MXPA98005254A - Vitronect receptor antagonists - Google Patents

Vitronect receptor antagonists

Info

Publication number
MXPA98005254A
MXPA98005254A MXPA/A/1998/005254A MX9805254A MXPA98005254A MX PA98005254 A MXPA98005254 A MX PA98005254A MX 9805254 A MX9805254 A MX 9805254A MX PA98005254 A MXPA98005254 A MX PA98005254A
Authority
MX
Mexico
Prior art keywords
carbon atoms
acid
alkyl
mmol
compound
Prior art date
Application number
MXPA/A/1998/005254A
Other languages
Spanish (es)
Inventor
Samanen James
E Bondinell William
E Ali Fadia
H Miller William
Wen Fu Ku Thomas
M Keenan Richard
Original Assignee
E Ali Fadia
E Bondinell William
M Keenan Richard
Wen Fu Ku Thomas
H Miller William
Samanen James
Smithkline Beecham Corporation
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 E Ali Fadia, E Bondinell William, M Keenan Richard, Wen Fu Ku Thomas, H Miller William, Samanen James, Smithkline Beecham Corporation filed Critical E Ali Fadia
Publication of MXPA98005254A publication Critical patent/MXPA98005254A/en

Links

Abstract

Described are compounds of the formula (I) in which: A is a template of fibrinogen antagonists, W is a linker portion having the form -) CHRg = aU- (CHRg) b- V-; Q1, Q2, Q3 and Q4 are independently N or C-Ry, provided that not more than one of Q1, Q2, Q3, Q4 is N; R 'is H or alkyl of 1 to 6 carbon atoms, C3-7 cycloalkyl-alkyl of 0 to 6 carbon atoms or Ar-alkyl of 0 to 6 carbon atoms, Rg is H or alkyl of 1 to 6 carbon atoms, Het alkyl of 0 to 6 carbon atoms, C3-7 cycloalkyl-alkyl of 0 to 6 atoms of carbon, or Ar-alkyl of 0 to 6 carbon atoms, Rk is Rg, -C (O) Rg or C (O) ORg, Ri is H, alkyl of 1 to 6 carbon atoms, Het alkyl of 0 to 6 carbon atoms, C3-7cycloalkyl-alkyl of 0 to 6 carbon atoms, Ar-alkyl of 0 to 6 carbon atoms, Het-alkyl of C0-6-U'-alkyl of 1 to 6 carbon atoms, C3-7-alkylcycloalkyl-alkyl of C0-6-U'-alkyl of 1 to 6 carbon atoms or Ar-alkyl of C0-6-U'-alkyl of 1 to 6 car atoms bond: Ry is H, halogen, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S (O) -, -CO2Rg, -CORg or -CONRg2, or alkyl of 1 to 6 carbon atoms, optionally substituted with halogen, -ORg-SRg, -CN, -NRgR '", -NO2, CF3, R'S (O) 3-, CO2Rg, -CORg or -CONRg2; U and V are absent or are CO, CRg2, C (= CRg2), S (O) c, O, NRg, CRgORg, CRg (ORk) CRg2, CRg2CRg (ORk), C (O) CRg2, CRg2C (O), CONRi, NRiCO, OC (O), C ( O) O, C (S) O, OC (S), C (S) NRg, NRgC (S), S (O) 2NRg, NRgS (O) 2N = N, NRgNRg, NRgCRg2, NRgCRg2, CRg2O, OCRg2, CRg = CRg, C = C, Ar or Het, a is 0, 1, 2 or 3, b is 0, 1, or 2, c is 0, 1 or 2, r is 0, 1, or 2; 0 or 1: or its pharmaceutically acceptable salts, which are antagonists of the vitronectin receptor, useful in the treatment of osteoporos

