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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D487/04—Ortho-condensed systems

Definitions

• This invention relates to pharmaceutically active compounds which inhibit the vitronectin receptor and are useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.
• Integrins are a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpllb /Ilia, the fibrinogen receptor, and ⁇ v 6 3 , the vitronectin receptor. The fibrinogen receptor gpllb /Ilia is expressed on the platelet surface and it mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, et al, Blood., 1988, 71, 831.
• the vitronectin receptor oty ⁇ ⁇ is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions.
• the ⁇ v B 3 receptor expressed on the membrane of osteoclast cells mediates the bone resportion process and contributes to the development of osteoporosis. Ross, et al, J. Biol. Chem., 1987, 262, 7703.
• the 0 ⁇ -3 receptor expressed on human aortic smooth muscle cells stimulates their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al, Cardiovascular Res., 1994, 28, 1815.
• a oty ⁇ ⁇ antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Brooks, et al, Cell, 1994, 79, 1157.
• agents that would block the vitronectin receptor would be useful in treating diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer.
• the vitronectin receptor is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif.
• WO 93/08174 Bondinell, et al., WO 93/00095, Blackburn, et al. WO 95/04057, Egbertson, et al, EP 0478 328, Sugihara, et al. EP 529,858, Porter, et al., EP 0 542 363, and Fisher, et al., EP 0 635 492 disclose certain compounds that are useful for inhibiting the fibrinogen receptor. It has now been discovered that certain appropriately substituted compounds are potent inhibitors of the vitronectin receptor. In particular, it has been discovered that such compounds are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor and such compounds contain a fibrinogen receptor antagonist template.
• This invention comprises compounds of the formula (I)-(V) and (XXI)-(XXII) as described hereinafter, which have pharmacological activity for the inhibition of the vitronection receptor and are useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone reso ⁇ tion is a factor, such as osteoporosis.
• This invention is also a pharmaceutical composition comprising a compound according to formula (I)-(V) (XXI)-(XXII)and a pharmaceutically carrier.
• This invention is also a method of treating diseases which are mediated by the vitronectin receptor.
• the compounds of this invention are useful for treating atherosclerosis, restenosis, inflammation, cancer and diseases wherein bone reso ⁇ tion is a factor, such as osteoporosis.
• This invention comprises novel compounds which are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.
• the compounds of the instant invention comprise a fibrinogen receptor antagonist template that is linked to a nitrogen-containing five-membered ring, which is optionally fused to an aromatic six-membered ring.
• the fibrinogen receptor antagonist template is substituted by an aliphatic substituent which contains an acidic moiety. It is preferred that about fourteen intervening covalent bonds via the shortest intramolecular path will exist between the acidic group of the fibrinogen receptor antagonist template and the nitrogen of the optionally fused five-membered ring.
• fibrinogen receptor antagonist template means the core structure of a fibrinogen receptor antagonist, said core being substituted by an acidic group and said core being linked to an organic group substituted with a basic nitrogen moiety.
• a fibrinogen receptor antagonist is an agent that inhibits the binding of fibrinogen to the platelet-bound fibrinogen receptor GPIIb-IIIa. It is an object of this invention that a fibrinogen receptor antagonist is converted to a vitronectin receptor antagonist by replacing the organic group substituted with a basic nitrogen moiety in a fibrinogen receptor antagonist with an optionally fused nitrogen-containing five-membered ring, preferably an imidazole ring and, most preferably, a benzimidazole ring.
• This invention comprises compounds of formula (I)-(V):
• A is a fibrinogen receptor antagonist template
• V' is CONR 21 or NR 21 CO;
• G is NR e , S or O;
• Rg is H, C , -6 alkyl, Het-C 0 . 6 alkyl, C 3 . 7 cycloalkyl-C 0 . 6 alkyl or Ar- C 0 _ 6 alkyl;
• R2l is Het-C 0 _ 6 alkyl-U'-C ⁇ . 6 alkyl-, C 3 . 7 cycloalkyl-C 0 . 6 alkyl-U'-C 1 . 6 alkyl-, or
• U' is CONR f or NR f CO;
• R f is H, C 1-6 alkyl or Ar-C ⁇ alkyl
• R e is H, C,. 6 alkyl, Ar-C,. 6 alkyl, Het-C 1 _ 6 alkyl, C 3 . 7 cycloalkyl-C 1 _ 6 alkyl, (CH 2 ) q OH or (CH 2 ) k CO 2 Rg; k is 0, 1 or 2; q is 1 or 2; b is 0, 1 or 2; Rb and R c are independently selected from H, Het-
• N(R f ) 2 CO(NRf) 2 , and CH 2 N(Rf) 2 , or methylenedioxy; or a pharmaceutically acceptable salt thereof.
• This invention also comprises compounds of formula (XXI)-(XXII):
• B is a linking moiety of the form -(CHRg) a -U- (CHRg)b-V-;
• A is a fibrinogen receptor antagonist template;
• G is NR e , S or O;
• Rg is H, C ] -6 alkyl, Het-C 0 . 6 alkyl, C 3 . 7 cycloalkyl-C 0 . 6 alkyl or Ar- C 0 . 6 alkyl ;
• R k is Rg, -C(O)Rg, or -C(O)OR f ;
• R 1 is is H, C ] _ 6 alkyl, Het-Co ⁇ alkyl, C 3 . 7 cycloalkyl-C 0 .6alkyl, Ar- C 0 . 6 alkyl,
• R e is H, C,. 6 alkyl, Ar-C 1 _ 6 alkyl, Het-C ⁇ galkyl, C 3 .7cycloalkyl-C,_ 6 alkyl,
• CRgORg CRg(OR k )CRg 2 , CRg 2 CRg(OR k ), C(O)CRg 2 , CRg 2 C(O), CON R> N R' CO OC(O), C(O)O, C(S)O, OC(S), C(S)NRg, NRgC(S), S(O) 2 NRg,
• CRg CRg- Ar or Het; k is 0, 1 or 2; q is 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2;
• Rb and R c are independently selected from H, C j .galkyl, Ar-Co ⁇ alkyl, Het-
• ⁇ is CONR f or NR f CO.
• Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
• this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques.
• compounds may have unsaturated carbon- carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
• compounds may exist in tautomeric forms, such as
• the compounds of formula (I) - (V) and (XXI) - (XXII) inhibit the binding of vitronectin and other RGD-containing peptides to the vitronectin (0 ⁇ ,63) receptor.
• Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone reso ⁇ tion and is useful in the treatment of diseases wherein bone reso ⁇ tion is associated with pathology, such as osteoporosis. Additionally, since the compounds of the instant invention inhibit vitronectin receptors on a number of 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 anti-metastatic and antitumor agents.
• the compounds of this invention are of the formula (II), wherein R b and R c are joined to form an aromatic ring containing up to two nitrogen atoms.
• R b and R c are joined to form an optionally substituted phenyl ring according to formula (Ila):
• W is -(CHR g y ⁇ CO- or , or, when G is CH, W is
• R 1 is H, substituted by one to three groups chosen from halogen, CN, NRg 2 , ORg, SRg, CO Rg, and CON(R g ) 2 , Ar, Het or C3 -7 cycloalkyl.
• R 1 is H, methyl, butyl, cyanomethyl, carboxymethyl, phenylethyl or benzimidazolylmethyl.
• R x , Ry and R z are independently chosen from C j .galkyl, methoxy, nitro, trifluoromethyl, fluoro, chloro, amino or R and Ry are adjacent to one another and are joined to form a methylenedioxy group.
• G is NR e .
• R e is H, C h alky., Ar, Het or C j . 4 alkyl substituted by Ar or Het. More suitably, R e is H, methyl or benzimidazolylmethyl.
• R b and R c form a six membered aromatic ring containing one or two nitrogen atoms according to formulas (Ilb-d):
• the compounds of this invention are comprised of a nitrogen- containing optionally fused five-membered ring, a linking group W, and a fibrinogen receptor antagonist template A.
