AU2013201895B2 - Hypophosphorous acid derivatives and their therapeutical applications - Google Patents

Hypophosphorous acid derivatives and their therapeutical applications Download PDF

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AU2013201895B2
AU2013201895B2 AU2013201895A AU2013201895A AU2013201895B2 AU 2013201895 B2 AU2013201895 B2 AU 2013201895B2 AU 2013201895 A AU2013201895 A AU 2013201895A AU 2013201895 A AU2013201895 A AU 2013201895A AU 2013201895 B2 AU2013201895 B2 AU 2013201895B2
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formula
derivatives
alkyl
cooh
group
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AU2013201895A1 (en
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Francine Acher
Hugues-Olivier Bertrand
Jean-Philippe Pin
Chelliah Selvam
Nicolas Triballeau
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Centre National de la Recherche Scientifique CNRS
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

HYPOPHOSPHOROUS ACID DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS Abstract Hypophosphorous acid derivatives having Formula (I) wherein M is a [C(R3,R4)]nl - C(E,COOR1, N(H, Z)) group, or an optionally substituted o Ar-CH(COOR1, N(H, Z)) group, or an a, B, or a 3, g-cyclic aminoacid; . R1 is H or R, IR- R being an hydroxy or a carboxy protecting group; . Z is H or an amino protecting group 2 - P-M R', benzyl oxycarbonyl, benzyl or benzyl substituted; . E is H or a C1-C3 alkyl, aryl, an hydrophobic group;. R2 is selected in the group comprising: D-CH(R)- C-(R7 , Rs), OH (Rt,R12)CH- C(R9, Rio), D - CH(OH), D- [C(R13, R14)] 3 -, C[(R15, R16, R17)]. 4, D-CHz, (Ri8)CH = C(R19), D-(Mi), 6 -CO, Formula (II), PO(OH)2-CH2 or (PO(OH) 2-CH2), (COOH-CH2 )-CH 2 , with - D = H, OH, OR, (CH 2 ),2OH, (CHL2 ). 1 OR, COOH, COOR, (CH2).ZCOOH, (CHI2) 1COOR, SR, S(OR), SO2R, NO2 , heteroaryl, C1-C3 alkyl, cy cloalkyl, heterocycloalkyl, (CH2), 2-alkyl, (COOH, NH2)-(CH 2)ui-cyclopropyl-(CH2)1 -, CO-NH-alkyl, Ar, (CH2). 2-Ar, CO-NI-Ar; - R3 to Rig being H, OH, OR, (CH2),2OH, 0 (CH2 ).1OR, COOH, COOR, (CHz),COOH, (CH2) 1COOR, CI-C 3 alkyl, cycloalkyl, (CH2)nl-alkyl, aryl, (CHz)nt-aryl, halogen, CF3, S03H, (CH2)x PO3 H2, with x = 0, 1 or 2, B(OH) 2 , Formula (III), NO2 , SO 2NH 2 , SO2NHR; SR, S(O)R, SO 2R, benzyl; - M1 is an alkylene or arylene group; - nl= 1, 2 or 3, n2= 1, 2 or 3, n3= 0, 1, 2 or 3 and n4- 1, 2 or 3, n5= 1,2 or 3, n6= 0 or 1, u1 and u2, identical or different = 0,1 or 2, with the proviso that Formula (I) does not represent the racemic (3R, S) and the enantiomeric form (3R) of 3 amino,3-carboxy-propyl-2'-carboxy-ethylphosphinic acid; 3 N-N amino,3-carboxy-propyl- 4'carboxy,2'carboxy-butanoylphosphinic acid; 3 amino,3-car boxy-propyl- 2'carboxy-butanoylphosphinic acid; 3 amino,3-carboxy-propyl- amino, 3'carboxy-propylylphosphinic acid; and 3 anino,3-carboxypropyl -7'amino-2', 7-dicarboxyheptylphosphinic acid, said hypophosphorous acid derivatives being diasteroisomers or enantiomers. Application as drugs.

Description

1 Hypophosphorous acid derivatives and their therapeutical applications The invention relates to hypophosphorous acid derivatives having agonist or antagonist properties for metabotropic glutamate receptors (mGluRs), in particular agonist or antagonist properties for group III, subtype 4, metabotropic glutamate receptors (mGlu4Rs) and their therapeutical applications. MG1uRs are of particular interest in medicinal chemistry because they are believed to be suitable targets for treating a large variety of brain disorders such as convulsions, pain, drug addiction, anxiety disorders, and several neurodegenerative diseases. The eight known subtypes of mGluRs are classified into three groups. Group III contains subtypes 4 and 6-8. Mainly located presynaptically, where they act as autoreceptors, group III mGluRs decrease adenylyl cyclase activity via a G 11 1o protein and are specifically activated by L-AP4. Among this group, mGlu4R is thought to be a possible new target for Parkinson's disease, but the lack of a highly specific agonist has seriously impaired target validation studies. Furthermore, despite many chemical variations around the structure of glutamate, L-AP4 remains the strongest mGlu4R agonist with an EC 50 of only 0.32 pM and its a-methyl analogue, a competitive antagonist with an IC 50 of 100pm. New chemotypes of higher potency and specificity are to be found. The inventors' researches in that field lead them to develop methods of synthesis of hypophosphorous acids making it possible to obtain a large number of valuable agonists or antagonists for mGlu4Rs, particularly analogs of 3-amino-carboxy-propyl-2'-carboxy ethylphosphinic acid (PCEP in short), with improved activity and selectivity compared to PCEP and valuable antagonists corresponding to the a-substituted derivatives thereof. An object of the invention is then to provide new hypophosphorous acid derivatives, particularly having agonist or antagonist properties for group III mGluRs. Another object of the invention is to provide new methods of synthesis of biologically active hypophosphorous acid derivatives with a large variety of substituents. According to still another object, the invention takes advantage of the mGlu4Rs agonists or antagonist properties of the hypophosphorous acid derivatives thus obtained and aims to provide pharmaceutical compositions useful for treating brain disorders.