Description

VITRONECTINE RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This invention relates to pharmaceutically active compounds that inhibit the vitronectin receptor and are useful for the treatment of inflammation »cancer and cardiovascular disorders, such as atherosclerosis and restenosis» and to diseases in which bone resorption is a factor.
BACKGROUND OF THE INVENTION Integrins are a superfamily of adhesion receptors A cells, which are transmembrane glycoproteins, expressed in a variety of cells. These cell surface adhesion receptors include gpIIb / IIIa, in fibrinogen receptor and v3, the vi ronectin receptor.
The fibrinogen receptor gpIIb / IIIa is expressed on the surface of the platelet and mediates the aggregation of platelets and the formation of a hemostatic clot at the site of a bleeding wound. Philips and co-authors, BTood »1988, 71, 831.
The vitronectin receptor c.vß3 is expressed in numerous cells "including endothelial cells, smooth muscle, osteoclasts and tumor cells and, in that way" have a variety of functions. The receptor at 33 is expressed in the membrane of osteoclast cells mediates the process of bone resorption and contributes to the development of osteoporosis. Ross and coauthors, J. Biol. Chem. 1987, 262, 7703, Fisher and co-authors, Endoc inology 1993, 132, 1411; Bertoli "and co-inventors, Bone Min. Res., 6, Suppl 1, S146, 252, EP 528 587 and 528 586. The avt33 receptor expressed in human aortic smooth muscle cells stimulates their migration to the neointima, What leads to the formation of atherosclerosis and restenosis after angioplasty, Brown and co-authors, Cardiovascular Res. 1994, 28, 1815. Aditionally, a recent study has shown that an av? 33 antagonist is capable of promoting tumor regression by inducing apoptosis of angi ogenic blood vessels BrooKs and coauthors, Cel 1, 1994, 79, 1157. Thus, agents that block the tronecti receptor would be useful for treating diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer Alig and co-inventors, EP 0 381 033, Hartman and co-venitors, EP 0 540 443, Blackb? rn and co-venitors, WO 93/08174, Bondinell and co-venitors, WO 93/00095, BlacKburn and co-inventors, WO 95/04057., Egbertson and covenant Res, EP 0 478 328, Sugihara and co-inventors, EP 529 858, Porter and co-inventors EP 0 542 363 and Fisher and co-inventors EP 0 635 492, describe certain compounds that are useful for inhibiting the fibrinogen receptor. PCT / US95 / 08306, filed June 29, 1995 (SmithKline Beecham Corp.) and PCT / US95 / OT146, filed June 29, 1995 (Spp h line Beecham Corp.), describe selective vi-ronectin receptor antagonists. . However, there are few reports of compounds that are potent antagonists of the vi-ronectin receptor. It has now been discovered that certain appropriately substituted aminopyrimidine compounds are potent inhibitors of the vitronectin receptor. In particular, it has been discovered that the pyridine portion can be combined with an ibrinogen antagonist template to prepare compounds that are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.
BRIEF DESCRIPTION OF THE INVENTION This invention comprises compounds of the formula (I) which are subsequently cisplated, which have armacological activity for the inhibition of the vi tronectin receptor and which are useful for the treatment of inflammation, cancer, cardiovascular disorders, such as atherosclerosis and restenosis, and diseases in which bone resorption is a factor, such as osteoporosis. This invention is also a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. This invention is also a method for treating diseases that are mediated by the vi tronectin receptor.
In a particular aspect, the compounds of this invention, the compounds of this invention with useful for treating atherosclerosis »restenosis» inflammation, cancer and osteoporosis.
DETAILED DESCRIPTION The invention comprises novel compounds that are more potent inhibitors of the vi-ronectin receptor than the fibrinogen receptor. The compounds of the present invention comprise a fibrinogen receptor antagonist template which is linked to an optionally substituted 2-p-rα-diamine portion, according to formula (I): (D where: A is a template of Br? Nógens antagonist; W is a linking portion of the formula - (CHR °) a? -U- (CHR =), SV; Q »Q-2 and Q3 i are dependently N or CR * "-, provided that no more than one of Q-3, Qs> Q-3 and Q- * are N; R * is H or alkyl of 1 to S carbon atoms , cycloalkyl of C3-, - alkyl of O to 6 carbon atoms or Ar-to the chyle of O to S carbon atoms; R ° is H or alkyl of 1 to 6 carbon atoms, Het-to the chyle of 0 to 6 carbon atoms »C3-cycloalkyl, -alkyl of 0 to 6 carbon atoms or Ar-aT-chyl of 0 to 6 atoms of carbon; R't is H, alkyl of 1 to 6 carbon atoms »Het-alkyl of 0 to 6 carbon atoms, cycloalkyl of C3_v-alkylo of O to 6 carbon atoms» Ar-to the quilo of O to 6 atoms of carbon carbon, Het- alkyl of C0_É3-U * -a1 qui 1 of 1 to S carbon atoms-, cycloalkyl of C3 _-, -alkyl of C0_ < 3-U r-to the one of 1 to 6 carbon atoms- or Ar-alkyl of C0 _ ^ - W-to the uilo of 1 to S carbon atoms-. R > - is H. halogen, OR ", -SR», -C ^ it -NR »R, -N0Z, -CF3, - CF3S (0),» - O ^ ß, -COR »or -CONR» -, or alkyl of 1 to 6 carbon atoms optionally substituted by halogen, -OR », -SRβ» -CN, -NR «R", - Oa »-CF3, R'SCO) 3, -C02R» or -CONRβ; U and V are absent or are CO, CR «2» C (= CR »2), S (0) c, O, NR», CR »OR«, CR «(0R") CR «a? CR »2CR« (OR *), C (0) CR «2, CR» 2C < 0), CONR *, NR-'CO, 0C (0), C (0) 0, C (S) 0, OC (S), C (S) NR », NR« C (S), S (0 ) aNR «» NR »S (O) ZN = N, NR» NR », N ^ CRß ^, NR« CR »- ,, CR» 20, OCR * = 2, CR »= CR», C = C, Ar or Het; a is 0, 1, 2 or 3; b is O, i or 2; c is o, l or 2; u is o or i; and their pharmaceutically acceptable salts. Preferably Q * -, Qz, Q3 and Q "** are all CH; and u is o .. Suitably, Rt is H and R" is H or alkyl of 1 to 4 carbon atoms. A fibrinogen receptor antagonist is an agent that inhibits the binding of fibrinogen to the platelet-bound fibrinogen GPIIb-Illa receptor. Many fibrinogen antagonists are known in the art. As used herein, the term "ibrinogen receptor antagonist template" means the central structure of a fibrinogen receptor antagonist, said central portion containing an acidic group and being linked to an organic group substituted with a of basic nitrogen. Typically, the core structure adds some form of rigid separation between the acid portion and the basic nitrogen portion, and contains one or more ring structures or amide bonds to effect this. It is preferred that from 12 to 15, better still, from 13 to 14 intermediate covalent ligations, exist through the shorter intramolecular path between the acid group of the fibrinogen receptor antagonist template and the nitrogen of the substituent or to the ino pi pi na portion of the formula (I). It is an object of this invention that a fibrinogen receptor antagonist is converted to a vitronectin receptor antagonist by replacing the basic nitrogen group in? N f? Br? Nogen receptor antagonist with a pyr? D-2? Optionally substituted l-amino. In addition, the number of intermediate covalent bonds between the acid portion and the nitrogen of the substituent or ammonium in the pin ring will be from 2 to 5, preferably three or four, covalent bonds shorter than the number. of intermediate covalent ligations between the acid portion and the basic nitrogen group of the fibrinogen antagonist The identity of the linker portion W may be selected to obtain the appropriate separation between the acid portion of the fibrinogen antagonist and the nitrogen atom of the ridiculous., a fibrinogen antagonist will have a tramolecular distance of about 16 angstroms, between the acidic portion (for example, the atom that yields the proton or accepts the electron pair) and the basic portion (for example, the one that accepts a proton). or donate a pair of electrons) while the vitronectin antagonist will have about 14 angstroms between the respective acid and basic centers. For illustrative purposes, by using the fibrinogen antagonist template 7-2, 3,4'-tetrahydro-3-o? O-4-methyl-1-benzoyazepi a, described in WO 93/08174, as a Adequate fibrinogen antagonist template »is converted to the acid compound (R, S) -7-CCC4- (ami noiminómeti 1) fe" 13ami o_lcarbon? 13-4- (2-feni leti 1) -1,3, 4 , 5-tetrahydro-3-oxo-2H-1,4-ben? Od? Azep? N-2-acetic, which is a selective and potent fibrinogen antagonist, to a potent and selective vitronectin receptor antagonist, replacing the portion 4- (ami nominomethyl 1) feni lo with the portion (pir? d-2-i 1) eti 1. As illustrated below in Fig. 1, in the first case, there are 16 intermediate covalent bonds between the acid portion and the basic portion; while in the fibrinogen antagonist, in the latter case, there are thirteen intermediate covalent linkages in the vronectin antagonist of this invention.
Figure 1 In fact, the 4- (amidocinomethyl) fem portion is a substitute and common in the fibrinogen antagonist templates known in the art, and the simple replacement of this portion with a portion (pi id-2-i 1) optionally substituted, it may serve as a guide for converting the known fibrinogen template compounds to vitronectin receptor antagonists, and also include, in this invention, the pharmaceutically acceptable addition salts, the complexes and the prodrugs The compounds of this invention are considered to be any covalently bonded carriers that release the active parent drug according to formula (I) in vivo, in cases where the compounds of this invention may have one or more chiral centers "unless otherwise specified, this invention includes each of the unique non-racemic compounds that can be synthesized and be resolved by conventional techniques. In cases where the compounds have carbon-to-carbon double-unsaturated ligatures, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases where compounds can exist in tautomeric forms, such as OR OR 'the keto-enol tautomers, for example: ^ - "^ and .---« ss- and each tautomeric form is included within this invention, whether it exists in equilibrium or is assured in a way by substitution. suitable with Rt. The compounds of the formula (I) inhibit the binding of vi tronecti and other peptides containing RGD to the vitronectin receptor (vS3) .Inhibition of the vitronectin receptor in osteoclasts inhibits osteoclastic bone resorption and is useful in the treatment of diseases in which bone resorption is associated with the pathology, such as osteoporosis, in addition, since the compounds of the present invention inhibit the vitronectin receptors in numerous different types of cells, said compounds would be useful in the treatment of inflammation and cardiovascular diseases »such as atherosclerosis and restenosis, and would be useful as antimetastatic and antitumor agents The following Table I describes certain fibrinogen receptor antagonists, whose central structures are useful for carrying out the present invention. Reference should be made to patent applications and their publications for their full descriptions, which include the methods for preparing the templates and the specific compounds that incorporate such templates. The full description of the annotated patent applications and other annotated publications is incorporated herein by reference, as if it were made completely. The following list is not intended to limit the scope of the invention, but only illustrates some known templates.
TABLE I Adir et Co pagnie FR 928004, June 30, 1992 »Fauchere, J.L. and co-inventors, EP 0578535, June 29, 1993, Fauchere, J.L. and co-inventors, CA 21285SO, dated January 24, 1995, Godfroid, J-J and co-inventors.
Aßahi Breweries, Ltd. JP 05239030, September 17, 1993.
Asahi Glass WO 90/02751, Ohba, M. and coi ventores, September 9, 1989, WO 90/115950, March 22, 1990, Ohba, M, and co-inventors. EP 0406423, of January 9, 1991. WO 92/09627, Isoai, A. and coi ventores, of November 29, 1991.
Cassella AS DE 4207254, (Der 93-289298-37) of March 7, 1992, Zoller, G. and coinventores, EP 93904010, of February 24, 1993, EP 0565896 »of March 18, 1993, Kli ger, O. and co-inventors. EP 0566919 (Der 93-338002 / 43) of April 3, 1993, Zoller, G. and coinventores, EP 580008 (Der 94-027663 / 04) of July 6, 1993, Zoller »G. and co-inventors, DE 224424, July 6, 1993, Zoller, T. and coinventores, discloses, EP 584694 (Der 94-067259 / 09) of April 2, 1994, DE 4301747 (der 94-235891 / 29) of the July 28, 1994, Zoller and co-inventors, DE 4308034 (Der 94-286666 / 36) of September 15, 1994, Klinger »O. and co-inventors, DE 4309867, dated September 29, 1994, Klínger» O. and co-inventors .
Chiron WO 93/07169 (Der 93-134382 / 16) of March 15, 1993, Devlí, J.J. and coi ventores.
Ciba Geigy EP 0452210 (Der 91-305246 / 42) of April 5, 1990, EP 0452257, of March 26, 1991, Alien and co-inventors.
COR Therapeutics WO 90/15620"of June 15, 1990, EP 0477295, April 1, 1992, Scarborough and co-inventors.
WO 92/08472 »of May 29, 1992, Scarborough and coi ventores. WO 93/223356, dated April 27, 1993, Swift and co-inventors, EP 0557442, September 1, 1993 Scarborough and coi ventores. Scarborough, and co-inventors J. Biol. Chem., 266, 9359, 1991.
Daiichi Pharm Co Ltd. JP 05078344-A (Der 93-140339 / 17), March 30, 1993, DuPont MercK WO 93/07170, April 15, 1993 »WO 94/11398, May 26, 1994 , Wells and co-inventors, IL 109237 of July 31, 1994. WO 94/22909 (Der 94-333113 / 41) of October 13, 1994, DeGrado and coi ventores. WO 94/22910 (Der 94-333114 / 41) of October 13, 1994, DeGrado and co-inventors, WO 94/22494 (Der 94-332838 / 41) dated October 13, 1994, DeGrado and coi ventores. EP 625164, of November 23, 1994, Degrado and co-inventors, Mousa and co-inventors, Circulation, 89, 3, 1994. JacKson J. Amer. Chem. Soc., 116, 3220, 1994.
Elle Ind Farma Spa GB 2207922 of August 3, 19BB.
Farmi tal ia Erba SRL Cario EP 611765 (Der 94-265375 / 33), of August 24, 1994, Cozzi, and co-inventors.
Fuji Photo Film JP 04208296-A (Der 92-303598 / 38) of November 30, 1990, JP 04213311-A (Der 92-305482 / 38), of November 27, 1990, JP 04217693-A (Der 92- 312284/38) of October 23, 1990, JP 04221394-A (Der 92-313678 / 38) of October 26, 1990, JP 04221395-A (Der 92-313679 / 38) of October 26, 1990, JP 04221396-A (Der 92-313680 / 38) of October 26, 1990, JP 04221397-A (Der 92-313681 / 38) of December 20, 1990, EP 0482649 A2, of April 29, 1992, Koj? Ma and co-inventors, EP 048B258A2, dated June 3, 1992, Komazawa and co-inventors, EP 503301-A2, dated February 14, 1991, Kitaguch? and coi ventores, JP 05222092, of May 21, 1993, N? s? Kawa and co-inventors, JP 06239885 (Der 94-313705 / 39) of August 30, 1993, Nishikawa and coi ventores »WO 9324448 (Der 93-405663 / 50) of December 9, 1993, Nishikawa and coi ventores, JP 06228189 (Der 94-299801 / 37) of August 16, 1994, EP 619118 (Der 94-311647 / 39) of October 12, 1994, Nishikawa and co-inventors.
Fujisawa EP 0513675, of May 8, 1992, Ume ita and coi ventores, WO 9409030-A1, of April 28, 1994, Takasugi and co-inventors, EP 0513675 (Der 92-3835B9 / 47), WO 9500502, of 5 January 1995, Oku and co-inventors, FR 144633, Thromb Haem, 69, 706, 1993 Cox and coinventores, Thromb, Haem. 69, 707, 1993.
Genentech WO 90/15072 (Der 91007159), WO 91/01331 (Der 91058116) of July 5, 1990, Barker and co-venitors, WO 91/04247, September 24, 1990, Webb, WO 91/11458 (Der 91252610 ) of January 28, 1991 »Barker and coi ventores, WO 92 / 07B70, dated October 24, 1991, B? rm'er and co-inventors» WO 92/17492, of October 15, 1992, B? Rnier and co-inventors, CA 2106314 of October 6, 1992, B? Rnier and co-inventors.
WO 93/08174, of October 15, 1991, Blackburn and coi ventores, CA 2106314 of October 6, 1992, Burnier and coi ventores.
EP 0555328, of August 18, 1993, Burnier and co-inventors. WO 95/04057, February 9, 1995, Blackburn and co-inventors, Scarborough and co-authors, J. Biol. Chem. 26B, 1066, 1993. Dennis and coauthors, Proc. Nati Acad. Sci. USA, B7, 2471, 1989.
Barker and co-authors J. Med. Chem. 35, 2040, 1992. McDoweli; Gadek, T.R., J. Amer. Chem. Soc., 114, 9245, 1992.
Glaxo EP 537980, October 13, 1992, Porter and coi ventores, EP 0542363 of November 10, 1992, Porter and coi ventores » WO 93/22303, of January 11, 1993, Middlemiss et coi ventores, WO 93/22303, of January 11, 1993, Middlemiss et coi ventores, WO 93/14077, of January 15, 1993, Porter and coinventores » EP 609282 Al, of August 10, 1994, Porter and co-inventors, EP 612313, of August 31, 1994, Porter and co-inventors, EP 93911769, of April 20, 1994, Mi dlemíss y coi ventores. EP 637304 Al, February 8, 1995, Meddlemíss and coi ventores, Hann, and coauthors, An Investigation of the Bioactive Conformation of ARG-GLY-ASP Containing Cyclic Peptides and Snake Venom Peptides Which Inhibit Human Platelet Aggregation, in Molecular Recognition: Chemical and Biochemical Problems II ", SM Roberts, Ed. The Royal Society of Chemistry, Cambridge, 1992. Ross, BC," Nonpeptide Fibrinogen Receptor Antagonists ", (SAR that led to the discovery of GR144053) at Seventh RSC-SCI Medical Chemistry Symposium , The Royal Society of Chemistry and Fine Chemicals and Medicines Group and SCI Fine Chemicals Group, ChurchiTl College, Cambridge, 1993, L20, P? Ke and Quaternors, Thromb. Haem, 69, 1071, 1993.
Hoechst DE 4009506, dated March 24, 1990, Ko 'g and co-inventors, Hoffmann-La Roche AU 9344935 (Der 94-11878315) of March 10, 1994, EP 0592792, of April 20, 1994, Bannwarth and co-inventors, Kogyo Gijutsuín JP 06179696 of June 28, 1994.
Kyowa Hakko Kogyo KK JP 05078244-A, March 30, 1993.
Laboratoire Chauvin WO 9401456, of January 20, 1994, Regno? F and coi ventores.
La Jolia Cancer Res. Fndn WO 9500544, January 5, 1994, Pierschbacher and co-inventors. US 079441, of January 5, 1994, Pierschbacher and coi ventores.
Lilly / COR EP 635492, January 25, 1995, Fisher and co-inventors.
Medical University of South Carolina EP 587770, dated March 23, 1994, Halushka and co-inventors.
Merck EP 0368486 (Dei-149427/20) of November 10, 1988, EP 0382451 (Der 90248531), EP 0382538 (Der 90248420), EP 0410537, July 23, 1990, Nutt et coi ventores, EP 0410539, del July 25, 1990, Nutt and co-inventors »EP 0410540, July 25, 1990, N? Tt and co-inventors, EP 0410541, July 25, 1990, Nutt et coi ventores, EP 0410767, July 26, 1990 , Nutt and co-inventors »EP 0411833, of July 26, 1990, Nutt and coi ventores, EP 0422937 of October 11, 1990, Nutt and co-inventors, EP 042293B of October 11, 1990, Nutt and coi ventores, EP 0487238, of October 13, 1991, Connolly and co-inventors, EP 0437367 (Der 91209968), Sato and co-inventors, EP 576898, January 5, 1994, Jonczyk and co-inventors, WO 9409029"of April 28, 1994, Nutt et coi ventores, EP 61B225 (Der 94-304404 / 38) of October 5, 1994. DE 4310643 (Der 94-311172 / 39), of October 6, 1994, Jonczyk and co-inventors, NO 9404093, of October 27, 1994, Jonczyk Y co-inventors. EP 0632053, of January 4, 1995, Jonczyk and co-inventors, EP 0479481, of September 25, 1991, Duggan and coi ventores, EP 0478328, September 26, 1991, Egbertson and co-inventors, EP 0478362, of September 27, 1991, D? Ggan and coinventores, EP 0478363, of September 27, 1991, Laswel 1 and coinventores, EP 0512829, of May 7, 1992, Duggan and co-inventors, EP 0512831, of 7 May 1992, Duggan and co-inventors » EP 0528586 »of August 5, 1992» Egbertson and co-inventors, EP 0528587, of August 5, 1992, Egbertson and co-inventors, EP 0540334, of October 29, 1992, Hartman and co-inventors, US 5227490, of February 21, 1992, Hartman and co-inventors, CA 2088518, of February 10, 1993, Egbertson and coi ventores, US 5206373-A (Der 93-151790 / 18) of April 27, 1991, Chung and co-inventors, WO 9316994 (Der 93-288324 / 36), September 2, 1993, Chung and co-inventors, US 5264420-A, of November 23, 1993, US 5272158, of December 21, 1993, Hartman and co-inventors, US 5281585, of January 25, 1994, Ihle et coi ventores, GB 945317 A, March 17, 1994 GB 2271567 A, dated April 20, 1994, Hartman and co-inventors, US 5294616 (Der 94-091561 / 11) of March 15, 1994, Egbertson and co-inventors. US 5292756 (Der 94-0B2364) of April 8, 1994, Hartman and co-inventors. WO 9408577, dated April 28, 1994, Hartman and co-inventors.
WO 9408962, dated April 28, 1994, Hartman and co-inventors.
WO 9409029 (Der 94-151241 / 18) of April 28, 1994, Hartman and co-inventors, US 5312923, May 17, 1994, Chung and co-inventors.
HU 9400249, dated May 30, 1994, Ghent and co-inventors, WO 9412181 (Der 94-199942 / 24), of June 9, 1994, Egbertson and co-inventors, US 5321034, of June 14, 1994, Duggan and co-inventors, US 5334596, of August 2, 1994, Hartman and co-inventors.
EP 0608759 A, dated August 3, 1994, Ghent and co-inventors, WO 9418981 (Der 94-293975 / 36) of September 1, 1994, Claremon and co-inventors, GB 22763B4 (Der 94-287743 / 36), dated September 28, 1994, Claremon and co-inventors. WO 9422825, dated October 13, 1994, Claremon and co-inventors, EP 0623615A, dated November 9, 1994, Raddats et coi ventores, WO 9504531, February 16, 1995, Hartman and coi ventores, Nutt and co-authors; Development of Novel, Híghly SeTective Fíbrinogen Receptor Antagonists as Potentíally Useful Ant? thro botic Agents, in Peptides, Chemistry and Biology, Proc. 12th. Amer. Peptidß Symp., J.A. S? Th and J.E. River, Editors, ESCOM, Leiden, 1992, 914. Hartman and co-authors, J. Med. Chem. 35, 4G40, 1992. Gould and co-authors,. Thromb. Haem. 69, 539, 1993.
Merrel 1 Dow WO 93/24520 of May 14, 1993, Harbeson and co-inventors, WO 9324520, of December 9, 1993, Harbeson and co-inventors, WO 9429349, of December 22, 1994, Harbeson and co-inventors, Nippon steel Corp WO 9405696, dated March 17, 1993, Sato and co-inventors, EP 628571, of December 14, 1994 »Sato and co-inventors, WO 9501371, dated January 12, 1995, Sato and co-inventors.
ONO Pharmaceuticals JP 05286922 (Der 93-383035 / 48).
Roche EP 038,362, of February 19, 1990, Muller and co-inventors, EP 0372486, of June 13, 1990, Allig et coi ventores. EP 0381033, July 8, 1990, Allig and co-inventors. EP 0384362, of August 29, 1990, Allig and co-inventors, EP 0445796, of September 11, 1991 »Allig and co-inventors, EP 0505868, of September 30, 1992, Allig and co-inventors, US 5273982-A (Der 94- 006713/01), of December 28, 1993, Alli and coauthors, J. Med. Chem. 35, 4393, 1992.
Rhone-Poulenc Rorer US 495262, of September 29, 1989, Klein and co-inventors, US 5064814 '(Der 91-353169 / 48) of April 5, 1990, WO 9104746, of September 25, 1990, Klein and co-inventors, O 91/05562, dated October 10, 1989, Klein and co-inventors, WO 91/07976 (Der 91-192965), dated November 28, 1990, Klein and co-inventors »WO 91/04746, Klein and co-inventors, WO 9218117 , of April 11, 1991 »Klein and co-inventors, US 5086069 (Der 92-064426 / 08) of April 2, 1992, WO 92/17196, of March 30, 1992, Klein and co-inventors, US 5328900 (Der 94 -221950/27) of July 12, 1992, US 5332726 (Der 94-241043 / 29) of July 26, 1994, WO 93/11759, of December 7, 1992, Klein and co-inventors, EP 0577775, of 12 January 1994, Klein and co-inventors. CA 2107088, of September 29, 1992, Klein and co-inventors.
Sandoz EP 0560730, of March 8, 1993, Kottirisch and co-inventors. Kottirisch and coaters, Biorg. Med. Chem. Lett 3, 1675-1680, 1993.
Schering AG E 530937, March 10, 1993, Noes i'-Jungblut and coi ventores.
Sear1e / Monsanto EP 0319506 (Der 89-3195506) of December 2, 1988, Adams, and co-inventors, EP 0462,960, of June 19, 1991, Tjoeng and co-inventors, US 4B57508, Adams and co-venitors, EP 0502536 ( Der 92-301855) of March 3, 1991, Garland and coi ventores, EP 0319506, of December 2, 1988, Adams and coi ventores, US 4992463, of August 18, 1989, US 5037808, of April 23, 1990, EP 0454651 A2, of October 30, 1991, Tjoeng and co-inventors, US 4879313, of July 20, 1988, WO 93/12074 , of November 19, 1991, Abood and co-inventors, WO 93/12103, of December 11, 1991, Bovy and coi ventores, US 5091396, of February 25, 1992, Tjoeng and co-inventors, WO 92/15607, dated March 5, 1992, Garland and co-inventors, WO 93/07867, dated April 29, 1993, Bovy and co-inventors, US 888686, May 22, 1992, Bovy and co-inventors. CA2099994, of September 7, 1992, Garland and co-inventors.
US 5254573, dated October 6, 1992 »Bovy and co-inventors, (PF54C06) EP 0539343, of October 14, 1992, Bovy and coi ventores, WO 93/12074, of November 27, 1992, Abood and co-inventors, WO 93/12103, of December 11, 1992, Bovy and co-inventors, EP 0 539343, of April 28, 1993, Bovy and co-inventors. EP 0542708, dated May 19, 1993, Bovy and co-inventors. WO 94/00424, of June 23, 1993, Abood and co-inventors, WO 93/16038, of August 16, 1993, Miyano and co-inventors, WO 93US7975, of August 17, 1993, Zablocki and co-inventors, WO 93/18058, of September 16, 1993, Bovy and co-inventors, US 5254573, of October 19, 1993, Bovy and co-inventors, US 5272162, of December 21, 1993, Tjoeng and co-inventors, EP 0574545, of December 22, 1993. December 1993, Garland and co-inventors, WO 9401396, dated January 20, 1994 »Tjoeng and co-inventors, WO 9405694 (Der 94-101119 / 12) of March 17, 1994, Zabloc i and coi ventores, US 5314902, of May 24, 1994, Adams and co-inventors WO 9418162, of August 18, 1994, Adams and co-inventors, WO 9419341, dated September 1, 1994, Tjoeng and co-inventors »US 5344837 (Der 94-285503 / 35), dated September 6, 1994, Zablocki and co-inventors. EP 614360, of September 14, 1994, Bovy and co-inventors. WO 9420457 (Der 94-302907 / 37) of September 15, 1994, Tjoeng and co-inventors, WO 9421602 (Der 94-316876 / 39), September 29, 1994, Tjoeng and co-inventors, WO 9422820, October 13 1994, Abood and co-inventors, EP 630366, dated December 28, 1994 »Bovy and co-inventors. US 5378727, of January 3, 1995, Bovy and coi ventores. Fok and coauthors, Int. J. Peptide Prot. Res., 38, 124-130, 1991, Zabloc and coauthors, J. Med. Chem. 35, 4914-4917, 1992, Tjoeng and coauthors, Peptide Mime ics of the RGD Sequence, in Peptides, Chem. And Biol. Proc. 12th. Amer. Peptide Symp., J.A. Smith and J.E. Rivier, editors, ESCOM, Leiden, 1992, 752.
Nicholson and co-authors, Thromb. Haem. , 69. 975, 1993.
SmithKIine Beech an Corporation EP 341 915, Ali and coinventores, EP 425 212, Al i and coi ventores, EP 557 406 Callahan and co-inventors, WO 93/09133, Callahan, and co-venitors, WO 93/00095, Bondinell and co-inventors, WO 94/14776 Bondinell and co-inventors, WO 95/18619, Bondinell and co-inventors, WO 94/12478, Keenan and co-inventors, WO 94/12478, Callahan and co-inventors, WO 94/12478, Callahan and co-inventors, WO 94/12478, Samanen and co-inventors, Sumí I take Pharm. Co. Ltd. WO 9501336, of June 6, 1994, Ikeda and co-inventors, Sumí I take Seiyaku KK JP 06025290 (Der 94-077374 / 10), of February 1, 1994, Taisho Pharm (Teijín, Ltd) JP 05230009 (Der 93-317431 / 40) of February 24, 1992, JP 9235479, of February 24, 1992, WO 94/17804, of August 18, 1994, M? Zushima. EP 634171, of January 18, 1995, Nizushima.
Takeda EP 0529858, dated April 3, 1993, Sugi ara and co-inventors, EP 606881 of July 20, 1994, EP 614664, of September 14, 1994, Miyake and co-inventors, Tanabe WO 89/07609, Lobl and coi ventores, WO 92/00995, of July 9, 1991, Lobl and co-inventors, WO 93/08823, of November 6, 1991, Mck'enz? E, CA 2087021, of the lO January 1991, Lobl and co-inventors »WO 92/08464, November 15, 1991, McKenzie et al.
Tel ios / La Jolla Cancer Research US 4578079, November 22, 1983, Rouslahti and co-inventors, US 4614517, June 17, 1985, Ro? Slahti and co-inventors US 4792,525, June 17, 1985, Rouslahti and co-inventors, US 4879237 (Der 90-154405 / 20), May 24, 1985, WO 91/15515 (Der 91-325173 / 44) April 6, 1985 1990, US 5041380 »1991, Rouslahti and coi ventores, WO 95/00544, dated January 5, 1995, Craig and co-inventors. Cheng and co-authors, J. Medicin. Chem. 37, 1, 1994. Col len and coauthors, 71, 95, 1994.
Temple U. WO 9409036 (Der (94-151248 / 18), of April 2, 1994, Terumo KK JP 6279389, of October 4, 1994, Obama and coi ventores, Karl Thomae / Boehringer Ingelheim EP 0483667, dated May 6, 1992, Himmel Sbach and co-inventors, EP 0496378, of January 22, 1992, Himmel Sbach and co-inventors, EP 0503548, of September 16, 1992, Him elsbach and coi ventores, AU A-86926/9, of May 7, 1992 »Himmel Sbach and co-inventors, EP 0528369, dated February 24, 1993, Austel and co-inventors, EP 0537696, dated April 21, 1993, Linz and co-inventors, DE 4124942, of January 28, 1993, Him elsbach and co-inventors, DE 4129603, of March 11, 1993, Píeper and co-inventors, EP 0547517 Al (Der 93-198544) of June 23, 1993, Soyka and co-inventors, EP 0567966, of November 3, 1993 Himmel Sbach and coi ventores, EP 0567967, of November 3, 1993 »Weisenberger and coi ventores, EP 0567968» of November 3, 1993, L? Nz y coinventores, EP 0574B08, of 11 June 1993, Pieper and co-inventors, Der 93/406657/51, Austel et coi ventores, EP 587134 (Der 94-085077 / 11) of March 16, 1994, Hímmelsbach and co-inventors, EP 5S9B74, of April 6, 1994, Grel 1 and coi ventores. (P534005) DE 4234295, of April 14, 1994, Pieper and coi ventores, EP 0592949, of April 20, 1994, Pieper and co-inventors, EP 596326 of May 11, 1994, Maier and coi ventores, DE 4241632, of June 15, 1994, Himmel sbach and coinventores, EP 0604800 A, of July 6, 1994, Himmel Sbach and co-inventors, DE 4302051 (Der 94 -235999/29) of July 28, 1994, EP 0608858 A, of August 3, 1994, Li zy coi ventores, DE 4304650 (Der 94-256265 / 32) of August 18, 1994, A? Stel and co-inventors, EP 611660, of August 24, 1994, Austel and co-editors, DE 4305388 (Der 94-264904 / 33) of August 25, 1994, Hi Mel sbach and coi ventores, (P5D4005), EP 612741 (Der 94-265886 / 33) of August 31, 1994, Himmel Sbach and coi ventores, EP 0639575 A, of February 22, 1995, Línz and co-inventors, DE 4324580, January 26, 1995, Linz and co-inventors. EP 0638553, of February 15, 1995, Himmel sbach and coi ventores.
Himmel Sbach and co-authors, at Xllth Int. Symp. on Med. Chem. Basel, Book of Abstracts, 47, 1992. Austel and coauthors, ati. Mtg. Amer. Chem. Soc. Book of Abstracts, Denver, Div. Med. Chem., 1993. Muller and coauthors, Orally Acti vii of BIBU 104, a Prodrug of the Non-peptide Fibrinogen Antagonist Receptor BIBU 52,? N Míce and Monkeys, Thromb. Haem. 69, 975, 1993.
Univ. California WO 94/14848, July 7, 1994, Zanetti.
Univ. New York WO 94/00144, of June 29, 1993, O? Ma and co-inventors, Yeda Res. And Dev. Co. WO 93/09795 (Der 93-182236 / 22), Lido and coinventores, Zeneca WO 9422834, of October 13, 1994, Wayne and co-inventors, WO 9422835, of October 13, 1994, Wayne and coinventores, EP 632016, of January 4, 1995, Brewster and co-inventors, EP 632019, of January 4 of 1995, Brown and coinventores, EP 632O20, of January 4, 1995, Brown and co-inventors. In a particular embodiment, the fibrinogen receptor antagonist template A is the 6- to 7-membered ring bicyclic ring, defined in Bondinell and co-inventors, WO 93/00095, published on January 7, 1993, as defined by subframe (VI): where: A - * - a As form a ring of seven members, substituted, accessible, which may be saturated or unsaturated, which optionally contains up to two heteroatoms chosen from the group of 0, S and N, where S and N they may be oxidized optionally; D3- to D- * form a six-membered, substituted, accessible ring »optionally containing up to two nitrogen atoms; R is at least one substituent selected from the group of R7 or Q-alkyl of 1 to 4 carbon atoms, Q-alkenyl of 2 to 4 carbon atoms, Q- to the one of 2 to 4 carbon atoms, opc ? Onally substituted with one or more of = 0, R - * - 1- or R7; R ** is H, Q-to the quilo of 1 to 6 carbon atoms, Q-oxoalkyl of 1 to 6 carbon atoms, Q-alkoxy of 2 to 6 carbon atoms, Q-oxoal queni 3 to 4 carbon atoms, Q-oxoalkynyl of 3 to 4 carbon atoms, Q-alkynyl of 2 to 4 carbon atoms, loa! 3 to 6 carbon atoms, Ar or Het, optionally substituted with one or more of Ria-; Q is H »1 to 3 to 6 carbon atoms, Het or Ar R7 is -C0RT, -C0CR'2RT, -C (S) RT, -S (0) mOR ', -S (0) mNR' R ", -PO (OR '), PO (OR') a, -B (OR ') - ,, -N0a and Tet? Ra is -OR1, -NR'R", -NR'SO ^ R', -NR'OR », -0CR'aC (0) 0R ', -OCR' 20 (0) -R ', -OCR' 2C (0) NR '2, CF3 or AA3-? R * »is -0Rr, -CN, -S (Q) _, RT, S (0) mNR, -? - C (0) RrC (O) NRtz O C02Rt; R * »- 4 is H, halogen, -OR * - 2, -CN, -NR'R3-2, -N02, -CF3, CF3S (0), _, -COsR ', -CONR' z, Q-to the quilo of 0 to 6 carbon atoms-, Q-oxoalkyl of 1 to 6 carbon atoms-, Q-alquem "lo of 2 to 6 carbon atoms-, Q-to which nyl of 2 to 6 carbon atoms-, Q -alkyloxy of 0 to 6 carbon atoms-, Q-alkylamine of O to 6 carbon atoms- or Q-alkyT of C0_ß -s (O) -; RiZ is -C (0) R '-C (0) NR'. -C (0) OR- -S (0) mRf or S (0) mNR'2; R13 is R ', -CF3, -SR1? -OR "; R3 - * - is R ', C (0) R", CNr N02, S02R' or C (0) ORi <; RS is H, alkyl of 1 to 6 carbon atoms or alkyl of 0 to 4 carbon atoms, R 'is H, alkyl of 1 to 6 carbon atoms, the alkyl of C3_7-alk 1 or of 0 to 4 carbon atoms or Ar- alkyl of O to 4 carbon atoms. carbon; R "is R", -C (0) R 'or -C (0) ORi =; R "t is R" or AA2; AAl is an amino acid linked through its a? No group and that has s? optionally protected carboxyl group, and AA2 is an amino acid linked through s? carboxyl group and having its optionally protected amino group; m is 1 or 2; n ss or a 3; p is O or i; and t is O to 2; or their pharmaceutically acceptable salts. With reference to formula (II), suitably: A3- is CR ^ -R3- *, CR3-, NR3-, N, 0 or S (0) ... 5 A3 is C ^ R2 ', CRZ, NR2; A3 is CRaR-3 > , CR-3, NR3, N, O or S (0) ..:? A- * is CR- * R- * ', CR "*, NR? Or N; Aß is C SR °', CRS, NR * -5, N, O or S (0) ...; D _D- »Are R3-3-, CRS or N; R3- and R3-" are R * "or R, or together they are = 0; 2 and Rz 'are R ** or R, o = 0; R3 and R3 'are R ** or R, o = o; R- * and R- * 'are R ** or R, o = 0; Rß and Re »are R ** 0 R, o = 0; and x is O to 2. More suitably, A1 is CR ^ -R3- ', CR3-, NR1, N »0 or S; A2 is CR2R2 * »NR2 O CR2» A3 is CR3R3 '; A- * is CR- * R ^ *, CR- *. NR- * O N; AS is CRSRÍS ', CRß, NRS, N, 0; D - ^ - D- »are CH; R2 or R- »are R; R-3, R3 'and Rβ, R-5' SOn = 0 QR ~, H. Preferably A4- is CHR-3-, CR3-, NR ", N or S; A2 is CR2 or CR2RS '; A3 is CR ^ R3 '; A- * is C ^ R - ** or R- * As is CR'SR * -5' and D1-D "* - are CH. In one embodiment, A3- is CR3-, A2 is CR2, A3 is C = 0 »A ^ is R- * and As is CHR85. In another embodiment, A3- is NR1, A2 is CHCR2, A3 is CR-aR3 '»A-4 is NR- * and Aβ is o__o. In another modality more »A1 and A? are C = 0 »A2 is NR2, A3 is CHR3 'and Aβ is NR1-5. In a preferred embodiment A1 is NR1, A2 is CHR2, A3 is C = 0, A- »is NR» and As is CHRS. The representative formulas of (II) are given for each of the formulas (I? A) - (IIi) that come next A preferred template is given by the formula where: (? D A _._ A_. is NR-L-CH, MC (0) R3-CH, N = C, CR1 = C, CHR1-CH, 0-CH or S-CH; R1 is H, alkyl from 1 to 6 carbon atoms or benzyl, R2 is (CH2) -.CO-H, R * 4 is H, alkyl of 1 to 6 carbon atoms »Ar-to the quilo of 0 to 6 carbon atoms, Het- to the quilo of O to 6 carbon atoms or C3 io cycloalkyl, -alkyl of O to 6 carbon atoms, and Q is 1, 2 or 3. Preferably A1-A2 is NH-CH and R2 is CH_.CO. 3H.
Suitably, R3 is methyl and W (as defined in the formula (I)) is CH ^ NR'CO. Suitably, R "1 is substituted with NHRT, CN, CO ^ H, biotin, benzimidazole, or femotropically substituted. The specific axes of vi tronectin antagonists that employ this template are: Ac i do (S) -2, 3, 4, 5-tetrahi dro-4-meti 1 -3-oxo-7-CL L2 -L2- (pyridinyl) amino3et? 1 lapiinolcarboni 1 H-lH-l »4-benzod? aze in-2-acetic; Ac i do (S) -2, 3, 4, 5- e to í dro-4-me? 1 -3-oxo-7-C C C2-C (l-oxo-2-pyridini 1) a? M'no3et? 13arn? No carboni 13-lH-l, 4-benzodiazepin-2-acetic; Acid (S) -2,3,4,5-tetrahydro-3-oxo-7-CCC2-C2- (p? D? 'Ni 1) ami o3-eti 13 aminocarboni 13-lH-l, 4- benzod? azepin-2-acetic; Ac i do (S) -2, 3, 4, 5-tetrahydro-3-oxo-7-C LZ-C2- (pi ri di ni 1) ami no3-eti 1 amino3carboni 3-4- (2 , 2, 2-tri luoroetí 1) -lH-l, 4-benzodi-azepí n-2-acéti co; Acid (±) -2 »3,4,5-tetrahydro-3-oxo-4- (pheni leti 1) -7-CCC2-C2- (pyridi il) aroi no leti 1 Han» i no ..carbóni 13- lH-1, 4-benzodiazene-2-acetic acid; Acid (S) -2,3,4,5-tetrahydro-4-methyl-7-CCC2-C2- (6-met? 'L-pyridinyl) amino3eti 1 ami no 3carbo i 13-3-oxo-1H-1 , 4-benzodi-azepin-2-acetic; Acid (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7-CCC2-C2- (pyridinyl) ami o3eti 13me i 1 ai no3carbom "13-ÍH-1,4-benzodi-azepin- 2-acetic; Ac i do (±) -2, 3, 4, 5-tetrahi dro-4-meti 1-3-oxo-7-CC C2-C2- (piri di ni 1) ami or eti 1 amino3carboni 13 -1H-1, 4-benzodiazepi n-2-acetic acid (±) -2, 3,4 »5-tetrah idro-4-meti l-7-EC2-C- (6-methy1-3-pyridazine 1) ami o3et? 1 lamino carboni 1 - -oxo-lH-1,4-enzodi- azepin-2-acetic; and Ac i do (± > -2 »3» 4 »5-tetrah i dro-4- methy1 -3-oxo-7-C C2-C3- (pyridazin-1) amine and 1-ami-3-carbonyl-1H-1,4-benzodiazepine-2-acetic acid.
A preferred compound is (S) -2, 3,4,5-tetrahydro-4-methyl-3-oxo-7-CCC2-C2- (p? 'R? Dini 1) amino3et? 1 -ami no3carbom "13-1H-1, 4 ~ benzodi azepi n-2-acetyl Another embodiment of benzod? Azep? A fibrinogen receptor template A is represented by 1,4-benzodiazep? N- 2,5-dione of the sub-formula (IV) Or Rh or (IV) wherein: Y is H, alkyl of 1 to 4 carbon atoms, to the cox i of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, F, Cl »Br, I, CF3, OR" ", S (0) 1 < R ^, COR-, N02, NÍR "- *) - ,, COí R- ^ í-j., CH2N (R ^) 2, methylene dioxide, CN, CO ^, 0C (0) Rf or NHC (0) R "p; and R - * is (CHs) c, C02R-F. Suitably R * - * is CH3CHsC02H. Annotations (V) - (XV) in Table II summarize other illustrative fibrinogen receptor templates which are included within the scope of the present invention.