• the fibrinogen receptor antagonist template A is as defined in Bondinell, et al., WO 93/00095, published January 7, 1993, of the sub-formula (VI):
• a 1 to A 5 form an accessible substituted seven-membered ring, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen from the group of O, S and N wherein S and N may be optionally oxidized;
• D 1 to D 4 form an accessible substituted six membered ring, optionally containing up to two nitrogen atoms;
• R is at least one substituent chosen from the group of R 7 , or Q-C j ⁇ alkyl,
• R* is H, Q-Cj. 6 alkyl, Q-C]_6 o ⁇ °alkyl, Q-C 2 .6alkenyl, Q-C3.4 ⁇ xoalkenyl, Q-C3.4 ⁇ xoalkynyl, Q-C 2 _ 4 alkynyl, C3.6cycloa.kyl, Ar or Het, optionally substituted by one or more of R 1 ' ;
• Q is H, C3-6cycloalkyl, Het or Ar;
• R 7 is -COR8, -COCR' 2 R9, -C(S)R8, -S(O) m OR', -S(O) m NR'R", -PO(OR'), -PO(OR') 2 , -B(OR') 2 , -NO 2 and Tet;
• R 8 is -OR', -NR'R", -NR'SO 2 R', -NR'OR', -OCR' 2 C(O)OR', -OCR' 2 OC(O)-R', -OCR' 2 C(O)NR' 2 , CF 3 or AA 1 ;
• R 9 is -OR', -CN, -S(O) r R', S(O) m NR' 2 , -C(O)R' C(O)NR' 2 or -CO 2 R';
• R 1 1 is H, halo, -OR 12 , -CN, -NR'R 12 , -NO 2 , -CF 3 , CF 3 S(O) r , -CO 2 R', -CONR' 2) Q-C 0 . 6 alkyl-, Q-C,. 6 oxoalkyl-, Q-C 2 . 6 alkenyl-, Q-C 2-6 alkynyl-, Q-C 0- 6 alkyloxy-, Q-C 0- 6alkylamino- or Q-C 0 . 6 alkyl-S(O) ;
• R 12 is R', -C(O)R', -C(O)NR' 2 , -C(O)OR 15 , -S(O) m R' or S(O) m NR' 2 ;
• R 13 is R', -CF 3 , -SR', or -OR';
• R 14 is R', C(O)R', CN, NO 2 , SO 2 R' or C(O)OR 15 ;
• R 15 is H, C,_ 6 alkyl or Ar-C 0 - 4 alkyl
• R' is H, C j . ⁇ alkyl, C3. cycloalkyl-Co-4alkyl or Ar-Co-4alkyl;
• R" is R', -C(O)R' or -C(O)OR 15 ;
• R'" is R" or AA2;
• AA1 is an amino acid attached through its amino group and having its carboxyl group optionally protected
• AA2 is an amino acid attached through its carboxyl group, and having its amino group optionally protected
• m is 1 or 2
• n is 0 to 3
• p is 0 or 1
• t is 0 to 2; or pharmaceutically acceptable salts thereof.
• a 1 is CR ⁇ R 1' , CR 1 , NR 1 , N, O or S(O) x
• a 2 is CR 2 R 2' , CR 2 , NR 2
• a 3 is CR 3 R 3' , CR 3 , NR 3 , N, O or S(O) x
• a 4 is CR 4 R 4' , CR 4 , NR 4 , or N;
• a 5 is CR 5 R 5' , CR 5 , NR 5 , N, O or S(O) x ;
• O l -O 4 are CR u , CR 6 o ⁇ N;
• a 1 is CR'R 1 ' , CR 1 , NR 1 , N, O or S;
• a 2 is CR R 2' , NR 2 or CR 2 ;
• a 3 is CR R 3' ;
• a 4 is CR R 4' , CR 4 , NR 4 , or N;
• a 5 is CR R 5' , CR 5 , NR 5 , N, O;
• D 1 - D 4 are CH;
• R 2 or R 4 are R;
• R 3 ,R 3' and R 5 ,R 5' O or R*,H.
• a 1 is CHR 1 , CR 1 , NR", N or S;
• a 2 is CR 2 or CR 2 R ;
• a 3 is CR 3 R 3 ';
• a 4 is CR R 4' or NR 4 ;
• a 5 is CR 5 R 5 , and D 1 - D 4 are CH.
• a 1 is CR 1
• a 2 is CR 2
• a 4 is NR 4
• a 5 are CHR 5 .
• a 1 is NR 1
• a 2 is CHCR 2
• a 3 is CR 3 R 3 '
• a 4 is NR 4
• a 1 is NR 1
• a 2 is CHR 2
• a 4 is NR'
• a 5 is CHR 5 .
• fibrinogen receptor antagonist template A is of the sub-formula (VI) are named in the Examples.
• Preferred compounds of this invention are: 5-[[[(Benzimidazol-2-yl)methyl]methylamino]carbonyl]-lH-benzimidazole-
• Vitronectin fibrinogen receptor antagonism is particularly pronounced when the A-W- substituent is attached to the 7-position of the 3-oxo-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine ring system.
• fibrinogen receptor template A Another embodiment of a preferred fibrinogen receptor template A is represented by the 1 ,4-benzodiazepine 2,5-dione of sub-formula (VII);
• Y is H, C ⁇ _ 4 -ukyl, C.. 4 alkoxy, C alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR f ,
• R 1 and R 22 independently are H or -Z-CO 2 R f or Z-CON(R f ) 2 with the proviso that one of A 1 or A 2 is -Z-CO 2 R f or Z-CON(R f ) 2 ;
• Z is -CH 2 -, -O(CH 2 ) q -, -NRf(CH 2 ) q -, -S(CH 2 ) q , -CH 2 CH 2 -, -CH(CH3)CH 2 -,
• Y is H, C ⁇ _ 4 alkyl, F, Cl, Br, I, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 , methylenedioxy or Z-COR f , in Alig, et al., EP 0 381 033, published August 8, 1990.
• R6 is aryl, C j . j oalkyl, C3.6cycloa.kyl, C4_ ⁇ oaralkyl, C ⁇ _ ⁇ oalkoxyalkyl,
• C4-iQaralkanoyl, or Ci- Qcarboxyalkyl is H, C ⁇ . 4 alkyl, C,. 4 alkoxy, C alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR f ,
• M J is CH or N
• M 2 is CH or N, with the proviso that when M 1 is CH, M 2 is N; and G' is N or N ⁇ R", in Eldred, et al., EP 0542 363, published May 19, 1993.
• M 2 is CH or N, with the proviso that when M 1 is CH, M 2 is N, in Porter, et al., EP 0 537 980, published April 21, 1993.
• Y is H, C j .4a.kyl, C ] . 4 alkoxy, C ] . 4 alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR f ,
• R h is (CH 2 ) q CO 2 R f , in Klinnick, et al., EP 0 635,492, published January 25, 1995.
• Y is H, C ⁇ . 4 alkyl, C,_ 4 alkoxy, C ] . 4 alkoxycarbonyl, F, Cl, Br, I, CF 3 , OR f , S(O) k R f , CORf, NO 2 , N(R f ) 2 , CO(NRf) 2 , CH 2 N(R f ) 2 , methylenedioxy, CN, CO 2 R f ,
• R h is (CH 2 ) n CO 2 R f ;
• L* is -C(O)NR8-(CH 2 K -C(O)-(CH 2 ) q -, NRg-(CH 2 ) q -, -O-(CH 2 ) q -, or
• Y is H, C ] . 4 alkyl, C alkoxy, F, Cl, Br, I, CF 3 , OR f ,
• R d is Het-C 0 . 6 alkyl
• Z" independently are hydrogen, C 1 . 4 alkyl, halo, OR f , CN, S(O) k R f , CO 2 R f , or OH, in Bovy, et al., EP 0 539 343, published April 28, 1993.
