135.7, 132.5, 132.4, 131.0, 130.0, 128.7, 128.4, 128.2, 128.1, 120.4, 68.2, 63.3, 53.2, 52.5, 37.2; MS (ESI +) for C29H27C12N306S m / z 637.8 (M + Na) *; (MS (ESI-) for C29H27C12N306S m / z 613.8 (MH) "; Anal Caled for C29H27C12N306S .0.1 H20: C, 56.39; H, 4.43; N, 6.80. Found: C, 56.31; H, 4.67; N, 6.71. percent Water (KF): 0.19. Example 21: Ester 3-phenylmethyl acid [S- (R *, R *)] -4- [[[1- Carboxy 2 - [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Esguema A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is phenylmethyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 21 was prepared from Example 20 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3290, 3034, 1666, 1606, 1562, 1537, 1516, 1431, 1413, 1351, 1326, 1270, 1215, 1195, 799 cm "1; XH NMR (DMS0-d6) d 12.85 (1 H), 10.65 (1 H), 7.39 (10 H), 7.18 (2 H), 4.98 (2 H) , 4.65 (2 H), 4.55 (1 H), 4.33 (1 H), 3.06 (1 H), 2.83 (2 H), 13 C NMR (CD3OD) d 172.6, 163.7, 154.4, 136.8, 136.2, 136.1, 131.9 , 130.9, 129.6, 128.1, 127.9, 127.8, 127.7, 127.6, 120.0, 67.5, 66.7, 53.4, 36.5; MS (ESI-) for C_8H25C12N306S m / z 599.7 (MH) "; MS (FAB) m / z (relative intensity) 602 (MH +, 99), 678 (37), 604 (74), 603 (33), 602 (99), 560 (32), 558 (48), 468 (35), 466 (51), 371 (50), 91 (73); HRMS (FAB) caled for C28H25C12N306S + H? 602.0919, found 602.0913; Anal. Caled for C28H25C12N306S .0.23 H20: C, 55. Four. Five; H, 4.23; N, 6.93. Found: C, 55.53; H, 4.46; N, 6.88. percent Water (KF): 0.67. Example 22 3- (tricyclo [3.3.1.13, 7] dec-1-yl) acid ester [S- (R *, R *) 3 -4- [[[1- [[4- [(2, 6 -Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA.?, RA.2 are equal and equal to H, R3 is 1-adamantyl, Y is C02, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 22 was prepared as described in Scheme A from D-cysteine using 1-adamantyl fluoroformate to form the required carbamate. The physical data are as follows: IR (Mull) 3284, 3271, 1747, 1690, 1684, 1666, 1557, 1532, 1436, 1412, 1355, 1298, 1194, 1053, 799 crn "1; R NMR (DMSO-d6 ) d 10.67 (1 H), 8.41 (1 H), 7.53 (5 H), 7.17 (2 H), 4.51 (3 H), 4.23 (1 H), 3.63 (3 H), 3.22 (1 H), 3.04 (1 H), 2.90 (1 H), 2.75 (1 H), 2.01 (9 H), 1.56 (6 H), 13 C NMR (DMSO-d6) d 172.1, 162.3, 152.7, 137.6, 136.9, 133.2, 131.8, 131.6, 130.0, 128.7, 119.8, 53.8, 52.4, 36.7, 36.1, 30.6, MS (ESI +) for C32H35Cl2N306S m / z 659.7 (M + H) *; (MS (ESI-) for C32H3SCl2N30gS m / z 657.7 ( MH) -; MS (FAB) m / z (relative intensity) 660 (MH +, 8), 662 (5), 660 (8), 618 (6), 616 (8), 480 (5), 173 (7 ), 136 (11), 135 (99), 123 (14), 93 (8); Anal Caled for C 32 H 35 Cl 2 N 3? 6 S .0.04 H20: C, 58.12; H, 5.35; N, 6.35. Found: C, 58.19; H, 5.62, N, 6.25 percent Water (KF): 0.10 Example 23 3- (tricyclo [3.3.1.13, 7] dec-l-il) acid ester [S- (R *, R *)] -4- [[[l-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is 1 -admantyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
Example 23 was prepared from Example 22 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3287, 1667, 1606, 1562, 1537, 1516, 1431, 1412, 1353, 1326, 1299, 1274, 1220, 1194, 1049 cm "1; XH NMR (DMSO-dg) d 12.70 (1 H), 10.67 (1 H), 8.21 (1 H), 7.58 (5 H), 7.17 (2 H) , 4.51 (3 H), 4.22 (1 H), 3. 20 (1 H), 3.04 (1 H), 2.88 (1 H), 2.76 (1 H), 2.07 (9 H), 1.12 (6 H); 13 C NMR (DMSO-dg) d 173.1, 162.3, 152.7, 137.5, 136.9, 133.8, 131.8, 131.6, 130.1, 128.7, 119.7, 80.0, 53.8, 36.8, 36.1, 30.6; MS (ESI +) for C 31 H 33 C 12 N 306 S m / z 645.8 (M + H) +; HRMS (FAB) caled for C31H33C12N306S-H1 646.1545, found 646. 1564; Anal. Caled for C3? H33Cl2N306S .0.29 H20: C, 57.13; H, 5.19; N, 6.45. Found: C, 56.82; H, 5.21; N, 6.32. percent Water (KF): 0.80. Example 24 3- [2- (4-morpholinyl) ethyl] ester of acid [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino]] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazo-idinocarboxylic (Scheme A, A-7: where RA.?, RA_2 are equal and equal to H, R3 is 2- ( 4-morpholinyl) ethyl, Y is C02, R5 is 4-5 [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is. {S, S)). ^ p.0 Example 24 was prepared as described in Scheme A from D-cysteine using 4- (2-hydroxyethyl) morpholine to form the required carbamate. The physical data are as follows: IR (Mull) 1745, 1705, 1679, 1605, 1536, 1515, 1431, 1414, 1344, 1323, 1269, 1216, 1194, 1183, 15 1117 cm "1; XH NMR (300 MHz , CDC13) d 7.82 (1 H), 7.56 (2 H), 7.31 (3 H), 7.12 (2 H), 6.95 (1 H), 4.65 (3 H), 4.39 (3 H), 3.74 (3 H) ), 3.69 (3 H), 3.34 (1 H), 3.18 (3 H), 2,763 (5 H); 13C NMR (75 MHz, CDC13) d 171.5, 169.8, 162.9, 154.4, 136.8, 136.1, 132.1, 130.6, 129.7, 127.9, 120.2, 66.3, 62.7, 57.0, 20 53.4, 53.2, 52.4, 36.7, 29.5; MS (ESI-) for C28H32C12N407S m / z 636. 8 (M-H) -; HRMS (FAB) caled for C28H32C12N407S -H_, 639.1447, found 639.1419. Anal Caled for C2ßH32Cl2N407S: C, 52.58; H, 5.04; N, 8.76. Found: C, 52.47; H, 5.17; N, 8.69. Example 25 3- [2- (4-morpholinyl] ethyl) acid ester [S- (R *, R *)] -4- [[[1-Carboxi-2- [4- [(2, 6- dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-8: where RA_ ?, RA.2 are equal to and equal to H, R3 is 2- (4-morpholinyl) ethyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
Example 25 was prepared from Example 24 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3278, 1667, 1606, 1562, 1541, 1515, 1431, 1413, 1351, 1326, 1270, 1195, 1134, 1118, 799 cm "1; H NMR (300 MHz, DMS0-d6) d 10.64 (1 H), 8.25 (1 H), 7.50 (5 H), 7.16 (2 H), 4.60 ( 2 H), 4.44 (1 H), 4.27 (1 H), 4.06 (2 H), 3.51 (4 H), 3.43 (2 H), 3.29 (4 H), 2.42 (4 H), 13 C NMR (75) MHz, DMSO-d6) d 173.0, 172.4, 169.8, 162.3, 137.5, 136.8, 133.5, 131.7, 130.1, 128.6, 119.7, 66.6, 63.3, 57.0, 53.7, 36.7, 21.5, MS (FAB) m / z (intensity relative) 614 (MH +, 55), 629 (9), 628 (14), 627 (39), 626 (21), 625 (55), 308 (7), 141 (19), 114 (99), 113 (24), 100 (7); HRMS (FAB) caled for C 27 H 30 Cl 2 N 4 O 7 S + H 625.1290, found 625.1309.
EXAMPLE 26 3- (1, 1-dimethyl) acid ester [S- (R *, S *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amins] phenyl] methyl ] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA.?, RA-2 are equal to and equal to H, R3 is t-butyl, and is C02, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (-5, - ??)).
Example 26 was prepared as described in Scheme A from D-cysteine using di-t-butyl dicarbonate to form the required carbamate. The physical data are as follows: IR (Mull) 3293, 1746, 1666, 1606, 1562, 1538, 1516, 1432, 1413, 1324, 1260, 1216, 1195, 1162, 799 was "1; XH NMR (CDC13) d 7.55 (2 H), 7.37 (4 H), 7.14 (2 H), 4.89 (1 H), 4.66 (2 H), 4.25 (1 H), 3.75 (3 H), 3.39 (1 H), 3.24 ( 3 H), 1.44 (9 H), 13 C NMR (CDC 13) d 171.2, 169.8, 162.3, 136.3, 135. 8, 132.4, 132.3, 131.0, 130.2, 130.1, 129.9, 128.2, 128.1, 127. 9, 120.5, 120.2, 120.1, 82.2, 53.2, 52.5, 37.3, 31.0, 28.4, 28.2; MS (ESI +) for C 26 H 29 Cl 2 N 3? 6S m / z 603.9 (M + Na) +; MS (ESI-) for C26H29Cl2N30gS m / z 580.0 (MH) "; HRMS (FAB) caled for C26H29C12N306S + H? 582.1232, found 582.1231.Anal Caled for C26H29Cl2N3O6S.0.26 H20: C, 53.18; H, 5.07; N, 7.16 .
Found: C, 52.78; H, 5.14; N, 6.91. percent Water (KF): 0.66.
Exemplar 27 3- (1, 1-dimethylethyl) acid ester [S- (R *, S *)] -4- [[[1-Carboxi-2 - [4 - [(2,6-dichlorobenzoyl) amino]] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-8: where RA.lf RA-2 are equal to and equal to H, R3 is t-butyl, Y is C02, R5 is 4- [ (2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is {S, R)).
Example 27 was prepared from Example 26 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3286, 1665, 1606, 1562, 1538, 1516, 1432, 1413, 1394, 1326, 1259, 1216, 1195, 1161, 799 cm "1; XH NMR (DMSO-d6) d 12.70 (1 H), 10.63 (1 H), 8.13 (1 H), 7.51 (5 H), 7.20 (2 H) , 4.45 (4 H), 2.96 (3 H), 1.23 (9 H), 13 C NMR (DMS0-d6) d 173.1, 170.5, 162.3, 153.2, 137.5, 136.9, 131.8, 131.6, 130.0, 128.7, 119.7, 80.4 , 62.2, 54.0, 49.8, 36.5, 28.3, 21.5; MS (ESI +) for C25H27C12N306S m / z 567.9 (M + H) *; MS (ESI-) for C25H27C12N306S m / z 565.9 (MH) "; HRMS (El) caled for C25H27C12N306S .0.34 H20; C, 52.82; H, 4.79; N, 7.39. Found: C, 52.17; H, 4.90; N, 7.25. percent Water (KF): 1.07.
Example 28 3- (1, 1-dimethylethyl) acid ester [S- (R *, R *)] -4- [[[1- [[4 - [(2,6 -Dichlorobenzoyl) amino] phenyl] methyl ] - 2-met oxy-2-oxoethyl] amino] carbonyl] -5,5-dimethyl-3-thiazolidinocarboxylic acid (Scheme A, A-7: in. Where RA- ?, RA_2 are equal and equal to CH3, R3 is t-butyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)) - Example 28 was prepared as described in Scheme A from D-penicillamine using di-t-butyl dicarbonate to form the required carbamate. The physical data are the following: IR (Mull) 1744, 1707, 1688, 1678, 1657, 1606, 1562, 1541, 1516, 1431, 1414, 1326, 1253, 1161, 1140 crn "1; XR NMR (CDC13) d 7.58 (2 H), 7.36 (3 H), 7.14 (2 H), 6.55 (1 H), 4.87 (1 H), 4.56 (2 H), 4.10 (1 H), 3.72 (3 H), 3 H), 3.08 (2 H), 1. 53 (3 H), 1.44 (9 H), 1.40 (3 H); 13C NMR (CDC13) d 171.6, 162.3, 153.6, 136.4, 135.8, 132.6, 132.4, 131.0, 130.1, 129.9, 129. 8, 128.2, 120.7, 120.5, 120.3, 81.7, 73.0, 52.8, 52.6, 52.4, 48.4, 39.8, 39.5, 37.6, 30.3, 28.3, 28.0, 23.5; MS (ESI-) for C28H33C12N306S m / z 607.9 (MH) "; MS (FAB) m / z (relative intensity) 610 (MH +, 6), 512 (26), 510 (44), 117 (30), 115 (16), 99 (16), 87 (16), 59 (99), 57 (27), 57 (20), .41 (23); HRMS (FAB) caled for C28H33Cl2N3? 6S + H? 610.1545, found 610.1501; Anal Caled for C28H33Cl2N3b6S.0.67 H20: C, 54.97; H, 5.46; N, 6. 87. Found: C, 54.92; H, 5.54; N, 7.11. percent Water (KF): 0.21. EXAMPLE 29 3- (1, 1-dimethylethyl) acid ester [S- (R *, R *)] -4- [[[1-Carboxi-2 - [4 - [(2,6-dichlorobenzoyl) amino]] phenyl] ethyl] amino] carbonyl] -5,5-dimethyl-3-thiazolidinocarboxylic acid (Scheme A, A-8: where RA- ?, RA-2 are equal and equal to CH3, R3 is t-butyl, and is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is. {S, S)).
Example 29 was prepared from Example 28 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1739, 1666, 1606, 1562, 1535, 1516, 1432, 1413, 1394, 1325, 1270, 1260, 1194, 1160, 799 cm "1;: H NMR (DMS0-d6) d 12.62 (1 H), 10.62 (1 H), 8.18 (1 H), 7.51 (5 H), 7.19 (2 H) ), 4.50 (3 H), - 4.24 (1 H), 2.91 (2 H), 1.33 (12 H), 1.04 (3 H), 13 C NMR (DMS0-d6) d 172.8, 168.7, 161.9, 153.2 , 137.2, 136.5, 133.1, 131.4, 131.3, 129.6, 128.3, 119.5, 80.0, 70.9, 53.7, 48.5, 37.0, 30.7, 28.1, 27.9, 24.6, MS (ESI +) for C27H31C12N306S m / z 595.9 (M + H ) +; MS (ESI-) for C27H31C12N306S m / z 593.8 (MH) "; MS (FAB) m / z (relative intensity) 596 (MH +, 19), 672 (17), 596 (19), 499 (15), 498 (60), 497 (26), 496 (99), 494 ( 35), 173 (20), 116 (27), 57 (48); Anal. Caled for C27H3? Cl2N306S .0.27 H20; C, 53.93; H, 5.29; N, 6.99. Found: C, 53.73; H, 5.39; N, 7.10. percent Water (KF): 0.80. EXAMPLE 30 3-Ethyl acid ester [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy- 2-oxoethyl] amino] carbonyl] -5,5-dimethyl-3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA.?, RA-2 are equal and equal to CH3, R3 is ethyl, Y is C02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
Example 30 was prepared as described in the Scheme from D-penicillamine using ethyl chloroformate to form the required carbamate. The physical data are as follows: IR (Mull) 3292, 1748, 1666, 1606, 1562, 1538, 1516, 1445, 1431, 1414, 1341, 1325, 1271, 1212, 1194 was "1;? RMN (CDC13) d 7.57 (2 H), 7.37 (4 H), 7.11 (2 H), 6.49 (1 H), 4.86 (1 H), 4.59 (2 H), 4.14 (3 H), 3.75 (3 H), 3.09 ( 2 H), 1.60 (3 H), 1.54 (3 H), 1.23 (3 H), 13 C NMR (CDC 13) d 171.6, 162.3, 154.5, 136.3, 135.8, 132.6, 132.4, 131.1, 130.2, 130.1, 129.8, 128.2, 120.5, 120.4, 72.7, 62.5, 52.7, 52.5, 37.3, 30.2, 23.7, 14.6, 14.1; MS (ESI +) for C26H29C12N306S m / z 581.9 (M + H) +; MS (ESI-) for C2gH29Cl2N306S m / z 579.8 (MH) "; HRMS (El) clcd for C2gH29Cl2N3OgS, 581.1154, found 581.1132; Anal Caled for C2gH29Cl2N3O6S.0.16 H20; C, 53.35; H, 505; N, 7.18.
Found: C, 53.74; H, 5.12; N, 7.12. percent Water (KF): 0.49. EXAMPLE 31 3-Ethyl Ester of [S- (R *, R *)] -4 - [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -5,5-dimethyl-3-thiazole idinocarboxylic (Scheme A, A-8: where RA.?, RA_2 are equal and equal to CH3, R3 is ethyl, Y is C02, R5 is 4- [ (2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
Example 31 was prepared from Example 30 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3287, 3070, 1666, 1606, 1562, 1538, 1516, 1431, 1414, 1342, 1328, 1271, 1213, 1194, 799 cm "1;? NMR (DMS0-d6) d 12.58 (1 H), 10.63 (1 H), 8.22 (1 H), 7.51 (5 H), 7.20 (2 H) , 4.51 (3 H), 3.95 (3 H), 3.04 (1 H), 2.86 (1 H), 1.35 (3 H), 1.16 (6 H), 13 C NMR (DMSO-dg) d 223.3, 184.1 , 183.9, 172.8, 168.4, 161.7, 136.9, 136.3, 133.1, 131.2, 131.0, 129.4, 128.1, 119.2, 70.6, 61.1, 53.6, 53.4, 48.6, 36.2, 30.1, 25.4, 24.3, 21.0, 14.1, MS (ESI + ) for C25H27Cl2N30gS m / z 568.0 (M + H) +; MS (ESI-) for C25H27C12N306S m / z 565.9 (MH) -; MS (FAB) m / z (relative intensity) 568 (MH +, 86), 644 ( 18), 571 (19), 570 (61), 569 (30), 568 (86), 335 (16), 188 (99), 173 (19), 141 (53), 116 (23); HRMS (FAB) caled for C25H27C12N306S + H? 568.1075, found 568.1096; Anal. Caled for C25H27C12N306S .0.4 H20; C, 52.16; H, 4.87; N, 7.30. Found: C, 52.46; H, 4.90; N, 7.15. percent Water (KF): 1.25. Example 32 3- (1, 1-dimethylethyl) acid ester [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] methyl ] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA.?, RA_2 are equal to and equal to H, R3 is t-butyl, and is C02- , R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (S, S)).
Example 32 was prepared as described in Scheme A from D-cysteine using di-t-butyl dicarbonate to form the required carbamate. The physical data are the following. IR (liq) 1745, 1702, 1565, 1511, 1467, 1439, 1368, 1299, 1241, 1197, 1177, 1162, 1017, 778, 768 crn'1; XH NMR (CDC13) d 7.36 (2 H), 7.25 (1 H), 7.06 (2 H), 6.94 (2 H), 5.23 (2 H), 4.75 (3 H), 4.12 (1 H), 3.72 ( 3 H), 3.37 (1 H), 3.14 (3 H), 1.45 (9); 13 C NMR (CDCl 3) d 171.5, 157.9, 136.9, 132.0, 130.3, 128.4, 128.2, 115.0, 81.9, 65.1, 62.8, 53.2, 52.3, 49.2, 36.9, 28.1, 27.9; MS (ESI +) for C2gH30Cl2N2O6S m / z 568.9 (M + H) *; MS (ESI-) for C 26 H 30 Cl 2 N 2 O 6 S m / z 566.7 (MH) "; Anal Caled for C 26 H 30 Cl 2 N 2 O 6 S.0.09 H20; C, 54.68; H, 5.33; N, 4.91. Found: C, 54.62; H, 5.41; N, 4.73. percent Water (KF): 0.28 Example 33 3- (1, 1-dimethylethyl) acid ester [S- (R *, R *)] -4- [[[l-Carboxi-2- [4 - [ (2,6-dichlorofenyl) methoxy] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-8: where RA.?, RA_2 are equal to and equal to H, R3 is t-butyl, Y is C02-, Rs is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (S, S)).
Example 33 was prepared from Example 32 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1734, 1704, 1676, 1612, 1565, 1511, 1439, 1393, 1300, 1241, 1196, 1178, 1162, 777, 769 cnr1; XH NMR (DMSO-d6) d 8.24 (1 H), 7.50 (3 H), 7.13 (2 H), 6.93 (2 H), 5.16 (2 H), 4.52 (3 H), 4.21 (1 H), 2.91 (4 H), 1.31 (9 H); 13 C NMR (DMSO-dg) d 172.7, 169.7, 157.1, 152.6, 135.9, 131.7, 131.5, 130.2, 129.8, 128.7, 114.2, 79.8, 64.8, 61.6, 53.2, 49.2, 36.0, 34.8, 27.8, 21.0; MS (ESI +) for C25H28C12N206S m / z 554.9 (M + H) +; MS (ESI-) for C25H28C12N206S m / z 552.8 (M-H) -; Anal. Caled for C25H28C12N206S .0.15 H20; C, 53.79; H, 5.11; N, 5.02. Found: C, 54.17; H, 5.17; N, 5.00. percent Water (KF): 0.50. EXAMPLE 34 3-Ethyl acid ester [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] methyl] -2-methoxy- 2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA- ?, RA.2 are equal and equal to H, R3 is ethyl, Y is C02-, R5 is 4- [ (2,6-dichlorofenyl) methoxy] phenyl, and stereochemistry is (S, S)).
The example was prepared as described in Scheme A from D-cysteine using ethyl chloroformate to form the required carbamate. The physical data are as follows: IR (Mull) 3282, 1742, 1705, 1692, 1664, 1562, 1509, 1436, 1352, 1343, 1236, 1196, 1175, 1015, 786 crn "1; lH NMR (CDC13) d 7.37 (2 H), 7.25 (1 H), 7.05 (2 H), 6.94 (2 H), 6.74 (1 H), 5.23 (2 H), 4.77 (3 H), 4.34 (1 H), 4.18 ( 2 H), 3.74 (3 H), 3.37 (1 H), 3.13 (3 H), 1.31 (3 H), 13 C NMR (CDC 13) d 171.6, 171.4, 158.0, 137.0, 132.1, 130.5, 130.4, 128.5, 128.2, 115.0, 65.2, 63.6, 63.2, 62.7, 53.6, 53.2, 52.4, 36.9, 14.5; MS (ESI +) for C24H26C12N206S m / z 540.9 (M + H) *; HRMS (El) caled for C24H26Cl2N2OgS 540.0889, found 540.0878; Anal Caled for C24H26C12N206S .0.26 H20; C, 52.79; H, 4.89; N, 5.13.
Found: C, 52.41; H, 4.82; N, 4.96. percent Water (KF): 0.85. EXAMPLE 35 3-Ethyl Ester of [S- (R *, R *)] -4- [[[1-Carboxy-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] carbonyl] -3-t iazole idinocarboxylic (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is ethyl, Y is C02-, R5 is 4- [(2, 6- dichlorofenyl) methoxy] phenyl, and stereochemistry is (S, S)).
Example 35 was prepared from Example 34 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) iy09, 1675, 1612, 1565, 1511, 1439, 1416, 1346, 1300, 1241, 1196, 1179, 1115, 1018, 768 cm-1; XH NMR (CDC13) d 7.34 (2 H), 7.23 (1 H), 7.12 (2 H), 6.94 (2 H), 6.85 (1 H), 5.22 (2 H), 4.77 (4 H), 4.34 (1 H), 4.16 (2 H), 3.33 (4 H), 1.26 (3 H); 13C NMR (CDC13) d 174.0, 170.2, 158.1, 155.1, 137.0, 132.0, 130.5, 128.5, 128.1, 115.0, -65.2, 63.9, 63.0, 62.9, 53.3, 36.4, 21.9, 14.5; MS (ESI +) for C23H24C12N206S m / z 527.0 (M + H) *; MS (ESI-) for C23H24Cl2N20gS m / z 524.9 (M-H) "; HRMS (El) caled for C23H24C12N205S 526.0732, found 526.0726; Anal. Caled for C 23 H 24 Cl 2 N 2 O 6 S.0.20 H20; C, 52.02; H, 4.63; N, 5.27.
Found: C, 52.12; H, 4.73; N, 5.34. percent Water (KF): 0.69. Example 36 3 [2- (4-morpholinyl) ethyl] acid ester [S- (R *, R *)] -4- [[[1 - [[4 - [(2,6 -Dichlorophenyl) methoxy] phenyl] ] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA.?, RA_2 are equal to and equal to H, R3 is 2- (4-morpholinyl ethyl), Y is C02-, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (£?, £?)).
Example 36 was prepared as described in Scheme "A from D-cysteine using 4- (2-hydroxyethyl) morpholine to form the required carbamate.The physical data are as follows: Mp 138-140 ° C; Mull) 3286, 1743, 1705, 1660, 1559, 1513, 1435, 1428, 1302, 1245, 1226, 1215, 1176, 1015, 764 cm "1; XH NMR (300 MHz, DMS0-d6) d 8.43 (1 H), 7.48 (3 H), 7.13 (2 H), 6.94 (2 H), 5.16 (2 H), 4.59 (2 H), 4.48 (1 H), H), 4.26 (1 H), 4.07 (2 H), 3.63 (3 H), 3.51 (4 H), 3.23 (1 H), 3.01 (1 H), 2.84 (1 H), 2.71 (1 H) 2.41 (6 H); 13 C NMR (75 MHz, DMSO-dg) d 172.2, 157.7, 153.9, 136.5, 132.2, 132.0, 130.8, 130.1, 129.2, 114.8, 66.6, 65.4, 63.4, 57.0, 53.9, 53.8, 52.4, 36.4; MS (ESI +) for C28H31C12N307S m / z 625.8 (M + H) *; Anal Caled for C28H31C12N307S: C, 53.67; H, 5.31; N, 6.71. Found: C, 53.69; H, 5.27; N, 6.69. EXAMPLE 37 3- [2- (4-morpholinyl) ethyl] ester of acid [S- (R *, R *)] ~ 4 - [[[1-Carboxi-2 - [4 - [(2,6-dichlorophenyl)] ) methoxy] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-8: where RA.?, RA.2 are equal to and equal to H, R3 is 2- (4-morpholinyl) ethyl, Y is C02-, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (S, S)).
Example 37 was prepared from Example 36 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1710, 1610, 1585, 1565, 1511, 1439, 1408, 1351, 1301, 1240, 1196, 1179, 1116, 1017, 767 cm "1; H NMR (300 MHz, DMSO-d6) d 8.27 (1 H), 7.55 (2 H), 7.45 (1 H), 7.13 (2 H), 6.94 ( 2 H), 5.16 (2 H), 4.57 (2 H), 4.40 (1 H), 4.27 (1 H), 4.04 (2 H), 3.52 (4 H), 3.21 (1 H), 2.86 (3 H) ), 2.44 (6 H), 13 C NMR (75 MHz, DMSO-d6) d 173.2, 172.5, 157.6, 136.5, 132.2, 132.0, 130.8, 130.4, 129.2, 114.7, 66.5, 65.3, 63.2, 57.0, 53.9, 53.7 , 36.5, 21.5; MS (ESI +) for C27H3? Cl2N307S m / z 611.9 (M + H) *; Anal Caled for C27H3? Cl2N307S .1.0 C2H4O2.0.63 H2O.0.28 HCl: C, 50.13; H, 5.31; N 6.03; Cl, 11.59 Found: C, 49.80, H, 5.30, N, 6.05, Cl, 11.20, percent Water (KF): 1.58 Example 38 3- [2-pyridinyl) methyl] acid ester [S - (R *. R *)] -4- [[[1 - [[4 - [(2,6-Dichlorophenyl) methoxy] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbon il] -3-iazolidinocarboxílico (Scheme A, A-7: where RA.?, RA_2 are equal and equal to H, R3 is 2-pyridinylmethyl, Y is C02-, R5 is 4- [(2,6-dichlorophenyl) ) methoxy] phenyl, and stereochemistry is (S, S)).
Example 38 was prepared as described in Scheme A from D-cysteine using 2-pyridinemethanol to form the required carbamate. The physical data are as follows: Mp 123-125 ° C; IR (Mull) 3334, 1728, 1709, 1668, 1531, 1511, 1441, 1405, 1345, 1294, 1286, 1236, 1228, 1015, 762 cm "1; XH NMR (300 MHz, DMSO-d6) d 8.57 ( 2 H), 7.79 (1 H), 7.54 (2 H), 7.42 (1 H), 7.27 (2 H), 7.12 (2 H), 6.92 (2 H), 5.13 (4 H), 4.69 (2 H) ), 4.49 (1 H), 4.34 (1 H), 3.59 (3 H), 3.24 (1 H), 2.89 (3 H); 13 C NMR (75 MHz, DMS0-d6) d 172.2, 169.9, 157.7, 156.5, 153.6, 137.3, 136.5, 132.2, 132.0, 130.8, 130.1, 129.2, 123.2, 121.0, 114.8, 67.7, 65.3, 62.0, 54.0, 52.4 , 50.3, 36.3, 35.3; HRMS (El) caled for C28H27C12N306S 603.0997. Anal Caled for C28H27Cl2N3OgS: C, 55.63; H, 4.50; N, 6.95. Found: C, 55.56; H, 4.59; N, 6.93. Example 39 3- [2- (1-pyrrolidinyl) ethyl] ester of [S- (R *, R *)] -4 - [[[1 - [[4 - [(2,6-dichlorophenyl) methoxy]] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme A, A-7: where RA-_, RA.2 are equal and equal to H, R3 is 2 - ( 1-pyrrolidinyl) ethyl, Y is C02-, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (£?, £?)).
Example 39 was prepared as described in Scheme A from D-cysteine using 1- (2-hydroxyethyl) pyrrolidine to form the required carbamate. The physical data are the following: Mp 130-132 ° C; IR (Mull) 1745, 1702, 1661, 1556, 1513, 1435, 1426, 1303, 1245, 1226, 1214, 1176, 1017, 8.25, 765 crn "1; XH NMR (300 MHz, DMSO-d6) d 8.42 ( 1 H), 7.48 (3 H), 7.13 (2 H), 6.94 (2 H), 5.16 (2 H), 4.59 (2 H), 4.48 (1 H), 4.27 (1 H), 3.99 (2 H), ), 3.63 (3 H), 3.24 (1 H), 2.68 (9 H), 1.62 (4 H), 13 C NMR (75 MHz, DMSO-d6) d 172.2, 170.0, 157.7, 136.5, 132.2, 132.0, 130.8 130.1, 129.2, 114.8, 65.3, 65.1, 54.4, 53.9, 52.42 36.35 23.6, MS (ESI +) for C28H33Cl2N3OgS 609.8 (M + H) *, Anal.
C28H33C12N306S: C, 55.08; H, 5.45; N, 6.88. Found: C, 54.72; H, 5.58; N, 6.60. Example 40 3- (1, 1-dimethylethyl) acid ester [R- (R *, S *)] -4- [[[1 - [[4 - [(2,6-dichlorophenyl) methoxy] phenyl] methyl ] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA.?, RA_2 are equal to and equal to H, R3 is t-butyl, and is C02- , R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (R / S)).
Example 40 was prepared as described in Scheme A from L-cysteine using di-t-butyl dicarbonate to form the required carbamate. The physical data are as follows: IR (Mull) 1746, 1702, 1611, 1565, 1511, 1439, 1299, 1241, 1197, 1177, 1162, 1118, 1016, 777, 768 was "1;? RMN (CDC13) d 7.39 (2 H), 7.25 (1 H), 6.93 (2 H), 6.93 (2 H), 5.24 (2 H), 4.72 (3 H), 4.20 (1 H), 3.74 (3 H), 3.35 ( 1 H), 3.12 (3 H), 1.44 (9 H), 13 C NMR (CDCl 3) d 171.7, 170.0, 169.5, 158.3, 137.3, 132.4, 130.7, 130.6, 128.8, 128.5, 115.2, 115.1, 82.4, 65.5, 53.5, 52.6, 50.3, 37.3, 28.4; MS (ESI +) for C26H30Cl2N2O6S 554.9 (M + H) +; MS (ESI-) for C26II30Cl2N2O6S m / z 552.8 (MH) "; Anal. Caled for C 26 H 30 Cl 2 N 2 O g S .0.1 H20: C, 54.65; H, 5.33; N, 4.90. Found: C, 54.59; H, 5.30; N, 4.88. percent Water (KF): 0.33 E emplo 41 3- (1, 1-dimethylethyl) acid ester [R- (R *, S *)] -4- [[[1-carboxy -2- [4- [ (2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] carbonyl] -3-iazolidinocarboxylic acid (Scheme A, A-8: where RA._, RA.2 are equal to and equal to H, R3 is t-butyl , Y is C02-, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (R, S)).
Example 41 was prepared from Example 40 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1737, 1705, 1679, 1612, 1565, 1512, 1439, 1300, 1241, 1196, 1178, 1163, 1117, 777, 769 cm'1; a H NMR (DMS0-d6) d 8.07 (1 H), 7.54 (2 H), 7.44 (1 H), 7.16 (2 H), 6.93 (2 H), 5.16 (2 H), 4.56 (1 H), 4.39 (3 H), 3.56 (1 H), 2.84 (3 H), 1.23 (9. H); 13C NMR (DMS0-d6) d 172.7, 169.9, 157.0, 152.6, 135.9, 131.6, 131.4, 130.1, 129.9, 129.8, 128.7, 114.1, 79.8, 66.9, 64.7, 61.7, 53.5, 49.3, 35.6, 34.8, 27.9, 27.6; MS (ESI +) for C25H28C12N206S m / z 554.9 (M + H) *; MS (ESI-) for C25H28C12N206S m / z 552.8 (M-H) "; Anal.Called for C25H28Cl2N2O6S.0.27 H20: C, 53.59; H, 5.13; N, 5.00; Found: C, 53.97; H, 5.14; N, 4.96. percent Water (KF): 0.86. Example 42 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- (ethylsulfonyl) -4-thiazolidinyl] carbonyl] -L-phenylalanine methyl ester (Scheme A, A-7: where RA.?, RA.2 are equal and equal to H, R3 is ethyl, Y is S02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (£?, £?)).
Example 42 was prepared as described in Scheme a from D-cysteine using ethanesulfonyl chloride to form the required sulfonaminase. The physical data are as follows: IR (Mull) 1743, 1666, 1605, 1561, 1535, 1515, 1432, 1413, 1328, 1269, 1219, 1195, 1146, 799, 782 cm-1; K NMR (CDCl 3) d 7.58 (2 H), 7.46 (1 H), 7.32 (3 H), 7.17 (2 H), 7.07 (1 H), 4.85 (1 H), 4.73 (2 H), 4.28 ( 1 H), 3.76 (3 H), 3.54 (1 H), 3.26 (lH), 3.05 (4 H), 1.40 (3 H); 13C NMR (CDC13) d 171.3, 168.2, 162.4, 136.4, 135.8, 132.4, 132.3, 131.0, 130.1, 128.2, 120.6, 64.9, 53.2, 52.6, 51.5, 45.8, 37.1, 34.2, 31.0, 29.3, 7.7; MS (ESI +) for C23H2SC12N306S2 m / z 573.9 (M + H) *; MS (ESI-) for C 23 H 25 Cl 2 N 306 S 2 m / z 571.1 (M-H) -; HRMS (FAB) caled for C23H25C12N306S2 + H? 574.0640, found 574.0634; Anal. Caled for C23H25C12N306S2.0.1 H20: C, 47.97; H, 4.40; N, 7.30. Found: C, 48.36; H, 4.59; N, 6.80. EXAMPLE 43 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- (ethylsulfonyl) -4-thiazolidinyl] carbonyl] -L-phenylalanine (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is ethyl, Y is S02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 43 was prepared from Example 42 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1734, 1664, 1605, 1562, 1536, 1516, 1432, 1414, 1330, 1272, 1234, 1195, 1146, 799, 781 cm "1; XH NMR (DMSO-dg) d 12.91 (1 H), 10.65 (1 H), 8.15 (1 H), 7.51 (5 H), 7.17 (2 H) , 4.77 (2 H), 4.43 (1 H), 4.29 (1 H), 3.94 (6 H), 1.20 (3 H), 13 C NMR (DMS0-d6) d 172.5, 168.9, 161.9, 137.1, 136.5, 133.2 , 131.4, 131.3, 129.8, 128.3, 119.3, 63.7, 53.6, 51.4, 45.3, 36.1, 34.7; MS (ESI +) for C_2H23Cl2N30gS2 m / z 559.9 (M + H) *; MS (ESI-) for C22H23C12N306S2 m / z 557.8 (M-H) -; HRMS (FAB) caled for C22H23C12N306S2 + H? 560.0483, found 560.0488; Anal. Caled for C22H23C12N306S2.0.72 H20: C, 46.08; H, 4.30; N, 7.33. Found: C, 46.42; H, 4.37; N, 7.01. percent Water (KF): 2.26. Example 44 4- [(2,6-Dichlorobenzoyl) amino] -N - [[(4S) -3 - [[5- (trifluoromethyl) -2-pyridinyl] sulfonyl] -4-thiazolidinyl] carbonyl] - methyl ester L-phenylalanine (Scheme A, A-7: where RA.?, RA_2 are equal to and equal to H, R3 is 2- (5-trifluoromethylpyridyl), Y is S02, R5 is 4- [(2,6-dichlorobenzoyl ) amino] phenyl, and stereochemistry is IS, S)) - Example 44 was prepared as described in Scheme A from D-cysteine using 2- (5-trifluoromethylpyridyl) sulfonyl chloride to form the required sulfonamide. The physical data are as follows: IR (Mull) 1745, 1668, 1603, 1535, 1515, 1432, 1413, 1327, 1219, 1179, 1142, 1108, 1073, 1016, 616 cm "1; XH NMR (CDCl3) d 8.76 (1 H), 8. 17 (2 H), 7.90 (1 H), 7.51 (2 H), 7.32 (4 H), 7.17 (2 H), 5. 18 (1 H), 4.96 (1 H), 4.66 (1 H), 4.31 (1 H), 3.78 (3 H), 3.52 (1 H), 3.15 (3 H); 13 C NMR (CDCl 3) d 171.3, 168.4, 162.2, 147. 2, 136.2, 136.0, 132.4, 131.0, 130.3, 128.2, 123.0, 120.4, 120. 3, 65.7, 53.6, 52.5, 51.4, 37.3, 34.0; MS (ESI +) for C27H23C12N406S2 m / z 690.8 (M + H) +; MS (ESI-) for C 27 H 23 Cl 2 N 40 g S 2 m / z 712.9 (M + Na) *; Anal. Caled for C27H23Cl2N4OgS2.0.2 H20: C, 46.68; H, 3.39; N, 8.06. Found: C, 46.60; H, 3.52; N, 7.92. percent Water (KF): 0.47. EXAMPLE 45 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- [[5- (tri f luoromethyl) -2-pyridinyl] sulphonyl] -4-thiazolidinyl] carbonyl] -L-phenylalanine (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is 2- (5-trif luoromethylpyridyl), Y is S02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, stereochemistry is Example 45 was prepared from Example 44 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1740, 1666, 1602, 1562, 1533, 1517, 1432, 1354, 1327, 1179, 1143, 1108, 1074, 1016, 613 cm "1; H NMR (DMSO-dg) d 10.63, (1 H), 9.24 (1 H), 8.54 (1 H), 8.46 (1 H), 8.18 (1 H) ), 7.50 (5 H), 7.17 (2 H), 5.00 (1 H), 4.74 (1 H), 4.42 (2 H), 3.04 (2 H), 2.90 (1 H), 2.78 (1 H); 13 C NMR (DMSO-dg) d 172.8, 1.68.9, 162.2, 162.3, 159.0, 147.8, 137.5, 137.4, 136.9, 133.5, 131.8, 131.7, 130.2, 128.7, 123.8, 119.7, 64.7, 53.9, 52.3, 36.7, 35.1; MS (ESI +) for C2gH2? Cl2F3N4OgS2 m / z 676.5 (M + H) *; MS (ESI-) for C26H21Cl2F3N4OgS2 m / z 674.5 (M-H) "; Anal. Caled for C26H21Cl2F3N4? 6S2.0.33: C, 45.69; H, 3.20; N, 8.20. Found: C, 45.81; H, 3.38; N, 8.13. percent Water (KF): 0.88. EXAMPLE 46 4- (2,6-Dichlorobenzoyl) amino] -N - [[(4S) -3- (phenylsulfonyl) -4-thiazolidinyl] carbonyl] -L-phenylalanine methyl ester (Scheme A, A-7: where RA.?, RA.2 are equal and equal to H, R3 is phenyl, Y is S02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)) - Example 46 was prepared as described in Scheme a from D-cysteine using benzenesulfonyl chloride to form the required sulfonamide. The physical data are as follows: IR (Mull) 1744, 1668, 1604, 1531, 1515, 1432, 1413, 1355, 1324, 1268, 1220, 1195, 1167, 1090, 730 cm'1; tR NMR (CDC13) d 7.84, (2 H), 7.65 (5 H), 7.45 (1 H), 7.30 (6 H), 4.90 (1 H), 4.63 (2 H), 4.37 (1 H), 3.75 (3 H), 3.32 (1 H), 3.15 (2 H), 2.53 (1 H); 13 C NMR (CDCl 3) d 171.2, 168.2, 162.4, 136.4, 136.3, 134.1, 132.4, 131.0, 130.2, 129.6, 128.2, 128.1, 127.9, 120.6, 65.3, 53.3, 52.6, 51.8, 37.4, 33.3; MS (ESI +) for C27H25C12N306S2 m / z 621.8 (M + H) *; MS (ESI-) for C27H25C12N306S2 m / z 619.8 (M-H) "; Anal. Caled for C27H25C12N306S2.0.2 H20: C, 51.84; H, 4.18; N, 6.72. Found: C, 51.72; H, 4.18; N, 6.52. percent Water (KF): 0.48. Example 47 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- (phenylsulfonyl) -4-thiazolidinyl] carbonyl] -L-phenylalanine (Scheme A, A-8: wherein RA .?, RA_2 are equal and equal to H, R3 is phenyl, Y is S02, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 47 was prepared from Example 46 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1735, 1666, 1605, 1562, 1533, 1516, 1432, 1414, 1352, 1328, 1195, 1180, 1167, 5 1090, 731 cm "1;? NMR (CDC13) d 8.11, (1 H), 7.82 (2 H), 7.66 (3 H), 7.56 (2 H), 7.23 (6 H), 4.91 (1 H), 4.66 (1 H), 4.60 (1 H), 4.35 (1 H), 3.30 (1 H), 3.19 (2 H), H) 2.59 (1 H); 13 C NMR (DMSO-dg) d 172.2, 168.2, 161.7, 137.0, 136.9, 136.3, 133.6, 133.0, 131.2, 131.1, 129.6, 129.3, 128.1, 127.6, 119.2, 63.9, '10 53.4, 51.5, 48.4, 36.0, 33.8; MS (ESI +) for C26H23Cl2N3OgS2 m / z 607. 9 (M + H) S-MS (FAB) m / z (relative intensity) 608 (MH +, 85), 610 (67), 608 (85), 466 (30), 371 (41), 228 (38) , 193 (38), 149 (30), 129 (31), 118 (99), 63 (35); HRMS (FAB) caled for C26H23C12N306S2 + H1 608.0483, found: 608.0491; Anal. Caled 15 for Ca6H23Cl_N306S2 0.27 H20: C, 50.91; H, 3.87; N, 6.85.
Found: C, 50.68; H, 4.05; N, 6.65. percent Water (KF): 0.79. - Example 48: 4- [(2,6-Dichlorobenzoyl) amino] -N- 20 [[(4S) -3- [[5- (dimethylamino) -1-naphthalenyl] sulfonyl] -4-thiazolidinyl] methyl ester carbonyl] -L-phenylalanine (Scheme A, A-7: where RA__., RA_2 are equal and equal to H, R3 is 5-dimethylamino-l-naphthyl, Y is S02, R5 is 4- [(2, 6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (£?, _?)). Example 48 was prepared as described in Scheme A from D-cysteine using 5-dimethylamino-1-naphthalenesulfonyl chloride to form the required sulfonamide. The physical data are as follows: IR (Mull) 1744, 1684, 1605, 1562, 1533, 1515, 1431, 1412, 1350, 1324, 1231, 1202, 1163, 1145, 798 car1; JH NMR (CDC13) d 8.64, (1 H), 8.34 (2 H), 7.53 (5 H), 7.29 (4 H), 6.87 (3 H), 4.93 (1 H), 4.75 (1 H), 4.64 (1 H), 4.31 (1 H), 3.69 (3 H), 3.47 (1 H) 2.84 (8 H), 2.46 (1 H); 13C NMR (CDC13) d 171.2, 167.7, 162.5, 136.3, 135.9, 132.4, 132.3, 131.9, 131.5, 131.0, 130.1, 129.7, 129.2, 128.2, 124.4, 120.4, 65.1, 53.3, 52.5, 50.1, 45.9, 37.1, 33.3; MS (ESI +) for C33H32C12N406S2 m / z 736.8 (M + Na) +; Anal. Caled for 0.17 H20: C, 55.15; H, 4.54; N, 7.79. Found: C, 55.20; H, 4.73; N, 7.49. percent Water (KF): 0.43. Example 49 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- [[5- (dimethylamino) -1-naphthalenyl] sulfonyl] -4-thiazolidinyl] carbonyl] -L- phenylalanine (Scheme A, A-8: where RA-? RA-2 are equal and equal to H, R3 is 5-dimethylamino-l-naphthyl, Y is S02, R5 is 4- [(2, 6- dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 49 was prepared from Example 48 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1666, 1605, 1587, 1577, 1562, 1532, 1516, 1431, 1412, 1395, 1325, 1163, 1145, 798, 631 cm "1; XH NMR (DMSO-d6) d 10.60 (1 H), 8.54, (1 H), 8.28 (2 H), 7.54 (8 H), 7.25 (1 H) ), 6.93 (2 H), 4.95 (1 H), 4.84 (1 H), 4.39 (1 H), 4.17 (1 H), 2.95 (2 H), 2.80 (7 H) 2.54 (1 H); 13C NMR (DMSO-dg) d 167.2, 161.7, 151.4, 136.6, 136.3, 133.6, 133.1, 131.1, 130.8, 130.3, 129.5, 129.3, 129.0, 128.8, 128.1, 123.6, 118.9, 118.3, 115.3, 63.6, 54.2, 50.3 44.9, 36.7, 33.9, 21.0; MS (ESI +) for C32H30Cl2N4OgS2 m / z 700.8 (M + H) *; HRMS (FAB) caled for C32H30Cl2N4O6S2 + H? 701.1062, found 701.1039.
Example 50 O- [(2,6-Dichlorophenyl) methyl] -N- [[(4S) -3- (methylsulfonyl) -4-thiazolidinyl] carbonyl] -L-tyrosine methyl ester (Scheme A, A-7: wherein RA__, RA_2 are equal and equal to H, R3 is methyl, Y is S02, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (_?, _?)).
Example 50 was prepared as described in Scheme A from D-cysteine using methanesulfonyl chloride to form the required sulfonamide. The physical data are as follows: IR (Mull) 1742, 1680, 1611, 1564, 1510, 1439, 1345, 1299, 1240, 1179, 1158, 1016, 976, 779, 768 cm "1; XH NMR (CDCl3) d 7.36 (2 H), 7.24, (1 H), 7.08 (3 H), 6.97 (2 H), 5.25 (2 H), 4.77 (3 H), 4.29 (1 H), 3.74 (3 H), 3.43 (1 H), 3.53 (1 H), 3.10 (2 H), 2.93 (3 H); 13 C NMR (CDCl 3) d 171. 4, 168.0, 158.2, 137.0, 132.1, 130.3, 128.5, 127.9, 115.3, 65. 2, 65.0, 59.4, 53.5, 53.3, 52.5, 51.9, 42.2, 37.3, 36.9, 34.2; MS (ESI +) for C22H24C12N206S2 m / z 546.8 (M + H) *; MS (ESI +) for C22H24C12N206S2 m / z 568.8 (M + H) *; HRMS (El) caled for C22H24C12N206S2 546.0453, found 546.0448; Anal. Caled for C22H24C12N206S2 0.07 H20: C, 48.15; H, 4.43; N, 5.10. Found: C, 48.17; H, 4.51; N, 5.02. percent Water (KF): 0.24. Example 51 O- [(2,6-Dichlorophenyl) methyl] -N- [[(4S) -3- (methylsulfonyl) -4-thiazolidinyl] carbonyl] -L-tyrosine (Scheme A, A-8: wherein RA .1 # RA.2 are equal and equal to H, R3 is methyl, Y is S02, R5 is 4- [(2,6-dichlorofenyl) methoxy] phenyl, and stereochemistry is (S, S)).