2 The hypophosphorous acid derivatives of the invention are diasteroisomers or enantiomers of formula (I) 0 R2- P-M II OH (Jy) wherein . M is a [C(R 3
,R
4 )]ni - C,(E,COOR 1 , N(H, Z)) group, or an optionally substituted Ar-CE,(COORI, N(H, Z)) group (Ar designating an aryl or an heteroaryl group), or an a, p cyclic aminoacid group such as , [C(R 3 , R 4 )]
CO
2 R, N(H, Z) or a P, y-cyclic aminoacid group such as C(E, COOR,, N(H, Z)) . R 1 is H or R, R being an hydroxy or a carboxy protecting group, such as C 1
-C
3 alkyl, Ar (being aryl or heteroaryl), . Z is H or an amino protecting group R', such as C 1
-C
3 alkyl, C 1
-C
3 acyl, Boc, Fmoc, COOR, benzyl oxycarbonyl, benzyl or benzyl substituted such as defined with respect to Ar; .E is H or a C1-C3 alkyl, aryl, an hydrophobic group such as (CH 2 )ni-alkyl, (CH 2 )ni-aryl (or heteroaryl), such as a benzyl group, or a xanthyl, alkyl xanthyl or alkyl thioxanthyl group, or - (CH 2 )ni-cycloalkyl, -(CH 2 )n-(CH 2 -Ar) 2 , a chromanyl group, particularly 4-methyl chromanyle, indanyle, tetrahydro naphtyl, particularly methyl-tetrahydronaphtyl;
R
2 is selected in the group comprising:
D-CH(R
6 )- C-(R 7 , Rs) (R 11
,R
12 )CH- C(R 9 , Rio) D - CH(OH) D- [C(R 1 3 , R 1 4 )]n 3 C[(Ri 5 , R 16 , R 17 )]n 4 D-CH 2 (Ris)CH = C(R 19 ) D)-(M 1 )-r-C) 3 0
PO(OH)
2
-CH
2 or (PO(OH) 2
-CH
2 ), (COOH-CH 2
)-CH
2 with - D = H, OH, OR, (CH 2 )n 2 OH, (CH 2 )n 1 OR, COOH, COOR, (CH 2 )n 2 COOH, (CH 2 )n 1 COOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 1
-C
3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 -alkyl, (COOH, NH 2
)-(CH
2 )ui-cyclopropyl-(CH 2
).
2 -, CO-NH-alkyl, Ar, (CH 2 )n 2 -Ar, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, - R 3 to R 19 , identical or different, being H, OH, OR, (CH 2 )n 2 OH, (CH 2 )n 1 OR, COOH, COOR,
(CH
2 )n 2 COOH, (CH 2 )niCOOR, CI-C 3 alkyl, cycloalkyl, (CH 2 )ni-alkyl, aryl, (CH 2 )ni-aryl, N-N halogen, CF 3 , SO 3 H, (CH 2 )x P03H 2 , with x = 0, 1 or 2, B(OH) 2 , , NO 2 , SO 2
NH
2 ,
SO
2 NHR; SR, S(O)R, SO 2 R, benzyl; one of RI, or R 1 2 being COOR, COOH, (CH 2 )n 2 -COOH, (CH 2 )n 2 -COOR, P03H 2 the other one being such as defined for R 9 and RIO; - one of R 15 , R 16 and R 17 is COOH or COOR, the others, identical or different, being such as above defined; - one of R 18 and R 19 is COOH or COOR, the other being such as above defined; - M 1 is an alkylene or arylene group; - nl= 1, 2 or 3; - n2= 1, 2 or 3, - n3= 0, 1,2 or 3 and -n4= 1, 2 or 3; -n5= 1,2 or 3; - n6= 0 or 1, - ul and u2, identical or different = 0,1 or 2, Ar, and alkyl groups being optionally substituted by one or several substituents on a same position or on different positions, said substituents being selected in the group comprising: OH, OR, (CH 2 )n 1 OH, (CH 2 )n 1 OR, COOH, COOR, (CH 2
),
1 COOH, (CH 2 )niCOOR, C 1
-C
3 4 alkyl, cycloalkyl, (CH 2 )n-alkyl, aryl, (CH 2 )nI-aryl, halogen, CF 3 , SO 3 H, (CH 2 )x P0 3
H
2 , with N-N x = 0, 1 or 2, B(OH) 2 , , NO 2 , SO 2
NH
2 , SO 2 NHR; SR, S(O)R, SO 2 R, benzyl; R being such as above defined, with the proviso that formula I does not represent the racemic (3R, S) and the enantiomeric form (3R) of 3 amino,3-carboxy-propyl-2'-carboxy-ethylphosphinic acid; 3 amino,3-carboxy propyl- 4'carboxy,2'carboxy-butanoylphosphinic acid; 3 amino,3-carboxy-propyl- 2'carboxy butanoylphosphinic acid; 3 amino,3-carboxy-propyl- 3'amino, 3'carboxy-propylylphosphinic acid; and 3 amino,3-carboxypropyl -7'amino-2', 7'-dicarboxyheptylphosphinic acid.. In the above defined hypophosphorous acid derivatives of the invention, D is preferably Ar (optionally substituted), Ar-(CH 2 )n 2 (with Ar optionally substituted), C-C 3 alkyl or cycloalkyl ; alkyl - (CH 2 )n 2 , or COOH. Preferably Ar is a phenyl group (optionally substituted) or a carboxyalkyl group (optionally substituted). Alternatively, Ar is an heterocyclic group (optionally substituted). Advantageous groups are thiophenyl or furanyl group (optionally substituted). A first preferred family corresponds to hypophosphorous acid derivatives of formula (II) 0 - D-CH(R)-C-(R 7 , R OH (II) wherein the substituents are as above defined. In particularly preferred derivatives of this family, D is Ar or a substituted Ar, especially a phenyl group optionally substituted by 1 to 5 substituents. The substituents are in ortho and/or meta and/or para positions. Preferred substituents comprise: OH, OR, (CHA 2
)
2 OH,
(CH
2 )n20R, COOH, COOR, (CH 2 )n2COOH, (CH 2 )n2COOR, Cl-C3 alkyl or cycloalkyl,
(CH
2 )n 2 -alkyl, aryl, (CH 2 )n 2 -aryl, halogen, CF 3 , SO 3 H, P0 3
H