TABLE II (V) where: R21 and R22 are independently H or -Z-CO ^ R * or Z-CO (R ^) -, with the proviso that q? e one of R2 or E22 is -Z-CO¡2R'F or Z -CON (R *) if it is -CH- • 0 (CH2) q-, -NR- * 7 (CH2), _, -, -SÍCHa) ^) "CH ^ Í-'H ^" * " -CH (CH3) CH2-, - (CHa) 3- -CH = CH-, -C (CH3) = CH-, CH2-CH = CH- or CH = CHCH2; and Y is H, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, C, -carbonyl alkoxy, F, Cl, Br, I, CF-OR-P, S (0) R < r, COR- * 1, N02, N (R-fr) 2, CO (NR "F) 2, CH2N (R * -) sß» metí lendioxí or Z-COR ^, described in Alig and coi ventores, EP O 381 033, published on August 8, 1990. where: Rβ is aryl, alkyl of 1 to 10 carbon atoms »cycloalkyl of 3 to 6 carbon atoms, aralkyl of 4 to 10 carbon atoms, coxyalkyl 1 or 1 to 10 carbon atoms, alkaryl of 1 to 10 carbon atoms, alkyl 1 to 1 to 1 to 10 carbon atoms, alkoxy to thioalkyl to 1 to 10 carbon atoms, alkylamine of 1 to 10 carbon atoms, ara! q? i lamino of 4 to 10 carbon atoms »alkanoi lamino of 1 to 10 carbon atoms, aralcanoi lamino of 4 to 10 carbon atoms, alkanoyl of 1 to 10 carbon atoms, aralkanoyl of 4 to 10 carbon atoms or carboxyalkyl of 1 to 10 carbon atoms; and Y is H, alkyl of 1 to 4 carbon atoms »to the coxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, F, Cl, Br, I, CF3, OR ^, S (0 ) RR ^, COR *, N02, NIR *)., »COIN-, CH2tN (Rp) 2, meti 1 endio ?? , CM, C02Rf, 0C (0) R * or NHC (0) R ^; described in Egbertson and co-inventors, EP O 478328 »published on April 1, 1992. where: M1 is CH or N; M2 is CH or l \ l, provided that when M-1 is CH »M2 it is N; and G 'is N or N ^ R ", described in Eldred and co-inventors, EP 0542 363, published on May 19, 1993. (vpi) where: M1 is CH or N; M2 is CH or N, with the proviso that when M1 is CH, M2 is N; described in Porter and co-inventors, EP 0 537 980, published on April 21, 1993. where: M1 is CH or N; Y is H, alkyl of 1 to 4 carbon atoms, coxy of 1 to 4 carbon atoms, alkoxy of Cs. .-carbonyl, F, Cl, Br, I, CF3, OR ^, S (0) μ.R- < r, COR- ", N02, N (R ^) 2, CO R ^ - ,, CH2N (R") 2, I put I tend ox? , CN, COsR- ", OC (0) R- =" or HCíOR ^ and D3 is CHW or 0 = 0; and R * '1 is (CHz) c, C02R-, r; described in Klin 'ck and coinventores »EP 0 635 492, published on January 25, 1995. wherein: Y is H, alkyl of 1 to 4 carbon atoms, alkoxy of 4 carbon atoms, alkoxy of C, 4-carbs, and F, Cl, Br, I, CF3, OR * »S (0 ) kR '< r, COR *, N02, N < R *) af CO (NR) 2, CH2N (R *) 2, methylenedioxy, CN, C02-F, OC (0) R * or NHC (0) R *; and R "- is (CH2) c.C02R *; Y B is described in Blackburn and co-venitors, WO 95 / 04O57, published on February 9, 1995. ÍM? where: L * »is -C (0) NR» - (CHß) -, -C (0) - (CHas) -, -, NR = - (CH2) "-, -O- (CH2) ,,, -, or S (0) k .- (CH2) c, -; described in Hartman and co-inventors »EP O 540 331, published on May 5, 1993. described in Sugihara and coi ventores, EP 0 529,858, published on March 3, 1993. wherein: Y is H, alkyl of 1 to 4 carbon atoms, coxi of 1 to 4 carbon atoms, alkoxy of C 1 - carbonyl, F, Cl, Br, I, CF 3 »OR *, S ( 0) R *, COR *, N02, N (R *) 2 »CO (NR *) 2, CH2N (R *) 2, methylenedioxy, CN, C02R *, 0C (0) R * or NHC (0) R *; described in Himmeissbach and coi ventores, EP O 483 667, published on May 6, 1992. ßOV} described in Linz and co-inventors, EP 0 567 968, published on November 3, 1993. wherein: R is Het-to the quilo of O to 6 carbon atoms; and Z ", Z" 'are independently hydrogen »alkyl of 1 to 4 carbon atoms, halogen »OR *, CN, S (0)? R *, C02R * or OH; described in Bovy and coi ventores, EP 0 539 343, published on April 28, 1993. The above descriptions of fibrinogen receptor templates for use in the present invention are taken from published patent applications, in process. Reference should be made to patent applications for complete descriptions, including possible variations for such templates and the methods for preparing them, the entire description of such patent applications being incorporated herein. In cases where the compounds of the invention may have one or more chelateral centers, unless specified in this manner, "this invention includes each single non-racemic compound" that can be synthesized and resolved by conventional techniques. In cases where the compounds have unsaturated carbon-to-carbon double bonds "both the cis (Z) and trans (E) isomers are within the scope of this invention. The meaning of any listener in any occurrence is independent of its meaning or any other meaning of substituent in any other occurrence. Abbreviations and symbols commonly used in the techniques of peptides and in chemical techniques are used in the present to describe the compounds of this invention. In general, the abbreviations of amino acids follow the nomenclature of the IUPAC-IUB, Joint Commission on the Biochemical Nomenclature, which is described in E? R. J. Biochem. , 158 »9 (1984). Alkyl of 1 to 4 carbon atoms, as used herein, means an alkyl group opc? It is optionally substituted, with 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Alkyl of 1 to 6 carbon atoms further includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl, and their isomers to simple isáticos. Alkyl of 0 to 4 carbon atoms and alkyl of 0 to 6 carbon atoms further indicates that it is not necessary for an alkyl group to be present (for example, that a covalent bond is present). Any alkyl of 1 to 4 carbon atoms or alkyl of 1 to 6 carbon atoms »alkenyl of 2 to 6 carbon atoms, at the one of 2 to 6 carbon atoms or oxoalkyl of 1 to 6 carbon atoms can to be optionally substituted with the R group, which may be on any carbon atom that results in a stable structure, and is available, by conventional synthesis techniques. Suitable groups for R are alkyl of 1 to 4 carbon atoms, 0R? SR ', alkyl of 1 to 4 carbon atoms, alkyl isul or 1 to 4 carbon atoms, alkoxy isulfoxy, or 1 to 4 carbon atoms. to 4 carbon atoms, -CN, N (RT) 2, CH2N (Rr) 2, -N02, -CF3, -C02R'-CON (') a), -COR', NR'C (0) R ' , OH, F, Cl, Br, I, N3 or CF, S (0) r-, where r is 0 to 2 and R 'is as defined with respect to Ta formula (II). "Aryl" or "aryl", when applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted with one to three stents "such as those defined above for alkyl, especially alkyl of 1 to 4 carbon atoms, alkoxy from 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, trifluoroalkyl, N3, OH, C02H, F, Cl, Br or I. Het, or heterocycle, denotes a five or six membered monocyclic ring, optionally substituted, or a nine- or ten-membered bicyclic ring, which contains one to three heteroatoms, selected from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Exemplary heterocycles are benzofaryl, benzyl idazole, benzopyran, benzothioen, biotin, furan, imidazole, indoline, morpholine, p? Per? Dine, piperazine, pyrro! Pyrro! idina, pyridine »tetrahydropyridine, pyridine» thiazole »thiophene, quinal ina, isoquinoline and tetra and perhydroquinoline and isoquinoline. Any combination accessible up to three listeners in the ring Het, such as those defined above for alkyl, which are available, by chemical synthesis, and are stable, are within the scope of this invention. Cycloalkyl of 3 to 7 carbon atoms refers to an optional carbocyclic system substituted by three to seven carbon atoms, which may contain up to two carbon-to-carbon unsaturated bonds. Cyclones with 3 to 7 carbon atoms typical with cyclopropyl, cyclobothyl, cyclopentyl, cyclopentemyl, cyclohexyl, cyclohexamyl and cycloheptyl. Any combination of up to three substituents, such as those defined above for alkyl, in the cycloalkyl ring what is available, by conventional chemical synthesis, and is stable, is within the scope of this invention. - The ring represented by is a six-membered ring that has at least one nitrogen, which is substituted at position 2 with a nitrogen atom. The ring may optionally have an additional nitrogen atom in the ring and thus may be a pyrazine »pyridazine or a pyriraidine. The next one R > "can be in any position of Q1-Q- * which results in a stable structure.It will be evident that when the value of u is 1, the described compound will be an N-oxide, on the other hand, when the value of u Either there is no oxygen substitute in the nitrogen, a ring of pyridine is preferred, some radical groups are abbreviated here, t-Bu refers to the tertiary butyl radical, Boc refers to the ter-butyl radical. icarbo i lo, Fmoc refers to the radical fluoreni lmetoxicarboni lo, Ph refers to the radical ilo faith, Cbz refers to the radical benci loxicarboni lo, BrZ refers to the radical o-bromobenci loxicarboni lo, CIZ refers to the radical o-chlorobenci loxícarbó i, Bzl refers to the benzyl radical, 4-MBzl refers to the radical 4-me i 1 benzyl, Me refers to methyl, Et refers to ethyl, Ac refers to acetyl, Alk refers to alkyl of 1 to 4 carbon atoms, Nph refers to 2-naphtyl and cHex refers to cyclohexyl. e refers to 5-tetrazole i lo. Some reagents are abbreviated herein. DCC refers to dicyclohexy lcarbodiimide, DMAP means dimethy lami opiridin, DIEA means diisopropy leti lamína, EDC means l- (3-di eti lamí opropí 1) -3-ethycarbodiimide hydrochloride »HOBt refers to l- Hydroxybenzotriazole, THF stands for tetrahydrofuranao »DIEA means di isopropi leti lamina, DME stands for di ethoxy ethane, DMF refers to imet? Iformam? a, NBS means N-bromosuccinimide, Pd / C refers to a palladium-on-carbon catalyst, PPA f refers to cyclic propanephosphonic acid anhydride, DPPA means diphosphine Ifosphorus, BOP refers to benzotriazole hexafluorophosphate-1-loxyl "(dimethylamino) phosphom" or, "HF" refers to hydrofluoric acid, "TEA" means "trietí lamina", "TFA" refers to tri-luoroacetic acid, "PCC" means "pyridinium chlorochromate." The compounds of the formula (I) are generally prepared by reacting a compound of the formula (XVI) with a compound of the formula (XVII), wherein L1 and L2 are groups that can react to form a covalent bond in the portion W, by methods generally known in the art.
(XVI) (xvp) (i) Typical methods include coupling to form amide bonds, n? C Theroyl displacement reactions and palladium catalyzed couplings. For example, when W contains an ether or amine ligature, the ligation can be formed by a displacement reaction, and one of L and L2 will contain an amino or hydroxy group and the other will contain a displaceable group such as chlorine, bromine or iodo. When W contains an amide ligature, typically one of L1 and L2 will contain one amine group and the other will contain a carboxylic acid group. In another approach, L1 may be bromide, aryl iodide or heteroaryl or trifloromethyl derivative Is? Lfom "loxí and L2 may contain an amino group, and the amide bond may be formed by palladium catalyzed aminocarboni lation, With carbon monoxide in an appropriate solvent, such as Di-Iformamide or Toluene, it will be evident that the precise identity of L1 and L2 will depend on the site of the ligation that is being formed. CHR ") __- U- (CHR) ß- V- are described, for example, in EP-A 0 372 486 and in EP-A O 381 033 and in EP-A O 478 363, which are incorporated herein by reference. For example, if V is CONH, L1 can be -NH.A-, L-2 can be OH (as in an acid) or Cl (as in an acid chloride) For example, it can be reacted (p? R d-2-i 1) - ami or eti 1 (CH 2) β-C 0 Cl with suitable α-amine. When L2 is OH, it is a coupling agent. Similarly, if V is NHCO, L1 can be -C02H or CO-Cl, L2 can be -NH2. For example, it can be reacted (pi rid-2-i 1> to i nornet? 1 (CH2) to -NHR 'with an appropriate carboxylic acid When V is NHS02, L1 can be S02C1, L2 can be -NH2, as above. When V is S02NH, L1 can be -NH2 and L2 can be S0-.C1. Methods for preparing said sulfonyl chlorides are described, for example, in J. Orq. Chem., 23, 1257 (1958). If V is CH = CH, L can be -CHO »L2 can be CH = P-Ph..¡, and L2 can be CHO. For example, it can be reacted (pi ríd-2-i 1> am? No eti 1 (CH2) to? -CHO with an appropriate osphorane.When V is CH2CH2, it can be obtained by reduction of a suitably protected compound. , where V is CH = CH When V is CH2, CH2N or C = C, L can be -OH, -NH or -C = CH, respectively, L2 can be -Br or -I. when U or V is OCH2, NR'CH2 or C = C, L1 can be -CH2Br and L2 can be -OH, -NH or -C = CH, respectively For example, it can be reacted (pyrid-2-i) 1) aminomethyl 1 (CH2) a-Br with an appropriate amine, alkoxide or acetylene Alternatively, when U or V is C = C, L can be Br, I or CF3S03, L2 can be C = CH and can be catalyze the coupling by palladium and na base.Compounds in which V is CHOHCH2 can be prepared from a suitably protected compound, wherein V is CH = CH, by the procedure described in J. Org. Chem. 1354 (1989). Compounds in which V is CH2CHOH can be r obtained from a suitably protected compound "wherein V is CH = CH, by hi-robbing and basic oxidation, as described in Tet. Lett. , 31, 231 (1990). The fused ring system 6-7 of the formula (II) is prepared by methods well known in the art "for example, Hynes, and co-authors, J. Het. Chem., 19BB, 25, 1173; M? Ller and coautares, Helv. Chim. Acta, 1982, 65, 2118; Mori and co-authors, Heterocycles, 19B1, 16, 1491. Similarly, methods are described for preparing benzazepines, 1,4-benzothia? Epinas, 1,4-benzoxazepines and 1,4-benzodiazepines, for example, in Bondinell and co-inventors , international patent application WO 93/00095. Representative fibrinogen antagonist templates can be prepared according to the A-CC schemes, which follows: Scheme A describes a method for preparing exemplary fibrinogen receptor templates, described in Blackburn et al., WO 93/08174.
SCHEME A (a) C0C12, Na2C03, toluene; (b) 3-alanine benzyl ester tosylate, DMAP, pyridine; (c) CH3I, 2,6-lutidine, DMF; (d) cx-bromoacetyl bromide »Et3N, CH2C12; (e) NaH, DMF; (F) Pd (OAC). dppf, CO, DMSO. 65 ° C, 18 hours; (g) N- (2-pyridim '1) eti lendiamine, EDC, HOBt-H20, DIEA, CH3CN; (h) H2, 10% Pd / C, EtOH. Scheme B describes a method for preparing exemplary fibrogen receptor templates, described in Blackburn et al., WO 94/04057.
SCHEME B < a) C0Cl2, NaHCO3, toluene; (b) (3-alanine ethyl ester hydrochloride, DMAP, pyridine, (c) cx-bromoacetyl bromide or, Et3N, CH-gCl-, (d) NaH, DMF, (e) Lawesson's reagent, THF , 50 ° C, 2 hours, (f) CH3I, NaOH, (n-Bu) ^ N-HSO ^, CH2 12 / H20, room temperature, 2 hours, (g) proparg? 1 amine, toluene, piri di na, reflux, 6 hours; (h) Pd (0Ac) 2, dpp, CO, DMSO, 65 ° C, 18 hours; (i) N- (2-p? r? d? 'm "1) eti lendiamine, EDC, H0Bt-H20, DIEA, CH3CN; (j) LiOH, H20, THF, 18 hours Scheme C describes a method for preparing exemplary fibrinogen receptor templates, described in Porter and co-inventors, EP 0542363.
EXAMPLE C DC (a) NaBH3CN, HCl, CH30H; (b) HCl, dioxane, CH2C12; (c) 1-chloro-3-C (2-pyridyl) amino3propane, DIEA, THF; (d) NaOH, H20, CH .... OH. Scheme D describes a method for preparing exemplary fibrinogen receptor templates described in Porter et al., EP 0537980.
SCHEME D (a) l-chloro-3-C (2-pyr? dim'l) amino3propane, DIEA, THF; (b) NaOH, H20, CH3OH. D-1 is alkylated with l-chloro-3-C (2-pyridyl-1) ami-nopropane with DIEA in THF, the resulting ester is saponified with NaOH in aqueous CH 3 OH to give D-2. it can divide the tert-butyl ester with TFA or HCl in a suitable solvent, such as CH2C12 or dioxane Scheme E describes a method for preparing exemplary fibrinogen receptor templates, described in Porter and co-inventors, EP 0542363.
SCHEME E c, d, e (a) NaBH3CN, HCl, CH30H, EtOH, molecular sieves (b) TFA, CH2C12; (c) Chloropyridine N-oxide, NaHCO3, butane !; (d) HC02K, 10% Pd / C, CH30H; < e > NaOH IN, CH 3 OH. Reductive amination of E-l with E-2 using NaBH3CN, HCl and molecular sieves in CH30H and EtOH, followed by treatment of the product with TFA in CH2C12, produces E-4. Scheme F describes a method for preparing exemplary ibrinogen receptor templates, described in Porter and co-inventors, EP 0537980.
SCHEME F (a) NaBH3CN, HCl, CH30H, EtOH, molecular sieves; (b) TFA, CH2C12; (c) 2-chloropyridine N-oxide, NaHC03 »butanol; (d) HC02K, 10% Pd / C, CH30H; (e) 1N NaOH, CH30H. The reductive amination of F-1 with F-2 using NaBH3CN, HCl and molecular sieves in CH30H and EtOH, followed by treatment of the product with TFA in CH2C12 gives F-3. Treatment of E-3 with 2-chloropyridine N-oxide in NaHCO 3 in butanol with heating, followed by reduction of N-oxide with HC02K and 10% Pd / C in CH30H, and saponification of the ethyl ester with NaOH 1N in CH3OH, gives F-4. Scheme G describes a method for preparing exemplary fibrogen receptor templates described in Beavers and co-inventors »WO 95/25091.
SCHEME G (a) N-C2- (pyridinyl) amino3butyl acid, BOP-Cl, NMM, CH2C12; (b) L OH, H20, THF; (c) β-alamine benzyl ester, EDC, HOBT, NMM, CH2C12; (d) H2, 10% Pd / C, AcOH, THF, H20. Following the procedures of Beavers and co-inventors, WO 95/2509 »Example 1, except that N -Boc-D-lysyCbz) -OH is substituted with N-C2- (pyr? D? M" 1) amino3butyric acid), F-4, Scheme H describes a method for preparing exemplary fibrinogen receptor templates described in Hartman et al., EP 0540334.
SCHEME H (a) N- (2-pyridini 1) et? lendiami na, Et - =, N, benzene; (b) 1.0 N LiOH, H20, CH3OH; (c) ethyl ester of ß-al aniña, BOP, Et3N, CH3CN; (d) LiOH, H20, THF, CH3OH. It is treated 4- (bro ometi 1) benzene-1 »3-dimethyl carboxylate, H-1, with a suitable functional amine, such as N- (2-pyrridinyl) eti lendiamine, under the general conditions described for 2, 3-dihydro- - (2-carboxy et? 1) -2-C2- (piper? dim'l) et 1 -3-o? o-lH-? soi dol-5-carboxyaraide in Hartman and co-inventors, EP 0540334, to give H-4. Scheme I describes a method for preparing exemplary fibrinogen receptor templates described in Egbertson et al., EP 0478363.
SCHEME I (a) 4-C (2-p? r? di "1) amine3butanol» Ph3P, DEAD, CH2C12, benzene; (b) 1.0 N LiOH, THF, unicated alcohol, such as 4-C (2-pyr? dim "1) amino3butanol" to give 1-3 Scheme J describes a method for preparing exemplary fibrinogen receptor templates described in Duggan and co-authors, J. Med. Chem., 1995 »38, 3332.
SCHEME J (a) piployl chloride, Et3N, THF: (S) -4-benzyl-2-oxazole idinone, (b) Ti (O-i-Pr) C12, acrylonitrile, DIEA, CH2C12; (c), H2, Pt02, CH3OH, CHC13; (d) NaHCO 3, CH 3 CN; (e) NaHMDS, bro or ethyl acetate; (f) NaOH IN, CH 3 OH; (g) ethyl ester hydrochloride of 3 (R) -methyl 1-β-al ayl, EDC, HOBt, Et 3 N, DMF; (h) NaOH IN, CH 3 OH. A suitable univated carboxylic acid is activated, such as 5-C (pyr? D-2? "1) am? No3pentanoic acid, J-1, GO and is reacted with a quiraT auxiliary, such as (S) -4-benzyl 1-2-oxazole idione to form a chiral Evans reagent. The alkylation of the titanium enolate with tri-acetyl, followed by the reduction of the nitrile and the formation of lactam, produces lactam J-2, the addition to the lactam with agents such as lime bromoacetate, followed by Saponification of the ester yields the carboxylic acid J-3 The resultant carboxylic acid derivative J-3 is converted to an activated form of the carboxylic acid using, for example, EDC and HOBt or SOCl- »and subsequently reacted the activated form with an appropriate amine, for example, the ethyl ester of 3 (R) -eti-1-ß-al ani a, in a suitable solvent such as DMF, CH2C12 or CH3CN. Depending on whether acid neutralization is required, an additional base may be used, such as DIEA or pyridine. Many additional methods for converting a carboxylic acid to an amide are known and can be found in standard reference books such as "Compendium of Organic Synthetic Methods", Vol. I-IV (edited by Wi l and-Interscience) or Bodansky " The Practice of Peptide Synthesis "(edited by Sprínget-Verlag). The hydrolysis of the ethyl ester is achieved according to the general conditions described for the conversion of J-2 to J-3 to provide the carboxylic acid J-4. Alternatively, the intermediate carboxylate salt can be isolated "if desired" or a carboxylate salt of the free carboxylic acid can be prepared by methods well known to those skilled in the art.
Scheme K describes a method for preparing exemplary fibrinogen receptor templates described in WO 93/07867.
SCHEME K (a) 2-Chloropyridine N-oxide hydrochloride, NaHC0 ?, tert-amyl alcohol; (b) HCO ^ NH ^, Pd / C, EtOH; (c) TsCl, NaH, THF; (d) p-TsOH-H20, acetone, H2o; (e) NH20H-HC1, NaOAc; (i) ethyl 3-aminobutyrate, EDC, HOBt-H20, DIEA, CH3CN; (j) LiOH l.O N, THF, H_, 0. The 2- (3-a-inopropyl-1) -1,3-dioxolane, K-1, easily obtainable, is converted to Chem. Pharm. Bul !. 1982, 30, 909-914, to the pyridyl derivative K-2 according to the general protocol described by Misra, Bioorg. Med. Chem. Lett. 1994, 4, 2165-2170. The protection of one of the nitrogen atoms in the aminopyridine moiety in K-2 can be achieved by reaction with a sulfonyl chloride "lo" eg "p-toluensulfon chloride" lo » in the presence of a suitable base, generally sodium hydroxide or an aqueous alkali metal hydroxide, in an inert solvent, preferably THF, to give K-3. Alternative protecting groups known to those skilled in the art can be used as long as they are compatible with the subsequent chemistry and can be eliminated when desired. Said protective groups are described in Greene "Protective Groups in Organis Synthesis" (edited by Wiley-Interscience). Removal of the dioxolanyl protecting group from K-3 »to produce K-4 can be achieved conveniently under moderately acidic conditions, for example, with p-toluenesulfonic acid, in an appropriate solvent, preferably aqueous acetone. The aldehyde is converted to the K-5 aldoxime by normal procedures known to those skilled in the art, and this aldoxime is oxidized to the oximinoyl chloride derivative K-6 by methods described in WO 95/14682 and WO 95/14683. The reaction of K-6 with an olefin, such as tet-butyl 3-b-tentoate (Tet-Lett, 1985, 26, 381-384) in the presence of a suitable base, eg, Et3N or DIEA, in an inert solvent, such as benzene or toluene, according to the protocol described in WO 95/14682 and WO 95/14683 »gives the K-7 cycloaduct. The terbutyl ester of K-7 is removed under normal acidic conditions, generally TFA in CH2C12 or HCl in dioxane, to give the carboxylic acid K-8. The carboxylic acid is activated using, for example, EDC or HOBt or SOCl. ^, And subsequently the activated form is reacted with an appropriate amine, for example, with a suitable derivative of Q-alanine, in a neutral solvent, such as DMF, CH2C12 or CH3CN, to give K-9. Depending on whether acid neutralization is required, an additional base, such as DIEA or pyridine, can be used. Many other methods are known for converting an α-amide carboxylic acid, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods," Vol. I-IV (edited by Wi-Law-Interscience) o Bodansky "The Practice of Peptide Synthesis" (edited by Spr? ngei-erlag). The ß-al a i a derivatives can easily be found in racemic or optically pure form by a variety of methods known to those skilled in the art. A representative method is described in WO 93/07867. The K-9 ethyl ester and sulfonyl protecting groups are removed using an aqueous base, for example, LiOH in aqueous THF or NaOH in CH3OH or EtOH. The intermediate carboxylic salt is acidified with a suitable acid, for example, TFA or HCl, to produce the carboxylic acid K-10. Alternatively, the intermediate carboxylate salt can be isolated, if desired, or a carboxylate salt of the free carboxylic acid can be prepared by methods known to those skilled in the art. Scheme L describes a method for preparing exemplary ibrinogen receptor templates described in Alig and co-inventors, EP 0372486.
SCHEME L (a) N- (Z-pyridinyl) -β-alanine, EDC, DIEA, DMF; (b) NaOH, H-, 0, CH, .rOH. L-1, prepared as described in Alig and coi ventores, EP 0372486, is condensed with a substituted carboxylic acid, such as N- (2-pyr? d? m "1) -β-alam" na, in the presence of EDC and DIEA, and in a suitable solvent, for example, DMF or CH . ,, CN »to give L-2. Many additional methods are known for converting an α-amide carboxylic acid, and can be found in common and current reference books, such as "Compendium of Organic Synthetic Methods," Vol. I-IV (edited by Springer-Verl. ag). Hydrolysis of the ester in L-2 is achieved by saponification with a suitable reagent, for example, NaOH, in a suitable solvent, for example, aqueous CH30H. Alternately, the benzyl ester in L-2 can be converted to the acid by treatment with hydrogen and a suitable catalyst, for example, Pd / C, in a suitable solvent, for example, CH30H, ethanol or AcOH. Scheme M describes a method for preparing exemplary rRNA receptor templates described in Alig et al., EP 0505868.
GG SCHEME M (a) N- (2-pyridinyl) -β-alanine, EDC »DIEA, DMF; (b) CF3C02H, CH2C12. M-1, prepared as described in Alig and coi ventores, EP 0505868, is condensed with an appropriately substituted carboxylic acid, such as N- (2-pyridini 1) - β-alanine, in the presence of EDC and DIEA, in An appropriate solvent »for example, DMF or acetonitrile» to give M-2. Many additional methods are known for converting the carboxylic acid to an amide, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods," Vol. I-IV (edited by Springer-Verl ag). The hydrolysis of the ester in M-2 is achieved with trifluoroacetic acid or with hydrogen chloride to give M-3. Alternatively, the ester of M-2 can be saponified with a suitable reagent, for example, 1N NaOH, in a suitable solvent, for example, CH..HOH. Scheme N describes a method for preparing exemplary fibrinogen receptor templates described in WO 93/07867.
SCHEME N (a) 3- (carbomethoxy) propion chloride? it, DIEA, CH2C12; (b) 1.0 N NaOH; CH3OH; (C) ethyl 3-amino-4-pentynoate, EDC, H0Bt-H2O, DIEA, CH3CN; (d) LiOH l.O N, THF, H20. A suitable univalentized amine is reacted, such as 2- (3-ami noprop-1-yl) amine 3p? R? D? Na with a 3- (carbomethoxy) propionium chloride in the presence of a scrubber. appropriate acid, such as Et3N, DIEA or pyridium, in a neutral solvent, generally CH2C12, to produce N-2. The N-2 methyl ester is hydrolyzed using an aqueous base, for example, L OH in aqueous THF or NaOH in aqueous CH30H or EtOH, and the carboxylate salt is acidified with a suitable acid with an appropriate acid. for example, TFA or HCl to produce the N-3 carboxylic acid. Alternatively, N-1 can be reacted with succinic anhydride in the presence of a suitable base, such as Et .. ,, N, DIEA or pyridine in a neutral solvent, generally between CH2C12, to produce N-3 directly. The resultant carboxylic acid derivative N-3 is also converted to an activated form of the carboxylic acid using, for example, EDC or HOBt or S0C1:?, And subsequently the activated form is reacted with an appropriate amine, for example, the known ethyl 3-ami or 4-pentyl (WO 93/07867) in a suitable solvent, such as DMF, CH2Cl2 or CH3CN to N-4. Depending on whether acid neutralization is required, an additional base may be used, such as DIEA or pyridine. Many additional methods for converting carboxylic acid to α-amide are known and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I-IV (edited by Wí 1 ey-Interscí ence ) or Bodansky "The Practice of Peptide Synthesis" (edited by Springer-Verlag). The hydrolysis of the ethyl ester of N-4 is achieved according to the general conditions described for the conversion of N-2 to N-3, to provide the carboxylic acid N-5. Alternatively, the intermediate carboxylate salt can be isolated, if desired, or a carboxylate salt of the free carboxylic acid can be prepared by methods well known to those skilled in the art. Scheme 0 describes a method for preparing exemplary fibrinogen receptor templates described in S? Gihara and co-inventors, EP 0529858.
SCHEME O (a) N- (2-pyridinyl) -β-alanine, EDC, DIEA, DMF; (b) CF3C02H »CH2C12. 0-1, prepared as described in S? Gihara and co-venitors, EP 0529858, is condensed with a suitably substituted carboxylic acid, such as N- (2-pyr? Din? 1) -β-alanine, to give 0-2, and the tert-butyl ester is separated with TFA, following the general procedure of Sugihara and co-inventors, example 59, to give 0-3. Many other methods for converting a carboxylic acid to an amide are known and can be found in standard reference books, such as "Compendium of Orga 'c Synthetic Methods", Vol. I-IV (edited by Springer-Verlag ). Scheme P describes a method for preparing exemplary fibrinogen receptor templates described in Hi melsbach and co-inventors, AU-A-86926/91.
SCHEME P (a) 4-C (6-am? no-2-p? ri ini 1) methyl 3-phenol »Cs2CO3, DMF; (b) NaOH IN, O-OH. The compound Pl, prepared as described in Himmel sbach and co-inventors, AU-A-86926/91, example VK2S), is treated with an appropriately substituted phenol, such as 4-C2-C2- (pyridinium 1) amine3etiol 13 »Following the general method of Himrnelsbach and co-inventors, example 3 (51), to give P-2. The tert-butyl ester is hydrolysed in P-2 with IN NaOH in CH 3 OH to give P-3. Alternatively, the tert-butyl ester can be separated with TFA or HCl, in a suitable solvent such as __ * C »" Scheme Q describes a method for preparing exemplary fibrinogen receptor templates described in Linz and co-inventors, EP 0567968.
SCHEME Q (a) N- (2-p? 'r? "dinil) eti lendia ina, Ph2POCl, Et3N, DMAP, THF; (b) NaH, BrCH2C02CH3, DMF; (c) KOtB ?, CH3I, DMF; < e ) LiOH, H20 »THF Following the procedures of izy coinventores, EP 0567968, except that N- (2-pyridine "1) eti lendia is substituted for 4-cyanoani 1 ina, Q-5 is obtained. Scheme R describes a method for preparing exemplary fibrinogen receptor templates described in Wayne and coi ventores, WO 94/22834.
SCHEME R C02H (a) N-methyl-N '- (2-p? Rid? M "l) eti lendiamine, CH,; CN, (b) NaOH 1N, CH" OH. Following the procedures of Wayne and co-inventors, WO 94/22834, Example 1-2, except that it is substituted with N-methyl-N '- (2-pyridinium 1) eti Tendi ami to 1- (4-pi rid 1) prazrazin, R is obtained The Scheme S describes a method for preparing exemplary fibrinogen receptor templates described in Wayne et al., WO 94/22834.
SCHEME S (a) N-methyl-N '- (2-pyridini 1) and lendiamine »CH ... CN; (b) NaOH IN »CH ,, OH. Following the procedures of Wayne and co-inventors, WO 94/22834, example 3-4, except that it is replaced with N-met? T-Nr- (2-pi ridin 1) eti lend ai na 1- (4-pi r di 1) piperaz? na, you get S-3. Scheme T describes a method for preparing exemplary fibrinogen receptor templates described in Alig and co-inventors, EP 0381033.
SCHEME T (a) (Boc) 20, NaOH, di oxano, H20; (b) BrCH2C02Bn, K2C03 acetone; (c) 4M HCl, dioxane, (d) N- (2-pyridin din 1) -β-alanine, EDC »DIEA, DMF; (e) NaOH IN »CH3OH. Tl is treated with di-tertiary dicarbonate and sodium hydroxide in aqueous dioxane to produce T-2, which is alkyl in phenolic oxygen with benzyl bromoacetate and potassium carbonate in acetone, to give T-3 . The Boc group in T-3 is removed with hydrogen chloride in dioxane and the resulting T-4 is nitrated with N- (2-? I id? 1) -ß-alam "na, EDA and DIEA in DMF for give T-5 The benzyl ester is saponified at T-5 to give T-6 Alternatively the benzyl ester can be divided by treatment with H2 and a suitable catalyst, such as Pd / C, in a suitable solvent such as CH3OH , EtOH or AcOH Scheme U describes a method for preparing exemplary fibrin receptor templates described in 5 Alig and co-venitors »EP 0381033.
U SCHEME (a) (Boc) 20, NaOH »dioxane» H20; (b) BrCH2C02CH3, K2C03, acetone; (c) 4M HCl, dioxane, (d) N- (2-pyr? d? ni 1) -β-alanine, EDC, DIEA, DMF; (e) NaOH IN, CH 3 OH. U-1 is treated with di-tert-bicarbonate dicarbonate and sodium hydroxide in aqueous dioxane to produce U-2 »which is alkyl in the phenolic oxygens with methyl bromoacetate and potassium carbonate in acetone, to give U -3. The Boc group in U-3 is removed with hydrogen chloride in dioxane and the resultant U-4 is acylated in the nitrogen with N- (2-pyrid? N? 1) -β-alanine, EDA and DIEA in DMF to give U -5. The methyl esters are cleaved in U-5 by treatment with NaOH ÍM in CH 3 OH to give U-6. Scheme V describes a method for preparing exemplary phosphonogen receptor templates described in Híí? Tmel sbach and co-inventors »EP 0587134.
SCHEME V CD (a) dimer of gl i col to dehydrated, NaBH3CN, H_0, CH3CN »pH 6-7; (b) N- (2-pir? "Din? 1) eti lendíamí na, COCÍ (c) CH3S02C1, Et_N, CH-gCi 2; (d) Nal, KN (TMS) 2, THF, acetone, reflux; (e) NH2NH2-H20; (f) NaOH IN, EtOH. Scheme V provides a method for the preparation of 2-oxo-β-midazole-idine compounds, eg, V-5, wherein the reductive amination of an amine, eg, V-1 with the dimer of gl-cola! dehyde and sodium cyanoborohydride, gives a secondary amine, such as V-2. A primary amine, as exemplified by N- (2-píridiní 1) eti lendíami na, is treated with phosgene to give an isocyanate is then reacted, with isolation, with h? Dro ?? eti secondary lamina to give? na hydroxyethics »as exemplified by the compound V-3. The hydroxyl compound is converted to a substitutable group, such as meesulfonate or iodide, and a 2-oxo-imidazole is allowed to pass through V-4 using techniques known in the art. Himmelsbach and coinvenors EP 0587134. for example, by treating hydroxyethylurea 4 with trifluoromethyl chloride and Et.:1N, followed by Nal and then bis (trimethyl Isi 1 and T) potassium azide, as described in Hi melsbach. and co-inventors, EP 0587134, example III. The treatment of V-4 with hydrazine and the saponification of the ester gives V-5. Scheme W provides a method for the preparation of 1,2,3,4-tetrahydroisoquinolone compounds as exemplary f? Bronogen receptor antagonists, as described in M.J. Fisher and co-inventors, EP 0635492.
SCHEME W (a) ClCH2C02Et, Et3N, DMF; (b) BBr3, CH2C12; (O (CF3S02) 20, pin 'di na; (d) CO, Pd (0Ac) 2, PPh3, DIEA, NMP, NH_ -iC03, H20; (e) N- (2-pyridinyl) eti 1 endi a i a, EDC, HOBt, DIEA, DMF; (f) N- (2-pyridinyl) eti lendiamine »CO» PD (OAc) 2, PPh3, DIEA, NMP, NH ^ HC03, H20? (g) 1N NaOH, EtOH. Consequently, 6-me-oxo-3,4-dihydroisoquinol ina is prepared, such as compound W-1, by the method described by D.J. Salt! and G.L. Gr? NewaTd, J. Med. Chem., 1987, 30, 2208-2216. The isoquinoline is treated with a halogenated acid ester in the presence of a tertiary amine to produce the 2-acetic acid ester, which is exemplified by the compound W-2. The 6-methoxy compound is converted to the corresponding 6-hydroxy compound, by methods known in the art, for example, BBr3, which is converted to the triflate with trifluoronic acid anhydride. The carbon? The palladium-catalyzed reaction produces the 6-carboxy compound, such as the compound W-5, which is then condensed with an amine, as exemplified by N- (2-pyridin-1) -ethylenediamine, using a forming reagent. of normal amide bond, to give the desired amide, such as compound W-6 The saponification yields the title compound of example W, W-7. At the ternati vament, the palladium catalyzed carbonylization reaction with the triflate "exemplified by the compound W-4" can be entrapped with n- (2-pyridine "I) and lendiamine to provide, after saponification, W-7. Scheme X provides a method for the preparation of 3,4-dih-droisaquinol in-l-one compounds as exemplary fibrinogen receptor antagonists, as described in M.J. Fisher and co-inventors, EP 0635492.
SCHEME X (a) 1. LiN (TMS) 2; 2. ClCH2C02Et, DMF; (b) BBr3, CH2C12; (O (CF3S02) 20, pyridine; (d) CO, Pd (0Ac) 2, PPh3, DIEA, NMP, NH_-HC03, H20; (3) N- (2-pyridim "l) eti lendiami a, EDC, HOBt, DIEA, DMF; (f) N- (2-p? "R? D? M" 1) eti lendiamína, CO, Pd (OAc) -., PPh3, DIEA, NMP, NH_, HC03, H20; g) NaOH, EtOH, Consequently, the compound 1-oxo Xl, prepared by the method described by DJ Sal! and GL Grunewald, J. Med. Chem., 1987, 30, 2208-2216, is treated with a base, such as LiN (TMS) - and "n-haloacetic acid ester" to give the 2-acetic acid ester, as exemplified by compound X-2, then the 1-oxo compound is used in the analogous series of reactions described in Scheme U »by substituting the corresponding 1-oxo analog, as shown in Scheme U, to provide the title compound of Example X, X-7. As in Scheme U, alternatively, the carboni reaction TaTiCed taTTiOn, with tripTaT eT, axis pT if ticated by eT Compound X-4, can be trapped with an amine, as exempli fi ed with N- (2-pyridine 1) eti lendiamine, which provides, after saponification, the amide exemplified by the title compound X, X-7. The Y scheme provides a method for the preparation of 6-ací lami notetra compounds! ina, as exemplary antagonists of the fibrinogen receptor, as described by M.J. Fisher and coi ventores »EP 0635492.
SCHEME AND (a) N- (2-pyridin-1) -ß-al-aniña, EDC, HOBt, DIEA, DMF; (b) TFA, CH2C12. Accordingly, a 6-ami-2-tert-b-yl-loxi-carboni-1-tetra-l-one is condensed, exemplified by compound Y1, which is prepared according to the methods described by MJ Fisher and co-inventors, EP 0635492, with an activated derivative of a carboxylic acid obtained from N- (2-pi ridi "1) -S-a1am" na, to provide "after deesterification, the amide Y-2. method for the preparation of 6-aminoacetyl tetranona compounds, as exemplary antagonists of the fibrinogen receptor, as described by MJ Fisher et al., EP 0635492.
Z SCHEME (a) (CF3S02) 0, pyridine: (b) CO, Pd (0Ac) 2, PPh3, DIEA, NMP, NH ^ HC03, H20; (c) N- (2-pii di ni 1) eti 1 endi ami na, EDC, HOBt, DIEA, DMF; (d) N- (2-pyridi "1) eti lendiamine, CO, Pd (0Ac)", PPh3, DIEA, NMP, NH ^ HC03, H20 (e) NaOH, EtOH, Consequently, an ethoxycarbon is treated " 1 metí 1-6-hydroxy-tetral-1-one, exemplified by the compound Zl, q? E is prepared according to the methods described by MJ Fisher and co-venitors, EP 0635492, with triflic anhydride to provide the triflate, as exemplified by the compound Z-2, which is employed in a palladium-catalyzed carbohydration reaction, to give a carboxylic acid, such as the compound Z-3, which is then condensed with an amine, such as N- (2-pyrridin-1) -lendiamine, to provide, after deesterification, the 6-amino acyl compound exemplified in the example Z »Z -5. Alternatively, the palladium catalyzed carbonylation reaction, with the triflate exemplified by the compound Z-2, can be trapped with N- (2-pi ri di ni 1) ethyl endiami a to provide, after saponification, the compound 6 -ai oaci corresponded, exemplified by the example Z, Z-5. The AA scheme provides a method for the preparation of 5-acyl lamidobenzofuran and 5-acyl laminodihydrobenzofuran compounds, as exemplary antagonists of the fibrinogen receptor, as described by M.L. Denney and co-inventors, EP 0655439.
SCHEME AA - * .g f.g (a) BrCH2C02Et, K2C03, Nal, THF; (b) 1. DBU, EtOH; 2. HCl, EtOH; (c) DiBAL, -7S ° C, THF; (d) NaH, THF; (e) H2, 10% Pd / C, EtOH; (f) N- (2-p? r? diII) -β-alamine, EDC, HOBt, Et3N, DMF; (g) 1N NaOH, CH3OH.Therefore, a 5-nitrosal? This is exemplified by the compound AA-1, with a halogen-acetic acid ester to give the phenoxyacetic acid ester, exemplified by the compound AA-2, there is obtained 2-alkoxycarbonyl-furan, exemplified by the compound AA -3, treating the aTdehyde with a base, for example DBU.The group 2-alkoxylcarboxylate is reduced to the aldehyde, for example with DiBAL.The Wittig reaction produces the 2-acrylate ester, exemplified by the compound AA -5, which is reduced to the benzofuran-2-propionic acid ester, exemplified by the compound AA-6 »and the dihydrobenzofuran-2-propionic acid ester» exemplified by eT compound AA-7 The amine AA-6 is condensed then there is an activated derivative of a carboxylic acid, such as N- (2-pyrid? ni T) -ß-alam'na, to provide after desterification, Ta amide exemplified by eT compu this deTituTo, eT example AA, AA-8. Alternately, it condenses. Ta AAA-7 with an activated derivative of carboxylic acid, such as N- (2-pyridim "1) -β-alanine, to provide, after deesterification, the axis amide pliced by AA-9. Schemes BB-1, BB-2 and BB-3, give a method for the preparation of the compounds of 5-aminoacyl-1-enzyme and 5-amino-1-dihydrobenzo-urane, which are exemplary fibrinogen receptor antagonists, as described in ML Denney and coi ventores, EP 0655439 SCHEME BB-1 from (a) TBDMS-Cl, imidazole, THF? (b) DiBAL, -78 ° C, THF; (c) NaH, THF? (d) H ... v, 5% Pd / C, EtOH; (e) Et ^ NF, THF.