• fibrinogen receptor templates for use in the present invention were taken from pending published patent applications. Reference should be made to such patent applications for their full disclosures, including the methods of preparing said templates and specific compounds using said templates, the entire disclosure of such patent applications being incorporated herein by reference.
• WO 90/02751 Ohba, M. et al.: Sept. 8, 1989: Describes cyclic RGD-containing peptides.
• Ciba Geigy EP 0452210 (Der 91-305246/42) Apr, 5, 1990, describes aminoalkanoyl-GDF analogs.
• JP 05078344-A (Der 93-140339/17) Mar. 30, 1993: Describes Bis- amidinoheterocycles, eg. benzofurans.
• WO 94/11398 May 26, 1994: Wells, G. J. et al. Describes cyclic RGD containing peptides. IL 109237, Jul. 31, 1994.
• WO 94/22909 (Der 94-333113/41) Oct. 13, 1994: DeGrado W. F., et al.
• WO 94/22910 (Der 94-333114/41 Oct. 13, 1994: DeGrado W. F., et al. Prodrugs.
• WO 94/22494 (Der 94-332838/41) Oct. 13, 1994: DeGrado W. , et al. Cyclic peptides EP 625164, Nov. 23, 1994: Degrado, W. F., et al. Cyclic peptides. Mousa, S. A.; Bozarth, J. M.; Forsythe, M. S.; Jackson, S. M.; Leamy, A.; Diemer,
• GPIIb/IIIa Receptor Antagonist Circulation , 89, 3, 1994. Jackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.; Higley, A.; Krywko, J.; Rockwell, A.; Markwalder, J.; Wells, G.; Wexler, R.; Mousa, S.; Harlow, R.,
• JP 04208296-A (Der. 92-303598/38), Nov. 30, 1990, Describes RGD peptides.
• JP 04213311 -A (Der. 92-305482/38), Nov. 27, 1990, Describes multimeric RGD peptides.
• JP 04217693-A (Der 92-312284/38), Oct. 23, 1990, Descirbes multimeric RGD peptides.
• JP 04221394-A (Der. 92-313678/38), Oct. 26, 1990, Describes multimeric RGD peptides.
• JP 04221395-A (Der. 92-313679/38), Oct. 26, 1990, Describes multimeric RGD peptides.
• JP 04221396-A (Der. 92-313680/38), Oct. 26, 1990, Describes multimeric RGD peptides.
• JP 04221397-A (Der. 92-313681/38), Dec. 20, 1990, Describes multimeric RGD peptides.
• EP 503301-A2 Feb. 14, 1991, Kitaguchi, H. et al. Describes RGD peptides.
• JP 05222092 May 21, 1993, Nishikawa, N., et al.: DescribesLinear X-RGDS. JP 06239885, (Der 94-313705/39) , Aug 30, 1993, Nishikawa, N. et al.: Describes multimeric RGD peptides.
• WO 9324448 (Der 93-405663/50), Dec. 9, 1993, Nishikawa, N., et al.: Describes multimeric retro-inverseo RGD peptides. JP 06228189, (Der 94-299801/37), Aug. 16, 1994. Describes RGD peptides. EP 619118, (Der 94-311647/39) , Oct. 12, 1994, Nishikawa, N. et al.: Describes linear RGD peptides.
• EP 0513675 May 8, 1992, N. Umekita, et al.: Describes amidinophenyloxyalkanoyl-Asp-Val-OH analogs.
• WO 9500502 Jan, 5, 1995, Oku, T., et al.,: Describes "aminopiperazine derivatives.”
• FR 144633 Thromb Hae . 69, 706, 1993.
• Nonpeptide GPIIb/IIIa Antagonist Thromb. Haem. , 69, 707, 1993.
• RGD-containing peptides WO 91/04247, Sept. 24, 1990, T. R. Webb Describes (guanidinoalkyl)Pro-GD analogs. WO 91/11458 (Der 91252610), Jan. 28, 1991, P. L. Barker, et al.: Describes cyclic RGD-containing peptides WO 92/07870, Oct. 24, 1991 J. P. Burnier, et al.: Describes cyclic RGD- containing peptides. WO 92/17492, Oct. 15, 1992, Burnier, J. P. et al.: Describes cyclic RGD-containing peptides.
• EP 612313 Aug. 31, 1994, Porter, B., et al. Describes alpha-alkylpiperidineacetic acid derivatives.
• EP 93911769 Apr. 20, 1994, Midlemiss, D., et al.
• EP 0368486 (Der 90-149427/20), Nov. 10, 1988: Describes X-R-Tyr-D-Y analogs.
• EP 0382451 (Der 90248531 ): Descirbes RGD-containing snake venom inhibitors.
• EP 0382538 (Der 90248420): Descirbes RGD-containing snake venom inhibitors.
• EP 0410539, July 25, 1990, R. F. Nutt, et al. Describes cyclic RGD-containing peptides.
• EP 0410540 July 25, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides.
• EP 0410541 July 25, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides.
• EP 0411833 July 26, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides.
• EP 0422937 Oct. 11, 1990, R. F. Nutt, et al.: Describes cyclic RGD-containing peptides.
• Duggan et al. Describes X-Gly-(3- phenethyl) ⁇ Ala analogs.
• JP 05286922 (Der 93-383035/48), Describes guanidinophenol alkylbenzoic acid esters.
• JP 05230009 (Der 93-317431/40, Feb. 24, 1992: Describes amidino-Cbz-meta- aminophenylpropionate.
• EP 0608858 A Aug, 3, 1994, Linz, G. D., et al., Describes amidino-biphenyl compounds.
• DE 4304650 (Der 94-256165/32), Aug, 18, 1994, Austel, V., et al., describes compounds with a 5,6 template.
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• DE 4305388 (Der 94-264904/33), Aug. 25, 1994, Himmelsbach, F., et al..
• Receptor Antagonist BIBU 52 in Mice and Monkeys, Thromb. Haem. , 69,
• Zeneca WO 9422834 Oct. 13, 1994, Wayne, M. G., et al. Describes pyridinopiperazino- phenylcarbonyl-amino acids.
• WO 9422835 Oct. 13, 1994, Wayne, M. G., et al. Describes pyridinopiperidino- amidophenylacetic acids.
• EP 632016, Jan. 4, 1995, Brewster, A. G.., et al. Describes pyridinopropiony lhy drazinylbenzoy 1 analogs .
• EO 632019 Jan. 4, 1995, Brown, G., Shute, R. E.
• EO 632020 Jan. 4, 1995, Brown, G., Shute, R. E.
• this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques.
• compounds have unsaturated carbon-carbon double bonds
• both the cis (Z) and trans (E) isomers are within the scope of this invention.
• the meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence.
• C ⁇ alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
• Co ⁇ alkyl and C 0 _6alkyl additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
• Any Cj. 4 alkyl or Cj. 6 alkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl or C ] _ 6 oxoalkyl may be optionally substituted with the group R x , which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques.
• Suitable groups for R x are C alkyl, OR ' , SR ' , C,.
• Ar, or aryl as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, especially C 1 . 4 alkyl, Cj. 4 a.k0xy, Cj_ alkthio, trifluoroalkyl, N 3 , OH, CO 2 H
• Het, or heterocycle indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
• heterocycles are benzofuran, benzimidazole, benzopyran, benzothiophene, biotin, furan, imidazole, indoline, mo ⁇ holine, piperidine, piperazine, pyrrole, pyrrolidine, pyridine, tetrahydropyridine, pyridine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline. Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl that are available by chemical synthesis and are stable are within the scope of this invention.
• C3-7cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.
• Typical of C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as those defined above for alkyl, on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
• R b and R c When R b and R c are joined together to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which R b and R c are attached, the ring formed will generally be a five- or six-membered heterocycle selected from those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl ring.
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical
• BrZ refers to the o-bromobenzyloxycarbonyl radical
• C1Z refers to the o-chlorobenzyloxycarbonyl radical
• Bzl refers to the benzyl radical
• 4-MBzl refers to the 4-methyl benzyl radical
• Me refers to methyl
• Et refers to ethyl
• Ac refers to acetyl
• Alk refers to C].