2 , B(OH) 2 alkylamino, fluorescent N-N group (dansyl, benzoyl dinitro 3, 5, N , NO 2 , SO 2
NH
2 , SO 2 (NH,R) SR, S(O)R,
SO
2 R, OCF 3 , heterocycle, heteroaryl, substituted such as above defined with respect to Ar. Adonntno-nlv R, qnd/nr R, qnd/nr R o aI R 2.. lvl ON CT, NN, 5 0
(R
11 , R 12 )CH-C(R, R 1 )-P-M OH (III) wherein the substituents are as above defined. In preferred derivatives, one of Ru 1 or R 12 is COOH. Advantageously, the other one of R 11 or R 1 2 , and/or R 9 and/or Rio are H, C 1
-C
3 alkyl, OH,
NH
2 , CF 3 . A third preferred family corresponds to hypophosphorous acid derivatives of formula (IV) 0 D-CH(OH)-P-M OH (IV) wherein the substituents are as above defined. In preferred derivatives, D is as above defined with respect to formula (II) In a fourth preferred family, the hypophosphorous acid derivatives have formula (V) 0 D-- (R, R 14 ) -P-M OH (V wherein the substituents are as above defined, one of R 13 or R 14 representing OH. In preferred derivatives, D is as above defined with respect to formula (II). The substituent R13 or R1 4 which does not represent OH is advantageously H, C 1
-C
3 alkyl, OH, CF 3 , NH 2 . In a fifth preferred family, the hypophosphorous acid derivatives have formula (VI) 0 C(R~e R~e R) --
-
LCR15' R 1 6 , R 1 7 ) p-M . n4 OH (VI) wherein the substituents are as above defined. In preferred derivatives, in the first group of the chain, one or two of R 15 , R 16 or R 17 are COOH, the other(s) advantageously beine H. C 1 -Ci alkvl. OH. NH, CF 2 0 D-CHF--P-M OH (VII) wherein the substituents are as above defined. In preferred derivatives, D is as above defined with respect to formula (II). In a seventh family, the hypophosphorous acid derivatives have formula (VIII) 0
(R
1 )CH=C(Rj)-P M OH (VIII) wherein the substituents are as above defined. In preferred derivatives, R 18 is COOH. Advantageously, R 19 is H, C-C 3 alkyl, OH. An eighth family corresponds to hypophosporous acid derivatives of formula (LIX) 0 D M, CO-P-M OH (LIX) wherein the substituents are as above defined. In preferred derivatives, either n6= 0, or n6= 1 and M 1 is an alkylene or arylene group such as above defined. In a preferred embodiment of the invention, M is a [C(R 3
,R
4 )],i -C (E, COOR 1 , N (H,Z)) group, in the above defined hypophosphorous acid derivatives. Preferably R 3 and/or R 4 are H and n1=1 or 2, more preferably 2. In another preferred embodiment, M is an Ar group or a substituted arylene group, particularly a C 6 11 4 group or a substituted C 6 11 4 group, the substituents being as above defined with respect to formula I.
7 In still another embodiment, M comprises a cyclic aminoacid group, particularly, M is an a, p C(Ra1 R4) CO2R1 n12\ cyclic aminoacid group such as N(H, Z) or a P, y-cyclic aminoacid group such as C(E, COOR,, N(H, Z)) The invention particularly relates to the above mentioned derivatives wherein E represents H, which are group III mGluR agonists, and more particularly mGlu4R agonists of great interest. The invention also particularly relates to the above mentioned derivatives wherein E is different from H and is more especially a Cl -C3, alkyl, an aryl, an hydrophobic group such as a (CH 2 )ni - alkyl group, or a (CH2)ni-aryl group, as above defined, particularly a benzyl group, or a methylxanthyl group or alkylxanthyl or alkylthioxanthyl. Advantageously, such derivatives are valuable mGluR antagonists, particularly mGlu4 antagonists. The invention also relates to a process for preparing hypophosphorous acid derivatives of formula I 0 11 R2--OHM wherein the substituents are as above defined. According to method A), said process comprises al) treating a derivative of formula (IX) 0 i+-M with either trimethylsilylchloride (TMSCl) and triethylamine (Et3N), or N,O-(bis triethylsilyl)acetamide (BSA), (Et representing a C 2 Hs group). a2) adding to the reaction product one of the following derivatives having, respectively, formula X: D-C(R 6 )= C(R 7 , Rs), or formula XI: (Ru,R1 2 )C= C(R 9 , Rio) formula XII: 0 formula XIII: D - CH(=O) formula XIV: D- [C(R 13 , R 14 )]1 3 - Br formula XV: [C(R 15 , R 1 6 , R 17 )]n 4 - Br formula XVI: D - I formula XVII: (Ri 8 )C C(R 19 ) a3) treating the reaction product under acidic conditions or with catalysts to obtain the final desired product; a4) recovering the diastereoisomers or the enantiomer forms, a5) if desired, separating diastereoisomers, when obtained, into the enantiomers. According to method B, said process comprises b 1) treating a derivative of formula (XVIII) (R"SiO) 2 - P-H (XVIII) wherein R" is a C 1
-C