SCHEME BB-2 11 (a) (CF_S02) _0, pyridine; (b) CO, Pd (OAc): PPh_ ,, DIEA, NMP, NH ^ HC03, H20; (c) N- (2-pyridinium 1 leti I tendin amine, EDC, HOBt, DIEA, DMF; (d) N- (2-piri dini 1) et i 1 endiami na, CO, PD (OAc) - ,, PPh3 , DIEA, NMP, NH "HC03, H20; (e) 1N NaOH» EtOH.
SCHEME BB-3 12 14 13 (a) (CF3S02) 20, pyridine; (b) CO, Pd (OAc) 2, PPh3, DIEA, NMP, NH_, HC03, H20, "(c) N- (2-pyridini 1) eti lendiamine» EDC, HOBt, DIEA, DMF; (d) N- (2-pi ridinyl) eti lendiamine, CO, PD (OAc) - ,, PPh3, DIEA, NMP, NH ^ HC03, H20; (e) 1N NaOH, EtOH, Consequently, an ester of 5- hydroxy-benzoran-2-carboxylic acid is treated, such as the compound BB- 1-1, prepared in the manner described in ML Denney and co-inventors, EP 0655439, with TBDMS-Cl to give the TBDMS derivative of the ester, BB-1-2 The ester is reduced to an aldehyde, such as compound BB-1-3 The Wittig reaction produces an ester of acrylic acid, which is exemplified by the compound BB-1-5 The catalytic reduction produces an ester of benzofuran-2-acetic acid and an acid ester dihydrobenzo-2-acetic acid Separation of the ester group from each ester, by methods known in the art, produces a benzofuran-2-acetic acid ester as exemplified by the compound BB-1- 6 y? N dihydric acid ester Uran-2-acetic acid, which is exemplified by the compound BB-I-7. As shown in examples BB-2 and BB-3, each phenol can be converted to a carboxylic acid by means of palladium-catalyzed carbonization, such as the compound BB-2-9 or BB-3-13, which it is then condensed with an amine, such as N- (2-pyridine 1) eti lendiamy to provide, after desestepification, the amide of the title compound of example CC (BB-2-11) or DD ( BB-3-15). Alternatively, the palladium-catalyzed carbonyl reaction can be trapped with the triflates exemplified by the compounds BB-2-B or BB-3-12, with N- (2-pyridine-1) -eti-lendiamine to provide, after Deesterification, the 6-aminoac compounds? the corresponding, example CC (BB-2-11) or DD (BB-3-15). Scheme CC describes a method for preparing another additional exemplary fibrinogen receptor template.
CC SCHEME (a) Boc-Gly, EDC, HOBt, DIEA, CH3CN; (b) TFA, CH2C12; (c) 5-C (pyrid-2? 1) amine-3-pentanoic acid, EDC, HOBt, DIEA, DMF; (d) LiOH IN, THF, CH 3 CN. The preparation of intermediary CC-2 begins with the coupling of the known ethyl 3-amino-4-pentanoate (WO 93/07867) with ter-b? To? Icarbom "Igl icin (Boc-Gly) obtainable in the Trade, under normal conditions for the formation of the peptide binding, described in the Bodansky a Ta publication which was previously referenced.The product of this reaction is deprotected to CC-2 under acidic conditions, which is known to be Do the removal of a Boc protective group.
These conditions are described in the Godansky and Greene publications referred to above. The two intermediates CC-2 and 5-C (pyrid-2-yl) amine-3-pentanoic acid are coupled under normal peptide coupling conditions, to give CC-3, which is hydrogenated to CC-4 with idrox? a lithium in aqueous THF and acetoni tri 1 o. The acid addition salts of the compounds are prepared in a common and ordinary manner in a suitable solvent, from the original compound and an excess of an acid such as hydrochloric, hydrobromic, hydrochloric, sulfuric, phosphoric, acetic, trihydric acids. luoroacetic, male? co »succinic or methanesulfonic. Some of the compounds form internal salts or hybrid ions that may be acceptable. The cationic salts are prepared by treating the original compound! with an excess of alkaline reagent, such as hydroxide, a carbonate or an alkoxide, which contains the appropriate cation, or with an appropriate organic amine. Cations such as Li "-1-" Na-, K-, Ca- * "4-" Mg- * and NH ^ * are specific examples of cations present in pharmaceutically acceptable salts. The invention also provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. Consequently, the compounds of the formula (I) can be used in the manufacture of a medicament. The pharmaceutical compositions of the compounds of the formula (I) prepared as described hereinabove, can be formulated as solutions of Tiofi Tizados powders for parenteral administration. Can the powders be reconstituted by adding a suitable diluent? another pharmaceutically acceptable carrier, before use. The liquid formulation can be an isotonic aqueous solution, with regulator. Examples of suitable diluents are a normal isotonic saline, normal 5% dextrose in water or sodium acetate or ammonium-regulated solution. Said formulation is especially suitable for parenteral administration, but can also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be convenient to add excipients such as pol i vi or 1 pyrro! idona, gelatin, hi drox i celuí osa, acacia, pol ietí lengl icol, peanut, sodium chloride or sodium citrate. Alternatively, these compounds can be encapsulated, formed into tablets or prepared in an emulsion or syrup for oral administration. The pharmaceutically acceptable solid or liquid carriers can be added to increase or stabilize the composition or to facilitate the preparation of the composition. Solid carriers include: starch, lactose, calcium sulphate d? H? D, alba earth, magnesium stearate or stearic acid »talc, pectin» acacia, agar or gelatin. Liquid carriers include syrup, peanut oil »olive oil, saline and water. The carrier can also include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about ZO mg and about 1 g per unit dose. Pharmaceutical preparations are made following conventional pharmacy techniques, which involve milling, mixing, granulating and compressing procedures when necessary, for tablet forms; or grind, mix and fill, for hard geta atina capsule forms. When a liquid carrier is present, the preparation will be in the form of a syrup, an eTixir, an emuTsion, or an aqueous or non-aqueous suspension. Said form Tíq? Ida can be administered directly via OraT or can be filled with it a soft gelatin capsule. For rectal administration, the compounds of this invention can also be combined with excipients such as cocoa butter, glycerin, gelatin, or polyethylene glycols, and can be molded into a suppository. The compounds described herein are antagonists of the vitronectin receptor and are useful for treating diseases in which the underlying pathology is attributable to ligands or to cells that interact with the vi tronectin receptor. For example, these compounds are useful for the treatment of diseases in which the loss of bone matrix creates pathology. Thus, the compounds of the present invention are useful in the treatment of osteoporosis, hyperparathyroidism, hypercalcemia, osteolytic lesions caused by metastasis, bone loss due to mobilization or sexual hormone deficiency. It is also believed that the compounds of this invention have utility as anti-tumor, anti-inflammatory, antianginal and antimetastatic agents, and may be useful in the treatment of cancer, atherosclerosis and restenosis. The peptide is administered orally or parenterally to the patient, in such a way that the concentration of the drug is sufficient to inhibit bone resorption,? another one of said indications. The pharmaceutical composition containing the peptide is administered at an oral dose of between about O.l and about 50 mg / kg, in a manner consistent with the condition of the patient. Preferably, the oral dose would be around O.5 to 20 mg / kg. For acute therapy, parenteral administration is preferred. An intravenous infusion of the peptide in 5% dextrose in ag? A or normal saline, or a similar formulation, with suitable excipients, is very effective, although intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to 100 mg / kg, preferably between 0.1 and 20 mg / kg. Cough compounds are administered one to four times a day, at a level that yields a total daily dose of approximately 0.4 to 400 mg / kg / day. The precise level and the method by which the compounds are administered are easily determined by those who have routine experience in the field, comparing the blood level of the agent with the concentration necessary to have a therapeutic effect. The compounds can be tested in one of several biological analyzes to determine the concentration of the compound that is necessary to have a given armacological effect.
INHIBITION OF VITRONECTIN UNION Binding of C3H3-SKSF-107260 in solid phase to «vß3. Vß3 from human placenta or human platelet (0.1-0.3 mg / Ml) was diluted in regulator T (containing 2 M CaCT2 and 1% octylglucoside) with reguTadsr T containing 1 mM CaCl2 + 1 mM MnCl2, 1 M MgCl2 (regulator A) and 0.05% NaN3, and was immediately added to 96-well concavity ELISA plates (Corning, New York, NY) at 0.1 ml per concavity. 0.1-0.2 μg of _cxvß3 was added per concavity. The plates were incubated overnight at 4 ° C. At the time of the experiment, the concavities were washed once with regulator A and incubated with 0.1 ml of 3.5% bovine serum albumin in the same regulator for at least one hour, at room temperature. After incubation, the concavities were completely aspirated and washed twice with 0.2 ml of regulator A. The compounds were dissolved in 100% DMSO to give a 2 M master solution, which was diluted with binding buffer (15 M Tris). -HCl (pH 7.4), 100 M NaCl, 1 mM CaCl 2, 1 mM MnCl 2, 1 M MgCl 2), at a final compound concentration of 100 μg. This solution is then diluted to the final concentration of compound required. To the concavities, in triplicate, were added various concentrations of unlabeled antagonists (O.001-100 μM) followed by the addition of 5.0 nM of C3H3-SKdF-107260 (65-86 Ci / mmol). The plates were incubated for one hour at room temperature. After incubation, the concavities were completely aspirated and washed once with 0.2 ml of regulator A cooled with ice, in a concave to concave manner. The receptors were solubilized with 0.1 ml of 1% SDS and the bound C3H3-SK8-F-107260 was determined by flash counting in liquid with the addition of 3 ml of Ready Safe in a liquid flash counter Beckman LS with 40% efficiency. The non-specific binding of C H3-SKSF-107260 was determined in the presence of 2 μmoles of SK &F-107260 and was consistently less than 1% of the radio input! igando The Cies,., (Concentration of the antagonist to inhibit 50% of the binding of C3H3-SK &F-107260) was determined by means of a less square curve fitting routine, which was modified from the LUND0N-2 program. The K., (antagonist dissociation constant) was calculated according to the equation:,.
= C2 / (l + L / Ka), where L and Kd were the concentration and Ta constant of dissociation of C3H3-SK_.F-107260, respectively. The compounds of the present invention inhibit the binding of vitronectin to SK6F-107260 in the concentration range of about O.OOl to 25 micromolar. Preferred compounds inhibit the binding of vitronectin to a concentration of less than 1 micromolar. The compounds of this invention were also tested for bone resorption n vi tro and in vivo in standard tests in the art to evaluate the inhibition of bone formation "such as the pit formation analysis described in EP 528 587, which also it can be done using human osteoclasts instead of rat osteoclasts, and the ovarectile rat model "described by Wronski and coauthors, Cells and Materials 1991» Sup. 1 »69-74.
MODEL OF RATA PARATIROIDECTOMIZADA Each experimental group consisted of 5 to 6 male Sprague-Dawley rats. The rats were stopped (by the seller, Taconic Far s) seven days before using them.
Twenty-four hours before use, the levels of ionized, circulating calcium were measured in whole blood Ta, immediately after it had been extracted by venipuncture in Ta coTa to heparimized tubes. Ca ionized (measured with a Cyba-Cor íng model 634 pH pH analyzer) is 21.2 mmole / liter, then the rats are placed on a diet of calcium-free feed and deionized water At the beginning of the experiment the rats weigh approximately 100 g) The levels of basic line calcium are measured and administered to the control vehicle (saline) or compound (saline disterate) rats in a single intravenous bolus injection (caudal vein) followed immediately by a nausea. single subcutaneous injection of peptide 1-34 of the hormone for human iroid (hPTHl-34, dose 0.2 mg / kg in saTin / 0.1% of albumin and bovine serum, Bachem »CaTíform'a) or eT vehicle PTH. CaTce ica response to PTH (and C? placed in this response) two hours after Ta compound admiistration / PTH.
ULNA DISPLACEMENT MODEL IN RATS Each experimental group consists of 8 to 10 Sprague-Dawley or Wistar rats, males, approximately 30 to 40 g of body weight at the beginning of the experiment. Once the agent is tested »it is administered by an appropriate route as a single dose or as multiple daily doses» for a period of seven days. Prior to administration of the first dose, the rats are given a single dose of a fluorescent marker (tetracycline, 25 mg / kg, or calcium IO mg / kg) to mark the position of the forming surfaces. of the bone in that period of time. After the compound is dosed, the rats are sacrificed and both forelegs are removed at the elbow and the leg is removed at the ankle and the skin is removed. The sample is frozen and mounted vertically in a microtome carrier, cross sections are cut from the median horn region in the cryostat, and the rate of bone resorption in the middle dorsal portion of the cortical bone is measured morometrically. The measurement is made in the following way: The amount of bone reabsorbed on the periosteal surface is equal to the distance at which the periosteal surface has advanced in the fluorescent marker that had been incorporated into the endosteal surface of bone formation on day zero This distance is calculated by subtracting the bone width between the marker and the periosteal surface on day 7 of the width on day zero.The rate of reabsorption in microns per day is calculated by dividing the result by 7.
ANALYSIS OF REPOSSESSION OF HUMAN OSTEOCLASTE ("SCALED ANALYSIS") - Aliquots of suspensions of osteoclast-derived cells are withdrawn from storage in liquid nitrogen, Tas is quickly heated to 37 ° C and washed once in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). - The medium is aspirated and replaced with murine anti-HLA-DR antibody, di Tuido 1: 3 in RPMI-1640 medium. Incubate for 30 minutes on ice and mix the cell suspension. - Wash the cells twice with RPMI-1S40 cold by centrifugation (1000 rpm, 5 minutes at 4 ° C) and transfer to a sterile 15 ml centrifuge tube. The number of onon? Clea cells is enumerated in an improved Ne? Bauer counter chamber. - Sufficient magnetic beads (5 / mononuclear cell) »coated with Ig < 3 goat anti-mouse, from its storage bottle and placed in 5 ml of fresh medium (this removes the preservative of toxic azide by washing). The medium is removed by immobilizing the globules in a magnet and replacing with fresh medium. - Mix the globules with the cells and incubate the suspension for 30 minutes on ice. The suspension is mixed frequently. - The cells coated with globules are immobilized in a magnet and the remaining cells are decanted (osteoclast-rich fraction) in a sterile 50 ml centrifuge tube. - fresh medium is added to the cells coated with globules to dislodge any trapped osteoctases. This washing procedure is repeated ten times. The coated cells are discarded with beads. - The osteoclasts are enumerated in a counting chamber using a disposable plastic pasteur, with a large hole, to load the chamber with the sample. Pellets are formed with the cells by centrifugation and the density of the osteoclasts is adjusted to 1.5 x 10-Vml in EMEM medium, supplemented with 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate.
LOL - 3 ml aliquots of the cell suspension are decanted (by treatment) in 15 ml centrifuge tubes. Pellets are formed from the cells by centrifugation *. - It is added to each tube 3.ml of the appropriate treatment (diluted to 50 μmol in the EMEM medium). Also included are appropriate vehicle controls, a positive control (87 MEM1 diluted to 100 μg / ml) and an isotypic control (IgG2a diluted to 100 μg / ml). Incubate at 37 ° C for 30 minutes. - Aliquots of 0.5 ml of the cells are seeded in sterile dentin plates in a 48-concave plate, and incubated at 37 ° C for 2 hours. Each treatment is discriminated in quadruplicate. - The plates are washed in six changes of hot PBS (10 l / concavity in a 6-plate concavity) and then placed in fresh treatment or control. Incubate at 37 ° C for 48 hours.
PROCEDURE OF TARTRATQ RESISTANT ACID PHOSPHATASE (TRAP) (SELECTIVE DYE FOR CELLS OF THE LINEAGE OF QSTEOCLASTO) - The slides are washed in phosphate-buffered saline and fixed in 2% gluteraldehyde (in 0.2 mole of sodium cacodylate) for 5 minutes. They are washed in water and incubated in TRAP buffer for 5 minutes at 37 ° C. - After a cold wash, they are incubated in a cold acetate / fixed red garnet regulator for 5 minutes at 4 ° C. - The excess regulator is aspirated and the slides are air dried, after washing with water. - TRAP positive osteoclasts are enumerated by bright field microscopy and then removed from the dentine surface by sonic treatment. - The sting volumes are determined using the Nikon / Lasertec ILM21W confocal microscope.
INHIBITION OF UNION OF GPIIb-IIIa, MEDIATED BY RGD Purification of GPIIb-IIIa 10 units of washed human platelets were washed before the date (obtained from the Red Cross) by means of moderate agitation in 3% of octylglucoside, 20 mmol of Tris-HCl, pH 7.4, 140 mmol, of NaCl, 2 mmole »of CaCl2 at 4 ° C for 2 hours. The lysate was centrifuged at 100,000 g for 1 hour. The obtained supernatant was applied to 5 ml of lenti! lectin, in column 4B of sepharose (E.Y. Labs) pre-dried 1 with 20 immoles of Tris-HCl, pH 7.4, 100 mmoles of NaCl, 2 mmoles of CaCl 2, 1% of glycosides (regulator A). After 2 hours of incubation, the column was washed with 50 ml of cold regulator A. GPIIb-IIa retained in lectin was eluted with regulator A containing 10% dextrose. All procedures were carried out at 4 ° C. The GPIIb-Illa obtained was more than 95% pure as demonstrated by electro-pression of SDS in pol acri lamide gel.
Incorporation of GPIIb-Illa into liposomes A mixture of osfatidi Iserine (70%) and phosphatidium Icol ina (30%) (Avant? Polar Lipids) was dried to the walls of a glass tube under a stream of nitrogen. Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg / ml and mixed with the phospholipids at a protein: phospholipid ratio of i: 3 (by weight: weight). The mixture was resuspended and treated with sound in a bath bath for 5 minutes.The mixture was dialyzed at night using 12,000-14,000 molecular weight dialysis tubing cuts against a thousand fold excess. of 50 mmole of Tris-HCl, pH 7.4, 100 mmoles of NaCl, 2 mmoles of CaCl 2 (with two changes). The liposomes containing GPIIb-Illa were centrifuged at 12,000 g for 15 minutes and resuspended in a dialysis regulator at a protein concentration of approximately 1 mg / ml The liposomes were stored at -70 ° C until needed.
Competitive binding to GPIIb-IIIa The binding of the f? (GPIIb-Illa) in an indirect competitive binding method using C H3-SKS.F-107260 as a ligand of type RGD. Binding analysis was carried out on 96-well filtration plate assembly (Millippore Corporation, Bedford, MA) using hydrophilic 0.22 micrometer diaphragm membranes. The concavities were precoated with 0.2 ml of 10 μg / ml of polysinylamine (Sigma Chemical Co., St. Louis, MO) at room temperature for 1 hour to block non-specific binding. Several concentrations of unlabeled benzodiazepines were added to the concavities, in quadruplicate. C3H3-SK &F-107260 was applied to each concavity to a final concentration of 4.5 nano oTes, followed by the addition of 1 μg of the liposomes containing GPIIb-IIIa, from purified platelet. The mixtures were incubated for 1 hour at room temperature. ET C3H3-SKSF-107260 bound to GPIIb-IIIa nonTigadoT was separated by filtration, using a Millippore filtration method, followed by washing with an ice-cooled regulator (2 times each with 0.2 ml). The bound radioactivity that remained on the filters was counted in 1.5 ml of Ready SoTve (Beckman Instruments, F? TTerton, CA), in a Beckman TED counter (model LS6800) with 40% efficiency. Non-specific binding was determined in the presence of 2 μmol of unlabeled SKSF-107260, and was consistently less than 0.14% of the total radioactivity added to the samples. All data points are the average of determinations in quadruplicate. Competitive union data was analyzed by the less squared, non-linear curve fitting procedure. This method provides the CI for the antagonists (concentration of antagonists that inhibit the specific binding of C3H3-SK & amp; amp;; F-107260 in 50%, in equilibrium). The CIBO is related to the dissociation constant (K.,) in equilibrium of the antagonist »based on the equation of Cheng and Pr? Soff: Ki = IC50 / (1 + L / Kd), where L is the concentration of C3H -SK &F-107260 used in competitive binding analysis (4.5 nanomoles) and Kd is the dissociation constant of C3H3-, SK &F-107260, which is 4.5 nanomoles »as determined by the Scatchard analysis. Preferred compounds of this invention have an activity to the victronectin receptor with respect to the fibrinogen receptor of more than 4: 1. It is more preferred that the compounds have an activity ratio of more than 10: 1.
ANALYSIS OF VASCULAR SMOOTH MUSCLE CELL MIGRATION The compounds of the present invention were tested for their ability to inhibit the migration and proliferation of smooth muscle tissue in an artery or vein in order to determine its ability to prevent restenosis of an artery, such as occurs typically after angioplasty. Rat or human aortic smooth muscle cells were used. The migration of cells in a Transwell cell culture chamber was monitored using a polycarbonate membrane with 8 micrometer pores (Costar). The lower surface of the filter was coated with vi tronectin. Cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 1.5 to 5.0 x 10 * 3 cells / mT, and pretreated with the test compound at various concentrations for 20 minutes at 20 ° C. . Only solvent was used as control. 0.2 ml of the cell suspension was placed in the upper compartment of the chamber. The lower compartment contained 0.6 mT of DMEM supplemented with 0.2% bovine serum albumin. Incubation was carried out at 37 ° C in an atmosphere of 95% air / 5% C0. , during . 24 hours. After incubation, non-migrated cells were removed on the upper surface of the filter by moderate scraping. After fixing the filter in methanol and stained with 10% Giemsa dye. The migration was measured: (a) counting the number of cells that had migrated to the lower surface of the filter, or (b) extracting the cells stained with 10% acetic acid, followed by the determination of the absorbance at 600 nM.
EXAMPLES Nuclear magnetic resonance spectra were recorded at 250 or 400 MHz, using, respectively, Br? Ker AM 250 or BruKer AC 400 spectrometer. CDCl,., Is orofarm deuteriacl, DMS0-ds is hexadecylated dimethylsulfoxide and CD30D is tetradetectad methanol. Chemical shifts are reported in parts by -million (6), downfield of tetrameti 1 if internal standard. The abbreviations for the NMR data are as follows: s = a single band; d = double band, t = triple band »c = quad band, rn = multiple bands, dd = double band double, dt = triple band double, app = apparent, br = extends. J indicates the NMR coupling constant measured in Hertz. The continuous-wave infrared (IR) spectra were recorded on Perkin-Elmer 683 infrared spectrometer and the Fourier transform infrared (FTIR) spectra were recorded on a Nicolet I pact 400 D infrared spectrometer. The IR and FTIR spectra were recorded in the transmission mode, and the band positions are reported in inverse wave numbers (era-1). The mass spectra were taken in instruments VG 70 FE, PE Syx API III or VG ZAB HF, using fast atom bombardment (FAB) or electroerosion ionization (ES) techniques. The elemental analyzes were obtained using a Perkin Elmer 240C elemental analyzer. The melting points were measured in a Thomas Hoover melting point apparatus, and are not corrected. All temperatures are reported in Celsius. Thin-film plates Analtech Silica Gel GF were used. and E. Merck Silica Gel 60 F-254 for thin layer chromatography. The chromatography was carried out rapidly and in gravity on silica gel E. Merck kieselgel SO (230-400 mesh). Preparatory and analytical HPLC was carried out in Raí ni n or BecKman cro atographs. ODS refers to the chromatographic support of silica gel with derivation of octadeci Isi 1 í lo. 5 mieras apex ODS indicates a chromatographic support of silica gel with derivation of octadeci Isi 1 í which has a nominal particle size of 5 microns, manufactured by Jones Chromatography, Latvian Lit, Colorado. YMC ODS-AQR is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd, Kyoto, Japan. PRP-1R is a polymeric chromatographic support (styrene-di-vinyl-1-benzene) and is a trademark of Hamilton Co., Reno, Nevada). Celite "is a filter aid composed of diatomaceous silica washed with acid, and is a trademark of Manvílle Corp., Denver, Colorado. (±) -7-carboxy-2, 3,4,5-tetrahydro-4 was prepared. -methi 1- 3-oxo-1H-1, 4-enzodiazep n-2-methyl acetate and (±) -7-carboxy-2,3,4,5-tetrahydro-3-oo-4-em " 1 eti 1-1H-1,4-benzodi azepi-2-methyl acetate by the method of Bondinell and co-inventors WO 93/00095. (S) -7-carboxy-2, 3,4,5-tetrahydro-4-methyl-1-3-oxo-1H-1,4-benzodi azepi n-2-aceta or methyl was prepared by the method of Bondinell and co-inventors WO 95/18619.
PREPARATION OF INTERMEDIATE COMPOUNDS PREPARATION PREPARATION OF 3-C3.4-DIHIDR0-B-CARB0XI-1-METHYL-2.5-DI0X0-1H-1, 4-BENZQDIAZEPIN3-4-BENCILO PROPAN0AT0 (a) 4-iodo-2 acid -aminobenzoic The oxidation of 4-iodine-2-ni troto! ? eno according to Sasson and co-authors, J. Org. Chem. 1986, 51, 2880-2883, to give 4-iodo-2-nor robenzoic acid, followed by reduction of the group . nitro using iron and acetic acid, gives the title compound. (b) 7-iodoisatoic anhydride To a mechanically stirred ice-cooled solution of the compound of preparation A (a) (26.3 g, 0.1 mol), 10.6 g, 0.1 mol of sodium carbonate and 250 ml of water, a solution of 80 ml of C0C12 1.93 M in toluene was slowly added by means of an addition funnel. After 2 hours the precipitated product is isolated by filtration and the solid is washed successively with 20 ml of water, 300 ml of a mixture of EtOH: Et20 i: i and 200 ml of Et20, and dried under vacuum to produce the title compound. (c) Benzyl N- (2-amino-4-iodobenzoyl) -β-alanine A magnetically stirred solution of 5.0 g, 0.0173 mol, of the compound of preparation A (b), 5.85 g, 0.0173 mol, of ester tosylate ß-alanine benzyl and 0.5 g »0.0041 mol, of DMAP in 35 ml of pyridine, is heated for 2 hours at 80 ° C. The reaction mixture is allowed to cool to room temperature and concentrated. The resulting residue was dissolved in 100 ml of EtOAc and washed successively with 2 x 50 ml of 10% cupric sulfate, 1 x 50 ml of saturated sodium bicarbonate, and 1 x 50 ml of brine, dried over sodium sulfate. , filter and concentrate to give the title compound, after chromatography (silica gel, 1: 1 EtOAc / hexanes). (d) Benci! N- (2-Methylamino-4-iodobenzoi 1) -β-alanine A magnetically stirred solution of 2.0 mmole of the compound of preparation A (c), 0.35 ml, 3.0 mmol, is heated at 50 ° C for 15 hours, of 2,6-l? tidine and 0.19 ml, 3.0 mmoles, of CH .-. I in 15 ml of DMF. The reaction mixture is allowed to cool to room temperature and concentrated. The resulting residue is dissolved in 75 ml of EtOAc and washed successively with 1 x 50 ml of 10% citric acid, 1 x 50 ml of saturated sodium bicarbonate and 1 x 5? ml of brine, dried over sodium sulfate, filtered and concentrated to give the title compound, after chromatography (silica gel, gradient 35-65% EtOAc / hexanes). (e) 3-C3,4-dihydro-8-iodo-l-methyl-2,5-dioxo-lH-l »4-benzodi-azepin3-4-benzyl propanoate To a magnetically stirred solution cooled to -30 ° C, 0.305 g, 0.69 mmole »of the preparation compound A (d), 0.144 g, 1.04 mmol, of Et3N to 3 mL of CH2C12, 0.09 mL, 1.04 mmol, of β-bromoacetyl bromide in 2 mL of CH2C12 was added slowly, under argon atmosphere. The mixture is allowed to warm to room temperature for 2 hours. The mixture is diluted with 40 ml of methylene chloride and washed successively with 1 x 50 ml of 10% citric acid, 1 x 50 ml of saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrate The resulting residue is dissolved in 3 ml of DMF and a suspension funnel of NaH in 2 ml of DMF is added by means of an addition funnel to 25 mg, 1.04 mmol, which is cooled to 0 ° C. After stirring for 2 hours, the mixture is poured into an ice-cold solution of 50 ml of 10% citric acid and extracted with 3 x 40 ml of EtOAc. The combined extracts are washed with 1 x 50 ml of saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to yield the title compound, after chromatography (silica gel, gradient 40-70% of EtOAc / hexanes). (f) 3-C3 »4-dihydro-8-carboxy-l-methyl-2» 5-dioxo-lH-l »4-benzodi-azepin3-4-benzyl propanoate A solution of 3.2 mmol, from the composed of preparation A (e), 0.16 mmol of Pd (OAc) ..? and 0.64 mmol of 1.1 '-bi s (dipheni-1-phosphino) errocene in 20 ml of DMSO, at 65 ° C, under balloon of carbon monoxide for 18 hours. The reaction mixture is diluted with acid, acidified with 1N HCl and extracted with CH2C12. The combined organic extracts are washed with water, dried over sodium sulfate, filtered and concentrated to give the title compound, after chromatography on silica gel.
PREPARATION B ETHYL ETHYL 3-C4H-IMIDAZ0LCl, 2-a3Cl, 43BENZ0DIAZEPIN-5 (6H) -l- METHYL-6-0X0-9-CARB0XI3-5-PR0PAN0IC0 (a) Ethyl N- (2-amino-4-iodobenzoyl) -β-a1-one A solution of 0.0173 mol, of the compound of preparation A (b), is heated for 2 hours at 80 ° C. 0.0173 mole, of ethyl ester hydrochloride of β-aTanine and 0.5 g, 0.0041 oT, of DMAP in 35 mT of pyridine. The reaction mixture is allowed to cool to room temperature and concentrated. The resulting residue was dissolved in 100 mT of EtOAc and washed successively with 2 x 50 ml of 10% acetic acid, Tfate, 1 x 50 mT of saturated sodium bicarbonate and 1 x 50 ml of brine, dried over magnesium sulfate. Sodium, filtered and concentrated to yield the title compound, after chromatography (silica gel, 1: 1 EtOAc / hexanes). (b) 3-C3 »4-dihydro-8-iodo-2,5-dioxo-lH-1» 4-benzodiazepin3-4-ethyl propanoate A? magnetically stirred solution »at -30 ° C, 0.69 mol of the compound of preparation B (a) and 0.144 g, 1.04 mmol, of Et3 in 3 ml of CH2C12, is slowly added a solution of 0.09 ml, 1.04 mol of oc-bromaacet bromide? in 2 ml of methylene chloride »under an argon atmosphere. The reaction mixture is allowed to warm to room temperature and is stirred for 2 hours. The mixture is diluted with 40 ml of CH2C12 and washed successively with 1 x 50 ml of 10% citric acid, with 1 x 50 ml of saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The resulting residue is dissolved in 3 ml of DMF and added through an addition funnel to a suspension of 25 mg, 1.04 mmol, of NaH in 2 ml of DMF, which is cooled to 0 ° C. After stirring for 2 hours, the mixture is poured into an ice-cold solution of 50 ml of 10% citric acid and extracted with 3 x 40 ml of EtOAc. The combined extracts are washed with 1 x 50 ml of saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to give the title compound, after chromatography on silica gel. c) 3-C3,4-di hydro-8-iodo-2-thioxo-5-oxo-lH-l, 4-benzodiazapin3 -4-ethyl propanoate To a solution of 10 g, 2.49 mmol, of the compound of preparation B (b) in 10 ml of THF at room temperature and under a nitrogen atmosphere, 10 g of Lawesson's reagent was added and the reaction was heated to 50 °. C for two hours. The reaction mixture was allowed to cool to room temperature and concentrated. Purification of the residue by chromatography (silica gel, gradient of 40-60% EtOAc / hexane) gives the title compound. d) 3-C4H-imidazoCl, 2-a3Cl »43-benzodiazepin-5 (6H) -l-methyl 1-6-o? o-9-iodo3-5-ethyl propanoate To a vigorously stirred, biphasic solution of 0.95 g, 2.27 mmol, of the compound of preparation B (c), and a catalytic amount of tetrab.Ti sulfate, Tamom'o in 10 T of methylene chloride and 10 ml of water, 1.2 ml of 2N sodium hydroxide is added at room temperature. After 2 hours, layers are separated and the aqueous layer is washed with 2 x 25 ml of ethylene chloride. The combined organic extracts are dried over sodium sulfate, filtered and concentrated. The resulting residue is dissolved in 10 mL of toluene and allowed to react with 0.64 mL of propargi lamina and 0.23 g of pyridine hydrochloride. The reaction is heated at reflux for six hours and allowed to cool to room temperature and concentrated to give the title compound after chromatography (silica gel, EtOAc). e) eti-3-C4H-imidazoCl acid »2-a3Cl» 43benzodiazepin-5 (6H) -l-methyl 1-6-oxo-9-carboxy 3-5-propanoic acid A solution of 3-2 mmol of the compound of preparation B (d), 0.16 mmol of Pd (0Ac) 2 and 0.64 mmol of l-1-bis (differem-l-phosphine) ferrocene is heated to 65 ° C. in 20 ml of DMSO »under a carbon monoxide flask, for 18 hours, dilute the reaction mixture with water, acidify with IN HCl and extract three times with methylene chloride.The combined organic extracts are washed with water , dried over sodium sulfate, filtered and concentrated to give the title compound after chromatography (on silica gel).
PREPARATION C PREPARATION OF 4- (1-PIPERAZINID-1-PIPERIDINACETAT0 OF ETHYL a) 4-C4- (ethyl tarbutoxy carboni 1) -1-piparazini 1 -1-piperidinacetate.
The title compound is prepared from 1-piperazyl carboxylate terbyl (Aldrich) and ethyl 4-oxo-1-piperidinacetate, Porter and co-inventors, EP 0 542 363 A2, by reductive ination with NaBH -, .CN according to the method of Porter and co-vendors, EP 0 542 353 A2. b) Ethyl 4- (l-Píperaziní l) -l-píperidinacatato A solution of preparation C (a) and 4M HCl in dioxane / methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is concentrated to give the title compound, such as the hydrochloride salt.
PREPARATION D PREPARATION OF 3-CL0R0-l- (2-PYRIDINYL) PR0PILAMINE a) 3-C (l-o? o-2-pyridyl) a i or -l-propanol The mixture is heated at 100 ° C for 18 hours to a mixture of 3-ami o-1-propanol, 2-cl oropi-di-a-N-oxide hydrochloride and sodium bicarbonate in n-b-tanol. The mixture is filtered, concentrated, partitioned between aqueous sodium bicarbonate and EtOAc. The aqueous phase is extracted with EtOAc, dried, concentrated and purified to give the title compound. b) 3- (2-pyridinyl) amino-1-propanol A mixture of the compound of preparation D (a), potassium formate and 10% Pd / C in ethanol is heated to reflux under argon for 48 hours. The mixture is filtered, concentrated and purified by chromatography to give the title compound. c) 3-chloro-l- (2-pyridini 1) propi sheet A solution of preparation D (b) is treated with thionyl chloride in methylene chloride for 18 hours. The mixture is concentrated to give the title compound.
PREPARATION AND PREPARATION OF 4-C4- (2-AMIN0ETIL) -l-PIPERAZINIL3-l-PIPERIDIN- ETHYL ACETATE * - a) 4-C4-C2- (butoxycarbonylamino) ethyl 3-1-piparazini 13-1- ethyl pjperidinacetate Following the general procedure of Porter and coi ventores, EP O 542 363 A2, except that it is replaced with 4- O C2C (butoxicarbom "lamino) eti 13-1-piperazi na 1-benzyl Ipiperazine and with 4-oxo-l- The ethylpperidinacetate, 4-oxo-1-piperidinacetate, 1,1-di etiyl, gives the title compound. b) 4-C4- (2-ami oeti 1) -1- iperazi ni 13-1- ethylperidinacetate Treat the compound of preparation E (a) with TFA in methylene chloride to give the title compound. 0 PREPARATION F PREPARATION OF ETHYL-HIDR0XI-4-C4- (2-AMIN0ETIL) -l- PIPERAZINIL3CICL0HEXANACETAT0 Following the procedure of preparation E »except that ethyl 4-oxo-1-pperidinacetate is replaced with ethyl 1- (hydroxy) cyclohexanacetate, the title compound is obtained.
PREPARATION G PREPARATION OF ACID N-C2- (PIRIDINIL) AMINQ3BUTIRICQ Following the procedure of the preparation V (c), except that it is replaced with acid N- (l-oxo-2-pyridinium 1) -ami obut rico, Tortore! and co-inventors, Gazz. Chim. Ital. , 1967, 97, 85-95, the compound of Ta preparation V (b), eT composed of TITuTo is obtained.
PREPARATION H PREPARATION OF 2- (4-HIDRQXIBUT-l-ILAMIN03PIRIDINE a) N-oxide of 2- (4-hydroxy but-1-ylamino) pyridine A mixture of 1.76 g, 20 mmol, 4-amino-1-butanol, 3.98 g, 24 mmol, N-oxide hydrochloride of 2-chloropyridyne and 8.40 g, 100 mmol of sodium bicarbonate is heated at reflux. sodium in teramyl alcohol SO ml. After 48 hours the reaction is cooled, diluted with ethanol, filtered and concentrated. The residue is reconcentrated in toluene and chromatographed on silica gel to give the title compound. b) 2- (4-hydroxybut-l-i lamino3pyridine A precipitated mixture of 1.82 g »10 mmol» of the compound of preparation H (a), 3.15 g »50 mmol of ammonium formate and 10.64 g» 10 mmol of Pd / is heated overnight at 40 ° C overnight. 10% C in 50 ml of absolute ethanol; it is then cooled to room temperature and filtered through Celite (R). The filtrate is concentrated and the residue is divided between 50 ml of water and 50 ml of chloroform. Separate the layers and extract the aqueous layer with chloroform. Dry the combined organic layers over sodium sulfate, concentrate and chromatograph the residue (on silica gel) to give the title compound.
PREPARATION I PREPARATION OF 5-C ACID (PIRID-2-IL) AMIN03PENTAN0IC0 a) N-oxide of ethyl 5-C (pjrid-2-yl) amino-3-pentanoate A mixture of 2.9 g, 20 mmol, of ethyl 5-aminopentanoate »3.98 g, 24 mmol, of 2-chloropyridine N-oxide hydrochloride and 8.40 g, 100 mmol of sodium bicarbonate is heated to reflux under argon. sodium in 50 ml of ethyl tera alcohol. After 48 hours the reaction is cooled, diluted with ethanol and concentrated. The residue is again concentrated in toluene and chromatographed on silica gel to give the title compound, b) 5-C (picrid-2-yl) amino-3-pentanoate gives ethyl The mixture is heated at 40 ° C overnight to a vigorously stirred mixture of 2.38 g, 10 mmol, of the compound of the preparation Ka), 3.15 g, 50 mmol, of ammonium formate and 10.64 g, IO mmol of Pd / C to the 10% in 50 ml of absolute ethanol; it is then cooled to room temperature and filtered through Celite (R). The filtrate is concentrated and the residue is divided between 50 ml of water and 50 ml of chloroform. Separate the layers and extract the aqueous layer with chloroform. The combined organic layers are dried in sodium sulfate and concentrated. Silica gel chromatography gives the title compound. c) 5-C (pyrid-2-yl) amino-3-pentanoic acid A mixture of 444 mg, 2.0 mmol, of the compound of preparation Kb), 3.0 ml, 3.0 mmol, LiOH 10 N, 10 ml of THF and 7 ml of ag? A is stirred at room temperature overnight. then concentrate. The residue is taken up in 5 ml of water and neutralized with 1.0 N HCl. The precipitate is collected and dried under vacuum to give the title compound.