• Nph refers to 1- or 2-naphthyl
• cHex refers to cyclohexyl.
• Tet refers to 5-tetrazolyl.
• DCC refers to dicyclohexylcarbodiimide
• DMAP refers to dimethylaminopyridine
• DIEA refers to diisopropylethyl amine
• EDC refers to l-(3-dimethylaminopropyl)-3- ethylcarbodiimide, hydrochloride.
• HOBt refers to 1-hydroxybenzotriazole
• THF tetrahydrofuran
• DIEA diisopropylethylamine
• DME dimethoxyethane
• DMF dimethylformamide
• NBS N- bromosuccinimide
• Pd/C a palladium on carbon catalyst
• PPA 1- propanephosphonic acid cyclic anhydride
• DPPA diphenylphosphoryl azide
• BOP refers to benzotriazol-l-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate
• HF refers to hydrofluoric acid
• TEA triethylamine
• TFA trifluoroacetic acid
• PCC pyridinium chlorochromate.
• Typical methods include coupling to form amide bonds, nucleophilic displacement reactions and palladium catalyzed couplings.
• W when W contains an ether or amine linkage, the bond may be formed by a displacement reaction, and one of L 1 and L 2 will contain an amino or hydroxy group and the other will contain a displaceable group, such as a chloro, bromo or iodo group.
• W when W contains an amide bond, typically one of L 1 and L 2 will contain an amino group, and the other will contain a carboxylic acid group.
• L 1 may be an aryl or heteroaryl bromide, iodide or trifluoromethylsulfonyloxy derivative and L 2 may contain an amino group and the amide linkage may be formed by palladium- catalyzed aminocarbonylation with carbon monoxide in a suitable solvent such as dimethylformamide or toluene. It will be apparent that the precise identity of L 1 and L 2 will be dependent upon the site of the linkage being formed.
• R 6" may be (benzyloxycarbonyl-amidino)benzoyl- or (N ⁇ -Boc,N8 uan -Tos)arginyl-.
• L 2 is OH
• a coupling agent is used.
• L 1 may be -CO 2 H or CO-C1
• L 2 may be -NH 2
• R 6 " may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR' 2 ) s -.
• R 6 " may be
• L 1 may be SO 2 Cl
• L 2 may be -NH 2 and R 6" may be as above.
• V is SO 2 NH
• L 1 may be -NH 2
• L 2 may be SO 2 Cl.
• L 1 may be -CHO
• R 6" may be W- (CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR' 2 ) s -.
• L 2 may be CHO, e.g., R 6" may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR' 2 ) s . 1 -CHO.
• L 1 may be -OH, -NH or
• L 2 may be -Br; and R 6" may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR' ) s -.
• R 6 " may be
• U or V is OCH 2
• L 1 may be Br, I or CF3SO3
• V is CHOHCH 2
• V is CH 2 CHOH
• the core 6-7 fused ring system is prepared of formula (VI) by methods well known in the art, e.g., Hynes, et al., J. Het. Chem., 1988, 25, 1173; Muller, et al,
• deoxybenzoin such as 2-(4-methoxyphenyl)-l- phenylethanone (Chem. Ber. 1958, 91, 755-759)
• an aldol-type reaction with the enolate of ethyl acetate, which can be generated from ethyl acetate on exposure to an appropriate amide base, for instance lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide (LiN(TMS) 2 ), to afford 1-2.
• LDA lithium diisopropylamide
• TMS lithium bis(trimethylsilyl)amide
• THF is the solvent of choice for an aldol reaction, although THF in the presence of various additives, for instance HMPA or TMEDA, is often used.
• olefinic product can be conveniently converted to 1-3 by hydrogenation over a palladium catalyst, such as palladium metal on activated carbon (Pd/C), in an appropriate inert solvent, for instance methanol, ethanol, or ethyl acetate.
• a palladium catalyst such as palladium metal on activated carbon (Pd/C)
• Pd/C palladium metal on activated carbon
• methyl ether of 1-3 to give 1-4 can be accomplished by reaction with ethanethiol (EtSH) in the presence of a Lewis acid catalyst, preferably anhydrous aluminum trichloride (A1C1 3 ), in an inert solvent, for instance CH 2 C1 2 .
• a Lewis acid catalyst preferably anhydrous aluminum trichloride (A1C1 3 )
• A1C1 3 anhydrous aluminum trichloride
• Alcohol 1-4 is converted to its trifluoromethanesulfonate ester 1-5 by reaction with trifluoromethanesulfonic anhydride (Tf 2 O) in the presence of a suitable non-nucleophilic amine base, such as 2,6-lutidine, in an inert solvent, generally CH 2 C1 2 . 1-5 reacts with carbon monoxide (CO) in the presence of potassium acetate, l,l'-bis(diphenylphosphino)ferrocene (dppf), and a palladium catalyst, for instance palladium acetate (Pd(OAc) 2 ), in a suitable solvent, preferably DMSO, according to the general method described by Cacchi and Lupi (Tet. Lett.
• benzoic acid derivative 1-6 is converted to an activated form of the carboxylic acid using, for example, EDC and HOBt, or SOCl , and the activated form is subsequently reacted with an appropriate amine, for instance 2- (methylaminomethyl)methylbenzimidazole dihydrochloride, in a suitable solvent such as DMF, CH 2 C1 2 , or CH 3 CN, to afford 1-7.
• an added base such as diisopropylethylamine ((i-Pr) 2 NEt) or pyridine, may be used.
• Reduction of the ⁇ , ⁇ -unsaturated ester of II-3 to afford the saturated compound H-4 occurs under standard hydrogenation conditions, for instance reaction with hydrogen gas in the presence of a suitable catalyst, preferably palladium metal on activated carbon (Pd/C), in an inert solvent, generally methanol, ethanol, ethyl acetate, or mixtures thereof.
• a suitable catalyst preferably palladium metal on activated carbon (Pd/C)
• Pd/C palladium metal on activated carbon
• the methyl ester of II-4 is hydrolyzed using aqueous base, for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol, and the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HCl, to afford the carboxylic acid II-5.
• HMPA tetramethylethylenediamine
• DMPU l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
• the tert-butyl ester group of II-7 is removed under acidic conditions, generally with TFA or HCl, in an inert solvent, usually CH 2 C1 2 , 1 ,4-dioxane, or mixtures thereof, to afford the acid II- 8.
• an inert solvent usually CH 2 C1 2 , 1 ,4-dioxane, or mixtures thereof.
• II-8 is converted to II-9 under the general conditions described in Scheme I for the conversion of 1-6 to 1-7, and II-9 is converted to 11-10 by the general conditions described in Scheme I for the conversion of 1-7 to 1-8.
• III-l can be reacted with succinic anhydride in the presence of an appropriate base, such as triethylamine, diisopropylethylamine, or pyridine, in a neutral solvent, generally CH 2 C1 2 , to afford III-3 directly.
• III-3 is converted to III-4 by reaction with the known ethyl 3-amino-4-pentynoate (WO93/07867) under the general conditions described in Scheme I for the conversion of 1-6 to 1-7.
• Hydrolysis of the ethyl ester of III-4 to provide III-5 is accomplished according to the general conditions conditions described in Scheme I for the conversion of 1-7 to 1-8.
• IV-8 The synthesis of IV-8 is accomplished by the reaction of two separately prepared intermediates, IV-3 and IV-6.
• the preparation of intermediate I -3 begins with commercially available 2,3-diaminopyridine (IV-1).
• IV-1 is acylated with methyl 4-(choloroformyl)butyrate in the presence of a suitable acid scavenger, such as triethylamine, diisopropylethylamine, or pyridine, in a neutral solvent, generally CH 2 C1 2 or THF, to afford an intermediate monoacylated derivative.