Example 51 was prepared from Example 50 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1737, 1675, 1611, 1565, 1511, 1439, 1345, 1300, 1241, 1197, 1179, 1157, 1016, 778, 769 cm-1; H NMR (CDCl3) d 7.34 (2 H), 7.16, (5 H), 6.99 (2 H), 5.23 (2 H), 4.85 (1 H), 4.68 (2 H), 4.27 (1 H), 3.51 (1 H), 3.32 (1 H), 3.15 (2 H), 2.93 (3 H); 13C NMR (CDC13) d 174.8, 168.7, 158.3, 137.0, 132.1, 130.5, 130.4, 128.5, 127.6, 115.4, 115.2, 65.2, 64.9, 53.1, 52.0, 37.1, 36.4, 34.3; MS (ESI +) for C2? H22Cl2N206S2 m / z 532.8 (M + H) *; MS (ESI-) for C21H22C12N206S2 m / z 530.7 (M-H) -; HRMS (FAB) caled for C2? H22Cl2N20gS2 + H? 533.0374, found 533.0386; Anal. Caled for C2? H_2Cl2N2OgS2 0.06 H20: C, 47.19; H, 4.17; N, 5.24. Found: C, 47.58; H, 4.35; N, 5.10. percent Water (KF): 0.20. EXAMPLE 52 4- [(2,6 -Dichlorobenzoyl) amino] -N- [[(4S) -3- [[(1, 1-dimethylethyl) amino] carbonyl] -4-1-aiazolidinyl] carbonyl] -L-phenylalanine ( Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is t-butyl, Y is CONH-, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 52 was prepared from Example 6 by the procedure described in Preparation 6. The physical properties are as follows: IR (Mull) 3289, 1728, 1664, 1607, 1580, 1561, 1536, 1432, 1414, 1394, 1326, 1270, 1242, 1213, 1195 cm "1; XH NMR (300 MHz, CD3OD) d 7.47 (2 H), 7.24, (3 H), 7.04 (2 H), 4.63 (2 H), 4.37 (1 H), 4.17 (1 H), 3.09 (4 H), 1.22 (9 H), 13 C NMR (75 MHz, CDCl 3) d 176.9, 174.8, 167.2, 159.9, 140.5, 140.0, 136.4, 136.1, 134.6, 133.8, 131.8, 124.5, 66.6, 57.1, 55.3, 53.0, 40.1, 37.1, 32.9; MS (ESI +) for C25H28C12N405S m / z 566.9 (M + H) *; 588.9 (M + Na) +; MS (ESI +) for C25H28C12N405S m / z 566.9 (M + H) +; HRMS (FAB) caled for C25H28C12N405S + H? 567.1235, found 567.1253.Example 53 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3 - [(diethylamino) carbonyl] -4-thiazolidinyl] carbonyl] -L-phenylalanine (Scheme A, A-8: where RA.?, RA.2 are equal and equal to H, R3 is ethyl, Y is CON (CH2CH3) -, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
Example 53 was prepared from Example 7 by the procedure described in Preparation 6. The physical properties are as follows: IR (Mull) 3269, 1734, 1663, 1607, 1562, 1535, 1515, 1431, 1415, 1348, 1325, 1269, 1213, 1195, 799 crn "1; XH NMR. (300 MHz, CD3OD) d 7.57 (2 H), 7.35, (3 H), 7.09 (2 H), 5.09 (1 H), 4.76 ( 1 H), 4.38 (2 H), 3.31 (3 H), 3.13 (5 H), 1.05 (6 H), 13 C NMR (75 MHz, CD3OD) d 176.6, 173.9, 167.1, 166.3, 140.7, 140.1, 136.1 , 134.6, 133.8, 131.8, 124.1, 68.5, 57.4, 56.6, 45.9, 40.4, 36.6, 16.8; MS (ESI +) for C25H28C12N405S m / z 567.1 (M + H) *; Anal. Caled for C2c.H28Cl2N40cS: C, 52.91; H, 4.97; N, 9.87. Found: £ »52.60; H, 5.13; N, 9.47 Example 54 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- [[Methyl [2- (2-pyridinyl) ethyl] amino] carbonyl] -4-methyl ester -thiazolidinyl] carbonyl] -L-phenylalanine (Scheme A, A-7: where RA.?, RA-2 are equal and equal to H, R3 is 2- (2-pyridyl) ethyl, and is C0N (CH3) -, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 54 was prepared as described in Scheme A from D-cysteine using 2- (2-methylaminoethyl) pyridine to form the required urea. The physical data are as follows: Mp 80-90 ° C (dec); IR (Mull) 1743, 1665, 1606, 1561, 1538, 1514, 1489, 1432, 1413, 1395, 1323, 1268, 1216, 1195, 799 cm-1; ? NMR (300 MHz, DMS0-d6) d 8.44 (1 H), 8.34 / (1 H), 7.66 (1 H), 7.51 (5 H), 7.19 (4 H), 4.72 (1 H), 4.48 (1 H), 4.40 (1 H), 4.20 (1 H), 3.58 (4 H), 3.42 (1 H), 3.89 (10 H); 13 C NMR (75 MHz, DMS0-d6) d 172.1, 170.3, 162.3, 161.8, 159.4, 149.4, 137.6, 137.0, 136.8, 133.3, 131.8, 131.7, 130.0, 128.7, 123.8, 122.0, 119.8, 64.58, 53.8, 52.7, 52.5, 49.7, 36.5, 36.2, 35.7, 33.4; MS (ESI +) for C 30 H 31 Cl 2 N 5 O 5 S m / z 643.9 (M + H) *; Anal. Caled for C30H3? Cl2N5OsS: C, 55.90; H, 4.85; N, 10.86. Found: C, 55.52; H, 5.09; N, 10.64. Example 55 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- [[methyl [2- (2-pyridinyl) ethyl] amino] carbonyl] -4-thiazolidinyl] carbonyl] - L-phenylalanine (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is 2- (2-pyridyl) ethyl, Y is C0N (CH3) -, R5 is 4- [( 2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _ >)) • Example 55 was peparated from Example 54 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1682, 1656, 1606, 1561, 1540, 1513, 1432, 1413, 1398, 1323, 1268, 1242, 1195, 799, 780 cm "1; XH NMR (300 MHz, DMS0-d6) d 10.66 (1 H), 8.45 (1 H), 8.09, (1 H), 7.66 (1 H), 7.51 (5 H), 7.20 (4 H), 4.72 (1 H), 4.40 (2 H), 4.23 (1 H), 3.61 (1 H), 3.40 (1 H), 3.04 (7 H), 2.79 (3 H); MS (ESI +) for C29H29C12N505S m / z 629.9 (M + H) +; Anal.Called for C29H29Cl2N505S 0.61 H20: C, 54.29; H, 4.75; N, 10.92 Found: C, 54.29; H, 5.00 N, 10.32 percent Water (KF): 1.72 Example 56 Methyl ester of 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4S) -3- (4-morpholinylcarbonyl) -4- thiazolidinyl] carbonyl] -L-phenylalanine (Scheme A, A-7: where RA-X, RA_2 are equal and equal to H, R3 and Y together with the CO-morpholino form, R5 is 4- [(2, 6 -dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 56 was prepared as described in Scheme a from D-cysteine using morpholine to form the required urea. The physical data are the following: Mp 223-225 ° C; X H NMR (300 MHz, DMSO-d 6), d 10.66 (1 H), 8.25 (1 H), 7.51, (5 H), 7.16 (2 H), 4.81 (1 H), 4.60 (1 H), 4.50 (1 H), 4.28 (1 H), 3.64 (3 H), 3.53 (4 H), 3.09 (8 H); 13 C NMR (75 MHz, DMSO-dg) 172.1, 170.3, 162.3, 161.4, 137.6, 136.8, 133.3, 131.8, 131.7, 130.0, 128.7, 119.8, 66.2, 64.3, 53.8, 528, 52.5, 46.8, 36.1, 33.7; HRMS (FAB) caled for C2gH28CL2N4OgS + H? 595.1185, found 595.1189; Anal. Caled for C26H28CL2N4OgS: C, 52.44; H, 4.74; N, 9.41. Found: C, 52.42; H, 4.96; N, 9.23. Example 57 Methyl ester of N - [[(4S) -3 - [[Bis (2-hydroxyethyl) amino] carbonyl] -4-thiazolidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L- phenylalanine (Scheme A, A-7: where RA- ?, RA.2 are equal and equal to H, R3 is 2 -hydroxyethyl and Y CON (CH2CH2OH), R5 is 4- [(2,6-dichlorobenzoyl) amino) ] phenyl, and stereochemistry is (_ ?, £?)).
Example 57 was prepared as described in Scheme A from D-cysteine using diethanolamine to form the required urea. The physical data are as follows: Mp 105-107 ° C; IR (Mull) 3284, 1743, 1662, 1608, 1561, 1539, 1516, 1432, 1414, 1355, 1326, 1270, 1217, 1196, 799 cm "1; XH NMR (300 MHz, DMSO-dg) d 10.69 ( 1 H), 8.28 (1 H), 7.56, (4 H), 7.47 (1 H), 7.16 (2 H), 4.87 (3 H), 4.66 (1 H), 4.47 (1 H), 4.25 (1 H), 3.63 (3 H), 3.47 (6 H), 3.02 (6 H), MS (ESI +) for C26H30Cl2N4O7S m / z 612.9 (M + H) +, Anal.
C2gH30Cl2N4O7S.0.47 H20: C, 50.21; H, 5.01; N, 9.01.
Found: C, 50.02; H, 45.00 N, 8.93. percent Water (KF): 1.36. Example 58 N- [[(4S) -3- [[Bis (2-hydroxyethyl) amino] carbonyl] -4-thiazolidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L-phenylalanine (Scheme A , A-8: where RA._., RA_2 are equal and equal to H, R3 is 2 -hydroxyethyl and Y CON (CH2CH2OH), R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 58 was prepared from Example 57 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3281, 3196, 1724, 1660, 1608, 1580, 1561, 1542, 1515, 1431, 1415, 1354, 1328, 1271, 1196 cm "1; K NMR (300 MHz, DMSO-dg) d 10.65 (1 H), 8.13 (1 H), 7.55, (4 H), 7.47 (1 H), 7.16 (2 H), 4.85 (2 H), 4.66 (1 H), 4.40 (1 H), 4.27 (1 H), 3.48 (6 H), 3.01 (6 H); MS (ESI +) for C25H28C12N407S m / z 598.9 (M + H) +; Anal. Caled for C2SH28C12N407S .1.04 H20: C, 58.58; H, 4.90; N, 9.06.
Found: C, 48.88; H, 5.05; N, 8.79. percent Water (KF): 3.02. EXAMPLE 59 3-Methyl Acid Ester [S- (R *, S *)] -4- [[[1- [[4- [(2,6-dichlorobenzoyl) aming] phenyl] methyl] -2-methoxy- 2-oxoethyl] amino] carbonyl] -d-oxo-3-thiazolidinopentanoic (Scheme A, A-7: where RA- ?, RA.2 are equal and equal to H, R3 is CH2CH2CH2C02CH3, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_?, _?)).
Example 59 was prepared as described in Scheme A from D-cysteine using methylglutaryl chloride to form the required amide. The physical data are as follows: IR (Mull) 3266, 1741, 1734, 1685, 1678, 1630, 1610, 1560, 1545, 1441, 1435, 1414, 1327, 1268, 1227 cm "1; XH NMR (DMS0-d6 ) d 10.65 (1 H), 8.43 (1 H), 7.50, (5 H), 7.15 (2 H), 4.72 (2 H), 4.44 (2 H), 3.63 (3 H), 3.56 (3 H) , 3.10 (4 H), 2.15 (4 H), 1.70 (2 H), 13 C NMR (CDC13) d 171.6, 170. 6, 170.1, 169.9, 169.6, 161.9, 137.2, 136.5, 132.9, 131.3, 129. 7, 128.3, 119.4, 61.4, 53.7, 53.5, 52.0, 51.3, 48.7, 36.4, 35.8, 35.1, 33.1, 32.8, 32.5, 25.4, 19.8; MS (ESI +) for C27H29N307SC12 m / z 610.0 (M + H) *; MS (ESI-) for. C27H29N307SC12 m / z 608.0 (M-H) -; Anal. Caled for C27H29C12N307S: C, 53.12; H, 4.79; N, 6.88. Found: C, 52.81; H, 4.90; N, 6.88. Example 60 Acid [S- (R *, R *)] -4- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -d- oxo-3-thiazole idinopentanoic (Scheme A, A-8: where RA.?, RA_2 are equal to and equal to H, R3 is CH2CH2CH2C02H, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino) ] phenyl, and stereochemistry is (S, S)) - Example 60 was prepared from Example 59 by the procedure described in Preparation 12. The physical data are as follows: IR (Mull) 3271, 3193, 3124, 1725, 1661, 1607, 1561, 1539, 1516, 1432, 1414, 1327, 1271, 1195, 799 cm "1; XH NMR (DMSO-d6) d 12.40 (1 H), 10.63 (1 H), 8.31, (1 H), 7.50 (5 H), 7.16 (2 H) ), 4.75 (2 H), 4.34 (2 H), 2.95 (4 H), 2.15 (4 H), 1.66 (2 H), 13 C NMR (CD3CN) d 175.0, 172. 7, 172.6, 171.0, 163.5, 137.8, 137.0, 134.4, 132.7, 132.3, 131.1, 130.9, 129.1, 120.7, 63.2, 54.5, 49.9, 37.2, 34.1, 33.3, 20.7; MS (ESI +) for C25H25C12N307S m / z 582.0 (M + H) *; MS (ESI-) for C2SH25C12N307S m / z 579.9 (MH) "; Anal Caled for C25H25C12N307S, H20: 50.01; H, 4.53; N, 7.00, Found: C, 49.61; H, 4.38; N, 6.61, Example 61 N- [[(4S) -3-Acetyl-4-thiazolidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L-f-enylalanine methyl ester (Scheme A, A-7: wherein RA .?, RA.2 are equal and equal to H, R3 is CH3, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (S, S)).
Example 61 was prepared as described in Scheme A from D-cysteine using acetyl chloride to form the required amide. The physical data are as follows: IR (Mull) 3260, 3067, 1748, 1686, 1623, 1608, 1561, 1542, 1515, 1445, 1429, 1419, 1324, 1267, 1221 cm-1; XH NMR (DMSO-dg) d 8.44 (1 H), 7.52 (5 H), 7.17, (2 H), 4.78 (2 H), 4.37 (2 H), 3.63 (3 H), 3.06 (4 H) 1.94 (3 H); 13C NMR (DMF-d7) d 172.4, 170.6, 138.4, 137.5, 133.8, 132.3, 131.9, 130.6, 128. 9, 120.0, 70.9, 63.6, 62.4, 54.7, 52.3, 50.2, 49.8, 49.2, 37.2, 36.6, 22.7; MS (ESI +) for C23H23C12N305S m / z 523.9 (M + H) +; MS (ESI +) for C 23 H 23 C 12 N 305 S m / z 545.8 (M + Na) +; HRMS (FAB) caled for C23H23C12N305S + H? 524.0814, found 524.0812; Anal. Caled for C23H23C12N305S .0.1 H20; C, 52.46; H, 4.45; N, 7.98.
Found: C, 52.85; H, 4.42; N, 8.00 percent Water (KF): 0.24. Example 62 N- [[(4S) -3-Acetyl-4-thiazolidinyl] carbonyl] -4- [(2,6-dichlorobenzoyl) amino] -L-phenylalanine (Scheme A, A-8: wherein RA-? , RA_2 are equal and equal to H, R3 is CH3, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is. {S, S)).
Example 62 was prepared from Example 61 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3070, 1747, 1682, 1663, 1625, 1608, 1580, 1561, 1548, 1514, 1443, 1431, 1416, 1278, 1220 cm'1; 2 H NMR (DMS0-d 6) d 12.48 (1 H), 10.63 (1 H), 8.29 (1 H), 7.50, (5 H), 4.73 (2 H), 4.34 (2 H), 2.97 - (4 H) ), 1.93 (3 H); 13C NMR (DMSO-d6) d 172.4, 169.6, 169.2, 168.5, 168.0, 161.7, 136.9, 136.3, 133.2, 133.0, 131.2, 129.6, 128.1, 119.2, 62.2, 61.0, 53.5, 53.3, 49.3, 48.4, 36.3, 35.7, 35.0, 33.1, 22.4, 20.9; MS (ESI-) for C22H2? Cl2N305S m / z 507.9 (M-H) -; Anal. Caled for C22H2? Cl2N305S .0.1 H20; C, 51.57; H, 4.18; N, 8.20. Found: C, 51.49; H, 4.36; N, 8.07. percent Water (KF): 0.40.
EXAMPLE 63 Acid [S- (R *, R *)] -4- [[[1- Carboxy 2 - [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -5, 5-dimethyl-d-oxo-3-thiazolidinobutanoic (Scheme A, A-8: where RA.?, RA.2 are equal and equal to CH3, R3 is CH2CH2C02H, Y is CO, R5 is 4- [(2 , 6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (_ ?, £ >)).
Example 63 was prepared as described in Scheme A from D-penicillamine using methylsuccinyl chloride to form the required amide. The physical data are the following: IR (Mull) 3264, 3198, 3071, 1721, 1660, 1608, 1562, 1541, 1516, 1432, 1415, 1327, 1270, 1195, 799 cm "1; XH NMR (DMSO-d6) d 10.62 (1 H), 8.15 (1 H), 7.52, (5 H) ), 7.18 (2 H), 4.72 (2 H), 4.43 (3 H), 2.91 (4 H), 2.17 (2 H), 1.36 (3 H), 1.07 (3 H), 13 C NMR (DMSO-d6) ) d 173.5, 172.6, 170.2, 169.7, 168.4, 168.1, 161.7, 136.9, 136.3, 133.3, 131.1, 129. 6, 129.4, 128.1, 119.2, 70.6, 53.8, 53.5, 51.6, 48.4, 47.7, 35.9, 30.7, 30.5, 28.9, 28.6, 24.1; MS (ESI +) for C 26 H 27 C 12 N 307 S m / z 596.0 (M + H) *; MS (ESI +) for C 26 H 27 C 12 N 307 S m / z 617.9 (M + Na) + MS (ESI-) for C 26 H 27 C 12 N 307 S m / z 593.8 (MH) "; MS (FAB) m / z (relative intensity) 596 (MH +, 20) , 598 (15), 596 (20), 331 (11), 193 (13), 141 (15), 139 (99), 116 (16), 107 (13), 105 (50), 89 (25); HRMS (FAB) caled for C2gH27Cl2N307S + H? 596.1025, found 596.1036.Example 64 Acid [S- (R *, R *) J -4- [[[1-Carboxi-2 - [4- [(2, 6-di chloro phenyl) methoxy] phenyl] ethyl] amino] carbonyl] -? - oxo-3-yiazole idinobutanoic (Scheme A, A-8: where RA.?, RA_2 are equal and equal to H, R3 is CH2CH2C02H , Y is CO, R5 is 4- [(2,6-dichlorofenyl) methoxy] phenyl, and stereochemistry is (_?, _?)).
Example 64 was prepared as described in Scheme a from D-cysteine using methyl succinyl chloride to form the required amide. The physical data are as follows: IR (Mull) 3073, 3031, 1725, 1640, 1612, 1585, 1565, 1535, 1511, 1439, 1300, 1241, 1196, 1179, 768 ern "1; XH NMR (DMS0-d6 ) d 8.26 (1 H), 7.53 (2 H), 7.44, (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.75 (2 H), 4.40 (2 H) , 4.20 (1 H), 2.81 (4 H) 2.32 (2 H), 2.07 (1 H), 13 C NMR (DMSO-d6) d 173.8, 172. 6, 170.0, 169.3, 157.1, 136.0, 131.5, 130.4, 130.0, 129.8, 128. 7, 114.2, 64.8, 61.5, 53.6, 48.5, 36.1, 35.5, 35.0, 33.1, 28.9, 28.6, 21.0; MS (ESI +) for C 24 H 24 C 12 N 207 S m / z 554.8 (M + H) +; MS (ESI-) for C24H24C12N207S m / z 552.7 (MH) "; HRMS (FAB) caled for C24H24C12N207S + H? 555.0750 Example 65 N- [[(4S) -3-Acetyl-4-thiazolidinyl] carbonyl methyl ester ] -0- [(2,6-Dichlorophenyl) methyl] -L-tyrosine (Scheme A, A-7: where RA., RA-2 are equal and equal to H, R3 is CH3, Y is CO, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (_?, _?)).
Example 65 was prepared as described in Scheme A from D-cysteine using acetyl chloride to form the required amide. The physical data are the following IR (Mull) 1744, 1657, 1612, 1585, 1564, 1511, 1438, 1405, 1352, 1299, 1240, 1197, 1179, 1016, 768 cm "1; XH NMR (CDC13) d 7.36 (2 H), 7.24 (1 H), 6.97 (5 H), 5.24, (2 H), 5.04 (1 H), 4.78 (1 H), 4.50 (2 H), 3.74 (3 H), 3.45 (1 H), 3.17 (3 H), 2.02 (3 H); 13 C NMR (CDCl 3) d 172.7, 171.6, 171.4, 169.8, 168. 9, 168.7, 157.8, 136.9, 131.9, 130.3, 129.9, 128.6, 128.4, 114. 9, 65.1, 61.6, 56.0, 53.6, 53.3, 49.6, 36.7, 31.7, 22.5; MS (ESI +) for C 23 H 24 Cl 2 N 205 S m / z 532.9 (M + Na) +; MS (El) m / z (relative intensity) 510 (M +, 1), 338 (42), 337 (12), 336 (63), 267 (12), 265 (18), 163 (10), 161 (63), 159 (99) , 130 (9), 88 (43); Anal. Caled for C23H24C12N20SS .0.19 H20; C, 53.66; H, 4.77; N, 5.44. Found: C, 53.81; H, 4.75; N, 5.33. percent Water (KF): 0.66. Example 66 N- [[(4S) -3-Acetyl-4-thiazolidinyl] carbonyl] -O- [(2,6-dichlorophenyl) methyl] -L-tyrosine (Scheme A, A-8: wherein RA., RA.2 are equal and equal to H, R3 is CH3, Y is CO, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and stereochemistry is (_?, _?)) • Example 66 was prepared from Example 65 by the procedure described in Preparation 6. The ical data are as follows: IR (Mull) 1730, 1646, 1612, 1585, 1565, 1511, 1439, 1414, 1299, 1240, 1196, 1179, 1016, 779, 768 cm "1; aH NMR (DMSO-d6) d 8.26 (1 H), 7.543 (2 H), 7.44 (1 H), 7.13, (2 H), 6.92 (2 H) ), 5.16 (2 H), 4.72 (2 H), 4.31 (2 H), 2.91 (5 H), 1.92 (3 H), l3 C NMR (DMSO-d6) d 172.6, 169.2, 168.0, 157.1, 136.0, 131.7, 131.5, 130.3, 128.7, 114.2, 64.8, 62.2, 61.0, 53.7, 49.4, 48.5, 36.1, 35.5, 35.1, 33.2, 22.4, 21.0, MS (ESI +) for MS (ESI-) for C22H_2C12N205S m / z 494.8 (MH) "; MS (FAB) m / z (relative intensity) 497 (MH +, 99), 617 (29), 573 (12), 539 (25), 500 (11), 499 (78), 498 (38), 497 ( 99), 496 (11), 225 (62), 130 (14); HRMS (FAB) caled for C22H22Cl2N205S + H? 497.0705, found 497.0713; Anal. Caled for C22H22Cl2N2OsS .0.41 H20; C, 52. 35; H, 4.56; N, 5.55. Found: C, 52.65; H, 4.51; N, 5. 50. percent Water (KF): 1.46. Example 67 Acid [R- (R *, S *)] - 4 - [[[1-Carboxy-2- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -? - oxo-3-thiazolidinobutanoic (Scheme A, A-8: where RA.?, RA.2 are equal and equal to H, R3 is CH2CH2C02H, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino) ] phenyl, and stereochemistry is { R, S)).
Example 67 was prepared as described in Scheme A from L-cysteine using methyl succinyl chloride to form the required amide. The ical data are as follows: * H NMR (CD3CN) d 8.86 (1 H), 7.55 (2 H), 7.42, (3 H), 7.24 (2 H), 7.11 (1 H), 4.90 (1 H) , 4.65 (2 H), 4.33 (1 H), 3.14 (3 H), 2.47 (6 H) 1.80 (1 H); 13C NMR (CD3CN) d 174.7, 172.6, 172.3, 170.7, 163.4, 137.7, 137.0, 134.4, 132.7, 132.2, 130.9, 129.1, 63.2, 60.9, 54.4, 49.7, 37.1, 36.7, 32.7, 30.6, 30.0, 29.5, 21.1, 14.4; MS (FAB) m / z (relative intensity) 568 (MH +, 99), 646 (11), 644 (16), 572 (13), 571 (12), 570 (73), 569 (38), 568 (99), 567 (15), 216 (22), 88 (27); Anal. Caled for C24H23Cl2N307S .0.5 H20: C, 49.92; H, 4. 19; N, 7.23. Found: C, 50.01; H, 4.54; N, 7.05. Example 68 Acid [R- (R *, S *)] -4- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -d- oxo-3-t iazole idinopentanoic (Scheme A, A-8: where RA.?, RA.2 are equal and equal to H, R3 is CH2CH2CH2C02H, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl ) amino] phenyl, and stereochemistry is (R, S)).
Example 68 was prepared as described in Scheme A from L-cysteine using methyl glutaryl chloride to form the required amide. The ical data are the following: XH NMR (CD3CN) d 8.85 (1 H), 7.55 (2 H), 7.44, (3 H), 7.17 (3 H), 4.86 (1 H), 4.64 (2 H), 4.34 (1 H), 3.64 (1 H), 3.13 (3 H), 2.27 (4 H) 1.79 (4 H) ); 13C NMR (CD3CN) d 175.0, 172.9, 172.7, 170.6, 163.4, 137.7, 137.0, 134.2, 132.7, 132.2, 131.0, 129.1, 120.7, 68.2, 63.1, 54.2, 49.8, 37.1, 36.9, 34.0, 33.2, 32.6, 26.2, 20.6; MS (FAB) m / z (relative intensity) 582 (MH +, 99), 585 (12), 584 (68), 583 (35), 582 (99), 581 (11), 88 (23), 69 (8), 57 (9), 55 (11) , 43 (11); Anal. Caled for C25H2SC12N307S .0.2 H20: C, 51.24; H, 4.37; N, 7.17. Found: C, 51.25; H, 4.68; N, 6.92. EXAMPLE 69 N- [[(4R) -3-Acetyl-4-thiazolidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L-phenylalanine methyl ester (Scheme A, A-7: wherein RA ., RA__ are equal and equal to H, R3 is CH3, Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is {R, S)).
Example 69 was prepared as described in Scheme A from L-cysteine using acetyl chloride to form the required amide. The physical data is as follows: IR (Mull) 3268, 1743, 1662, 1607, 1561, 1538, 1515, 1431, 1413, 1354, 1324, 1270, 1217, 1195, 799 cm'1; XH NMR (CDC13) d 7.56 (3 H), 7.31 (4 H), 7.14 (2 H), 4.92, (2 H), 4.49 (1 H), 4.29 (1 H), 3.77 (3 H), 3.54 (1 H), 3.26 (1 H), 3.00 (2 H), 2.11 (3 H); 13C NMR (CDC13) d 171.5, 170.3, 168.9, 152.5, 135.9, 135.7, 132.9, 132.3, 131.0, 130.1, 129.9, 128.2, 128.0, 127.9, 120.4, 63.9, 61.4, 53.1, 52.5, 49.7, 37.0, 31.2, 22.6; MS (ESI +) for C23H23Cl2N3? CS m / z 523.8 (M + H) *, Example 70 N- [[(4R) -3-Acetyl-4-thiazolidinyl] carbonyl] -4- [(2,6-dichlorobenzoyl) amino] -L-phenylalanine (Scheme A, A-8: where RA- ?, RA_2 are equal and equal to H, R3 is CH3, .Y is CO, R5 is 4- [(2,6-dichlorobenzoyl) amino) ] phenyl, and stereochemistry is [R, S)).
Example 70 was prepared from Example 69 by the procedure described in Preparation 6. The physical data is as follows: IR (Mull) 3276, 3068, 1727, 1661, 1607, 1561, 1540, 1516, 1444, 1431, 1414, 1327, 1271, 1218, 1195 crn "1; H NMR (DMSO-d6) d 12.78 (1 H) , 10.67 (1 H), 8. 27 (1 H), 7.49, (4 H), 7.19 (2 H), 4.75 (2 H), 4.45 (3 H), 3.01 (3 H), 1.96 (3 H); 13C NMR (DMS0-d6) d 172.6, 172.3, 169.4, 168.6, 168.2, 161.7, 136.9, 136.3, 133.3, 132.8, 131.1, 129.6, 128.1, 119.1, 62.2, 60.9, 53.4, 49.3, 48.7, 35.9, 35.1, 32.7, 22.4; MS (ESI +) for C22H2? Cl2N305S m / z 509.8 (M + H) *; MS (ESI-) for C22H2? Cl2N3? 5S m / z 507.8 (M-H) '; HRMS (FAB) caled for 510.0657, found 510.0667. EXAMPLE 71 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4R) -4-thiazolidinyl] carbonyl] -L-phenylalanine salt monochlorohydrate (Scheme A, A-10: wherein RA., RA_2 are equal and equal to H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is. {R, S)).
Example 71 was prepared as described in Scheme A from L-cysteine. The physical data are as follows: IR (Mull) 3249, 3190, 3036, 1729, 1662, 1605, 1578, 1562, 1541, 1516, 1432, 1414, 1328, 1271, 1195 cm-1; XH NMR (DMS0-d6) d 10.71 (1 H), 8.83 (1 H), 7.56 (5 H), 7.24, (2 H), 4.50 (1 H), 4.25 (1 H), 4.21 (2 H) , 3.62 (1 H), 3.01 (4 H); 13C NMR (DMS0-d6) d 172.0, 166.8, 161.8, 137.7, 132.7, 131.3, 131.0, 129.5, 128.1, 119.4, 72.0, 70.4, 62.3, 53.8, 49.0, 35.7, 33.4; MS (ESI +) for C20H? 9Cl2N3O4S m / z 468.1 (M + H) *.
Scheme B B2 Rß- « -Rß2% OH B 3 I N B- «H Where R _-? # R_- ". R_-3 and RB- are defined as R-. and in addition RB.3 and RB.4 can be attached to the same carbon atom and form a cyclic ring of 5-8 atoms of formula: • together with the carbon atom to which they are attached; RB_5 is defined as OH or O- (alkyl having from 1 to 6 carbon atoms) Scheme B describes a general method for the preparation of thiazolidine-4-carboxylic acid derivative of general structure B-6. B-7 and B-8 are disubstituted at position 2 (ie, RB.3 and RB_4 are not equal to H). Within this class of structures, nitrogen is immediately derived after forming the heterocyclic ring. Accordingly, an easily prepared or commercially available sulfur containing amino acid of structure Bl (which is the same structure as Al) is condensed with a readily prepared or commercially available ketone to produce thiazolidine-4-carboxylic acid in the form general B-3 (preparation 15) (for a general discussion of the condensation of aldehydes and ketones with cysteine or similar sulfur-containing amino acids see: Coppola, GM; Scuster, H.F. Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids; John Wiley: New York, 1987; Chapter 6, 171). The amino group can be reacted with a variety of electrophilic reagents such as sulfonyl chlorides, carbonates, chloroformates, isocyanates, phosgene (or a suitable equivalent) and an amine, acid chlorides, and > carboxylic acid anhydrides as described in Scheme 5 A for the reaction of A-6. Preparation 16 is provided as a specific example of the synthesis of a compound of general structure B-4. The condensation of B-4 with the amino acid derivative B-5 under standard peptide synthesis conditions provides the compound of general structure B-6 '10 (preparation 17). The mild base hydrolysis of methyl ester of general structure B-6 (where RB_5 is 0CH3) can be carried out as described and exemplified in Scheme A (preparation 6 or 13) to produce compounds of the general structure B-7. Alternatively, in those cases where RB_5 is O- -Bu, mild acidolysis can also provide compounds of the general structure B-7 (by the process described in preparation 4 of Scheme A). In the case of analogs derived from t-butoxycarbonyl of general structure B-7 (ie, when R3 is t-butyl and Y is C02), acidolysis Mild produces compounds of general structure B-8 (by the procedure described in preparation 4 of Scheme A). Preparation 15 (Scheme B, B-3: where RB_? And RB_2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, and the 25 stereochemistry is (R)).
A suspension of L-cysteine hydrochloride monohydrate (Scheme B, Bl: where RB.? And RB_2 are equal and equal to H and the stereochemistry is (R)) (20 grams, 0.11 mol) in acetone (Scheme B, B-2: where RB.3 and RB_4 are equal to CH3) (800 milliliters) was heated under reflux for 8 hours. Cooling to room temperature resulted in precipitation of a solid which was collected by filtration, washed with acetone and dried under vacuum to yield the title compound (17.46 grams) as a white solid: mp 165-167 ° C; (Lit. 165-168 ° C: Sheehan, JC; Yang, DD.HJ Am. Chem. Soc. 1957, 80, 1159) * H NMR (D20) d 4.75 (1 H), 3.59 (1 H), 3.44 (1 H), 1.73 (3 H), 1.71 (3 H); MS (ESI-) for CgH ?? N02S m / z 159.9 (MH). "Preparation 16 (Scheme B, B-4: where RB.? And RB.2 are equal and equal to H, RB.3 and RB. .4 are equal and equal to CH3, Y is C02, R3 is t-butyl and the stereochemistry is (R)).
A solution of B-3 (Scheme B, where RB.X and RB_2 are equal and equal to H, RB.3 and RB_4 are equal and equal to CH3 / and the stereochemistry is (R)) (17.46 grams, 0.11 mol ) in acetonitrile (250 milliliters) at room temperature was added di-t-butyl dicarbonate (25.64 grams, 0.117 mol) followed by N, N-di-isopropylethylamine (16.9 milliliters 0.097 mol). The reaction mixture was stirred for 2 days and the volatiles were removed in vacuo. The residue was formed as a slurry in diethyl ether and filtered through a celite cloth. The filtrate was washed with 0.1 N HCl, water, brine, dried (Na 2 SO 4), filtered and concentrated in vacuo. Crystallization of the clear hexane oil gave the title compound (3.85 grams) as a white solid: mp 125-126 ° C (Lit. 114 ° C: oodward, RB; Heusler, K.; Gosteli, J. Naegeli, P Oppolzer, W., Ramage, R., Ranganathan, S. Vorbruggen, HJ Am. Chem. Soc. 1966, 88, 852) XYL NMR (CDC13) d 8.70 (1 H), 4.89 (1 H), 3.27 (2 H), 1.81 (6 H); MS (ESI-) for C H19N04S m / z 260.1 (MH). "Preparation 17 and Example 72 3- (1, 1-dimethylethyl) acid ester [R- (R *, S *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] -yl] -2-methoxy-2-oxo-ethyl] amino] carbonyl] -2,2-dimethyl-3-thiazolidinocarboxylic acid ( Scheme B, B-6: where RB.X and RB_2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, Y is C02, R3 is t-butyl, RB_5 is OCH3, R5 is 4- [ (2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is {R, S)).
A cooled suspension (0-5 ° C) of B-4 (Scheme B where RB__ and RB.2 are equal and equal to H, RB_3 and RB.4 are equal and equal to CH3, Y is C02, R3 is t-butyl and the stereochemistry is (R)) (1.0 gram, 3.83 mmol) and HOBt (638 milligrams, 4.17 mmol) in CH2C12 (20 milliliters) was added an EDC solution (799 milligrams), 4.17 mmol) in CH2C12 (20 milliliters). After 30 minutes at 0-5 ° C, B-5 (Scheme B where RB_5 is OCH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (S)) (1.93 grams, 4.77 mmol) was added followed by 4-methylmorpholine (520 microliters, 4.77 mmol). The reaction mixture was gradually warmed to room temperature, stirred for an additional 18 hours and diluted with CH2C12. The organic layer was separated and washed with 0.1 N HCl, saturated aqueous NaHC03, brine, dried (Na_04), filtered and concentrated in vacuo. Flash chromatography of the residue using CH2Cl2 / acetone (3 percent) as eluent afforded the title compound (2.05 grams) as a white solid: IR (Mull) 1746, 1666. 1606, 1562, 1537, 1515, 1432, 1413, 1347, 1325, 1259, 1214, 1195, 1169, 799 crn'1; * H NMR (CDC13) d 7.54 (2 H), 7.32 (4 H), 7.20 (2 H), 6.90 (1 H), 4.78 (2 H), 3.74 (3 H), 3.17 (4 H), 1.74 (3 H), 1.43 (9 H); 13C NMR (CDC13) d 171.6, 136.7, 136.2, 135.9, 132.7, 132.4, 132.3, 131.0, 130.6, 130.4, 130.0, 129.9, 128.2, 127.9, 120.5, 120.2, 120.1, 67.3, 53.4, 52.4, 42.8, 37.3, 36.9, 34.9, 30.9, 28.3; MS (ESI +) for C28H33Cl2N3? 6S m / z 607.9 (M-H) "; Anal. Caled for C 28 H 33 Cl 2 N 3? 6 S.0.13 H20: C, 54.88; H, 5.47; N, 6.86.
Found: C, 54.66; H, 5.57; N, 6.73. percent Water (KF): 0.37. Example 73 3- (1, 1-dimethylethyl) acid ester [R- (R *, S *)] -4- [[[1-Carboxi-2 - [4 - [(2,6-dichlorobenzoyl) amino]] phenyl] ethyl] amino] carbonyl] -2, 2-dimethyl-3-thiazolidinocarboxylic acid (Scheme B, B-7: where RB.? and RB_2 are equal and equal to H, RB_3 and RB.4 are equal and equal to CH3, Y is C02, R3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (R, S)).
Example .73 was prepared from Example 72 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1738, 1665. 1606, 1562, 1535, 1516, 1432, 1413, 1347, 1259 , 1213, 1194, 1167, 799, 777 cm "1; XH NMR (CD3CN) d 8.89 (1 H), 7.54 (2 H), 7.41 (3 H), 7.25 (2 H), 4.66 (2 H), 3.15 (4 H), 1.72 (3 H), 1.70 (3 H), 1.35 (9 H), 13 C NMR (CD3CN) d 177.3, 171.8, 163.4, 137.9, 137.1, 133.9, 132.7, 132.3, 131.3, 129.1, 120.7, 81.2, 79.3, 68.0, 54.5, 37.4, 28.4; MS (ESI-) for C27H3? Cl2N306S m / z 593.9 (MH) '; Anal Caled for C27H31Cl2N3? 6S .0.5 H20: C, 53.56; H, 5.33; N, 6.94 Found: C, 53.77; H, 5.39; N, 6.70, Example 74 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(4R) -2,2-dimethyl-4- thiazolidinyl] carbonyl] -L-phenylalanine (Scheme B, B-8: where RB.? and RB_2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, Rs is 4- [(2, 6 - dichlorobenzoyl) amino] phenyl and the stereochemistry is [Rr S)).
Example 74 was prepared from Example 73 by the procedure described in Preparation 4. The physical data are as follows: IR (Mull) 3244, 3192. 3049, 1726, 1664, 1605, 1578, 1562, 1541, 1516, 1432, 1414, 1327, 1195, 799 ern "1; XH NMR (DMSO-d6) d 13.00 (1 H), 10.69 (1 H), 7.52 (6 H), 7.24 (2 H), 4.52 (2 H) , 3.12 (2 H), 2.93 (1 H), 1.62 (9 H), 13 C NMR (CD3OD) d 166.9, 136.8, 136.0, 133.5, 131.8, 130.9, 129.5, 129.4, 127.9, 120.4, 120.2, 120.1, 60.8 , 54.3, 54.0 / 36.2, 36.0, 25.1; MS (ESI +) for C22H23C12N304S m / z 496.2 (M + H) +; MS (ESI-) for C22H23C12N304S m / z 494.2 (MH) "; Anal. Caled for C22H23C12N304S. HCl.0.50 H20: C, 48.76; H, 4.65; N, 7.75.
Found: C, 48.56; H, 4.72; N, 7.49. Example 75 3- (1, 1-dimethylethyl) acid ester [S- (R *, R *)] -4- [[[1- [[4- [(2,6 -Dichlorobenzoyl) amino] phenyl] methyl ] -2-methoxy-2-oxoethyl] amino] carbonyl] -2, 2-dimethyl-3-thiazolidinocarboxylic (Scheme B, B-6: where RB.? And RB_2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, Y is C02, R3 ilO is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is IS, S)) • Example 75 was prepared as described in Scheme B from D-cysteine and acetone using di-t-butyl dicarbonate to form the required carbamate. The physical data are as follows: IR (Mull) 1745, 1686, 1666, 1605, 1537, 20 1515, 1432, 1413, 1349, 1325, 1259, 1213, 1206, 1195, 1169 cm "1; * H NMR (CDC13) d 7.56 (2 H), 7.32 (3 H), 7.16 (2 H), 6.92 (1 H), 4.83 (2 H), 3.73 (3 H), 3.20 (4 H), 1.78 (6 H), 1.45 (9 H), 13 C NMR (CDCI 3) d 171.6, 170.0, 136.2, 132.6, 132.4 , 131.0, 130.9, 130.1, 129.9, 128.2, 120.5, 120.4, 67.3, 53.3, 52.5, 52.4, 25 37.4, 28.4; MS (ESI +) for C28H33C12N306S m / z 610.0 (M + H) +; MS (ESI-) for C28H33Cl2N3? 6S m / z 607.9 (MH) "; Anal Caled for C28H33Cl2N3OgS: C, 55.08; H, 5.45; N, 6.88; Cl, 11.61; S, 5.25. Found: C, 58.47; H, 5.47; N, 6.78, Example 76 3- (1, 1-dimethylethyl) acid ester [S- (R *, R *)] -4- [[[1-Carboxi-2- [4- [( 2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -2,2-dimethyl-3-thiazolidinocarboxylic acid (Scheme B, B-7: where RB.? And RB_2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, Y is C02, R3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (-9, -9)) - Example 76 was prepared from Example 75 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3280, 1739, 1665, 1606, 1562, 1535, 1516, 1432, 1413, 1348, 1272, 1259, 1195, 1167, 799 cm-1; XH NMR (CD3CN) d 8.83 (1 H), 7.55 (2 H), 7.43 (3 H), 7.22 (2 H), 6.83 (1 H), 4.68 (2 H), 3.07 (5 H), 1.73 ( 6 H), 1.40 (9 H); 13C NMR (CD3CN) d 172.6, 163.3, 137.9, 133.4, 133.3, 132.7, 132.1, 131.1, 130.2, 130.1, 129.1, 128.1, 128.0, 120.6, 119.5, 54.1, 37.4, 29.4, 28.5, 27.6; MS (ESI +) for C27H31C12N306S m / z 595.9 (M + H) *; MS (ESI-) for C27H31Cl2N30gS / z 593.7 (M-H) "; MS (FAB) m / z (relative intensity) 596 MH +, 16), 598 (12), 596 (16), 500 (16), 499 (19), 498 (71), 497 (32), 496 (99), 173 (16), 116 (19), 57 (51); HRMS (FAB) caled for 596.1389, found 596.1364; Anal. Caled for C27H3? Cl2N3? 6S .0.5 H20: C, 53.56; H, 5.33; N, 6.94. Found: C, 53.86; H, 5.35; N, 6.90. EXAMPLE 77 4-Ethyl Ester of [S- (R *, R *)] -3- [[[1- [[2,6- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy- ester 2-oxoet il] amino] carbonyl] -l-thia-4-azaspiro [4, 4] nonane-4-carboxylic acid (Scheme B, B-6: where RB.? And RB_2 are equal and equal to H, RB .3 and RB_4 together form a carbocyclic ring of 5 atoms, Y is C02, R3 is ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (£?, £?)).
Example 77 was prepared as described in Scheme B from D-cysteine and cyclopentanone using ethyl chloroformate to form the required carbamate. The physical data are as follows: IR (Mull) 1760, 1739, 1694, 1656, 1607, 1560, 1543, 1517, 1445, 1429, 1411, 1334, 1273, 1253, 1116 cm "1; XH NMR (CDC13) d 7.56 (2 H), 7.44 (1 H), 7.34 (3 H), 7.11 (2 H), 6.70 (1 H), 4.84 (2 H), 4.14 (2 H), 3.74 (3 H), 3. 12 (4 H), 2.67 (1 H), 2.51 (1 H), 1.73 (6 H), 1.25 (3 H); 13C NMR (CDC13) d 171.4, 170.7, 162.3, 136.3, 135.8, 132.5, 132.4, 131.0, 130.1, 128.2, 120.2, 66.4, 62.1, 53.1, 52.5, 37.3, 32.3, 31.9, 25.1, 24.6, 14.5, 14.1; MS (ESI +) for C28H3? Cl2N306S m / z 630.0 (M + Na) -; HRMS (El) caled for C28H3? Cl2N30gS 607.1310, found 607.1315; Anal. Caled for C28H31Cl2N3? 6S .0.75 H20: C, 54.06; H, 5.27; N, 6.90. Found: C, 53.98; H, 5.16; N, 6.72. EXAMPLE 78 4-Ethyl Ester of [S- (R *, R *)] -3- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -1-thia-4-azaspiro [4, 4] nonane-4-carboxylic acid (Scheme B, B-7: where RB_? and RB.2 are equal and equal to H, RB_3 and RB_4 together form a ring carbocyclic of 5 atoms, Y is C02, R3 is ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (S, S)) - Example 78 was prepared from Example 77 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3276, 1664, 1606, 1562, 1537, 1515, 1445, 1432, 1413, 1335, 1273, 1239, 1195, 1116, 799 cm "1; H NMR (CDC13) d 8.08 (1 H), 7.62 (2 H), 7.24 (3 H), 7.14 (2 H), 6.72 (1 H), 4.85 (2 H), 4.13 (2 H), 3.21 (4 H), 2.53 (2 H), 1.75 (6 H), 1.22 (3 H); 13 C NMR (CDCl 3) d 175.2, 171.2, 162.6, 136.7, 135.7, 132.3, 132.0, 130.7, 130.2, 127.9, 120.2, 66.3, 62.2, 53.2, 37.3, 36.6, 32.3, 25.2, 24.6, 20.5, 14.5; MS (ESI +) for C27H29C12N306S m / z 593.8 (M + H) *; MS (ESI-) for C27H29Cl2N3OgS m / z 591.8 (M-H) "; HRMS (FAB) caled for C27H29C12N306S + H? 594.1232, found 594.1226; Anal. Caled for C27H29Cl2N306S .0.37 H20: C, 53.95; H, 4.99; N, 6.99.
Found: C, 54.28; H, 5.10; N, 7.03. percent Water (KF): 1.10. EXAMPLE 79 4-Ethyl Ester of [S- (R *, R *)] -3 - [[[1- [[2,6- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy- ester 2-oxoethyl] amino] carbonyl] -l-thia-4-azaspiro [4, 5] decane-4-carboxylic acid (Scheme B, B-6: where RB.? And RB_2 are equal and equal to H, RB. 3 and RB_4 together form a carbocyclic ring of 6 atoms, Y is C02, R3 is ethyl, R5 is 4 - [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is [S, S)).
Example 79 was prepared as described in Scheme B from D-cysteine and cyclohexanone using ethyl chloroformate to form the requisite carbamate.
The physical data are as follows: IR (Mull) 1745, 1704, 1683, 1668, 1607, 1561, 1538, 1514, .1431, 1413, 1327, 1269, 1213, 1196, 1117 cm-1; XH NMR (CDC13) d 7.57 (2 H), 7.46 (1 H), 7.33 (3 H), 7.11 (2 H), 6.72 (1 H), 4.88 (2 H), 4.14 (2 H), 3.74 (3 H), 3.13 (4 H), 2.51 (1 H), 1.69 (8 H), 1.22 (5 H); 13C NMR (CDC13) d 171.4, 170.7, 168.1, 162.3, 136.3, 135.7, 132.4, 131.0, 128.2, 120.3, 66.9, 62.8, 62.0, 55.1, 53.1, 52.5, 42.0, 39. 9, 37.3, 36.9, 31.1, 29.6, 27.6, 27.1, 26.0, 25.3, 24.7, 23. 1, 14.5; MS (ESI-) for m / z 621.9 (M) "; HRMS (FAB) caled for 622.1545, found 622.1536. EXAMPLE 80 4-Ethyl Ester of [S- (R *, R *)] -3 - [[[1-Carboxy- 2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -1-thia-4-azaspiro [4,5] decane-4-carboxylic acid (Scheme B, B-7: where RB.? and RB_2 are equal and equal to H, RB_3 and RB_4 together form a carbocyclic ring of 6 atoms, Y is C02, R3 is ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is. {S, S)).
Example 80 was prepared from Example 79 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3276, 1710, 1664, 1606, 1562, 1537, 1515, 1432, 1413, 1329, 1272, 1256, 1195, 1117, 800 cm "1; * H NMR (CDCl 3) d 8.07 (1 H), 7.62 (2 H), 7.24 (3 H), 7.14 (2 H), 6.75 (1 H), 4.88 (2 H), 4.12 (3 H), 3.14 (4 H), 2.74 (1 H), 2.50 (1 H), 1.69 (6 H), 1.19 (5 H), 13 C NMR (CDCl 3) d 175.4, 175.1, 171.3, 162.6, 136.7, 135.7, 132.3, 132.3, 132.0, 130.7, 130.3, 130.1, 128.0, 120.2, 66.8, 62.1, 53.2, 42.0, 36.9, 30.5, 27.0, 26.0, 25.3, 25.0, 24.6, 20.5, 14.4, 3.7; MS (ESI +) for C28H31Cl2N3? 6S m / z 608.1 (M + H) *; MS (ESI-) for C28H31C12N306S m / z 605.9 (MH) "; HRMS (El) caled for C28H31C12N306S 607.1310, found 607.1309; Anal. Caled for C 28 H 31 Cl 2 N 3? 6S .0.3 H20: C, 54.78; H, 5.19; N, 6.85. Found: C, 54.56; H, 5.24; N, 6.90. percent Water (KF): 0.87. EXAMPLE 81 3-Ethyl acid ester [S- (R *, R *)] -4- [[[1- [[4- [(2,6 -Dichlorobenzoyl) amino] phenyl] methyl] -2 -me oxy -2-oxoethyl] amino] carbonyl] -2,2,5,5-tetramethyl-3-thiazolidinocarboxylic acid (Scheme B, B-6: where RB.?, RB-2 / RB3 and RB4 are equal and equal to CH3 , Y is C02, R3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (S, S)).
Example 81 was prepared as described in Scheme B from D-penicillamine and acetone using ethyl chloroformate to form the requisite carbamate. The physical data are as follows: IR (Mull) 1748, 1666, 1606, 1562, 1538, 1516, 1432, 1413, 1327, 1275, 1233, 1215, 1195, 1080, 799 cm'1; 1 H NMR (CDCl 3) d 7.55 (2 H), 7.33 (4 H), 7.09 (3 H), 6.59 (1 H), 4.91 (1 H), 4.47 (1 H), 4.16 (2 H), 3.75 (3 H), 3 H), 3.13 (2 H), 1.92 (3 H), 1.75 (3 H), 1.67 (3 H), 160 (3 H), 1.21 (3 H); 13C NMR (CDCl3) d 171.5, 170.0, 162.2, 136.1, 135.7, 132.5, 132.3, 131.9, 130.9, 130.7, 129.7, 128.1, 120.3, 120.1, 120.0, 61.6, 61.4, 52.9, 52.4, 52.2, 49.3, 37.4, 37.3, 34.1, 31.4, 30.8, 29.5, 24.9; MS (ESI-) for C28H33Cl2N3? SS m / z 607.9 (M-H) -; HRMS (El) caled for C 28 H 33 Cl 2 N 3 6S 609.1467, found 609.1461; Anal. Caled for C28H33Cl2N3OfiS .0.19 H20: C, 54.77; H, 5.48; N, 6.84. Found: C, 55.04; H, 5.48; N, 6.78. percent Water (KF): 0.56 Example 82 3-Ethyl acid ester [S- (R *, R *)] -4- [[[1-Carboxi-2 - [4- [(2,6-dichlorobenzoyl)] amino] phenyl] ethyl] amino] carbonyl] -2,2,5, 5-tetramethyl-3-thiazolidinocarboxylic acid (Scheme B, B-7: where RB__, RB-2, RB.3 and RB. are the same and equal) to CH3, Y is C02, R3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (£?, £?)).
Example 82 was prepared from Example 81 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 3275, 1750, 1735, 1678, 1666, 1609, 1562, 1543, 1516, 1432, 1413, 1333, 1276, 1195, 1077 cm "1; X H NMR (DMSO-d 6) d 12.48 (1 H), 10.63 (1 H), 8.36 (1 H), 7.53 (5 H), 7.19 (2 H), 4.49 (2 H), 3.96 (2 H), 3.03 (1 H), 2.79 (1 H), 1.78 (6 H), 1.48 (3 H), 1.15 (3 H), 0.90 (3 H); 13 C NMR (DMSO-dg) d 172.9, 168.7, 161.7, 152.3, 137.0, 136.3, 132.9, 131.2, 131.1, 129.5, 128.1, 119.2, 74.7, 71.3, 60.5, 53.5, 49.0, 48.4, 38.3, 36.7, 33.5, 31.8, 28.1, 24.7, 21.0, 14.0; MS (ESI +) for C27H31C12N306S m / z 595.8 (M + H) *; MS (ESI-) for C27H31C12N306S m / z 593.8 (M-H) "; HRMS (FAB) caled for C27H31C12N306S + H? 596.1389, found 596.1362; Anal. Caled for .0.56 H20: C, 53.46; H, 5.34; N, 6.93.
Found: C, 53.73; H, 5.35; N, 6.73. percent Water (KF): 1.67. EXAMPLE 83 N- [[(4S) -3-Acetyl-2,2-dimethyl-4-thiazolidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L-phenylalanine methyl ester (Scheme B, B-6: where RB.? And RB_2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, Y is CO, R3 is methyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (S, S)).