3 alkyl . with either a derivative of formula (X) D - C (R 6 )= C(R?, R 8 ) (X) or with a derivative of formula (XI) (R 1
,R
12 )C= C(R 9 , Rio)
(XI)
9 wherein one of R 9 or Rio is COOalk, alk being a CI-C 3 alkyl b2) treating the condensation product with a dibromo derivative of formula (XIX) Br - [C(R 3
,R
4 )]ni- Br (XIX) under reflux conditions; and adding HC(Oalk) 3 wherein alk is a C1-C3 alkyl b3) treating the condensation product with a derivative of formula (XX)
NH(Z)-CH(CO
2
R)
2 (XX) in the presence of K 2 C0 3 , BuO 4 NBr, under reflux conditions; b4) treating the condensation product under acidic conditions or with catalyts to obtain the final desired product; b5) recovering the diastereoisomers or the enantiomer forms, and b6) if desired, separating diastereoisomers, when obtained, into the enantiomers. Alternatively, the reaction product obtained at step bI) is reacted according to step b2i), with a derivative of formula (XXI)
[(R
3 , R 4
)C]
1 = C (COOR 1 , NH(Z)) (XXI) In step b3i), the reaction product is treated under acidic conditions to give the final desired product. According to method C, said process comprises c1) reacting, as defined in step al), a derivative of formula (XXII) 0 H-P-Ar--T OH (XXII) wherein Ar is as above defined and preferably an optionally substituted C 6
H
4 group and T cz) carrying out reacuon step az) oy using one or tne aerivatives or tormula (X) to (x vii) 10 c3) treating the reaction product with NBS, AIBN to have bromo derivatives with Ar substituted by T'-Br, with T'= CH2 c4) reacting the bromo derivative thus obtained with (CH) 6
N
4 in an organic solvent, then AcOH/H 2 0 to obtain cetone derivatives with Ar substituted by-C=O; c5) treating the cetone derivatives with KCN, NH 4 Cl and NH 4 0H to obtain aminocyano derivatives, with Ar substituted by -C (CN, NH 2 ), c6) treating under acidic conditions to obtain derivatives with Ar substituted by -C (COOR, NH 2 ), and c7) treating with catalysts to obtain the final desired product. In method A, according to a preferred embodiment . the use of derivatives of formula (X)
D-CH(R)=C(R
7 , R 8 ) (X) with derivatives of formula (IX) results, in step a2), in intermediate derivatives of formula (XXIII) 0 D-CH(R 6)-C(R 7, R8)- H---C(R 3, R4)ln CH(COOR1, NH(Z)) OH (XXIII) and, in step a3), in a final product of formula (XXIV) 0 D-CH(R )-C(Ry, R )--- C(R 3 , R 4 )1-CH(COOH, NH 2 ) OH (XXIV) . the use of derivatives of formula (XI) or formula (XII) (Rn 1
,R
12 )C= C(R 9 , Rio)
(XI)
11 O (XII) results, in step a2), in intermediate derivatives of formula (XXV) 0 11 (R, R2CH-( R,R,')C- -- C(R3, R4)]CH(COORJ,,NH(Z)) OH (XXV) and, in step a3), in a final product of formula (XXVI) 0 11
(R
1 , R 12 )CH--(Rg, R~O)C-P--[C(R, R 4 )] CH(COOH, NH 2 ) OH (XXVI) the use of derivatives of formula (XIII) D-CH (=0) (XIII) results, in step a2), in intermediate derivatives of formula (XXVII) 0 11 D-C(OH)- -[C(R 3 , R 4 )1-CH(COOR,, NH(Z)) OH (XXVII) and, in step a3), in a final product of formula (XXVIII) O D--C(OH)- P-C(R3, R4)]-CH(COOH, NH2) OH
(XXVIID
12 the use of derivatives of formula (XIV) D- [C(R 13 , R 14
)]
3 - Br (XIV) results, in step a2), in intermediate derivatives of formula (XXIX) 0
D-[C(R
1 3 , R4) C(R 3 , R 4 )]-CH(COOR,, NH(Z)) (XXIX) and, in step a3), in a final product of formula (XXX) 0 Il
D-[C(R
1 3 , R 1 4 )]- H C(R 3 , R 4 )]-CH(COOH, NH 2 ) (XXX) the use of derivatives of formula (XV) [C(Ri 5 , R 1 6 , R 17 )]n 4 - Br (XV) results, in step a3), in intermediate derivatives of formula (XXXI) 0
C(R
5 , R 1 , R ) P-[C(Ra, R 4 )]-CH(COOR,, NH(Z)) M H (XXXI) and, in step a3), in a final product of formula (XXXII) 0 C(R, R, R 7 ) 4 P-[-C(R 3 , R 4 )]-CH(COOH, NH 2 ) 15, 16, 7) - P - 2 13 the use of derivatives of formula (XVI) D-I (XVI) results, in step a2), in intermediate derivatives of formula (XXXIII) 0 D-CHg--- [C(R3, R4)]-CH(COOR,, NH(Z)) OH (XXXIII) .and, step a3), in a final product of formula (XXXIV) 0 11 D-CH -- -- [C(R,, R 4 ){ CH(COOH, NH 2 ) OH (XXXIV) . the use of derivatives of formula (XVII) (Ri8)C=C(R19) (XVII) results, in step a2), in intermediate derivatives of formula (XXXV) 0 (R1)-CH==C(R,)-- H---C(RR 4 )] CH(COOR,, NH(Z)) (XXXV) and, in step a3), in a final product of formula (XXXVI) 0
(R
1 ,)-CH=C(R,,)----[C(R, R 4 )1-CH(COOH, NH 2 )
(XXXVI)
14 the use of derivatives of formula (LIX) 0 D- M 1 CHOH---M-CH(COOH,
NH
2 ) OH (LIX) wherein M 1 is as above defined with respect to M and n6= 0 or 1, and results by oxidation in a product of formula (LXI) 0 D-( M CO-P- M-CH(COOH,
NH
2 ) OH (LXI) In method B, . the use, with derivatives of formula (XVIII), (R"SiO) 2 - P-H (XVIII) of derivatives of formula (X)