• a suitable acid scavenger such as triethylamine, diisopropylethylamine, or pyridine
• a neutral solvent generally CH 2 C1 2 or THF
• V-2 is conveniently prepared by reaction of the readily available V-l with di-tert-butyl dicarbonate ((Boc) 2 O) in the presence of an acylation catalyst, preferably 4-dimethylaminopyridine (DMAP) or 4- pyrrolidinopyridine, in a neutral solvent, for example CH 3 CN, THF, or CH 2 C1 2 .
• an acylation catalyst preferably 4-dimethylaminopyridine (DMAP) or 4- pyrrolidinopyridine
• DMAP 4-dimethylaminopyridine
• a neutral solvent for example CH 3 CN, THF, or CH 2 C1 2 .
• V-3 is reacted with isobutyl chloroformate in the presence of a suitable amine base, such as triethylamine, diisopropylethylamine, or 4-methylmo ⁇ holine, in a neutral solvent, generally CH 2 C1 2 or THF, to afford an intermediate mixed anhydride derivative.
• a suitable amine base such as triethylamine, diisopropylethylamine, or 4-methylmo ⁇ holine
• a neutral solvent generally CH 2 C1 2 or THF
• Reaction of V-4 with bis(tributyltin) to produce V-5 occurs under palladium catalysis using, for example bis(triphenylphosphine)palladium (II) chloride ((PPh 3 ) 2 PdCl 2 ), in an inert solvent, usually DMF.
• Stille-type coupling of V-2 with V-5 to afford V-6 is mediated by a palladium catalyst, for instance bis(triphenylphosphine)palladium (II) chloride ((PPh 3 ) 2 PdCl 2 ), in the presence of copper (I) iodide (Cul), in a suitable neutral solvent, generally DMF.
• the protecting groups of V-6 are removed by well-established methods known to those of skill in the art and described in the previously cited Greene publication.
• the Boc protecting group is removed under acidic conditions, such as 4 M HCl in dioxane or TFA in CH 2 C1,, and the methyl ester is hydrolyzed as generally described in Scheme 1 for the conversion of 1-7 to 1-8.
• Compound VI-1 is reacted with 3-butyne-l-ol in the presence of a catalytic amount of a palladium salt, usually bis(triphenylphosphine)palladium (II) chloride ((PPh 3 ) 2 PdCl 2 ), together with a catalytic amount of copper (I) iodide (Cul), in an amine solvent, such as triethylamine (Et 3 N), to afford VI-2.
• a phosphine ligand such as triphenylphosphine (PPh 3 ), can be added to improve the efficiency of the reaction.
• VII-1 4-pentenoic acid
• VII -2 is converted to the benzimidazole derivative VII -2 using to the general procedures described previously. Protection of one of the nitrogen atoms of the benzimidazole moiety in VII -2 can be accomplished by reaction with a sulfonyl chloride, for instance p- toluenesulfonyl chloride, in the presence of a suitable base, generally sodium hydride or an aqueous alkali metal hydroxide, in an inert solvent, preferably THF, to afford VII -3.
• a suitable base generally sodium hydride or an aqueous alkali metal hydroxide
• Alternative protecting groups known to those of skill in the art may be used, as long as they are compatible with the subsequent chemistry and can be removed when desired.
• Oxidative cleavage of the olefin of VII -3 to afford the aldehyde VII -4 can be conveniently accomplished by ozonolysis in an inert solvent, usually CH 2 C1 2 or a mixture of CH 2 C1 2 and MeOH, followed by in-situ reduction of the ozonide with a suitable reducing agent, generally dimethylsulfide (DMS) or triphenylphosphine.
• a suitable reducing agent generally dimethylsulfide (DMS) or triphenylphosphine.
• DMS dimethylsulfide
• triphenylphosphine triphenylphosphine
• the aldehyde is converted to the aldoxime VII -5 by standard procedures known to those of skill in the art, and this aldoxime is oxidized to the oximinoyl chloride derivative VII -6 by the methods described in WO 95/14682 and WO 95/14683. Reaction of VII -6 with an olefin, such as tert- butyl 3-butenoate (Tet. Lett.
• the carboxylic acid is activated using, for example, EDC and HOBt, or SOCl 2 , and the activated form is subsequently reacted with an appropriate amine, for instance a suitable derivative of ⁇ -alanine, in a neutral solvent, such as DMF, CH 2 C1 2 , or CH 3 CN, to afford VII -9.
• an added base such as diisopropylethylamine ((i- Pr) 2 NEt) or pyridine, may be used.
• an added base such as diisopropylethylamine (DIEA) or pyridine
• DIEA diisopropylethylamine
• pyridine pyridine
• the benzyl ester of VIII -6 is removed to afford VIII -7 under standard hydrogenolysis conditions well-known to those of skill in the art.
• the benzyl ester can be saponified using aqueous base, for example, LiOH in aqueous THF, or NaOH in aqueous methanol or ethanol.
• the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HCl, to afford the carboxylic acid.
• the intermediate carboxylate salt of VIII -7 can be isolated, or a suitable salt of the carboxylic acid can be prepared by methods well-known to those of skill in the art.
• ⁇ -alanine ethyl ester hydrochloride DMAP, pyridine; b) BrCH 2 COBr, Et 3 N, CH 2 C1 2 ; c) NaH, DMF; d) Lawesson's reagent, THF, 50° C; e) CH 3 I, (n-Bu) 4 NHSO 4 , NaOH, CH 2 C1 2 , H 2 O; f) propargylamine, pyridine • HCl, toluene; g) CO, (Ph 3 P) 2 PdCl 2 , DIEA, 2-(methylaminomethyl)benzimidazole dihydrochloride, NMP; h) LiOH, THF, H 2 O.
• the reaction is generally conducted under acidic catalysis, usually with HCl, in a hydroxylic solvent, for instance methanol or ethanol.
• the Boc protecting group is removed under acidic conditions, preferably HCl/dioxane or TFA, in a suitable solvent, such as CH 2 C1 2 , to the give amine X-3.
• This reacts with 2-(2- chloroethyl)benzimidazole (X-5) in the presence of an appropriate acid scavenger, for instance diisopropylethylamine (DIEA), in a polar solvent, preferably DMF, to give the coupled product X-6.
• DIEA diisopropylethylamine
• 2-(2-Chloroethyl)benzimidazole can be prepared from 2-(2-hydroxyethyl)benzimidazole by reaction with a suitable halogenating reagent, such as thionyl chloride, or carbon tetrachloride in the presence of triphenylphosphine, in an inert solvent, for example CH 2 C1 2 .
• a suitable halogenating reagent such as thionyl chloride, or carbon tetrachloride in the presence of triphenylphosphine, in an inert solvent, for example CH 2 C1 2 .
• the ethyl ester of X-6 is removed using aqueous base, for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol.
• the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HCl, to afford the carboxylic acid X-7.
• the intermediate carboxylate salt can be isolated
• a suitably functionalized amine such as 2-(aminomethyl)benzimidazole
• 2-(aminomethyl)benzimidazole is reacted with dimethyl 4-bromomethylbenzene-l,3-dicarboxylate (XIII- 1; synthesized as in EP 0540334A1) under the general conditions described for the preparation of l-H-isoindole-5-carboxamide, 2,3-dihydro-N-(2-carboxy-ethyI)-2-[2- (piperidinyl)ethyl]-3-oxo (preparation 1-12, EPA 0 540 334 Al), to afford XIII -2.
• the methyl ester of XIII -2 is hydrolyzed using aqueous base, for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol, and the intermediate carboxylate salt is acidified with a suitable acid, for instance TFA or HCl, to afford the carboxylic acid XIII -3.
• aqueous base for example, LiOH in aqueous THF or NaOH in aqueous methanol or ethanol
• a suitable acid for instance TFA or HCl
• the carboxylic acid of XIII -3 is converted to an activated form of the carboxylic acid using, for example, EDC and HOBt, SOCl 2 , or BOP reagent, and the activated form is subsequently reacted with an appropriate amine, for instance ⁇ -alanine ethyl ester, in a suitable solvent such as DMF, CH 2 C1 2 , or CH 3 CN, to afford XIII -4.