PREPARATION J PREPARATION OF 4-CN-PIRID-2-IL-N- (TOLUENSULFQNIL) AMINQ3BUTANAL- QXIMA a) N-oxide of 4-CN-pyrid-2-i! -N- (toluenesulfoni 1) amino3butanal A mixture of 100 mmol of 2- (3-ami opropi 1) -1,3-dioxola or 120 mmol of N-oxide hydrochloride of 2-cToropyridium and 500 mmol of sodium bicarbonate is heated at reflux under argon. sodium in 250 ml of ethyl tera alcohol. When complete, the reaction is cooled, diluted with ethanol, filtered and concentrated. The residue is concentrated in toluene and chromatographed on silica gel to give the title compound. b) 2-C3- (Pyrid-2-i 1) aminoprop-1-i 13-1, 3- ioxolane A stirred mixture of 60 mmol of the compound of 1 to preparation J (a), 300 mmol of ammonium formate and 60 mmol of 10% Pd / C in 300 ml of ethanol is heated overnight at 40 ° C overnight. absolute; it is then cooled to room temperature and filtered through Cel i te (R). The filtrate is concentrated and the residue divided between ag? A and chloroform. Separate the layers and extract the aqueous layer with chloroform. The combined organic layers are dried over sodium sulfate and concentrated. Chromatography (on silica gel) gives the title compound. c) 2-C3-CN-pyrid-2-y1- (tol? ens? lfoni 1) amino propyl-1-l, 3-dioxolane .5 55 mmol of sodium hydride is carefully added to a solution of 50 mmol of the compound of preparation J (b) and 55 mmol of 4-toluenesulfonyl chloride in 200 ml of dry THF. The reaction is stirred at room temperature until it is complete; it is then quenched with 200 ml of saturated ammonium chloride and the mixture extracted with EtOAc. The combined organic extracts are dried over magnesium sulfate and concentrated and the residue purified by chromatography on silica gel to give the title compound. 5 d) 4-CN-Prid-2-i l-N- (toluenesulfonyl) ami no butane! A solution of 40 mmol of the compound of preparation J (c) and 4 mmol of p-0 Ts0HpHx; 0 in 180 ml of acetone and 20 ml of ag? A is stirred at room temperature. When complete, dilute the reaction with ether and wash successively with 5% sodium bicarbonate and saturated brine. Drying over magnesium sulfate, Ta concentration and chromatography on silica gel give the title compound. e) 4-CN-pyrid-2-i l-N- (toluenesulfonyl) amino-3-butanal-oxime 33 mmol of hydroxylahydrochloride is added to a solution of the compound of preparation J (d) (30 mol) and 66 mmol of anhydrous sodium acetate in 150 ml of ethanol at 0 ° C. The reaction is stirred at 0 ° C until complete, then concentrate and partition the residue between water and EtOAc. Separate the layers and extract the aqueous layer with ethyl acetate. The organic layers combined with 5% sodium bicarbonate and with saturated brine are dried sequentially in magnesium sulfate and concentrated to give the title compound.
PREPARATION K PREPARATION OF 2-C DICHLORHYDRATE (3-AMIN0PR0P-1-IL) AMIN03- PIRIDINE a) N-oxide of 2-C3-C (terbutoxycarbonyl) amino propyl-1-lamino-pyridine.
A mixture of 3.48 g, 20 mmol, of N-Boc-1,3-diami-opropane, 3.98 g, 24 mmol, of 2-chloropyridine N-oxide hydrochloride, 8.40 g, 100 is heated under reflux under argon. mmol of sodium bicarbonate in 50 ml of teramyl alcohol. After 48 hours the reaction is cooled »diluted with ethanol, filtered and concentrated. The residue is concentrated in toluene and chromatographed on silica gel to give the title compound. b) 2-C3- (terbuto icarboni 1) amino prop-l-i lamino3pyridine An agitated mixture of 2.67 g, 10 mmol, of the compound of Preparation K (a), 3.15 g, 50 mmol of ammonium formate and 10.64 g »* 10 mmol of Pd is heated overnight at 40 ° C overnight. / C at 10% in 50 ml of absolute ethanol; it is then cooled to room temperature and filtered through Celite (R). The residue is concentrated and the residue divided between 50 mT of water and 50 ml of chloroform. The layers are separated and the aqueous layer is brought with chloroform. Dry the combined organic layers over sodium sulfate and concentrate. Chromatography on silica gel gives the title compound. c) 2- (3-aminopro-1-yl) amino-3-pyridine dihydrochloride 4 M HCl in 25 ml »100 mmol, dioxane, is added to a solution of 1.26 g, 5.0 mmol, of the compound of preparation K (b) in 25 ml of dichloromethane at 0 ° C. The reaction is stirred at room temperature overnight and concentrated to give the title compound.
PREPARATION L PREPARATION OF 4-C2-C2- (PYRIDINYL) AMINQ3ETYL3PHENOL Following the procedure of the preparation Via) and (c), except that the N- (aceti 1) eti lendiami na is substituted with 4- (2-ami oe i 1) phenol, the title compound is obtained.
PREPARATION M PREPARATION OF 4-C2- (METHYLAMIN0) CHLORHYDRATE BENZYL ACETYL3FEN0XIACETAT a) 4-C2f (Boc-meti lamino) aceti 1 pheno1 A solution of 5.96 g, 27.3 mmol, of diterbityl dicarbonate in 25 was added dropwise at 0 ° C. of 1,4-dioxane, to a mixture of 5.0 g, 24.8 mmol, of 4- hydrochloride C2- (methylamino) acetyl 13 phenol, 30 ml of 1,4-dioxane, 25 ml of water and 25 ml, 25 mmol of lOH NaOH. After 24 hours, the reaction is warmed to room temperature and stirred for 1.4 hours. 25 ml is added. 25 mmol more 1.0 N NaOH) and the reaction is stirred for another 0.5 hour at room temperature and concentrated. The residue is diluted with 80 ml of EtOAc and the mixture was acidified to pH 2 using 1.0 M sodium bisulfate. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and dried over sodium sulfate. Filtration and concentration gave 6.459 g, 99% of the title compound. NMR with AH (250 MHz, CDC13) delta 6.70-8.05 (m, 4 H), 4.53 (s, 2H), 2.98 (s, 3H), 1.50 (s, 9H). b) 4- 2- (Boc-meti lamino) acetyl 1-phenoxy benzyl acetate A mixture of 5.04 g, 19.0 mmol, of the compound of preparation L (a) and 2.63 g »19.0 mmol, of potassium carbonate in 100 ml of acetone was stirred at reflux under argon for one hour. The mixture was cooled to room temperature and 5.23 g, 22.8 mmol, of benzyl bromoacetate was added. The reaction was heated to reflux for 18 hours, then cooled and filtered. The filter cake was washed with acetone and the filtrate was concentrated. The residue was dissolved in 300 ml of dichloromethane and washed sequentially with 50 ml of ag? A and 50 ml of brine. Drying over sodium sulfate, concentration and flash chromatography (silica gel, 1: 3 EtOAc / hexanes) yielded 7.28 g, 93%, of the title compound. NMR with H (250 MHz, CDC13) delta 6.85-7.95 (m, 9 H); 5.23 (s, 2H); 4.71 (s, 2H), 4.55 (d, 2H), 2.95 (d, 3H), 1.45 (d, 9H). c) 4-C2f (methylamino) acetyl phenoxy benzyl acetate hydrochloride.
A mixture of 7.26 g, 17.57 mmol »of the compound of preparation L (b) and 4 M of HCl in 150 ml of 1,4-dioane was stirred for a period of 1 hour at room temperature. Concentration and trituration with ether gave 5.93 g, 97% of the title compound as a white powder. NMR with J-H (250 MHz, CD3OD) delta 7.05-8.00 (m, 9 H), 5.23 (s, 2H), 4.88 (s, 2H); 4.65 (s, 2H), 2.80 (s, 3H).
PREPARATION N PREPARATION OF 4-C2- (METILAMINQ) ACETYL3-1, 2-PHENYLENDIOXIDI- ACETATE OF DIMETHYL a) 4-C2- (Boc-meti lamino) aceti 1 -1,2-dihydroxybenzene Following the procedure of preparation L (a) »except that 5.0 g, 23.O mmol, of adrenaline hydrochloride, 4-C2- (methylamino) acetyl 13 phenol hydrochloride was substituted, 1.2 g, 19% was prepared of the title compound, after flash chromatography (silica gel, 1: 1 EtOAc / hexanes). MS (ES) m / e 282.2 (M + H) *. b) 4-C2- (Boc-meti lami no) aceti-1, 2-phenyl-diazo dimethyl acetate.
Following the procedure of the preparation L (b) »except that 0.9 g» 3.2 mmol of the compound of preparation M (a) is replaced by the compound of preparation L (a) and with 1. 23 g »8.0 m oT» of methyl bromoacetate the benzyl bromoacetate, l.ll g, 81%, of the title compound MS (ES) m / e 426.2 (M + H) * was prepared. c) 4- 2- (Methylamino) acetyl 13-l »2-phenylenedium-i-dimethyl diacetate hydrochloride Following the procedure of the preparation L (c) »except that it is replaced with l.ll g» 2.6 mmoT »of the compound of Ta preparation M (b) eT composed of the preparation L (b), the title compound was prepared. To (1.1 g »quantitative). MS (ES) m / e 326.0 (M + H) *.
PREPARATION OR PREPARATION OF (6-CARB0XI-1.2, 3.4-TETRAHIDR0IS0QUINQLIN-2-IL) - ETHYL ACETATE a) (6-methoxy-l »2» 3 »4-tetrahydroisoquinolin-2-yl) ethyl acetate A solution of 1.1 mmol of water is stirred for 18 hours. 6-methoxy-l »2,3,4-tetrahi roísoq ?? nol ina, Sal! and Gr? newald, J. Med. Chem. 1987, 30, 2208-2216, 1.17 mmol of ethyl chloroacetate and 1.17 mmol of potassium carbonate in 10 ml of acetoni tri 1 or. The mixture is partitioned between EtOAc and ag? A. The organic phase is concentrated to an oil which is purified by chromatography (silica gel, gradient, 20-80% EtOAc / hexane) to give the title compound. b) (6-hydroxy-l, 2,3 '4-tetrahydroisoguinol in-2-yl) ethyl acetate A solution of 0.249 g, 1.0 mmol "of the compound of preparation Oía), 1.0 ml, 1.0 mmol, of 1M BBr 3 in dichloromethane is stirred for two hours" and then stirred at room temperature for 12 hours. The solution is concentrated and the resulting oil solution is washed with EtOAc, with 5% sodium bicarbonate and with water, dried over magnesium sulfate, filtered and concentrated in oil to give 0.223. g, 95% of the title compound. c) C6- (trif1 uorometi 1 sul foni 1 oxy) -1, 2, 3,4-tetrahydroisoguino-lin-2-i 1 ethyl acetate It is stirred for 8 hours? A 0.235 g solution, 1.0 mmol, of! compound of preparation 0 (b), 0.23 rnl, 1.1 mmol, of trifluorosulic anhydride and 0.32 ml, 1.5 mmol, of Et3N in 5 ml of di-chloromethane. The solution is concentrated to an oil, which is taken up in EtOAc. The organic phase is washed and dried over sodium sulfate, filtered and concentrated to give 0.300 g, 82%, of the title compound. d) (6-carboxy-l, 2,3 '4-tetrahydroisoguinol in-2-yl) ethyl acetate The mixture is stirred for 8 hours under a CO atmosphere, a 0.367 g solution, 1.0 mmol, of the compound of preparation 0 (c), 0.022 g, 0.1 mmol, of Pd (OAc) .T, 0.262 g, 1.0 mmol, of Ph .. ,, P, 0.34 ml, 2.5 mmol, of isopropyl lamella and 5 ml of NMP in 10% NH ^ C03. The solution is concentrated to an oil, which is purified by chromatography (silica gel, gradient, 10-33% ethanol / dichloroethane) to give 0.19 g, 72%, of the title compound.
PREPARATION P PREPARATION OF (6-CARB0XI-1, 2, 3,4-TETRAHIDR0-l-0X0-I50QUIN0LIN- 2-ETHYL IDEATE a) (6- ethoxy-l-oxo-l »2» 3,4-tetrahydroisoguinol in-2-i 1) ethyl acetate It is heated to reflux for an hour or a mixture of 0. 39 mmol of 6-methoxy-2, 3,4-tetrahydro-l-oxo-isoquinol ina, Sal! and Grunewald, J. Med. Chem., 1987, 30, 2208-2216, and 0.17 g, 0.43 mmol, of NaH as a 60% dispersion in oil, in 5 mT of THF; It is allowed to cool to room temperature. 0.43 mmol of ethyl chloroacetate is added and the mixture is left to stir for one hour. The mixture is quenched with 10 ml of water and washed with EtOAc. The organic layers are combined, washed with 10 ml of water and concentrated to an oil, which is purified by chromatography (silica gel, gradient, 10-33% ethanol / di-chloromethane) to give the Title. b) 6- (Hiroxyl-l-oxo-l, 2,3,4-tetrahydroisoguinol in-2-yl) -acetic acid ethyl ester.
A solution of water is stirred at -70 ° C for two hours. 0. 263 g »1.0 mmol» of the compound of preparation Pia) and 1 M of BBr3 in 1.1 ml of dichloroethane; and then at room temperature for 4 hours. The solution is concentrated to an oil which is taken up in EtOAc. The organic phase is washed with ag? A »with 5% sodium bicarbonate, with water, dried over magnesium sulfate, filtered and concentrated to give 0.20 g, 80% of the title compound. c) C6- (trifl? orometi Isulfoni loxi) -1,2 »3,4-tetrahydro-1-o? o-isoguinolin-2-yl ethyl acetate.
A solution of 3.4 mmol of the compound of preparation P (b) and 3.4 mmol of trifluorosulphonic anhydride in 5 ml of pyridine is cooled to 0 ° C and allowed to warm to room temperature for one hour. The mixture is quenched with 5 ml of water and washed with EtOAc. The organic layers are combined, washed with 7 ml of water and concentrated in an oil. The residue is purified by chromatography (silica gel, gradient »14-75% EtOAc / hexane) to give the title compound. d) (6-carboxy-l-oxo-l »2» 3,4-tetrahydroisoquinolin-2-i 1) -acetic acid ethyl ester It is stirred for 8 hours, under a CO atmosphere, a 0.23 g solution, 1.0 mmol, of the preparation compound P (C), 0.026 g, 0.1 mmol, of Pd (OAc), 0.262 g, 1.0 mmol. , Ph ... P, 0.23 ml »2.0 mmol, of di i sopropy" 1 amine and 7 ml of NMP in 10% ammonium carbonate. The solution is concentrated to an oil which is purified by chromatography (gel silica, gradient, 25-75% ethanol / dichloromethane) to give 0.31 g, 70%, of the title compound.
PREPARATION Q PREPARATION OF (6-CARB0XI-TETRALIN-2-IL) ETHYL ACETATE a) C6- (trifl? orometi Isulfom ~ loxi) tetra! i -2-i ethyl acetate.
Following the procedure of preparation 0 (c), but substituting with (6-hydroxy-tetral i -Z-? 1) ethyl acetate, Fisher and co-inventors, EP 0635492, scheme 6 and example 20, parts AD, the compound of the preparation 0 (b), the title compound is obtained. b) (6-carboxy-tatral in-2-yl) ethyl acetate Following the procedure of the preparation Oíd), but substituting the compound of the preparation Q (a >) with the compound of the preparation Oic), the title compound is obtained.
PREPARATION R PREPARATION OF ETHYL (5-AMINQBENZ0FURAN-2-IL) PR0PI0NAT0 AND (5-AMIN0-2,3-DIHIDR0-BENZ0FURAN-2-IL3PRQPI0NAT0 OF ETHYL a) 2- (ethoxycarbonyl) methoxy? -5- and trobenzal dehyde.
Heat at 80 ° C for 24 hours, a solution of 0.167 g, 1.0 mmol, of 5-ni trosal ici 1 aldehyde (Aldrich), 0.166 g, 1.0 mmo!) Of ethyl bromoacetate »0.276 g, 2.0 mmol. of potassium carbonate and 0.015 g »0.1 mmol, of Nal in 10 ml of THF. The solution is concentrated and the residue is purified by chromatography (silica gel, gradient, 5-20% Ethane in methylene chloride) to give 0.20 g, 87%, of the title compound. b) (5-nitrobenzofuran-2-y1) ethyl carbohydrate.
A solution of 0.229 g, 1.0 mmol, of the compound of the preparation Ria) is left stirring at room temperature for 18 hours. The solution is concentrated and the residue is treated with 10 ml of EtOH. The solution is bubbled with gaseous HCl for two minutes and allowed to reflux for 5 hours. The solution is concentrated and the residue treated with EtOAc. The organic phase is washed with water, with 5% citric acid »with water, with 5% sodium bicarbonate and with water. The organic phase is concentrated to yield 0.19 g, 81%, of the title compound. c) eti 1- (5-nitrobenzof? ran-2-i 1) carboxyaldehyde Treat a cooled solution at -78 ° C of 0.235 g, l.O mmol, of the compound of preparation R (b) in 5 ml of THF, with 1.0 ml, 1.0 mmol, of 1 M DiBAL in THF. The solution is stirred at -78 ° C for 30 minutes and at room temperature for 3 hours. The solution is treated with 3 ml of CH3C02H, and then with 2 ml of ag? A. The solution is concentrated and the residue is treated with toluene to expel the acetic acid as an azeotrope. Vacuum drying produced 0.100 g, 52%, of the title compound. d) (5-nitrobenzofuran-2-i 1) ethyl pro-enoate A solution of 0.224 'g »1.0 mmol, of triethyl fasphonoacetate in 5 ml of THF» is treated with 0.04 g, 1.0 mmol, of NaH as a 60% suspension in mineral oil, at 0 ° C for one hour. 0.235 g »1.0 mmol of the compound of the preparation R (c) is added to the solution. The solution is stirred at room temperature for 18 hours, concentrated and the residue purified by chromatography (silica gel, gradient, 5-20% EtQAc / hexane) (EtOAc / hexane 0.5: 9 to 4: 1) for give 0.2 g, 77%, of the title compound. e) ethyl (5-a -benzofibofuran-2-yl) propionate and ethyl (2-amino-2'-3-ihi-robenzofan-2-yl) -propyl ether.
A solution of 0.261 g, 1.0 mmol "of the compound of preparation R (d) in 5 ml of ethanol containing 0.026 g of 10% Pd / C was hydrogenated at 3.16 kg / cm2 during a" hour ". The solution is filtered through Celite and the filtrate is concentrated and chromatographed (silica gel, gradient, 25-75% EtOAc / hexane) to yield the title compounds.
PREPARATION OF PREPARATION OF ETHYL (5-CARBOXI-BENZ0FURAN-2-IL) PR0PI0NAT0 a) C5- (terbuti ldimeti Isi 1 i loxi) = benzofuran-2-i 13carboxi ethyl acetate A solution of 0.206 g, 1.0 mmol, of C5- (idroxy) enzofuran-2-i 13-ethylcarboxylate, Denny and co-vendors, EP-0655439, 0.23 ml, 1.0 mmol, of chloride is left stirring for 4 hours. of teributi 1) dimeti Isi 1 i lo and 0.34 g »1.0 mmol, of imidazole in THF. The solution is concentrated and the residue treated with EtOAc. The organic phase is washed with water, dried over sodium sulfate and concentrated to give 0.35 g, 90%, of the title compound. b) C5-ter (butyl) -di eti Isyl i loxi 3bsnzofuran-2-yl 13propenoate ethyl Following the procedure of the preparation R (c) and (d), but substituting the compound of the preparation S (a) with the compound of the preparation R (b), the title compound is obtained. c) ethyl C5- (hydroxy) benzofuran-2-yl 3-propionate and C5-hydroxy-2,3-di hydro-benzofuran-2-yl ethyl 1-propionate.
A mixture of 0.234 g, 1.2 mmol, of the compound of the preparation S (b) and 0.023 g, 10% by weight, of Pd / C a! Is hydrogenated at 3.5 kg / cm2 for one hour. 10% in 5 ml of ethanol. The mixture is filtered through CeTi and concentrated. A solution of 0.34 g »1.0 mmoT, of residue and 0.149 g, l.O mmoT, of Et ^ NF in 10 rnl of THF, is left stirring at room temperature» for 18 hours. The solution is concentrated and purified by chromatography on silica gel to give 0.25 g, 57% of the title compounds. d) C5- (trifluoromethyl 1 sulfoni loxi) benzofan-2-ethyl-1-propionate Following the procedure of the preparation 0 (c), except that it is substituted with C5- (idroxy) benzofuran-2-yl 13-propionate of the preparation S (c) the compound of the preparation 0 (b), the compound is obtained of the title. e) (ethyl 5-carboxy benzofuran-2-yl) propionate Following the procedure of the preparation 0 (d), except that it is substituted with the compound of the preparation S (d) the compound of preparation 0 (c), the compound of tit? To is obtained.
PREPARATION AND PREPARATION OF (5-CARB0XI-2, 3-DIHYDRO-BENZQFURAN-2-IDPROPIONATE OF ETHYL a) C5- (trifluoromethyl lysulfoni loxi) -2,3-dihydro-benzofuran-2-yl ethyl propionate.
Following the procedure of the preparation Síd), except that it is replaced with ethyl C5-hydroxy-2, 3-dihydrobenzo-uran-2-ι-13-propionium the C5-hydroxy) -ofi-3-ien-13-ethyl-propionate of Preparation Sic), the title compound is obtained. b) ethyl (5-carboxy-2,3- i hydro-benzofuran-2-yl) propionate Following the procedure of the preparation S (e), except that the compound of preparation T (a) is replaced with the compound of preparation Si d), the title compound is obtained.
PREPARATION OR PREPARATION OF TRIFLUQROACETATE OF (±) -3- (GLICIL) AMIN03-4- ETHYL PENTINOATE a) (±) -3- C (N-terbutoxycarbonyl) gl ici 13am or ethyl-4-pentanoate 0.92 ml »5.32 mmol of DIEA was added to a stirred solution of 0.3 g, 2.13 mmol, of (±) -3-ami or-4-pentyl ethyl acetate, 0.56 g »3.19 mmol, of Boc-Gly, 0.43 g, 3.19 mmol, of HOBtpH.vO and 0.61 g, 3.19 mmol, of EDC in 15 ml of anhydrous acetonitrile at room temperature. After 34 hours the reaction mixture was concentrated, diluted with 70 ml of dichloromethane and washed sequentially with 2 x 15 ml of sodium bicarbonate and 15 ml of brine. Drying with magnesium sulfate, concentration and chromatography (silica gel »1: 1 EtOAc / hexane) gave 0.5 g, 79%, of the title compound, as a colorless oil. MS (ES) m / e 299.2 (M + H) *. b) ethyl (3-) -3-C (gl icyl) amino3-4-pentynoate trifluoroacetate.
A solution of 5 ml of TFA and 15 ml of dichloromethane at room temperature, 0.5 g, 1.68 mmol, of the compound of preparation Sía) was added in one go. After 30 minutes, the solution was concentrated and the residue was concentrated again in toluene (to eliminate the residual TFA, to provide 0. 55 g, 106%) of the title compound, as a light yellow syrup. MS (ES) m / e 199.2 (M + H) *.
PREPARATION AND PREPARATION OF N-Í2-PYRIDINIL) ETILENDIAMINE a) N-Acetyl-Nt- (l-oxo-2-pyridinyl) ethylenediamine The mixture was heated at 100 ° C for 18 hours, a mixture of 0.5 g, 5 mmol, of N- (aceti 1) etí lendia ia, 1.6 g »10 mmol, of 2-chloropy-N-oxide hydrochloride and 5 ml of nb? tanol. The mixture was then allowed to cool and filtered and the filtrate was concentrated. The resulting residue was purified by chromatography (silica gel, gradient gradient, 2% -10% ethanol / dichloroethane) to give 0.40 g, 45%, of the title compound, as a pale yellow solid. MS (ES) m / e 196 (M + H) *. b) N- (l-oxo-2-pyridini 1) eti lendiamine A mixture of 0.4 g of the compound of preparation V (a) and 50 ml of concentrated HCl was heated at 90 ° C for 4 days, and the residue was recrystallized (ethanol, chloroform) to give the title compound as white needles. mate (3.2 g, 82%). MS (ES) m / e 154.2 (M + H) *. c) N- (2-pyridinium 1 leti lendiamine) It was heated to reflux, under argon for 48 hours, a mixture of 1.0 g, 5 mmol, of the compound of preparation V (b), 2.2 g, 25 mmol, of potassium formate, 0.30 g of Pd / C 10% and 20 ml of ethanol. The mixture was filtered, the filtrate was concentrated and the residue was purified by chromatography (silica gel, 10% ethanol / dichloromethane) to give 0.30 g, 41% of the compound as? Amber oil. MS (ES) m / e 138.1 (M + H) *.
PREPARATION W PREPARATION OF (S) -2.3.4.5-TETRAHIDR0-7-Y0D0-3-QX0-lH-l, 4- BENZ0DIAZEPIN-2-ACETAT0 OF METHYL a) 0-triflate of (R) -dimethyl malate Droplet solution was added dropwise under argon at 0 ° C. 12. 96 g, SO mmol, of (R) -dimethylmaltolate and 6.8 ml, 84 mmol, of p? Rdina in 50 ml of methylene chloride or a solution of 14.2 ml, 84 mmol of anhydride triflic in 40 ml of methylene chloride or dry, in a flame-dried flask. The resulting yellow-orange mixture was stirred at 0 ° C for 30 minutes and T? Ego at room temperature for 4 hours. The reaction was quenched by adding 50 ml of water and the organic phase was washed three times with water and with brine, dried over magnesium sulfate and concentrated to give 22.45 g, 95%, of the title compound, as? matt white solid. MS (ES) m / e 295. O (M + H) *. b) N- 2- (cyano) phenyl - (S) -apaparate dimethyl A solution of 22.4 g, 76.2 mmol, of the compound of preparation W (a) in 80 ml of 1: 1 chloroform: hexane, was added to a solution of 9.0 g, 76.2 mmol) of 2-ami obenzoni ri 1 and 14.5 g, 76.2 mmol, of 2,6-di-terboyl-1-pyridine in 100 ml of chloroform-hexane 1: 1, in a flame-dried flask, under argon at 0 ° C. The resulting mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 3 days. The resulting mixture was concentrated, the residue was taken up in EtOAc, washed with 5% HCl and with brine, dried over magnesium sulfate. The resulting mixture was concentrated and the residue was purified by flash chromatography (silica gel, 12% EtOAc / hexane) to give 12.3 g, 62%, of the title compound, as a clear oil. MS (ES) m / e 263.3 (M + H) *. c) (S) -2,3,4,5-tetrahydro-3-oxo-lH l »4-benzodiazene-2-methyl acetate.
The mixture was stirred at room temperature for two days, under a flask of hydrogen, a mixture of 12 g, 45.7 mmol, of the preparation compound Wíb), 7.64 ml, 54.84 mmol, of Et3N and 46 g of Raney nickel prewash by ethanol) in 200 ml of ethanol. The mixture was filtered and the catalyst was washed three times with methanol. The filtrate was concentrated and the residue was purified. by flash chromatography (silica gel, gradient gradient, 0-5% ethanol / ethyl ester chlorine) to give the title compound as 7.93 g, 75%, of a white solid. MSI) m / e 235.3 CM + H) *. It was shown that e! The title compound contained approximately 23% of the (R) -enantiomer by NMR. d) (S) -2 »3.4» 5-tetrahydro-7-iodo-3-oxo-1H-1,4-benzodi aze i n-2-methyl acetate. 100 ml of pyridine-IC1 complex was added slowly: 1M iodine monoclone in methylene chloride to a solution of 8.5 ml »105 mmol, of a-pyridine in 20 ml of methylene chloride; stirred under argon and pre-cooled to 5 ° C, in order to maintain an internal temperature between 10-15 ° C. The mixture was stirred at 5 -10 ° C for 20 minutes. 50 ml of hexane was added and the mixture was stirred in a cold bath for another 30 minutes. The solid that formed was collected by filtration, washed with hexane and with petroleum ether and dried to yield 22.5 g of the a-ICl pyrid complex, as a yellow solid which was used without further purification. 1.27 g, 5.28 mmol, of pyridine-ICl complex was added in portions to a solution of 1.18 g, 4.8 mmol, of the compound of preparation W (c) in 40 ml of 1: 1 of methylene chloride: ethanol. The resulting mixture was stirred at room temperature for 40 minutes, treated with 20 ml of NaHCO 3, and the resulting solid was collected by filtration, washed with ether and dried to give 1.72 g, quantitative yield, of the title compound , like a matt white solid. MS (ES) m / e 361.2 (M + H) *.
PREPARATION X PREPARATION OF (S) -7-CARBOX1-2 »3,4,5-TETRAHIDR0-3-0X0-4- (2.2.2- TRIFLU0R0ETIL) -lh-l, 4-BENZ0DIAZEPIN-2-ACETAT0 OF METHYL a) 4-f! uoro-3-C (2 »2» 2-trifluoroethyl) aminomethyl-13-benzoate gives terbuti lo The mixture was stirred under argon at room temperature for 4 days, a mixture of 14 g, 48 mmol, of 3-bromomethyl-1-4-fl-orobenzoate and 25 g »250 mmol. of 2,2,2-trifluoroethylamine in 300 ml of THF; The residue was concentrated and the residue was partitioned between ether and 10% potassium carbonate. The organic phase was washed with 10% potassium carbonate and brine, dried and concentrated. The residue was purified by chromatography (silica gel, gradient gradient, 0-8% ethyl acetate / hexane, to give the title compound as 10.7 g »72%, of a pale yellow oil, MS (ES) m / e 308.3 (M + H) *. b) (S) -4-fluoro-3- 2- (benzyloxycarbonyl) ami no-1,4-ioxo-4-meto? i-1-butyl (2, 2 »2-trifluoroeti-1) amino-3-methyl-benzoate of terbuti the. 2.8 ml, 36 mmol »of cyanuric fluoride were added dropwise to an ion solution, 36 mmol, of the beta-methyl ester of Cbz-L-aspartic acid and 2.8 ml, 36 mmol of pyridine in 100 ml of chloride of I met him; and stirred under argon at room temperature. The resulting mixture was stirred at room temperature overnight, diluted with 100 ml of methylene chloride and quenched with 100 ml of ag? A. The mixture was filtered, the phases were separated and the organic phase was dried with magnesium sulfate and concentrated to give the acid fluoride of the Cbz-L-aspartic acid beta-methyl ester. The acid fluoride was dissolved in 50 ml of methylene chloride Te and was added dropwise to a solution of the compound of Ta preparation X (a) (5 g, 16 mmol) in 200 ml of methylene chloride and 3 ml »37 mmol of pyridine, stirred under argon at 0 ° C. After the addition was complete, the resulting solution was stirred at room temperature overnight, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel, methylene chloride) to give 10 g, 100%, of the title compound, as a colorless syrup. MS (ES) m / e 571.2 (M + H) *. c) (S) -4-fluoro-3-CCC2-amino-l, 4-dioxy-4-methoxy-l-butyl 1- (2, 2,2-trifluoroethyl) to n-butylmethyl-tert-butylbenzoate.
A mixture of 10 g of the compound of preparation X (b) and 2 g of 10% Pd / C in 200 ml of ethanol was shaken in an atmosphere of 3.16 kg / cm 2 of hydrogen for two hours. The mixture was filtered, the filtrate was concentrated and the residue was purified by chromatography (silica gel, gradient T gradient, 0-2% methane / methylene chloride to give 6 g, 78% of the title as a colorless syrup MS (ES) m / e 436.9 (M + H) *.
) (S) -7- (terbutoxycarboni 1) -2,3 »4» 5-tetrahydro-3-oxo-4-1,2,2,2-trifluoroeti 1) -lH-l, 4-benzodiazepin-2-acetate I got it.
A solution of 5.8 g of the compound of preparation Xic) in 60 ml of DMSO was heated under argon at 120 ° C for six hours. The mixture was allowed to cool, poured into ice water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, gradient gradient 0% -5% methanol / methylene chloride to give 3 g »50%, of the title compound, as a white foam. NMR (400 MHz, CDCT3) from T 7.72 d, J = 8.4 Hz, 1H), 7. 59 (s, HH), 6.53 (d, J = 8.4 Hz, HH), 5.49 (d, J = 16.7 Hz, HH), 5.15 mm, 1H), 4.57 dd, J = 6 Hz, HH), 4.31 m , ÍH), 3.99 (d, J = 16.7 Hz, ÍH), 3.80 (m, ÍH), 3.75 (s, 3H), 3.00 (dd, J = 16. 2, 6.4 Hz, 1H), 2.72 (dd, J = 16, 6.4 Hz, 1H>, 1.57 (s, 9H). e) (S) -7-carboxy-3,4,5,6-tetrahydro-3-oxo-4- (2,2, -tr fl uoro-1) -IH-1,4-benzo iaze i - 2-methyl acetate. 1.56 g, 14 mmol, of anisole was added to 25 ml of stirred TFA at 0 ° C under argon, and then there was added dropwise to a solution of 3 g, 7 mmol of the compound of preparation X (d) in 25 ml of methylene chloride. After the addition was compl the solution was allowed to warm to room temperature and was stirred for two hours. The mixture was concentrated and the residue was dissolved in EtOAc. The organic phase was extracted with concentrated NH 4 OH to bring the pH of the aqueous phase to 10. The aqueous layer was washed twice with EtOAc, brought to pH 4 with 3N hydrochloric acid and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give the title compound as a matt white solid (2.1 g, 81%). MSI) m / e 361.1 ÍM + H) *.
PREPARATION AND PREPARATION OF N-6-METHYL-2-PYRIDINYL) ETHYLENDIAMINE Following the procedure of Preparation V, except that 6-methyl 1-2-chloropyldine N-oxide was replaced with 2-chloropyridine N-oxide, the title compound was obtained. MS (ES) m / e 152 ÍM + H) *.
PREPARATION Z PREPARATION OF N-METHYL-Nt- (2-PYRIDINYL) ETHYLENDIAMINE a) N-Boc-N-methyl-N * - (l-oxo-2-iridini 1) eti lendiamine It was heated to reflux, under argon, a mixture of 849. 2 mg, 4.87 mmol, of N-Boc-N- (methyl 1 leti lendiamine (Synth, Comm? N., 1993, 23, 2443-2449), 970 mg, 5.84 mmol »of N-oxido hydrochloride 2- chloropi idine and 2.05 g »24.4 mmol» of sodium bicarbonate in 12 ml of terayl alcohol After 41.5 hours the reaction was cooled, diluted with EtOH, filtered and concentrated, the residue was concentrated again in toluene. and chromatographed (silica gel, 5% methanol / chloroform) to give 863.1 mg, 66%, of the title compound, as a viscous yellow oil which was used without further purification MS (ES) m / e 268 ( M + H) *. b) N-Boc-N-methyl-Nt- (2-pyridinyl) ethylenediamine A stirred mixture of 863.1 mg, 3.23 mmol, of the compound of preparation Z a), 1.02 g, 16.2 mmol, of ammonium formate and 344 mg »0.32 mmol, of 10% Pd / C was heated to reflux. absolute ethanol (16 ml). After 8 hours the reaction was cooled to room temperature and 2.04, 32.4 mmol more, of ammonium fordiate and 3.44 g, 3.23 mmol of 10% Pd / C were added. The reaction was stirred at 40 ° C for 14.5 oras, cooled to room temperature and filtered through Celite (R). The filtrate was concentrated and the residue was partitioned between 20 ml of ag? A and 20 ml of chloroform. The phases were separated, the aqueous phase was extracted with 2 x 20 ml of chloroform and the combined organic phase was dried over sodium sulfate and concentrated. The resulting yellow oil was chromatographed on silica gel, 5% chloroform in 1: 1 of EtOAc / cTorofor or to give eT compound of TITUE as a yellow oil (267.4 mg, 33%). MS (ES) m / e 252 (M + H) *. c) N-meti l-N'-í 2-? iridini dihydrochloride 1) eti lendiamine .3 mol, 21.2 mmol was added. of 4M HCl dioxane »in a stream» to a solution of 267.4 mg »1.06 mmol, of the compound of preparation Z (b) in 5.3 ml of anhydrous methylene chloride at 0 ° C. The reaction was stirred at room temperature for 16 hours and concentrated to yield the title compound as a yellow, hygroscopic solid (229.4 mg, 97%). MS (ES) m / e 152 (M + H) *.
PREPARATION AA PREPARATION OF N- (2-PYRIMIDINYL) ETILENDIAMINE a) N-Boc-N '- (2-pyrimidini 1) eti lendiamine 0.80 g, 5.0 mmoT »of N- (Boc) et was dissolved. lendiamine (Syn. Commun., 1990, 20, 255-2S4) in 12 ml of 1-propanol and treated with 1.2 g, 9.0 mmol) of potassium carbonate, followed by 0.91 g »8.0 mmol, of 2-cTopopyrimidine, and it was set to T ref Tujo Ta mix for 24 hours. The reaction mixture was poured into 30 ml of water and extracted with 3? 30 mT EtOAc. The combined organic fractions were dried over magnesium sulfate and concentrated to give 1.6 g of the title compound as a yellow solid. MS (ES) m / e 238.9 (M + H) *. b) N- (2-pyrimidini 1) eti lendiamine hydrochloride 1.6 g, 6.7 mmol, of the compound of the preparation AAia) was dissolved in 6 ml of methylene chloride and treated with 4M HCl in 16.7 ml of dioxane. The reaction mixture was stirred for 2 hours, concentrated and azeotroped with 3 x 10 ml of methylene chloride to give 1.2 g, 100% of the title compound, as a yellow salt. MSI) m / e 139.O (M + H) *.
PREPARATION BB PREPARATION OF N-6-METHYL-3-PYRIDAZINIL) ETHYLENDIAMINE a) N-Acetyl-Nr- (6-methyl-3-iridazinyl) eti lendiamine At reflux, under argon, for 20 hours, a mixture of 1.29 g, 10 mmol, of 3-chloro-6-eti ipiridazine, 638 mg, 6.25 mmol, of N-iaceti 1) was introduced, and the mixture was 1.6. g of sodium bicarbonate in 10 ml of DMF. The mixture was filtered, filtered and concentrated, and the residue was taken up in methylene chloride and purified by flash silica gel chromatography, gradient gradient »0-8% ethanol / methylene chloride) to give 700 mg, 44% ! composed of the title, as a solid yellow. MSI) m / e 195.0 (M + H) *. b) N- (6-methy1-3-pyridazim "1) eti lendiamine A mixture of 700 mg, 3.6 mmol of the compound of preparation BB (a) and 10 ml of concentrated HCl was heated at 90 ° C for 48 hours. The reaction mixture was concentrated and triturated with ether to give the title compound as a purple solid (691 mg). MS (ES) m / e 152.9 (M + H) *.
PREPARATION CC PREPARATION OF N- (3-PYRIDAZINIL) ETILENDIAMINE a) 3-chloropyridazine 1 g, 10.4 mmol of 3- (2H) -pyridazinone was treated with 10 ml of phosphorus oxychloride at 90 ° C for 4 hours. The mixture was poured into 100 g of ice, made basic with 50% NaOH and extracted with 3 x 150 ml of methylene chloride. The combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound as a yellow solid (750 mg, 63%). MS (ES) m / e 115 (M + H) *. b) N-acetyl-N'-O-pyridazi il) eti lendiamine A mixture of 750 g, G. G of the compound of preparation CC (a), 673 mg, 6.6 mmol, of N-aceti 1) eti lendiami a and 2 g was left under reflux for 20 hours. of sodium bicarbonate in 10 ml of DMF. The mixture was filtered, the filtrate was concentrated and the residue was dissolved in methylene chloride and purified by silica gel flash chromatography, gradient gradient 0-8% chloroform / methylene chloride) to give 710 mg, 60%, of the composed of the title, like a yellow solid. MSI) m / e 180.8 ÍM + H) *. c) N- (3-pyridazine 1) eti lendiamine The mixture of 700 mg, 3.9 mmol of the compound of the CCib preparation) and 10 ml of the mixture was heated at 90 [deg.] C. for 72 hours.
Concentrated HCl. The reaction mixture was concentrated and triturated with ether to give the title compound as a yellow solid. MS (ES) m / e 138.1 (M + H) *.
EXAMPLES EXAMPLE 1 PREPARATION OF ACID (S) -2,3,4,5-TETRAHIR0-4-METHYL-3-0XQ-7- CCC2-C2- (PYRIDINYL) AMIN03ETIL3AMINQ3CARBONIL3-lH-l, 4-BENZODIA-ZEPIN-2 -ACETIC0 a (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7-CCC2-C2- (pyridinyl) amino-3-amino-3-carbonyl 13-lH-l »4-benzodiazepin-2-acetate of methyl A mixture of 0.15 g, 11 mmol, of the compound of preparation V (c), 0.325 g, 1.1 mmol, of (S) -7-carboxy-2,3,4,5 was stirred at room temperature for four days. -t trahydro-4-methyl 1-3-o? o-lH-l, 4-benzodiazepin-2-methyl acetate, 0.19 g »1.3 mmol, of HOBT, 0.27 g, 1.3 mmol, of EDC and 1.6 ml, 9 mmol, of DIEA in 5 ml of acetonitrile. The mixture was concentrated and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic extract was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel), gradual gradient, 2% -5% methanol / methylene chloride or, to give the title compound as a colorless foam (O.175 g »39%). (ES) m / e 412.4 ÍM + H) *.
Acid (S) -2,3,4,5-tetrahydro-4-me i 1-3-oxo-7-CCCZ-C2- (pyridinyl) amino-3-methyl-3-aminocarbonyl-13-lH-l »4-benzo-iazepi-2-acetic acid.
The mixture was stirred at room temperature overnight (a solution of the compound of Example 10) (0.175, 0.42 mmol), 0.027 g »0.65 mmol of LiOH.H20, 5 mL of THF and 5 mL of water. The mixture was concentrated and the residue dissolved in ag? A. The aqueous solution was extracted with EtOAc and brought to pH 5 with 3N HCl. The solution was warmed briefly and allowed to stand overnight. The resulting crystals were collected by filtration and dried to give 0.13 g, 77%, of the title compound, white solid. MS (ES) m / e 398.4 (M + H) *. Analysis calculated for C2oH23NT0 ^ F5 S H20: C, 58.78; H, 5.98; N, 17.14. Found: C, 58.65; N, 6.03; N »16.96.
EXAMPLE 2 Preparation of (S) -2,3,4,5-tetrahydro-4-mati 1-3-oxo-7- CC 2-C (lfoxo-2-pyridinyl) acid to ethyl amino carboni 13-lH-l » 4- benzodi azepín-2-acéti co a) (S) -2, 3,4, 5-tetrahydro-4-methy1-3-oxo-7-CC C2 (l-oxo-2-iridinyl!) -amino3-ethyl-aminocarboni 13-1H-1, 4- benzodiazepin-2-methyl acetate.
Following the procedure of Example Ka), except that the compound of preparation V (c) »is replaced with the compound of preparation V (b), the title compound is obtained as a colorless foam. MS (ES) m / e 428.4 M + H) *. b) acid (S) -2,3.4"5-tetrahydro-4-methyl-3-oxo-7- C2-C (lfo? o-2-pyridinyl) amino-3-ethyl-3-aminocarbonyl 3-lH-l, 4-benzodiazepin-2 -acetic Following the procedure of Example Ka), except that it is replaced with the compound of example 2 (a) eT composed of the example lía), the title compound was obtained. MSI) m / e 414.5 (M + H) *. Analysis calculated for C2OH23Ns0B p5H20: C »56.86; H, 5.73; N, 16.58. Found: C, 56.63; H, 5.67; N, 16.32.
EXAMPLE 3 Preparation of (S) -2,3,4,5-tetrahydro-3-oxo-7- CC2-C2- (pyridini-1) amino-3-amino-3-carbon-1-lH-1,4-benzodiazepin-2-acetic acid a) (S) -2 »3» 4 »5-tetrahydro-3-oxo-7- CC2-C2- (pyridinyl) -amino3eti 1 amino3carboni 13-H-l» 4-benzodiazepin-2-methyl acetate.
A mixture of 720 mg, 2 mmol, of the compound of the preparation W (d), 672 mg, 3 mmol, of the compound of the preparation Víc) was heated at HO ° C, under a flask of CO »for three hours», 1.8 ml, 10 mmol, of DIEA and 140 mg, 0.2 mmol, of PhP3P) -_ PdCl2 in ZO ml of N-methyl 1-2-pyrrole idinone. The mixture was concentrated and the residue was purified by flash chromatography (silica gel, gradient gradient »0-7% methane / methylene chloride) to give the title compound as a pale yellow solid. ) m / e 398.2 ÍM + H) *. b) (S) -2 »3» 4,5-tetrahydro-3-oxo-7-CCC2-C2- (pyridini-1) -amino-3-ethyl-amino-3-carbonyl-lH-l, 4-benzodiazepin-2-acetic acid 3.8 ml »3.8 mmol, 1M LiOH was added dropwise to a solution of 1 g, 2.5 mmol» of the compound of Example 3 (a) in 20 ml of i: i ethanol: THF »at room temperature. The resulting mixture was stirred for 20 hours and concentrated. The residue was dissolved in water, acidified with 20% TFA, purified by chromatography (ODS »6% acetone" water / 0.1% TFA). "Fractions containing the desired product were pooled * concentrated and lyophilized to give the title compound (may contain approximately 23% of the enantiomer R, see preparation Wic)), as a pale yellow powder MS (ES) m / e 384.2 (M + H) *. C TH2; tNs0 ^ p2.5 TFA: c »41.87; H, 3.44; N, 10.17. Found: C, 42.01; H, 3.62, "N, 10.15.