D-CH(R
6
)-C(R
7 , R.) (X) results, in step b 1), in intermediate derivatives of formula (XXXVII)
D-CH(R
6 )-C (R 7 ,Rs)-P-(OSiR") 2 (XXXVII) in step b2), in intermediate derivatives of formula (XXXVIII) 0
D-CH(R
6
)-C(R
7 , R8)- C(R 3 , R 4 ) -Br OR"
(XXVTTT)
15 in step b3), in intermediate derivatives of formula (XXXIX) 0 NHZ D-CH(R )--C(Ry, R8)- C(R 3 ,--CO2 R 6) 7 -I 31 R4. n 1
CO
2 R (XXXIX) and, in step b4), in a final product of formula (XXXX) 0
D-CH(R
6
)--C(R
7 , R8)-PI C(R 3 , R 4 ) -C(COOH, NH 2 ) OH (XXXX) the use, with derivatives of formula (XVIII), of derivatives of formula (XI)
(R
11
,R
12 )C= C(R 9 , Rio) (XI) results, in step b 1), in intermediate derivatives of formula (XXXXI) (Rn 1 , R 12
)CH-C(R
9 , Rio)-P-(OSi R") 2 (XXXXI) in step b2), in intermediate derivatives of formula (XXXXII) 0 (R,,, R12)CH-C(Re, Rjo)-P -- C(R3, R4)]--Br I w OR (XXXXII) in step b3), in intermediate derivatives of formula (XXXXIII) o NHAc III
(R
1 , R 2 )CH-C(R., R,,)-P-- - R OH CO 2 R
(YYYYTTT
16 in step b4), in final products of formula (XXXXIV) 0
(R
1 ,, R 1 2 )CH-CH-C(R, Rl,)-P C(R 3 , R4) -- C(COOH, NH 2 ) OH (XXXXIV) or, alternatively, . the use with derivatives of formula (XXXXI) obtained according to step b1)
(R
1 1 , R 1 2
)CH-C(R
9 , Rio)-P-(OSi R") 2 (XXXXI) of derivatives of formula (XXXXV) (R3, R 4 ) C =C (COOR 1 , NH(Z) (XXXXV) results in intermediate derivatives of formula (XXXXVI) 0 (R,, R 1 2 )CH-C(R, RIO)-P C(R 3 , R4) -C(COOR, NHZ) OH (XXXXVI) the treatment under acidic conditions giving the final product of formula (XXXXVII) 0 (RW, R 12 )CH-P
C(R
3 , R 4 ) C(COOH,
NH
2 ) n i OH (XXXX VII) 17 In method C, the use, of a derivative of formula (XXII), 0 |1 H-P-Ar-T OH (XXII) with a derivative of formula X: D-C(R 6 )= C(R 7 , R 8 ), or formula XI: (R 1 1
,R
12 )C= C(Rg, Rio) formula XII: O formula XIII: D - CH(=0) formula XIV: D- [C(R 1 3 , R 14 )]n 3 - Br formula XV: [C(R 1 5 , R 16 , R 17 )]n 4 - Br formula XVI: D - I formula XVII: (Ri 8 )C = C (R 19 ) results in intermediate derivatives respectively having formulae (XXXXVIII) to (LIV) 0
D-CH(R)--C-(R
7 , R,)-P--Ar- T OH (XXXXVIII) 0 (R,,, R 1 )CH-C(Rg, Rjo)-P---Ar-T 18 0 D- CH(OH)-P---Ar--T OH (L) 0 D- C(R, R 4 ) P-Ar--T OH (LI) 0 C(R15, R1, R )7Ar-T IC ~ n4I OH (LII) 0 D-CH -P--Ar-T 2 1 OH (LIII) 0
(R
1 )CH=C(R,)---Ar-T OH (LIV) In method A, the derivatives of formula IX H-- C(R 3 , R 4 ) -CH(COOR,, NH(Z)) . . n1 19 0 OH (LV) with a derivative of formula LVI
(R
3 , R 4 )n 1
C=CH-C(E,COOR
1 , NH(Z)) (LVI) Preferably, the derivative of formula (LVI) is Z-vinyl-glyOMe or a derivative thereof with E different from H, E being as above defined, and has formula (LVIa). MeO 0 CbzNE Cbz = carbobenzoxy Cbz-L-a-akylvinylglycine methyl ester Z-vinyl-glyOMe is advantageously synthesized from methionine or glutamate according to references (1), (2) or (3). Z-vinyl-glyOMe derivatives with E different from H can be prepared from c-alkyl methionine or alpha alkyl glutamate (see reference 4). Alpha amino acids can be stereoselectively c alkylated using imidazolinones or oxazolidinones (references 5 and 6). Other methods for obtaining Z-vinyl-glyOMe derivatives are given in Example 9. The reaction is advantageously carried out in the presence of AIBN by heating above 50'C - 100*C, preferably at about 80*C. In method B, the derivatives of formula (XVIII) (R"SiO) 2 - P-H (XVIII) are advantageously obtained by reacting an hypophosphorous acid ammonium salt of formula
(LVII)
20 0 H-P--H 0~
NH
4 + (LVII) with a disilazane derivative of formula (LVIII) (alk 3 Si) 2 -NH (LVIII) The reaction is advantageously carried out under an inert gas, by heating above 1004C, particularly at about 120*C, or by reacting hypophosphorous acid with N,O-(bis-triethylsilyl)acetamide (BSA) at room temperature. In method C, the derivatives of formula (XXII) 0 H-P-Ar-T IH OH (XXII) are advantageously obtained by reacting a mixture of H 3
PO
2 , Ar-NH 2 , Ar-Br and a catalyst Pd(O) Ln. (Ln=n ligands). According to method D, intermediate derivatives of formula O H- C(R 3 , R 4 ) / C0 2 R N(H, Z) are prepared as disclosed in example 8. The hypophosphorous acid derivatives which are intermediates in the above disclosed process, enter into the scope of the invention. As above mentioned, said hypophosphorous acid derivatives have mGluRs agonist or antagonist properties of great interest and therefore are particularly valuable as active principles in pharmaceutical compositions to treat brain disorders. They are particularly mGlu4Rs agonists or antagonists of great value.