Example 83 was prepared as described in Scheme B from D-cysteine and acetone using acetyl chloride to form the required amide. The physical data are as follows: IR (Mull) 1745, 1682, 1662, 1628, 1610, 1579, 1561, 1541, 1515, 1431, 1412, 1326, 1270, 1240, 1211 cm "1; lH NMR (CDC13) d 7.55 (3 H), 7.32 (3 H), 7.19 (1 H), 7.11 (1 H), 6.66 (1 H), 4.89 (1 H), 4.60 (1 H), 3.78 (3 H), 3.24 ( 4 H), 2.04 (3 H), 1.87 (3 H), 1.79 (3 H), 13 C NMR (DMSO-dg) d 171.6, 171.5, 169.9, 169.4, 167.9, 161.8, 137.1, 136.3, 132.8, 132.6, 131.1, 129.5, 128.1, 119.2, 72.6, 66.5, 53.7, 53.3, 52.0, 51.9, 35.8, 31.7, 29.0, 26.9, 24.7, 24.5; MS (ESI +) for C25H27C12N305S m / z 551.9 (M + H) *; HRMS (El) caled for C25H27C12N305S 551.1049, found 551.1053; MS (El) m / z (Relative Intensity) 551 (M +, 7), 351 (46), 349 (68), 278 (16), 186 (14), 175 (63), 173 (98), 158 (23), 116 (99), 100 (20) , 99 (69). EXAMPLE 84 N- [[(4S) -3-Acetyl -2,2-di-methyl-4-thiazolidinyl] carbonyl] -4- [(2,6-dichlorobenzoyl) amino] -L-phenylalanine (Scheme B, B -7: where RB_- and RB.2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, Y is CO, R3 is methyl, R5 is 4- [(2,6-dichlorobenzoyl) amino) ] phenyl and the stereochemistry is { S, S)).
Example 84 was prepared from Example 83 by the procedure described in Preparation 6. The physical data is as follows: IR (Mull) 3279, 1723, 1661, 1608, 1562, 1542, 1516, 1432, 1413, 1349, 1329, 1270, 1238, 1207, 1195 cm-1; XH NMR (DMS0-d6) d 12.47, (1 H), 10.62 (1 H), 7.51 (5 H), 7.18 (2 H), 4.80 (1 H), 4.67 (1 H), 4.47 (1 H) 2.98 (3 H), 1.68 (9 H); 13C NMR (DMSO-d6) d 184.2, 172.6, 171.9, 169.8, 169. 2, 167.8, 136.9, 136.3, 133.1, 131.2, 131.0, 129.5, 128.1, 119.2, 72.6, 66.6, 53.7, 53.3, 36.2, 31.7, 29.0, 27.0, 24.8, 24.6, 21.0; MS (ESI +) for C2SH2SCl2N3OsS m / z 538.0 (M + H) S-MS (ESI-) for C25H25C12N305S m / z 535.9 (MH) "; HRMS (FAB) caled for CasH.sCl.NjOsS + Hx 538.0970, found 538.0961 Example 85 Acid [S- (R *, R *)] -4- [[[1-Carboxy-2- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] - 2, 2-dimethyl-β-oxo-3-thiazolidinobutanoic (Scheme B, B-7: where RB.?, And RB, 2 are equal and equal to H, RB_3 and RB_4 are equal and equal to CH3, and is C02, R3 is CH2CH2C02H, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (£?, _?)).
Example 85 was prepared as described in Scheme B from D-cysteine and acetone using methyl succinyl chloride to form the required amide. The physical data are as follows: IR (Mull) 3264, 3125, 3071, 1724, 1658, 1607, 1562, 1537, 1517, 1432, 1414, 1326, 1241, 1195, 1181 Cltr1; ? NMR (DMSO-dg) d 12.31 (1 H), 10.65 (1 H), 8.20 (1 H), 7.50 (5 H), 7.19 (2 H), 5.81 (1 H), 4.50 (1 H), 3.02 (3 H), 2.30 (3 H), 1.71 (6 H); 13 C NMR (DMSO-dg) d 174.1, 172.8, 169.4, 161.9, 137. 1, 136.5, 133.2, 131.4, 131.3, 129.7, 128.3, 119.3, 73.1, 65.7, 53.5, 36.3, 32.0, 30.5, 29.1, 29.0, 27.1; MS (ESI +) for C2gH27Cl2N307S m / z 595.9 (M + H) *; MS (ESI-) for C 26 H 27 C 12 N 307 S m / z 593.8 (M-H) -; Anal. Caled for C26H27C12N307S .0.51 H20: C, 51.55; H, 4.66; N, 6.94. Found: C, 51.71; H, 4.85; N, 6.93. percent Water (KF): 1.53 Example 86 Methyl ester of acid [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] me il] -2-methyl-2-oxoethyl] amino] carbonyl] -2,2,5,5-tetramethyl-β-oxo-3-thiazolidinobutanoic acid (Scheme B, B-6: where RB-_, RB. 2, RB.3 and RB.4 are equal and equal to CH3, Y is CO, R3 is CH2CH2C02CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (5.5)).
Example 86 was prepared as described in Scheme B from D-penicillamine and acetone using methyl succinyl chloride to form the required amide. The physical data are as follows: IR (Mull) 3287, 1741, 1660, 1608, 1562, 1540, 1516, 1432, 1413, 1323, 1267, 1241, 1225, 1196, 1168 crn "1;? RMN (CDC13) d 7.55 (2 H), 7.29 (3 H), 7.13 (2 H), 6.94 (1 H), 4.95 (1 H), 4.39 (1 H), 3.74 (3 H), 3.67 (3 H), 3.27 ( 1 H), 3.10 (1 H), 2.80 (1 H), 2.57 (3 H), 2.18 (1 H), 1.95 (3 H), 1.77 (3 H), 1.72 (3 H), 1.68 (3 H) ), 1.63 (3 H); 13C NMR (CDC13) d 173.3, 171.6, 170.3, 169.9, 162.4, 136.3, - 132.5, 132.4, 131.0, 130.2, 129.8, 128.2, 120.8, 120.7, 120.5, 73.8, 53.1, 52.6 , 51.8, 49.9, 40.0, 37.4, 33.9, 31.6, 31.4, 29.4, 29.1, 24. 3; MS (ESI +) for C 30 H 35 Cl 2 N 3 O 7 S m / z 652.1 (M + H) *; Anal.
Caled for C30H35Cl2N3O7S .0.31 H20: C, 54.75; H, 5.45; N, 6.38.
Found: C, 55.04; H, 5.50; N, 6.69. percent Water (KF): 0.84.
EXAMPLE 87 N- [[(4S) -3-Acetyl-2, 2,5,5-tetramethyl-4-thiazolidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L-phenylalanine methyl ester (Scheme B, B-6: where RB__, RB-2 / RB-3 and RB-4 are equal and equal to CH3, Y is CO, R3 is methyl, R5 is 4- [(2,6-dichlorobenzoyl ) amino] phenyl and the stereochemistry is (S, S)).
Example 87 was prepared as described in Scheme B from D-penicillamine and acetone using acetyl chloride to form the required amide. The physical data are as follows: IR (Mull) 1741, 1692, 1676, 1629, 1606, 1563, 1538, 1516, 1431, 1410, 1352, 1320, 1276, 1251, 1223 cm "1; XH NMR (DMS0-d6 ) d 10.70 (1 H), 8.57 (1 H), 7.56 (4 H), 7.22 (2 H), 4.63 (1 H), 4.49 (1 H), 3.65 (3 H), 3.30 (1 H), 3.12 (1 H), 2.84 (1 H), 1.92 (3 H), 1.82 (3 H), 1.78 (3 H), 1.51 (3 H), 0.80 (3 H), 13 C NMR (DMS0-d6) d 184.2, 171.9, 168.9, 168.1, 168.1, 137.1, 136.3, 132.4, 131.3, 131.2, 131.0, 129.4, 128.1, 119.3, 75.9, 72.8, 53.5, 52.0, 49.2, 48.4, 36.0, 33.5, 31.9, 27.6, 24.9, 24.5; MS (ESI +) for C27H3? Cl2N305S / z 580.1 (MS (ESI-) for C27H3? Cl2N305S m / z Sil .9 (MH) '; Anal.Called for C27H3? Cl2N3? 5S.0.12 H20: C, 55.66; H, 5.4.0; N, 7.21.
Found: C, 55.68; H, 5.39; N, 7.16. percent Water (KF): 0.36. Example 88 Acid [R- (R *, S *)] -4- [[[1-Carboxy-2 - [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -2, 2,5,5-tetramethyl-d-oxo-3-thiazolidinopentanoic acid (Scheme B, B-6: where RB._, RB-2 / RB-3 and R_- are equal and equal to CH3, Y is CO, R3 is CH2CH2CH2C02H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (RS)).
Example 88 was prepared as described in Scheme B from D-penicillamine and acetone, using methyl glutaryl chloride to form the required amide. The physical data are as follows: XH NMR (DMSO-d6) d 10.65 (1 H), 8.45 (1 H), 7.53 (5 H), 7.22 (2 H), 4.51 (1 H), 3.11 (3 H) , 2.77 (1 H), 2.21 (4 H), 1.89 (3 H), 1.82 (3 H), 1.11 (2 H), 1.48 (3 H), 0. 77 (3 H); 13 C NMR (DMS0-d6) d 184.2, 174.2, 173.1, 170.1, 168.7, 161.7, 137.0, 136.3, 133.1, 131.3, 131.1, 129.4, 128.1, 119.2, 74.9, 73.0, 53.8, 49.3, 36.1, 34.8, 33.5, 32.7, 31.9, 27.7, 24.5, 20.0; MS (ESI +) for C29H33C12N307S m / z 638.0 (M + H) +; MS (ESI-) for C29H33Cl2N307S m / z 635.9 (MH) "; HRMS (FAB) caled for C29H33Cl2N3? 7S + H? 638.1494, found 638.1481; Anal.Called for C29H33C12N307S .0.75 H20: C, 53.42; H, 5.33; N, 6.44.
Found: C, 53.20; H, 5.26; N, 6.45.
Diagram C Amink resin MBHA of Rink O: C-2 NH-Fmoc H C-4 fr C-5 Scheme C (continued) Where: R -i Rc-a / and R- -3 are independently defined as Rx. Rc.4 is defined as R2 .. Scheme C describes a method for the preparation of the examples of the formula C-10. The commercially available MBHA Amide resin is deprotected under normal solid phase peptide synthesis conditions (Atherton, E., Sheppard R.C. Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press: Oxford, 1989) to produce the amine of formula C-2. Acylation with an easily prepared or commercially available amino acid residue of general formula C-3 yields the resin binding derivative of formula C-4. Removal of the Fmoc group under normal conditions provides amide of general structure C-5 which is acylated with a commercially available or readily prepared thiazolidine-4-carboxylic acid of general formula C-6 to produce the resin binding intermediate C- 7 Normal Fmoc deprotection produces the resin binding amine of general formula C-8 which can be reacted with a variety of electrophilic reagents as described in Scheme A to produce the resin binding amides, ureas, sulfonamides and carbomatos of general structure C-9. Preparation 18 details an example of the reaction of a mixed carbonate to produce a carbamate of general structure C-9 (where Y is equal to C02). Normal acidolysis produces amide of general structure C-10. Preparation 18 and Example 89 3- [2- (4-Morpholinyl) ethyl] [S- (R *, R *)] - 4 - [[[l - [[4- [2,6 -Dichlorophenyl)} methoxy] phenyl] methyl] 2-amino-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme C, C-10: where RC- ?, RC-2 / Rc-3 and Rc-4 are equal and equal to the proton, R3 is 2- (4-morpholinyl) ethyl, R5 is 4- [2,6-dichlorophenyl) methoxy] phenyl, Y is C02 and the stereochemistry is (_ ?, £?)).
To a mixture of MBHA Amide resin from Rink (Scheme, C, C-1) (Nova Biochem., 1.2 g, ca. 0.59 mmol) in methylene chloride (20 milliliters) was added a solution of piperidine in DMF (30 ppm). one hundred, 20 milliliters). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 minutes. The resin was filtered and washed with DMF. The resin was suspended in a solution of piperidine in DMF (30 percent, 40 milliliters) and mixed for 40 minutes. The resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride to yield a C-2 resin, which was diluted with DMF (40 milliliters). To this mixture was added Fmoc-Tyr (2, 6-Cl2-Bn) (Scheme C, C-3: where R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (5)) (Advanced Chemtech, 1.32 g, 2.35 mmol), HOBt (0.36 g, 2.35 mmol), PyBOP (1.20 g, 2.35) and DIEA (1.03 milliliters, 5.90 mmol). The reaction mixture was mixed for 4 hours and the resin was filtered and washed with DMF, methylene chloride, MeOH and methylene chloride to yield the amino acid derivative bonded to intermediate resin C-4 (Scheme C, where R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S)) which was used without characterization. To a mixture of C-4 resin described above in methylene chloride (20 milliliters) was added a solution of piperidine in DMF (30 percent, 20 milliliters). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 minutes. The resin was filtered and washed in DMF. The resin was suspended in a solution of piperidine in DMF (30 percent, 40 milliliters) and mixed for 40 minutes. The resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride to yield the resin of structure C-5 (Scheme C, wherein R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (5)), where it was diluted with DMF, (40 milliliters). To this mixture was added Fmoc-D-thiazolidine-4-carboxylic acid (Scheme C, C-6: wherein Rc, RC-2 / Rc-3 and Rc-4 are equal and equal to proton and the stereochemistry is ( 5) ) (Advanced Chemtech, 832 milligrams, 2.35 mmol), HOBt (0.36 gram, 2.35 mmol), PyBOP (1.20 gram, 2.35) and DIEA (1.03 milliliters, 5.90 mmol). The reaction was mixed for 4 hours and the resin was filtered and washed with DMF, methylene chloride, MeOH and methylene chloride to yield the derivative linked with intermediate resin C-7 (Scheme C, where Rc ?, Rc-2 Rc-3 and Rc_4 are equal and equal to the proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S, S)) which was used without characterization. To a mixture of resin C-7 described above e? Methylene chloride (20 milliliters) was added a solution of piperidine in DMF (30 percent, 20 milliliters). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 minutes. The resin was filtered and washed with DMF. The resin was suspended in a solution of piperidine in DMF (30 percent, 40 milliliters) and mixed for 40 minutes. The resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride to provide the intermediate of structure C-8 (Scheme C, wherein Rc-i / R_-2 / Rc-3 and Rc-4 they are equal and equal to the proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (5.5)), where it was diluted with methylene chloride (10 milliliters). To this mixture was added a mixed carbonate solution prepared from 4- (2-hydroxyethyl) morpholine (2.15 milliliters, 1.77 mmol) and N, N-disuccinimidyl carbonate (4.53 grams, 17.7 mmol) as described in the preparation 8 in methylene chloride (20 milliliters) followed by triethylamine (0.33 milliliters, 2.36 mmol). The reaction was mixed for 24 hours and the resin was filtered and washed extensively with DMF, methylene chloride, MeOH, and anhydrous ethyl ether. The resin was dried under vacuum to produce the carbamate linked with C-9 resin (Scheme C, where Rc- ?. Rc-2 'Rc-3 and Rc-. they are equal and equal to the proton, R3 is 2- (4-morpholinyl) ethyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, Y is C02 and the stereochemistry is (S, S)). The C-9 resin was swelled with a minimum of methylene chloride (approximately 2 milliliters) and suspended with 95 percent aqueous TFA (20 milliliters). The mixture was mixed by magnetic stirring for one hour and filtered. The resin was washed with additional TFA (2 X 5 milliliters), followed by methylene chloride and methanol. The combined filtrates were evaporated in vacuo, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with brine, dried (MgSO 4), filtered and evaporated in vacuo. The residue was purified by flash chromatography using methylene chloride / methanol (1 to 3 percent) as eluent to yield the title compound (215 milligrams) as an amorphous powder: IR (Mull) 3288, 1676, 1657, 1611, 1564, 1511, 1439, 1424, 1346, 1302, 1237, 1179, 1116, 1021, 767 en.-1; ? NMR (CDCl3, 300 MHz) d 7.24 (5 H), 6.93 (2 H), 5.20 (2 H), 4.63 (3 H), 4.34 (1 H), 4.22 (2 H), 3.63 (4 H), 3.11 (4 H), 2.50 (6 H); 13 C NMR (CDC13, 75 MHz) d 173.4, 170.1, 157.9, 154.5, 136.9, 132.0, 130.4, 129.1, 128.4, 115.1, 66.8, 65.2, 63.4, 57.1, 54.0, 53.7, 53.7, 53.5, 49.4, 35.2; MS (El) m / z (relative intensity) 610 M +, 1), 323 (13), 321 (20), 161 (34), 159 (53), 114 (31), 113 (98), 100 (99 ), 88 (13), 70 (8), 56 (11); MS (FAB) m / z (relative intensity) 611 (MH +, 71), 614 (18), 613 (49), 612 (27), 611 (71), 123 (60), 114 (99), 113 ( 76), 112 (19), 107 (22), 100 (28); HRMS (FAB) caled for C27H32C12N406S + HX 611.1498, found 611.1494. Anal. Caled for C27H32C12N406S: C, 53.03; H, 5.27; N, 9.16. Found: "C, 52.74; H, 5.17; N, 9.01 Example 90 3-Ethyl acid ester [S- (R *, R *)] -4- [[[1- [[4- [(2, 6 -Dichlorophenyl) methoxy] phenyl] methyl] 2-amino-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (Scheme C, C-10: wherein Rc * n c-2r R-3 Y "& -4 are equal and equal to the proton, R3 is ethyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, Y is C02 and the stereochemistry is IS, S)) - Example 90 was prepared as described in Scheme C. The physical data are as follows: IR (Mull) 3369, 3308, '3192, 1713, 1667, 1650, 1629, 1539, 1513, 1441, 1344, 1290, 1240, 1016, 768 cp.-1; XH NMR (CDCl3, 300 MHz) d 7.33 (3 H), 7.16 (2 H), 6.95 (2 H), 5.25 (2 H), 4.48 (4 H), 4.20 (2) H), 3.03 (4 H), 1.26 (3 H); 13 C NMR (CDCl 3, 75 MHz) d 173.6, 170. 5, 157.8, 154.7, 136.8, 313.9, 130.4, 130.2, 129.0, 128.4, 114. 9, 67.9, 65.1, 63.1, 62.5, 53.8, 36.5, 14.3; MS (El) m / z (relative intensity) 525 M *, 1), 323 (44), 322 (13), 321 (68), 267 (9), 265 (14), 163 (12), 161 (65), 160 (35), 159 (99), 88 (30); MS (FAB) m / z (relative intensity) 526 (MH *, 58), 528 (40), 527 (19), 526 (58), 321 (27), 188 (29), 161 (37), 160 (99), 159 (48), 107 (26), 88 (39); HRMS (FAB) caled for C23H25C12N305S + H? 526.0970, found 526.0942. Anal. Caled for C23H2c.Cl2N30cS: C, 52.47; H, 4.79; N, 7.98. Found: C, 52.34; H, 4.81; N, 7.90 Scheme D R. 0-1 Fmoc. OH H, NOf-Bu D-2 R-D-I RD-2 and "RD-3 are independently defined as Rx, RD.4 is defined as R2, Scheme D describes a method for the preparation of the examples of general formula D-9, Na-Fmoc protected amino acids easily prepared or Commercially available structures of general structure D-1 are coupled with O- (er-butyl) hydroxylamine (D-2) under standard coupling conditions as previously mentioned to produce the t-butyl hydroxamate of general structure D-3. Standard Fmoc yields the intermediate amine of formula D-4 The coupling of this amine with commercially available or commercially available N- -Fmoc-thiazolidine-4-carboxylic acid of general structure D-5 produces the intermediate pseudopeptide of general structure D-6 The standard Fmoc deprotection produces the intermediate amine of general structure D-7 which can be reacted under the variety of conditions described in Scheme A to produce amides, carbamates, its lfonamides and ureas of general structure D-8. Preparation 22 provides a specific example of the reaction of an amine of general structure D-7 with a carbonate to produce a carbamate of general structure D-8. The average acidolysis produces the hydroxamate of general structure D-9. Preparation 19 (Scheme D, D-3: wherein R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (5)).
To a cooled solution (0-5 ° C) of Fmoc-Tyr (2, 6-Cl2-Bn) (Scheme D, D-1: wherein R5 is 4- [2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (5)) (Advanced Chemtech, 6.0 grams, 10.7 mmol), HOBt (1.63 grams, 10.7 mmol), O- (er-butyl) hydroxylamine hydrochloride (Scheme D, D-2) (1.61 g, 12.80 mmol ) in methylene chloride (30 milliliters) was added PyBOP (6.66 grams, 12.80 mmol) followed by DIEA (6.51 milliliters, 37.35 mmol). The mixture was stirred at 0-5 ° C for one hour, gradually allowed to warm to room temperature and stirred for an additional 2 hours. The mixture was diluted with methylene chloride and 0.25 N HCl, the organic layer was separated and washed with saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography using methylene chloride / methanol (0-2.5 percent) as eluent to give the title compound (5.87 grams) as an amorphous powder: XH NMR (CDCl3, 300 MHz) d 8.08 (1 H ), 7.76 (2 H), 7.54 (2 H), 7.29 (9 H), 6.95 (2 H), 5.43 (1 H), 5.30 (2 H), 4.28 (4 H), 3.06 (2 H), 1.19 (9 H); 13 C NMR (CDCl 3, 75 MHz) d 169.7, 157.8, 156.3, 143.6, 141.2, 136.8, 132.0, 130.4, 128.9, 128.4, 127.7, 127.9, 125.0, 119.9, 115.0, 82.3, 67.1, 65.1, 54.0, 46.9, 37.6, 26.0; MS (ESI +) for C35H34C12N205 m / z 632.9 (M + H) * MS (ESI +) for C35H34C12N205 m / z 654.9 (M + Na) *. Preparation 20 (Scheme D, D-6: where RD., RD-2 / RD-3 and RD-4 are equal and equal to proton, R5 is 4- [(2,6-dichlorofenyl) methoxy] phenyl and the stereochemistry is { S, S)).
To a solution of D-3 (Scheme D, wherein R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S)) (5.87 grams, 9.28 mmol) in anhydrous DMF (94 milliliters) Diethylamine (9.40 milliliters, 90.84 mmol) was added at room temperature. The solution was stirred for 9 minutes and the volatiles were removed in vacuo to yield the intermediate amine D-4 (Scheme D, where R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S) ) and an oil that was used without further purification. To a cooled solution (0-5 ° C) of Fmoc-D-thiazolidine-4-carboxylic acid) (Scheme D, D-5: where RD.?, RD-2 / RD-3 and RD-4 are equal and equal to proton and the stereochemistry is (5)) (Advanced Chemtech, 3.93 grams, 11.10 mmol) and HOAt (1.51 grams, 11.10 mmol), in methylene chloride / DMF (4: 1, 30 milliliters) was added EDC (2.12 grams, 11.10 mmol). The reaction mixture was allowed to stir for 15 minutes and the solution of the amine (D-4 described above) in methylene chloride / DMF (4: 1, 30 milliliters) was added followed by DIEA (1.61 milliliters, 9.28 mmol). . After one hour at 0.-5 ° C, an additional equivalent of DIEA (1.61 milliliters, 9.28 mmol) was added and the mixture was allowed to warm to room temperature. After stirring overnight, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and 0.25 N aqueous HCl. The organic layer was separated and washed with water, saturated aqueous NaHCO3, and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography using CH_Cl2 / acetone (3 percent) containing isopropanol (0.1 percent) as eluent to afford the title compound (2.4 grams) as an amorphous solid: XH NMR (300 MHz, CDC13) d 7.77 (2 H), 7.55 ( 2 H), 7.32 (7 H), 7.12 (2 H), 6.92 (2 H), 6.70 (1 H), 5.19 (3 H), 4.55 (5 H), 4.26 (2 H), 3.30 (1 H) ), 3.11 (3 H), 1.14 (9 H); 13C NMR (75 MHz, CDC13) d 170.0, 168.8, 158.0, 143.4, 141.3, 137.0, 132.1, 130.4, 128.5, 127.9, 127.2, 124.9, 120.1, 115.3, 82.5, 68.4, 65.3, 52.8, 47.1, 36.5, 26.2; MS (ESI +) for C39H39Cl2N3? 6S m / z 747.9 (M + H) + MS (ESI +) for CsjHigCljNjOeS m / z 769.8 (M + Na) *; MSI (ESI-) for C39H39Cl.N306S m / z 745.7 (M-H) -.
Preparation 21 (Scheme D, D-7: where RD- ?, RD-2, RD-3 and RD-4 are equal and equal to proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S, S)).
To a solution of D-6 (Scheme D, where RD.?, RD.2, RD.3 and RD.4 are equal and equal to proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S, S)) (500 milligrams, 0.67 mmol) in anhydrous DMF (7 milliliters) was added diethylamine (0.70 milliliters, 6.55 mmol) at room temperature. The solution was stirred for 90 minutes and the volatiles were removed in vacuo. The residue was washed with ethyl ether / hexane (3: 2) to yield the title compound (352 milligrams) as an amorphous solid which was used without further purification: H NMR (300 MHz, DMSO-d6) d 10.61 (1 H), 8.27 (1 H), 7.54 (2 H), 7.44 (1 H), 7.15 (2 H), 6.94 (2 H), 5.15 (2 H), 4.50 (1 H), 4.03 (2 H), 3.75 (1 H) , 3.19 (1 H), 2.82 (3 H), 2.57 (1 H), 1.06 (9 H); MS (ESI +) for C24H29C12N304S m / z 526.1 (M + H) + MS (ESI-) for C24H29C12N304S m / z 524.1 (MH). "Preparation 22 (Scheme D, D-8: wherein RD.?, RD- 2 / RD-3 and RD-4 are equal and equal to proton, R3 is 2- (4-morpholinyl) ethyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, Y is C02 and the stereochemistry is (H.H) ) .
To a solution of 4- (2-hydroxyethyl) morpholine (1.22 milliliters, 10.05 mmol) in CH3CN (55 milliliters) at room temperature was added N, N-disuccinimidyl carbonate (2.49 grams, 10.05 mmol) and triethylamine (4.20 milliliters, 30.15 mmol). The solution was stirred at room temperature for 4 hours and concentrated in vacuo to give a viscous oil. The oil was dissolved in a minimum amount of methylene chloride (15 milliliters) and added to a solution of D-7 (Scheme D, where Rp-j., RD.2, RD.3 and RD-4 are the same). and equal to proton, R5 is 4 - [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S, S)) (350 milligrams, 0.67 mmol), triethylamine (0.10 m, 0.74 mmol) and DMAP (1 milligram) in CH2C12 (4 milliliters). The reaction mixture was stirred overnight and diluted with CH2C12 (15 milliliters). Propylamine (8.6 milliliters, 100.5 mmol) was added slowly [exothermic] and the solution was stirred vigorously for 15 minutes, then diluted with water. The organic layer was separated and washed with 0.1 M HCl, saturated aqueous NaHCO 3, and brine, dried (MgSO 4), filtered and concentrated, in vacuo. Purification of the residue by flash chromatography using ethyl acetate / acetone (3: 1) as eluent afforded the title compound (251 milligrams) as a white powder: IR (Mull) 3264, 1709, 1661, 1564, 1531, 1512, 1439, 1419, 1345, 1301, 1241, 1181, 1118, 1016, 767 cm "1; XH NMR (300 MHz, CDC13) d 8.48 (1 H) , 7.36 (2 H), 7.24 (1 H), 7.17 (2 H), 6.96 (2 H), 5.23 (2 H), 4.60 (3 H), 4.31 (3 H), 3.71 (4 H), 3.33 (4 H), 2.59 (6 H), 1.15 (9 H), 13 C NMR (75 MHz, CDC13) d 168.9, 158.0, 137.0, 132.1, 130.5, 128.7, 128.5, 115.3, 82.5, 66.8, 65.3, 63.4, 57.2, 53.7, 52.9, 36.4, 30.6, 29.3, 26.2, 19.1, 13.7; (ESI +) for C 31 H 40 Cl 2 N 4 O 7 S m / z 682.9 (M + H) * MS (ESI-) for C3? H40Cl2N4O7S m / z 705.0 (M + Na) *; Anal. Caled for C 31 H 40 Cl 2 N 4 O 7 S.0.35 H20: C, 53.97; H, 5.95; , 7.95. Found: C, 54.22; H, 6.11; N, 7.95. percent Water (KF): 0.91. Preparation 23 and Example 91 (Scheme D, D-9: where RD_ ?, RD-2 / RD-3 and D-4 are equal and equal to proton, R3 is 2- (4-morpholinyl) ethyl, R5 is 4 - [(2,6-dichlorophenyl) methoxy] phenyl, Y is C02 and the stereochemistry is (S, S)).
Hydroxamate D-8 (Scheme D, where RD., RD-2 f RD-3 RD_4 are equal and equal to proton, R3 is 2- (4-morpholinyl) ethyl, Rs is 4- [(2, 6 -dichlorophenyl) methoxy] phenyl, Yes C02 and the stereochemistry is [S, S)) (150 milligrams, 0.22 mmol) was dissolved in anhydrous TFA (12 milliliters) at room temperature and gradually warmed to 40 ° C. After 5 hours at 40 ° C, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO 3. The organic layer was separated and washed with brine, dried (MgSO 4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride / methanol (5 percent) as eluent afforded the title compound (51 milligrams) as an amorphous solid: IR (Mull) 3273, 3229, 1708, 1652, 1564, 1546, 1511, 1439, 1422, 1346, 1236, 1180, 1114, 1022, 768 cm "1; 1 H NMR (300 MHz, DMSO-dg) d 10.70 (1 H), 8.93 (1 H), 8.32 (1 H), 7.54 (2 H), 7.45 (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.56 (2 H), 4.36 (1 H), 4.25 (1 H), 4.06 ( 2 H), 3.51 (4 H), 3.15 (1 H), 2.76 (3 H), 2.36 (4 H), 13 C NMR (75 MHz, DMSO-dg) d 169.8, 167.9, 157.6, 136.5, 132.2, 132.0 , 130.8, 130.5, 129.2, 114.7, 66.7, 65.3, 63.3, 59.1, 57.1, 53.8, 52.1, 37.8, 31.3, 30.1; MS (ESI +) for C27H32C12N407S m / z 627.0 (M + H) + MS (ESI-) for C27H32C12N407S m / z 624.9 (MH) -; Anal Caled for C27H32C12N407S .0.46 H20: C, 51.00; H, 5.22; N, 8.81 Found: C, 51.34; H, 5.23; N, 8.67. KF): 1.31 Example 92 (Scheme D, D- 9: where RD__, D-2 RD-3 and D- 4 are ll2 equal and equal to proton, R3 is ethyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, Y is C02 and the stereochemistry is (S, S)).
Example 92 was prepared as described in Scheme D from Fmoc-Tyr (2, 6-Cl2-Bn) using ethyl chloroformate to provide the required carbamate. The physical properties are as follows: IR (Mull) 3278, 1654, 1612, 1585, 1564, 1547, 1511, 1439, 1347, 1237, 1195, 1179, 1022, 782, 769 cm "1; 1 H NMR (300 MHz, CDC13) d 7.39 (3 H), 7.17 (2 H), 6.94 (2 H), 5.24 (2 H), 4.53 (4 H), 4.18 (2 H), 3.15 (2 H), 2.87 (2 H) 1.28 (3 H); 13 C NMR (75 MHz, CD3OD) d 127.7, 170.1, 159.4, 156.2, 138.1, 133.7, 132.1, 131.6, 130.8, 129.8, 115.9, 66.3, 64.4, 63.6, 38.6, 36.8, 35.1, 15.0; HRMS (FAB) caled for + H? 542.0919, found 542.0921; Caled Anal for C23H25CL2N306S: C, 50.93; H, 4.64; N, 7.75, Found: C, 50.79; H, 4.79; N, 7.52 .Example 93 (Scheme D, D-9: where RD-? »D-2 &D-3 and RD-4 are equal and equal to proton, R3 is 2- (1-piperidinyl) ethyl, R5 is 4- [( 2,6-dichlorophenyl) methoxy] phenyl, Yes C02 and the stereochemistry is [S, S)) - Example 93 was prepared as described in Scheme D from Fmoc-Tyr (2,6-Cl 2 -Bn) using 1- (2-hydroxyethyl) piperidine to provide the required carbamate. physical ages are as follows: IR (Mull) 3276, 1707, 1653, 1611, 1584, 1564, 1511, 1439, 1237, 1195, 1179, 1144, 1113, 1093, 1021 was "1; XH NMR (300 MHz, DMS0-d6) d 7.54 (2 H), 7.44 (1 H), 7.12 (2 H), 6.93 (2 H), 5.16 (2 H), 4.58 (2 H), 4.36 (1 H), H), 4.25 (1 H), 4.00 (3 H), 2.76 (3 H), 2.31 (3 H), 1.62 (1 H), 1.42 (3 H), 1.26 (8 H); 13 C NMR (75 MHz, DMSO-dg) d 172.2, 168.9, 167.3, 157.0, 135.9, 131.7, 131.4, 130.2, 129.9, 128.7, 114.1, 64.7, 63.0, 54.0, 51.6, 36.2, 30.9, 25.5, 24.7, 23.8 , 22.0, 21.5, 13.9; MS (ESI +) for C2ßH34Cl2N406S m / z 624.9 (M + H) *.
Scheme E, Rs H2N E-5 E-6 Scheme E (continued) Preparation 24 (Scheme E, E-2 wherein the stereochemistry is (5)). , 5- (2-ethoxy-2-oxoethylidene) -1- (phenylmethyl) -L-Proline 1-dimethylethyl ester YY '' To a stirred solution of El (Scheme E wherein the stereochemistry is (S) (3.62 grams, 12.4 mmol), prepared by the Rapoport method (". Am. Chem. Soc. 1984, 106, 4539), in CH3CN (10 milliliters) methyl bromoacetate (1.4 milliliter, 14.9 mmol) was added.After stirring for 70 hours, CH2C12 (70 milliliters) was added.The solution was stirred for 10 minutes before Ph3P (4.89 grams) was added. 18.6 mmol), and after 2 minutes Et3N (5.2 milliliters, 37.3 mmol) was added.After stirring for 20 hours, the solution was washed with ÍM NaH2P04 (100 milliliters), and the aqueous phase was extracted with CH2C12 (50 mL). milliliters) The combined organic phases were washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo The resulting yellow oil white solid was dissolved in CHC13, and chromatographed on silica gel (300 grams, 230 ml). 400 mesh, 70 millimeter OD column, was packed CHC13, eluted with CHC13, 3 liters, then 10:90 EtOAc-CHCl3, 250 milliliters in fractions) using the instantaneous technique. Fractions 19-23 gave the title compound (3.23 grams) as a pale yellow oil. XH NMR (300 MHz, CDC13) d 7.17-7.36 (5 H), 4.75 (1 H), 4.54 (1 H), 4.20 (1 H), 3.96 (1 H), 3.61 (3 H), 3. 36-3.47 (1 H), 3.08 (l H), 2.04-2.28 (2 H), 1.41 (9 H); EI / MS (70eV) m / z (relative intensity): 331 (MS 17.3), 275 (11.9), 230 (95.0), 170 (26.0), 91 (base); IR (clean): 2979, 2948, 1735, 1692, 1600, 1454, 1435, 1414, 1369, 1299, 1277, 1184, 1137, 1059, 964, 483, and 789 citr1; HRMS: Caled. For C? 9H25N-.04: 331.1783. Found: 331.1771; [OI] D25: + 107 ° (c = 0.939, CH2C12). Preparation 25 (Scheme E, E-3 wherein the stereochemistry is (2R, 5S)). Methyl ester of (2R-cis) -5 - [(1,1-dimethylethoxy) carbonyl] -1- (phenylmethyl) -2-pyrrolidinoacetic acid ((2R, 5S)) Raney-Nickel (20 grams of a 50 percent slurry in H20) was washed with EtOH abs. (3x25 milliliters) and suspended in EtOH abs. (50 milliliters), and a solution of E-2 (Scheme E, where the stereochemistry is (S)) (9.34 grams, 28.2 mmol) in EtOH abs. (50 milliliters) was added. After shaking during 3 hours, the Ra-Ni was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc (100 milliliters), 5 percent Pt / C (3.0 grams) was added, and the mixture was hydrogenated under 3.5 kg / cm2 for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (300 grams, 230-400 mesh, 70 mm OD column, packed and eluted with 15:85 fractions of EtOAc-hexanes, 270 milliliters) using the flash technique. Fractions 5-8 gave the title compound (6.55 grams) as a clear, colorless oil. 1 H NMR (300 MHz, CDCl 3) d = 7.22-7.34 (5 H), 3.86 (1 H), 3.79 (1 H), 3.62 (3 H), 3.21-3.29 (2 H), 2.57 (1 H), 2.33 (1 H), 1.64-2.05 (4 H), 1.37 (9 H); EI / MS (70eV) / z (relative intensity): 232 (base) 91 (39.8); IR (nujol): 2977, 1739, 1454, 1437, 1367, 1295, 1251, 1197, 1153, 1074, 844, 753, and 699 crn "1; Anal: Caled." For C19H27N? 04: C, 68.44; H, 8.16; N, 4.20, Found: C, 68.39; H, 8.15; N, 4. eleven; [a] D25: -22 ° (c = 1.051, CH2Cl2). Preparation 26 (Scheme E, E-4 wherein the stereochemistry is (2R, 5S)) (2R, 5S)) (2R-cis) -5- [q, q-dimethylethoxy) carbonyl] -1- (phenylmethyl) -2-pyrrolidinoacetic acid To a stirred solution of E-3 (Scheme E wherein the stereochemistry is (2R, 5S)) (2.00 grams, 6.00 mmol), in MeOH (60 milliliters) was added ÍM K2C03 (20 milliliters). After stirring for 12 hours, the reaction mixture was evaporated in vacuo, the residue was dissolved in H20 (0.1 liter), the pH was adjusted to approximately 6 with IM HCl, and the mixture was extracted with CHC13 (2 X 0.1 liter). The combined extracts were washed with H20, brine, dried (Na2SO4), and evaporated in vacuo to yield the title compound (1.89 g) as a white solid. Mp: 95-96 ° C (lit. 98-101 ° C); H NMR (300 MHz, CDCl 3) d 7.30-7.37 (5 H), 4.00 (1 H), 3.68 (1 H), 3.45 (1 H), 3.20 (1 H), 2.59 (1 H), 2.46 (1 H), 1.76-2.21 (4 H), 1.31 (9 H); EI / MS (70eV) m / z (relative intensity): 218 (base), 91 (86.7); IR (nujol): 1719, 1497, 1451, 1367, 1296, 1285, 1260, 1160, 1153, 1079, 965 and 757 crn "1; Anal: Caled." For C18H25N? 04: C, 67.69; H, 7.89; N 4.39, Found: C, 67.55, H, 7.97, N, 4.15, [a] D25: + 27 ° (c = 0.795, CH2Cl2), Preparation 27 (Scheme E, E-6 where R5 is 4- [( 2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry of the pyrrolidine ring is (2R, 5S)) and the amino acid is (5)). 1, 1-dimethylethyl ester of ((1S, 5R, L)) ( 5R) -5- [2- [[(SS) -l-Methoxycarbonyl-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] -2-oxoethyl] -1- (phenylmethyl) -L-proline To a stirred solution of E-4 (Scheme E wherein the stereochemistry is (2R, 5S)) (0.48 gram, 1.50 mmol), in CH2C12 (10 milliliters) was added l- (3-dimethylaminopropyl) -3-ethylcarbodi-imide hydrochloride (0.29 gram, 1.50 mmol), 1-hydroxybenzotriazole hydrate (0.20 gram, 1.50 mmol), 4-dimethylaminopyridine (0.05 gram, 0.45 mmol), and methyl ester 2,6-dichlorobenzyl-L-tyrosine hydrochloride (Scheme E, E-5: wherein R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry is (5)) (0.59 gram, 1.50 mmol) to give a heterogeneous mixture. After the addition of triethylamine (0.3 milliliters) the reaction mixture became homogeneous and stirred for 12 hours. The reaction mixture was partitioned between CH2C12 (50 milliliters) and IN HCl (50 milliliters). The organic phase was washed with saturated aqueous NaHCO3, H20, brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on silica gel (150 grams, 230-400 mesh, 70 mm OD column, packed and eluted with 5:95 acetone / CH2Cl2, 40 milliliter fractions). Fractions 36-48 provided the title compound (0.90 gram) as a glass. X H NMR (300 MHz, CDC13) d = 9.09 (1 H), 7.38 (2 H), 7. 10-7.30 (8 H), 6.97 (2 H), 5.22 (2 H), 4.75 (1 H), 3.81 (1 H), 3.68 (3 H), 3.60 (1 H) 3.15-3.35 (3 H), 3.04 (1 H), 2.42 (1 H), 2.21 (1 H), 1.86-2.07 (4 H), 1.37 (9 H); FAB / MS m / z (relative intensity): 655 (M + H, 46.4), 599 (11.3), 553 (23.6), 260 (18.8), 204 (91.4), 91 (base); IR (nujol): 3262, 3001, 1733, 1665, 1612, 1585, 1565, 1512, 1439, 1392, 1240, 1226, 1197, 1177, 1153, 1018, and 768 cm "1; Anal: Caled.
C 35 H 40 N 2 O 6 Cl 2: C, 64.12; H, 6.15; N, 4.27: Cl, 10.82.
Found: C, 63.75; H, 6.29; N, 4.11; Cl, 10.88; [] D25: + 6 ° (c = 0.863, CHC13). Preparation 28 (Scheme E, E-7 wherein R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry of the pyrrolidine ring is (2R, 5S)) and the amino acid is (5)). ((1S, 5R, L)) (5R) -5- [2- [[(SS) -l-Carboxy-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] - 2-oxoethyl] -1- (f -methylmethyl) -L-proline 1,1-dimethylethyl ester To a stirred solution of E-6 (Scheme E, wherein Rs is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry of the pyrrolidine ring is (2R, 5S) and the amino acid is (S) ) (1.00 gram, 1.53 mmol) in MeOH (50 milliliters) was added with IM K2C03 (10 milliliters). After stirring for 12 hours, the reaction mixture was evaporated in vacuo, the residue was dissolved in H20 (0.1 liter), the pH was adjusted to approximately 6 with IM HCl, and the mixture was extracted with CHC13 (2 X 0.1 liter). The combined extracts were washed with H20, brine, dried (Na2SO4), and evaporated in vacuo to yield the title compound (0.85 grams) as a white solid. Mp: 80-83 ° C; H NMR (300 MHz, CDC13) d = 9.87 (1 H), 7.35 (2 H), 7.21-7.26 (7 H), 7.13 (2 H), 6.94 (2 H), 5.22 (2 H), 4.64 (1 H), 3.80 (1 H), 3.55 (1 H), 3.29-3.37 (3 H), 3.04 (1 H), 2.48 (1 H), 2.26 (1 H), 1.94 (1 H), 1.76 (1 H), 1.59 (1 H), 1.41 (1 H), 1.34 (9 H); FAB / MS m / z (relative intensity): 641 (M + H, 45.8), 585 (13.0), 260 (6.1), 204 (base), 91, (96.8); IR (nujol): 1732., 1642, 1612, 1585, 1565, 1534, 1511, 1439, 1240, 1230, 1196, 1178, 1153, 1018, 779, and 767 was "1; HRMS: Caled." For C34H38C12N206: 641.2185 Found: 641.2164; [a] D25: + 5 ° (c = 0.795, CHC13), Preparation 29 and Example 94 (Scheme E, E-8 where R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl , and the stereochemistry of the pyrrolidine ring is (2R, 5S) and the amino acid is (5)). ((ÍS, 5R, L)) (5R) -5- [2- [[(ÍS) -l-Carboxi -2- [4- [(2,6-Dichlorophenyl) methoxy] phenyl] ethyl] amino] -2-oxoethyl] -1- (phenylmethyl) -L-proline To a stirred solution of E-7 (Scheme E, wherein Rs is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry of the pyrrolidine ring is (2R, 5S) and the amino acid is (5) ) (0.85 gram, 1.32 mmol) in H2? / N-PrOH (1: 1, 0.1 liter) was added HOAc (6 milliliters), and the solution was refluxed for 5 hours, then stirred at room temperature for 12 hours. hours. Evaporation in vacuo afforded the title compound (0.78 gram) as a white solid. Mp: 198-202 ° C; X H NMR (300 MHz, DMSO) d = 8.56 (1 H), 7.56-7.59 (2 H), 7.45-7.50 (1 H), 7.25-7.29 (5 H), 7.21 (2 H), 6.96 (2 H) ), 5.18 (2 H), 4.41 (1 H), 3.89 (1 H), 3.74 (1 H), 3.31 (1 H), 3.03-3.09 (2 H), 2.85 (1 H), 2.18-2.34 ( 2 H), 1.88-2.00 (1 H), 1.63-1.84 (2 H), 1.44-1.58 (1 H); FAB / MS m / z (relative intensity): 585 (M + H, 21.6), 539 (2.1), 246 (14.5), 204 (60.9), 159 (12.6), 91 (base); IR (nujol): 3309, 3083, 3037, 3014, 1662, 1644, 1562, 1514, 1440, 1377, 1348, 1241, 1197, 1178, 1018, 998, 815, and 771 was "1; Anal: Caled. C30H30N2OgCl20.38H20: C, 60.83; H, 5.24; N, 4.73. Found: C, 60.83; H, 5.33; N, 4.69; Karl Fischer water: 0.42 percent, Example 95 (Scheme E, E-8 where R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry of the pyrrolidine ring is (2S, 5R) and the amino acid is (5)). ((ÍS, 5S, D)) (5S) - 5- [2- [[(SS) -l-Carboxy-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] -2 -oxoethyl] -1- (phenylmethyl) -D- proline Example 95 was prepared as described in Scheme E for El (Scheme E wherein the stereochemistry is (i?) Prepared by the Rapoport method (J. Am. Chem. Soc. 1984, 106, 4539: physical data ! H NMR (300 MHz, DMSO) d = 8.60 (1 H), 7.54-7.68 (3 H), 7.26-7.41 (8 H), 7.05 (2 H), 5.27 (2 H), 4.57 (1 H), 3.96 (1 H), 3.82 (1 H), 3.40 (1 H), 3.14 (2 H), 2.86-2.94 (1 H), 2.27-2.47 (2 H) ), 1.96-2.10 (1 H), 1.72-1.88 (1 H), 1.55-1.72 (1 H), 1.30-1.42 (1 H); FAB / MS m / z (relative intensity): 585 (M + H , 50.5), 539 (4.5), 332 (32.1), 331 (18.1), 246 (6.2), 244 (6.0, 204 (77.2), 91 (base); IR (nujol): 3211, 3033, 3006, 1724 , 1647, 1610, 1565, 1512, 1438, 1354, 1301, 1273, 1240, 1196, 1018, 871 and 767 era-1; Anal: Caled.For C30H30N2OgCl2? .43H20: C, 60.77; H, 5.24; N, 4.72 Found: C, 60.76; H, 5.37; N, 4.69; Karl Fischer water analysis: 1.71 percent.
Scheme F J and O .. F-2 H2N wherein RF_3 is defined as proton or alkyl having from 1 to 6 carbon atoms. Scheme F describes a general method for the preparation of examples of the formula F-4, F-5, F-6, F-7 and F-8. An easily prepared or commercially available sulfur containing amino acid of structure F-1 is condensed with amino acid derivative F-2 under standard peptide synthesis conditions as described in Scheme A. Deprotection of carbamate from F-3 provides the useful intermediary F-4. The amino group can be reacted with a variety of electrophilic reagents as described in Scheme A to provide esters of general structure F-5. The hydrolysis of soft base provides acids of structure F-6. Soft hydrolysis of esters of general structure F-3 provides acid of formula F-7. In the cases in which RF_3 is equal to t-butyl, the mild acidolysis of compounds of general structure F-3 produces the amino acid of general structure F-8. Preparation 30 and Example 96 (Scheme F, F-3: where RF.X and Rr_2 are equal and equal to proton, RF_3 is CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [R, S)).
To a cooled solution (0 ° C) of Boc-L-thiomorpholine-3-carboxylic acid ((a) Van Der Auwera, C., Anteunis, MJO Int. J. Peptide Protein Res. 1987, 29; 574: (b) ) Kogami, Y., Okawa, K. Bull, Chem. Soc. Jpn. 1987, 60, 2963: ® Larsson U.; Carlson R. ACTA Chemica Scand 1994, 48, 517: (d) Carson JF; Wong FF " Org Chem. 1964, 29, 2203.) (Scheme F, F-1: where RF.? And RF-2 are equal and equal to proton, and the stereochemistry is (R)) (6.7 grams, 27 mmol) in CH2C12 (100 milliliters) was added HOBt (40.0 grams, 29.7 mmol), DMAP (700 milligrams), EDC (5.7 grams, 29.7 mmol) and triethylamine (13.5 milliliters, 97 mmol) .The reaction mixture was stirred for 10 minutes. minutes, then the amino acid derivative F-2 (Scheme F, wherein R 5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, RF_3 is CH3, and the stereochemistry is (5)) (10.0 grams, 24.7 mmol) was added. After 20 hours, the volatiles were removed in vacuo and the residue was partitioned between 2.5 percent aqueous HCl (100 milliliters) and H20 (100 milliliters). The organic layer was separated and washed with saturated aqueous NaHCO3 (100 milliliters), dried and concentrated in vacuo. Purification of the residue by chromatography on SiO2 (500 grams) using CH2Cl2 / ethyl acetate (10 percent) as eluent afforded the title compound (12.31 grams) as a solid: XH NMR (CDC13) d 1.44 (9 H), 2.35 (1 H), 2.70 (3 H), 3.13 (2 H), 3.33 (1 H), 3.77 (3 H), 4.22 (1 H), 5.00 (1 H), 6.48 (1 H), 7.18 ( 2 H), 7.31 (3 H), 7.44 (1 H), 7.56 (2 H); 13C NMR (CDC13) d 171.6, 168.9, 162.5, 136.5, 135.9, 132.4, 131.0, 130.2, 128.2, 120.5, 81.7, 77.3, 53.3, 52.6, 37.0, 28.2, 26.5; IR (Mull): 3296, 2924, 1744, 1685, 1668, 1605, 1536, 1515, 1432, 1412, 1321, 1294, 1260, 1244, 1213, 1195, 1161, 798 was "1; MS (FAB) m / z (relative intensity) 598 (M + H, 3), 596 (M + H, 5) Anal: Caled.For C27H31Cl2N3? 6S: C, 54.36; H, 5.24; N, 7.04 Found: C, 54.23; H, 5.24; N, 6.86, Corrected for 0.60 percent H20, found by Karl Fischer analysis, Preparation 31 and Example 97 (Scheme F, F-4: where RF.? And RF_2 are equal and equal to proton, R F-3 is CH 3 / R 5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [R, S)) Acetyl chloride (1.75 milliliters, 24 mmol) was slowly added to MeOH (26 milliliters) at 0-5 ° C. After 15 minutes, a solution of the carbamate F-3 was added (Scheme F,: where RF.? And RF_2 are equal and equal to proton, RF_3 is CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino) ] phenyl, and the stereochemistry is (R, S)) (2.4 grams, 4.0 mmol) in methanol (8 milliliters). After 50.5 hours at 0 ° C, the solvent was removed under vacuum to yield the title compound (2.11 grams): XH NMR (300 MHz, DMS0-d6) d 2.68 (1 H), 3.00 (6 H), 3.47 (1 H), 3.64 (3 H), 4.02 (1 H), 4.52 (1 H), 7.28 (2 H), 7.54 (5 H), 9.15 (1 H), 9.3 (1 H), 9.70 (1 H), H), 10.7 (1 H); GO (Mull): 3191, 3031, 1742, 1664, 1604, 1577, 1561, 1540, 1516, 1432, 1414, 1326, 1271, 1210, 799 cm "1; MS (El) m / z (relative intensity) 495 ( M + H, 1), Preparation 32 and Example 98 (Scheme F, F-5: where RF.1 and RF.2 are equal and equal to proton, RF.3 is CH3, R3 is CH2CH2C02CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is CO-, and the stereochemistry is (R, 5)).