• an added base such as diisopropylethylamine ((i-Pr) 2 NEt) or pyridine, may be used.
• XIV- 1 is treated with di-tert-butyl dicarbonate and sodium hydroxide in aqueous dioxane to afford XIV -2, which is alkylated on oxygen with benzyl bromoacetate and potassium carbonate in acetone to give XIV -3.
• the Boc group in XIV -3 is removed with hydrogen chloride in dioxane, and the resulting XIV -4 is acylated on nitrogen with 29benzimidazolyl)acetic acid, EDC and DIEA in DMF to give XIV -5.
• the benzyl ester in XIV -5 is cleaved by treatment with hydrogen and palladium-on-carbon in methanol to give XIV -6.
• XI- 1 prepared as described in Alig et. al., EPA 0372486, is condensed with a suitable substituted carboxylic acid, such (2-benzimidazolyl)acetic acid, in the presence of EDC and DIEA, and in a suitable solvent, e.g., DMF or acetonitrile.
• a suitable substituted carboxylic acid such (2-benzimidazolyl)acetic acid
• a suitable solvent e.g., DMF or acetonitrile.
• a suitable solvent e.g., DMF or acetonitrile.
• Hydrolysis of the ester is accomplished by saponification with a suitable reagent, e.g., sodium hydroxide, in a suitable solvent, e.g., aqueous methanol.
• a benzyl ester may be converted to the acid by treatment with a suitable catalyst, e.g., Pd C, and hydrogen in a suitable solvent, e.g
• the ester in XVI -2 is accomplished with trifluoroacetic acid or hydrogen chloride to give XVI -3.
• the ester in XVI -2 may be saponified with a suitable reagent, e.g., IN NaOH, in a suitable solvent, e.g., methanol.
• XVII-1 prepared as described in Sugihara, et. al., EP 0529858, is condensed with a suitable substituted carboxylic acid, such as (2-benzimidazolyl)acetic acid, to give XVII -2, and the tert-butyl ester is cleaved with TFA, following the general procedure of Sugihara, et. al., Example 59, to give XVII -3.
• a suitable substituted carboxylic acid such as (2-benzimidazolyl)acetic acid
• Compound XVIII-1 prepared as described in Himmelsbach, et. al., Australian Patent Application AU-A-86926/91, Example VI(28), is treated with a suitable substituted phenol, such as 4-[2-(benzimidazolyl)methyl]phenol, prepared by the general procedure of Wahlgren and Addison, J. Heterocycl. Chem., 1989, 26, 541-3, following the general method of Himmelsbach, et. al., Example 3(51), to give XVIII -2.
• the tert-butyl ester in XVIII -2 is hydrolyzed with IN NaOH in CH 3 OH following the general procedure of Himmelsbach, Example 7(3) to give XVIII -3.
• the tert-butyl ester may be cleaved with TFA or HCl.
• Scheme XX provides a method for the preparation of 1,2,3,4- tetrahydroisoquinoline compounds as exemplary fibrinogen receptor antagonists, as described in M. J. Fisher et al. (EP 0635492, Jan. 25, 1995). Accordingly, a 6- methoxy-3,4-dihydroisoquinoline, such as compound XX-1 is prepared by the method described by D. J. Sail and G. L. Grunewald (J. Med. Chem. 7957, 30, 2208-2216). The isoquinoline is treated with a haloacetic acid ester in the presence of a tertiary amine to afford the 2-acetic acid ester, as exemplified by compound XX-2.
• the 6-methoxy compound is converted into the corresponding 6-hydroxy compound by methods known in the art, for example with BBr 3 , which is converted into the triflate with trifluorosulfonic acid anhydride.
• Palladium catalyzed carbonylation affords the 6-carboxy compound, such as compound XX-5, which is then condensed with an amine, as exemplified by (2-benzimidazolyl)acetic acid, employing a standard amide bond forming reagent to give the desired amide, such as compound XX-6. Saponification affords XX-7.
• the palladium catalyzed carbonylation reaction with the triflate, exemplified by compound XX-4, may be trapped with said aminomethyl compound to provide, after saponification, the corresponding 6-(2-benzimidazolyl)methylaminocarbonyl compound, XX-7.
• the palladium catalyzed carbonylation reaction with the triflate exemplified by compound XXI-4, may be trapped with an amine to provide, after saponification, the amide, XXI-7.
• Scheme XXII provides a method for the preparation of 6-acylaminotetraline compounds as exemplary fibrinogen receptor antagonists, as described M. J. Fisher et al. (EP 0635492, Jan. 25, 1995). Accordingly, a 6-amino-2-tert- butyloxycarbonyl-tetral-1-one, exemplified by compound XXII-1, which is prepared according to the methods described in M. J. Fisher et al. (EP 0635492, Jan. 25, 1995), is condensed with an activated derivative of a carboxylic acid, such as the activated derivative of (2-benzimidazolyl)acetic acid, to provide, after deesterification, the amide, XXII-2.
• an activated derivative of a carboxylic acid such as the activated derivative of (2-benzimidazolyl)acetic acid
• Scheme XXIII provides a method for the preparation of 6-aminoacyltetraline compounds as exemplary fibrinogen receptor antagonists, as described M. J. Fisher et al. (EP 0635492, Jan. 25, 1995). Accordingly, an ethyloxycarbonylmethyl-6- hydroxy-tetral-1-one, exemplified by compound XXIII- 1, which is prepared according to the methods described in M. J. Fisher et al. (EP 0635492, Jan.
• triflic anhydride to provide the triflate, as exemplified by compound XXIII -2, which is employed in a palladium catalyzed carbonylation reaction to afford a carboxylic acid, such as compound XXIII -3, which is then condensed with an amine to provide, after deesterification, the 6-aminoacyl compound, XXIII -5.
• the palladium catalyzed carbonylation reaction with the triflate exemplified by compound XXIII -2 may be trapped with said amine compound to provide, after saponification, the corresponding 6-aminoacyl compound, XXIII -5.
• a 4-nitrosalicylaldehyde exemplified by compound XXIV-1
• a haloacetic acid ester to give the phenoxyacetic acid ester, exemplified by compound XXIV -2.
• a 2-alkoxycarbonylfuran exemplified by compound XXIV -3, is obtained by treating the aldehyde with base, for example with DBU.
• the 2-alkoxycarbonyl group is reduced to the aldehyde, for example with DiBAL.
• Wittig reaction affords the 2-acrylate ester, exemplified by compound XXIV -4, which is reduced to the benzofuran-2-propionic acid ester, exemplified by compound XXIV -5 and the dihydrobenzofuran-2-propionic acid ester, exemplified by compound XXIV -6.
• the amine XXIV -5 is then condensed with an activated derivative of a carboxylic acid to provide, after deesterification, the amide 5, XXIV - 8.
• the amine XXIV -6 is condensed with an activated derivative of a carboxylic acid to provide, after deesterification, the amide, XXIV -7.
• Scheme XXV provides a method for the preparation of 5- aminoacylbenzofuran and 5-aminoacyldihydrobenzofuran compounds as exemplary fibrinogen receptor antagonists, as described in M. L. Denney, et al. (EP 0655439, 31/5/95).
• a 5-hydroxybenzofuran-2-carboxylic acid ester such as compound XXVa-1, prepared in the manner of M. L. Denney, et al. (EP 0655439, 31/5/95)
• TBDMS-Cl is treated with TBDMS-Cl to provide the TBDMS derivative of the ester, XXVa-2.
• the ester is reduced to an aldehyde, such as compound XXVa-3.
• Wittig an aldehyde
• each alcohol in turn may be converted to a carboxylic acid via palladium catalyzed carbonylation, such as compound XXVb-2 or XXVc-2, which is then condensed with an amine to provide, after deesterification, the amide XXVb-4 or XXVc-4.
• palladium catalyzed carbonylation reaction with the triflate exemplified by compound XXVb- 1, or XXVc-1, may be trapped with said aminomethyl compound to provide, after deesterification, the corresponding 6-aminoacyl compound, XXVb-4 or XXVc-4.