21 The invention thus also relates to pharmaceutical compositions, comprising a therapeutically effective amount of at least one of the hypophosphorous acid derivatives of formula I in combination with a pharmaceutically acceptable carrier. The invention also relates to the use of at least one of hypophosphorous acid derivatives of formula I for preparing a drug for treating brain disorders. The pharmaceutical compositions and drugs of the invention are under a form suitable for an administration by the oral or injectable route. For an administration by the oral route, compressed tablets, pills, capsules are particularly used. These compositions advantageously comprise 1 to 100 mg of active principle per dose unit, preferably 2.5 to 50 mg. Other forms of administration include injectable solutions for the intravenous, subcutaneous or intramuscular route, formulated from sterile or sterilizable solution. They can also be suspensions or emulsions. These injectable forms, for example, comprise 0.5 to 50 mg of active principle, preferably 1 to 30 mg per dose unit. The pharmaceutical compositions of the invention prepared according to the invention are useful for treating convulsions, pain, drug addiction, anxiety disorders and neurodegenerative diseases. By way of indication, the dosage which can be used for treating a patient in need thereof, for example, corresponds to doses of 10 to 100/mg/day, preferably 20 to 50 mg/day, administered in one or more doses. The conditioning with respect to sale, in particular labelling and instructions for use, and advantageously packaging, are formulated as a function of the intended therapeutic use. According to another object, the invention relates to a method for treating brain disorders, comprising administering to a patient in need thereof an effective amount of an hypophosphorous acid derivative such as above defined. According to still another object, the invention relates to the use of at least one hypophosphorous acid derivative such as above defined for preparing a drug for treating drug disorders. Other characteristics and advantages of the invention will be given in the following examples illustrating the synthesis of hypophosphorous acid derivatives. In the examples, it - 1E: mGlu4 activation inhibition by DCG-IV by (3R)-PCEP 22 Experimental section: Example 1: Synthesis of hypophosphorous acid derivatives according to Method A Scheme 1 0 OO 0I H-P H O- - H H N O O HN 0 6 H 02 N H 2 O H 7 Reagents and conditions: (a) AIBN, CH 3 0H, reflux at 80*C, 5h; (b) TMSCl, EtsN; (c) ethyl acrylate, 6h; (d) 8N HOl, reflux (3S)-3-[((3-(N--Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl] propanoic Acid Ethyl Ester (6). The compound 5 (180mg, 0.57mmol) was treated with a mixture of trimethylsilyichloride (TMS Cl, 130.4mg, 1 .2mmol)/ triethylamine (EtsN, 121mg, 1 .2mmol) in dichloromethane at 0 0 C, then stirred at room temperature for one hour under a argon atmosphere. Then again cooled to 0*C and ethyl acrylate was carefully added dropwise. The mixture was stirred at room temperature for 6h. The reaction mixture was treated with iN HCl and extracted with ethylacetate. The organic layer was dried over MgSO 4 and evaporated under vacuum to give 6 (130mg, 55% yield). 'H NMR (CD 3 0D): 6 1.26 (t, J= 7.0 Hz, 3H), 2.01 (in, 6H), 2.60 (in, 2H), 3.73 (s, 3H), 4.15 (q, J= 7.0 Hz, 2H), 4.29 (mn, 1H), 5.12(s, 2H), 7.34(m, 5H). 31 P NMR (CD 3 0D): 6 53.6. (3S)-3-[((3-Amino-3-carboxy)propyl)(hydroxy)phosphinyllpropanoic Acid (7). A solution of 6 (130mg, 0.31Immol) in 6N HCl was refluxed overnight and the solution was evaporated ~tJuweA J.uouS' LAomum, ni , zo-JJu mesa,1 m.')u. I L1in, wULeI ViLIuuo). equa~1utave yieiuj; ra 23 NMR (D 2 0): 8 1.69 (m, 2H), 1.89 (m, 211), 2.08 (m, 2H), 2.55 (m, 2H), 4.00 (t, J= 5.9 Hz, 1H). "P NMR (D 2 0): 8 57.4. [M]D +12.80 (c 1.0, H20) (lit. [a]D +12.50 (c 1.2, H20), Ragulin et al., JP-2001-213887). Scheme 2 0 O O1 O
H-P'