To a solution of amine F-4 (Scheme F,: where RF.? And RF_2 are equal and equal to proton, RF_3 is CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and stereochemistry is (R, S)) (650 milligrams, 1.2 mmol) was added monomethyl succinate (320 milligrams, 2.4 mmol), EDC (460 milligrams, 2.4 mmol), pyridine (10 milliliters) and DMAP at room temperature. After 27 hours, the mixture was diluted with 25 milliliters of saturated NaHCO 3 extracted with methylene chloride. The combined organic extracts were dried and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride / ethyl acetate (3: 2) as eluent followed by lyophilization afforded the title compound (600 milligrams) as an amorphous solid: IR (Mull): 1742, 1659, 1657 , 1608, 1537, 1516, 1432, 1414, 1324, 1269, 1259, 1228, 1214, 1195, 1176 cnr1; X H NMR (300 MHz, CDCl 3) d 2.63 (7 H), 3.21 (3 H), 3.68 (3 H), 3.78 (3 H), 3.90 (1 H), 4.80 (2 H), 5.50 (1 H) , 6.56 (1 H), 7.29 (5 H), 7.57 (2 H); 13 C NMR (75 MHz, CDCl 3) d 173.9, 172.0, 171.7, 168.5, 162.7, 136.1, 135.9, 133.3, 132.3, 131.0, 130.1, 128.2, 121.0, 120.7, 53.1, 52.5, 52.3, 52.0, 44.4, 36.7, 29.4 , 27.7, 26.9, 26.4; MS (El) m / z (relative intensity) 609 (M + H, 5). Anal Caled for C27H29C12N307S: C, 53.12; H, 4.79; N, 6.88. Found: C, 53.04; H, 4.81; N, 6.83. Corrected for 0.74 percent H20 found by Karl Fischer analysis. Preparation 33 and Example 99 Acid [R- (R *, S *)] -3- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -? - oxo-4-thiomorpholinobutanoic (Scheme F, F-6: where RF- ?, RF_2 are equal and equal to proton, RF_3 is proton, R3 is CH2CH2CH2C02H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, is CO- the stereochemistry is (J., 5)).
To a solution of diester F-5 (Scheme F, where RF_, RF.2 are equal and equal to proton, RF_3 is CH3, R3 is CH2CH2C02CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is C0-, and the stereochemistry is (R, S)) (490 milligrams, 0.80 mmol) in THF (20 milliliters) and MeOH (6 milliliters) was added a solution of LiOH.H20 (178 milligrams, 4.25 mmol) in H20 (6 milliliters). After 22 hours the mixture was concentrated in vacuo. The residue was partially dissolved in 10 percent HCl (20 milliliters) and the resulting solid was collected by filtration. The solid was washed with water and lyophilized from aqueous acetonitrile to yield the title compound (400 milligrams) as an amorphous solid: IR (Mull): 3267, 3193, 3058, 3034, 2924, 1725, 1658, 1607, 1562, 1537, 1516, 1432, 1414, 1326, 1195, 1178, 800 was "1; XH NMR (300 MHz, DMS0-d6) d 2.62 (7 H), 3.17 (3 H), 3.95 (1 H), 4.57 (2 H), 5.26 (1 H), 7.18 (2 H), 7.55 (5 H), 8.02 (1 H), 10.64 (1 H), 12.34 (1 H), MS (FAB) m / z ( relative intensity) 582 (M + H, 18).
Preparation 34 and Example 100 (4- (1, 1-dimethylethyl) acid ester [R- (R *, S *)] -3- [[[1-Carboxi-2- [4- [(2, 6- dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -4-thiomorpholinecarboxylic acid (Scheme F, F-7: where RF.?, RF_2 are equal and equal to proton, RF_3 is proton, R5 is 4- [(2, 6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is {R, S)).
To an ester solution F-3 (Scheme F, where RF.?, RF_2 are equal and equal to proton, RF_3 is CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is ( JR, 5)) (656 milligrams, 1.02 mmol) in MeOH (25 milliliters) was added K2CO3 (550 milligrams, 4 mmol) and H20 (13 milliliters). After 3 hours, the volatiles were partially removed and the solution was diluted with 10 percent HCl (20 milliliters) causing the precipitation of a solid. This product was collected by filtration, washed with H20 and dried in a vacuum oven to produce the product (610 milligrams). IR (Mull): 1736, 1665, 1606, 1562, 1537, 1516, 1432, 1413, 1323, 1294, 1260, 1244, 1211, 1195, 1160 cm "1; XH NMR (300 MHz, DMS0-d6) d 1.35 (9 H), 2.45 (2 H ), 2.74 (5 H), 4.00 (1 H), 4.47 (1 H), 4.70 (1 H), 7.19 (2 H), 7.52 (5 H), 7.92 (1 H), 10.60 (1 H), 12.75 (1 H) MS (FAB) m / z (relative intensity) 582 (M + H, 12) Anal Caled for C2gH29Cl2N306S: C, 53.61; H, 5.02; N, 7.21; Found: C, 53.20; H, 5.12; N, 7.10 Corrected for 2.30 percent H20 found by Karl Fischer analysis Preparation 35 (Scheme F, F-3: where RF.? And RF_2 are equal and equal to proton, RF_3 is t- butyl, R5 is 4- [(2,6-dichloro-benzoyl) amino] phenyl, and the stereochemistry is (R, S)).
To a cooled solution (0-5 ° C) of Boc-L-thiomorpholine-3-carboxylic acid (Scheme F, F-1: where RF.? And RF.2 are equal and equal to proton, and the stereochemistry is (R)) (1.34 grams, 5.4 mmol) in methylene chloride (20 milliliters) was added HOBt (800 milligrams, 5.94 mmol), DMAP (140 milligrams), EDC (1.14 gram, 5.94 mmol) and triethylamine (2.7 milliliters, 19.4 mmol). After 10 minutes, F-2 (Scheme F, where RF.? And RF.2 are equal and equal to proton, RF_3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (5)) (2.02 grams, 4.94 mmol) was added, the reaction was allowed to warm to room temperature and was stirred for 24 hours. The volatiles were removed in vacuo and the residue was partitioned between methylene chloride and 2.5 percent aqueous HCl. The organic layer was separated and washed with saturated aqueous NaHCO3, dried and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride / ethyl acetate (5 percent) as eluent afforded the title compound (1.64 grams): IR (Mull): 1730, 1687, 1667, 1606, 1538, 1515, 1431 , 1412, 1395, 1320, 1294, 1258, 1250, 1194, 1158 cm "1; aH NMR (300 MHz, CDC13) d 1.44 (9 H), 1.46 (9 H), 2.35 (1 H), 2.67 (3 H), 3.22 (3 H), 4.25 (1 H), 4.73 (1 H), 4.97 (1 H), 6.52 (1 H), 7.29 (5 H), 7.53 (3 H), MS (FAB) m / z (relative intensity) 638 (M + H, 2) Anal: CaCld For C30H37Cl2N3O6S: C, 56.42; H, 5.84; N, 6.58. Found: C, 56.13; H, 5.98; N, 6.58. and Example 101 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(3R) -thiomorpholinyl] carbonyl] -L-phenylalanine monochlorohydrate (Scheme F, F-8: wherein RF.? and RF_2 are equal and equal to proton, RF-3 is proton, R5 is 4- [(2,6-dichloro-benzoyl) amino] phenyl and the stereochemistry is (R, S)).
To a solution of saturated HCl in ethyl ether (5 milliliters) at room temperature was added carbamate F-3 (Scheme F, where RF.? And RF_2 are equal and equal to proton, RF_3 is t-butyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (R, S)) (100 milligrams, 0.15 mmol) with vigorous stirring. After 43.5 hours the precipitate was collected by filtration and washed with ethyl ether to yield the title compound (90 milligrams): IR (Mull) 3241, 3189, 3033, 2731, 1725, 1661, 1605, 1578, 1562, 1542 , 1515, 1432, 1414, 1328, 1195 cm "1; XH NMR (300 MHz, DMSO-dg) d 2.66 (1 H), 2.99 (6 H), 3.50 (1 H), 3.98 (1 H), 4.45 (1 H), 7.26 (1 H), 7.52 (5 H), 9.00 (2 H), 9.30 (1 H), 10.69 (1 H), MS (FAB) m / z (relative intensity) 482 (M + H, 83), 540 (32), 539 (9), 538 (42), 486 (13), 485 (16), 484 (60), 483 (24), 482 (83), 173 (11), 102 (99) Anal: Caled For C21H21C12N304S .HCl: C, 48.61; H, 4.27; N, 8.10; Cl, 20.50; S, 6.18. Found: C, 48.92; H, 4.27; N, 7.79; Cl, 19.68. Corrected for 6.53 percent H20 found by Karl Fischer analysis. EXAMPLE 102 4- [(2,6-Dichlorobenzoyl) amino] -N- [[(3R) -4- [l-oxo-3- (lH-tetrazol-S-yl) propyl] -3-thiomorpholinyl methyl ester ] carbonyl] -L-phenylalanine (Scheme F, F-5: where RF.? and RF_2 are equal and equal to proton, RF_3 is CH3, R3 is 2- (5-lH-tetrazolyl) ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is CO-, and the stereochemistry is (R, S)).
Example 102 was prepared as described in Scheme F using lH-tetrazole-5-propanoic acid (Hutchinson, D.W.; Naylor, M. Nucleic Acids Res. 1985, 13, 8519) to form the required amide. The physical data are as follows: IR (Mull) 3264, 3047, 1742, 1659, 1607, 1561, 1537, 1516, 1432, 1415, 1324, 1268, 1219, 1195, 799 cm'1; XH NMR (300 MHz, DMSO-dg) d 2.26 (1 H), 2.66 (2 H), 3.02 (8 H), 3.61 (3 H), 3.87 (1 H), 4.56 (1 H), 5.25 (1 H), 7.21 (2 H), 7.50 (5 H), 8.18 (1 H), 8.45 (1 H), 8.64 (1 H); MS (FAB) m / z (relative intensity) 620 (M + H, 61). EXAMPLE 103 4- [(2,6 -Dichlorobenzoyl) amino] -N- [[(3R) -4- [l-oxo-3- (lH-tetrazol-5-yl) propyl] -3- iomorfol inyl] carbonyl ] -L-phenylalanine (Scheme F, F-6: where RF.? And RF.2 are equal and equal to proton, RF.3 is proton, R3 is 2- (5-lH-tetrazolyl) ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is CO-, and the stereochemistry is (R, S)).
Example 103 was prepared from Example 102 by the procedure described in Preparation 34. The physical data are as follows: IR (Mull) 3376, 3296, 3267, 3127, 1746, 1683, 1669, 1641, 1623, 1610, 1542, 1444, 1436, 1411 cm "1; MS (ESI +) for C25H25C12N705S m / z 605.8 (M + H) +; MS (FAB) m / z (relative intensity) 606 (MH *, 51), 682 (17), 608 (40), 607 (28), 606 (51), 605 (16), 254 (99), 226 (23), 175 (17), 137 (20), 102 (33); HRMS (FAB) caled for C25H25Cl2N705S + H? 606.1093, found 606.1105. EXAMPLE 104 N- [[(3R) -4- (3-Cyano-l-oxopropyl) -3-thiomorpholinyl] carbonyl] -4- [[2,6-dichlorobenzoyl) amino] -L-phenylalanine (Scheme F, F -6: where RF.? And RF_2 are equal and equal to proton, RF.3 is proton, R3 is CH2CH2CN, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is CO-, and the stereochemistry is (RS)).
Example 104 was prepared as described in Scheme F using 3-cyanopropanoic acid (readily prepared from commercially available 3-cyanopropanoic acid) to form the required amide. The physical data are as follows: IR (Mull) 2251, 1735, 1655, 1612, 1585, 1565, 1512, 1439, 1298, 1240, 1196, 1179, 1016, 1000, 779, 768 crir1; H NMR (300 MHz, CDC13) d 2.40 (12 H), 4.88 (1 H), 5.22 (2 H), 6.72 (1 H), 6.96 (2 H), 7.23 (5 H). EXAMPLE 105 Acid [R- (R *, S *)] - 3 - [[[1-Carboxy-2 - [4- [(2,6-dichlorophenyl) methoxy] -phenyl] ethyl] amino] carbonyl] -? -oxo-4-thiomorpholinobutanoic (Scheme F, F-6: where RF.?, RF_2 are equal and equal to proton, RF.3 is proton, R3 is CH2CH2C02H, R5 is 4- [(2,6-dichlorophenyl)) methoxy] phenyl, Y is CO-, and the stereochemistry is (R, S)).
Example 105 was prepared as described in Scheme F using monomethyl succinate to form the required amid. The physical data are as follows: IR (Mull) 3031 1726, 1646, 1612, 1585, 1565, 1511, 1439, 1421, 1297, 1240 1196, 1179, 1016, 768 crn-1; ? NMR (300 MHz, DMSO-d6) d 2.62 (H), 3.64 (3 H), 4.39 (2 H), 5.20 (2 H), 6.92 (2 H), 7.15 (2 H) 7.50 (3 H), 7.98 (2 H); .39 (2 H), 5.20 (2 H), 6.92 (2 H), 7.15 (2 H); 13 C NMR (75 MHz, DMS0-d 6) d 174.5, 173.2, 171.9, 168.9, 136.5, 132.3, 132.0, 130.8, 130.7, 129.2, 114.8, 65.3, 54.3, 52.5, 36.0, 29.7, 28.0, 27.0; MS (FAB) m / z (relative strength) 569 (M + H, 24). Anal: Caled. For C25H26C12N207S: C, 52.73; H, 4.60; N, 4.92; Cl, 12.45. Found: C, 52.51 H, 4.60; N, 4.94; Cl, 12.78. Corrected for 3.37 per scientist H20 found by the Karl Fischer analysis.
Scheme G G-6 Where RQ.J. and RQ_2 are independently defined as H or CH3; RG.3 is defined as H, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms; and g is defined as 0 or 2. Scheme G describes a general method for preparing examples of lactam of general structure G-5 and G-6. The readily prepared lactams of general structure G-1 can be alkylated by the reaction of a suitable alkylation in the presence of a convenient base as described in preparation 37 to provide intermediates of general structure G-2. The mild hydrolysis provides the monoacid of general structure G-3 which can be condensed by an amino acyl intermediate of structure G-4 as described in Scheme A. The complete hydrolysis of the diester of general structure G-5 produces the structure diacid G-6 Preparation 37 (Scheme G, G-2: where Re--, and RG.2 are CH3, R ^ is CH3, and gr equals 2).
To a cooled solution (0-5 ° C) of dimethyl ester G-1 (Scheme G, where RQ.X and RG., Are CH3, RQ * 2 is H, and g equals 2) (Thomas, E T. Rynbrandt, F.H. Zimmermann, D.C .; Bell, L.T.; Muchmore, C.R .; Yankee, E.W. < J. Org. Chem. 1989, 54, 4535) (25.7 grams, 0.1 mol) and iodomethane (30 milliliters, 0.48 mol) in THF (200 milliliters) was added with NaH (4.8 grams, 0.12 mmol, 60 percent in oil dispersion). After 22 hours, the reaction was quenched by the addition of H20 (100 milliliters) and diluted with CH2C12 (50 milliliters). The organic layer was separated, filtered and dried in vacuo. The crude brown oil was triturated with hexanes (20 milliliters) and the residue was concentrated in vacuo to yield the crude product (18.44 grams) which was used without further purification: 1 H NMR (300 MHz, CDC13) d 2.03 (12 H) , 2.64 (3 H), 3.64 (6 H). Preparation 38 (Scheme G, G-3: where RQ.2 is CH3, R ^ is CH3, and g equals 2).
To a cooled solution (0-5 ° C) of G-2 diester (Scheme G, where and RG.2 are CH3, R <3_3 is CH3, and g equals 2) (10.0 grams, 36.9 mmol) in aqueous methanol (66 percent, 75 milliliters) was added LiOH.H20 (1.55 grams, 36.9 mmol). After 22 hours, the mixture was partially concentrated in vacuo and diluted with water. The aqueous layer was washed with methylene chloride and acidified (pH about 2) with 10 percent HCl. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried and concentrated in vacuo to yield the title compound (3.63 grams) as a yellow solid: IR (Mull) 1735, 1630, 1442, 1429, 1418, 1405, 1330, 1308, 1287, 1255, 1217, 1185, 1122, 1016, 642 cm "1; XH NMR (300 MHz, CDCl 3) d 1.90 (6 H), 2.24 (4 H), 2.43 (2 H), 2.68 ( 3 H), 3.67 (3 H), 13 C NMR (75 MHz, CDCl 3) d 176.3, 175.5, 173.2) 64.6, 52.0, 33.1, 32.9, 29.9, 28.41, 28.38, 26.0, 24.9, MS (El) m / z (Relative intensity) 257 (M +, 1) Preparation 39 and Example 106 2- [3- [[(ÍS) -1 - [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] methyl ] -2-methoxy-2-oxoethyl] amino] -3-oxopropyl] -1-methyl-5-oxo-2-pyrrolidinopropanoic acid (Scheme G, G-5: where RG_2 and RG_3 are both equal to CH3, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, g equals 2 and the stereochemistry is (5)).
To a solution of G-3 acid (Scheme G, where Ra.2 and RQ.3 are equal to CH3, and g equals 2) (1.0 gram, 3.9 mmol), amine G-4 (Scheme G, where R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, and the stereochemistry is (5)) (1.82 gram, 4.67 mmol), and DMAP (100 milligrams, 0.8 mmol) in pyridine (15 milliliters) was added EDC (895 milligrams, 4.67 mmol). After 21 hours, the reaction was diluted with saturated aqueous NaHCO3 and methylene chloride. The organic layer was separated and washed with 10 percent aqueous HCl, dried and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride / ethyl acetate (20 percent) as eluent followed by lyophilization from aqueous acetonitrile yielded the title compound (1.71 gram), as an amorphous solid: IR (Mull) 3284 , 2924, 1738, 1666, 1665, 1564, 1539, 1511, 1439, 1398, 1299, 1240, 1198, 1178, 1117, 1016, 768 hearing1; XH NMR (300 MHz, CDC13) d 2.10 (12 H), 2.66 (3 H), 3.07 (2 H), 3.66 (3 H), 3.73 (3 H), 4.83 (1 H), 5.24 (2 H) , 5.98 (1 H), 6.95 (2 H), 7.02 (2 H), 7.25 (1 H), 7.36 (2 H); 13 C NMR (75 MHz, CDCl 3) d 174.7, 174.66, 173.2, 172.0, 171.2), 158.1, 137.0), 132.1, 130.5, 130.3, 128.5, 128.3, 115.2, 65.2, 64.3, 53.3, 52.4, 51.9, 37.0, 33.2 , 30.2, 30.17, 28.4, 26.0, 24.7; MS (El) m / z (relative intensity) 592 (M +, 4). Anal: Caled. For C29H34C12N207: C, 58.69; H, 5.77; N, 4.72; Cl, 11.95. Found: C, 58.33; H, 5.65; N, 4.76; Cl, 11.89. Preparation 40 and Example 107 2- [3 - [[(lS) -l-Carboxy-2- [4- [(2,6-Dichlorophenyl) methoxy] phenyl] ethyl] amino] -3-oxo-propyl] - l-methyl-5-oxo-2-pyrrolidinopropanoic (Esguema G, G-6: where RG_3 is equal to CH3, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, g is equal to 2 and the stereochemistry is (5)).
To a solution of diester G-5 (Scheme G, where RQ. 2 and RG-3 are equal to CH3, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, g equals 2 and the stereochemistry is (5)) (1.0 gram, 1.68 mmol), in THF ( 30 milliliters) and MeOH (9 milliliters) was added LiOH-H20 (370 milligrams, 8.8 mmol). After 22.5 hours, the reaction mixture was acidified with 10 percent aqueous HCl (30 milliliters) causing the precipitation of a solid. The solid was collected by filtration and lyophilized from aqueous acetonitrile to yield the title compound (0.91 grams) as an amorphous solid: IR (Mull) 3031, 2925, 1727, 1637, 1585, 1564, 1543, 1511, 1439 , 1424, 1404, 1299, 1240, 1196, 1179, 768 c "1; XH NMR (300 MHz, DMSO-d6) d 1.77 (12 H), 2.76 (l H), 3.97 (1 H), 4.36 (1 H), 5.16 (2 H), 6.94 (2 H), 7.15 (2 H), 7.49 (3 H), 8.16 (1 H); 13 C NMR (75 MHz, CDCl 3) d 174.6, 174.1, 173.6, 172.2, 157.6, 136.5, 132.2, 132.0, 130.7, 130.6, 129.2, 114.7, 65.3, 64.1, 54.0, 36.5, 33.7, 33.1, 30.1, 30.05, 29.8, 28.7, 25.7, 24.6, MS (FAB) m / z (relative intensity ) 565 (M + H, 99) Anal: Caled For C27H30Cl2N2O7: C, 57.35; H, 5.35; N, 4.95; Cl, 12.54 Found: C, 56.93; H, 5.15; N, 5.02; Cl, 12.42 Corrected for 1.03 percent H20 found by Karl Fischer analysis Example 108 Acid methyl ester 2- [3- [[(ÍS) -1- [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] -3-oxopropyl] -1- (3-methyl-2-butenyl) -5-oxo-2-pyrrolidinopropanoic acid (Scheme G, G-5: where Rg_2 is CH3, R ^ is 1- (3-methyl -2-butenyl), R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, g equals 2 and the stereochemistry is (S)).
Example 108 was prepared as described in Scheme G using l-bromo-3-methyl-2-butene to form the required N-alkyl lactam. The physical data are as follows: IR (Mull) 32.95, 29.52, 1740, 1678, 1662, 1564, 1538, 1512, 1439, 1414, 1300, 1279, 1240, 1199, 1178, 1017, 768 citr1; X H NMR (300 MHz, CDCl 3) d 1.64 (3 H), 1.70 (3 H), 2.06 (12 H), 3.09 (2 H), 3.66 (3 H), 3.74 (2 H), 3.74 (3 H) , 4.85 (1 H), 5.20 (1 257 H), 5.24 (2 H), 6.95 (2 H), 7.02 (2 H), 7.25 (1 H), 7.36 (2 H); 13C NMR (75 MHz, CDC13) d 174.7, 173.3, 172.1, 172.0, 171.3, 158. 1, 137.0, 135.1, 132.1, 130.5, 130.3, 128.5, 128.3, 119.7, 115. 2, 65.2, 65.1, 53.2, 52.4, 51.9, 37.5, 37.0, 34.4, 34.2, 30.6, 29.9, 28.6, 26.6, 25.6, 25.5, 17.9; MS (FAB) m / z (relative intensity) 647 (M + H, 24). Example 109: Acid 2- [3- [[(lS) -l-Carboxi-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] -3-oxo-propyl] -1- ( 3-methyl-2-butenyl) -5-oxo-2-pyrrolidinopropanoic acid (Scheme G, G-6: where RG.3 is 1- (3-methyl-2-butenyl), Rs is 4 - [(2, 6-dichlorofenyl) methoxy] phenyl, g equals 2 and the stereochemistry is (5)).
Example 109 was prepared from Example 108 by the procedure described in Preparation 40. The physical data are as follows: IR (Mull) 3290, 2921, 1726, 1635, 1585, 1565, 1545, 1511, 1439, 1419, 1341, 1299, 1240, 1197, 1179, 780, 768 ctn "1; XH NMR (300 MHz, DMSO-d6) d 1.57 (3 H), 1.62 (3 H), 1.72 (6 H), 2.02 (6 H) ), 2.77 (1 H), 2.98 (1 H), 3.55 (2 H), 5.05 (1 H), 5.16 (2 H), 6.94 (2 H), 7.15 (2 H), 7.49 (2 H), 7.54 (2 H), 8.15 (1 H); 13 C NMR (75 MHz, DMSO-dg) d 174.6, 174.3, 173.6, 172.56, 172.2, 157.6, 136.5, 134.0, 132.2, 132.0, 130.6, 129.2, 121.1, 121.0 , 114.7, 65.2, 65.0, 54.1, 54.0, 37.1, 36.5, 34.5, 34.1, 30.0, 29.9, 28.8, 26.3, 25.84), 25.81, 18.1, MS (FAB) m / z (relative intensity) 619 (M + H, 99) Example 110 2- [3 - [[(SS) -1 - [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl ] amino] -3-oxopropyl] -1-methyl-5-oxo-2-pyrrolidinopropanoic acid (Scheme G, G-5: where RQ.2 and RG.3 are equal to C H3, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, g equals 2 and the stereochemistry is (5)).
Example 110 was prepared as described in Scheme G using iodomethane to form the required N-alkyl lactam. The physical data is as follows: IR (Mull) 3258, 2922, 1738, 1662, 1606, 1561, 1539, 1515, 1432, 1414, 1401, 1323, 1268, 1196, 1177, 799 was "1;? NMR (300 MHz, CDCl3) d 2.01 (12 H), 2.61 (3 H), 3.09 (2 H), 3.64 (3 H), 3.75 (3 H), 4.84 (1 H), 6.15 (1 H), 7.09 (2 H), 2.31 (3 H), 7.58 (2 H), 7.99 (1 H); MS (El) m / z (relative intensity) 607 (M +, 4), 605 (M +, 6); Anal. Caled for C29H33C12N307: C, 57.43; H, 5.48; N, 6.93; Cl, 11.69. Found: C, 57.18; H, 5.56; N, 6.85; Cl, 11.68. Corrected for 0.93 percent H20, found by Karl Fischer analysis. Example 111: Acid 2- [3- [[(lS) -l-Carboxi-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] -3 -oxo-propyl] -l-methyl -5-oxo-2-pyrrolidinopropanoic acid (Scheme G, G-6: where RG.3 is CH3, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, s equals 2 and the stereochemistry is ( 5) ) .
Example 111 was prepared from Example 110 by the procedure described in Preparation 40. The physical data are as follows: IR (Mull) 3265, 3056, 2925, 1724, 1658, 1609, 1579, 1561, 1542, 1516, 1432, 1414, 1327, 1271, 1217, 1195, 800 was "1; XH NMR (300 MHz, DMSO-d6) d 1.89 (12 H), 2.49 (3 H), 2.78 (1 H), 2.99 (1 H) ), 4.38 (1 H), 7.18 (2 H), 7.51 (5 H), 8.17 (1 H), 10.64 (1 H), MS (FAB) m / z (relative intensity) 580.5 (M + H, 68 ).
EXAMPLE 112 Methyl ester * of 2- [3- [[(SS) -1 - [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] - 3-oxopropyl] -5-oxo-2-pyrrolidinopropanoic acid (Scheme G, G-5: where RG_2 is CH3, RG.3 is proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, s is equal to 2 and the stereochemistry is [S)).
Example 112 was prepared as described in Scheme G Physical data is as follows: IR (Mull) 3276, 3029, 1738, 1686, 1564, 1538, 1511, 1439, 1299, 1279, 1239, 1197, 1178, 1016, 767 crn "1; * H NMR (300 MHz, CDC13) d 1.85 (6 H), 2.24 (2 H), 2.35 (4 H), 3.03 (2 H), 3.66 (3 H), 3.74 (3 H), 4. 82 (1 H), 5.24 (2 H), 6.50 (2 H), 6.95 (2 H), 7.05 (2 H) 7.27 (1 H), 7.37 (2 H); MS (El) m / z (relative intensity) 578 (M +, 0.2); Anal. Caled for C28H32C12N207: C, 58.04; H, 5.57; N, 4.83. Found: C, 57.93; H, 5.43; N, 4.97. Corrected for 1.14 percent H20, found by Karl Fischer analysis. Example 113 Acid 2 - [3 - [[(SS) -l-Carboxy-2 - [4 - [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] -3-oxo-propyl] -5-oxo -2-pyrro1idinopropanoic acid (Scheme G, G-6: where RG_3 is proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, g equals 2 and the stereochemistry is (5)).
Example 113 was prepared from Example 112 by the procedure described in Preparation 40. The physical data are as follows: IR (Mull) 3294, 3033, 1716, 1647, 1585, 1565, 1544, 1511, 1439, 1420, 1299, 1240, 1197, 1179, 768 cm "1; XH NMR (300 MHz, DMS0-d6) d 1.60 (6 H), 2.12 (6 H), 2.78 (1 H), 2.99 (1 H), 4.36 ( 1 H), 5.19 (2 H), 6.97 (2 H), 7.17 (2 H), 7.45 (1 H), 7.58 (2 H), 7.70 (1 H), 8.22 (1 H), MS (FAB) m / z (relative intensity) 551 (M + H, 99); Anal.Called for C26H28C12N207: C, 56.63; H, 5.12; Cl, 12.86; N, 5.08. Found: C, 56.28; H, 5.01; Cl, 13.08; N, 5.24, Corrected for 1.47 percent H20 found by Karl Fischer analysis Example 114 2- [3- [[(ÍS) -1- [[4- [(2,6-Dichlorobenzoyl) methyl ester ) amino] -3-oxopropyl] -5-oxo-2-pyrrolidinopropanoic acid (Scheme G, G-5: where RQ.2 is CH3, RG_3 is proton, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, g is equal to 2 and the stereochemistry is (5)).
Example 114 was prepared as described in Scheme G Physical data are as follows: 1 H NMR (300 MHz, CDC13) d 1.81 (6 H), 2.27 (6 H), 3.10 (2 H), 3.63 (3 H) ), 3.75 (3 H), 4.89 (1 H), 6.46 (1 H), 6.58 (1 H), 7.10 (2 H), 7.26 (3 H), 7.58 (2 H), 8.14 (1 H); MS (FAB) m / z 592 (M + H) *, 568, 367, 349, 307, 278, 226, 194, 173. Example 115 Acid 2- [3 - [[(lS) -1-Carboxy-1 - [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] -3-oxopropyl] -5 -oxo-2-pyrrolidinopropanoic acid (Scheme G, G-6: where RG.3 is proton, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, g equals 2 and the stereochemistry is (5)).
Example 115 was prepared from Example 114 by the procedure described in Preparation 40. The physical data are as follows: IR (Mull) 3272, 3195, 3121, 3063, 2953, 2923, 2868, 2855, 1715, 1659, 1608, 1579, 1561, 1541, 1516, 1456, 1432, 1414, 1377, 1367, 1326, 1271, 1221, 1195, 800 cm "1; XH NMR (300 MHz, DMS0-d6) d 1.63 (6 H), 2.13 (6 H), 2.79 (1 H), 3.00 (1 H), 4.38 (1 H), 7.19 (2 H), 7.51 (5 H), 7.64 (1 H), 8.16 (1 H), 10.58 (1 H), 12.37 (2 H); MS (FAB) m / z 564 (M + H) *, 546, 519, 335, 280, 194, 173. Anal. Caled for C26H27C12N307: C, 55.33; H, 4.82; Cl, 12.56; N, 7.44.
Found: C, 55.10; H, 4.76; Cl, 12.56; N, 7.36.
Corrected for 2.49 percent H20 found by Karl Fischer analysis. Example 116 2- [3- [[(SS) -1 - [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] ethyl] -2-methoxy-2-oxoethyl] amino] -3 acid methyl ester -oxopropyl] -5-oxoproline (Scheme G, G-5: where RG.2 and RG.3 are equal to proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, g equals 0 and the stereochemistry is (5)).
Example 115 was prepared as described in Scheme G from 2-carboxy-5-oxo-2-pyrrolidinepropnoic acid (Majer, Z .; Kajtar, M .; Ticky, M.; Blaha, K. Coil. Czech, Chem. Commun. 1982, 47, 950). The physical data are as follows: IR (Mull) 3302, 1736, 1671, 1612, 1585, 1564, 1535", 1511, 1439, 1298, 1240, 1197, 1179, 1016, 768 cm" 1; X H NMR (300 MHz, CDCl 3) d 2.12 (8 H), 3.02 (2 H), 3.65 (3 H), 4.81 (1 H), 5.21 (2 H), 6.94 (2 H), 7.07 (2 H) , 7.22 (1 H), 7.35 (2 H), 7.86 (1 H), 8.34 (1 H); MS (FAB) m / z (relative intensity) 537 (M + H, 99). Example 117 2- [3- [[(SS) -l-Carboxy-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] -3-oxo-propyl] -5-oxoproline ( Scheme G, G-6: where RQ_3 is proton, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl, g is equal to 0 and the stereochemistry is (5)).
Example 117 was prepared from Example 115 by the procedure described in Preparation 40. The physical data are as follows: IR (Mull) 3292, 3059, 3029, 1718, 1650, 1612, 1585, 1565, 1537, 1511, 1439, 1240, 1196, 1179, 768 cm "1;? NMR (300 MHz, CDCl3) d 2.11 (8 H), 2.83 (1 H), 3.20 (1 H), 4.74 (1 H), 5.24 (2 H) ), 6.95 (2 H), 7.15 (2 H), 7.25 (1 H), 7.36 (2 H), MS (FAB) m / z (relative intensity) 523 (M + H, 99), Anal. C24H24C12N207: C, 55.08; H, 4.62; N, 5.35, Cl, 13.55, Found: C, 54.68; H, 4.66; N, 5.13: Cl, 13.70, Corrected for 1.59 percent H20 found by Karl Fischer analysis.
Essuema H .OH C H-1"Cl rs OH -N ^ CI Scheme H shows a general method for the preparation of 6-chloroazatyrosine examples of structures H-4 and H-5, by adapting the methodology for the preparation of protected azathyrosine reagents as described by Kawata, S .; Ashizawa, S .; Hirama, M. J ". Am.
Chem. Soc. 1997, 119, 12012-12013 and references cited therein. Thus the regioselective iodination of 2-chloro-3-pyridinol gives the chloro-iodopyridinol H-2, which is O-alkylated as exemplified by the synthesis of H-3. The palladium-catalyzed reaction of H-3 with organic zinc from a suitably protected ß-iodoalanine provides the 5-chloroazatyrosine H-4. N-deprotection of H-4 gives the amino ester H-5, which is used (as exemplified by reagent A-4 of the Scheme A, and by reagent B-5 of Scheme B) for the synthesis of the examples of this invention. Preparation 41 (Scheme H: H-2) 2-Chloro-6-iodo-3-pyridinol (C5H3CII? O). To a solution of 2-chloro-3-pyridinol Hl (10.2 grams, 78.7 mmol) and K2CO3 (38.9 grams, 0.274 mol) in H20 (120 milliliters) was added I2 (24.3 grams, 95.8 mmol), and the mixture of The reaction was stirred at room temperature for 4 hours.
The reaction mixture was quenched by the addition of α2S203.5H20, saturated aqueous, and its pH lowered to pH 2 with the addition of 12 M aqueous HCl. The mixture was extracted with EtOAc.
The combined EtOAc extracts were dried, filtered and concentrated to a yellow solid, which was crystallized from 120: 25 heptane / EtOAc (145 milliliters) to give, as a yellow solid, 11.2 grams of the title compound: 1 H NMR ( CD3SOCD3, 300 MHz) d 9.87, (1 H), 7.59 (1 H), 7.59 (1 H), 7.06 (1 H); 13 C NMR (CD3SOCD3, 75 MHz) d 150.68, 138.07, 134.98, 127.02, 101.18. Preparation 42 (Scheme H: H-3) 2-Chloro-3- [(2,6-dichlorophenyl) methoxy] -6-iodopyridine (C12H7C13IN0). To a solution of H-2 (5.11 grams, 20.0 mmol), PPh3 (5.30 grams, 20.0 mmol), and 2,6-dichlorobenzyl alcohol (3.54 grams, 20.0 mmol) in dry THF (100 milliliters) at 0 ° C under Ar was added DEAD (3.15 milliliters, 20.0 mmol). The reaction mixture was kept at 0 ° C for 1.5 hours and at room temperature for 1.5 hours. Concentrate to a residue, purify by silica flash chromatography (17.3 hexanes / EtOAc) to give 7.61 grams of the title compound: TLC (17: 3 hexanes / EtOAc) RÍO.57; XH NMR (CD3SOCD3 300 MHz) d 7. 85, (1 H), 7.62 (1 H), 7.58-7.45 (3 H), 5.34 (2 H). Preparation 43 (Scheme H: H-4) Methyl ester of (S) -2-Chloro-3- [(2,6-dichlorophenyl) methoxy] - - [[(1,1-dimethylethoxy) -carbonyl] amino] -6-pyridinopropane (C2? H23Cl3N205). To an amber flask containing activated Zinc powder (0.777 grams, 11.89 mmol) under argon was added N- methyl ester sequentially. [(1,1-dimethylethoxy) carbonyl] -3-iodo-L-alanine [93267-04-0] (3.91 grams, 1.89 mmol), THF (11.9 milliliters), and dimethylacetamide (11.9 milliliters). The reaction mixture was purged of oxygen by bubbling argon through the mixture for 5 minutes. Stirred at 65 ± 5 ° C for 2 hours and cooled to room temperature. To this mixture was added PdCl2 (PPh3) 2 (0.412 grams), followed immediately followed by a degassed solution of H-3 (2.46 grams, 5.94 mmol) in 1: 1 THF / dimethylacetamide (11.8 milliliters). The reaction mixture was stirred at 65 ± 5 ° C for 5 hours. It was cooled to 0 ° C and quenched with saturated aqueous? H 4 Cl (100 milliliters). The reaction mixture was extracted with EtOAc. The combined extracts were washed with brine, dried, filtered and concentrated to a yellow-green oil; which was purified by flash chromatography on silica to give 1.90 grams of the title compound: TLC (7: 3 hexanes / EtOAc) Rf0.32; ? RM? (CDC13 300 MHz) d 7.76, (1 H), 7.57 (2 H), 7.48 (1 H), 7.29 (1 H), 7.27 (1 H), 5.30 (2 H), 4.32 (1 H), 3.60 (3 H), 3.01 (1 H), 2.98 (1 H), 1.21 (9 H). Preparation 44 - (Scheme H: H-4) (S) -2-Chloro-3- [(2,6-dichlorophenyl) methoxy] -α-amino-6-pyridinopropanoic acid methyl ester dihydrochloride .2HC1 ). A solution of H-4 (1.90 g, 3.88 mmol) in 4 M HCl in dioxane (35 milliliters) is stirred at room temperature under argon for 20 hours. The reaction mixture is concentrated in vacuo. The residue is taken up in H20 (40 milliliters) and extracted with Et20. The aqueous solution is frozen and lyophilized to give 1.39 grams of the title compound: XH NMR (CD3SOCD3, 300 MHz) d 8.62, (3 H), 7.81 (1 H), 7.58 (2 H), 7.48 (1 H), '7.38 (1 H), 5.32 (2 H), 4.37 (1 H), 3.72 (3 H), 3.27 (2 H), H). Example 118 (Scheme A: A-5) Ester (1, 1-dimethylethyl) of acid [S- (R *, R *)] -4- [[[1- [[2-Chloro-3- [(2)] , 6-dichlorophenyl) methoxy] -6-pyridyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (C30H37Cl3N3? 6S). Example 118 was prepared as described in Scheme A from D-cysteine using the product of preparation 44 as the intermediate amino acid A-4. The physical properties are as follows: TLC (1: 1 hexanes / EtOAc) R £ 0. twenty-one; ? NMR (CDC13 300 MHz) d 8.43, (1 H), 7.74 (1 H), 7.58 (2 H), 7.48 (1 H), 7.29 (1 H), 5.29 (2 H), 4.67 (1 H), 4.53 (1 H), 4.44 (1 H), 4.23 (1 H), 3.62 (3 H), H), 3.06 (3 H), 2.82 (1 H), 1.27 (9 H). Example 119 (Scheme A: A-9) Ester (1, 1-dimethylethyl) of acid [S- (R *, R *)] -4- [[1-Carboxi -2- [[2-Chloro-3-] [(2,6-dichlorofenyl) methoxy] -6-pyridyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (C24H26Cl3N3? 6S). Example 119 was prepared from Example 118 by the procedure described in Preparation 12. The physical data are as follows: mp 93-95 ° C, TLC (600: 400: 2 EtOAc / hexanes / HC02H) i_f0.38; tR NMR (CD3SOCD3 300 MHz) d 8.30, (1 H), 7.74 (1 H), 7.57 (2 H), 7.48 (1 H), 7.27 (1 H), 5.29 (2 H), 4.67-4.36 (2 H), 4.53 (1 H), 4.23 (1 * H), 3.37-3.11 (3 H), 2.97 (1 H), 1.27 (9 H).
Scheme I G? OH J_l Scheme I shows a general method for the preparation of azathirosine reagents 1-3, 1-4, 1-5, 1-6 and I- 7, by adapting the methodology for the preparation of protected azathyrosine reagents as described by Kawata, S .; Ashizawa; S .; Hirama, M. J. Am. Chem. Soc. 1997, 119, 12012-12013 and the references cited therein. In this way the O-protection of chloroiodopyridinol 1-1 (identical to H-2) is followed by the reaction with organic zinc, derived from a protected ß-iodo alanine to provide the protected 6-chloroazatyrosine 1-3. The reductive dehalogenation of 1-3 gives 1-4, which is O-deprotected to give 1-5. The reagent 1-5 is O-alkylated, as exemplified by the preparation of I-6. N-deprotection of 1-6 gives aminoester 1-7, which is used (as exemplified by reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of the examples of this invention. Preparation 45 (Scheme I, 1-2) (±) -2-Chloro-3- [(2-tetrahydropyranyl) oxy] -6-iodopyridine (C10H ?? CII? O2). To a solution of chloroiodopyridinol 1-1 (equal to H-2, the product of preparation 41) (1.00 gram, 3.91 mmol) and dihydropyran (1.0 milliliter, 10.6 mmol) in CH2C12 (10 milliliters) under argon at room temperature was add pyridinium chloride (0.050 gram). The reaction mixture is stirred for 72 hours. Dilute with CH2C12 and wash with saturated aqueous NHC03 and brine. The CH2C12 solution is dried, filtered and concentrated to an oil, which is purified by flash chromatography on silica (19: 1 hexanes / EtOAc) to give 1.06 gram of the title product: TLC (19: 1 hexanes / EtOAc) f0.24; X H NMR (CDCl 3 300 MHz) d 7.55, (1 H), 7.17 (1 H), 5.50 (1 H), 3.77 (1 H), 3.61 (1 H), 2.07-1.57 (6 H). Preparation 46 (Scheme I, 1-3) (S) -2-Chloro-a - [[(1,1-dimethylethoxy) carbonyl] amino] -3 - [(2-tetrahydropyranyl) oxy] -6-methyl ester -pyridinopropane (C? 9H27CIN206). To an amberized flask containing activated zinc powder (0.349 grams, 5.51 mmol) under argon is added THF (2 milliliters) and 1,2-dibromoethane (0.018 milliliters, 0.21 mmol). The suspension is refluxed for several minutes, cooled to about 30 ° C, and TMSCl (0.17 milliliters of 1 M solution in THF) is added. The reaction mixture is stirred at 40 ± 5 ° C for 30 minutes and then cooled to below room temperature. A solution of methyl ester of N- [(1,1-dimethylethoxy) carbonyl] -3-iodo-L-alanine [93267-04-0] (1.81 g, 5.50 mmol) in 11: 7 dimethylacetamide / THF (9.0 milliliters) is added, and the resulting reaction mixture is stirred at 45 ° C for 5 hours. The reaction mixture is cooled to below room temperature and added PdCl2 (PPh3) 2 (0.192 grams) solid, followed immediately by the addition of a degassed solution of iodopyridine (0.936 grams, 2.76 mmol) in 1: 1 THF / dimethylacetamide (5.6 milliliters). The reaction mixture was stirred at 45 ° C for 4 hours. It was cooled to # 0 ° C, quenched with saturated aqueous NH 4 Cl, and extracted with EtOAc. The combined EtOAc portions were washed with saturated aqueous NH4C1 and with brine.
The EtOAC solution was dried, filtered and concentrated to give a green-yellow colored foam, which after purification by flash silica chromatography (7: 3 hexanes / EtOAc) gives 0.879 grams (1.85 mmol, 60 percent) of the title product: TLC (7: 3 hexanes / EtOAc) Rf0.21; 1H NMR (CDC13 300 MHz) d 7.39, (1 H), 7.00 (1 H), 5.46 (1 H), 4.61 (1 H), 4.13 (1 H), 3.80 (3 H), 3.62 (1 H), 3.20 (1 H), 2.13-1.53 (6 H), 1.42 (9 H). Preparation 47 (Scheme I, 1-4) (S) -OÍ- [[(1,1-Dimethylethoxy) carbonyl] amino] -3 - [(2-tetrahydropyranyl) oxy] -6-pyridinopropanoic acid methyl ester C19H28N206). A suspension of pre-reduced Pd / CaC03 (3.5 grams), and 1-3 (1.15 grams, 2.77 mmol) in EtOH (40 milliliters) was hydrogenated (2.1 kg / cm2 H2) for 19 hours at room temperature. The mixture was filtered and the filtrate was evaporated to give a yellow colored foam, which was purified by flash silica chromatography (600: 400: 1 hexanes / EtOAc / iPrOH) to give 0.367 gram of the title compound: TLC (1: 1 hexanes / EtOAc) R £ 0. 27; XR NMR (CDCl 3 300 MHz) d 8.30, (1 H), 7.29 (1 H), 7.03 (1 H), 5.81 (1 H), 5.39 (1 H), 4.65 (1 H), 3.86 (1 H) , 3.73 (3 H), 3.62 (1 H), 3.21 (2 H), 1.96-1.53 (6 H), 1.42 (9 H). Preparation 48 (Scheme I, 1-5) Methyl ester of (S) -OÍ- [[(1, 1-Dimethylethoxy) carbonyl] amino] -5-hydroxy-2-pyridinopropanoic acid (C14H20N205). A solution of 1-4 (0.346 g, 0.91 mmol) and pyridinium p-toluenesulfonate (0.031 g, 0.12 mmol) in EtOH (8 milliliters) was stirred at 55 + 5 ° C for 20 hours. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The residue was taken up in EtOAc. The solution was washed with brine, and dried, filtered and concentrated to a pale yellow colored oil which was purified by flash silica chromatography (500: 500: 1 hexanes / EtOAc / iPrOH). Evaporation of the fractions from the column gives 0.132 g of the title compound: TLC (1: 1 hexanes / EtOAc) i_f0.18; * H NMR (CDC13 300 MHz) d 8.13, (1 H), 7.13 (1 H), 7.03 (1 H), 5.71 (1 H), 4.65 (1 H), 3.70 (3 H), 3.20 (2 H) ), 1.39 (9 H).
Preparation 49 (Scheme I, 1-6) Methyl ester of (S) -5 - [(2,6-Dichlorophenyl) methoxy] -c .- [[(1, 1-dimethylethoxy) carbonyl] amino] -2- pyridinopropane (C21H244Cl2N205). A solution of 1-5 (0.126 gram, 0.43 mmol), 2,6-dichlorobenzylalcohol (0.075 gram, 0.43 mmol) and PPh3 (0.113 grams, 0.43 mmol) in dry THF (4 milliliters) 0 ° C under argon was added DEAD (0.068 milliliters). The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. Concentrate, and the residue was purified by flash silica chromatography (700: 300: 1 hexanes / EtOAc / iPrOH) to give 0.149 grams of the title compound: TLC (7: 3 hexanes / EtOAc) Rf0.34; X H NMR (CDCl 3 300 MHz) d 8.31, (1 H), 7.37 (2 H), 7.25 (2 H), 7.08 (1 H), 5.81 (1 H), 5.29 (2 H), 4.65 (1 H) , 3.70 (3 H), 3.24 (2 H), 1.63 (1 H), 1.43 (9 H). Preparation 50 (Scheme I: 1-7) Dihydrogen chloride salt of (S) -α-Amino-5 - [(2,6-dichlorophenyl) methoxy] -2-pyridinopropanol (C16H16C12N203.2HC1) methyl ester. A solution of carbamate 1-6 (0.546 gram, 1.20 mmol) in 4 M HCl in dioxane (12 milliliters) is stirred at room temperature under argon for 16 hours. The reaction mixture is concentrated in vacuo. The residue was dissolved in H20 (40 milliliters) and the solution was extracted with Et20. The aqueous solution was frozen and lyophilized to give, as a light yellow colored solid, 0.485 grams of the title compound: XH NMR (CD3SOCD3, 300 MHz) d 8.75, (3 H), 8.47 (1 H), 7. 81 (1 H), 7.57 (3 H), 7.48 (1 H), 5.35 (2 H), 4.49 (1 H), 3.67 (3 H), 3.42 (2 H). Example 120 (Scheme A: A-5) Ester (1, 1-dimethylethyl) of [S-. { R * -. R *)] - 4- [[[1 - [[3 - [(2,6-dichlorofenyl) methoxy] -6-pyridyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3- thiazolidinocarboxylic acid Example 120 was prepared as described in Scheme A from D-cysteine using the product of preparation 49 as the intermediate amino acid A-4. The physical properties are as follows: TLC (1: 1 hexanes / EtOAc) Rf0.22; XH NMR (CDC13 300 MHz) d 8.28, (2 H), 7.38 (2 H), 7.28 (2 H), 7.09 (1 H), 5.29 (2 H), 4.90-4.74 (3 H), 4.40 (1 H), 3.67 (3 H), 3.38-3.22 (3 H), 1.61 (2 H) , 1.40 (9 H). Example 121 (Scheme A: A- 9) Ester (1, 1-dimethylethyl) of acid [S-. { R *, R *)] -4- [[[1-Carboxy-2- [-3- [(2,6-dichlorophenyl) methoxy] -6-pyridyl] ethyl] amino] sarbonyl] -3-ylazidinecarboxylic The example 121 was prepared from Example 120 by the procedure described in Preparation 12. The physical data are as follows: mp 92-94 ° C, TLC (500: 500: 3 hexanes / EtOAc / HC02H) Rf0.10; ? NMR (CDC13 300 MHz) d 8.31, (1 H), 8.26 (1 H), 7.55 (2 H), 7.28 (2 H), 7.46 (1 H), 7.21 (1 H), 5. 25 (2 H), 4.72-4.38 (2 H), 4.60 (1 H), 4.23 (1 H), 3.21-3.12 (2 H), 3.09-2.94 (1 H), 2.74 (1 H), 1.29 (9 H).