EXAMPLE 4 Preparation of (S) -2,3'-4,5-tetrahydro-3-oxo-7-CC2-C2- (iridi nyl) amino eti! amino carboni 1 -4- (2.2 »2-trifluoroethyl) - ÍH-1» 4-benzodi azapin-2-acetic a) (S) -2, 3,4 »5-tetrahydro-3-oxo-7-CC2-C2-I Piri di ni 1) -amino3ethyl 3amino3carboni 13-4- (2» 2 »2-trifluoroeti 1) - lH-l »4-benzodiazepin-2-methyloyl acetate.
Following the procedure of the example lía), except that q? E is substituted with the compound of the preparation Xíe) the S) -7-carbo? I-2 »3,, 5-tetrahi dro-4-meti 1 -3- oxo-lH-1, 4-benzodiazepi-2-methyl acetate, the title compound was obtained or a white foam. MS (ES) m / e 479.7 M + H) *. b) (S) -2,3 »4» 5-tetrahydro-3-oxo-7-CC2-C2- (pyridinyl) -5-amino-3-ethyl-3-aminocarbonyl-1-4- (2 »2» 2-trifluoroeti 1) -1H acid -1.4- benzodiazepin-2-acetic Following the procedure of Example Kb) "but substituting the compound of Example 4 (a) with the compound of Example 10), the title compound was obtained as a white solid? N. MSI) m / e 466.1 ÍM + H) *. Analysis calculated for C2a.H22F3NsO_F ° -a H2Q: C »52.56; H, 4.96; N, 14.60. Found: C. 52.88; H, 5. OO 15 N, 14.10.
EXAMPLE 5 Preparation of acid (±) 2 »3» 4 »5-tetrahydro-3-oxo-4- (fani leti 1) - 7-CCC2-C2- (pyridinyl!) Amino3ethyl 3-aminocarbonyl-1H-1,4-20 benzodiazepin- 2-acetic a) (t) 2,3,4,5-tetrahydro-3-oxo-4- (phenylethyl) -7-CCC2-C2- (pyridinyl) amino-3-methyl-3-aminocarbonyl-13-lH-1,4-benzodiazepin-2-methyl acetate •? 5 2 mmol of (±) -7-carboxy-2,3 »4,5-tetrahydro-3-oxo-4-pheni leti 1-1H-1, 4-methyl-methyl-2-acetate-ethyl acetate» 0.38 g, 2 mmol, EDC, HBO water and 1.65 mmol of the compound of the preparation Víc), and stirred at room temperature overnight. The mixture was concentrated and the residue was treated with 5% sodium carbonate and extracted with methylene chloride. The combined organic extracts were washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed to yield the title compound as a white foam. MSI) m / e 502 ÍM + H) *. b) (±) 2,3,4,5-tetrahydro-3-oxo-4- (phenylethyl) -7-CCC2-C2- (pyridinyl) amino3eti 1 amino3carboni 1-lH-l, 4-benzodiazepin-2-acetic acid 0.16 g, 0.4 mmol »of the compound of Example 5 (a) were dissolved in 10 ml of ethanol and 1 ml of THF» and treated with 0.5 ml of 1 N NaOH. The mixture was stirred overnight, concentrated and concentrated. The residue was dissolved in water and extracted with methylene chloride. The pH of the aqueous phase was adjusted to 5.5-6 with dilute HCl and the solid that formed was filtered, washed with water and ether and dried to give the title compound. MS (ES) m / e 488 (M + H) *. Analysis calculated for C2-H-; s > N? 0 ^ p? .625 H20: C, 65.01; H, 6.11; N, 14.04. Found: C, 64.95; H, 5.92; N, 13.94.
EXAMPLE 6 Preparation of (S) -2 »3» 4,5-tetrahydro-4-methyl-1-7-CCC2-C2- (S-methyl-pyridinyl) acid to indoxyethyl 3-aminocarbonyl-3-oxo-lH-l, 4-benzodiazepine -2-acetic a) (S) -2,3,4,5-tetrahydro-4-rnethyl-7-CCC2-C2- (6-methyl-pyridinyl) amino3eti-13-aminocarbonyl-3-oxo-1H-1 »4-benzodiazepin- 2-methyl acetate Following the procedure of Example 5 (a) »except that the compound of preparation Y the compound of preparation Víc) was replaced with the compound of the title. MSI) m / e 426 ÍN + H) * b) (S) -2 »3» 4,5-tetrahydro-4-methyl-7-CCC2-C2- (6-methyl-pyridinyl) amino3-ethyl-amino-3-carbon-1 -3-oxo-lH-l, 4-benzodiazepin- 2-acetic Following the procedure of Example 5 (b), but substituting the compound of Example 6 (a) with the compound of Example 5), the title compound was obtained. MSI) m / e 412 ÍM + H) *. Analysis calculated for C2iH: 2ßN !: s0-4.pO .5 H20: C, 59.99; H, 6.23; N, 16.66. Found: C, 59.69; H, 6.15; N, 16.37.
EXAMPLE 7 Preparation of (S) -2,3,4,5-tetrahydro-4-methyl 1-3-oxo-7- 2-C2- (pyridini1) amino ati 13methi-aminocarboni 13-1H-1,4-benzodi azepi n -2-acetic a) (S) -2,3,4,5-tetrahydro-4-methyl 1-3-oxo-7- 2- 2- (pyridinyl) amino-3-methyl-methyl-lamino-1H-1,4-benzodiazepin-2-methyl acetate 195.5 mg »1.02 mmol» of EDC was added to a solution of 248.4 mg »O.85 mmol, of" (S) -7-carboxy-Z, 3,, 5- etrahi drs-4- meti 1-3- oxo-lH-1,4-benzodi azepi n-2-methyl acetate, 229.4 mg, 1. 02 mmol, of the compound of preparation Z (c), 137.8 mg, 1.02 mmol, of HOBt. H20 and 0.74 ml, 4.25 mmol, of DIEA in 4.3 ml of acetoni tri lo. at room temperature. After 21 hours the reaction was concentrated and the silica gel residue, 10% ethanol / cl orofor or to give 353.8 mg was chromatographed. 98% of the title compound as a light yellow foam. MS (ES) 426 (M + H -) *. 1S3 b) acid (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7- 2-C2- (pyridinyl) ami o3eti! 3meti lami o3carboni 1 -1H-1,4-benzo ia-zepin -2-acetic 1.0 ml, 1.0 mmol, L? OH was added in one go I N to a solution of 353.8 mg, 0.83 ol »of the compound of example 7 (a) in 4.2 ml of THF and 3.2 ml of ag? A» at room temperature. After O.5 hour, the reaction was concentrated to dryness and the residue was dissolved in 4 ml of water. The solution was extracted with 2 x 4 mL EtOAc and the EtOAc layers were discarded. The aqueous solution was acidified to pH 6 with HCl and allowed to stand at 5 ° C overnight. The solution was chromatographed (ODS, 12% acetonium / 0.1% TFA) and the fractions containing the desired product were combined, concentrated and lyophilized to give 399.7 mg, 81%, of the title compound. , like a colorless powder. MS (ES) m / e 412 (M + H) *. Analysis calculated for C21N26SNs0 ^ pl .STFA O.75 H20: C, 48.37; H, 4.74; N, 11.75. Found: C, 48.25; H, 4.89; N, 11.86.
EXAMPLE 8 Preparation of (±) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7- CCC2-C2- (pyrimidinyl) amino-3-ethyl-3-aminocarbonyl-13-1H-1,4-benzodiazene-2-acetic acid a) (±) -2 »3,4,5-tetrahydro-4-methyl-1-3-oxo-7- CC2-C2- (pyrimidinyl!) amino3eti 13amino3carboni 13-Ib-1,4-benzodiazepin-2-acetate of methyl 1.2 g »6.7 mmol, of the compound of preparation AA (b), 1.8 g, 6.1 mmol, of ±) -7-carboxy-2,3,4,5-tetrahydro-4-methyl-3 was dissolved. -oxo-lH-l, 4-benzodia? epi n-2-methyl acetate, 1.7 g, 9.2 mmol, EDC and 3.7 ml, 21.4 mmol, of DIEA, in 35 ml of DMF and the mixture was stirred to the room temperature for 24 hours. The mixture was poured into 50 ml of 5% sodium bicarbonate and extracted with 3 x 30 ml of EtOAc. The combined extract was washed with 4 x 50 ml of aq., Dried over magnesium sulfate and concentrated. It was chromatographed e! residue on silica gel, 3% ethanol / methylene chloride) to give 300 mg, 12%, of the title compound. Further purification was obtained by preparatory HPLC (ODS-AQ, 50 X 250 mm, 80 mT / i'n »14% acetoni tri To / water-0.1% TFA» UV detection at 220 nm). MS (ES) m / e 412-9 (M + H) *. NMR with * H (400 MHz »DMS0-dβ) from T 8.28 (d, J = 2 Hz, 2H), 8.18 (bt, 1H), 7.51 (rn, 2H), 7.19 (bt, ÍH), 6.57 6, J = 9.3 Hz, 1H), 6.53 (d, J = 8 Hz, ÍH), 6.32 (d , J = 2 Hz, 1H), . 50 (d, J = 16 HZ, ÍH), 5.14 m, ÍH), 3.84 d, J = 16 Hz, ÍH), 3. 38 (s, 4H), 2.81 dd, J = 16.9 Hz, ÍH), 2.67 (dd, J = 17.4 HZ, ÍH). Analysis calculated for C2H2 ^ Ncg0-4 l .5 TFA: C »47.34; H, 4.40; N, 14.40. Found: C »47.21; H, 4.49 *. N, 14.13. b) (±) -2, 3 »4, 5-tetrahydro-4-methyl-1-3-oxo-7-C2-C2- (pyrimidinyl) amino-3-ethyl-1-amino-3-carbonyl-lH-l» 4-benzodiazepin-2 -acetic The compound of example 8 (a) was dissolved in 5 ml of methane! containing 3.4 ml of IN NaOH and 2 ml of water, and the mixture was stirred, concentrated and purified by preparative HPL (ODS-AQ, 50 x 250 mm, 80 ml / min, 14% acetom "tri. 0.1% TFA, UV detection at 220 nm) to yield 80 mg, 35%, of the title compound as a white solid, MS (ES) m / e 399.1 (M + H) *. NMR with H (400 MHz, DMSO-d ^) delta 8.30 (d, J = 3 Hz, 2H), 8.15 lb); 7.50 μm, 2H), 7.23,, HH), 6.57,, J = 7.3 Hz, HH); 6.52 (d.J = 8 Hz, HH), 6.30 (d.J = 3 Hz, HH), 5.49 (d, J = 18 Hz, HH), 5.08 mm, 1H), 3.84 dd, J = 19 Hz, ÍH), 3.43 ís »4H); 2.81 (d, J = 19.9 H? »1H), 2.55 (d, 1H). Analysis calculated for CATH22N < SO: C, 57.28; H, . 57; N, 21.09. Found: C, 57.59; H, 5.43; N, 20.97.
EXAMPLE 9 Preparation of (±) -2, 3,4'-5-tetrahydro-4-methyl-7-CC2-C (6-methy1-3-pyridazo and 1) amino3-ethyl-1-amino-3-carbon-1 -3-oxo- lH-l, 4-benzodiazepin-2-acetic (SB 240375) a) (±) -2,3,4,5-tetrahydro-4-methyl-7-CCC2-C (6-methyl-3-pyridazine!) amino3eti! 3 amino3carbonyl 13-3-oxo-lH-l »4-benzodiazene in-2-aceto methyl 759 mg »3.96 mmol, from EDC to a solution of 3. 6 mmol of the compound of preparation BB (b), 1.06 g, 3.6 mmol, of (±) -7-carboxy-2,3,4,5-tetrahydro-4-methyl-3-o? O- 1H-1,4-benzodiazepine-2-methyl acetate, 535 mg, 3.96 mmol, of HOBT.H:; 0 and 2.07 ml, 11.88 mmol, of DIEA in anhydrous DMF at room temperature. After 20 hours the reaction was concentrated and the residue was dissolved in methylene chloride and chromatographed on silica gel »gradient gradient 9-10%. ethanol / methylene chloride) to give the title compound, as a pale yellow solid (960 mg, 63%). MSI) m / e 427 + H) *. b) (±) -2,3,4 »5-Tetrahydro-4-methyl-7-CCC2-C (6-methyl-3-pyridazine 1) amino3eti 1 amino3carboni 13-3-oxo-lH-l» 4 acid -benzodia-zepi n-2-acetic 4.0 ml »4.0 mmol, 1M NaOH was added dropwise to a solution of 800 mg» 1.94 mmol »of the compound of Example 9 (a) in 20 ml of i: i methanol: THF at room temperature. The resulting mixture was stirred for 20 hours, concentrated and the residue was dissolved in water, acidified with 20% TFA and chromatographed, gradient gradient, 5-7% acetoni tri lo / ag? A-0.1% TFA) to give the title compound as a white powder. MSI) m / e 41.2 ÍM + H) *. Analysis caTc? Side for C2oH2_ \ ¡ß0? Pi.5TFAp0.75 H20: C, 46.27; H »4.56» N »14.08. Found: C, 46.03; H, 4.27; N, 13.78.
EXAMPLE 10 Preparation of (±) -2,3,4,5-tetrahydro-4-methyl 1-3-oxo-7-CCC2-C3- (pyridazine!) Amino-3-amino-3-carbonyl-1H-1,4-benzodiazepine n-2 acid acetic a) (1) -2,3,4,5-tetrahydro-4-methyl-1-3-OXO-7-CCC2-C3- (pyridazin-1) amine-ethyl-amino-3-carbonyl 13-lH-1 > 4-benzodiazepin-2-methyl acetate Following the procedure of Example 9 (a), except that the compound of the preparation BBib) was replaced with the compound of the CCiq preparation, the title compound was obtained as a pale yellow solid (1.12 g, 76%). A 200 mg sample was purified additionally, by IODS chromatography, 10% acetonic acid / 0.1% TFA). MSI) m / e 413.2 ÍM + H) *. Analysis calculated for C2OH2_tN < ? 0_, Fl .5 TFApO.5 H20: C, 46.63; H, 4.51; N, 14.18. Found: C, 46.54; H, 4.65; N, 14.46. b) acid (±) -2, 3 »4.5-tetrahi dro-4-meti 1-3-QXQ-7- C2-3 (pyridazo i 1) to indole to o3carbonyl-iH-1,4-benzodiazepi-2-acetic Following the procedure of example 9 (b), except that the compound of example 1 (a) is replaced with the compound of example 9 (a)), the title compound is obtained as a white powder. MSI) m / e 399.2 ÍM + H) *. Analysis calculated for C-LS > H22N { 30 ^ pl .5 TFApH20: C, 44.98; H, 4.37; N, 14.31. Found: C, 44.82; H, 4.3; N, 14.31.
EXAMPLE 11 Preparation of 3-C3 »4-dihydro-B-CCC (2-pyridinyl-1) -2-aminoethyl-amino-3-carbonyl-1-methyl-1-2.5-dioxo-lH-1,4-benzodiazepine acid n3-4- ropanoico a) 3-C3,4-Dihydro-8-CCC (2-pyridinyl) -2-aminoethyl-amino-3-carbonyl-1-methyl 1-2,5-dioxo-lH-l »4-benzodiazepin-3-4-benzyl propanoate 0.25 g, 1.3 mmol »of EDC is added to a solution of 1. 1 mmol of the compound of preparation A (f), 1.1 mmol, of the compound of preparation V (c), 170 mg, 1.3 mmol, of HOBT.H-, 0 and 0.9 ml, 4.4 mmol, of DIEA in 5 ml of anhydrous acetonitrile, at room temperature. After 21 hours the reaction is concentrated and the residue purified by silica gel chromatography) to give the title compound. b) 3-C3.4-dihydro-8-CCC (2-pyridinyl) -2-aminoeti-13-aminocarbonyl-1-methyl-1-methyl-5-dio-3-hydroxy-3-benzodiazepine3-4- propanoic A mixture of 2 mmol of the compound of example lKa) and 0.02 g of 10% Pd / C in 100 ml of EtOH is hydrogenated under a hydrogen atmosphere (3.5 kg / cm2) for 6 hours. The catalyst is filtered off and the filtrate is concentrated to give the title compound.
EXAMPLE 12 Preparation of 3-C4H-ylidazoCl, 2-a3Cl, 43-benzodiazepin-5 (6H) -l-methyl-1-6-oxo-9CCC (2-pyridyl) -2-aminoethyl acid; amino-3-carbon 13-5-propanoic acid a) 3-C4H-i-idazoCl, 2-a3Cl, 43-benzodiazepin-5 (6H) -1-methyl-1-6-oxo-9CCC (2-pyridyl) -2-aminoethyl-1-amino-3-carbon-3-ethyl-3-propanoate O.25 g, 1.3 mmol, of EDC is added to a solution of 1. 1 mmol of the compound of preparation B (e), 1.1 mmol of the compound of the preparation Víc), 170 mg, 1.3 mmol, of HOBT.H-, 0 and 0.9 ml, 4.4 mmol, of DIEA in 5 ml of anhydrous acetonitrile at room temperature. After 21 hours the reaction is concentrated and the residue is purified by chromatography (on silica gel) to give the title compound. b) 3-C4H-imidazoCl, 2-a3Cl, 43-benzodiazepin-5 (6H) -l-methyl-6-o? o-9CCC (2-pyridyl) -2-aminoeti-1-amino-3-carbon-13-5-propanoic acid A solution of 54 mmol of the compound of Example Ka9, 0.79 mmol of HCl, HCl, 0.5 mL of THF and 2 mL of water is stirred at room temperature overnight. The mixture is concentrated and the residue is dissolved in water. The resulting solution is brought to pH 5 with 3N HCl to give the title compound.
EXAMPLE 13 Preparation of 4-C4-C3- (2-pyridinyl-1) amino-3-propyl-3-piperazinyl-1-piperidineacetic acid a) Ethyl 4-C4-C3- (2-pyridinyl) amino3propyl piperazinyl-1-piperidineacetate.
The mixture of the preparation of C (b) »the compound of the preparation Díc) and DIEA in THF is stirred at room temperature for 4 hours. The mixture is diluted with aqueous sodium bicarbonate and extracted with EtOAc. The organic phase is dried over sodium sulfate and concentrated to give the title compound. b) 4-C4-C3- (2-pyridinyl) amino3propi 13 dinacetic acid "13-1-pipen" The solution of Example 13 (a) and aqueous NaOH in ethanol is stirred at room temperature. After 18 hours the mixture is neutralized with HOAc, desalted over a XAD-2 column and lyophilized to give the title compound.
EXAMPLE 14 Preparation of l-hydro? I-4-C4f-C3-C (2-pyridini 1) amino3 propyl 1-1-cyclohexanacetic piperazine acid Following the general procedure of Example 13, except that 1-hydroxy-1-4- (1-piperazin-1) cyclohexanacetate of 1, 1-dimethyi or the compound of Preparation C (b) is replaced with the compound of Title.
EXAMPLE 15 Preparation of 4- 4-C 2 -I 2 -pyridinium 1) amino 3eti 1 -1- iperazi acid or 13-1-piperidi acetic acid a) 4- 4-C2- (l-oxo-2-pyridini 1) amino ethyl-1-piperazine 13-1-ethyl piperidinacetate The compound of 1 to the preparation is heated in butanol E (b), N-oxide of 2-cl oropi ridi a and sodium bicarbonate. The mixture is cooled, filtered and the filtrate is concentrated. The residue is partitioned between water and EtOAc and the organic phase is dried over sodium sulfate and concentrated. The residue is purified by chromatography (silica gel) to give the title compound. b) 4-C4-C2- (2-pyridini 1) amino3eti 13-1-pjpera i i 13-1- ethyl jperidinacetate The compound of Example 15 (a), potassium formate, 10% Pd / C and ethanol were heated, cooled, filtered and concentrated. The residue was chromatographed on silica gel to give the title compound. c) 4-C4- 2- (2-pyridinyl) amino eti 1 -1-piperazine 13-1- piperi di nacetic acid The compound of Example 15 (b)) and NaOH IN in ethanol are stirred. The mixture is adjusted to pH 5 with dilute HCl and concentrated to give the title compound.
EXAMPLE 16 Preparation of l-hydroxy-4-C4-C2- (2-pyridyl "l) amino3 eti 13-l-piperazine 13-cyclohexane acetic acid Following the procedure of Example 15 »except that the compound of preparation E (b) is replaced with the compound of preparation F. the title compound is obtained.
EXAMPLE 17 Preparation of N-C3-Cl-CCC (2- i ridinyl) amino3propi 13carboni 13- 3-piperidim "13carboni 13beta-alanine Following the procedure of Beavers and co-inventors, WO 95/25091, example 1, except that the compound of preparation G is replaced with -Boc-D-Lys (Cbz) -OH, the title compound is obtained.
EXAMPLE 18 'Preparation of 5-C2- (carboxy-etyl! 9-aminocarbonyl-2-C2-C2-pyridini-1) -amin-3-yl-1, 3-dihydro-3-oxo-lH-i soo ndol Following the procedures of preparation 1-12 in Hartman and co-inventors, EP O 650 334 Al, for the preparation of 2,3-dihydro-N- (2-carboxy-et? 19-2-C2-p? Perid? I 1) eti 1 -3-oxo-1H-isoi ndol-5-carboxyamide, except that the N-Boc-4-pipep "di-2-yl-laminate is replaced with the compound of the preparation Víc), the composed of the title.
EXAMPLE 19 Preparation of (S) -2- (buti 1 sulfoni lamino) -3-C4-C4- (N-irid-2-i lami o) 3b? Ti loxifem "1-propionic acid Following the procedures of Egbertson and co-inventors »EP 0478363 A2 for the preparation of acid (S) -2- butylsulphonylamino) -3-C4-yN-benzyl 1 oi carboni 1 pipen 'in-4-i 1 ) - 2, 2-dimetí 1 but? loxi em "Ipropi ónico" except that it is replaced with the compound of the preparation Híb) 4-C4- <N-benzyloxycarboni 1pipen "din- -i 1) -2- et i 13pentan-2-ol, the title compound is prepared.
EXAMPLE 20 Preparation of N-C3 (R)) -C3-C (2-pyridinium T) amino3propyl 3-2-oxo-1-piperidinium-3-acetyl 3-3 (R) -methyl-1-beta-al aniña Following the procedure of D? Ggan and co-authors »J.
Med. Chem., 1995, 38, 3332 »except that it is replaced with the compound of the preparation l ee) eT N-Boc-piperidin-4-y-T-butanoic acid, the title compound is prepared.
EXAMPLE 21 Preparation of 3-3-C3-C (2-pyridini-1) amino-3-propane-13-iso-azole in-5 (R »S) -i-13-acetyl-1-amino-3 (R» s) -methyl-1-propanoic acid a) Chloride of 4-CN-pyrid-2-i 1-N- (toluenesulfoni 1) amino3-butane imi no11 or Following the procedure of WO 95/14682, example lib), but replacing with the compound of preparation Jie) the 4-cyanobenzoxime, the title compound is prepared. b) C3-3-N-pyrid-2-i l-N- (tol-ens-1-phonyl) amino-3-propy1-iso-azole in-5 (R »s) -3-tert-butyl acetate.
Following the procedure of WO 95/14682, example l (d), except that it is replaced with the compound of the example 21 (a) 4-Cia aben? Ox? N.inoyl chloride and replacing methyl 3-b-tenadorate with tert-butyl 3-butenoate, prepare the title compound. c) C3-C3- N-pi-Rid-2-i-1-N-t-toluenesulfoni acid 1) to i3-pipi-13-isoxazole in-5 (R, S) -i-13-acetic acid ml of 4M HCl in dioxane is added to a solution of the compound of example 2Kb) (5 mmol in 40 ml of ethylene chloride at 0 ° C.) The reaction is stirred at room temperature until it is complete to produce the compound of the title. d) 3-C C3-C3-CN-pyrid-2-i! -N- (toluensulfonyl) amino propyl-3-isoxazole ind-5 (R »S) -i-13-acetyl-13-amino-3 (R» S) - ethyl methylpropanoate. 1.2 mmol of EDC is added to a solution of 1 mmI of the compound of Example 21 (c), 1.2 mmol of ethyl e-t, S) -aminobutyrate, 1.2 mmol of H0Bt.H, Δ 0 and 4 mmol of DIEA in 5 ml of anhydrous acetonitrile. The reaction is stirred at room temperature until it is complete and concentrated. The residue is purified by chromatography (silica gel) to produce eT composed of the title. e) 3-CC3-C3-C (2-pyridini-1) amino-3-propane-13-isoxazoin-5 (R, S) -yl acsti-13-amino-3 (R »s) -methyl-1-propanoic acid 2.5 mmol of LiOH.NO.sub.N is added to a solution of the compound of example 21 (d). 0.5 mmol in 2.5 ml of THF. The reaction is stirred at room temperature until it is complete; it is then neutralized with 1.0 N HCl. The solution is concentrated and the residue is purified by reverse phase chromatography to produce the title compound.
EXAMPLE 22 Preparation of N-C3-C2-C2- (pyridini 1) amino3eti 13-cartaoni 13-aminobenzoi-1-beta-alanine a) N-C3-CCC2-C2- (pyridinium 1) amino3eti 13carboni 13 amino3-benzoyl-benzoyl-1-beta-alanine A mixture of 1 mmol of N- (3-aminobenzoi-1) -beta-benzyl anion is stirred at room temperature at room temperature, Alig and co-inventors, EP 0372486, 1 mmol of N- (2-pyridin-1) - beta-alam'na (Chowdhary and co-authors, Indian J. Chem. »1990» 29A, 280-2B4, 1.5 mmol of EDC and 3 mmol of DIEA in 25 ml of DMF.) Pour the mixture into 5% sodium bicarbonate. and extracted with EtOAc, wash the combined organic phase with water, dry over magnesium sulfate and concentrate, chromatograph the residue on silica gel) to give the title compound. b) N-C3-CCC2-C2- (pyridine 1) amino3eti 1 carboni 13 amino3benzoyl 3 -beta-a1 aniña A mixture of 1 mmol of the compound of Example 22 (a) and 1.5 mT of 1 N NaOH in 20 mT of ethanol is stirred and concentrated. The residue is dissolved in water, extracted with methylene chloride and the aqueous phase is adjusted to pH 5 with dilute HCl, to give the title compound.
EXAMPLE 23 Preparation of acid CCl-CN-CC2-C (2-pyrridin-1) amine-3-one-1-carbonyl-1-pyrimidine 13-4-piperidim-13-oxyacetic acid a) CC1-CN-CC2- (2-pyridinium) 1) amino3at 13 carboni 13tirosi 13-4- Piperidi i 13oxy tert-butyl acetate The mixture is stirred at room temperature to a mixture of 1 mmol of C íl-tirosi 1-4-piperidim 1) tert.-oxyethoxy acetate »Alig and coinventores. EP 372486, 1 mmol of N- (2-p? "P" dín? 1) -beta-alam'na »Chowdhary and co-authors» Ind? An J. Chem., 1990, 29A, 280-284, 1.5 mmol of EDC and 3 mmol of DIEA in 25 ml of DMF. The mixture is poured into 5% sodium bicarbonate and extracted with EtOAc. The combined organic phase is washed with water, dried over magnesium sulfate and concentrated. Chromatograph the residue on silica gel to give the title compound. b) l-CN-C2-C (2-pi ridinyl) amyl oethyl 3-carbonyl-thirosi 13-4-piperidinium-3-oxo-3-acetic acid A mixture of 1 mmol of the compound of Example 23 (a) and CF3C02H in methylene chloride is stirred and concentrated to give the title compound.
EXAMPLE 24 Preparation of (±) -3- 3- (2-pyridinium-1) amino-3-propyl-13-amino-3-succinic acid 13 amino-3-pyridinic acid a) Methyl 4-3-C (2-pyridyl) amino3propi-13-amino-3-4-oxobutyrate 0.74 ml, 6. O mmol, of 3-carbomethoxypropionyl chloride or, at 0 ° C, is added to a stirred solution of 5.0 mmol of the compound of the preparation Kíc) and 4.4 ml, 25 mmol of DIEA in 50 ml. ml of dry wood methylene chloride. After stirring for 1.5 hours at room temperature, the reaction mixture is diluted with 50 ml of methylene chloride and washed with 25 ml of water and 25 ml of 5% sodium bicarbonate. The organic layer is dried over magnesium sulfate, concentrated and re-concentrated in toluene. Chromatography on silica gel gives the title compound. 1BO b) 4- C3-C (2-pyridi 1) acid to ino3propi-13-amino-3-4-oxo-organic.
A mixture of 530.6 mg, 2.0 mmol »of the compound of example 24 (a), 3.0 ml, 3.0 mmol, 1.0 N LiOH, 10 ml of THF and 7 ml of water is stirred at room temperature overnight. then concentrate. The residue is taken up in 5 ml of water and neutralized with 1 N HCl. The precipitate is collected and dried under vacuum to give the title compound. c) (±) -3-CCC 3-C (2-pyridinyl) amino propyl 13amino3succinoi 1 -amino3-4-ethyl pantinoate 230 mg, 1.2 mmol of EDC is added to a solution of 203.3 mg, 1.0 mmol of the compound of example 24 (b), 169.4 mg, 1.2 mmol of ethyl (+) - 3-ami-4-pentynoate , WO 93/07867, 162.2 mg, 1.2 mmol, H0Bt.H - .. 0 and 0.70 ml, 4 mmol of DIEA in 5 mT of anhydrous tri-acetyl, at room temperature, the reaction is stirred at room temperature. The mixture is concentrated overnight and concentrated.The residue is chromatographed (on silica gel) to give the title compound. d) acid (±) -3-E 3-C (2-pi ridinyl) amino propi 13 amino3succi-noil amino-4-pentynoic The mixture is stirred at room temperature overnight to a mixture of 187.2 mg »0.5 mmol, of the compound of example 24 (c9, 0.75 ml, 0.75 mmol, of LiOH 10 N, 2.5 ml of THF and 1.7 ml of water; The residue is taken up in 2 ml of water and acidified with TFA, followed by ODS chromatography followed by purification of the purified material to give the title compound.
EXAMPLE 25 Preparation of (S) -4-CCC2-C2f (pyridinyl) amine-3-ethyl-3-carbonyl-3-glycyl 3-3-methoxycarbonyl acid Imeti 1-2-oxopiperazine-1-acetic acid Following the procedure of Sug? ara and co-inventors, EP 0529858, example 59, but replacing with N- (2-pyridin-1) -beta-alanine, Chowdhary and co-authors »Indian J. Chem., 1990, 29A, 280-284, 4- Hydrochloride amidinobenza? co »the title compound is obtained.
EXAMPLE 26 Preparation of (3S, 5S) -3-carboxymethyl-5-CC45-C2-C2- (pyridini1) amino3eti 13f or 13oximeti 13-2- irro! idinone a) (3S, 5S) -3-C (terbutoxycarbonyl) methyl 3-5-C 4-C2-C2- (pyridine) amino3eti! 3-phenyl-13-oxi-13-2-pyrrole idinone.
Following the procedure of - Himmelsbach and co-inventors, AU-A-B6926 / 91, example 3 (51), except that the preparation 4r-cyana-3"- 1 uors-4-idroxy) bfem" 1 or , the title compound is obtained. b) (3S »5S) -3-carboxymethyl-5-CC45-C2-C2- (pyridinyl) amino3-eti-1-phenyl-oxy-2-pyrrol-idinone Following the procedure of Hirnmelsbach and co-inventors, AU-A-86926/9, example 7 (93), but replacing with the compound of example 26 a) the (3S »5S) -3-C terbuti loxi" ca bóni 1 Imeti 13 -5-C (4T-ami ino-3 * -fluoro-4-bipheni-1) 1) oxymethyl-1-pyrrolidone, the title compound is obtained.
EXAMPLE 27 Preparation of 1-C2- 2-f (pyridini 1) amino3eti 13-3-C4- (2-carboxyetyl) phenyl-3-4-ethoxy-3-pyrro! in-2-one Following the procedures of Linz and co-inventors »EP 0567968, but replacing with the compound of the preparation V (c) the 4-cyanoam" 1 ina, the title compound is obtained.
EXAMPLE 28 Preparation of 4-CCC2-C (2-pyridyl-1) amino-3-methyl-1-phenoxyacetic acid a) 4-CCC2-C (2-pyridini 1) amino3eti 1 meti T-amino3aceti! phenoxy-methyl acetate Following the procedure of Wayne and co-inventors »WO 94/22834, example 1, but replacing with 1 mmol of the compound of the preparation Z (c) the l-4-pirridi 1 Ipiperazi a, the title compound is obtained. b) 4- 2-C (2-pyridinium T) ami or ethylmethyl-1-aminoacetic acid 13-phenoxyacetic acid Following the procedure of Wayne and co-inventors, WO 94/22834, example 2, except that the compound of Example 2B (a) is replaced with 4- 2-C4- (4-pyridinyl) piperazin-1-yl-1-acetyl-1-phenoxy methyl acetate, the title compound is obtained.
EXAMPLE S Preparation of 2,2'-CC4-CCC2-C (2-pyridinyl) ami o3ethyl-3-methylamino-3 -aceti-13-1, 2-phenyl-3-bis-oxi) 3-bisacetic acid a) 2,2 * -C-C4-C-C2-C (2-pyrid-di-n-1) amino-3-ethyl-13-methyl-1-amino-3-acetyl 13-l, 2-phenylene-3-bis (oxy) -3-dimethyl-bisacetate Following the procedure of Wayne and co-inventors, WO 94/22834, example 3, but replacing with the compound of the preparation Z (c) the 1- (4-pi id 1) piperazine, the title compound is obtained. b) 2, Z'-CC4-CCC2-C (2-pyridinium-1) amino-3-ethyl-3-methylamino-3-acetyl-1, 2-phenyl-3-bis-dioxy) -3-bisacetic acid Following Wayne's procedure and co-inventors, WO 94/22834, example 4, except that the compound of example S (a) is replaced with 2,2'-C4-C2-C4-γ4-pyridini 1) piperazin-li 1) aceti 13pheni len-1 , Dimethyl 2-dioxy diacetate, the title compound is obtained.
EXAMPLE 29 Preparation of 4-C-CC2-C2-pyridinyl) ami3-ethylcarbamate and 1-methyl-3-phenoxyacetic acid a) 4- CC 2-C (2-pyridim'l) amino-3-ethyl-3-carbon-1-methyl-1-methyl-3-acetyl-phenoxyacetate A mixture of 1 mmol of the compound of the preparation Mie) is stirred at room temperature. 1 mmol of N- (2-pyridyl) -1-beta-alanine, Chowdhary and co-authors, Indian J. Chem., 1990, 29A, 280-284, 1.5 mmol of EDC and 3 mmol of DIEA in 25 ml of DMF. The mixture is poured into 5% sodium bicarbonate and extracted with EtOAc. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel to give the title compound. b) 4- CCC2-C (2-pyridinyl) amino3ethyl carbonyl 13-methyl-amino-3-acation-13-phenoxyacetic acid Stir and concentrate 1 mmol of the compound of Example 29 (a) and 1.5 ml of 1N NaOH in 20 ml of ethanol. The residue is dissolved in water, extracted with methylene chloride and the aqueous phase is adjusted to pH 5 with dilute HCl to give the title compound. 1B6 EXAMPLE 30 Preparation of 4-CCCC2-C (2-pyridim'l) amino-3-methoxycarbonyl-13-methylamino-3-acetyl-131,2-phenylenedioxydiacetic acid a) 4- C 2-C (2-pyridin-1) amino-3-ethyl-13-carbon-1-methyl-3-dimethyl-acetyl-2-phenylenedioxydiacetic acid Following the procedure of Example 29 (a), except that compound of the preparation Nic) is replaced with the compound of preparation Mie), the title compound is obtained. b) 4- 2-C (2-pyridinium-1) ami or ethyl-3-carbomethyl-13-amino-3-acetyl-131,2-phenylene-oxydi-acetic acid Following the procedure of Example 29 (b), except that the compound of Example 30 (a) is replaced with the compound of Example 30 (a), the title compound is obtained.
EXAMPLE 31 Preparation of l-C2-C (2- (pyridinyl) amino3ethyl -3-C4-C2- (carboxy) eti 13pheni 13-3-oxo-imidazole idine a) Ethyl 2-C4- (2-hydroxyethylamino) pheni 1 propionate Following the procedure of Himmel sbach and co-inventors, EP 0587134, Example V, 1 mmol of dimer of glycoaldehyde (Aldrich) is added to a solution of 1 mmol of methyl 2- (4-aminophene) -1-propionate in 10 ml of aqueous acetonitrile (pH 6-7), followed by 1.2 mmol of NaBH3CN and the mixture was allowed to stir for na hour.The mixture was concentrated to an oil and the residue was dissolved in a mixture of water with ice and EtOAc. The aqueous layer is neutralized with 4N NaOH and washed with EtOAc, the organic phase is concentrated to oil, chromatographed on an oil solution in silica gel EtOAc, gradient, 5-30% ethanol / chlorine. metí leno-O.1% of HOAc), combine the fractions containing the product and concentrate them to give the title compound. b) N-C2-C2-PJridi-yl) amino-3-ethyl-N'-hydroxy-1-N'-C4-C2- (ethoxycarboni 1) eti 1) pheni 1 urea Following the procedures of Him elsbach and * co-inventors »EP 0587134 and EP 0612741, a solution of 1 mmol of the compound of preparation V (c) and 10 ml of COCÍ- in 10 ml of THF is left stirring at -20 ° C for 20 minutes. After 20 minutes, 1 mmol of the compound of Example 31 is added to the solution and the resulting mixture is allowed to stir for 18 hours. The resulting solution is concentrated and a solution of the residue is washed in EtOAc with 5% citric acid, followed by ag? A. The organic phase is concentrated and chromatographed to a solution of the resulting oil in EtOAc (silica gel, gradient, 5-30% ethane 1 / c1 methyl metal oruro-0.1% HOAc). The fractions containing the product are combined and concentrated to give the title compound. c) N3- 2-C (2-pyridinyl) amino-3-ethyl-3Na) -C4-C2- (ethoxycarboni-1) -eti-1) 3-phenyl-1-oxo-imidazole-idine Following the procedures of Himmelsbach and co-venitors, EP 0587134, Example III and EP 0612741, a solution of 1 mmol of the compound of Example 31 (b), 1.1 mol of methanesulfonium chloride was left stirring at 0 ° C for one hour. it and 1.1 mmol of ether in 10 ml of methylene chloride. Divide the mixture between ag? A and methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated. A solution of the residue and 1.1 mmol of Nal in 10 ml of acetone is heated at reflux for 3 hours, and then concentrated to oil. 1.1 mmol of bi s (trismethyl Is 1 1) potassium azide is added to a solution of the residue in 5 ml of DMF, cooled to 0 ° C. The solution is allowed to warm to room temperature for 30 minutes and then concentrated to an oil. The residue is divided between water and methylene chloride. The organic phases are combined, dried over sodium sulfate and concentrated. Chromatograph to a solution of the oil in EtOAc (silica gel, gradient 5-30% ethanol / chlorine methyl-O.1% HOAc). The fractions containing the product are combined and concentrated to give the title compound. d) N3-C2- 2-pyridinyl 1) to ino3ethyl 3-N3-C4- - (carboxy) eti! 3-phenyl 3-3-oxo-i i azol i ina Following the procedures of Himmelsbach and co-inventors, EP 0587134, Example III and EP OS12741, wherein a solution of the compound of Example 31 (c) l mmol) and 1.2 mL, 1.2 mmol of NaOH IN is left stirring for 18 hours. The mixture is neutralized with HCl and chromatographed on silica gel »gradient 5-30% ethanol / chlorine methyl ene-0.1% HOAc). The fractions containing the product are combined and concentrated to give the title compound.
EXAMPLE 32 Preparation of acid C6-CCC2-C (pyridin-2-y1) amino3ethyl amino3 carbonyl 3-1, 2, 3,4-te rahi droi sogui no! i -2-acetic acid a) C6- C2-C (pyridin-2-y1) amino3ethyl 3a-indo3 carbonyl 3-1 »2» 3 »4-tetrahydroisoguinolin-2-yl-ethyl acetate The mixture is stirred for 8 hours at a solution of 0.263 g »1.0 mmol of the compound of the preparation Oíd), 0.32 g» 1.0 mmol, of the compound of preparation V, 0.191 g, 1.0 mmol, of EDC, 0.151 g, 1.0 mmol, of HOBt and O.235 ml, 2.0 mmol, of Et3N in 7 ml of DMF. Concentrate the solution and purify the residue by silica gel chromatography, gradient, 10-50% ethanol / methylene chloride) to give 0.32 g, 68% of the title compound. b) C6-CCC2-C (pyridin din-2-yl) amino3eti acid! 3amino3 carboni 13-1 »2» 3 »4-tetrahydroisoguinol in-2-i 1 acetic A solution of 0.40 g > 1.0 mmol, of the compound of example 32 (a) in 1.5 ml, 1.5 mmol of aqueous NaOH and 8 ml of EtOH. Concentrate the solution and purify the residue by silica gel chromatography, gradient »25-73% ethanol / methyl chloride or to give 0.32 g, 69% of the title compound.
EXAMPLE 33 Preparation of acid C6-CCC2-C (pyridin-2-y1) amino3eti 1 amino3 carboni 13-1.2 »3,4-tetrahydro-l-oxo-ioguino1 -in-2-io-13-acetic acid Following the procedure of example 32 (a), except that it is replaced with the compound of preparation P (d) eT composed of preparation 0 (d), the title compound is obtained.
EXAMPLE 34 Preparation of C6-2-C (pyridin-2-yl) amino3-ethyl-1-carboni-13-amino-3-in-2-i-13-acetic acid a) C6-CCC2-C (pyridin-2-yl) amino-3-ethyl-3-carbonyl-13-amino-3-ethyl-3-ethyl acetate Following the procedure of example 32 (a). but replacing with the < 6-am? "Or-tetra1 i n-2-i 1) terbutyl acetate» Fisher and co-inventors, EO 0635492, scheme 12 and example 28, parts A-D, the compound of the preparation Oíd), and replacing with N -i 2-pi p "di ni 1) -beta-alam" na, Chowdhary and co-authors, Indian J. Che., 1990, 29A, 280-284, the compound of preparation V »yields the title compound. b) C6- C2- (pyridin-2-1) ami or eti 1 carbo i 1 a ino tetra! in-2-i 13acetic A solution of 0.20 g, 0.85 mmol, of the compound of Example 34 (a) and 3 ml of the same is left stirring for one hour.
TFA in 3 ml of methylene chloride. The solution is concentrated in oil, which is treated with ether. Filtration and vacuum drying afforded the title compound (0.173 g, 74%).
EXAMPLE 35 Preparation of C6-CCC2- (pyridin-2-yl) amino3eti-13-aminocarbonyl tetralin-2-yl3-acetic acid a) C6-2-C (pyridin-2-yl) amino-3-ethyl-amino-3-carbon-13-tetra! in 2-i 1 ethyl acetate Following the procedure of example 32ía) > but replacing with the compound of example 27b) the compound of example 25), the title compound is obtained. Alternatively, a solution of 0.31 g, 10 mmol of the compound of the preparation Qia), 0-32 g, 1.0 mmol of the compound of Preparation V, 0.023 g, 0.1 mmol, is stirred for 8 hours »under a CO atmosphere, 0.025 g, of Pd (OAc). ,, 0.262 g, 1.0 mmol, of Ph3P, 0.23 ml, 2.1 mmol, of isopropyl sheet and 8 ml of NMP in 10% NH ^ C03. The solution is concentrated and the residue is purified by silica gel chromatography, gradient, 10-66% ethanol / methylene chloride, 8: 1, to 1: 2) to give 0.28 g »50%, of the compound of the Title. b) C6-C C2-C (pyridin-2-yl) amino and il 3-aminocarbonyl acid! 3 tetralin-2-i 13acetic Following the procedure of Example 32 (b), except that the compound of Example 35 (a) is replaced with the compound of Example 32a), the title compound is obtained.
EXAMPLE 36 Preparation da! C5-CCC (6-amino-2-pyridinium-1) -methyl-13-carbonyl-1-amino-3-benzofuran-2-yl-1-propionic acid Following the procedure of Example 32, except that the preparation Rie) for the compound of the preparation Oíd) is replaced with ε-ami obenzofuran-2-y1) ethyl propionate, the title compound is obtained.
EXAMPLE 37 Preparation of acid C5-CCCC2-C (pyridin-2-yl) aminp3eti 1 carbonyl 3 amino32 »3-dihydrobenzofan-2-i 13propionic acid Following the procedure of Example 32, except that it is replaced with (5-amino-2, -di-hydro-benzof? Ran-2-y1) ethyl-prodrone the preparation R) for the Ta-preparation compound Oíd) , you get eT composed of TITLE.
EXAMPLE 38 Preparation of Acid C5-CCCC2-C (Pyridin-2-yl) amino-3-ethyl-1-methylamine-3-carbon-1,3-benzofuran-2-yl 13propyl ester Following the procedure of example 35, except that the compounds of the preparation Si d) or i e) are replaced with the compounds of the preparation Q a) or ib), the title compound is obtained.
EXAMPLE 39 Preparation of C5-CCC2- (pyridin-2-y1) amino3eti 13 methylamino3carboni 132.3-ihydrobenzofan-2-i-1 propionic acid Following the procedure of Example 35, except that q is replaced with the compounds of the Aunt preparation) or (b) the compounds of the preparation Q (a) or (b), the title compound is obtained.
EXAMPLE 40 Preparation of acid (±) -3-CCC5- (pyridin-2-y1) amino3 pentanoi 1 gl ici 13a ino3-4-pentynoic a) (±) -3- CC5- ípirí in-2-il) amino3 pentanoi 13gl ici 13 amino3- 4- entinoate of eti! or .43 mmol of DIEA is added to a stirred solution of 1.76 mmol of the compound of preparation U (b), 1.55 mmol of the compound of preparation I (c), 2.33 mmol of HOBt.H,.,., And 2.33 mmol. of EDC in 15 ml of acetonitrile, at room temperature. The reaction mixture is stirred, concentrated, diluted with 100 ml of methylene chloride and washed sequentially with 5% sodium bicarbonate and with brine. Drying over magnesium sulfate, concentration and silica gel chromatography, ethanol / methylene chloride) gives the title compound. b) (±) -3-CCC5-C (pyridin-2-iT) amino3 pentanoi 13gl icyl 3 amino3-4-pentynoic acid. 0.71 mmol of 1.0 N LiOH is added dropwise at room temperature to a mixture of 0.285 mmol of the compound of preparation EE (a) in 5 ml of THF, 5 ml of water and 1 ml of acetonitrile. The mixture is stirred, concentrated to a small volume and cooled in an ice bath before neutralizing with 0.70 ml of 1 N AcOH. The solution is lyophilized and the residue is purified by ODS chromatography, acetone "0.1% TFA" to give the title compound The above description fully describes how to make and use the present invention. However, the present invention is not limited to the particular embodiments described above, but includes all its modifications within the scope of the following claims.The various references to newspapers, patents and other publications that are cited herein, comprise the state of the art. technique and are incorporated herein by reference, as if they were included in their entirety.