H- HN O OH 50 a C 0 0 N~O 0 O O -O O O0 p P O H HN 0 i HNYO 0 16 O 18 O H 0 0"-O-O b d H O OHO 6 > OH HO0 + 0 H OH H OH HO11O OHP P H 0 OH OH OHO 0 ~ 17 20 Reagents and conditions: (a) diethylglutaconate, CH2C12, BSA, 15h; (b) 6N HCl, reflux; (c) dimethylitaconate, CH2Cl2, BSA, 15h; (d) 6N HCI, reflux 24 Scheme 2a, 2b (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3- methoxycarbonyl)propyl)(hydroxy)phosphinyl) -methyl]pentane-1,5-dioic Acid Diethyl Ester (15). To a solution of 5 (0.8mmol) and diethylglutaconate (558mg, 3mmol) in 2 ml of methylene chloride at 0*C under an argon atmosphere was added dropwise N,O-(bis-triethysilyl)acetamide (BSA) (1.49ml, 6mmol). The mixture was allowed to warm to room temperature and stirred overnight, then cooled to 0*C and 25ml of iN HCI were added, then extracted with ethyl acetate. The organic layer was concentrated in vacuo. This residue was dissolved in 10ml of water, the pH was adjusted to 7 using saturated NaHCO 3 solution, then extrated with ethylacetate (2x50 ml). The organic layer was separated, and the aqueous phase was treated with IN HCl to adjust the pH to 1. The aqueous phase was extracted with ethyl acetate twice (2x50 ml). The combined acidic organic extracts were dried over MgSO 4 , filtered and concentrated in vacuo. 'H NMR
(CD
3 0D): S 1.26 (m, 6H), 2.40 (in, 9H), 3.74 (s, 3H), 4.13 (m, 4H), 4.37 (m, 1H), 5.12 (s, 2H), 7.37 (in, 5H). 3 'P NMR (CD 3 0D): 8 54.80. 13 C NMR (CD 3 0D): 8 13.78, 23.89 (d, J=90.70 Hz), 24.11, 31.85 (d, J=93.75 Hz), 33.17, 52.13, 54.92, 60.62, 66.84, 128.00, 128.20, 128.66, 137.19, 157.43, 171.81, 172.18, 172.71. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-methyllpentane-1,5-dioic Acid (16). Compound 15 was dissolved in 3ml of 6N HCL. The mixture was heated for 15h at reflux temperature, the resulting solution was cooled to room temperature. Volatile organic byproducts and water were removed under vacuo and the residue was purified using a Dowex AG50x4 column as described earlier (63% yield over two steps). 'H NMR (D 2 0): 6 1.63 (m, 2H); 2.00 (in, 2H); 2.33 (m, 3H); 2.58 (in, 2H); 3.91 (t, J=6.1 Hz, IH). "P NMR (D 2 0): 6 57.10. "C NMR (D 2 0) : 6 23.17, 23.42 (d, J=90.81 Hz), 31.84 (d, J=93.07 Hz), 33.62, 53.76 (d, J=14.6 Hz), 166.08, 172.16, 176.32 (d,J=12.26 Hz). 3-[((hydroxy)phosphinyl)-methyllpentane-1,5-dioic Acid (17). The title compound was formed as a byproduct during the preparation of compound 15 and deprotected in the next step (procedure described above). During the deposition of 16, compound 17 was not bound to the cation exchange resin (Dowex AG5Ox4) and recovered. 1 H NMR (D 2 0): 6 2.44 (in, 5H), 6.85 (d, J=568 Hz, 1H). "C NMR (D 2 0): 8 31.93, 31.97 (d, J=125.7 Hz), 175.41 (d, J=11.13 Hz).
25 Scheme 2c, 2d (3S)- 2 -[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -methyl]butane-1,4-dioic Acid Dimethyl Ester (18). The compound was prepared from 5 (0.8mmol) and diethylitaconate (474mg, 3mmol) by a procedure similar to that for the preparation of compound 15 (61% yield). 1H NMR (CD 3 0D): 8 2.10 (m, 6H); 2.83 (m, 2H); 3.20 (m, 1H); 3.75 (s, 3H); 3.72 (s, 3H); 3.71 (s, 3H); 4.30 (m, 1H); 5.13 (s, 2H) 7.38 (m, 5H). 3 'P NMR (CD 3 0D): 8 52.21. 13 C NMR (CD 3 0D): 8 24.26, 25.88 (d, J=93.39 Hz), 29.93 (d, J=93.39 Hz), 35.85, 36.27, 51.53, 52.05, 54.13, 54.62, 66.82, 127.99, 128.20, 128.64, 137.20, 157.47, 172.42, 172.71, 174.56 (d, J=9.94 Hz). (3S)-2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-methylbutane-1,4-dioic Acid (19). The compound was prepared from 18 by the removal of protecting groups following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 19 (quantitative yield). 'H NMR (D 2 0): 8 1.82 (m, 3H); 2.17 (m, 3H); 2.78 (m, 2H); 3.08 (m, 1H); 4.04 (t, J=6.1 Hz, 1H). 3 P NMR (D 2 0): 8 56.35. 1 3 C NMR
(D
2 0): 8 23.27, 25.49 (d, J=91.38 Hz), 30.34 (d, J=91.25 Hz), 36.02, 36.95 (d, J=7.61 Hz), 53.71 (d, J=15.09 Hz), 172.12, 175.92, 178.28 (d, J=8.81 Hz). (3S)-2-[(hydroxy)phosphinyl]-bismethylbutane-1,4-dioic Acid (20). The title compound was formed as a byproduct during the preparation of compound 18 and then deprotected in the next step (procedure described above). During the deposition of 19 on cation exchange resin, the compound 20 was not bound to the resin. 'H NMR (D 2 0): 8 1.84 (m, 2H); 2.08 (m, 2H); 2.56 (d, J=6.69 Hz, 4H); 2.92 (m, 2H). "P NMR (D 2 0): 8 62.83. 1 3 C NMR (D20): 8 30.26 (d, J=91.88 Hz), 35.49, 36.69, 175.46, 177.52 (d, J=8.74 Hz).