Scheme J ,? r J-1 Scheme J shows a general method for the preparation of para-acylamino derivatives of aza-phenylalanine. In this way the bis-acylation of 2-amino-5-iodopyridine J1 gives the imide J-2, which is reacted with organic zinc, derived from a ß-iodo alanine conveniently protected to provide the protected azaphenylalanine acylamino J- 3. N-deprotection of J-3 gives the amino ester J-4, which is used as exemplified for reagent A-4 of Scheme A, and by reagent B-5 of Scheme B) for the synthesis of the examples of this invention. Preparation 51 (Scheme J: J-2) 2 - [[Bis (2,6 -Dichlorobenzoyl)] amino] -5-iodopyridine (C19H9C14I? 202). To a solution of 2-amino-5-iodopyridine J-1 (2.20 grams, 10.0 mmol) and Et 3? (2.12 milliliters, 15.0 mmol) in dry THF (100 milliliters) at room temperature under argon, was added dropwise 2,6-dichlorobenzoylchloride (1.60 milliliters, 11. 0 mmol) for 45 minutes. The reaction mixture is stirred for 15 hours. Dilute with EtOAc (300 milliliters) and wash with cold aqueous 1 M aOH and brine. The solution is dried, filtered and concentrated to give a yellow waxy solid, which is purified by flash silica chromatography (3: 1 hexanes / EtOAc) to give 2.60 grams of the title compound: TLC (7: 3 hexanes / EtOAc) Rf0.60; X H NMR (CDCl 3 300 MHz) d 8.59, (1 H), 8.03 (1 H), 7.99 (1 H), 7.44-7.26 (6 H). Preparation 52 (Scheme J: J-3) (S) -2- [[Bis- (2,6-Dichlorobenzoyl) mino] - - [[(1,1-dimethylethoxy) carbonyl] amino] -5 methyl ester -pyridinopropane (C28H25C14N306). To an amberized flask containing activated Zinc powder (0.865 grams, 13.23 mmol) under argon was sequentially added N- [(1,1-dimethylethoxy) carbonyl] -3-iodo-L-alanine methyl ester (4.36 grams, 13.23). mmol), THF (13 milliliters), and -V /? - dimethylacetamide (13 milliliters). The reaction mixture was purged of oxygen by bubbling argon through the mixture for 5 minutes, and then heated at 65 ± 5 ° C for 7 hours. It was cooled to room temperature. To this mixture was added PdCl2 (PPh3) 2 (0.461 grams), followed immediately by a degassed solution of iodide J-2 (2.60 grams, 4.59 mmol) in 1: 1 THF / N, N-dimethylacetamide (18 milliliters). The reaction mixture was stirred at 45 ± 5 ° C under argon for 13 hours. It was cooled to 0 ° C and quenched with saturated aqueous? H 4 Cl (150 milliliters). The reaction mixture was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried / filtered and concentrated to a yellow-green paste, which was purified by flash chromatography on silica (700: 300: 1 hexanes / EtOAc / iPrOH) to give 1. 43 grams of the title compound: TLC (7: 3 hexanes / EtOAc) J-fO.29; X H NMR (CDCl 3 300 MHz) d 8.13, (1 H), 7.57 (1 H), 7.46 (1 H), 7.26 (6 H), 4.80 (1 H), 4.50 (1 H), 3.67 (3 H), 3.05 (2 H), 1.46 (9 H). Preparation 53 (Scheme J: J-4) Salt of acid methyl ester (S) -cx-Amino-2- [[bis- (2,6-dichlorobenzoyl) amino] -5-pyridinopropanoic acid dihydrochloride (C23H17C14N304.HC1) . i A solution of J-3 (0.69 gram, 1.08 mmol) in 4 M HCl in dioxane (15 milliliters) is stirred under argon for 20 hours. The reaction mixture is concentrated in vacuo, diluted with H20, and extracted with Et20. The aqueous solution is frozen and lyophilized to give, as a pale yellow colored solid, 0.627 grams of the title compound: XH NMR (CD3SOCD3, 300 MHz) d 8.80, (2 H), 8.27 (1 H), 7.82 (1 H), 7.67- 7.26 (7 H), 4.25 (1 H), 3.52 (3 H), 3.16 (2 H) ), 3.04 (1 H); MS (ESI +) m / z 541.7, Example 122 (Scheme A: A-5) Ester (1,1-dimethylethyl) of acid [S- (i? *, I - *)] - 4- [[[l- [ [2- [[Bis- (2,6-dichlorobenzoyl) amino] -5-pyridyl] ethyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (C 35 H 30 Cl 2 N 3 Og S).
Example 122 was prepared as described in Scheme A from D-cysteine using the product of preparation 52 as the intermediate amino acid A-4. The physical properties are as follows: TLC (1: 1 hexanes / EtOAc) Rf0. 22; XR NMR (CDCl 3 300 MHz) d 8.28, (2 H), 7.38 (2 H), 7.28 (2 H), 7.09 (1 H), 5.29 (2 H), 4.90-4.74 (3 H), 4.40 (1 H), 3.67 (3 H), 3.38-3.22 (3 H), 1.61 (2 H), 1.40 (9 H). Example 123 (Scheme A: A-9) Ester (1, 1-dimethylethyl) of acid [S-. { R *, R *)] -4- [[[[1-Carboxy-2 - [2- [[Bis- (2,6-dichlorobenzoyl)] amino] -5-pyridyl] ethyl] mino] carbonyl] - 3 - iazolidinocarboxílico (C31H28C14N407S). Example 123 was prepared from Example 122 by the procedure described in Preparation 12. The physical data are as follows: mp 15a-160 ° C, TLC (50: 50: 2 hexanes / EtOAc / HC02H) ß_0.18; XH NMR (CD3S0CD3 300 MHz) d 8.42, (1 H), 8.22 (1 H), 7.75 (1 H), 7.69-7.17 (5 H), 7.53 (1 H), 4. 59 (1 H), 4.40 (2 H), 4.19 (1 H), 3.19-3.02 (2 H), 2.84 (1 H), 1.34 (9 H).
Scheme K r s H-N A K-2 o- > H o UU n Scheme K shows a general method for the preparation of oxazolidinocarboxylic acid. Examples K-3 and K-4, wherein R3, R5 and Y are identical to the definitions in Scheme B. This coupling of oxazolidinocarboxylic acid K1 and amino ester K-2 (as exemplified by the reaction of reagents A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) provides Examples K-3, which are hydrolyzed to Examples K-4 of this invention. Example 124 (Scheme K: K-3, wherein R3 is (phenyl) methyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is C02 and the stereochemistry is [S- [R *, R *)]) 3-f-enylmethyl ester of acid [S- (R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2 -methoxy-2-oxoethyl] amino] carbonyl] -3-oxazolidinocarboxylic acid (C29H27C12N307). Example 124 was prepared by coupling the commercially available 3- (phenylmethyl) -3,4-oxazolidinedicarboxylic acid ester with amino acid K-2 (Scheme K, where R 5 is 4- [(2,6-dichlorobenzoyl)) amino] phenyl, and the stereochemistry is (S)) under the conditions described under preparation 3. The physical properties are as follows: TLC (3: 2 Heptane / EtOAc) Rf = 0.17; UV (MeOH) lmax 225 (e 12600, sh), 251 (17900); 13 C NMR (d6-dimethylsulfoxide) d 188.75, 171.96, 169. 86, 162.40, 162.30, 152.99, 137.59, 137.47, 136.87, 136.81, 133. 23, 131.79, 131.65, 130.08, 128.80, 128.67, 128.28, 127.76, 119. 84, 119.75, 79.82, 66.77, 57.85, 53.85, 52.47, 36.62 (23 expected lines, 26 observed lines); MS (FAB) m / z 602, 600, 558, 556, 531, 466, 371, 351, 349, 280, 278, 175, 173; MS (FAB) m / z 600.1312 (caled [M + H] + 600.1304; Anal. C, 57.75; H, 4. 75; N, 6.80; Cl, 11.86 (caled for 0.42 percent H20: C 57. 77, H 4.56, N 6.97, Cl 11.76). Example 125 (Scheme K: K-4, wherein R3 is (phenyl) methyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is C02 and the stereochemistry is [S- (i. *, .. *)]) 3-f enylmethyl ester of acid [S- (R *, R *)] -4- [[[1-Carboxi-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] -carbonyl] - 3-oxazolidinocarboxylic acid (C28H25C12N307). Example 125 was prepared from Example 124 by the procedure described in Preparation 12. The physical properties are as follows: TLC (950: 50: 1 CH2Cl2 / MeOH / HC02H) Rf = 0.34; XR NMR (d6-dimethylsulfide) d 10. 65, (1 H), 8.31 (1 H), 7.61-7.42 (5 H), 7.40-7.20 (5 H), 7.15 (2 H), 5.19-4.85 (2 H), 4.90 (1 H), 4.76 (1 H), 4.43 (1 H), 4.36 (1 H), 4.11 (1 H), 3.65 (1 H), 3.04 (1 H), 2.87 (1 H); MS (FAB) m / z 588, 586, 544, 542, 532, 391, 337, 335, 327, 269, 267, 161, 147, 133, 129, 117, 115, 103, 101, 91: MS (FAB) ) 586. 1132 (caled 586.1147). Example 126 (Scheme K: K-3, where R3 is benzyl, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is C02 and the stereochemistry is [R- (R *, S *) ]) 3-phenylmethyl acid ester [R- (R *, - 3 *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) mino] phenyl] methyl] -2-methoxy -2-oxoethyl] amino] carbonyl] -3-oxazolidinocarboxylic acid (C29H27C12N307). Example 126 was prepared as described in Scheme K for commercially available 3- (phenylmethyl) -3,4-oxazolidinedicarboxylic acid ester. The physical properties are as follows: TLC (3: 2 Heptane / EtOAc) Rf = 0.19; UV (MeOH)? ^ 225 (e 12400, sh), 252 (17700), 284 (2960, sh); 13C NMR (CDCl3) d 171.23, 169.14, 162.43, 154.26, 136.47, 135.93, 135.65, 137.37, 132.28, 130.91, 130.00, 128.62, 128.39, 128.11, 120.30, 79.66, 67.94, 58.38, 53.14, 52.49, 37.19 (23 lines) expected, 21 observed lines); MS (FAB) m / z 602, 600, 558, 556, 466, 351, 349, 280, 278, 175, 173; MS (FAB) m / z 600.1299 (caled [M + H] + 600.1304; Anal. C, 57.69; H, 4.90; N, 6.71; Cl, 11.49 (caled for 0.35 percent H20: C 57.81, H 4.56, N 6.97, Cl 11.77) Example 127 (Scheme K: K-4, where R3 is benzyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is C02 and the stereochemistry is [R- (R *, S *)]) 3-phenylmethyl acid ester [R- { R *, S *)] -4- [[[1- Carboxy 2 - [4- [(2,6-dichlorobenzoyl) amino] ] phenyl] ethyl] amino] -carbonyl] -3-oxazolidinocarboxylic acid (C28H2SC12N307). Example 127 was prepared from Example 126 by the procedure described in Preparation 12. The physical properties are as follows: TLC (950: 50: 1 CH_Cl2 / MeOH / HC02H) Rf = 0.31; XH NMR (d6-methanol) d 7.60, (2 H), 7. 49-7.23 (8 H) 7.21 (2 H), 5.23-4.97 (2 H), 4.95 (1 H), 4.88 (1 H), 4.70 (1 H), 4.36 (1 H), 4.14 (1 H), 3.85-3.73 (1 H), 3.23 (1 H), 3.00 (1 H); MS (FAB) m / z 588, 586, 544, 542, 532, 391, 371, 337, 335, 245, 177, 173, 149, 123, 105, 103, 91: MS (FAB) m / z 586.1163 ( caled 586.1147).
Scheme L Scheme L shows a general method for the preparation of N-alkylaryl acetyldinedicarboxylic acid Examples L-4 and L-5, where RL. is alkyl with 1 to 6 carbon atoms, RL_2 is aryl with 6 to 10 carbon atoms and R5 is defined as Scheme B. The stereoisomers of the N-phenylethyl-2,4-acetyldinedicarboxylic acid dimethyl ester of general structure Ll were prepared as described (Hoshino, J., Hiraoka, J .; Hata, Y .; Sawada, S .; Yamamoto. , Y. "Chem. Soc. Perkin Trans.I 1995, 693-697) and separated by flash silica chromatography.The partial saponification of L-1 diester gives the acidic medium L-2, which is coupled with the reagent. L-3 (as exemplified by the use of reagents A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) to provide Examples L-4, which are then hydrolysed for the Examples L-5 of this invention Preparation 54 (Scheme L: L-1 where RL_- is methyl, RL_2 is phenyl and the stereochemistry is [25- [1 (i? *), 2a, 4ß]]). dimethyl acid [2S- [1 (i- *), 2a, 4ß]] -1- (1-phenylethyl) -2,4-acetydinodicarboxylic acid [168647-92-5] (ClsH? 9N04) .The physical properties are as follows: TLC (4: 1 Hexanes / EtOAc) R £ = 0.42; 13 C NMR (CDCl 3); d 173.61, 142.41, 128. 31, 127.39, 127.35, 60.95, 60.67, 51.64, 24.96, 21.72. Preparation 55 (Scheme L: L-1 where RL.? Is methyl, RL_2 is phenyl and the stereochemistry is [2R- [1 (5 *), 2a, 4ß]]). Dimethyl acid ester [2R- [1 (5 *), 2a, 4β]] -1- (1-Phenylethyl) -2,4-acetydinodicarboxylic acid (^ H ^ NO *). The physical properties are as follows: TLC (4: 1 Hexanes / EtOAc) R £ = 0.31; 13 C NMR (CDC13); d 172.97, 141.21, 128.44, 128.07, 127.68, 61.54, 60.69, 51.61, 24.91, 19.55.
Preparation 56 (Scheme L: L-1 where RL.X is methyl, RL_2 is phenyl and the stereochemistry is [1 (5) -cis]). Dimethyl acid ester [1 (S) -sis] -1- (1-Phenylethyl) -2,4-acetyldinedicarboxylic acid [168753-32-0] (C1SH19N04). The physical properties are as follows: TLC (4: 1 Hexanes / EtOAc) Rf = 0.21; 13 C NMR (CDC13); d 172.58, 172.08, 140.84, 128.22, 128.15, 127.65, 66.32, 60.10, 59.65, 52.06, 51.59, 24.26, 19.91. JPrepation 57 (Scheme L: L-1 where RL_? Is methyl, RL_2 is phenyl and the stereochemistry is [2R- [1 (R *), 2a, 4ß]]). Dimethyl acid ester [2R- [1 (*), 2a, 4β]] -1- (1-phenylethyl) -2,4-acetydinodicarboxylic acid (C? 5H19N04). The physical properties are as follows: TLC (8: 2 Hexanes / EtOAc) R £ = 0.42; 13 C NMR (CDC13); d 173.61, 142.41, 128. 31, 127.39, 127.35, 60.95, 60.67, 51.64, 24.96, 21.72: MS (+ ESI) m / z 278.3. Preparation 58 (Scheme L: L-1 wherein Rx,.! Is methyl, RL_2 is phenyl and the stereochemistry is [25- [1 (5 *), 2, 4ß]]). Dimethyl acid ester [2S- [1 (S *), 2a, 4βJ] -1- (1-Phenylethyl) -2,4-acetydinodicarboxylic acid (C15H19N04). The physical properties are as follows: TLC (8: 2 Hexanes / EtOAc) R £ = 0.31; 13 C NMR (CDC13); d 172.97, 141.21, 128.44, 128.07, 127.68, 61.54, 60.69, 51.61, 24.91, 19.55: MS (+ ESI) m / z 278.3. Preparation 59 (Scheme L: L-1 where R is methyl, R?, _ 2 is phenyl and the stereochemistry is [1 (R) -cis]). Dimethyl acid ester [1 (R) -cis] -1- (1-Phenylethyl) -2,4-acetyldinedicarboxylic acid. The physical properties are as follows: TLC (8: 2 Hexanes / EtOAc) R £ = 0.21; 13 C NMR (CDC13); d 172.58, 172.08, 140.84, 128.22, 128.15, 127.65, 66.32, 60.10, 59.65, 52.06, 51.59, 24.26, 19.91: MS (+ ESI) m / z 278.3. Preparation 60 (Scheme L: L-2 where RL.? Is methyl, RL_2 is phenyl and the stereochemistry is [25- [1 (i? *), 2a, 4ß]]). Monomethyl ester of acid [25- [1 (R *), 2a, 4β]] -1- (1-phenylethyl) -2,4-acetydinodicarboxylic acid (C 14 H 7N04). A mixture of L-1 (Scheme L: where RL_? Is methyl, R?, _ 2 is phenyl and the stereochemistry is [2S- [1 (R *), 2, 4ß]]), the product of preparation 54 ) (7.95 grams, 28.7 mmol) and LiOH (30 mmol) in 1: 1 MeOH / H20 (240 milliliters) is stirred at room temperature for 42 hours. The reaction mixture is adjusted to pH 5 with HOAc, and concentrated. The resulting concentrate is diluted with brine and extracted repeatedly with CHC13. The combined CHC13 extracts are dried, filtered and concentrated to give a yellow foam (6.61 grams), which is purified by preparative C18 reverse phase chromatography to give the title compound as a crystalline solid: mp 112-113 ° C; TLC (650: 350: 1 hexanes / EtOAc / HC02H) R £ = 0.17; MS (FAB) m / z 527, 264, 248, 218, 204, 192, 186, 177, 160, 114, 105; Anal. C 64.04, H 6.57, N 5.37 (caled C 63.87, H 6.51, N 5.32). Preparation 61 and Example 128 (Scheme L: L-4 where RL.? Is methyl, R _2 is phenyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [25- [1 (1? *), 2, 4ß (R *)]]). Methyl ester of acid [2S- [1 (R *), 2a, 4β (i. *)]] -4- [[[1 - [[4 - [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -1- (1-phenylethyl) -2-acetyldinedicarboxylic acid (C3? H3iCl2N3? 6). A mixture of L-2 (Scheme L: where R?, _? Is methyl, RL_2 is phenyl and the stereochemistry is [25- [1 (*), 2a, 4β (R *)]], the product of preparation 60) (0.62 grams, 2.4 mmol), L-3 (Scheme L where R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (5)) (0.95 grams, 2.4 mmol), and BOP-Cl (0.68 grams, 2.7 mmol) in CH2C12 (10 milliliters) is treated with (i-Pr) 2NEt (1.7 milliliters, 9.8 mmol). The reaction mixture is stirred at room temperature under nitrogen for 19 hours. It is diluted with saturated NaHC03 and extracted with CH2C12. The CH2C12 extracts are dried, filtered and concentrated to give a cream colored foam (1.40 grams), which is purified preparatively (MeCN / H20 gradient). Evaporation of the fractions from the column gives a white solid, which dissolves in hot H20. The solution is frozen and lyophilized to give as a white solid, the title compound: mp 270 ° C; TLC (850: 150: 1 CHCl3 / MeOH / HC02H) Rf = 0.21-0.36; 13C NMR (CD30D) d 178.05, 174.59, 174.01, 162.20", 142.33, 135.09, 134.91, 133.04, 130.54, 129.24, 128.61, 126.46, 126.41, 126.17, 124.94, 118.33, 82.70, 61.70, 60.50, 53.30, 36.23, 25.85 , 18.65: MS (FAB) m / z 584.1350: Anal, C 55.17, H 5.01, N 6.63, Cl 11.16 (caled for 7.52 percent H20: C 54.02, H 4.75, N 6.52, Cl 11.21) Example 130 (Scheme L: L-4 where RL.? Is methyl, RL_2 is phenyl, Rs is 4- I (2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [2R- [1 (5 *), 2c, 4β (5 *)]]). Acid methyl ester [2R- [1 (fí *), 2a, 4ß (S *)]] -4- [[[l - [[4 - [(2,6-Dichlorobenzoyl ) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -1- (1-phenylethyl) -2-acetyldinedicarboxylic acid (C31H3? Cl2N306) Example 130 was prepared as described in Scheme L using the product of preparation 55 as intermediate L-1 The physical properties are as follows: TLC (3: 2 EtOAc / Hexanes) R £ = 0.43, [a] 25D +58 (c 0.91, MeOH); 13C NMR (CDCla) ); d 173.24, 172.15, 172 .05, 162.58, 140.75, 136.45, 136.01, 132.89, 132.38, 130.91, 129.60, 128.67, 128.39, 128.11, 127.97, 120.39, 63.54, 60.19, 59.54, 53.15, 52.16, 51.91, preparative (MeCN / H20 gradient). Evaporation of the fractions from the column gives a white solid, which dissolves in hot H20. The solution is frozen and lyophilized to give as a white solid, the title compound: mp 270 ° C; TLC (850: 150: 1 CHCl3 / MeOH / HC02H) R £ = 0.21-0.36; 13C NMR (CD30D) d 178.05, 174.59, 174.01, 162.20, 142.33, 135.09, 134.91, 133.04, 130.54, 129.24, 128.61, 126.46, 126.41, 126.17, 124.94, 118.33, 82.70, 61.70, 60.50, 53.30, 36.23, 25.85, 18.65: MS (FAB) m / z 584.1350: Anal. C 55.17, H 5.01, N 6.63, Cl 11.16 (caled for 7.52 percent H20: C 54.02, H 4.75, N 6.52, Cl 11.21). Example 130 (Scheme L: L-4 where R?, _? Is methyl, Rb_2 is phenyl, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [2R- [1 (5 *), 2a, 4ß (5 *)]]). Acid methyl ester [2R- [1 (S *), 2a, 4β (S *)]] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] - 2-methoxy-2-oxoethyl] amino] carbonyl] -1- (1-phenylethyl) -2-acetyldinedicarboxylic acid (C 31 H 3? Cl 2 N 3? 6). Example 130 was prepared as described in Scheme L using the product of preparation 55 as intermediate L-1. The physical properties are as follows: TLC (3: 2 EtOAc / Hexanes) R £ = 0.43; [a] 25D +58 (c 0.91, MeOH); 13C NMR (CDCla); d 173.24, 172.15, 172.05, 162.58, 140.75, 136.45, 136.01, 132.89, 132.38, 130.91, 129.60, 128.67, 128.39, 128.11, 127.97, 120.39, 63.54, 60.19, 59.54, 53.15, 52.16, 51.91, 37.86, 26.12, 18.37 : MS (El) m / z 613, 611, 598, 596, 554, 552, 527, 525, 508, 506, 450, 448, 351, 349, 218, 191, 175, 173, 160, 131, 114, 105; Anal. C 60.68, H 5.18, N 6.67 Cl 11.24 (caled C 60.79, H 5.10, N 6.86, Cl 11.58). Example 131 (Scheme L: L-5 where RL.X is methyl, R?, _ 2 is phenyl, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [2 - [1 ( 5 *), 2a, 4ß (5 *)]]). Acid dilithium salt [2R- [1 (S *), 2a, 4β (5 *)]] -4- [[[1-Carboxi-2- [4- [(2,6 -Dichlorobenzoyl) amino] phenyl] ] ethyl] -amino] carbonyl] -1- (1-phenylethyl) -2-acetyldinedicarboxylic acid Example 131 was prepared from Example 130 by the procedure described in Preparation 62. The physical properties are as follows: [a] 5D +84 (c 0.95, MeOH); 13C NMR (CD3OD) d 179.18, 176.55, 174.13, 163.58, 141.88, 136.32, 136.29, 134.96, 131.90, 130.86, 129.47, 128.49, 128.07, 127.87, 127.16, 119.74, 63.70, 63.49, 59.77, 56.27, 38.24, 26.25, 18.70: MS (FAB) m / z 598, 596, 592, 590, 552, 550, 546, 544, 161; Anal. C 55.20, H 5.22, N 6.59 (caled for 10.98 percent H20: C 52.00, H 4.99, N 6.27). Example 132 (Scheme L: L-4 where RL.? Is methyl, RL_2 is phenyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [1 (S), 2a, 4 (5)], a single diastereomer has a cis relative configuration but an absolute configuration unknown in C-2 and C-4 of azetidine). Methyl ester 2 of acid [1 (S), 2a, 4a (S)] -4- [[[1- [[2,6- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2 -oxoethyl] amino] carbonyl] -1- (1-f -methyl) -2-acetyldinedicarboxylic acid (C3? H3? Cl2N30g). Example 132 was prepared as described in Scheme L using the product of preparation 56 as intermediate L-1. The physical properties are as follows: TLC (9: 1 CHCl3 / acetone) R £ = 0.29; 13 C NMR (CDC13); d 172.70, 172. 29, 171.65, 162.49, 140.97, 136.71, 136.12, 132.47, 132.39, 130.81, 130.22, 128.35, 128.07, 127.82, 120.17, 66.61, 61.52, 59.99, 52.38, 52.24, 51.79, 37.73, 25.16, 20.09 Example 133 (Scheme L) : L-5 where RL.? Is methyl, RL_2 is phenyl, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [1 (5), 2c., 4a], a single diastereomer has a cis relative configuration but an absolute configuration unknown in C-2 and C-4 of azetidine). Acid [1 (S), 2a, 4c. (S)] -4- [[[1-Carboxy-2- [4- [(2,6-Dichlorobenzoyl) amino] phenyl] ethyl] -amino] sarbonyl] - 1- (1-f-phenylethyl) -2-acetyldinedicarboxylic acid (C 29 H 27 C 12 N 306). Example 133 was prepared from Example 132 by the procedure described in Preparation 62. The physical properties are as follows: [o.] 25D +20 (c 0.88, MeOH); 13 C NMR (CD3OD) d 173.70, 173.05, 172.61, 163.69, 140.09, 136.93, 136.20, 133.18, 131.89, 130.89, 129.95, 128.09, 127.89, 127.88, 127.65, 120.03, 66.07, 61.29, 59.86, 52.70, 36.98, 25.03, 18.81: MS (FAB) m / z 662, 660, 586, 584, 539, 482, 480, 436, 434, 204, 175, 173, 160, 133, 109, 105; Anal. C 57.90, H 5.01, N 6.93 (caled for 4.98 percent H20: C 56.63, H 4.98, N 6.83). Example 134 (Scheme L: L-4 where RL_? Is methyl, RL_2 is phenyl, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [2R- [l (i- * J , 2a, 4ß (5 *)]]). Acid methyl ester [2R- [1 (R *), 2a, 4ß { S *)]] -4 - [[[l - [[4- [ (2,6 -Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -1- (1-f-phenylethyl) -2-acetyldinedicarboxylic acid (C3? H3? Cl2N30g). Example 134 was prepared as described in Scheme L using the product of preparation 57 as intermediate L-1. The physical properties are as follows: TLC (1: 1 EtOAc / Hexanes) R £ = 0.30; 13 C NMR (CDC13); d 173.78, 172.76, 172.10, 162: 47, 141.81, 136.70, 135.96, 132.43, 132.38, 130.88, 129.79, 128.55, 128.10, 127.58, 127.00, 120.58, 63.32, 60.06, 59.27, 52.70, 52.50, 51.44, 37.08 25.76, 21.52; MS (+ ESI, 200: 1 MeOH / HC02H solution) m / z 613.8, 611.8. Example 135 (Scheme L: L-5 where RL.? Is methyl, RL_2 is phenyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [2R- [1 (R *) , 2a, 4ß (S *)]]) Acid dilithium salt [2R- [1 (R *), 2a, 4β (S *)]] -4- [[[1-Carboxi -2 - [4- [(2,6-Dichlorobenzoyl) amino] phenyl] ethyl] -amino] carbonyl] -1- (1-phenylethyl) -2-acetdidinecarboxylic acid Example 135 was prepared from Example 134 by the procedure described in Preparation 62. The physical properties are as follows: [a] 25D +76 (c 0.89, MeOH); 13C NMR (CD3OD) d 179.44, 176.71, 175.90, 163.55, 143.81, 136.54, 136.26, 134.47, 131.90, 120.81, 129.70, 127.83, 127.34, 126.33, 119.88, 63.06, 62.11, 58.71, 55.46, 37.17, 26.76, 20.56; MS (FAB) m / z 598, 596, 592, 590, 552, 550, 546, 544, 237, 105; Anal. C 55.12, H 5.24, N 6.59, Cl 10.56 (caled for 6.21 percent H20: C 54.78, H 4.66, N 6.61, Cl 11.15). Example 136 (Scheme L: L-4 where R?, _? Is methyl, R?, _ 2 is phenyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [2 = r - [? (£ r *;, 2a, 4ß (iR *)]]). Acid methyl ester [25- [1 (S *), 2a, 4ß (R *)]] -4- [[[1 - [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] ethyl] -2-methoxy-2-oxo-ethyl] amino] -carbonyl] -1- (1-phenylethyl) -2-acetyldinedicarboxylic acid (C3iH3? Cl2N3? 6) Example 136 was prepared as described in Scheme L using the product of preparation 58 as intermediate L-1 The physical properties are as follows: TLC (85:15 CHCl 3 / acetone) R £ = 0.54; 13 C NMR CDCl3); d 173.44, 172.62, 171.72, 162.79, 140.46, 136.69, 136.34, 133.12, 132.79, 131.29, 130.40, 129.08, 128.52, 128.45, 128.23, 120.57, 64.15, 60.51, 60.09, 53.11, 52.59, 52.19, 37.73, 26.70, 18.75, Anal.C 60.70, H 5.39, N 6.62 (caled C 60.79, H 5.10, N 6.86) Example 137 (Scheme L: L-5 where R_.? Is methyl, R?, _ 2 is phenyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl or, and the stereochemistry is [25- [1 (5 *), 2c., 4ß (R *)]]) Acid [25- [1 (5 *), 2a, 4ß (£ *)]] -4- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] -amino] carbonyl] -1- (1-phenylethyl) -2-acetyldinedicarboxylic acid (C 29 H 27 C 12 N 306). Example 137 was prepared from Example 136 by the procedure described in Preparation 62. The physical properties are as follows: [a] 25D +2 (c 1.00, MeOH); 13C NMR (CD3OD) d 172.31, 169.43, 167.37, 163.72, 161.39, 160.93, 136.98, 136.11, 134.40, 133.20, 131.84, 130.93, 129.42, 129.39, 128.60, 127.89, 120.11, 62.68, 61.41, 53.51, 36.35, 25.00, 16.17; MS (FAB) m / z 586, 584, 482, 480, 204, 175, 173, 106, 105; Anal. C 53.07, H 4.52, N 6.15, Cl 10.46 (caled for 0.80 equiv TFA and 2.13 percent H20: C 53.20, H 4.30, N 6.08, Cl 10.26). Example 138 (Scheme L: L-4 where RL.? Is methyl, RL_2 is phenyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [1 [R], 2a, 4a [S)], a single diastereomer has a cis relative configuration but an absolute configuration unknown in C-2 and C-4 of azetidine). Methyl ester 2 of acid [1 (R), 2a, 4a. { S)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] - 1 - (l-f-enylethyl) ) - 2-acetyldicarboxylic acid (C31H3? Cl2N306). Example 138 was prepared as described in Scheme L using the product of preparation 59 as intermediate L-1. The physical properties are as follows: TLC R £ = 0.47 (85:15 CHCl 3 / acetone); 13 C NMR (CDCl 3); d 173.42, 172.40, 171.74, 162.46, 140.80, 136.76, 136.03, 132.64, 132.35, 130.80, 129.82, 128.38, 128.04, 127.85, 127.69, 120.39, 66.11, 61.50, 59.78, 52.83, 52.42, 51.72, 37.12, 25.03, 20.20; MS (+ ESI, 200: 1 MeOH / HC02H solution) m / z 614.2, 612.2; Anal. C 60.66, H 5.18, N 6.80, Cl 11.42 (caled C 60.79, H 5.10, N 6.86, Cl 11.58). Example 139 (Scheme L: L-5 where RL.? Is methyl, RL_2 is phenyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is [1 (R), 2a, 4c. (5)], a single diastereomer has a cis relative configuration but an absolute configuration unknown in C-2 and C-4 of azetidine). Acid [1 (R), 2c., 4? (S)] -4- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl ethyl] -amino] carbonyl] 1- (1-f-phenylethyl) -2-acetyldinedicarboxylic acid (C 29 H 25 Cl 2 N 30 g). Example 139 was prepared from Example 138 by the procedure described in Preparation 62. The physical properties are as follows: [OI] 25D -30 (c 0.90, MeOH); 13C NMR (CD30D) d 172.71, 172.44, 171.81, 163.71, 138.03, 136.99, 136.15, 133.31, 131.89, 130.89, 129.45, 128.33, 128.29, 128.02, 127.86, 120.23, 65.62, 61.51, 59.60, 53.47, 36.04, 24.91, 17.68: MS (FAB) m / z 586, 584, 371, 298, 204, 177, 175, 173, 133, 105, 100; Anal. C 55.69, H 4.49, N 6.55, Cl 11.83. (caled for 0.38 equiv TFA and 2.06 percent H20: C 55.80, H 4.54, N 6.56, Cl 11.07).
Esque? Na M O ^ _ < A-Ao_ M__ Or,? -O-OA OH M ^ Scheme M shows a general method for the preparation of N-acyl acetidinocarboxylic acid Examples M-6 and M-7, where RM.X is alkyl with 1 to 6 carbon atoms, RM_2 is aryl with 6 to 10 carbon atoms, and R3, R5 and Y are defined as in Scheme B. Thus the removal of the N-alkylaryl substituents RM. and RM_2 of M-1 gives the amino-diester M-2, which is acylated to give M-3. The partial saponification of the M-3 diester gives the acidic medium M-4, which is coupled with the M-5 reagent (as exemplified by the use of reagents A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) to provide Examples M-6, which are then hydrolyzed to Examples M-7 of this invention. Preparation 63 (Scheme M: M-2 wherein the stereochemistry is (2R-trans)) Dimethyl diester of [2R-trans) -2,4-Acetyldinedicarboxylic acid (/ Hu? C.) A solution purged with nitrogen from a chromatographed preparation recently Ml (Scheme M where RM.? is methyl, RM_2 is phenyl and the stereochemistry is [2R- [1 (R *), 2OÍ, 4ß]] prepared as described by preparation 57) (656 milligrams, 2.37 mmol ) in MeOH (20 milliliters) is added 20 percent Pd (0H) 2 / C (120 milligrams), and this mixture is hydrogenated for 19 hours under a hydrogen atmosphere (approximately a pressure of 2.94 kg / cm2). it was filtered and concentrated to give the title compound as a colorless oil: TLC (4: 1 Hexanes / EtOAc) Rf = 0.04 1 H NMR (CDC13) d 4.33 (2 H), 3.77 (6 H), 3.38 (1 H), 2.71 (2 H); MS (+ ESI) m / z lié. 2 . Preparation 64 (Scheme M: M-3 wherein R3 is ethyl, Y is C02-, and the stereochemistry is (2R-trans)) 1-ethyl-2,4-dimethyltriester of (2R-fcrans) -1, 2,4-Acetyldinedicarboxylic acid (C10H? 5NOg). To a mixture of recently prepared amine M-2 (Scheme M wherein the stereochemistry is (2R-trans)) (14 mmol) in CH2C12 (20 milliliters) under nitrogen at 0 ° C was added Et3N (3.0 milliliters, 22 mmol), followed by the dropwise addition of ClC02Et ( 1.5 milliliters, 18 mmol). After 22 hours the reaction is quenched with saturated NaHCO 3, diluted with H 2 O, and extracted with EtOAc. The combined organic extracts are dried, filtered and concentrated to give 2.79 grams of the carbamate, which is purified by flash silica chromatography: TLC (4: 1 Hexanes / EtOAc) R £ = 0.17 [OI] 25D +183 (c 0.83, MeOH ); X H NMR (CDCl 3) d 4.77 (2 H), 4.15 (1 H), 4.10 (1 H), 3.80 (6 H), 2.58 (2 H), 1.23 (3 H); 13 C NMR (CD3OD) d 173.11, 173.05, 157.47, 63.30, 61.00, 60.18, 53.41, 26.43, 15.27; MS (El) m / z 245, 186, 172, 142, 114; Anal. C 48.90 H 6.21, N 5.73 (caled C 48.98, H 6.16, N 5.71).
-Preparation 65 (Scheme M: M-4 where R3 is ethyl, Y is C02-, and the stereochemistry is (2R- trans)) 1-ethyl-2-methyl acid diester (2R-fcraps) -1, 2,4-Acetyldinedicarboxylic acid (C9H13N06). To a mixture of M-3 (Scheme M, where R3 is ethyl, Y is C02-, and the stereochemistry is [2R-trans)) (1.68 grams, 6.85 mmol) and LiOH (7.00 mmol) in 1: 1 MeOH / H20) (40 milliliters) is stirred at room temperature for 45 hours and then concentrated. The residue is dissolved in half-saturated NaHC03 and the solution is extracted with Et20. The Et20 solution is discarded, and the aqueous solution is adjusted with concentrated HCl to pH 4, and concentrated to a yellow solid. This solid is triturated with CHC13. The CHC13 solution is filtered and concentrated to give, as a light brown oil, the title compound: TLC (600: 400: 1 Hexanes / Acetone / HC02H)) R £ = 0.21-0.45; 1 H NMR (CDCl 3) d 4.87 (1 H), 4.77-4.68 (1 H), 4.64-4.50 (1 H), 4.18-3.97 (2 H), 3.76 (3 H), 2.52-2.33 (2 H), 1.26-1.13 (3 H); MS (-ESI, MeOH solution) m / z 230.1. This material is used without further purification. Preparation 66 and Example 140 (Scheme M: M-6 wherein R3 is ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, Y is C02-, and the stereochemistry is [2R- (2c., 4β (5 *)]). L-Ethyl-2-methyl methyl diester of acid [2R- (2a, 4β (S *)] -4- [[[1- [[4- [Í2, 6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methyl-2-oxoethyl] amino] carbonyl] -1,2-acetyldinedicarboxylic acid (C26H27C12N308). To a mixture of the preparation M-4 (1.08 grams, 4.67 mmol) and H0Bt + H20 (0.63 gram, 4.7 mmol) in CH2C12 (10 milliliters) at 0 ° C is added an EDC solution (1.04 gram, 5.42 mmol) in CH2C12 (15 milliliters). This mixture is stirred at 0 ° C for 30 minutes. Then it is treated with M-5 (Scheme M where R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (5)) (1.88 gram, 4.66 mmol) and N-methylmorpholine (0.52 milliliters) 4.7 mmol). The resulting solution was stirred at 0 ° C for 2 hours and at room temperature for 2 hours. The reaction mixture was diluted with 10 percent KHS04 and extracted with CH2C12. The combined CH2C12 extracts were washed with saturated? AHC03 and brine, and combined, dried, filtered and concentrated to give a yellow foam (2.58 grams), which was purified by flash chromatography, to give, as a white solid, the compound of the title: mp 97-99 ° C; TLC (9: 1 CHCl3 / acetone) R £ = 0.30; [OI] 2SD +79 (c 1.02, MeOH); UV (MeOH)? Max 225 (e 12200: sh), 251 (17500); 13C RM? (CD3OD); d 171.50, 171.30, 171.08, 163.67, 156.23, 155.96, 136.92, 136.19, 133.21, 133.03, 131.87, 130.93, 129.64, 129.44, 127.92, 119.97, 61.61, 60.56, 59.82, 59.11, 58.41, 53.45, 51.58, 51.52, 36.57 , 36.29, 24.91, 13.43 (22 expected lines: 28 observed lines); MS (FAB) m / z 580.1260 (caled for [M + H] +, 580.1253); Anal. C 51.95, H 4.56, N 6.89, Cl 15.18 (caled for 0.61 percent H20: C 53.48, H 4.73, N 7.20, Cl 12.14). Preparation 67 and Example 141 (Scheme M: M-7 wherein R3 is ethyl, R5 is 4 - [(2,6-dichlorobenzoyl) amino] phenyl, Y is C02-, and the stereochemistry is [2R- (2a, 4ß (5 *)]) 1-ethyl ester of acid [2R- (2a, 4β (S *)] -4- [[[1-Carboxi-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ] ethyl] -amino] carbonyl] -1,2-acetyldinedicarboxylic acid (C24H23C12N308) To a suspension of M-6 (Example 140, Scheme M where R3 is ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] ] phenyl, Y is C02-, and the stereochemistry is [2R- (2c¿, 4ß (5 *)]) (0.201 grams, 0. 347 mmol) in MeOH (5 milliliters) is added H20 (4.3 milliliters) and 1.00 M LiOH (0.70 milliliters). The reaction mixture is stirred at room temperature for 23 hours. It concentrates in a vacuum. The aqueous concentrate is diluted with H20, and the solution is adjusted to approximately pH 12 with 1 N NaOH. It is extracted with Et20, and the Et20 extract is discarded. The aqueous solution is adjusted to approximately pH 3 with 1N HCl. Extract repeatedly with Et20. The combined Et20 extracts were dried, filtered and concentrated to give, as a white solid, the title compound: TLC (500: 500: 1 MeOH / CH2Cl2 / HC02H) R £ = 0.20 X H NMR (CD3OD) d 7.59 (2 H), 7.50-7.37 (3 H), 7.23 (2 H), 4.78-4.64 (2 H), 4.61-4.51 (1 H) ), 4.22-3.89 (2 H), 3.30-3.185 (1 H), 3.07-2.93 (1 H), 2.42-2.23 (2 H), 1.21 and 1.11 (3 H total); MS (FAB) m / z 552.0946 (caled for [M + H] + 552.0940); Anal. C 50.48, H 4.61, N 6.64, Cl 12.95 (caled for 1.60 percent H20: C 51.35, H 4.31, N 7.49, Cl 12.63).
Scheme N R5 H, N N-3 Scheme N shows a general method for the preparation of N-acyl acetidinocarboxylic acid Examples? -5 where n is equal to 0, 1 or 2, m equal to 0, 1 or 2, (m + n) equal to 2, X is nitrogen and R3, Rs and Y are defined as in Scheme B, and acetidinocarboxylic acid Examples? -6 where n is equal to 0, 1 or 2, m equal to 0, 1 or 2, (m + n ) equal to 2, X is nitrogen and R5 is defined as in Scheme B. In this way the acylation of the amino acid N1 gives the N-acyl acid? -2, which is coupled with the reagent? -3 (as exemplified by the use of reagents A-3 and A-4 of Scheme A, and B-4 and B-5 of Scheme B) to provide Examples? -4. The ester hydrolysis of? -4 provides Examples? -5. i-7-Deacylation of the Examples? -5 provides the Examples? -6. Preparation 68 (Scheme?:? -2 where n is 2, m is 0, X is?, Y is -C02-, R3 is (1,1-dimethyl) ethyl, and the stereochemistry is (5)) 1- (1, 1-dimethylethyl) ester of (S) -l acid, 2-Acetyldinedicarboxylic acid (C9H15? 04). To a mixture of (5) - (-) - 2-acetylcarboxylic acid (110 milligrams, 1.1 mmol), Boc20 (290 milligrams, 1.30 mmol), and DMAP (0.017 grams, 0.14 mmol) in 4: 1 DMF / H20 ( 10 milliliters) is Et3 added? (0.30 milliliters, 2.2 mmol). The reaction mixture is stirred at room temperature for 68 hours, and then concentrated. The concentrate is diluted with EtOAc, and the EtOAc solution is washed with cold 10 percent KHS04. The combined organic extracts are dried, filtered and concentrated to give the title compound as a colorless oil: TLC (750: 250: 1 Hexanes / acetone / HC02H) R £ = 0.26; XH RM? (CD3OD) d 4.97 (1 H), 4.57 (1 H), 3.98 (1 H), 3.87 (1 H), 2.57 (H), 2.13 (1 H), 1.42 (9 H); MS (-ESI) m / z 200.3. Preparation 69 and Example 142 (Scheme N: N-4 where n is 2, m is 0, X is N, Y is -C02-, R is (1,1-dimethyl) ethyl, Rs is 4- [(2 , 6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (5)). 1- (1, 1-dimethyl) ethyl ester of [2S- (R *, R *)] -2- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -1-acetyldinedicarboxylic acid (C 26 H 29 Cl 2 N 3? 6). To a mixture of N-2 acid (Scheme N, where n is 2, m is 0, X is N, Y is -C02-, R3 is (1,1-dimethyl) ethyl, and the stereochemistry is (5)) (1.04 grams, 5.17 mmol) and HOBt.H20 (0.71 grams, 5.3 mmol) in CH2C12 (10 milliliters) at 0 ° C during the addition of a mixture of EDC.HCl (1.00 grams, 5.22 mmol) in CH2C12 (20 milliliters). The reaction mixture is stirred at 0 ° C for 30 minutes, and then N-3 (Scheme N where R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (5)) (2.10 grams, 5.20 mmol) and N-methylmorpholine (0.60 milliliters, 5.46 mmol) is added. The reaction mixture is stirred at 0 ° C for 30 minutes and at room temperature for 3 hours. The reaction mixture is divided between 10 percent KHS04 and CH2C12. The aqueous phase is extracted twice more with CH2C12. The combined organic extracts are washed with saturated αHC03 and brine, and then dried, filtered and concentrated to a yellow oil (2.54 grams) which is purified by flash silica chromatography to give the title compound as a white foam: mp 106 -108 ° C; TLC (1: 1 Hexanes / EtOAc); R £ = 0.21; [α] 25D -38 (c 1.01, MeOH); 13C RM? (CD3OD) d 172.37, 171.58, 163.64, 156.68, 136.98, 136.22, 133.11, 131.87, 130.90, 129.49, 127.91, 120.00, 80.42, 61.87, 53.31, 51.45, 36.40, 27.16, 20.08; MS (El) m / z 551, 549, 478, 476, 451, 449, 396, 394, 351, 349, 280, 278, 175, 173; Anal. C 56.33, H 5.48, N 7.23, Cl 12.43 (caled for 0.52 percent H20: C 56.44, H 5.34, N 7.59, Cl 12.82). Preparation 70 and Example 143 (Scheme N: N-5 where n is 2, m is 0, X is N, Y is -C02-, R3 is (1,1-dimethyl) ethyl, Rs is 4- [(2 , 6-dichlorobenzoyl) amino] phenyl and the stereochemistry is [25- (R *, R *) 1). 1- (1, 1-dimethylethyl ester of 12S- (R *, R *)] -2- [[[1-C arboxi-2 - [4 - [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -1-acetyldinedicarboxylic acid (C2SH27C12N306) To a solution of N-4 (Scheme N, where n is 2, m is 0, X is N, Y is -C02-, R3 is (1, 1-dimethyl) ethyl, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (5)) (507 milligrams, 0.92 mmol) and LiOH (1.25 mmol) in 1: 1 MeOH / H20 (10 milliliters) CH2C12 (10 milliliters) is stirred at room temperature for 18 hours. The reaction mixture is diluted with cold 10 percent KHS04 and extracted with CH2C12. The organic extracts are dried, filtered and concentrated to a white foam (498 milligrams), which is purified by flash silica chromatography to give the title compound: TLC (750: 250: 1 hexanes / acetone / HC02H); Rf = 0.12; [? í] 5D -27 (c 0.94, CHC13); 13 C NMR (CD3OD) d 210.05, 172.70, 172.27, 163.63, 156.75, 136.89, 136.22, 133.36, 131.88, 130.90, 129.56, 127.91, 119.95, 80.47, 61.93, 53.18, 36.47, 27.15, 20.09; MS (-ESI) m / z 533.8; MS (El) m / z 435, 419, 417, 401, 399, 373, 371, 280, 278, 175, 173, 147, 145; Anal. C 55.23, H 5.25, N 7.42, Cl 12.87 (caled for 10 percent H20: C 55.36, H 5.14, N 7.75, Cl 13.07). Preparation 71 and Example 144 (Scheme N: N-6 where n is 2, m is 0, X is N, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is [25], L ). Salt of N- [[(2S) -2-Acetidinyl] carbonyl] -4- [2,6-dichlorobenzoyl) amino] -L-phenylalanine trifluoroacetic acid (C20H19Cl2N3O6.C2HF3O2). A solution of N-5 (Scheme N, where n is 2, m is 0, X is N, Y is -C02-, R3 is (1, 1-dimethyl) ethyl, Rs is 4- [(2.6 -dichlorobenzoyl) amino] phenyl and the stereochemistry is [25), R *, R *) l? ) (900 milligrams, 1.7 mmol) in 1: 1 TFA / CH2C12 (5 milliliters) is stirred at room temperature for 1.5 hours, and concentrated. The residue is diluted three times with CHC13 and reconcentrated. This residue is dissolved in MeOH and concentrated to a white foam, which is dissolved in 1: 1 MeOH / H20 and then concentrated to remove most of the MeOH. The solution is frozen and lyophilized to give the product as a white powder: [a] 25D -6 (c 0.72, MeOH); 13C NMR (CD3OD) d 172.62, 167.54, 163.78, 136.82, 136.13, 133.43, 131.84, 130.97, 129.38, 127.93, 120.15, 58.38, 54.03, 43.73, 36.27, 23.33; MS (+ ESI) m / z 436.0; MS (FAB) m / z 438, 436; Anal. C 46.77, H 3.75, N 7.24, Cl 12.44 (caled for 1: 1 TFA salt with 1.68 percent HzO: C 47.21, H 3.79, N 7.51, Cl 12.67). Example 145 * (Scheme N: N-4 where n is 1, m is 1, X is N, R3 is (1, 1-dimethyl) ethyl R, is [(2,6-dichlorobenzoyl) amino] phenyl, and is C02-, and the stereochemistry is (5)) . 1- (1, 1-dimethyl) ethyl ester of [S] -3- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl ] amino] carbonyl] -1-acetyldinedicarboxylic acid (C2gH29Cl2N30s). Example 145 was prepared as described in Scheme N from 3-acetidinocarboxylic acid. The physical properties are as follows: TLC (1: 1 EtOAc / hexanes) R £ = 0.22; [a] 2SD +18 (c 0.92, MeOH); 13C NMR (CD3OD) d 172.92, 171. 91, 163.68, 156.55, 136.87, 136.20, 133.27, 131.89, 130.91, 129.36, 127.90, 120.04, 79.80, 53.85, 51.45, 36.43, 32.26, 27. 24; MS (El) m / z 469, 467, 451, 359, 351, 349, 280, 278, 175, 173, 57; Anal. C 56.82, H 5.39, N 7.52, Cl 12.81 (caled for 0.06 percent H20: C 56.70, H 5.31, N 7.63, Cl 12.87). Example 146 (Scheme N: N-5 where n is 1, m is 1, X is N, R3 is (1,1-dimethyl) ethyl, R is 4 - [(2,6-dichlorobenzoyl) amino] phenyl , Y is C02-, and the stereochemistry is (5)). 1- (1, 1-dimethylethyl) ester of (S) -3 - [[[1-Carboxy] -2 - [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -1 -acetyldicarboxylic acid (C2SH27C12N306). Example 145 was prepared from Example 145 by the procedure described in Preparation 70. The physical properties are as follows: TLC (600: 400: 1 Hexanes / Acetone / HCO.H) R £ = 0.17; [α] 25D +33 (c 0.92, MeOH); 13C NMR (CD30D) d 173.05, 172.89, 163.69, 156.56, 136.78, 136.19, 133.59, 131.89, 130.91, 129.40, 127.90, 120.00, 79.78, 53.67, 51.72, 36.47, 32.31, 27.24; MS (-ESI) m / z 533.9; MS (FAB) m / z 538, 536, 438, 436, 337, 335, 280, 278, 175, 173, 57; Anal. C 55.03, H 5.21, N 7.52, Cl 12.81 (caled for 1.22 percent H20: C 55.30, H 5.15, N 7.74, Cl 13.06). Example 147 (Scheme N: N-6 where n is 1, m is 1, X is NH, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl, and the stereochemistry is (L)). Trifluoroacetic acid salt, JV - [[3-Azetidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L-f-enylalanine (C20H? 9Cl2N3O6, C2HF302). Example 147 was prepared from Example 146 by the procedure described in Preparation 71. The physical properties are as follows: [OI] 25D +32 (c 0.87, MeOH), - 13 C NMR (CD3OD) d 173.32, 170.57, 163.80, 136.70, 136.13, 133.76, 131.84, 130.97, 129.45, 127.93, 120.17, 54.03, 36.59, 35.32); MS (FAB) m / z 438, 436, 391, 331, 175, 173, 101, 55; Anal. C 46.85, H 4.07, N 7.33, Cl 12.39 (caled for 1: 1 TFA salt with 3.34 percent H20: C 46.41, H 3.92, N 7.38, Cl 12.45). EXAMPLE 148 3- (2-pyridinylmethyl) acid ester [S- [R *, R *)] -4- [[[1 - [[4 - [(2,6 -Dichlorobenzoyl) amino] phenyl] methyl] - 2-methoxy-2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic (Scheme A, A-7: where RA.? And RA_2 are equal and equal to proton, R3 is 2-pyridinylmethyl, Y is C02-, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is [H.H) ) .