Claims (4)

  1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound according to the formula (I) (D characterized in that A is a template of fibrinogen antagonist; W is a linker portion of the formula - (CHR = -) ß-U- (CHR = > c, -V; Q3-, Q2 and Q3 independently are N or CR ^ "provided that no more than one of Q3- »Q2» Q3 and Q- * is N »Rt is H or alkyl of 1 to 6 carbon atoms» cycloalkyl of C3 _ ^ - alkylo of O to 6 carbon atoms or Ar-alkyl of O to 6 atoms of carbon; R = »is H or alkyl of 1 to 6 carbon atoms» Het-alkyl of 0 to 6 carbon atoms »C3_7 cycloalkyl-alkyl of 0 to 6 carbon atoms or At-alkyl of O to 6 carbon atoms carbon; R * is R ° »-C (0) Rs or -C (0) ORT; R-- is H, alkyl of 1 to 6 carbon atoms» Het-alkyl of 0 to 6 carbon atoms »cycloalkyl of C3_-7-alkylo from 0 to 6 carbon atoms »Ar-alkyl from 0 to 6 carbon atoms» Het-alkyl from C0_eS-U, -alkyl from 1 to 6 carbon atoms- »C3_cycloalkyl-. -alkyl of C0_s-U "-alkyl of 1 to 6 carbon atoms- or Ai ^ - alkyl of C0_ < sU, -alkyl of 1 to 6 carbon atoms-; R- * 'is H. halogen, 0Rß, -SRβ, -CN, -NRs'R *, -N02, -CF3, -CF3S (0) ^ _ »-C02Ra» -COR ° or -CONR ° 2 or alkyl of 1 to 6 carbon atoms optionally substituted with halogen »-0Ra» -SRa »-CN, -NRβR, -N02, -CF3, R'S (0) 3, -C02Rβ or -CONRa2; U and V are absent or are CO, CR = 2, C (= CR ° 2) »S (0) c, 0, NRa» CR = 0R «, CR = (0R") CR ° 2, CR * 2CR ° (0R?), C (0) CR ° 2, CR «2C (0), CONR1, NR ^ CO, 0C (0), C (0) 0, C (S), 0C (S), C (S) ) NR °, NR = C (S), S (0) 2NRa, NR «S 0 0) 2N = N, NRßNRβ, NR =» CRß2, NRβCRa2, CRa20, 0CR «2» CR ^ CR *, C = C , Ar or Het; a is O, 1, 2 or 3, * b is o, 1 or 2, c is o, lo 2; r is O »lo 2; yu is O or 1." or their pharmaceutically acceptable salts.
  2. 2. A compound according to claim 1, further characterized in that each of Q3-, Q2, Q3 and R - ** is CH and? is O.
  3. 3. A compound according to claim 1, further characterized in that R 'is H.
  4. 4. A compound according to claim 1, further characterized in that W is ~ (CHRβ) β-CQNR - * - or - (CHR «) to -NR ^ CO-, 5.- A compound according to formula il), further characterized in that A is selected from the group of: Rh R ° ° * "z- CCLR3 ZOO and having 13-14 covalent ligations between the acid porcine and the first nitrogen of the pyridine ring. S. - A compound according to the rei indication 1, further characterized because it is: wherein A - ^ - A2 is NR3-CH, NC) R3-CH, N = C, CR3- = C, CHR3-CH, O-CH or S-CH; R is H, alkyl of 1 to 6 carbon atoms or benzyl; R2 is ÍCH2) c, C02H; R- * is H, alkyl of 1 to 6 carbon atoms, A »-alkyl from 0 to 6 carbon atoms; Het-alkyl of O to 6 carbon atoms; or cycloalkyl of C3_ < s-alk? i 1 or from O to 6 carbon atoms; and q is 1, 2 or 3. 7. A compound according to the claim 6, further characterized in that A3-A2 is NH-CH and R2 CH2C02H. 8. A compound according to the rei indication 7, further characterized because W is - < CHR «) a-C0NR- * or -íCHRβ) ß- NR-CO-. 9. A compound in accordance with the claim 1, further characterized in that it is: 3-C3 »4-dihydro-B-C C (2-pi ri di ni 1) -2-aminocene acid? 1 3ami nolcarbom "1 3-1- meti l -2» 5-di oxo-lH-l, 4-benzodi azepi n3-4-propanoi co; acid 3-C4H-? M? Dazo Cl »2-a 3 Cl, 43-benzodiazep? N-5 (6H) -l-methyl-6-oxo-9-CC (2-pyr? Dini 1) -2- to inoeti l amino3carbo "-5-propanoic acid; 4-C4- C3- (2- pirridini 1) amino3propi 13-1-piperazim "13-1-pipep" dinacetic; acid 1-hydroxy-1-4-C4-C3- 2-pyridinyl 1) amino propyl 13-1-pipera -zine 13-cyclohexane, 4-C4-2- (2-pyridinium-1) amino-3-ethyl-13-1-piperazine "13-1-piperidineacetic acid; l-hydroxy? -4-C4-C2- (2-pi? d?) 1) appno3eti 1-pi? erazi and 13-cyclohexaneacetic acid; N-C3-El-I __. C (2-pir? D?? 1) ami or prop? 1 carbom '13-3-piperidini "13carboni 13-b-al aniña; 5- 2- (car oxy-eti 1) amino car-boni 1 -2-C2-C (2-pyridini 1) amino3eti 13-2, 3-dihydro-3-oxo-lH-iso-indoT, "(S) -2-ibyride Is? Lphoni lamino) -3-C4-C4- (N-pic p'd-2-l) o) 3 buti loxif ní 1 propi ónico; N-C3Í R) - 3-C í 2-p? ridini 1) -ami o3propi 1 -2-o? o-l-pi peri di nil 3aceti 13-3 (R) -eti 1-b-a1 a i a; 3-CC2-E acid. ) 2-pi idiní 1) ami or propi 13isoxazol in-5 (R, S) -i 1 -aceti 1 amino-3 (R, S) -metí 1propanoico; N-C3- C2-C2f_ (pi ridi ni 1) - amino3eti 13carbom "13amino3benzoi 13-b-alanine; acid CC1-CN-CE2-> 2-pyridini 1) ami or eti 1 carboni 13tirosi 1-4-piperidini 1 3-acetic oxy, acid (±) -3- 3-2-pyridi i 1) amino propi 1 amino-succinanoi 13 amino3-4pentino, acid (S) -4-CCC2-C2 ~ ( pyridinyl) ami or eti 1 Icarbonyl gly-1 -3-methoxycarboni I eti 1-2- oxopyperazine-1-acetic; I3S, 5S) -3-carboxymethyl! -5- C4-C2-C2- (pyridine 1) amino3eti 13pheni 13ox? "I got 13-2-pirro! idinone; 1-C2- 2-pyridyl-yl) amyl o3eti 13-3-C4- (2-carboxyethyl) phenyl-13-4-ethoxy-3-pyrrole-2-one; 4-CC2-C (2-pyridinyl) amino-3-eti-1-methyl-3-acetyl-3-phenoxyacetic acid; 2, 2'-C, C4-C, CC2-C (2-pyridinyl) amino, 13methyl, acetyl, 13-1, 2-phenylenedi3, "yes, i) bis-acetic acid, A-Z, 2-C, 2-p ? ridi ni 1) amino eti 1 carbo i 1 .02 I got lame o3aceti 13fenoxi acetic; 4-CECC2-CÍ2-pyridine "1) amy o3eti 13carbom" 13meti la í nolaceti 13-1"2-phenylenedio-dioxyacetic acid; l-C2-C (2- (pyridinium1) amine3eti13-3-C4-C2-carboxy) eti1) 3fem "13-3-oxo-imidazole di, C6-CC2-C acid (piri din-2) -i 1) ai o3et? 13a io carbom "13-1,2, 3, 4-tetrahydro-isoquinol in-2-i1 acetic; acid C6-CCC2-C pi id n-2-i 1) am? or et 13a ino car oi 1 -1, 2, 3, -tetrahi dro-1-oxo-isoquinol i n-2- i 13acético »C6- C2-C acid (piri din-2-i 1) ai no3e 1 carb, 13-amino-3-in-2-a-13-acetic acid, C6-CCC2-C (pyridin-2-y1) -aminolethyl-13-olcarbon, 13-tetral in-2-1-lactatic acid; C5-CCC acid (6-amino-2-pyridinium 1) methyl 1 Icarboni 1 ami no benzofuran-2-i 13 propionic; C5-C 2-Cí? irídi -2-i 1) amino eti 1 carbom "13 amí no3-2" 3-dihydro-benzofuran-2-i 13propionic acid; C5-CCC2-C acid (pin "di -2-i 1) am?" no3e? " 13meti 1 ami no3carbom "13benzof? Ran-2-i 13- propionic acid; C5-CCCC2-C (pyridin-2-yl) amino3eti 13methi-amyl o3carboni 1 -2,3-dihydro-benzofuran-2-i 13- acid propionic acid, or γ) -3-CCC5-C (pyridin din-2-yl) amino-3-pentanoyl-1-glycryl-amino-4-pentynoic acid 10.- A compound according to claim 1, further characterized by: acid (S) -2,3,4,5-tetrahydro-4-methy1-3-oxo-7- C2-C2-y pi ri di ni 1) amino3 and 13-aminocarbonyl-1H-l »4-benzodiazepin-2 -acetic acid (S) - 2 »3» 4 »5-tetrahydro-4-methyl-l-3-oxo-7-CCC2-C2- (pyridini 1) amino3 eti 1 amino3carbonyl! 3-lH-1,4-benzodiazepin- 2-acetic acid (S) -2,3.4 »5-tetrahydro-4-methy1-3-oxo-7-EC 2- (l-oxo-2-pyridini 1) amino-3-yl 3-aminocarbon * 13-lH- l »4-benzodiazepin-2-acetic» Acid (S) -2,3,4,5-tetrahydro-3-oxo-7-CCC2-C2- (pyridini 1) amino3-eti 1 ai no3carbó i 1 -1H- 1,4-benzodia? Epi-2-acetic; Aci or (S) -2,3,4,5-tetrahydro-3-oxo-7-CC2-C2-p iridini 1) amino3-eti 13 ami no3carboni 13-4-2, 2, 2-trif1 uoroethyl) -1H-1,4-benzodi-azepi n-2-acetic; Acid (±) -2, 3,4, 5-tetrahydro-3-oxo-4-y-fem "letí 1) -7- CCC2-C2- (pyridini 1) amino3eti 13amino3carboni 13-1H-1,4-benzodi azepi n- 2-acetic acid (S) -2, 3 »4, 5-tetrahi dro-4-meti 1-7-CCC2-C2- (6-methyl-1-pyridinium-1) amino-3-ethyl-13-aminocarbonyl-3-oxo-lH- l, 4-benzodi-azepi-2-acetic acid (S) -2,3 »4» 5-tetrahydro-4-methyl-3-oxo-7-CC2-C2-pyridinyl) ami o3eti-13-methylamino-carbom "13 -lH-1, 4-benzodi-azepin-2-acetic; Acid ±) -2, 3,4,5-tetrahydro-4-methy1-3-oxo-7- CC2- 2-pi ri di ni 1) amino3eti 1 amino3carbonyl 3-lH-l, 4-benzodiazepin-2 -acetic; Acid (±) -2,3,4,5-tetrahydro-4-methyl-7-CC2-C-6-methy1-3-pyridazine 1) amino-3-ethyl-amino-3-carbon-3-oxo-lH-l, 4-benzodi-azepin -2-acetic acid and Acid (±) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7-CC2-C3- (pyridazin 1) amino3eti 13amino3carbonyl 3-lH-l »4-benzodiazepin- 2-acetic 11- A pharmaceutical composition, characterized in that it comprises a compound according to any of the rei indications 1-10 and a pharmaceutically acceptable carrier. 12. The use of a compound according to claim 1, in the manufacture of a medicament for treating a disease state in which the antagonism of the vi tronectin receptor is indicated. 13. - The use in accordance with claim 12, to inhibit Ta angiogenesis or to treat atherosclerosis, restenosis, inflammation, cancer? osteoporosis. 14. The use of a compound according to any of claims 1-10, in the manufacture of a drug for the inhibition of the victronectin receptor in a mammal in need thereof. 15. The use of a compound according to any of the claims 1-IO, in the manufacture of a drug to treat atherosclerosis, restenois? Inflammation, cancer? osteoporosis. 16. A process for preparing a compound of the formula (I) as defined in claim 1, characterized in that it comprises reacting a compound of the formula (XVI) with a compound of the formula XVII): (XVI) (XVH) where Q3-, Q2, Q3, O / ***, R * -, R,? and A are as defined in formula 1), with any protected reactive functional groups; and L3- and L2 are groups that react to form a covalent ligation in the portion W as defined in the formula (I); and subsequently removing any protecting groups and optionally forming a pharmaceutically acceptable salt. .05 SUMMARY OF THE INVENTION Compounds of the formula Il) are described: in which: A is a fibrinogen antagonist template; W is a linking portion that has the form - HR =) ß-U-CHCHRsa) c > - V-; Q3-, R =, Q3 and Gr * are independent N or C-R '-', provided that no more than one of Q3- »R2, Q3» Q- * is N, R 'is H or alkyl of 1 to 6 carbon atoms, cycloalkyl of C3 __, - a1q? i lo of O to 6 carbon atoms or Ar-to the chyle of 0 to 6 carbon atoms; Rβ is H or alkyl of 1 to 6 carbon atoms, Het-alkyl of 0 to 6 carbon atoms, cycloalkyl of C3_-to the chyle of 0 to 6 carbon atoms, or Ar-to the chyle of 0 to 6 atoms of carbon; R * is Rβ, -C (Q) Ra or -Cí0) 0Rβ; R3- is H, alkyl of 1 to 6 carbon atoms, Het-al that of 0 to 6 carbon atoms, cycloalkyl of C3 _-_- a1 q? I 1 or of 0 to 6 carbon atoms, Ar -alkyl of 0 to 6 carbon atoms, Het-al q? I! of Co ^ s-U'-aTTTTo of 1 to 6 carbon atoms, C3_T alkyl and C0_s- alkyl? -al q? i that of 1 to 6 carbon atoms or Ar-alkyl of C0_. { S-U'-alq? I that of 1 to 6 carbon atoms; R-4"is H, halogen, -0R = >, -SR = >, -CN, -βR- ^, -N02, -CF3, CF3S (0) -, -C02Ra» -COR * »or - CHNRa2, or alkyl of 1 to 6 carbon atoms, optionally substituted with halogen, -0Rβ, -SRβ »-CN, -NRβRtt, -N02, -CF3, R'SÍ0) 3-, -C02R =, -C0Ra or - C0NRa2; U and V are absent or are CO, CRa2, C (= CR <32), Yes0) or, O, NRa, CRßORa, CRa OR?) CRa2, CRa2CRaÍOR *), CíO) CRa2, CR 2, C (0). CONR3-, NR - ^ - CO, 0C (0) »CÍ0) 0, CIS) 0, OCÍS), CÍS) NRa, NR * = C í S), S (O) -» NRa, NRaS (0) 2N = N, NRaNRa, NRaCR => 2, NRaCR 2, CRa20, OCRß2, CR = CR «=, C = C, Ar or Het; a is O, 1, 2, 0 3; b is O, 1 OR 2; c is O, 1 OR 2; r is 0, 1, or 2; Y ? is O or 1"or its pharmaceutically acceptable salts, which are antagonists of the vi tronectin receptor, useful in the treatment of osteoporosis. CR / cgt * -P98 / 648F
MXPA/A/1998/005254A 1995-12-29 1998-06-26 Vitronect receptor antagonists MXPA98005254A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US009367 1995-12-29