• Amide coupling reagents as used herein denote reagents which may be used to form peptide bonds.
• Typical coupling methods employ carbodiimides, activated anhydrides and esters and acyl halides.
• Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride are typical.
• Coupling methods to form peptide bonds are generally well known to the art.
• the methods of peptide synthesis generally set forth by Bodansky et al, THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984, Ali et al. in J. Med. Chem., 29, 984 (1986) and J. Med. Chem., 30, 2291 (1987) are generally illustrative of the technique and are incorporated herein by reference.
• the amine or aniline is coupled via its free amino group to an appropriate carboxylic acid substrate using a suitable carbodiimide coupling agent, such as N,N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
• a suitable carbodiimide coupling agent such as N,N' dicyclohexyl carbodiimide (DCC)
• catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
• HABt 1-hydroxybenzotriazole
• DMAP dimethylamino pyridine
• Other methods such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in the presence of a base, are also suitable.
• a protected Boc-amino acid or Cbz-amidino benzoic acid is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran(THF), in the presence of a base, such as N-methyl morpholine, DMAP or a trialkylamine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or aniline.
• anhydrous solvent such as methylene chloride or tetrahydrofuran(THF)
• a base such as N-methyl morpholine, DMAP or a trialkylamine
• the compounds of formula (XIX) and (XX) are commercially available or are prepared by methods known in the art such as illustrated herein disclosed in standard reference books, like the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (Wiley-Interscience).
• a generally applicable route to benzimidazoles is disclosed in Nestor et al, J. Med. Chem. 1984, 27, 320.
• Representative methods for preparing compounds of formula (XX) are also common to the art and may be found, for instance, in EP-A 0 381 033.
• Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
• Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li + , Na + , K + , Ca ++ , Mg "1- * " and NH4 + are specific examples of cations present in pharmaceutically acceptable salts.
• This invention also provides a pharmaceutical composition which comprises a compound according to formula (I)-(V) and (XXI)-(XXII) and a pharmaceutically acceptable carrier. Accordingly, the compounds of formula (I)-(V) and (XXI)- (XXII) may be used in the manufacture of a medicament.
• Pharmaceutical compositions of the compounds of formula (I)-(V) and (XXI)-(XXII) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
• the liquid formulation may be a buffered, isotonic, aqueous solution.
• Suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
• Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
• these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
• Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
• Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
• Liquid carriers include syrup, peanut oil, olive oil, saline and water.
• the carrier may 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 20 mg to about 1 g per dosage unit.
• the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
• a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
• Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
• the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
• the compounds described herein are antagonists of the vitronectin receptor, and are useful for treating diseases wherein the underlying pathology is attributable to ligand or cell which interacts with the vitronectin receptor. For instance, these compounds are useful for the treatment of diseases wherein loss of the bone matrix creates pathology.
• the instant compounds are useful for the treatment of ostoeporosis, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilization or sex hormone deficiency.
• the compounds of this invention are also believed to have utility as antitumor, anti-angiogenic, antiinflammatory and anti-metastatic agents, and be useful in the treatment of atherosclerosis and restenosis.
• the compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption, or other such indication.
• the pharmaceutical composition containing the peptide is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.
• parenteral administration is preferred.
• An intravenous infusion of the peptide in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
• the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg.
• the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
• the precise level and method by which the compounds are administered is readily determined by one routinely skilled in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
• the compounds may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
• Solid-Phase ft HJ-SK&F- 107260 Binding to ⁇ v p3 Human placenta or human platelet ⁇ v ⁇ 3 (0.1-0.3 mg/mL) in buffer T (containing 2 mM CaCl2 and 1% octylglucoside) was diluted with buffer T containing 1 mM CaCl2, 1 mM MnCl2, 1 mM MgCl2 (buffer A) and 0.05% NaN3, and then immediately added to 96-well ELIS A plates (Corning, New York, NY) at 0.1 mL per well. 0.1 - 0.2 ⁇ g of ⁇ v ⁇ 3 was added per well.
• the plates were incubated overnight at 4°C. At the time of the experiment, the wells were washed once with buffer A and were incubated with 0.1 mL of 3.5% bovine serum albumin in the same buffer for 1 hr at room temperature. Following incubation the wells were aspirated completely and washed twice with 0.2 mL buffer A.
• 107260 was determined in the presence of 2 ⁇ M SK&F- 107260 and was consistently less than 1% of total radioligand input.
• the IC50 concentration of the antagonist to inhibit 50% binding of [ 3 H] -SK&F- 107260
• the Ki dissociation constant of the antagonist
• Compounds of the present invention inhibit vitronectin binding to SK&F 107260 in the concentration range of about 0.001 to 50 micromolar.
• Compounds of this invention are also tested for in vitro and in vivo bone reso ⁇ tion in assays standard in the art for evaluating inhibition of bone formation, such as the pit formation assay disclosed in EP 528 587, which may also be performed using human osteoclasts in place of rat osteoclasts, and the ovarectomized rat model, described by Wronski et al, Cells and Materials 1991, Sup. 1, 69-74.
• Rat or human aortic smooth muscle cells were used. The cell migration was monitored in a Transwell cell culture chamber by using a polycarbonate membrane with pores of 8 um (Costar). The lower surface of the filter was coated with vitronectin. Cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5 - 5.0 x 10 6 cells/mL, and were pretreated with test compound at various concentrations for 20 min at 20°C. The solvent alone 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 mL of DMEM supplemented with 0.2% bovine serum albumin.
• Incubation was carried out at 37°C in an atmosphere of 95% air/5% CO 2 for 24 hr. After incubation, the non-migrated cells on the upper surface of the filter were removed by gentle scraping. The filter was then fixed in methanol and stained with 10% Giemsa stain. Migration was measured either by a) counting the number of cells that had migrated to the lower surface of the filter or by b) extracting the stained cells with 10% acetic acid followed by determining the absorbance at 600 nM.
• Each experimental group consists of 5-6 male Sprague-Dawley rats.
• the rats are parathyroidectomized (by the vendor, Taconic Farms) 7 days prior to use. Twenty four hours prior to use, circulating ionized calcium levels are measured in whole blood immediately after it has been withdrawn by tail venipuncture into heparinized tubes. Rats are included if ionized Ca level (measured with a Ciba-Corning model 634 calcium pH analyzer) is _1.2 mM/L. The rats are then put on a diet of calcium-free chow and deionized water. At the start of the experiment the rats weigh approximately lOOg.
• Baseline Ca levels are measured and the rats are administered control vehicle (saline) or compound (dissolved in saline) as a single intravenous (tail vein) bolus injection followed immediately by a single subcutaneous injection of either human parathyroid hormone 1-34 peptide (hPTHl-34, dose 0.2mg/kg in saline/0.1% bovine serum albumen, Bachem, Ca) or the PTH vehicle.
• hPTHl-34 human parathyroid hormone 1-34 peptide
• the calcemic response to PTH is measured 2h after compound/PTH administration.
• Each experimental group consists of 8-10 male Sprague-Dawley or Wistar rats of approximately 30-40g body weight at the start of the experiment.
• the agent being tested is administered by an appropriate route as single or multiple daily doses for a period of seven days.
• the rats Prior to administration of the first dose, the rats are given a single dose of a fluorescent marker (tetracycline 25mg/kg, or calcein lOmg/kg) that labels the position of bone forming surfaces at that point in time.
• a fluorescent marker tetracycline 25mg/kg, or calcein lOmg/kg
• the rats are killed and both forelimbs are removed at the elbow, the foot is removed at the ankle and the skin removed.
• the sample is frozen and mounted vertically on a microtome chuck.
• the rate of bone resorption is measured morphometrically in the medial-dorsal portion of the cortical bone. The measurement is done as follows: the amount of bone resorbed at the periosteal surface is equal to the distance by which the periosteal surface has advanced towards the fluorescent label which had been incorporated at the endosteal bone formation surface on day zero; this distance is calculated by subtracting the width of bone between the label and the periosteal surface on day 7 from the width on day zero; the reso ⁇ tion rate in microns per day is calculated by dividing the result by 7.
• Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, are removed from their stock bottle and placed into 5 ml of fresh medium (this washes away the toxic azide preservative). The medium is removed by immobilizing the beads on a magnet and is replaced with fresh medium.
• the beads are mixed with the cells and the suspension is incubated for 30 mins on ice. The suspension is mixed frequently.
• the bead-coated cells are immobilized on a magnet and the remaining cells (osteoclast-rich fraction) are decanted into a sterile 50 ml centrifuge tube.
• Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process is repeated xlO. The bead-coated cells are discarded.
• the osteoclasts are enumerated in a counting chamber, using a large-bore disposable plastic pasteur to charge the chamber with the sample.
• the cells are pelleted by centrifugation and the density of osteoclasts adjusted to l ⁇ xl ⁇ /ml in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate.
• the slices are washed in six changes of warm PBS (10 ml / well in a 6-well plate) and then placed into fresh treatment or control. Incubate at 37°C for 48 hours.
• TRIP Tartrate resistant acid phosphatase
• the slices are washed in phosphate buffered saline and fixed in 2% gluteraldehyde (in 0.2M sodium cacodylate) for 5 mins.
• the TRAP positive osteoclasts are enumerated by bright-field microscopy and are then removed from the surface of the dentine by sonication.
• Resorption assay (with ELISA readout) Enriched preparations of osteoclasts are preincubated for 30 minutes at 37°C with test compound (4 doses) or controls. They are then seeded onto bovine cortical bone slices in wells of a 48-well tissue culture plate and are incubated for a further 2 hours at 37°C. The bone slices are washed in six changes of warm phosphate buffered saline (PBS), to remove non-adherent cells, and are then returned to wells of a 48 well plate containing fresh compound or controls. The tissue culture plate is then incubated for 48 hours at 37"C.
• PBS warm phosphate buffered saline
• the supernatants from each well are aspirated into individual tubes and are screened in a competitive ELISA that detects a collagen peptide that is released during the reso ⁇ tion process.
• a competitive ELISA that detects a collagen peptide that is released during the reso ⁇ tion process.
• This is a commercially available ELISA (Osteometer, Denmark) that contains a rabbit antibody that specifically reacts with an 8-amino acid sequence (Glu-Lys-Ala-His- Asp-Gly-Gly- Arg) that is present in the carboxy-terminal telopeptide of the ⁇ l -chain of type I collagen.
• the results are expressed as % inhibition of reso ⁇ tion compared to a vehicle control.
• Osteoclastoma-derived osteoclasts are preincubated with compound (4 doses) or controls at 37°C for 30 minutes. The cells are then seeded onto osteopontin-coated slides (human or rat osteopontin, 2.5ug/ml) and incubated for 2 hours at 37"C. Non adherent cells are removed by washing the slides vigorously in PBS and the cells remaining on the slides are fixed in acetone. The osteoclasts are stained for tartrate- resistant acid phosphatase (TRAP), a selective marker for cells of this phenotype, and are enumerated by light microscopy. The results are expressed as % inhibition of adhesion compared to a vehicle control. Inhibition of RGD-mediated GPIIb-HIa binding
• the column was washed with 50 mL cold buffer A.
• the lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were performed at 4°C.
• the GPIIb-IIIa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis.
• a mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) were 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 in a proteimphospholipid ratio of 1:3 (w:w). The mixture was resuspended and sonicated in a bath sonicator for 5 min.
• the mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes).
• the GPIIb-IIIa-containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg/mL. The liposomes were stored at -70C until needed.
• the binding to the fibrinogen receptor (GPIIb-IIIa) was assayed by an indirect competitive binding method using [ 3 H]-SK&F- 107260 as an RGD-type ligand.
• the binding assay was performed in a 96-well filtration plate assembly (Millipore Co ⁇ oration, Bedford, MA) using 0.22 um hydrophilic durapore membranes.
• the wells were precoated with 0.2 mL of 10 ⁇ g/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room temperature for 1 h to block nonspecific binding.
• Various concentrations of unlabeled benzadiazapines were added to the wells in quadruplicate.
• [ 3 H]-SK&F- 107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 ⁇ g of the purified platelet GPIIb-IHa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPIIb-IIIa-bound [3H]-SK&F- 107260 was seperated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 times, each 0.2 mL).
• 007260 with a Ki at the vitronectin receptor that is about ten-fold greater than that for the fibrinogen receptor.
• Preferred compounds have a Ki at the vitronectin receptor that is thirty-fold greater than that at the fibrinogen receptor.
• the most preferred compounds have a Ki at the vitronectin receptor that is a hundred-fold greater than that at the fibrinogen receptor.
• Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
• CDCI3 is deuteriochloroform
• DMSO-d ⁇ is hexadeuteriodimethylsulfoxide
• CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million ( ⁇ ) downfield from the internal standard tetramethylsilane.
• ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 ⁇ Apex- ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 ⁇ , made by Jones Chromatography, Littleton, Colorado.
• YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan.
• PRP-1® is a polymeric (styrene- divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada)
• Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Co ⁇ ., Denver, Colorado.
• Trifluoromethanesulfonic anhydride (1.4 mL, 8.4 mmole) was added rapidly dropwise to a solution of ethyl 4-(4-hydroxyphenyl)-3-phenylbutanoate ( 1.84 g, 6.47 mmole) and 2,6-lutidine (1.5 mL, 12.9 mmole) in anhydrous CH 2 C1 2 (32 mL) at - 78°C under argon. After 0.5 hr, the yellow solution was warmed to RT and stirred for 1 hr.
• Trifluoromethanesulfonic acid (0.18 mL, 2 mmole) was added dropwise to a mixture of 4-bromobenzoic acid (20.10 g, 100 mmole), anhydrous CH 2 C1 2 (100 mL), and condensed isobutylene (-78°C; 100 mL), and the resulting mixture was allowed to reflux under a dry ice/acetone condenser. After 40 min, more isobutylene (30 mL) was added, and reflux was continued for an additional 20 min.
• Methyl ( ⁇ )-2,3,4,5- tetrahydro-7-[[[(benzimidazol-2-yl)methyl]amino]carbonyl]-4-methyl-3-oxo-lH- 1 ,4-benzodiazepine-2-acetate (0.82 g, 1.9 mmole) was suspended in MeOH (2 mL) and THF (15 mL) and added dropwise to the above solution. The reaction was then stirred at 45°C for 24 h. The mixture was concentrated in vacuo, and was then treated with 10% CH-CN/H.O containing 0.1% TFA (5 mL). All material dissolved, and then a solid precipitated out.
• tert-Butyl 3-[(2,2,2-trifluoroethyl)amino]methyl-4-nitrobenzoate tert-Butyl 3-bromomethyl-4-nitrobenzoate (2.4 g, 8 mmol) was dissolved in dry THF (50 mL), and 2,2,2-trifluoroethylamine (3 mL, 38 mmol) was added all at once. The orangish-yellow solution was stirred at RT for 40 min, then was concentrated to remove the THF. The residue was diluted with E-2O (100 mL) and washed twice with 10 % aqueous Na 2 CO 3 (50 mL) and brine (50 mL).
• N-[[2-(N-4-hydroxybut-l-yl)aminomethyl-4-tert-butoxycarbonyl]phenyl]-L- aspartic acid ⁇ -methyl ester A mixture of N-[[2-formyl-4-tert-butoxycarbonyl]phenyl]-L-aspartic acid ⁇ - methyl ester (WO 95/18619; 2.55g, 7.26 mmol), 4A molecular sieves, and 4- hydroxybutylamine (0.64 g, 7.26 mmol) in MeOH (35 mL) was stirred under argon at RT for 30 min, then sodium cyanoborohydride (0.49 g, 0.79 mmol) and acetic acid (0.3 mL) were added.

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