Example 148 was prepared as described in Scheme A from D-cysteine using 2-pyridine methanol to form the required carbamate. The physical data are as follows: JH NMR (300 MHz, CDC13) d 8.37 (1 H), 7.70 (1 H), 7.51 (2 H), 7.27 (6 H), 7.08 (2 H), 6.92 (1 H) ), 5.24 (2 H), 4.77 (3 H), 4.40 (1 H), 3.74 (3 H), 3.37 (1 H), 3.15 (3 H); 13 C NMR (75 MHz, CDC13) d 171.4, 162.5, 155.2, 149.0, 137.1, 136.5, 136.0, 132.4, 130.7, 129.9, 128.0, 123.1, 120.6, 63.0, 53.4, 52.5, 36.8; MS (ESI +) for C28H26Cl2N4OgS m / z 616.8 (M + H) *; HRMS (El) caled for C28H2gCl2N406S: C, 54.46; H, 4.24; N, 9.07.
Found: C, 54.61; H, 4.32; N, 8.97 EXAMPLE 149 3- (2-pyridinylmethyl) acid ester [S- (R *, R *)] -4- [[[1-C arboxi-2 - [4 - [(2,6-dichlorobenzoyl)] amino] phenyl] ethyl] amino] carbonyl] -3-thiazole idinocarboxylic (Scheme A, A-8: where RA.? and RA_2 are equal and equal to proton, R3 is 2-pyridinylmethyl, Y is C02-, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is [S, S)).
Example 149 was prepared from Example 148 by the procedure described in Preparation 6. The physical data are as follows: IR (Mull) 1713, 1666, 1605, 1576, 1561, 1539, 1515, 1442, 1431, 1413, 1351, 1325, 1271, 1194, 766 cm -1. 1 H NMR (300 MHz, CD30D) d 8.80 (1 H), 8.56 (1 H), 7.99 (2 H), 7.58 (2 H), 7.45 (3 H), 7.25 (2 H), 5.43 (2 H), 4.60 (3 H), 3.30 (3 H), 2.93 (2 H); 13C NMR (75 MHz, CD3OD) d 172.7, 171.5, 163.7, 152.8, 151.3, 146.6, 141.9, 136.8, 136.1, 133.6, 131.8, 130.9, 129.6, 127.9, 126.1, 125.4, 120.1, 63.2, 62.8, 59.4, 53.5 , 36.4, 35.1; MS (ESI +) for C27H24C12N406S m / z 602.9 (M + H) *; MS (FAB) / z (relative intensity.) 603 (MH +, 59), 605 (43), 603 (59), 154 (51), 139 (99), 137 (46), 136 (47), 123 ( 67), 105 (58), 103 (61), 93 (38); HRMS (FAB) caled for C27H24C12N406S + H? 603.0872, found 603.0876; Anal. Caled for C27H24Cl2N4O6S.0.3 H20: C, 53.26; H, 4.07; N, 9.20. Found: C, 52.97; H, 4.23; N, 9.04. Example 150 Acid [S- (R *, R *)] -4 - [[[l- [[4 - [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino ] carbonyl] -d-oxo-3-thiazolidinopentanoic (Scheme A, A-7: where RA.? and RA_2 are equal and equal to proton, R3 is (CH2) 3C02H, Y is CO-, R5 is 4- [ (2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (S, S)).
Example 150 was prepared as described in Scheme A from D-cysteine using glutaric anhydride to form the required amide. The physical data are as follows: IR (mull) 3077, 3053, 3040, 1738, 1728, 1696, 1682, 1641, 1557, 1437, 1430, 1414, 1307, 1232, 1209 cm "1; * H NMR (300 MHz , CDC13) d 7.56 (2 H), 7.30 (3 H), 7.08 (2 H), 4.96 (1 H), 4.62 (3 H), 3.72 (3 H), 3.28 (4 H), 2.37 (4 H) ), 1.90 (2 H), 13 C NMR (75 MHz, CDCl 3) d 179.5, 176.0, 175.6, 173.6, 167.2, 140.6, 140.0, 136.1, 134.5, 133.7, 133.4, 131.8, 124.4, 66.7, 65.9, 57.2, 56.3 , 40.3, 39.3, 39.3, 37.3, 36.7, 36.2, 33.5, 23.6, MS (FAB) m / z (relative intensity.) 596 (MH *, 90), 598 (63), 597 (40), 596 (90 ), 341 (25), 263 (25), 230 (32), 225 (31), 193 (31), 141 (99), 88 (36); HRMS (FAB) caled for C2SH27C12N307S + H? 596.1025, found 596.1036 Anal Caled for C26H27Cl2N307S .0.3 H20: C, 51.88; H, 4.62; N, 6.98. Found: C, 51.69; H, 4.69; N, 6.59 Example 151 Acid methyl ester [S- [R *, R *)] -4- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -d-oxo-3-aiazolidinopentanoic acid (Scheme A, A - 8: where RA.? and RA_2 are equal and equal to proton, R3 is (CH2) 3C02CH3, Y is CO-, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is [S, S)).
Example 151 was prepared as described in Scheme A from D-cysteine using methyl glutaryl chloride to form the required amide. The physical data are as follows: IR (mull) 3287, 3196, 1724, 1662, 1607 , 1562, 1540, 1516, 1431, 1414, 1326, 1268, 1217, 1195, 799 cm "1: MS (FAB) m / z (relative intensity) 596 (MH +, 72), 598 (52), 596 (72 ), 229 (37), 193 (37), 167 (34), 133 (44), 129 (69), 121 (48), 103 (83), 89 (99); R NMR (300 MHz, CD30D) d 7.56 (2 H), 7.43 (3 H), 7.23 (2 H), 4.53 (3 H), 3.63 (3 H), 2.96 (4 H), 2.45 (3 H), 2.24 (2 H), 1.93 (2 H); 13 C NMR (75 MHz, CDC13) d 174.0, 172.1, 169.9, 162.9, 162.8, 136.1, 132.2, 130.6, 130.0, 137.9, 120.3, 62.9, 54.5, 51.6, 49.8, 36.8, 33.5, 33.0, 32.7, 29.6, 19.6; HRMS (FAB) caled for C26H27C12N307S + H? 596.1025, found 596.1047. MS (FAB) m / z (relative intensity) 596 (MHS 72), 598 (52), 596 (72), 229 ( 37), 193 (37), 167 (34), 133 (44), 129 (69), 121 (48), 103 (83), 89 (99) Example 152 Acid 3- [2- ( 1-piperidinyl) ethyl] ester [S- (R *, R *)] -4- [[[1- Carboxy-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] carbonyl ] -3-thiazolidinocarboxylic (Scheme A, A-8: where RA.? and RA.2 are equal and equal to proton, R3 is 2- (1-piperidinyl) ethyl, Y is C02-, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is [SU)) - Example 152 was prepared from Example 5 by the procedure described in Preparation 6. The physical data are as follows: IR (mull) 3254, 2654, 1711, 1565, 1547, 1512, 1438, 1344 , 1300, 1240, 1196, 1179, 1119, 1014, 767 cm "1; XH NMR (300 MHz, CD3OD) d 7.45 (2 H), 7.36 (1 H), 7.19 (2 H), 6.97 (2 H) , 5.26 (2 H), 4.50 (5 H), 3.60 (11 H), 1.83 (6 H); MS (ESI +) for m / z 610.0 (M + H) *; Anal. Caled for Ci8E33Cl2N306S .1.5 H20. HCl: C, 49.90; H, 5.53; N, 6.24; Cl, 15.78. Found: C, 49.86; H, 5.43; N, 6.29; Cl, 15.65. percent Water (KF): 3.99. Example 153 [S- (R *, R *)] -4- [[[1-Carboxi-2- [4- [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] carbonyl] -N-methyl -N- [2- (2-pyridinyl) ethyl] -3-thiazolidinocarboxamide (Scheme A, A-8: where RA.? And RA.2 are equal and equal to proton, R3 is 2- (2-pyridyl) ethyl, Y is C0 (CH3) -, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S, S)).
Example 153 was prepared as described in Scheme A using 2- (2-methylaminoethyl) -pyridine to form the required urea and hydrolysis according to the procedure described in preparation 6. The physical data are as follows: mp 80 ° C (soft), 125 ° C; IR (mull) 1661, 1611, 1585, 1565, 1511, 1489, 1439, 1394, 1300, 1240, 1196, 1179, 1017, 768 cm "* H NMR (300 MHz, CD3OD) d 8.44 (1 H), 7.75 (1 H), 7.35 (5 H), 7.12 (2 H), 6.93 (2 H), 5.22 (2 H), 4.83 (1 H), 4.65 (1 H), 4.32 (2 H), 3.77 (1 H), 3.45 (1 H) , 3.20 (1 H), 3.00 (5 H), 2.84 (3 H); 13C NMR (75MHZ, CDjOD) d 173.0, 170.8, 162.4, 158.4, 157.9, 147.9, 138.0, 136.6, 132.2, 130.6, 130.1, 129.3, 128.3, 124.2, 122.0, 114.5, 64.8, 64.7, 53.3, 52.5, 49.7 , 35.7, 34.8, 32.8; MS (ESI +) for C 29 H 30 Cl 2 N 4 O 5 S m / z 617.0 (M + H) *; Anal. Caled for C 29 H 30 Cl 2 N 4 O 5 S: C, 56.40; H, 4.90; N, 9.07.
Found: C, 56.31; H, 5.07; N, 8.98. Preparation 72 and Example 154 3-Ethyl ester of [S- [R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2 - [(4-pyridinyl) -methoxy] -2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid To a solution of Example 12 (Scheme A, A-8, where RA.? And RA_2 are equal and equal to H , R3 is ethyl, Y is C02, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (£ 7.5)) (400 milligrams, 0.74 mmol) in dimethylformamide (4 milliliters) was added tetramethylguanidine (204 microliters, 1.63 mmol) followed by 4-picolyl chloride (138 milligrams, 0.81 mmol). The solution was heated at 65 ° C for 3 hours and the volatiles were removed in vacuo. Purification of the residue by flash chromatography using methylene chloride / methanol (2 percent) as eluent afforded the title compound (320 milligrams) as an amorphous solid: IR (mull) 3275, 1748, 1677, 1608, 1561, 1539, 1515, 1431, 1415, 1344, 1325, 1271, 1222, 1194, 799 cm-1; 2 H NMR (300 MHz, CDC13) d 8.87 (1 H), 8.48 (2 H), 7.50 (2 H), 7.25 (3 H), 7.10 (2 H), 6.93 (2 H), 5.08 (2 H) , 4.79 (2 H), 4.61 (1 H), 4.28 (1 H), 4.13 (2 H), 3.16 (4 H), 1.21 (3 H); 13C NMR (75 MHz, CDCI3) d 174.6, 170.7, 170.6, 162.6, 149.2, 144.5, 136.9, 136.0, 132.3, 131.7, 130.7, 129.8, 128.0, 122.5, 120.3, 65.0, 63.0, 62.7, 53.3, 37.3, 20.9 , 14.5; MS (ESI +) for C29H28C12N406S m / z 630.8 (M + H) *; Anal. Caled for C29H28C12N406S: C, 55.15; H, 4.47; N, 8.87. Found: C, 54.85; H, 4.58; N, 8.74. Anal. Caled for C29H28Cl2N406S: C, 55.15; H, 4.47; N, 8.87; Cl, 11.23; S, 5.08. Found: C, 54.85; H, 4.58; N, 8.74 Preparation 73 and Example 155 4-ethyl ester of acid [S- [R *, R *)] -4- [[[1- Carboxy-2- [4 - [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] carbonyl] -8-methyl-1-thia-4,8-diazaspiro [4,5] decane-4-carboxylic acid (Scheme B, B-7: wherein RB.? and RB_2 are equal and equal to H, RB_3 and RB.4 together form a cyclic ring of 6 atoms of the formula -CH2CH2N (CH3) CH2CH2-, Y is C02, R3 is ethyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is [S, S)).
T-Butyl Ester B-6 (Scheme B where RB.? And RB_2 are equal and equal to H, RB_3 and RB_4 together form a cyclic ring of 6 atoms of the formula -CH2CH2N (CH3) CH2CH2-, Y is C02, R3 is ethyl, RB_5 is Ot-butyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is [S, S), prepared according to Scheme B from 1-methyl-4 - piperidone and D-cysteine (681 milligrams, 1.02 mmol) was dissolved in a solution of HCl in dioxane (4 M, 28 milliliters) at room temperature. After. 18 hours, the volatiles were removed under vacuum to produce a residue (650 milligrams) that was lyophilized from water. After further purification of a portion of this product (200 milligrams), it was done by chromatography on a Biotage Instantaneous 40® system using a 40 gram silica gel cartridge KP-C18-HS (35-70 micras) using aqueous acetonitrile (40 percent) as eluent to produce the title compound (94 milligrams) as an amorphous powder: IR (mull) 1696, 1611, 1585, 1565, 1511, 1439, 1404, 1335, 1303, 1271, 1239, 1196, 1178, 1017, 769 cm "1; ? NMR (DMS0-d6, 300 MHz) d 8.25 (1 H), 7.54 (2 H), 7.43 (1 H), 7.13 (2 H), 6.94 (2 H), 5.16 (2 H), 4.84 (1 H) ), 4.41 (1 H), 4.00 (2 H), 3.07 (4 H), 2.73 (4 H), 2.53 (3 H), 1.96 (1 H), 1.69 (1 H), 1.11 (3 H); 13 C NMR (CDC13, 75 MHz) d 173.9, 169.2, 157.7, 153.2, 136.9, 132.1, 130.7, 130.5, 129.3, 128.5, 114.7, 73.2, 66.7, 65.2, 62.8, 54.0, 43.5, 36.5, 14.6; MS (ESI +) for m / z 610.0 (M + H) +; MS (ESI-) for C28H33Cl2N3OgS m / z 607.9 (MH) ": HRMS (FAB) caled for C28H33Cl2N3? 6S + H? 610.1545, found 6101561. Anal.Called for C28H33Cl2N3? 6S .0.6 HCl.HO: C, 51.70; H, 5.52; N, 6.46; Cl, 14.17. Found: C, 51.28; H, 5.49; N, 6.50; Cl, 14.57 percent Water (KF): 2.72 Example 156 3- (3-tetrahydrofuranyl) acid ester [S- [R *, R *)] -4- [[[1- [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] methyl] -2-methoxy] -2-oxoethyl] amino] carbonyl ] -3-thiazolidinocarboxylic Scheme A, (Scheme A, A-7: where RA.X and RA_2 are equal and equal to proton, R3 is 3-tetrahydrofuranyl, Y is C02-, R5 is 4- [(2, 6 -dichlorobenzoyl) amino] phenyl and the stereochemistry is [S, S)).
Example 156 was prepared as described in Scheme A from D-cysteine using 3-hydroxytetrahydrofuran to form the required carbamate. The physical properties are as follows: mp 125-126.5 ° C. GO (mull) 3311, 1750, 1744, 1708, 1661, 1549, 1515, 1439, 1408, 1307, 1243, 1227, 1212, 1173, 1019 cm-1; XH NMR (300 MHz, CD30D) d 7.38 (3 H), 7.14 (2 H), 7.96 (2 H), 5.20 (1 H), 5.25 (2 H), 4.61 (4 H), 3.79 (4 H) , 3.74 (3 H), 3.19 (2 H), 2.84 (2 H), 2.29 (2 H); 13 C NMR (75 MHz, CDC13, complicated spectrum via the presence of diastereomers) d 171.7, 171.6, 158.1, 137.0, 132.1, 130.5, 130.4, 130.3, 128.5, 128.2, 115.1, 77.2, 77.2, 73.2, 67.0, 65.2, 63.1 , 63.0, 53.3, 52.5, 52.4, 36.9, 32.9; MS (ESI +) for C26H28C12N207S m / z 582.8 (M + H) *; Anal. Caled for C26H28C12N207S: C, 53.52; H, 4.84; N, 8.80. Found: C, 53.34; H, 4.87; N, 4.86.
Example 157 Acid [S- (R *, R *)] -2- [[[1-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -hexahydro- ? -oxo-1H-azepine-1-butanoic Example 157 was prepared as described by the preparation of Example 167. The physical properties are as follows: IR (mull) 1781, 1709, 1651, 1625, 1612, 1550, 1537, 1515, 1444, 1431, 1418, 1398, 1331, 1193, 798 crn "1; XH NMR (300 MHz, DMSO-dg) d 1.45 (8 H), 2.30 (4 H), 2.90 (3 H), 3.80 (1 H), 4.50 (2 H), 7.16 (2 H), 7.50 (5 H), 7.94 (1 H), 10.62 (1 H), 7.71 (1 H), MS (FAB) m / z (relative intensity) 578 (M + H, 43), 581 (9), 580 (29), 579 (19), 578 (43), 577 (10), 227 (11), 226 (99; 198 (18), 173 (9), 98 (46). 74 and Example 158 (Scheme N: N-6 where n is 2, m is 0, X is N, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is 25- (R *, R *)) 12S- (R *, R *) -2 - [[[1 - [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] azetidine (C21H21C12N304).
A solution of the product of example 142 (Scheme N: N-4 where n is 2, m is 0, X is N, Y is -C02-, R3 is (1,1-dimethyl) ethyl, R5 is 4- [ (2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry is (5) (512 milligrams, 0.93 mmol) in 1: 1 TFA / CH2C12 (10 milliliters) is stirred at room temperature for 1 hour. Concentrate under reduced pressure The residue is taken up in a mixture of CH2Cl2 and saturated aqueous NaHCO3 The aqueous phase 1 is extracted twice further with CH2C12 The combined CH2C12 portions are dried, filtered and concentrated to give a yellow oil (440 milligrams), which is purified by flash silica chromatography (95: 5 CH2Cl2 / Me0H) to yield the title compound (324 milligrams) as a white foam: mp 113-115 'C; TLC (95: 5 CH2Cl2 / MeOH) R £ = 0.10; [a] 25D -34 (c 0.96, MeOH); UV (MeOH) - u.224 (sh, e 12100), 251 (17700), 284 (sh, 2880); IR (mull mineral oil) 3260, 1744, 1664, 1606, 1561, 1537, 1515, 1431, 1414, 1323, 1270, 1223, 1195, 799, 782 cm "1; H NMR (CD3OD) d 7.61 (2 H), 7.50-7.38 (3 H), 7.25 (2 H) , 4. 86 (1 H), 4.75 (1 H), 4.21 (1 H), 3.73 (3 H), 3.61 (2 H), 3.39-3.28 (1 H), 3.23 (1 H), 3.05 (1 H), 2.63-2.50 (1 H), 2.21-2.08 (1 H); MS (+ ESI) m / z 480.0; MS (El) m / z 451, 449, 396, 394, 351, 349, 278, 211, 175, 173, 96, 70, 56; Anal. C 55.68, H 4.79, N 8.96, Cl 15.43 (caled for 1.08 percent H20: C 55.41, H 4.77, N 9.23, Cl 15.58).
Example 159 O- [(2,6-Dichlorophenyl) methyl] -N- [[(4S) -3- (methylsulfonyl) -4-thiazolidinyl] carbonyl] -L-tyrosinamide (Scheme C, C-10: wherein Rc - ?, c-2 / Rc-3 and Rc- «are equal and equal to the proton, R3 is methyl, Y is S02-, R5 is 4- [2,6-dichlorofenyl) methoxy] phenyl, and the stereochemistry is [H.H)) .
Example 159 was prepared as described in Scheme C using methanesulfonyl chloride to form the required sulfonamide. The physical properties are as follows: mp 228-230 ° C; XH RM? (300 MHz, DMSO-d6) d 8.03 (1 H), 7.54 (2 H), 7.44 (2 H), 7.14 (3 H), 6.92 (2 H), 5.16 (2 H), 4.69 (2 H) , 4.41 (1 H), 4.31 (1 H), 3.21 (1 H), 3.01 (3 H), 2.87 (3 H); 13C RM? (75 MHz, DMSO-d6) d 172.9, 169.1, 157.5, 136.5, 132.3, 132.0, 130.8, 130.6, 129.2, 114.6, 65.3, 64.4, 54.3, 52.0, 37.3, 35.0; MS (ESI-) for C2? H23Cl2? 3? 5S2 m / z 530.2; (MH) "; Anal.Called for C2? H23Cl2? 305S2: C 47.37, H 4.35,? 7.78. Found: C 47.43, H 4.46,? 7.81 Example 160 4-Ethyl ester of acid [S- (R *, R *)] -3- [[[1- [[4- [(2,6-Dichlorophenyl) methoxy] phenyl] -yl] -2-methoxy-2-oxoethyl] amino] carbonyl] -l-thia-4 -azaspiro [4, 4] nonane-4-carboxylic acid (Scheme B, B-6: where RB__ and RB.2 are equal and equal to H, RB_3 and RB_4 together form a carbocyclic ring of 5 atoms, RB.S is OCH3, Y is C02 / R3 is ethyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is (S, S)).
Example 160 was prepared as described in Scheme B. The physical properties are as follows: IR (mull) 1746, 1705, 1681, 1510, 1439, 1399, 1336, 1301, 1276, 1241, 1203, 1178, 1110, 769 crn "1;? NMR (CDC13) d 7.36 (2 H), 7.25 (1 H), 7.03 (2 H), 6.93 (2 H), 6.64 (1 H), 5.22 (2 H), 4.85 (2 H), 4.15 (2 H), 3.73 (3 H), 3.15"(4 H) , 2.69 (1 H), 2.48 (1 H), 1.76 (6 H), 1.23 (3 H); 13 C NMR (CDCl 3) d 171.5, 170.7, 158.0, 152. 5, 137.0, 132.0, 130.5, 130.3, 128.5, 128.2, 115.0, 66.4, 65.2, 61.9, 53.1, 52.4, 37.1, 32.3, 25.1, 24.6, 14.5; MS (ESI +) for C28H32C12N206S / z 594.9 (M + H) *; MS (ESI-) for C_8H3_C12N206S m / z 592.8 (M-H) "; Anal Caled for C28H32Cl2N2O6S.0.10 H20: C, 56.30; H, 5.43; N, 4.69.
Found: C, 56.20; H, 5.24; N, 4.69. percent Water (KF): 0.31. Example 161 [S- (R *, R *)] -3 - [[[1-Carboxy-2 - [4 - [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] carbonyl] -l-thia -4- azaspiro [4, 4] nonane-4-carboxylic acid ethyl ester 4 (Scheme B, B-7:.? where RB and RB_2 are identical and equal to H, and RB_4 RB_3 together form a carbocyclic ring 5 atoms, Y is C02, R3 is ethyl, R5 is 4- [(2,6-dichlorophenyl) methoxy] phenyl and the stereochemistry is [S, S)).
Example 161 was prepared from Example 160 by the procedure described in Preparation 6. The physical properties are as follows: IR (mull) 1737, 1708, 1675, 1612, 1511, 1439, 1402, 1338, 1301, 1241, 1197, 1179, 1115, 1018, 769 cm'1; XH NMR (DMSO-d6) d 8.07 (1 H), 7.54 (2 H), 7.45 (1 H), 7.12 (2 H), 6.94 (2 H), 5.15 (2 H), 4.63 (1 H), 4.33 (1 H), 3.91 (2 H), 3.05 (2 H), 2.79 (1 H), 2.60 (1 H), 1.60 (6 H), 1.07 (3 H); 13C NMR (DMSO-d6) d 172.7, 169.4, 157.1, 157.1, 155.7, 135.9, 131.6, 131.4, 130.3, 129.6, 128.7, 114.1, 83.9, 64.7, 60.5, 53.1, 38.0, 36.2, 31.8, 24.2, 24.1, 14.1; MS (ESI +) for C 27 H 30 Cl 2 N 2 O 6 S m / z 580.8 (M + H) *; MS (ESI-) for C 27 H 30 Cl 2 N 2 O 6 S m / z 578.8 (M-H) '; HRMS (El) caled for C27H3oCl2N206S 580.1202, found 580.1172; Anal. Caled for C27H30Cl2N2O6S.0.19 H20: C, 55.44; H, 5.24; N, 4.79.
Found: C, 55.24; H, 5.32; N, 4.79. percent Water (KF): 0.59.
Preparation 75 The amino ester product of preparation 75 is useful as a synthetic intermediate (e.g., reagent A-4 of Scheme A). To a cold solution (0-5 ° C) of anhydrous methanolic HCl was added 100 grams of L-4-nitrophenylalanine (Advanced Chem Tech) in portions over 15 minutes. The mechanically stirred mixture was heated at medium reflux for 48 hours. The mixture was allowed to cool and then filtered through a sintered glass filter funnel, the collected solids were washed with hot MeOH only until the insoluble residues remained. The filtrate was concentrated in vacuo to yield the methyl ester (120 grams) as a white waxy solid which was used without further purification. A suspension of methyl ester described above (87 grams, 0.33 mol) in CH2C12 (1500 milliliters) at room temperature was added di-t-butyldicarbonate (109 grams, 0.50 mol) followed by the dropwise addition of Et3N (51 milliliters, 0.37). mol). After 15 minutes additional Et3N (40 milliliters, 0.29 mol) was added to maintain a slightly basic mixture (approximately pH 8). The reaction mixture was stirred 18 hours and additional CH2C12 (1400 milliliters) and Et3N (15 milliliters, 0.11 mol) were added. After a further 2 hours the reaction mixture was quenched by slow addition of MeOH (100 milliliters), stirred for one hour and then partitioned between CH2C12 and cold 10 percent aqueous KHS04. The organic layer was washed with saturated NaHCO 3 and brine, dried (Na 2 SO 4), filtered and concentrated in vacuo. Flash chromatography of the residue using hexane and a gradient of a 1: 1 mixture of EtOAc / CH2Cl2) (25-33 percent) yielded the Boc-methyl ester (69 grams) as a white solid. The physical properties are the following: 1H NMR (300 MHz; CDCl 3) d 8.16 (2 H), 7.31 (2 H), 5.04 (1 H), 4.63 (1 H), 3.73 (3 H), 3.18 (2 H), 1.41 (9 H); MS (ES +) for C? 5 H20N2O6 m / z 325.2 (M + H) +. Palladium in carbon (10 weight / weight percent, 1. 25 grams) was added to a Parr hydrogenation flask under a nitrogen atmosphere and carefully moistened with 100 milliliters of MeOi / THF (1: 1). A solution of the Boc-methyl ester described above (25 grams, 77 mmol) in 400 milliliters of MeOH / THF (1: 1) was added and the mixture was shaken in a hydrogenation apparatus under a hydrogen atmosphere (1.4 kg / cm2). ) for 1 hour at room temperature. The reaction mixture was filtered through a celite pad and the solids were washed several times with MeOH. The combined filtrates were concentrated in vacuo to yield the 4-aminophenylalanyl derivative (22.7 grams) which was used without further purification. The physical properties are as follows: XH NMR (300 MHz, CDC13) d 6.89 (2 H), 6.61 (2 H), 4.96 (1 H), 4.50 (1 H), 3.69 (3 H), 2.95 (2 H), 1.41 (9 H); MS (ES +) for C? SH22N204 m / z 295.2 (M + H) +. A cold solution (0-5 ° C) of 2,6-dichlorobenzoyl chloride (11.1 milliliters, 11.5 mmol) in 125 milliliters of THF was treated dropwise with a solution of the 4-aminophenylalanyl derivative described above (22.7 grams). , 77.1 mmol) and Et3N (16 milliliters, 115 mmol) in 125 milliliters of THF. The reaction mixture was allowed to warm to room temperature and stirred an additional 18 hours. The mixture was diluted with EtOAc (2 liters) and then washed with IN HCl, H20, IN NaOH and brine. The organic extract was dried (Na2SO4), filtered, and concentrated in vacuo to give the crude product as a pale yellow solid. This material was recrystallized from acetone / hexanes (approximately 1: 1) to yield the amide (30.8 grams) as a crystalline solid. The physical properties are as follows: mp 192.2-193-l ° C; IR (mull) 3305, 1747, 1736, 1690, 1665, 1609, 1548, 1512, 1433, 1414, 1325, 1277, 1219, 1171, 781 cm "1; XH NMR (300 MHz; CDC13) d 7.57 (2 H ), 7.34 (4 H), 7.14 (2 H), 4.98 (1 H), 4.60 (1 H), 3.74 (3 H), 3.11 (2 H), 1.42 (9 H), MS (ES +) for C22H24C12N205 m / z 467.0 (M + H) +. To 650 milliliters of 4M anhydrous HCl in dioxane at room temperature the amide described above (30.6 grams, 65.5 mmol) was added in portions and the resulting mixture was stirred until the solids were dissolved (about 1 hour) The volatiles were removed in vacuo to give the light yellow solid which was divided between water (500 milliliters) and ether (1 liter) The water layer was separated and concentrated in vacuo in approximately 200 milliliters The aqueous solution was frozen and lyophilized to yield the amino ester product (25.6 grams) as a light yellow solid.The physical properties are as follows: [OI] 25D = +5 (c 1, MeOH); IR (mull) 3244, 3186, 3112, 174 7, 1660, 1604, 1562, 1539, 1516, 1431, 1416, 1327, 1273, 1243, 799 cm "1; XH NMR (300 MHz; CD30D) d 7.69 (2 H), 7.45 (3 H), 7.29 (2 H), 4.34 (1 H), 3.83 (3 H), 3.21 (2 H); 13 C NMR (300 MHz, CD 3 OD) d 169.0, 163.9, 137.8, 136.08, 131.8, 131.0, 130.3, 129.7, 127.9, 120.6, 53.8, 52.3, 35.4; MS (ES +) for C? 7H? 6Cl2N203 m / z 367.1 (M + H) *. Preparation 76 The amino ester product of preparation 75 is useful as a synthetic intermediate (e.g., reagent A-4 of Scheme A). To a cold solution (0-5 ° C) of anhydrous methanolic HCl (200 milliliters) was added 25 grams of N-a-t-Boc-O-2,6-dichlorobenzyl-L-tyrosine (Sigma) in portions over 15 minutes. After 30 minutes at 0-5 ° C, the mixture was heated at 50 ° C for 2 hours. The solution was cooled to room temperature and the volatiles were removed in vacuo. The solid was suspended in ethyl ether and collected by filtration to yield the title compound (21.4 grams) which was used without further purification. The physical properties are as follows: [] 25D = +16 (c 1.00, ethanol); XK NMR (300 MHz, CD30D) d 7.44 (2 H), 7.35 (1 H), 7.21 (2 H), 7.02 (2 H), 5.28 (2 H), 4.29 (1 H) 3.81 (3 H), 3.18 (2 H); MS (ES +) for C? 7H17Cl2N03 m / z 354.1 (M + H) *; Anal. Caled for C? 7H? 7Cl2N03.HCl: C, 52.26; H, 4.64; N, 3.59. Found: C, 52.17; H, 4.74; N, 3.61. EXAMPLE 162 1- [(1, 1-dimethyl) ethyl] ester of 2- [[[(S)) -1- [[4- [(2,6-Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy -2-oxoethyl] amino] carbonyl] -1-piperidinocarboxylic acid Example 162: The HCl gas was bubbled through a solution of N- (tert-butoxycarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (2.51 grams, 5.53 mmol) in MeOH (20 milliliters) for 10 minutes. The solution was stirred for an additional 2 hours at room temperature. The solvent was removed in vacuo and the excess HCl was removed by the addition of Et20 (3 x 15 milliliters) and evaporation under reduced pressure. The resulting gum was dissolved in THF (10 milliliters) and N-tert-butoxycarbonyl-pipecolinic acid (1.28 grams, 5.59 mmol), BOP reagent (2.69 grams, 6.09 mmol) and DIEA (2.9 milliliters, 16.6 mmol) were added and the The reaction mixture was stirred overnight. It was added (EtOAc (25 milliliters) and the mixture was extracted with IN HCl (20 milliliters) The organic phase was washed with saturated LiCl (20 milliliters) then with saturated NaHCO 3 (30 milliliters) .The organic layer was dried over Na 2 SO 4, Chromatography of the residue (silica gel, Hexanes-> 50 percent EtOAc / Hexanes gradient elution) gave Example 162 as a solid (1.45 grams, 45 percent): ESMS (m / z) 578.580 (MH *) Example 163 Acid 2 - [[[(lS) -l - [[4 - [(2,6 -Dichlorobenzoyl) amino] phenyl] methyl] -2-methoxy-2-oxoethyl] amino] carbonyl] -? -oxo-1-piperidinobutanoic The HCl gas was bubbled through MeOH (20 milliliters) in solution of Example 162 (1.27 grams, 2.20 mmol) for 10 minutes. Stirring was continued overnight at room temperature. The solvent was removed in vacuo and the excess HCl was removed by washing with Et20 (3 x 10 milliliters) on a vacuum filter. The HCl salt was dried completely under high vacuum to provide Compound 1 (1.09 grams, 97 percent) as a solid: ESMS (m / z) 578.580 (MH *). Example 163: Compound 1 (147 milligrams, 0.285 mml.) Was dissolved in DMF (5 milliliters) containing DIEA (150 μL, 0.88 mmol). To this solution was added succinic anhydride (59 milligrams, 0.59 mmol) and the mixture was stirred at 50 ° C for 5 hours under dry nitrogen. The solvent was evaporated and the residue was purified by column chromatography (silica gel, Hexanes-> EtOAc gradient elution) to provide Example 163 as a solid (164 milligrams): ESMS (m / z) 578.580 (MH * ). Examples 164-166 The following monomethyl esters were prepared in a manner similar to Example 163 Ex # R3 MS (m / z) 164 CW 646 HOOC- '° (MH +) 165 0 HOO w 62 C ^ ° (MHT) 166 HOOC' 574 ([M-H] -) Example 167 2- [[[(lS) -l-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -? - oxo-1-piperidinobutanoic acid Example 167 Example 163 (154 milligrams, 0.266 mmol) was treated with LiOH (26 milligrams, 1.07 mmol) in H20 (5 milliliters) for 3 hours. The product was then precipitated by the addition of 3 N HCl. The product was collected by vacuum filtration and washed with cold H20 (2 x 3 milliliters). Vacuum drying provided Example 167 as a solid (109 milligrams): ESMS (m / z) 562 ([M-H] ").
Example 168-170 The following compounds were prepared in a manner similar to 167.
Ej # R5 MS (m / z) 630 168 C xx? ° (IM-H) ") 169 w 604 ([M-H] -) 170? = R 560 ([M-H] -) Preparation 77 -u RrOP Merrifield resin Intermediary 1 P »Intermediary polymer-1: The binding of N-er-butoxycarbonyl- [4-.2,6-dichlorobenzoylamino)] -L-phenylalanine with Merrifield resin was made using Horiki's method (Horiki et al., Chem. Lett. 1978 (2) 165-168). In a 250 milliliter round bottom flask fitted with a drying tube, Merrifield resin (Biorad, 10.0 grams, 13.5 mmol / gram) and anhydrous potassium fluororide (Aldrich, 1.57 grams, 27.0 mmol) were added to a solution of N-tert-butoxycarbonyl- [4- (2,6-dichlorobenzoylamino)] - L-phenylalanine (Bachem California, 6.13 grams, 13.5 mmol) in dry DMF (100 milliliters). The reaction mixture was stirred at 80 ° C in an oil bath for 24 hours. The cooled resin was filtered and washed thoroughly with DMF (2 x 250 milliliters), 50 percent aqueous DMF (3 x 250 milliliters), methanol (3 x 250 milliliters), dichloromethane (3 x 250 milliliters), and finally methanol (3 x 250 milliliters). The resin was dried under reduced pressure to constant weight to give Intermediate-1. The incorporation of N-tert-butoxycarbonyl- [4- (2,6-dichlorobenzoylamino)] -L-phenylalanine into the resin was estimated to be 0.045 mmol / gram from the increase in resin mass. Example 171 JV- [[2 - (1,3-Benzodi-oxol-5-yl) -1-met-il-5-oxo-3-pyrrolidinyl] carbonyl] - 4 - [(2,6-dichlorobenzoyl) amino] - L-f enylalanine Example 171: Intermediary-1 (0.15 grams, 0.1065 mmol / gram) was pretreated with CH2C12 (2 x 3 milliliters). The swollen resin was deprotected with 50 percent TFA (CH2C12 (3 milliliters, 30 minutes). The resin was rinsed in the following order: CH2C12 (2 x 3 milliliters), CH30H (2 x 3 milliliters), CH2C12 (2 x 3 milliliters). The resin was swollen with DMF (2 x 3 milliliters), 2- (3,4-methylenedioxyphenyl) -l-methyl-5-oxo-3-pyrrolidine carboxylic acid (84 milligrams, 0.32 mmol) in DMF (1.0 milliliter). activated with 0.5 M HBTU / HOBT in DMF (0.7 milliliters) in DIEA (0.139 milliliters, 0.799 mmol), and then added to the swollen resin. The mixture was stirred for 2 hours at room temperature. The resin was filtered and washed in the following order: DMF (2 x 3 milliliters), CH2C12 (2 x 3 milliliters), CH3OH (2 x 3 milliliters), CH2C12 (2 x 3 milliliters), respectively. If a Kaiser test was positive on a small amount of the resin (blue) then the coupling procedure was repeated until a negative result was obtained. The resulting resin was dried in vacuo to constant weight. The resin was placed on the polypropylene column and pretreated with 3 milliliters of THF. Then the previously swollen resin 1.6 milliliters of THF, 0.48 milliliters of CH3OH, and 0.160 milliliters of 2N LiOH were added. The mixture was stirred for 15 minutes and filtered into a clean and previously weighed test tube. The resin was washed immediately with 2 milliliters of THF / 5 percent CH3OH (2 times) and the combined filtrates were evaporated. The resulting gum was dissolved in 1 milliliter of water. The solution was acidified with 1N HCl until pH 2.0. the precipitate was centrifuged, washed with water (5 milliliters, 2x) and dried under vacuum to yield 15.4 milligrams of Example 171 as a solid. ESMS (m / z) 596 ([M-H] ") Preparation 78 Intermediary-2F: N-tert-butoxycarbonyl- [4- (2,6-dichlorobenzoylamino)] -L-phenylalanine bound to the resin (Intermediary -1), (250 milligrams, 0.1125 mmol / gram) was placed in a 8.0 milliliter polypropylene filter column fitted with a 2-way polypropylene plug.
The resin was pretreated with CH2C12 (2 3 milliliters). The swollen resin was deprotected with 50 percent TFA / CH2Cl2 (3-4 milliliters, 30 minutes) with shaking. The resin was rinsed in the following order: CH2C12 (2 x 3 milliliters), CH3OH (2 x 3 milliliters), CH2C12 (2 x 3 milliliters). The resin swelled with DMF (2 x 3 milliliters). N-Ter-butoxycarbonyl-nipecotic acid (103 milligrams, 0.45 mmol) in DMF (1.0 milliliter) was activated with 0.5 M HBTU / HOB in DMF (0.910 milliliters) and DIEA (0.195 milliliters), then added to the swollen resin. The mixture was stirred for 2 hours at room temperature. The resin was washed in the following order: DMF (2 x 3 milliliters), CH2C12 (2 x 3 milliliters), CH3OH (2 x 3 milliliters), CH2C12 (2 x 3 milliliters) and dried (Intermediate-2F). If a Kaiser test is positive in a small amount of resin (blue) then repeat the coupling procedure until a negative result is obtained. Intermediary intermediary resins -2D, 2E, 2G, 2H, 21, 2 and 2K were produced following this procedure. EXAMPLE 172 Acid 5- [[(2S) -2- [[[(S)) -l-Carboxy-2- [4- [(2,6-di-cl-orobenzoyl) ami] -fl] ethyl] ami no] carboni l] - 1 piperidinyl] carbonyl] -3-pyridinecarboxylic Intermediary 2D Example 172 Example 172: The Intermediary-2D glued to the resin (2.0 grams, 1.3 mmol / gram) was pretreated with CH2C12 (2 x 20 milliliters). The swollen resin was deprotected with 50 percent TFA / CH2C12 (20 milliliters, 30 minutes). The resin was rinsed in the following order: CH2C12 (2 x 20 milliliters), CH30H (2 x 20 milliliters), CH2C12 (2 x 20 milliliters). The resin was swollen with DMF (2 x 20 milliliters) 3,5-pyridine dicarboxylic acid (652 milligrams, 3.9 mmol) in 20 milliliters of DMF was activated with 0.5 M HBTU / HOB in DMF (8.0 milliliters) and DIEA (1.7 milliliters, 9.75 mmol), then added to the swollen resin. The mixture was stirred for 2 hours at room temperature. The resin was filtered and washed in the following order: DMF (2 x 20 milliliters), CH2C12 (2 x 20 milliliters), CH30H (2 x 20 milliliters), CH2C12 (2 x 20 milliliters), respectively. If a Kaiser test (Kaiser et al., Anal. Biochem. 1970, 34, 594-598) on a small amount of resin is positive (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was then dried in vacuo to constant weight (2.2 grams). The resin was treated with 25 milliliters of liquid HF by stirring for 60 minutes at 0 ° C in an HF reaction apparatus (Peninsula Laboratories Inc., Belmont, CA). The HF was quickly evaporated by vacuum aspiration at 0 ° C. Then 100 milliliters of dry ethyl ether was added. The resin and the resulting precipitates were filtered and washed three times with 50 milliliters of ethyl ether, and dried in vacuo. The mixture was treated with 25 milliliters of IN NaOH (4x), and the combined solutions were lyophilized. The crude product was purified by HPLC using a C-18 column and a linear acetonitrile / 0.1 percent HCl gradient. The gradient ran from 60 percent solvent A (0.1 percent HC) to 80 percent solvent B (80 percent acetonitrile at 0.1 percent HCl) in 20 minutes. Lyophilization yielded 20 milligrams (2.5 percent of Example 172, ESMS (m / z): 612 ([M-H] ") Examples 173-267 Method-A (Example 173) 4- [(2,6-Dichlorobenzoyl) amino] -N- [[1- (3-methoxy-1-oxopropyl) -3-pyrrolidinyl] carbonyl] -L-phenylalanine Example 173 Intermediary-2F (0.25 grams, 0.1125 mmol / g) was pretreated with CH2C12 (2 x 3 milliliters). The swollen resin was deprotected with 50 percent TFA / CH2C12 (3 milliliters, 30 minutes). The resin was rinsed in the following order: CH2C12 (2 x 3 milliliters), CH30H (2 x 3 milliliters), CH2C12 (2 x 3 milliliters). The resin was swollen with DMF (2 x 3 milliliters). 3-methoxypropionic acid (53 milligrams, 0.45 mmol) in DMF (1.0 milliliter) was activated with 0.5 M HBTU / HOBT in DMF (0.910 milliliters) and DIEA (0.195 milliliters), then added to the swollen resin. The mixture was rotated for 2 hours at room temperature. The resin was filtered and washed in the following order: DMF (2 x 3 milliliters), CH2C12 (2 x 3 milliliters), CH30H (2 x 3 milliliters), CH2C12 (2 x 3 milliliters), respectively. If a Kaiser test is positive in a small amount of resin (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was dried in vacuo to constant weight. The resin was placed on a polypropylene column and pretreated with THF (3 milliliters). Then THF (3.5 milliliters), CH30H (1.0 milliliter) and 2N LiOH (0.175 milliliters) were added. The mixture was rotated for 15 minutes and filtered into a previously weighed and clean test tube. The resin was then washed with THF / 5 percent CH30H (2 milliliters) and the combined filtrates were evaporated. The resulting gum was dissolved in H20 (1 milliliter). The solution was acidified with IN HCl to pH 2.0. The precipitate was centrifuged, washed with water (2 x 5 milliliters) and dried under vacuum to yield 38.3 milligrams of Example 173 as a solid: ESMS (m / z): 548 ([MH] ") Method B (Example 174): 3- [[[(SS) -l-Carboxy-2- [4- [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] -? - oxo-1-piperidinobutanoic acid Intermediary-2F (0.25 grams, 0.1125 mmol / g) was pretreated with CH2C12 (2 x 3 milliliters). The swollen resin was deprotected with 50 percent TFA / CH2C12 (3 milliliters, 30 minutes). The resin was rinsed in the following order: CH2C12 (2 x 3 milliliters), CH30H (2 x 3 milliliters), CH2C12 (2 x 3 milliliters). The resin was then swelled with DMF (3 milliliters). Succinic anhydride (45 milligrams, 0.45 mmol) was dissolved in DMF (4 milliliters) was added to the swollen resin and stirred at 50 ° C for 2 hours. The resin was filtered and washed in the following order: DMF (2 x 3 milliliters), CH2Cl2 (2 x 3 milliliters), CH30H (2 x 3 milliliters), CH2C12 (2 3 milliliters), respectively. If a Kaiser test is positive in a small amount of resin (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was dried in vacuo to constant weight. The resin was placed on a polypropylene column and pretreated with THF (3 milliliters). Then to the swollen resin were added THF (3.5 milliliters), CH3OH (1.0 milliliter) and 2N LiOH (0.175 milliliters). The mixture was rotated for 15 minutes and filtered into a previously weighed and clean test tube. The resin was then washed with THF / 5 percent CH3OH (2 x 2 milliliters) and the combined filtrates were evaporated. The resulting gum was dissolved in H20 (1 milliliter). The solution was acidified with IN HCl to pH 2.0. The precipitate was centrifuged, washed with H20 (2 x 5 milliliters) and dried under vacuum to yield 30.5 milligrams of Example 174 as a solid: ESMS (m / z): 562 ([M-H] ").
Method C (Example 175): N- [[1- [[(4-Carboxyphenyl) amino] carbonyl] -4-piperidinyl] carbonyl] -4 - [(2,6-dichlorobenzoyl) amino] -L-phenylalanine Example 175 Intermediary-2G (0.25 grams, 0.1125 mmol / g) was pretreated with CH2C12 (2 x 3 milliliters). The swollen resin was deprotected with 50 percent TFA / CH2C12 (3 milliliters, 30 minutes). The resin was washed in the following order: CH2C12 (2 x 3 milliliters), CH3OH (2 x 3 milliliters), CH2C12 (2 x 3 milliliters). The resin was swollen with DMF (30 milliliters). Ethyl-4-isocyanatobenzoate (22 milligrams, 0.108 mmol) was dissolved in DMF (3 milliliters) and DIEA (47 μL, 0.27 mmol) was added to the swollen resin. This reaction mixture was rotated for 6-8 hours at room temperature. The resin was filtered and washed in the following order: DMF (2 x 3 milliliters), CH2Cl2 (2 3 milliliters), CH30H (2 x 3 milliliters), CH2C12 (2 x 3 milliliters), respectively. If a Kaiser test is positive in a small amount of resin (blue) then repeat the coupling procedure until a negative result is obtained. The resulting resin was dried under vacuum until constant. The resin was placed on a polypropylene column and pretreated with THF (3 milliliters). Then THF (3.5 milliliters), CH3OH (1.0 milliliter) and 2N LiOH (0.175 milliliters) were added respectively. The mixture was rotated for 15 minutes and filtered into a previously weighed and clean test tube. The resin was then washed with THF / 5 percent CH3OH (2 milliliters) and the combined filtrates were evaporated. The resulting gum was dissolved in H20 (1 milliliter). The solution was acidified with IN HCl to pH 2.0. The precipitate was centrifuged, washed with water (2 x 5 milliliters) and dried under vacuum to yield 38.3 milligrams of Example 183 as a solid: ESMS (m / z): 625 ([M-H] -). Examples 176-266 The following compounds were prepared in a manner similar to that described above.