Publications (1)

Publication Number Publication Date
MXPA98005254A true MXPA98005254A (en) 1999-02-24

Family

ID=

Similar Documents

Publication Publication Date Title
US6159964A (en) Vitronectin receptor antagonists
US6239138B1 (en) Vitronectin receptor antagonist
WO1997024122A1 (en) Vitronectin receptor antagonists
DE69332860T2 (en) BICYCLIC FIBRINOGEN ANTAGONISTE
CZ203698A3 (en) Antagonist of vitronectin receptor, pharmaceutical composition containing thereof, process of its preparation and use
AU736487B2 (en) Integrin receptor antagonists
JPH10504807A (en) Vitronectin receptor antagonist
IL129243A (en) Vitronectin receptor antagonists, process for their preparation, pharmaceutical compositions comprising the same and use thereof in the preparation of medicaments for treatment of osteoporosis and inhibition of angiogenesis
US5977101A (en) Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity
JP2001514253A (en) Integrin receptor antagonist
WO2000033838A1 (en) Vitronectin receptor antagonist
US6008213A (en) Integrin receptor antagonists
US20010034445A1 (en) Vitronectin receptor antagonists
MXPA98005254A (en) Vitronect receptor antagonists
CA2241755A1 (en) Vitronectin receptor antagonists
KR100459621B1 (en) Integrin Receptor Antagonists