Ej # Method Q X, MS (m / z) B or ^ ([MH] -) 560 13 -O-t0 A ([MH] -) or 560 4 -Of A ([MH] -) -OK 548 ([MH] -) Example 267 Acid 5- [[ [(1S) -l-Carboxi-2- [4 [(2,6-dichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] tetrahydro-β-oxo-1,4-thiazopine-4 [5H] -butanoic acid Intermediary-1 (0.3 grams, 0.195 mmol / g) was pretreated with CH2C12 (2 x 3 milliliters). The swollen resin was deprotected with 50 percent TFA / CH2C12 (3 milliliters, 30 minutes). The resin was rinsed in the following order: CH2C12 (2 x 3 milliliters), CH3OH (2 x 3 milliliters), CH2C12 (2 x 3 milliliters). The resin was swollen with DMF (2 x 3 milliliters). N-Ter-butoxycarbonyl-1,4-thiazoline-5-carboxylic acid (204 milligrams, 0.78 mmol) in DMF (2.0 milliliters) was activated with 0.5 M HBTU / HOBT in DMF (1.6 milliliters) and DIEA (0.340 milliliters, 1.95 mmol), then added to the swollen resin. 311 Scheme O Wang resin 0-6 312 Scheme O (continued) « 313 Where: _ * _._-. it is defined as R12; R0_2 is defined as alkyl having from 1 to 6 carbon atoms or arylalkyl having from 7 to 17 carbon atoms; R0-3 / Rc -. # Y Ro-s. they are independently defined as Rx. Ro_6 is defined as R2. Yj and Y2 are independently defined as Y. Scheme O describes a method for the preparation of the examples of the formula 0-9 and 0-12. The commercially available Wang resin (O-l) is acylated with commercially available N-c_-Fmoc-Phe (? 02) -OH (0-2) under normal conditions to provide the resin of formula 0-3. The reduction of the aromatic nitro group (Meyer et al., Mol. Diversi ty 1995, 1, 13-20) produces the aniline bound to the resin (0-4) which can be reacted with a variety of electrophilic reagents to produce the amides bound with resin (0-5 where Y1 is C (= 0)), ureas (0-5 where Y-, is C (= 0)? H), sulfonamides (0-5 where Ya is S02), and carbamates (0-5 where Y? is C (= 0) 0). Removal of the Fmoc group under standard conditions provides amine of general structure 0-6 which is acylated using standard solid phase peptide synthesis conditions (Atherton, E., - Sheppard RC Solid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989) with an easily prepared or commercially available thiazolidine-4-carboxylic acid of general formula 0-7 to produce the intermediate bound to the 0-8 resin. Gentle dissociation under standard conditions 314 (Atherton, E., Sheppard R.C. Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press: Oxford, 1989) produces the acid of general structure 0-9. In those cases where R0-2 is the 9-fluorenylmethyl group, removal of the standard Fmoc group produces the amine of general structure O-10, which can be reacted with a variety of electrophilic reagents as described in Scheme A to produce the amides, ureas, sulphonamides and carbamates attached to the resin of general structure O-ll. Mild dissociation under standard conditions produces acid of general structure 0-12. Preparation 79 and Example 268 3-Ethyl ester (45) -4- [[[(SS) -l-Carboxy-2- [4 [(benzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid To a Wang resin mix (1 percent DVB, Advanced Chemtech, 2.75 grams, 2.20 mmol based on the manufacturer's loading of 0.8 mmol / grams resin) in DMF (12 milliliters) was added N- -Fmoc-Phe (? 02) -OH, 0-2 (Advanced Chemtech, 1.90 grams, 4.40 mmol) at room temperature. After mixing for 10 minutes (passing a slow stream of nitrogen through the mixture), pyridine (587 μL, 7.26 mmol) and 2,6-dichlorobenzoyl chloride (630 μL, 4.40 mmol) were added. The mixture was stirred overnight by bubbling with nitrogen, filtered, washed with DMF, methylene chloride and methanol and dried in vacuo. In order to cap any unreacted hydroxymethyl group, the resin was suspended in dichloroethane (5 milliliters) and to this mixture was added benzoyl chloride (0.75 milliliters) and pyridine (0.75 milliliters). The mixture was stirred for 2 hours, filtered, washed with DMF, methylene chloride, methanol, methylene chloride, and methanol, and dried under vacuum to yield the resin 0-3 (3.30 grams). IR (diamond anvil) 1733, 1606 (resin), 1520 (resin), 1494 (resin, 1452 (resin), 1347, 1247, 1174, 1029 was "1. To the prewashed resin (2 x 20 milliliters DMF) resin 0-3 (1.0 gram, approximately 0.6 mmol based on an adjusted load of 0.6 mmol / gram) is added SnCl2.2 H20 (6 milliliters of a 2M solution in DMF, 12 mmol) The viscous suspension was stirred for 4 hours by bubbling under nitrogen, filtered and washed with DMF, (2 x 20 milliliters) The resin was resuspended with SnCl2.2 H20 (6 milliliters of a 2M solution in DMF, 12 mmol), stirred overnight via bubbling through nitrogen, filtered, washed extensively with DMF, water, 2-propanol, methylene chloride and methanol and dried in vacuo to yield resin 0-4 Examination of the FTIR spectrum of a small sample of resin 0-4 failed in exhibiting an absorption at 316 1347 cm "1. To a mixture of pre-washed 0-4 resin (2 x 20 milliliters CH2C12) (0.30 grams, approximately 0.18 mmol based on a at adjusted load of 0.6 mmol / gram) in 1,2-dichloroethane (3 milliliters) is added benzoyl chloride (174 μL, 1.50 mmol) and DIEA (313 μL, 1.80 mmol). The mixture was stirred overnight via bubbling in nitrogen, filtered, washed with methylene chloride, DMF, methanol, and methylene chloride and dried in vacuo to yield the 0-5 resin. To a mixture of 0-5 resin in methylene chloride (5 milliliters) was added a solution of piperidine in DMF (30 percent, 5 milliliters). A slow stream of nitrogen was bubbled through the mixture to effect mixing for 20 minutes. The resin was filtered, washed with DMF and resuspended in a solution of piperidine in DMF (30 percent, 10 milliliters). After gentle mixing for 40 minutes, the resin was filtered and washed with DMF, methylene chloride, methanol and methylene chloride and diluted with DMF (40 milliliters). To this mixture was added i 7 '-ethoxycarbonyl-D-thiazolidine-4-carboxylic acid (0-7), 0.15 grams, 0.72 mmol), HOBt (0.11 grams, 0.72 mmol), pYBOP (0.37 grams, 0.72 mmol) and DIEA (313 μL, 1.80 mmol). The reaction was mixed for 4 hours in which the point at which the qualitative Kaiser test was negative. The resin was filtered and washed with DMF, methylene chloride and MeOH and dried under vacuum to yield the 0-8 resin. After 317 swelling with a minimum of methylene chloride (approximately 0.5 milliliters), the 0-8 resin was resuspended with 95 percent aqueous TFA (5 milliliters). The mixture was mixed by magnetic stirring for 1 hour, filtered and washed with TFA (2 x 3 milliliters) and methylene chloride. The combined filtrates were evaporated in vacuo to yield a residue that was purified by flash chromatography using methylene chloride / methanol (2 percent) containing glacial acetic acid (0.1 percent) as eluent to produce the title compound (80 milligrams) . Freeze drying from glacial acetic acid produced an amorphous powder: IR (Drift) 3311, 3298, 1670, 1601, 1579, 1531, 1487, 1412, 1380, 1345, 1324, 1265, 1205, 1190, 709 crn "1;? NMR (300 MHz, DMS0-d6) d 10.39 (1 H), 8.39 (1 H), 8.14 (2 H), 7.86 (2 H), 7.74 (3 H), 7.36 (2 H), 4.83 (2 H), 4.59 (1 H), 4.48 (1 H), 4.22 (2 H), 3. 48 (2 H), 3.26 (1 H), 3.06 (2 H), 1.35 (3 H); 13 C NMR (75 MHz, DMSO-d 6) 5 173.4, 169.8, 165.8, 154.0, 138.0, 135.4, 133.3, 131.9, 129.8, 128.8, 128.0, 120.4, 61.8, 54.2, 48.8, 36.7, 14.8; MS (ESI +) for C23H25N306S m / z 472.0 (M + H) +; MS (ESI-) for C23H25N306S m / z 470.1 (MH) s MS (FAB) m / z (relative intensity) 472 (MH +, 99), 472 (99), 371 (31), 160 (31), 81 ( 31), 71 (45), 69 (46), 57 (71), 55 (58), 43 (47), 41 (42); HRMS (FAB) caled for C23H25N306S + H-_ 472.1542, found 472.1563; Anal. Caled for C23H2sN306S .1.5 H20: C, 55.41; H, 5.66; N, 8.43. Found: C, 55.47; H, 5.21; N, 8.00 318 Example 269 (45) -4- [[[(15) -l-Carboxy-2- [4 [(acetyl) amino] phenyl] ethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid ethyl ester The title compound was prepared as described in Scheme 0 using acetyl chloride to form the required amide. The physical data are as follows: IR (Drift) 3311, 1709, 1667, 1602, 1536, 1517, 1412, 1378, 1344, 1321, 1266, 1218, 1185, 1185, 1116, 769 cprS XH NMR (300 MHz, DMSO -d6) d 9.79 (1 H), 8.15 (1 H), 7.37 (2 H), 7.02 (2 H), 4.54 (2 H), 4.31 (1 H), 4.19 (1 H), 3.95 (2 H) ), 3.12 (1 H), 2.93 (1 H), 2. 75 (2 H), 1.82 (3 H), 1.09 (3 H); 13 C NMR (75 MHz, DMSO-d 6) d 173.2, 169.8, 168.5, 154.0, 138.2, 132.4, 129.8, 119.1, 62.1, 61.7, 53.9, 36.7, 24.4, 21.5, 14.8; MS (ESI +) for C18H23N306S m / z 410.0 (M + H) *; MS (ESI-) for C18H23N306S m / z 408.0 (M-H) S MS (FAB) m / z (relative intensity) 410 (MH +, 99), 486 (20), 411 (22), 410 (99), 409 (9), 205 (22), 188 (9), 177 (9), 160 (35), 148 (9), 88 (14); HRMS (FAB) caled for C18H23N306S + H_ 410.1385, found 410.1379; Anal. Caled for C18H23N306S .0.3 H20: C, 52. eleven; H, 5.73; N, "10.13, Found: C, 51.73; H, 5.73; N, 9.82. 319 Example 270 Ester 3 -amethyl acid (45) -4 - [[[(15) -l -Carboxi -2 - [4 [(3-f-enylpropanoyl) amino] f-enyl] -ethyl] -amino] carbonyl ] - 3-iazole idinocarboxylic The title compound was prepared as described in Scheme O using hydroccinmoyl chloride to form the required amide. The physical data is as follows: IR (drift) 3311, 2978, 2930, 1665, 1601, 1534, 1517, 1413, 1379, 1344, 1252, 1216, 1187, 1115, 700 cp.-1; XH NMR (300 MHz, CDC13 / CD30D (10 percent)) d 7.34 (2 H), 7.21 (5 H), 7.02 (2 H), 4.67 (3 H), 4.30 (1 H), 4.09 (2 H), 3.11 (4 H) ), 2.97 (2 H), 2.58 (2 H), 1.19 (3 H); 13 C NMR (75 MHz, CDCl 3) d 172.7, 171.3, 170.0, 154.8, 140.7, 137.0, 131.6, 129.7, 128.4, 128.2, 126.2, 119.9, 63.0, 62.6, 53.1, 38.9, 36.7, 31.5, 29.6, 14.2; MS (ESI +) for C25H29N3OsS m / z 500.2 (M + H) *; MS (ESI-) for C25H29N306S m / z 498.3 (M-H) -; Anal. Caled for C25H29N306S: C, 60.10; H, 5.85; N, 8.41. Found: C, 59.85; H, 6.07; N, 8.09. EXAMPLE 271 3-ethyl ester of (45) -4- [[[(15) -l-Carboxy-2- [4 [(3-pyridinylcarbonyl) amino] phenyl] ethyl] amino] carbonyl] -3- 320 aliazole idinocarboxí lico The title compound was prepared as described in Scheme O using nicotinoyl chloride to form the required amide. The physical data are as follows: IR (drift) 3301, 3061, 2983, 2935, 1709, 1675, 1603, 1535, 1517, 1415, 1380, 1345, 1326, 1204, 1140 cm-1; ? NMR (300 MHz, DMSO-d d 12.74 (1 H), 10.42 (1 H), 9.11 (1 H), 8.76 (1 H), 8.29 (2 H), 7.67 (2 H), 7.55 (1 H) , 7.19 (2 H), 4.62 (2 H), 4.44 (1 H) 4.29 (1 H), 4.05 (2 H), 3.24 (1 H), 3.04 (1 H), 2.88 (2 H), 1.15 ( 3 H), 13 C NMR (75 MHz, DMSO-d 6) d 173.1, 170.0, 164.3, 154.0, 152. 4, 149.0, 137.7, 135.9, 133.5, 131.1, 129.8, 123.9, 120.5, 62.4, 61.8, 53.8, 36.7, 14.8; MS (ESI +) for C22H24N4OsS m / z 473.3 (M + H) *; MS (ESI-) for C22H24N406S m / z All .3 (M-H) '; HRMS (FAB) caled for C22H24N406S + H2 473.1494, found 473.1509 Example 272 3-Ethyl ester of (45) -4- [[[(15) -l-Carboxi-2- [4 [(4-methoxybenzoyl) amino]] phenyl] ethyl] amino] carbonyl] - 3-thiazole idinocarboxylic 321 The title compound was prepared as described in Scheme O using p-anisoyl chloride to form the required amide. The physical data are as follows: IR (drift) 1709, 1667, 1604, 1532, 1514, 1439, 1412, 1379, 1343, 1323, 1255, 1221, 1178, 1027, 763 cm "1; XH NMR (300 MHz, CDCl3 / CD3OD (10 percent)) d 7.79 (2 H), 7.47 (2 H), 7.05 (2 H), 6.87 (2 H), 4.68 (2 H), 4.58 (1 H), 4.28 (1 H), 4.07 (2 H), 3.79 (3 H), 3.66 (2 H), 3.04 (4 H), 1.17 (3 H); 13 C NMR (75 MHz, CDCl 3) d 177.9, 174.0, 170.1, 166.3, 158.8, 141.1, 135.8, 141.1, 135.8, 133.7, 133.0, 130.8, 124.6, 117.7, 66.9, 66.6, 59.3, 40.7, 33.5, 24.5, 18.2; MS (ESI +) for C 24 H 27 N 307 S m / z 502.0 (M + H) +; MS (ESI-) for C24H27N307S m / z 500.1 (M-H) "; MS (FAB) m / z (relative intensity) 502 (MH ', 52), 503 (17), 502 (52), 297 (12), 240 (12), 160 (21), 135 (99), 88 (12), 73 (20), 69 (13), 57 (12); HRMS (FAB) caled for C24H27N307S + H_502.1648, found 502.1657. Anal. Caled for C24H27N307S .0.3 H20; C, 56. 86; H, 5.49; N, 8.29. Found: C, 56.65; H, 5.34; N, 7.92. EXAMPLE 273 3-Ethyl Ester of (45) -4- [[[(15) -1-Carboxy-2 - [4 [(4-methylbenzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-322-azole idinocarboxí lico The title compound was prepared as described in Scheme O using p-tolouyl chloride to form the required amide. The physical data are as follows: IR (drift) 3310, 2981, 2929, 1671, 1608, 1599, 1531, 1517, 1413, 1379, 1344, 1324, 1265, 1210, 1188 cm "1;? NMR (300 MHz, DMSO-d6) d 10. 10 (1 H), 8.24 (1 H), 7.85 (2 H), 7.67 (2 H), 7.33 (2 H), 7.17 (2 H), 4.62 (2 H), 4.41 (1 H), 3.28 ( 2 H), 4.02 (2 H) 3.23 (1 H), 3.04 (1 H), 2.87 (2 H), 2.38 (3 H), 1.15 (3 H); 1 C NMR (75 MHz, DMSO-d6) d 173.2, 169.8, 165.6, 154.0, 141.9, 138.1, 133.1, 132.5, 129.7, 129.7, 128.1, 120.4, 62.4, 61.8, 54.0, 36. 7, 21.4, 14.8; MS (ESI +) for C 24 H 27 N 306 S m / z 486.2 (M + H) +; HRMS (FAB) caled for C24H27N306S + HX 486.1699, found 486.1713. Anal. Caled for C24H27N306S .0.3 H20; C, 58.71; H, 5.67; N, 8.56. Found: C, 58.37; H, 5.67; N, 8.35. EXAMPLE 274 (45) -4- [[[(15) -l-Carboxi-2- [4 [[2- (trifluoromethyl) benzoyl) amino] phenyl] ethyl] amino] carbonyl] -3-ethyl ester -thiazolidinocarboxylic acid 323 The title compound was prepared as described in Scheme O using (2-trifluoromethyl) benzoyl chloride to form the required amide. The physical data are as follows: IR (drift) 3295, 1709, 1663, 1603, 1533, 1518, 1414, 1380, 1344, 1316, 1269, 1176, 1132, 1108, 769 cm'1; X H NMR (300 MHz, DMSO-d 6) d 10.48 (1 H), 8.23 (1 H), 7.77 (2 H), 7.58 (2 H), 7.17 (2 H), 4.64 (2 H), 4.44 (1 H), 4.29 (1 H), 3.99 (2 H), 3.24 (1 H) 3.05 (2 H), 1.09 (3 H); 13 C NMR (75 MHz, DMSO-d 6) d 173.2, 169.2, 165.8, 154.1, 137.8, 136.7, 133.0, 130.4, 129.9, 128.9, 126.7, 126.4, 126.0, 119.8, 62.2, 61.8, 54.0, 37.1, 14.7; MS (ESI +) for C24H26F3N306S m / z 540.0 (M + H) and-MS (ESI-) for C24H25F3N306S m / z 538.1 (M-H) s HRMS (FAB) caled for C24H2SF3N306S + Hj 540.1416, found 540.1423. Anal. Caled for C24H25F3N306S .0.5 H20; C, 51.49; H, 4.70; N, 7.83.
Found: C, 51.42; H, 4.42; N, 7.45. EXAMPLE 275 (45) -4- [[[(15) -l-Carboxy-2- [4 [(2, 4, 6- (trichlorobenzoyl) amino] phenyl] ethyl] amino] carbonyl] 3-ethyl ester -3-thiazolidinocarboxylic acid 324 The title compound was prepared as described in Scheme O using 2,4,6-trichlorobenzoyl chloride to form the required amide. The physical data is as follows: IR (drift) 3286, 2926, 1709, 1664, 1604, 1578, 1542, 1517, 1413, 1379, 1345, 1325, 1269, 1218, 1187 crn "1; H NMR (300 MHz, CDC13 / CD30D (10 percent)) d 7.58 (2 H), 7.41 (2 H), 7.20 (2 H), 4.84 (2 H), 4.69 (1 H), 4.41 (1 H), 4.19 (2 H), 3.27 (4 H), 1.26 (3 H); 13 C NMR (75 MHz, DMSO-d 6) d 173.0, 169.8, 161.5, 154.0, 137.2, 135.9, 135.1, 133.9, 132.6, 130.1, 128.5, 119.6, 62.2, 61.7, 54.0, 36.7, 14.8; MS (FAB) m / z (relative intensity) 574 (MH \ 95), 576 (96), 574 (95), 160 (99), 91 (79), 88 (40), 69 (64), 57 (59), 55 (59), 43 (56), 41 (39); HRMS (FAB) for caled for C23H22C13N306S + RX 574.0373, found 574. 0364. Anal. Caled for C23H22C13N306S: C, 48.06; H, 3.86; N, 7.31, Cl, 18.50. Found: C, 48.52; H, 4.13; N, 7.08. EXAMPLE 276 3-e-ethyl ester of (45) -4- [[[(15) -l-Carboxi-2- [4 [[(2,5-dichlorophenyl) sulfonyl] amino] phenyl] ethyl] amino] carbonyl] -3- idiocarboxylic iazol 325 The title compound was prepared as described in Scheme O using 2,5-dichlorobenzene sulfonyl chloride to form the required sulfonamide. The physical data are as follows: IR (drift) 1709, 1676, 1531, 1512, 1450, 1428, 1409, 1378, 1344, 1221, 1167, 1143, 1113, 1101, 1041 cm'1; 2 H NMR (300 MHz, DMSO-d 6) d 8.36 (1 H), 7.90 (3 H), 7.20 (2 H), 7.12 (2 H), 4.70 (2 H), 4.47 (1 H), 4.34 (1 H), H), 4.10 (2 H), 3.19 (4 H), 1.27 (3 H); 13 C NMR (75 MHz, DMSO-d 6) d 173.0, 169.8, 153.9, 138.7, 135.5, 134.8, 134.1, 132.6, 131.0, 130.5, 130.0, 120.0, 62.4, 61.7, 53.5, 36.3, 14.8; MS (FAB) m / z (relative intensity) 576 (MHy 99), 652 (27), 578 (83), 477 (31), 576 (99), 160 (98), 106 (47), 88 (40), 81 (32), 69 (31), 57 (28); HRMS (FAB) for caled for C22H23C12N307S2 + HX 576.0433, found 576.0400. Anal. Caled for C22H23C12N307S2.0.1 H20: C, 45.70; H, 4.04; N, 7.27. Found: C, 45.94; H, 4.04; N, 6.87. EXAMPLE 277 3-ethyl ester of (45) -4- [[[(15) -l-Carboxi-2- [4 [[(2,6-dichlorophenyl) amino] carbonyl] amino] phenyl] ethyl] amino ester ] carbonyl] -3-thiazolidinocarboxylic acid 326 The title compound was prepared as described in Scheme O using 2,6-dichlorophenyl isocyanate to form the required urea. The physical data are as follows: IR (drift), 3284, 3277, 1709, 1655, 1600, 1569, 1544, 1452, 1431, 1415, 1347, 1238, 1217, 1195, 771 cm "1;? RMN (300 MHz , DMSO-d6) d 9.09 (1 H), 8.41 (1 H), 8.09 (1 H), 7.52 (2 H), 7.31 (3 H), 7.08 (2 H), 4.62 (2 H), 4.35 ( 1 H), 4.28 (1 H), 3.27 (1 H), 3.02 (1 H), 2.85 (2 H), 1.10 (3 H), 13 C NMR (75 MHz, DMSO-d 6) d 173.6, 169.8, 154.0 , 152.8, 138.7, 134.4, 133.9, 131.3, 130.0, 128.8, 128.7, 118.1, 62.4, 61.8, 54.3, 36.7, 14.8; HRMS (FAB) caled for C23H24C12N406S + HX 555.0872, found 555.0877.
Anal. Caled for C23H24C12N406S .2 H20: C, 46.71; H, 4.77; N, 9.47. Found: C, 47.08; H, 4.53; N, 9.06. 327 Scheme P Wang Resin 3-28 Scheme P (continued) p-12 329 Where: RP.X is defined as R12; RP_2 is defined as alkyl having from 1 to 6 carbon atoms or arylalkyl having from 7 to 17 carbon atoms; Rp-3 Rp-, and Rp-s are independently defined as R_. RP_6 is defined as R2. Scheme P describes a method for the preparation of the examples of the formula P-9 and P-12. The commercially available Wang resin (P-1) is acylated with commercially available N-c.-Fmoc-Phe (I) -OH (P-2) under standard conditions to provide the resin of formula P-3. The carbonylation of the aryl iodide bonded to the resin with carbon monoxide and an amine in the presence of a palladium (0) source produces the resin-bound amide of general formula P-5 (for a general review of the carbonylation chemistry, see Colquhoun, HM, Thompson, DJ, Twigg, MV Carbonilation Plenum Press:? ew York, 1991). The gentle dissociation under standard conditions produces the amino acid of general structure P-5 which is esterified under mild acid catalyst to produce the amino ester of general structure P-6. Condensation with an easily prepared or commercially available thiazolidine-4-carboxylic acid of general formula P-7 under conditions described in Scheme A yields the pseudodipeptide of general structure P-8. The soft base hydrolysis of the ester of general structure P-8 produces the acid of general structure P-9. In the case where RP_2 is the 9-fluorenylmethyl group, the removal of the standard Fmoc group 330 (Atherton, E., Sheppard R.C.Eolid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989) produces the amine of general structure P-10, which can be reacted with a variety of electrophilic reagents as described in Scheme A to produce the amides, ureas, sulfonamides and carbamates of general structure P-ll. The low soft base hydrolysis of the ester of the general structure P-ll produces the acid of general structure P-12. Preparation 80 and Example 278 3-Methyl ester of (45) -4- [[[(15) -l-Carboxi-2- [4 [[(2,4,6-trichlorophenyl) amino] carbonyl] phenyl] ethyl ester ] amino] carbonyl] -3-thiazolidinocarboxylic acid To a cooled mixture (0-5 ° C) of polystyrene resin from Wang Pl (Advanced Chemtech, 2.0 grams, approximately 5.0 mmol) was added N-Boc-4-iodo-L-phenylalanine, P-2 (Bachem, 4.00 grams, 10 mmol) and PPh3 (1.30 g, 5.0 mmol) in THF (20 milliliters) was added diethyl azodicarboxylate (0.80 milliliters, 5.0 mmol) in 4 approximately equal portions at 5 minute intervals. When the orange color was discharged, the mixture was heated to room temperature and stirred for 5 hours. The mixture was diluted with THF (30 milliliters) and filtered. The resin was washed with DMF, THF and MeOH and dried in vacuo to yield the esterified P-3 resin (2.68 grams) as a colorless powder: 13 C NMR (100 MHz, CD2C12, 4 mm MAS probe) d 171.86, 155.33, 137.85, 136.40, 131.87, 128.00, 92.74, 80.09, 54.05, 38.05, 28.51. Nitrogen was bubbled through a mixture of N-Boc-4-iodo-L-phenylalanine functionalized with Wang P-3 resin (500 milligrams, approximately 0.3 mmol), PPh3 (0.21 grams, 0. 8 mmol), 2, 4, 6-trichloroaniline (0.98 grams, 5.0 mmol) and DIEA (3.48 milliliters, 20 mmol) in? MP (20 milliliters) for 10 minutes. Pd2dba3 (0.18 grams, 0.2 mmol) was added and the reaction mixture was placed under a CO atmosphere and heated (bath temperature 70 ° C) for 18 hours. After cooling to room temperature, the mixture was diluted with 3 percent (weight / volume) of sodium diethyldithiocarbamate in 95: 5? MP: DIEA (10 milliliters). After an additional 10 minutes, the mixture was filtered and the resin was washed with? MP, THF and MeOH and dried in vacuo to yield the functionalized resin P-4 as a colorless powder. Resin P-4 was swelled with methylene chloride (0.5 milliliters) and diluted with 95: 5 TFA: H20 (10 milliliters). After 90 minutes the mixture was filtered and the resin was washed with TFA (3 x 5 milliliters) and CH2C12. The combined filtrates 332 were concentrated in vacuo and the residue lyophilized from glacial acetic acid to provide the amino acid P-5 (152 milligrams) as a powder which was used without purification. The physical data were as follows: MS (FAB) m / z (relative intensity) 387 (M + H, 42), 427 (26), 426 (80), 389 (46), 387 (42), 366, ( 33), 279 (99), 177 (54), 146 (18), 119 (26), 23 (26); HRMS (FAB) caled for C16H13C13N203 + H-. 387.0070, found 387.0084. The amino acid P-5 was dissolved in methanolic HCl (20 milliliters) and stirred at room temperature for 18 hours. Concentration in vacuo produced methyl ester P-6 which was used without purification. The physical data are as follows: MS (ES +) for C17H15Cl3N203 m / z 400.9 (M + H) +. To a cooled solution (0-5 ° C) of N-ethoxycarbonyl-D-thiazolidine-4-carboxylic acid P-7 (82 milligrams, 0.4 mmol) and HOAt (54 milligrams, 0.4 mmol) in CH2C12 / DMF (1: 1.4 milliliters) EDC (76 milligrams, 0.4 mmol) was added. After stirring for 10 minutes, the solution was added to a P-6 amino ester described above at 0-5 ° C followed by DIEA (208 μL, 1.2 mmol). After an additional 30 minutes at 0-5 ° C, the solution was allowed to warm to room temperature and was stirred for an additional 1 hour. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and 0.1? Aqueous HCl. The organic layer was separated, washed with 0.1? Aqueous HCl, saturated aqueous aHC03, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using CH2Cl2 / ethyl acetate / hexanes (1: 1: 2) containing 2-propanol (0.1 percent) as eluent yielded the P-8 ester as a powder: aH NMR (300 MHz, CDC13) d 7.99 (1 H), 7.87 (2 H), 7.40 (2 H), 7.24 (2 H), 4.92 (1 H), 4.70 (2 H), 4.34 (1 H), 4.10 (2 H) , 3.74 (2 H), 3.74 (3 H), 3.20 (4 H), 1.25 (3 H); 13 C NMR (75 MHz, CDC13) d 171.2, 169.7, 165.4, 154.9, 140.6, 134.3, 133.4, 132.2, 131.3, 129.7, 128.4, 127.9, 63.1, 62.7, 60.4, 53.0, 52.6, 37.6, 21.0, 14.5; MS (ESI +) for C 24 H 24 C 13 N 306 S m / z 589.9 (M + H) +; MS (ESI-) for C24H24C13N306S m / z 588.0 (M-H). "To a * cooled solution (0-5 ° C) of P-8 ester (72 milligrams, 0.12 mmol) in THF (5 milliliters) and water (0.5 milliliters) was added a 0.1 N aqueous solution of NaOH (1.3 milliliter, 0.13 mmol) via a syringe pump for 1 hour. After an additional 45 minutes at 0-5 ° C, the reaction mixture was diluted with ethyl acetate and acidified with 0.25 N HCl to a pH of about 3. The organic layer was separated, washed with water and concentrated to the empty. Purification of the residue by flash chromatography using methylene chloride and methanol (0-5 percent) as eluent provided a solid which was crystallized from ethyl acetate / CH2Cl2 / hexanes to give the title compound (45 milligrams) as a colorless solid: IR (drift) 1743, 1726, 1709, 1691, 1675, 1663, 1553, 1521, 1490, 1428, 1415, 1379, 334 1345, 1290, 1189 crn "1; "NMR (300 MHz, DMSO-d6) d 10.27 (1 H), 8.35 (1 H), 7.92 (2 H), 7.81 (2 H), 7.37 (2 H), 4.62 (2 H), 4.53 ( 1 H), 4.29 (2 H), 4.00 (2 H), 3.11 (3 H), 2.77 (1 H), 1.12 (3 H), 13 C NMR (75 MHz, DMSO-d6) d 172.9, 170.0, 165.4 , 154.0, 142.5, 135.5, 133.9, 133.0, 131.6, 129.8, 128.0, 62.0, 61.7, 53.4, 37.0, 14.8, MS (FAB) m / z (relative intensity) 574 (MH +, 80), 576 (80), 574 (80), 379 (99; 160 (82), 91 (95), 81 (72), 69 (93), 57 (86), 55 (86), 43 (90); HRMS (FAB) caled for C23H22C13N306S + HX 574.0373, found 574.0358. 33 * 5 Scheme RQ-I S- T-RQ-2 OR YY? Y ° H «336 Where: RQ_! and RQ_2 are independently defined as R_; RQ_3 is defined as alkyl having from 1 to 6 carbon atoms or arylalkyl having from 7 to 17 carbon atoms; R_-, is defined as oxygen or N-RX1. QS is defined as a convenient protection group for a nitrogen (such as Boc or Fmoc) or oxygen (such as t-butyldimethylsilyl) (Greene, TW; Wuts, PGM, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991). Scheme Q describes a general method for the preparation of the examples of the formula Q-7. A readily prepared or commercially available sulfur-containing amino acid of structure (Q-1) is condensed with a suitably protected aldehyde to produce the thiazolidine-4-carboxylic acid of general formula Q-2. The standard deprotection (Greene, TW; Wuts, PGM, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991) produces the intermediate Q-3 which easily cyclizes to the bicyclo Q-4 using 1, 1 '- carbonildi-imidazole or phosgene or a convenient equivalent. For the preparation of bicycles of general structure Q-4 in which Z is CH2, see as examples: (a) Aszodi, J .; Bonnet, A .; Teutsch, G. Tetrahedron 1990, 46, 1579, (b) Baldwin, J.E .; Lee, V .; Schofield, C.J. Heterocycles 1992, 34, 903; ® Genin, M.J .; Johnson, R.L. "Am. Chem. Soc. 1992, 114, 8778, (d) Siddiqui, M.A.; Preville, P.; Tarazi, M.; Warder, S.E .; Eby, P.; Gorseth, E .; 337 Puumala, K.; Dimaio, J. Tetrahedron Lett, 1997, 38, 8807; (e) Subasinghe, M.L .; Bontems, R.J .; Mclntee, E .; Mishra, R.K .; Johnson R.L. J. "Med. Chem. 1993, 36, 2356. The removal of the ester protection group produces the acid of general structure Q-5 which is condensed with the amino acyl derivative Q-6 under standard peptide synthesis conditions to provide Q-7 (for a review of the peptide synthesis procedures see: Bodansky, M., Bodansky, A. The Practice of Peptide Syn thesis, Springer-Verlag, Berlin, 1984) . The soft base hydrolysis of the ester of general structure Q-7 provides the acid Q-8. Preparation 81 (Scheme Q, Q-2: where R ^ and RQ.2 are equal to hydrogen, RQ_3 is ethyl, R0_4 is NH, RQ_5 is Boc and the stereochemistry is (S)).
To a suspension of D-cysteine 1.5 hydrochloride hydrate (Ql, Scheme Q, Q-2: where RQ.! And RQ_2 are equal to hydrogen, RQ-3 is hydrogen and the stereochemistry is (5)) (5 grams, 27.1 mmol) in absolute ethyl alcohol (50 milliliters) is added triethyl orthoformate (13.5 milliliters, 81.2 mml.) At room temperature. An anhydrous HCl stream in gas was bubbled through the solution for 30 minutes. The 338 stream of anhydrous HCl gas was maintained as the mixture was heated at 70 ° C for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was triturated in diethyl ether to yield ethyl ester D-cysteine (4.43 grams) as a white solid which was used without further purification. The physical data are as follows: XH NMR (300 MHz, D20) d 4.36 (1 H), 4.27 (2 H), 3.12 (2 H), 1.25 (3 H); MS (ESI +) for C5H? A.N02S m / z 150.0 (M + H) SA a solution of ethyl ester of D-cysteine (1.89 grams, 10.2 mmol) in H20 (46 milliliters) was added potassium acetate (1.22 grams) , 12.4 mmol) and t-butyl N- [2-oxoethyl) carbamate (Aldrich, 2.38 grams, 12.0 mmol based on 80 percent purity as determined by ~? NMR) in ethyl alcohol (46 milliliters) at room temperature. After 8 hours, the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using methylene chloride / methanol (1 percent) as eluent to give the title compound (1.9 grams) as an oil: XH NMR (300 MHz, CDC13) d 5.01 (1 H), L.75 (1 H), 4.26 (2 H), 3.93 (1 H), 3.37 (2 H), 3.12 (1 H), 2.91 (1 H), H), 1.47 (9 H), 1.32 (3 H); MS (ESI +) for C12H22N204S m / z 288.9 (MH) "Preparation 82 (Scheme Q, Q-3: where R * Q * \ and RQ_2 are equal to hydrogen, RQ_3 is ethyl, RQ_4 is NH, and stereochemistry is is (5)). 339 To a cooled solution (10-15 ° C) of Q-2 (Scheme Q, where RQ. And RQ.2 are equal to hydrogen, RQ_3 is ethyl, RQ_4 is NH, RQ_5 is Boc and the stereochemistry is (5) )) (1.9 grams) in dioxane (38 milliliters) was added dropwise 4M anhydrous HCl in dioxane (156 milliliters). The solution was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was concentrated in vacuo and aceotropized three times with methanol which afforded the title compound (1.72 grams) as a viscous yellow solid: ~ H NMR (300 MHz, CDC13) d 8.57 (2 H), 5.80 (1 H), 5.25 (1 H), 4.39 (2 H), 4.17 (1 H), 3.79 (4 H), 1.37 (3 H); MS (ESI +) for C7H14N202S m / z 191.1 (M + H) +. MS (ESI-) for C7H14N202S .2HC1 m / z 261.0 (MH). "Preparation 83 (Scheme Q, Q-4: where RQ.- and RQ_2 are equal to hydrogen, R0_3 is ethyl, Z is NH, and stereochemistry is (5)).
To a cooled solution (0-5 ° C) of Q-3 (Scheme Q, where RQ.J. and R0.2 are equal to hydrogen, RQ_3 is ethyl, RQ_4 is NH, and the stereochemistry is (5)) (1.72 grams, 6.54 mmol) in THF (650 milliliters) was added triethylamine (2.83 milliliters, 20.3 340 mmol) and 1,1 '-carbonyldi-imidazole (1.11 grams, 6.87 mmol). After 3 days at room temperature, the mixture was re-cooled (0-5 ° C), treated with additional 1, 1'-carbonyldi-imidazole (530 milligrams, 3.27 mmol) and allowed to warm to room temperature. After 18 hours, the reaction mixture was concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and 0.25 N HCl. The organic layer was separated, washed with brine, dried (MgSO 4), filtered and concentrated in vacuo. The diastereomeric mixture was separated by chiral chromatography [5 x 25 cm (4.4) Whelk-O I, 50 milliliters / minute 40 percent Isopropanol / heptane, 210 nm,]. Further purification of each diastereomer isolated by flash chromatography using methylene chloride / ethyl acetate (25 percent) as eluent afforded the diastereomers (255 milligrams, 464 milligrams) as oils. The physical data for the fastest eluted diastereomer (conditions of the analytical column 0.46 x 25 cm (R, R) Whelk-O I, 0.5 milliliters / minute 40 percent IPA / heptane, 210 nm) as follows: "" H NMR (300 MHz, CDC13) d 5.51 (1 H), 5.15 (1 H), 4.32 (2 H), 3.96 (1 H), 3.86 (1 H), 3.53 (1 H), 3.26 (1 H), 3.13 (1 H), 1.34 (3 H); MS (ESI +) for C8H12N203S m / z 217.1 (M + H) +. MS (ESI +) for C8H12N203S m / z 239.0 (M + Na) +. MS (ESI-) for C8H12N203S .2HC1 m / z 215.1 (M-H). "Preparation 84 (Scheme Q, Q-5: where RQ.,., And RQ_2 are equal to 341 hydrogen, and Z is NH) To a cooled solution (0-5 ° C) of the fastest eluting diastereomer of general structure Q-4 (Scheme Q, where RQ._ and RQ.2 are equal to hydrogen, RQ_3 is ethyl, Z is NH, and stereochemistry is (5)) (100 milligrams, 0.46 mmol) in THF (13 milliliters) and H20 (1.5 milliliters) was added via syringe pump for 1 hour 0.1 N NaOH (9.7 milliliters, 0.97 mmol). The reaction mixture was stirred for 2 hours at 0 ° C, acidified with 1.0 N HCl (0.97 milliliters) and concentrated in vacuo. The resulting residue was dried over P205 in a vacuum desiccator to yield the title compound (87 milligrams) as a fatty solid which was used without further purification: MS (ESI +) for C6H8N203S m / z 189.0 (M + H) + . MS (ESI +) for C6H8N203S m / z 211.0 (M + Na) +. MS (ESI-) for C6H8N203S m / z 187.0 (MH) "Preparation 85 (Scheme Q, Q-7: where R ^ .-. And RQ_2 are equal to hydrogen, Z is NH, R5 is 4 - [( 2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry of the terminal amino acid C is (5)). 342 , To a cooled suspension (0-5 ° C) of Q-5 (Scheme Q, where RQ.X and R0_2 are equal to hydrogen, and Z is NH) (87 milligrams, 0.46 mmol) in methylene chloride (10 milliliters) was added 0- (7-azabenzotriaol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU) (175 milligrams, 0.47 mmol), Q-6 (Scheme Q where R5 is 4 - [ (2, 6-dichlorobenzoyl) amino] phenyl and the stereochemistry of the terminal amino acid C is (5)) (204 milligrams, 0.51 mmol) and N, N-di-isopropylethylamine (0.24 milliliters, 1.38 mmol). After 7 hours, the reaction mixture was diluted with methylene chloride, washed with 0.1? HCl and brine, dried (MgSO 4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using methylene chloride / ethyl acetate (25 percent) as eluent afforded the title compound (89 milligrams) as a white solid: "-H RM? (300 MHz, CDC13) d 7.57 ( 2 H), 7.31 (3 H), 7.13 (2 H), 4.97 (1 H), 4.82 (1 H), 4.47 (1 H), 3.80 (4 H), 3.55 (1 H), 3.46 (1 H) ), 3.34 (1 H), 3.08 (2 H); MS (ESI +) for C23H22Cl2? 40sS m / z 537.0 (M + H) +. MS (ESI +) for C23H22C12? 405S / z 558.9 (M +? A) +. 343 Preparation 86 and Example 279 4- [) 2,6-Dichlorobenzoyl) amino] -N- [[(7a5 (-hexahydro-5-oxoimidazol [5,1-J] thiazol-3-yl] -carbonyl] -L phenylalanine (Scheme Q, Q-8: where RQ. and RQ_2 are equal to hydrogen, Z is? H, R5 is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry of the terminal amino acid C is (5) ) .
To a cooled solution (0-5 ° C) of Q-7 (Scheme Q, where RQ and R0.2 are equal to hydrogen, Z is? H, R5 is 4- [(2,6-dichlorobenzoyl) amino) ] phenyl and the stereochemistry of terminal amino acid C is (5)) (88 milliligram, 0.16 mmol) in THF (5 milliliters) and H20 (0.5 milliliters) was added via syringe pump for 1 hour 0.1? αOH (3.4 milliliters, 0.34 mmol). After 2 hours, the reaction mixture was divided between ethyl acetate and 0.1? HCl (7 milliliters) and diluted with H20 (20 milliliters). The organic layer was separated, washed with H20, brine (MgSO4), filtered and concentrated in vacuo. The resulting white solid was lyophilized from glacial acetic acid to yield the title compound (22 milligrams) as white solid: IR (drift) 2924, 1726, 1720, 1663, 1657, 1608, 1515, 1456, 1431, 1402, 1398, 1243, 1194, 797, 780 cm "1; 344 X H NMR (300 MHz, CD 3 OD) d 8.05 (1 H), 7.61 (2 H), 7.46 (3 H), 7.25 (2 H), 4.93 (2 H), 4.74 (2 H), 4.47 (1 H) ), 3.77 (1 H), 3.39 (2 H), 3.25 (1 H), 3.04 (2 H); 13 C NMR (75 MHz, CD 3 OD) d 171.8, 165.2, 164.7, 138.2, 137.7, 135.1, 133.4, 132.4, 130.9, 129.4, 121.7, 66.3, 64.4, 54.5, 44.9, 37.4, 33.9; HRMS (FAB) for C22H20Cl2N4O5S + HX 523.0610, found 523.0629, MS (ESI +) for C22H20Cl2N4O5S m / z 523.0 (M + H) S MS (ESI-) for C22H20Cl2N4O5S m / z 521.1 (MH) "Example 280 4- [(2,6 -Dichlorobenzoyl) amino] -N- [[(7ai? (-hexahydro-5-oxoimidazo [5,1j] thiazol-3-yl] -carbonyl] -L-phenylalanine (Scheme Q, Q-8) : where RQ.! and RQ_2 are equal to hydrogen, Z is O, R5 is 4 - [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry of the terminal amino acid C is (5)).
Example 280 was prepared as described in Scheme Q from the lower eluting stereomer of general structure Q-4 (Scheme Q where RQ * 1 and RQ_2 are equal to hydrogen, RQ_3 is ethyl, and Z is? H). The physical data are as follows: IR (Drift) 3251, 3079, 1730, 1662, 1611, 1549, 1516, 1482, 1431, 1333, 1306, 1269, 1229, 1196, 792 cm "1; XH 345 NMR (300 MHz , CD3OD) d 7.59 (2 H), 7.44 (3 H), 7.24 (2 H), 4.65 (1 H), 3.81 (1 H), 3.44 (1 H), 3.23 (2 H), 3.08 (2 H) ); 13C NMR (75 MHz, CD3OD) d 175.3, 172.22, 164.6, 155.3, 139.7, 139.1, 136.1, 134.1, 133.9, 132.3, 131.8, 130.9, 122.0, 68.4, 64.6, 45.6, 44.0, 36.3, HRMS (FAB) ) calculated for C22H20Cl2N4O5S + H- 523.0610, Found 523.0629 MS (ESI +) for m / z 524.0 (M + H) + .MS (ESI-) for C22H20Cl2N4OSS m / z 523.0 (M + H) ". MS (ESI-) for C22H20Cl2N4O5S m / z 521.0 (M-H) - Anal. Caled for C22H20Cl2N4O5S .0.13 H20: C, 50.26; H, 3.88; N, 10.66. Found: C, 50.72; H, 3.96; N, 10.13. percent Water (KF): 0.45. Example 281 4- [(2,6-Dichlorobenzoyl) amino] -N- [(tetrahydro-5 -oxo-5H-thiazole [3,2- c] oxasol-3-yl) carbonyl] -L-phenylalanine (diastereomer less polar) (Scheme Q, Q-8: where RQ.! and R0_2 are equal to hydrogen, Z is O, R5 is 4 - [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry of the terminal amino acid C is [ S)).
Example 281 was prepared as described in Scheme Q using commercially available (t-butyldimethylsilyloxy) acetaldehyde 346 to form the required thiazolidine-4-carbonylic acid. The physical data are as follows: IR (drift) 3293, 3194, 1754, 1667, 1603, 1533, 1517, 1431, 1411, 1392, 1324, 1266, 1206, 798, 781 cm "1; XR NMR (300 MHz, DMSO-d6) d 8.44 (1 H), 7.53 (5 H), 7.21 (2 H), 5.00 (1 H), 4.84 (1 H), 4. 65 (1 H), 4.42 (2 H), 3.08 (2 H), 2.91 (1 H); 13 C NMR (75 MHz, CD 3 OD) d 169.4, 163.8, 160.6, 136.7, 136.2, 133.9, 131.9, 130.9, 129.5, 127.9, 120.4, 68.1, 64.4, 62.3, 53.4, 36.1, 33.7; MS (ESI +) for C22H19C12N306S m / z 524.0 (M + H) +. MS (ESI-) for C22H19C12N306S m / z 522.0 (M-H). "Anal. Caled for C 22 H 19 Cl 2 N 3 O 6 S.0.31 H20: C, 49.86; H, 3.73; N, 7.93.
Found: C, 49.61; H, 3.82; N, 7.54. percent Water (KF): 1.06 Example 282 4- [(2,6-Dichlorobenzoyl) amino] -N- [(tetrahydro-5-oxo-5H-thiazo [3,2- c] oxazol-3-yl) - carbonyl] -L-phenylalanine (more polar diastereomer) (Scheme Q, Q-8: where RQ.! and RQ_2 are equal to hydrogen, Z is O, Rs is 4- [(2,6-dichlorobenzoyl) amino] phenyl and the stereochemistry of the terminal amino acid C is (5)). 347 Example 282 (diastereomer of Example 281) was prepared as described in Scheme Q. The physical data are as follows: IR (drift) 3296, 1753, 1666, 1603, 1579, 1535, 1517, 1431, 1411, 1390 , 1324, 1267, 1207, 798, 781 crn "1; XH NMR (300 MHz, DMS0-d6) d 8.57 (1 H), 7.54 (5 H), 7.20 (2 H), 5.23 (1 H), 4.86 (1 H), 4.66 (1 H), 4.45 (2 H), 3.22 (1 H), 3.09 (1 H), 2.93 (m, 2 H), 13 C NMR (75 MHz, CD3OD) d 172.8, 169.7, 163.8, 160.6, 136.8, 136.2, 133.7, 131.9, 130.9, 129.5, 127.9, 120.2, 68.1, 64.9, 63.1, 53.6, 37.5, 36.2, 34.2; MS (ESI +) for C22H19C12N306S m / z 523.9 (M + H) + MS (ESI-) for C22H19C12N306S m / z 521.9 (MH) -. HRMS (El) for C22H19C12N306S 523.0372, found 523.0366, Anal.Called for C22H19C12N306S .0.35 H20: C, 49.79; H, 3.74; N, 7.92. : C, 50.14; H, 4.08; N, 8.13 percent Water (KF): 1.19 Example 283 3-ethyl acid ester (45) -4- [[[(15) -1-Carboxy-2 [4 - [(2,6-Dichlorobenzoyl) amino] phenyl] carbonyl] -2- (4-pyridinyl) -3 - thiazolidinecarboxylic Example 283 was prepared as described in Scheme B using D-cysteine and 4-pyridinecarboxaldehyde to form the thiazolidine carboxylic acid. The physical data is 348 as follows: IR (drift) 3055, 2981, 2928, 1679, 1604, 1535, 1515, 1450, 1431, 1406, 1378, 1131, 1194, 797, 778 crir1; XH NMR (300 MHz, CD30D) d 8.68 (2 H), 8.28 (2 H), 7.55 (2 H), 7.55 (2 H), 7.42 (4 H), 7.25 (2 H), 6.28 (1 H) , 4.70 (1 H), 4.09 (2 H), 3.46 (1 H), 3.16 (1 H), 2.94 (1 H), 2.73 (1 H), 1.17 (3 H); 13 C NMR (75 MHz, CD3OD) d 190.2, 171.1, 162.1, 153.8, 141.4, 135.3, 134.6, 131.9, 130.3, 129.4, 128.2, 126.4, 122.4, 118.5, 61.0, 51.7, 35.5, 26.6, 11.7; MS (FAB) / z (relative intensity) 617 (MH +, 99, 621 (35), 620 (72), 619 (99), 618 (91), 617 (99), 371 (22), 179 (23) , 173 (28), 124 (27), 57 (24); HRMS (FAB) caled for C28H26C12N406S + HX 617.1028, found 617.1019.Called for C28H26C12N406S .0.9 HCl- 1.1 H20: C, 50.19; H, 4.38; N, 8.36, Cl, 15.34 Found: C, 49.79; H, 4.49; N, 8.11; Cl, 15.05 percent Water (KF): 2.96 Example 284 3- [2 (1-pyrrolidinyl) ethyl] ester of 4- [[[(15) -2-Amino -1- [4- [(2,6-dichlorofenyl) methoxy] phenyl] methyl] -2-oxoethyl] amino] -carbonyl] -3-thiazolidinocarboxylic acid Example 284 was prepared as described in 349 Scheme C. The physical data is as follows: IR (drift) 1709, 1675, 1511, 1458, 1435, 1421, 1390, 1380, 1354, 1299, 1240, 1195, 1179 , 1114, 765 was "1; XH NMR (300 MHz, CD3OD) d 8.40 (1 H), 7.41 (3 H), 7.22 (2 H), 6.99 (2 H), 5.29 (2 H), 4.46 (6 H), 3.77 (2 H), 3.50 (2 H), 3.19 (4 H), 2.89 (1 H), 2.04 (1 H), 2.12 (4 H), 13 C NMR (75 MHz, CD3OD) d 174.5, 171.6, 171.1, 157.9, 153.3, 136.6 132.2, 130.6, 130.0, 129.7, 128.3, 114.5, 64.9, 63.2, 62.1, 60.9, 54.4, 53.6, 50.0, 49.0, 37.0, 36.5, 35.2, 22.6, MS (ESI +) for C27H32C12N405S m / z 595.1 (M + H) *. HRMS (FAB) caled for C27H32C12N405S + R-595.1548, found 595.1531. Example 285 3- (3-tetrahydrofuranyl) acid ester (45) -4- [[[( ) -1- Carboxy -2 [4 - [(2,6-dichlorophenyl) methoxy] phenyl] ethyl] amino] carbonyl] -3- thiazole idinocarboxylic Example 285 was prepared as described in Scheme A. The physical data are as follows: lR NMR (300 MHz, CD3OD) d 7.41 (3 H), 7.18 (2 H), 6.98 (2 H), 5.28 (2 H), 5.15 (1 H), 4.69 (2 H), 4.44 (1 H), 3.82 (4 H); 13 C NMR (75 MHz, DMS0-d6) d 172.8, 157.9, 136.7, 132.2, 130.6, 130.1, 129.5, 350 128.3, 114.5, 76.8, 72.7, 66.5, 64.9, 62.4, 53.5, 36.3, 34.9, 32.4; MS (FAB) m / z (relative intensity) 569 (MH +, 75), 571 (51), 570 (29), 569 (75), 322 (22), 161 (20), 159 (30), 89 ( 25), 73 (31), 71 (99), 43 (41); HRMS (FAB) caled for C25H26C12N207S + H3 569.0916, found 569.0939. Anal. Caled for C2sH26Cl2N207S. C, 52.73; H, 4.60; 6, 4.92; Found: C, 52.41; H, 4.80; N, 4.62. Example 286 3- [2- (1-piperidinyl) eti] ester of (45) -4- [[[(15) -2-amino-1- [[4- [(2,6-dichlorophenyl) methoxy]] phenyl] methyl] 2-oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid Example 286 was prepared as described in Scheme C. The physical data are as follows: 1 H NMR (300 MHz, CD 3 OD) d 7.43 (3 H), 7.22 (2 H), 6.98 (2 H), 5.28 (2 H), H), 4.66 (2 H), 4.59 (1 H), 4.47 (1 H), 4.47 (2 H), 3.05 (10 H), 1.78 (4 H), 1.62 (2 H); 13C NMR (75 MHz, CD30D) d 175.9, 172.9, 159.3, 138. 1, 133.6, 132.0, 131.4, 131.1, 129.7, 120.1, 115.9, 66.3, 64. 6, 63.7, 62.3, 61.9, 57.8, 55.8, 55.1, 51.3, 50.3, 38.5, 37.8, 36.6, 25.0, 23.5; MS (ESI +) for C28H34C12N4: 05S m / z 609.0 351 (M + H) +. EXAMPLE 287 3- (2- (4-Methyl-l-piperazinyl) ethyl] ester of (45) 4- [[[(15) -2-amino-1- [[4- [(2,6-dichlorofenyl)] ) methoxy] phenyl] methyl] 2-oxoethyl] amino] -carbonyl] -3-thiazolidinocarboxylic acid Example 287 was prepared as described in Scheme C. Physical data are as follows: XH NMR (300 MHz, CD30D) d 7.41 (3 H), 7.21 (2 H), 6.98 (2 H), 5.28 (2 H), 4.67 (1 H), 4.58 (1 H), 4.46 (1 H), 4.23 (2 H), 3.20 (2 H), 2.71 (13 H), 2.50 (3 H); MS (ESI +) for C28H35Cl2N5OsS m / z 624.0 (M + H) *. Anal. Caled for C28H35C12N505S .0.5 C2H402.0.5 H20: C, 49.82; H, 5.54; N, 10.02. found: C, 49.82; H, 5.77; N, 9.65. Example 288 3- [2 (4-morpholinyl) ethyl] ester of (45) -4- [[[(15) -2-amino-1- [[4- [(2,6-dichlorobenzoyl) amino] phenyl] ] methyl] -2 -oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid 352 Example 288 was prepared as described in Scheme C. The physical data are as follows: IR (drift) 1671, 1603, 1536, 1518, 1430, 1415, 1361, 1349, 1324, 1269, 1194, 1134, 1118, 1104, 799 crn "1; XH NMR (300 MHz, CD3OD) d 7.62 (1 H), 7.46 (3 H), 7.31 (2 H), 4.68 (3 H), 4.41 (3 H), 3.95 (4 H) ), 3.48 (5 H), 3.22 (3 H), 2.90 (2 H), 13 C NMR (75 MHz, CD3OD) d 175. 8, 173.1, 165.3, 154.7, 138.2, 137.6, 135.2, 133.3, 132.4, 130. 9, 129. X, 121.7, 121.5, 65.0, 64.8, 63.7, 60.6, 57.4, 55.8, 53.6, 51.4, 50.4, 38.6, 38.1, 36.6, 35.0; MS (ESI +) for C28H35Cl2N505S m / z 624.0 (M + H) *. Anal. Caled for C27H31C12N506S m / z 623.9 (M + H) -; HRMS (FAB) caled for C27H31C12NS06S + H 624.1450, found 624.1452. 353 Scheme R 354 Scheme R Scheme R shows a general method for the preparation of the Examples corresponding to structures R-4 and R-5, wherein R6 is nitrogen. In this way the reaction of the amide R-1 (obtained from the imide J-2), with the organic zinc derived from a suitable protected β-iodoalanine, provides the acylamino azaphenylalanine R-2. N-deprotection of R-2 gives the amino ester R-3, which is used (as exemplified by reagent A-4 of Scheme A, by reagent B-5 of Scheme B) for the synthesis of Examples R- 4 and R-5 of this invention. Preparation 87 (Scheme R: Rl wherein R6 is?, R7 is H, R8 is -? HC (O) -, and R9 is 2,6-dichloro) 2,6-Dichloro-N- (5-iodo-2) -pyridinyl) be zamida (CiaHvClal? .O). A mixture of J-2 and? H2? H2.H20 in MeOH is refluxed for 6 hours under argon. The reaction mixture is cooled, and the MeOh is removed in vacuo. The residue is partitioned between H20 and EtOAc. The EtOAc extracts are dried, filtered and concentrated to give a brown solid, which is purified by flash silica chromatography (99: 1 toluene / EtOAc) to provide Preparation 87: TLC (98: 2 toluene / EtOAc) R £ = 0.43; XH RM? (CDCl3, 75 MHz) d 10.23, (1 H), 8.26 (1 H), 7.99 (1 H), 7.57 (1 H), 7.41-7.31 (3 H); 13C RM? (CDC13, 75 MHz) d 163.40, 153.22, 150.95, 147.16, 135.83, 132.72, 355 131.90, 130.34, 128.65, 128.50, 117.09, 86.55; MS (ESI) 393, 391. Preparation 88 (Scheme R: R-2 wherein R6 is N, R7 is H, R8 is -NHC (O) -, R9 is 2,6-dichloro and the stereochemistry is S) Ester (S) -6 - [(2,6-Dichlorobenzoyl) amino] -OI- [[(1,1-dimethylethoxy) carbonyl] amino] -3-pyridinopropanoic acid (C12H23C12N305) methyl ester. To an amberized flask containing activated Zinc powder (0.0802 grams, 12.27 mmol) under argon is added dry THF (6 milliliters) and 1,2-dibromoethane. (0.045 milliliters). This suspension is briefly put in soft reflux, and then cooled to room temperature. A solution of TMSCL (1 M in THF, 0.39 milliliters) is added. The reaction mixture is stirred at 45 ± 5 ° C for 30 minutes and then cooled to room temperature. To this mixture is added a degassed solution of N- [(1,1-dimethylethoxy) carbonyl] -3-iodo-L-alanine methyl ester (4.04 grams, 12.27 mmol) in 2: 1 N, (18 milliliters). The reaction mixture is stirred at 45 ± 5 ° C for 5 hours, and then cooled to 0 ° CA this mixture is added PcLCl 2 (PPh 3) 2 (0.428 grams) followed immediately by a degassed solution of Preparation 87 in 1: 1 N, (19 milliliters). This reaction mixture is stirred at 45 ± 5 ° C for 44 hours. It is cooled to 0 ° C, and is quenched with cold saturated aqueous? H4C1. This mixture is extracted with EtOAc. The combined EtOAc extracts 356 are washed with aqueous NH 4 Cl and brine. The EtOAc extracts are dried, filtered and concentrated to give a brown-green oil, which is purified by flash silica chromatography (steps of 750: 250: 1, 700: 300: 1 and 650: 350: 1 heptane / EtOAc / iPrOH) to provide Preparation 88: TLC Rf = 0.28 (7: 3 hexanes / EtOAc). Preparation 89 (Scheme R: R-3 wherein R6 is N, R7 is H, R8 is -NHC (O) -, R9 is 2,6-dichloro, and the stereochemistry is S) Acid methyl ester dihydrochloride salt ( 2) -a-Amino-6- [(2,6-dichlorobenzoyl) amino] -3-pyridinopropanoic acid (C16H15C12N303.2HC1, R-3). A solution of Preparation 88 (0.812 grams, 1.73 mmol) in 4 M HCl in dioxane (20 milliliters) is stirred under argon at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and the residue was taken up in H20 (60 milliliters). This aqueous mixture is extracted with Et20 (3 60 milliliters), and the Et20 extracts are discarded. The aqueous solution is frozen and lyophilized to provide Preparation 89: IR (diffuse reflectance) 3021, 2995, 2953, 2893, 2884, 2866, 2853, 2844, 2341, 2015, 1916, 1749, 1646, 1569, 1252 crn "1; MS (El) 367 (M +), 282, 280, 262, 175, 173, 147, 145, 109, 107, 88. Preparation 90 and Example 289 Ester 3 -ethyl acid [5- (R * f R *) ] -4- [[[1- [[2- [(2,6-Dichlorobenzoyl) amino] -5-pyridinyl] methyl] -2-methoxy-2- 357 oxoethyl] amino] carbonyl] -3-thiazolidinocarboxylic acid (C23H24C12N406S ) (Scheme R: R-4 where R3 is H, R2 is H, R3 is -Et, X is S, (Y) is -C (0) 0, m is 2, n is 0, or is 1, R6 is N, R7 is H, R8 is -NHC (O) -, R9 is 2,6-dichlor and the stereochemistry is [5- (R *, R *)] To a mixture of N-acylthiazolidinocarboxylic acid (0.292 grams 1.42 mmol), HOAt (0.193 grams, 1.42 mmol) in 4: 1 CH2C12 / DMF (5.25 milliliters) at 0 ° C was added EDC (0.272 grams, 1.42 mmol). This reaction mixture is stirred at 0 C for 20 minutes. Preparation 89 solid (0.568 grams, 1.29 mmol) and? MM (0.316 milliliters, 3.27 mmol) is added. The resulting reaction mixture is stirred at 0 ° C for 4 hours, and then maintained at 4 ° C for 40 hours. The mixture is concentrated in vacuo, and the residue is taken up in CH2C12. The CH2C12 mixture is extracted with saturated H20,? AHC03 aqueous, and H20. The combined aqueous washings are re-extracted with CH2C12. The combined CH2C12 extracts are dried, filtered and concentrated to a pale yellow foam, which is purified by 358 silica flash chromatography (600: 400: 1 EtOAc / heptane (iPrOH) to give Preparation 90 (Example 289): IR (diffuse reflectance) 3275, 1742, 1697, 1665, 1586, 1559, 1531, 1476, 1427, 1398, 1382, 1351, 1344, 1311, 1284, 1279, 1242, 1223, 1196, 1100, 1023, 802, 787, 770, 697 crn "1; MS (El) TTR (M *), 495, 422, 395, 352, 315, 293, 280, 172, 160, 144, 116, 107, 88, 60. Example 290 Ethyl ester of acid [5- (R *, R *)] -4 - [[[l-Carboxi-2- [2- [(2,6-dichlorobenzoyl) amino] -5-pyridinyl] ethyl] amino] carbonyl] -3 -thiazolidinocarboxylic acid (C22H22C12N406S, Example 290) (Scheme R: R-4 where R? Is H, R2 is H, R3 is -Et, X is S, (Y) is -C (0) 0, m is 2, n is 0, or is 1, R6 is N, R7 is H, R8 is -NHC (O) -, RtJ is 2,6-dichlor and the stereochemistry is [S- (R *, R *)] To a solution of Preparation 89 (0.400 grams, 0.72 mmol) in 6: 1 THF / H20 (25.6 milliliters) at 0 ° C under argon is slowly added over 4 hours (via syringe pump) an aqueous solution of 359 NaOH (1 M, 7.92 milliliters). The reaction mixture is stirred for an additional hour and a half. The reaction mixture is partitioned between aqueous HCl and EtOAc. The aqueous solution is separated, and further separated with EtOAc. The combined EtOAc extracts are dried, filtered and concentrated to a cream colored foam. This foam is collected in 1: 1 MeCN / H20. This solution is frozen and lyophilized to give Example 290 as a cream solid: mp 142-144 ° C; IR (diffuse reflectance) 3169, 3094, 3031, 2980, 2964, 2935, 1735, 1691, 1591, 1556, 1531, 1480, 1431, 1400, 1379, 1344, 1308, 1288, 1266, 1216, 1194, 1148, 799 , 782, 272 cm "1; Anal. C 48.72, H 4.29, Cl 12.26, N 9.95, S 5.62 (caled C 48.81, H 4.10, Cl 13.10 N 10.35, S 5.92). 360 Biological assays Jurkat endothelial cell adhesion assays: The following assay established the activity of the present compounds to inhibit β-mediated cell adhesion. in a representative system in vi tro. This assay measures the adhesive interactions of a T cell cell line, Jurkat, which is known to express the c.4ßx integrin, to the endothelial monolayers in the presence of the test compounds. The test compounds were added in increasing concentrations of T cells and then the mixture of T cell compounds was added to monolayers of endothelial cells stimulated with IL-1. Plates were incubated, washed and the percentage of bound cells quantified. The present assay directly demonstrates the cell adhesion inhibitory activity and the adhesion modulating activity of the compounds. Human umbilical vein endothelial cells were found in Clonetics (San Diego, CA) in passage number 2. The cells were cultured in 0.5 percent porcine skin gelatin in pre-coated leaflets (Sigma, St. Louis MO) in EGM medium. UV (Clonetics, San Diego, CA) supplemented with 10 percent fetal bovine serum. Cells were fed again every 2-3 days reaching confluence on day 4 to 6. Cells were monitored for factor VIII antigen and the results showed that in passage 12, 361 cells were positive for this antigen. Endothelial cells were not used after passage 6. The Jurkat T cell line was obtained from the American Type Tissue Culture Collection (Rockville, MD) and the cells were cultured in RPMI containing 10 percent fetal calf serum. . Cells were washed twice with Hank's balanced salt solution (HBSS) and resuspended in Dulbecco's Eagle's Minimal Medium (DMEM) containing 2.5 milligrams / milliliter of human serum albumin (HSA). Jurkat cells (1 x 106 cells / milliliter) were stained with 10 ng / milliliter of BCECF-AM (Molecular Probes, Eugene, OR)) in HBSS without phenol red. The cells were loaded with BCECF for 60 minutes in the dark at 37 ° C, washed twice, and resuspended in DMEM-HSA solution. The confluent endothelial monolayers, grown in 96-well tissue culture plates, were stimulated for 4 hours at 37 ° C with 0.1 ng / milliliter (approximately 50 U / milliliter) of recombinant IL-1 (Amgen, Thousand Oaks, CA) . After this incubation, the monolayers were washed twice with HBSS and 0.1 milliliter of DMEM-HSA in solution was added. Jurkat cells (5 x 10 5 cells) were combined with the appropriate concentration of the test compound and 0.1 milliliter of the compound mixture of Jurkat cells was added to the monolayers of endothelial cells. Generally, 100, 20, 5 and 1.25 μM concentrations of the compound were tested. These 362 concentrations were adjusted downward for the analogs found or thought to be more potent. The plates were placed on ice for 5 minutes to allow the Jurkat cells to attach and the plates incubated at 37 ° C for 20 minutes. After this incubation, the monolayers were washed twice with PBS containing 1 mM calcium chloride and 1 mM magnesium chloride and the plates were read using a Millipore 2300 cytofluor (Marlboro, MA). The fluorescence in each well was measured as arbitrary fluorescence units and the percentage adhesion in the absence of the compound was adjusted to 100 percent and the percent adhesion in the presence of the compound was calculated. The monolayers were also fixed at 3 percent paraformaldehyde and evaluated microscopically to verify adhesion. This procedure is a modification of a previously published method (Cardarelli et al, J. "Biol. Chem. 269: 18668-18673 (1994).) Jurkat-CS-1 Assay The peptide derived CS-1, CLHPGEILDVPST, and the peptide of scrambled control, CLHGPIELVSDPT, were synthesized on a Beckman 990 synthesizer using t-Boc methodology.The peptides were immobilized on microtiter plates using the heterobifunctional crosslinker N-hydroxysuccinimide 3- (2-pyridyldithio) propionic acid ester (SPDP) as reported by Pierschbacher et al, Proc., Nati. 363 ¡75A. JLO: 1224-1227 (1983). The microtiter plates were coated with 20 micrograms / milliliter of HSA for 2 hours at room temperature, washed once with PBS and derived with 10 micrograms / milliliter SPDP for 1 hour. After washing, 100 microliters of 100 micrograms / milliliter of cysteine containing peptide solution which had recently been dissolved was added to the wells and the plates allowed to cross-link overnight at 4 ° C. The unbound peptide was removed from the plates by washing with PBS. To block the unreacted sites, the plates were coated with 100 microliters of a solution of 2.5 milligrams / milliliter of BSA in PBS for 1 hour at 37 ° C. 100 microliters of Jurkat cells (2.5 x 106 cells / milliliter) in DMEM plus BSA (2.5 milligrams / milliliter) were mixed with a suitable concentration of the compound to be tested and the mixture was added to the peptide-coated plates and incubated for 1 hour at 37 ° C. Generally concentrations of 100, 20, 5 and 1.25 μM of the compound were tested. The concentrations of the compound were adjusted downward for the compounds that were thought or found to be more potent. After this incubation the plates were washed once with PBS and the bound cells were fixed with 3 percent paraformaldehyde in PBS and stained with 0.5 percent toluidine blue in 3.7 percent formaldehyde. The cells were stained overnight at room temperature and 364 the optical density at 590 nm of the cells stained with toluidine blue was determined using a vertical path spectrophotometer to quantify the binding (VMAX Kinetic Microplate Reader, Molecular Devices, Menlo Park, CA). This procedure is a modification of a previously published method (Carderelli et al., J. Bol. Chem., 269: 18668-18673 (1994) and Cardarelli et al., Nati Procedure, Acad. Sci. USA, 83 .: 2647-2651 (1986)). Preferred compounds are those which have low IC50 values in the Jurkat EC assay or the Jurkat-CS-1 assay described above or which have at least moderate activity in both assays. All compounds of the present invention have an activity of less than 50 μM in the Jurkat CS-1 assay or less than 500 μM in the Jurkat EC assay. Compounds with activity in the Jurkat CS-1 assay preferably have ICSO values less than 1 μM, more preferably less than 0.5 μM, more preferably less than or equal to 0.8 μM. Compounds with assay activity of Jurkat EC preferably have IC 50 values less than 10 μM, more preferably less than 5 μM, and preferably less than or equal to 0.8 μM. In the Jurkat EC test, the ICS0 value ranges (μM) are represented by A, B, and C and in the Jurkat CS-1 test, the ranges of IC50 values are represented by D, E, and F. these Ranges are as follows: 365 Data in vi tro EC: A 2. 1 μM; 1 μM > B > 0.25 μM; C = 0.25 μM CS-1 D = 0.75 μM; 0.75 μM > E > 0.05 μM; F = 0.05 μM. 366 367 368 369 370 371 372 Biological activity in the pleurisy model by Dextran Certain compounds of the present invention were tested in the pleurisy model by Dextran *. Main reasoning to develop an integrin-c.4ß antagonist. to treat inflammatory diseases VLA-4, a member of the ßl integrin family of adhesion molecules, is thought to represent a critical function in several types of inflammatory disease processes by promoting leukocyte adhesion to the 373 vascular cell adhesion molecule (VCAM-1) and the CS-1 domain of fibronectin on extracellular tissue matrix (Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S. Hemler M., Lobb RR VCAM-1 on activated endothelium interactions with the leukocvte integrin VLA-4 at a site distinct from the VLA-4-fibronectin binding site Cell: 60: 577-584, 1990, Humphries MJ, Akiyama SK, Komoriya A. 01den K, Yamada KM.identification of an alternatively-spliced site in human plasma fibronectin that mediates cell tvpe-specific adhesion J Cell Biol; 103: 2637-2647, 1986. Wayner EA. Garcia-Pardo A, Humphries MJ. McDonald JA, Carter WG. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in fibronectin plasma. J Cell Biol; 109: 1321-1330, 1989, Guan J-L, Hynes RO. Lymphoid cells recognize an alternatively-spliced segment of fibronectin via the integrin O 3.! Cell: 60: 53-61, 1990). Of the cell types that VLA-4 represents, the major emphasis has been on eosinophils, lymphocytes, and monocytes. Validation of VLA-4 function rests predominantly on the use of anti-VLA-4 antibodies that have been shown to suppress delayed-type hypersensitivity responses (Issekutz TB, Dual inhibition of VLA-4 and LFA-1 maximallv cutaneous inhibits). delayed-type hypersensitivity-induced inflammation Am J Pathol; 143: 1286-1293, 1993, Scheynius A, Camp RL Puré E. Reduced contact sensitivitv reactions in mice with 374 monoclonal antibodies to leukocvte function-associated molecule-1 and intercellular adhesion molecule-1 .J Immunol; 150: 655-663, 1993, Ferguson TA, Kupper TS Antigen-independent processes in antigen-specific immunitv. J Immunol; 150: 1172-1182, 1993, Chisholm PL, Williams CA, Lobb RR Monoclonal antibodies to the integrin o "subunit inhibit the murine contact hypersensitivitv response, Eur J Immunol; 23: 682-688, 1993, Elices MJ, Tamraz S, Tollefson V, Vollger LW. The integrin VLA-4 mediates leukocvte recruitment to skin inflammatory sit It is in vivo. Clin Exp Rheumatol; 11 (Suppl 8) S77-80), 1993, experimental allergic encephalomyelitis (Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman LM, Karin N. Prevention of experimental autoimmune encephalomvelitis by antibodies against c.βß? Integrin Nature: 356: 63-66, 1992, Canella B, Raine CS, The VCAM-1 / VLA-4 pathway is involved in chronic lesion expression in multiple sclerosis (MS) J Neuropathol Exp Neurol; 52: 311, 1993), HIV-induced encephalitis (Sasseville VG, Newman W, Brodie SJ, Hesterberg P Pauley D, Ringler DJ. Monocvte adhesion to endothelium in simian immunodeficiencv virus-induced AIDS encephalitis is mediated bv vascular cell adhesion molecule-l / c. "ß? integrin reactions. Am J Pathol; 144: 27-40, 1994), pulmonary inflammation and hyper-reactivity in the respiratory tract in asthma (Abraham WM, Sielczak MW, Ahmed A, Cortes A, Lauredo IT, Kim J, Pepinsky, B, and collaborators, or. ^ - integrins mediate antigen-induced late 375 bronchial responses and prolonged airway hyperresponsiveness in sheep J Clin Invest; 93: 776-787, 1994, Pretolani M, Ruffié C, Roberto Lapae Silva J. Joseph D, Lobb RR, Vargaftig BB. Antibody to very late activation antigen 4 prevents antigen-induced bronchial hyperreactivity and cellular infiltration in the guinea-pig airways. J Exp Med; 180: 795-805, 1994), experimental models of autoimmune mediated diabetes (Yang X-D, Karin N, Tisch R, Steinman L, McDevitt HO. Inhibition of insulitis and prevention of diabetes in non-obese diabetic mice by blocking L- selectin and very late antigen 4 adhesion receptors Proc Nati Acad Sci USA; 90: 10494-10498, 1993, Burkly LC, Jakubowski A, Hattori M., Protection against adoptive transfer of autoimmune diabetes medicated through very late antigen-4 integrin.; 43: 529-534, 1994), and experimental colitis (Podolsky DK, Lobb R, King N. Benjamin CD, Pepinsky B, Sehgal P et al, Attention to colitis in the cotton-top Tamarin by anti-4 integrin monoclonal antibody J Clin Invest; 92: 372-380, 1993). Since eosinophils represent an important component of inflammatory cell influx in asthmatic lung tissue, we have developed an acute inflammatory model of integrin-dependent eosinophil infiltration VLA-4 which could be used to identify VLA-4 antagonists; these compounds would be of potential value in the treatment of asthma as well as other diseases in which VLA-4 represents a 376 function. Materials and Methods Animal, housing and viral tests: C57BL / 6 mice (Jackson, Bar Harbor, ME), 6-8 weeks old, weighing between 20-25 grams were used in all this. All mice were acclimated for at least 7-14 days after arrival and were kept at controlled temperature (20-22 ° C) and 12 hours of daily light cycle (6:00 A.M. -6.00 P.M.). The mice were housed in laminar flow shelves and checked twice a week for viral infections (mouse hepatitis virus, mouse minute virus, rodent orbital parvovirus, Sendai) with kits obtained from Oreganon Teknika (Durham, HC) using established enzyme-linked immunosorbent assays. Mice that tested positive for any of the above were omitted from the study. All mice were fed standard laboratory food (Upjohn Lab Rodent Irradiated Mouse Chow No. 5011-3, PMI Feeds, St. Louis, MO) and acidified drinking water (pH 5.0) to taste. Induction of inflammation by intrapleural injection of Dextran: Intrapleural injections were made using a 27G needle cut 3-4 millimeters and blunted by filing. Injections were made by inserting the 377 needle between the mid-ribs of the right side of the thoracic cavity. Dextran (MW 5-40 x 106, St Louis, MO) was injected as "a 10 percent solution in saline in a volume of 100 μl / mouse." Care was taken to avoid bleeding at the site of the injection in which the intercostal muscles were cut to facilitate the uniform insertion of the needle.
Quantification of pleural inflammatory leukocyte response Pleural leukocytes were collected as follows: 4 hours after induction, the pleural inflammatory exudate was removed by washing with 2 x 1.0 milliliter Ca * + / Mg ++ free of HBSS (Gibco, Grand Island, NY) containing 45 mg EDTA / 100 milliliters HBSS, 4 ° C. Total leukocyte counts were made by hemocytometer after lysis of erythrocyte in 2 percent acetic acid in PBS buffer; The exuded leukocyte granules were resuspended in serum for cytospin properties and stained (Diff Quik, Baxter Healthcare, McGraw Park, IL) for differential leukocyte counts (neutrophils, eosinophils, and mononuclear leukocytes). The pleural cavities of the mice that received either no intrapleural or saline injection were washed and the cells were counted in the same manner to estimate baseline or saline-induced pleural leukocyte counts respectively. 378 Administration of compounds: All drugs were dissolved in PBS and the pH was adjusted to 7.5 with NaOH. This compound was administered intravenously through the retro-orbital sinus at one-hour intervals (0-3 hours) beginning at time "0" as indicated. The mice were carefully monitored to determine side effects; none was noted for the series of compounds reported herein. The following compounds were tested for their inhibitory effects on the infiltration of leukocytes induced by dextran: Examples 3, 8, 9, 10, 12, 16, 37, 62, 66, 67, 99, 100, 111, 113, 115, 127, 131, 141, 184, 185, 192, PBS (saline) was administered intravenously as control. Inhibition as eosinophilic infiltration, which was suppressed with monoclonal antibody anti-alpha-4 PS / 2, 50 percent), was used with a VLA-4 antagonist activity of the compounds tested. Data for neutrophils were also reported. Results: Pleural leukocyte response with dextran. The total pleural leukocyte counts were 255 x 104 { +/- 16 SEM) cells in the normal pleural cavity; In the normal pleural leukocyte population, all cells were mononuclear (a similar response was observed after intrapleural saline injection). Four hours 379 after the intrapleural injection of dextran the total pleural leukocyte counts increased to 719 x 104 [+/- 61 SEM) and comprised 36.8 x 104 (+/- 4.1 SEM) eosinophils, 292 x 104 (+/- 25 SEM) neutrophils and 391 x 104 (+/- 48 SEM) mononuclear leukocytes. % inhibition of infiltration of Eosinophils A > 40; B: 20-39; C < 19 Example Dosage Eos 3 50 x 2 iv A 8 100 x 1 po C 9 50 x 2 iv A 10 100 x 1 po B 12 50x2iv A 16 50 x 2 iv A 37 50 x 2 iv A 62 50 x 2 iv B 66 50 x 2 iv A 67 50 x 2 iv A 99 50 x 2 iv A 100 50 x 2 iv B 111 50 x 2 iv C 113 50 x 2 iv C 115 50 x 2 iv B 127 50x2iv B 131 50 x 2 iv C 141 50 x 2 iv A 185 50 x 2 iv B 184 50 x 2 iv B 192 50 x 2 iv B

Claims (6)

  1. 380 NOVELTY OF THE INVENTION Having described the foregoing invention, it is considered a novelty and therefore the content of the following CLAIMS is declared as property 1. A compound of the formula: characterized because, R-. it can occur from one to four times and in each occurrence it is independently hydrogen or alkyl having from 1 to 6 carbon atoms; R2 is hydrogen, pyridyl, alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-R1: L, or -C02-R1; L; in addition, Rx and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they can be attached to the same carbon atom and form a ring of 5- 8 atoms of the formula:
  2. C NR.? 381 together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) -C02- R13, (alkenyl with 2 to 6 carbon atoms) -C02-R117 (alkyl with 1 to 6 carbon atoms) -CO-alkyl with 1 to 6 carbon atoms (alkyl with 1 to 6 carbon atoms) ) -O-alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl or one of the following:
  3. 3) 2 further, R2 and R3- (Y) 0- may be combined together at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: 382 R4 is -O-Rn, NH2, NHOH, -O- (arylalkyl with 7 to 10 carbon atoms), or is of the formula: R5 is a formula of the following R6 is N or CH, R7 is hydrogen or halogen, R8 is -NH-Yi.-, -OCH2-, or -CONH-, R9 can occur from one to three times and is a halogen, alkoxy with from 1 to 6. carbon atoms, alkyl having from 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl having from 1 to 6 carbon atoms, or (alkyl having from 1 to 6 carbon atoms) -OH, or hydrogen, Ru is hydrogen or alkyl having from 1 to 6 carbon atoms, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: 383 R13 is N or CH; W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Y? are independently -CO-, -C (= 0) 0-, -S02-, or -C (= O) N (R10) -; Z is O, CH2, or N-R1X; 1 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3; with the conditions that: (1) when Y is -C (= 0) 0-, R3 can not be hydrogen; (2) when R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to tert-butyl; (3) in the pyrrolidine structures (I is 1; m is 2; n is 0; or is 0; p is 1; X is CH2), W is equal to CH2; and (
  4. 4) the compound is not 2. The compound according to claim 1, characterized in that R5 is a formula of the following: wherein R7 is hydrogen or Cl. 3. The compound according to claim 2, characterized in that R2 is hydrogen or alkyl having from 1 to 6 carbon atoms; additionally, Rj. and 384 R2 can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they bind or bind to the same carbon atom and form a ring of 5-8 carbon atoms. the formula: together with the carbon atom to which they are attached; n is 0, m is 2 and p is 0. 4. The compound according to claim 3, characterized in that R1 is hydrogen or alkyl having from 1 to 3 carbon atoms, R2 is hydrogen or alkyl having from 1 to 4 carbon atoms; additionally, Rx and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or bound to the same atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) - C02-Rxl, (alkyl having 1 to 6 carbon atoms) -CN, adamantyl, phenyl, or one of 385 of the following: (Rent C, .6) "(Rent C, .6) R4 is -0-Ru, NH2, NHOH, or is of the formula; -O-CH Rn is hydrogen or CH3, and X is S or O. The compound according to claim 3, characterized in that Rx is hydrogen; R2 is hydrogen, and R3 is (alkenyl with 2 to 6 carbon atoms) -C02-Rn, (alkyl having 1 to 6 carbon atoms) -0- (alkyl having 1 to 3 carbon atoms), ( alkyl with 1 to 6 carbon atoms) -C02RU / or one of the following: oi-R R4 is 0-R117 R6 is CH, Rn is hydrogen, R7 is hydrogen, X is S, Y is -CO-, and 1 is 1. 6. The compound as claimed in 386 claim 3, characterized in that Rx is hydrogen; R2 is hydrogen, R3 is alkyl with 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-R_ ?, (alkenyl with from 2 to 6 carbon atoms) -COa-R__, (alkyl having from 1 to 6 carbon atoms) -CO- (alkyl with from 1 to 6 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -O- (alkyl having from 1 to 3 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -CN, or one of the following: R4 is OH, R6 is CH, RX1 is hydrogen, R7 is hydrogen, X is CH2, and Y is CO- or -C (= 0) NH-. 7. The compound according to claim 2, characterized in that W is (alkyl having 1 to 3 carbon atoms), X is CH2, Y is -C (= 0) 0-, R is hydrogen, R2 is hydrogen, (alkyl having 1 to 3 carbon atoms) -C02-Rxl / o -C02-Ru, R3 is hydrogen, arylalkyl with 7 to 10 carbon atoms, alkyl having 1 to 6 carbon atoms, or (alkyl having 1 to 6 carbon atoms) -C02-Rn, R4 387 is OH, R6 is CH, RxI is hydrogen, R7 is hydrogen, 1 is 1 or 3, and n is 0. 8. The compound in accordance with as claimed in claim 2, characterized in that W is alkyl with 1 to 3 carbon atoms, X is CH2, Rx is hydrogen, R2 is (alkyl having 1 to 4 carbon atoms) -C02-Rn, or C02- Rn, R3 is hydrogen, alkyl having from 1 to 3 carbon atoms, or alkenyl having from 2 to 7 carbon atoms, R4 is OH, R6 is CH, RX1 is hydrogen, R7 is hydrogen, I is 1, m is 1 , p is 1, or is 0 and p is 1. 9. The compound according to the claim in Claim 1, characterized in that the compound is 10. The compound according to claim 4, characterized in that R3 is hydrogen; R2 is hydrogen, and R3 is alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02Rxl, (alkenyl having from 2 to 6 carbon atoms) -C02Rn, (alkyl having 1 to 6 carbon atoms) -O-alkyl with 1 to 3 carbon atoms, or one of the following: 388 -O f. { L COJ-R, - HN- I and t- R4 is O-R11, R6 is CH, Ru is hydrogen or alkyl having from 1 to 6 carbon atoms, R7 is hydrogen, X is S, Y is -C (= 0) 0-, and 1 is 1. 11. The compound according to claim 1, characterized in that R-. it is hydrogen or alkyl having from I to 3 carbon atoms and R2 is hydrogen or alkyl having from 1 to 4 carbon atoms; additionally, Rx and R2 can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms, or can be attached to the same atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) - C02-Rn, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl, phenyl or one of the following: 3 89 N (Alkyl C,,). R4 is -O-Rn, NH2, NHOH, or R4 is of the formula R n is hydrogen or alkyl having from 1 to 6 carbon atoms, and X is S or O. 12. A compound of the formula: characterized in that R_ can occur from one to four times and each occurrence is independently hydrogen or alkyl with 1 to 6 carbon atoms, and R2 is hydrogen, pyridyl, alkyl 390 with 1 to 6 carbon atoms (alkyl with 1 to 6 carbon atoms) -CO.-Rn, or -C02-R__; additionally, Rx and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they can be attached to the same carbon atom and form a ring of 5- 8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) -C02- Rn, (alkenyl with 2 to 6 carbon atoms) -C02-R -.?, (Alkyl with 1 to 6 carbon atoms) -CO-alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 carbon atoms) -O-alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl and one of the following: 391 N (C3 alkyl) 2 further, R2 and R3- (Y) 0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: R4 is -O-Rn, NH2, NHOH, -O- (arylalkyl with 7 to 10 carbon atoms) or is of the formula: R5 is a formula of the following Rβ is N or CH, R7 is hydrogen or halogen, R8 is -NH-Yi-, -0CH2-, 0 -. 0 -CONH-, R9 can occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl with 1 to 6 carbon atoms, or (alkyl with 1 to 6 carbon atoms) -OH, or hydrogen, Ru is hydrogen or alkyl with 1 to 6 carbon atoms, R12 is alkyl with 1 to 6 carbon atoms or the following formula: R13 is N or CH, W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Yx are independently -CO-, -C (= 0) 0-, -S02- , or -C (= O) N (R10) -, Z is O, CH2, or N-Ru / I is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1 , p is 0 or 1, q is 0 or 1 and r is 0, 1, 2 or 3, with the conditions that: (1) when Y is -C (= 0) 0-, R3 can not be hydrogen; (2) when R 4 is equal to 0- (C 4 -alkyl), the C 4 -alkyl is not equal to tert-butyl; (3) in the pyrrolidine structures (I is 1; m is 2; n is 0; or is 0; p is 1; X is CH2), W is equal to CH2; (4) the compound has an IC50 value of less than 5 μM. in a Jurkat CS-1 assay and / or an IC 50 value of less than 50 μM in a Jurkat EC assay; and (
  5. 5) the compound is not 393 13. A pharmaceutical composition comprising: a therapeutically effective amount of the compound as presented in any of the preceding claims; and a pharmaceutically acceptable carrier or diluent. 14. A method to treat or prevent conditions mediated by adherence? Í4ß? in a human comprising administering to a patient an effective amount of the compound in accordance with claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. '10 15. The method according to claim 14, characterized in that the condition is selected from the group consisting of rheumatoid arthritis, asthma, allergic conditions, allograft rejection, psoriasis, eczema, contact dermatitis and other inflammatory diseases. skin, inflammatory and immunoinflammatory conditions including ophthalmic inflammatory conditions and inflammatory bowel diseases, atherosclerosis and ulcerative colitis 16. The method according to claim 20, characterized in that the condition is asthma. 17. A compound of formula 25 394 characterized in that Rx can occur from one to four times and each occurrence is independently hydrogen or alkyl having from 1 to 6 carbon atoms; R2 is hydrogen, pyridyl, alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-Rn, or -C02-Rn; additionally, R-. and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or can be attached to the same carbon atom and form a ring of 5-8 carbon atoms. the formula: together with the carbon atoms to which they are attached; R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) -C02-Rj.- .. (alkenyl with 2 to 6 carbon atoms ) -C02-RX1, (alkyl having from 1 to 6 carbon atoms) -CO- (alkyl having from 1 to 6 carbon atoms), (alkyl having from 1 to 6 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -O- (alkyl having from 1 to 6 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl or one of the following: 395 further, R2 and R3- (Y) 0- may be combined with one another at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: R4 is -0-RJL !, NH2, NHOH, -0- (arylalkyl with 7 to 10 carbon atoms), or is of the formula: Rs is a formula of the following. 396 Rs is N or CH, R7 is hydrogen or halogen, R8 is -NHCO-, R9 can occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms. carbon or trifluoromethyl, R 0 is alkyl having from 1 to 6 carbon atoms, or (alkyl having from 1 to 6 carbon atoms) -OH, or hydrogen, Ru is hydrogen or alkyl having from 1 to 6 carbon atoms, Ri2 is alkyl with 1 to 6 carbon atoms or the following formula: R13 is N or CH; W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Yx are independently -CO-, -C (= 0) 0-, -S02-, or -C (= O) N (R10) -; Z is O, CH2, or N-Rn; 1 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3; with the conditions that: (1) when Y is -C (= 0) 0-, R3 can not be hydrogen; (2) when R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to tert-butyl; (3) in the structures of pyrrolidine (1 is 1, n is 2, n is 0, or is 0, p is 1, X is CH2), W is equal to CH2. 397 18. The compound according to claim 17, characterized in that R5 is a formula of the following: wherein R7 is hydrogen or Cl. 19. The compound according to claim claimed in claim 18, characterized in that R2 is hydrogen or alkyl having from 1 to 6 carbon atoms; additionally, Rx and R_ can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or joined to the same carbon atom and form a ring of 5- 8 atoms of the formula: together with the carbon atom to which they are attached; n is 0, m is 2 and p is 0. The compound according to claim 19, characterized in that Rx is hydrogen or alkyl having from 1 to 3 carbon atoms, R2 is hydrogen or alkyl having from 1 to 4 carbon atoms; additionally, Rx and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom at 398 which bind or bind to the same atom and form a ring of 5-atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) - C02-Rn, (alkyl having 1 to 6 carbon atoms) -CN, adamantyl, phenyl, or one of the following: R4 is -0-R, NH2, NHOH, or is of the formula; Rii is hydrogen or CH3, and X is S or O. 21. The compound as claimed in claim 19, characterized in that Ri is hydrogen; R2 is hydrogen, and R3 is (alkenyl having from 2 to 6 carbon atoms 399) -C02-Rn, (alkyl having from 1 to 6 carbon atoms) -0- (alkyl having from 1 to 3 carbon atoms), (alkyl with 1 to 6 carbon atoms) -C02Ru, or one of the following: R4 is 0-Ru, R6 is CH, Rn is hydrogen, R7 is hydrogen, X is S, Y is -CO-, and 1 is 1. 22. The compound as claimed in claim 19, characterized in that R it is hydrogen; R2 is hydrogen, R3 is alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-Ru, (alkenyl having from 2 to 6 carbon atoms) -C02-Rn, (alkyl) with from 1 to 6 carbon atoms) -CO- (alkyl having from 1 to 6 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -O- (alkyl having from 1 to 3 carbon atoms), (alkyl having 1 to 6 carbon atoms) -CN, or one of the following: 400 R4 is OH, R6 is CH, Rxx is hydrogen, R7 is hydrogen, X is CH2, and Y is CO- or -C (= 0) NH-. 23. The compound as claimed in claim 18, characterized in that W is (alkyl having from 1 to 3 carbon atoms), X is CH2, Y is -C (= 0) 0-, Rx is hydrogen, R2 is hydrogen, (alkyl having from 1 to 3 carbon atoms) ) -C02-Rn, or -C02-Rn, R3 is hydrogen, arylalkyl with 7 to 10 carbon atoms, alkyl with 1 to 6 carbon atoms, or (alkyl with 1 to 6 carbon atoms) -C02 -R, R4 is OH, R6 is CH, R1X is hydrogen, R7 is hydrogen, I is 1 or 3, and n is 0. 24. The compound according to claim as claimed in claim 18, characterized in that W is alkyl with 1 to 3 carbon atoms, X is CH2, Rx is hydrogen, R2 is (alkyl having 1 to 4 carbon atoms) -C02-Ru, or C02-R?: L, R3 is hydrogen, alkyl with 1 to 3 carbon atoms, or alkenyl with 2 to 7 carbon atoms, R4 is OH, R6 is CH, RX? is hydrogen, R7 is hydrogen, I is 1, m is 1, n is 1, or is 0 and p is 1. 25. The compound according to claim 17, characterized in that the compound is 401 26. The compound according to claim 20, characterized in that Rx is hydrogen; R2 is hydrogen, and R3 is alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02R1; L, (alkenyl having from 2 to 6 carbon atoms) -C0_R__, (alkyl having 1 to 6 carbon atoms) -O-alkyl with 1 to 3 carbon atoms, or one of the following: HN-N 02 1 * * v \ Y -C02-Ru N ^ C02-R, R4 is O-Rn, R6 is CH, Ru is hydrogen or alkyl having from 1 to 6 carbon atoms, R7 is hydrogen, X is S, Y is -C (= 0) 0-, and 1 is 1. 27. The compound according to claim 17, characterized in that Rx is hydrogen or alkyl having from 1 to 3 carbon atoms and R2 is hydrogen or alkyl having from 1 to 4 carbon atoms; additionally, Rx and R2 can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms, or can be attached to the same atom and form a ring of 5-8 atoms of the formula: 402 together with the carbon atom to which they are attached; R3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) - C02-R__, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl, phenyl or one of the following: N (C3, C3 alkyl) 2 R4 is -O-R11, NH2, NHOH, or R4 is of the formula -D-CH2 - or Rn is hydrogen or alkyl having 1 to 6 carbon atoms, and X is S or O. 28. A compound of formula: 403 characterized in that R can occur from one to four times and each occurrence is independently hydrogen or alkyl having from 1 to 6 carbon atoms; R2 is hydrogen, pyridyl, alkyl having from 1 to 6 carbon atoms (alkyl having from 1 to 6 carbon atoms) -C02-Ru, or -C02-Rn, - additionally, Rx and R2 can be attached to the same atom carbon and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they can be attached to the same carbon atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) -C02- Rn, (alkenyl with 2 to 6 carbon atoms) -C02-Rn, (alkyl with 1 to 6 carbon atoms) -CO-alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 atoms carbon) -O-alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl and one of the following : - (Alkyl C, .
  6. 6) 404 N (Alkyl C, -) - further, R2 and R3- (Y) 0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are united: - R 4 is -O-Ru, NH 2, NHOH, -0- (arylalkyl with 7 to 10 carbon atoms) or is of the formula: -O-CH 2 -I R5 is a formula of the following R6 is N or CH, R7 is hydrogen or halogen, R8 is -NHCO-, R9 can be present from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms. carbon or trifluoromethyl, R10 is alkyl having from 1 to 6 carbon atoms, or (alkyl having from 1 to 6 carbon atoms) -OH, or hydrogen, R31 is hydrogen or alkyl having from 1 to 6 carbon atoms, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: R13 is N or CH, W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Yi are independently -CO-, -C (= 0) 0-, -S02- , or -C (= O) N (R10) -, Z is 0, CH2, or NR ^, I is 1, 2 or 3, m is 1 or 2, rt is 0 or 1, or is 0 or 1, p is 0 or 1, q is 0 or 1 and r is 0, 1, 2 or 3, with the conditions that: (1) when Y is -C (= 0) 0-, R3 can not be hydrogen; (2) when R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to tert-butyl; (3) in the pyrrolidine structures (1 is 1, m is 2, n is 0, or is 0, p is 1, X is CH2), W is equal to CH2; and (4) the compound has an IC50 value of less than 5 μM in Jurkat CS-1 assay and / or an IC50 value of less than 50 μM in a Jurkat EC assay. 29. A compound of the formula: 406 characterized in that, Rx can be presented from one to four times and in each occurrence is independently hydrogen or alkyl with 1 to 6 carbon atoms; R2 is hydrogen, pyridyl, alkyl having 1 to 6 carbon atoms, (alkyl having 1 to 6 carbon atoms) -C02-Rn, or -C02-Ru, - in addition, Rx and R2 can be attached to the same atom of carbon and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they can be attached to the same carbon atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) -C02- Rny (alkenyl with 2 to 6 carbon atoms) -C02-R117 (alkyl with 1 to 6 carbon atoms) -CO-alkyl with 1 to 6 carbon atoms (alkyl with 1 to 6 carbon atoms) -O-alkyl having from 1 to 6 carbon atoms, (alkyl with 407 of 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl or one of the following: further, R2 and R3- (Y) U- may be combined together at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which they are attached: R 4 is -O-Ru, NH 2, NHOH, -O- (arylalkyl with 7 to 10 carbon atoms), or is of the formula: -O-CH. rx 408 R5 is a formula of the following: R6 is N or CH, R7 is hydrogen or halogen, R8 is -OCH2-, R9 can occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms. carbon or trifluoromethyl, R10 is alkyl having from 1 to 6 carbon atoms, or (alkyl having from 1 to 6 carbon atoms) -OH, or hydrogen, Ru is hydrogen or alkyl having from 1 to 6 carbon atoms, Rx2 is alkyl having from 1 to 6 carbon atoms or the following formula: R 3 is N or CH; W is (alkyl having 1 to 6 carbon atoms), X is S, O, or CH2, Y and Y3 are independently -CO-, -C (= 0) 0-, -S02-, or -C (= O) N (R10) -; Z is O, CH2, or N-Rn; 1 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, q is 0 or 1, and r is 0, 1, 2 or 3; with the conditions that: (1) when Y is -C (= 0) 0-, R3 can not be hydrogen; (2) when R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to tert-butyl; (3) in the pyrrolidine structures (1 is 1, m is 2, n is 0, or is 0, p is 1, X is 409 CH2), W is equal to CH2; (4) when R3 is phenyl, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-Rn, (alkyl having from 1 to 6 carbon atoms) -0- (alkyl having from 1 to 6 carbon atoms), or (alkyl having from 1 to 6 carbon atoms) -OH, or is 0; and (5) the compound is not 30. The compound according to claim as claimed in claim 29, characterized in that R5 is a formula of the following: wherein R7 is hydrogen or Cl. 31. The compound according to claim 30, characterized in that R2 is hydrogen or alkyl having from 1 to 6 carbon atoms; additionally, Rx and R2 can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or bound to the same carbon atom and form a ring of 5-8 Formula atoms: 410 together with the carbon atom to which they are attached; n is 0, m is 2 and p is 0. 32. The compound as claimed in claim 31, characterized in that R is hydrogen or alkyl having from 1 to 3 carbon atoms, R2 is hydrogen or alkyl having from 1 to 4 carbon atoms; additionally, Ri and R2 can be attached to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached or bound to the same atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) - CO.-Ru, (alkyl having from 1 to 6 carbon atoms) -CN, adamantyl, phenyl, or one of the following: 411 )2 R 4 is -0-Rll NH 2 NH NHOH, or is of the formula; Rn is hydrogen or CH3, and X is S or O. 3.3. The compound according to claim 31, characterized in that R_ is hydrogen; R2 is hydrogen, and R3 is (alkenyl having 2 to 6 carbon atoms) -C0_-R? A., (Alkyl having 1 to 6 carbon atoms) -O- (alkyl having 1 to 3 carbon atoms) ), (alkyl having 1 to 6 carbon atoms) -C02R11 (or one of the following: R4 is O-Ru, R6 is CH, Ru is hydrogen, R7 is hydrogen, X is S, Y is -CO-, and I is 1. 34. The compound as claimed in claim 31, characterized by Rx it is hydrogen; R2 is hydrogen, R3 is alkyl with 1 to 6 carbon atoms, 412 (alkyl with 1 to 6 carbon atoms) -C02-Rn, (alkenyl with 2 to 6 carbon atoms) -C03-Ru, ( alkyl having from 1 to 6 carbon atoms) -CO- (alkyl having from 1 to 6 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -O- (alkyl having from 1 to 3 carbon atoms), (alkyl having from 1 to 6 carbon atoms) -CN, or one of the following: R4 is OH, R6 is CH, RX1 is hydrogen, R7 is hydrogen, X is CH2, and Y is CO- or -C (= 0) NH-. 35. The compound according to claim 30, characterized in that W is (alkyl having from 1 to 3 carbon atoms), X is CH2, Y is -C (= 0) 0-, Rx is hydrogen, R2 is hydrogen, (alkyl having from 1 to 3 carbon atoms) -C02-R1; L, or -C02-Rn, R3 is hydrogen, arylalkyl with from 7 to 10 carbon atoms, alkyl having from 1 to 6 carbon atoms , or (alkyl having 1 to 6 carbon atoms) -C02-Rn, R4 is OH, R6 is CH, Ru is hydrogen, R7 is hydrogen, I is 1 or 3, and n is 0. 413. The compound according to claim 30, characterized in that W is alkyl having from 1 to 3 carbon atoms, X is CH2, Rx is hydrogen, R2 is (alkyl having from 1 to 4 carbon atoms) -C02-Rn, or C02-Rn, R3 is hydrogen, alkyl with 1 to 3 carbon atoms, or alkenyl with 2 to 7 carbon atoms, R4 is OH, R6 is CH, R1X is hydrogen, R7 is hydrogen , I is 1, m is 1, n is 1, or is 0 and p is 1. 37. The compound according to claim 29, characterized in that the compound is 38. The compound according to claim 32, characterized in that Rx is hydrogen; R 2 is hydrogen, and R 3 is alkyl having from 1 to 6 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02R 17 (alkenyl having from 2 to 6 carbon atoms) -C02Rn, (alkyl having from 1 to 6 carbon atoms) -O-alkyl with 1 to 3 carbon atoms, or one of the following: 414 -or. HN-N N02 J * W ~ CC.-R? COrR ,, R4 is O-Rn, R6 is CH, Rn is hydrogen or alkyl with 1 to 6 carbon atoms, R7 is hydrogen, X is S, Y is -C (= 0) 0-, and 1 is 1 39. The compound as claimed in claim 29, characterized in that Rj. it is hydrogen or alkyl having from 1 to 3 carbon atoms and R2 is hydrogen or alkyl having from 1 to 4 carbon atoms; additionally, Rx and R2 can be attached to the same carbon atom and can form a carbocyclic ring of 5-8 atoms, or can be attached to the same atom and form a ring of 5-8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -OH, (alkyl having from 1 to 6 carbon atoms) - C02-Rn, (alkyl having 1 to 6 carbon atoms) -CN, adamantyl, phenyl or one of the following: 415 N (Alkyl C j.3) 2 R4 is -O-Rn, NH2, NHOH, or R4 is of the formula R31 is hydrogen or alkyl having from 1 to 6 carbon atoms, and X is S or O. 40. A compound of the formula: characterized in that Rx can occur from one to four times and each occurrence is independently hydrogen or alkyl having from 1 to 6 carbon atoms, and R2 is hydrogen, pyridyl, alkyl having from 1 to 6 carbon atoms (alkyl having from 1 to 6) carbon atoms) -C02-Ru, or -C02-Rn; additionally, Rx and R2 can be linked to the same carbon atom and form a carbocyclic ring of 5-8 atoms together with the carbon atom to which they are attached, or they can be attached to the same carbon atom and form a ring of carbon. -8 atoms of the formula: together with the carbon atom to which they are attached; R3 is hydrogen, phenyl, alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 6 carbon atoms, arylalkyl with 7 to 17 carbon atoms, (alkyl with 1 to 6 carbon atoms) -CO2- R1: L, (alkenyl with 2 to 6 carbon atoms) -C02-Ru, (alkyl with 1 to 6 carbon atoms) -CO-alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 carbon atoms) -O-alkyl with 1 to 6 carbon atoms, (alkyl with 1 to 6 carbon atoms) -OH, (alkyl with 1 to 6 carbon atoms) -CN, adamantyl and one of the following: 417 ilo C, .3) 2 further, R2 and R3- (Y) 0- may combine with each other at the terminal thereof to form a ring of the following formula together with the carbon atom and the nitrogen atom to which They are united : R4 is -O-Rii, NH2, NHOH, -O- (arylalkyl with 7 to 10 carbon atoms) or is of the formula: R5 is a formula of the following: R6 is N or CH, R7 is hydrogen or halogen, R8 is -OCH2-, R9 can occur from one to three times and is a halogen, alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms or trifluoromethyl, R10 is alkyl having 1 to 6 carbon atoms, or (alkyl having 1 to 6 carbon atoms) -OH, or 418 hydrogen, R1X is hydrogen or alkyl having 1 to 6 carbon atoms, R12 is alkyl having from 1 to 6 carbon atoms or the following formula: R 3 is N or CH, W is (alkyl having from 1 to 6 carbon atoms), X is S, O, or CH 2, Y and Y x are independently -CO-, -C (= 0) 0-, - SOa-, or -C (= O) N (R10) -, Z is O, CH2, or N-Rllf 1 is 1, 2 or 3, m is 1 or 2, n is 0 or 1, or is 0 or 1, p is 0 or 1, q is 0 or 1 and r is 0, 1, 2 or 3, with the conditions that: (1) when Y is -C (= 0) 0-, R3 can not be hydrogen; (2) when R 4 is equal to O- (C 4 -alkyl), the C 4 -alkyl is not equal to tert-butyl; (3) in the pyrrolidine structures [1 is 1; m is 2; n is 0; or is 0; p is 1; X is CH2), W is equal to CH2; (4) the compound has an IC50 value of less than 5 μM in Jurkat CS-1 assay and / or an IC50 value of less than 50 μM in a Jurkat EC assay; (5) when R3 is phenyl, alkyl having from 1 to 6 carbon atoms, arylalkyl having from 7 to 17 carbon atoms, (alkyl having from 1 to 6 carbon atoms) -C02-Rn, (alkyl having from 1 to 6 carbon atoms) -O- (alkyl having from 1 to 6 carbon atoms), or (alkyl having from 1 to 6 carbon atoms) -OH, or is 0; and "(6) the compound is not
MXPA00012765A 1998-06-23 1999-06-23 INHIBITORS OF alpha4. MXPA00012765A (en)

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