26 Scheme 3 0 0O OI O H-PI H HN O O H O 0e 0 0 OH OH 0 0 O HN O O i HNYO I~oOH 0OH -O 21 O O_ 23 0 b Id OHO OH O OH - H NH 2 IH NH 2 OH OH O 0 HO 22 OH 24 Reagents and conditions: (a) 2-formylmethylbenzoate, CH 2 Cl 2 , BSA, 18h; (b) 6N HCl, reflux; (c) 3 formylmethyl benzoate, CH 2 C1 2 , BSA, I 5h; (d) 6N HCI, reflux (3S)-2-{(((3-(N-Benzyloxycarbonyl)amino-3-metoxycarbonyl)propyl)(hydroxy)phosphinyl) -hydroxymethyllbenzoic Acid Methyl Ester (21). The compound was prepared from 5 (0.8mmol) and ethyl 2-formylbenzoate (492mg, 3mmol) by using the procedure described for preparation of compound 15 (37% yield). 'H NMR (CD 3 0D): 8 1.84 (m, 2H); 2.22 (in, 2H); 3.73 (s, 3H); 3.88 (s, 3H); 4.32 (in, 1H); 5.10 (s, 2H); 5.84 (d, J=8.12 Hz, 1H); 7.32 (in, 5H); 7.70 (m, 4H). "P NMR (CD 3 0D): 8 41.22. (3S)-2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyllbenzoic Acid (22). The removal of the protecting groups in compound 21 was accomplished following the same procedure as that followed for compound 16 and purified by anion exchange AG1x4 column using the procedurce as described for compound 10. The compound 22 was eluted 27 with 0.4-0.5M HCOOH (quantitative yield). 1H NMR (D 2 0): 6 1.67 (m, 2H), 2.08 (m, 2H), 3.98 (in, 1H), 5.74 (d, J=6.43 Hz, 1H), 7.63 (t, J=7.65 Hz, 1H), 7.69 (d, J=7.66 Hz, 1H), 7.79 (t, J=7.17 Hz, 1H), 7.91 (d, J=7.63 Hz, 1H). 31 P NMR (D 2 0): 6 43.20. 1 3 C NMR (D 2 0): 6 22.53 (d, J=89.68 Hz), 23.55, 54.16, 72.92 (d, J=107.11 Hz), 128.22, 129.13, 129.38, 130.10, 132.43, 138.77, 170.82, 172.49.
(
3
S)-
3
-[(((
3 -(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -hydroxymethyl]benzoic Acid Methyl Ester (23). The compound was prepared from 5 (0.8mmol) and methyl 3-fornylbenzoate (492mg, 3mmol) by using the procedure described for preparation of compound 15 (55% yield). 'H NMR (CD 3 0D): 5 1.79 (in, 4H), 3.60 (s, 3H), 3.76 (s, 3H), 4.26 (in, 1H), 4.95 (in, 1H), 5.02 (s, 2H), 7.30 (in, 5H), 7.83 (in, 4H). "P NMR (CD 3 0D): 6 53.09, 53.53.
(
3 S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl]benzoic Acid (24). The removal of the protecting groups in compound 21 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 24 (quantitative yield). 'H NMR (D 2 0): 6 1.77 (in, 2H), 2.11 (in, 2H), 3.99 (in, 1H), 4.93 (d, J=9.45 Hz, 1H), 7.50 (t, J=7.73 Hz, 1H), 7.66 (d, J=7.46 Hz, 1H), 7.92 (d, J=7.57 Hz, 1H), 8.00 (s, 1H). 3 P NMR (D 2 0): 6 50.53. 3 C NMR (D 2 0): 6 22.53 (d, J=89.68 Hz), 23.55, 54.16, 72.92 (d, J=107.11 Hz), 128.22, 129.13, 129.38, 130.10, 132.43, 138.77, 170.82, 172.49.
28 Scheme 4 0 O II 0 H-PH H HNY " OH 50 O O O A H OOH HNyO b 0 O 0 F 3 C HO OH H O H O OH OH 26 28 Reagents and conditions: (a) ethylbromnoacetate, CH 2 C1 2 , BSA, 1 5h; (b) 6N HCI, reflux; (c) ethyl 4,4,4-trifluoro crotonate, CH 2 Cl 2 , BSA, 15h; (d) 6N HCl, reflux (3S)-2-[((3-(N-Benzyloxycarbonyl)amino-3 methoxycarbonyl)propyl)(hydroxy)phosphinyl] ethanoic Acid Ethyl Ester (25). The compound was prepared from 5 (0.8mmol) and ethylbromoacetate (501mg, 3mmol) by following the procedure described for preparation of compound 15 (60% yield). 'H NMR
(CD
3 0D): 8 1.28 (t, J= 7.1 Hz, 3H), 2.07 (in, 4H), 3.00 (d, .J= 17.3 Hz, 2H), 3.76 (s, 3H), 4.19 (q, J= 7.1 Hz, 2H), 4.31 (mn, 1H), 5.13 (s, 2H), 7.34 (in, 5H). ' 3 C NMR (CD 3 0D): 8 13.5, 24.2, 25.6 (d, J= 99 Hz), 37.2 (d, J1= 82 Hz), 51.9, 54.8, 61.6, 66.8, 127.9, 128.1, 128.5, 137.1, 157.6, 167.1, 172.7. 31 P NMR (CD 3 0D): 8 45.7. MS (ESI): m/z 400.1 (M-1).
(3S)-2-[((3-amino-3-carboxy)propyl)(hydroxy)phosphinylethanoic Acid (26). The removal of the protecting groups in compound 25 was accomplished using the same procedure as that used for compound 16 and purified by Dowex AG5Ox4 column to afford 26 (quantitative yield). 'H NMR (D 2 0): 8 1.86 (m, 2H), 2.22 (m, 2H), 2.82 (d, J=16.9 Hz, 2H), 4.08 (t, J=6.2 Hz, 1H). 3 1 P NMR (D 2 0): 6 46.61. "C NMR (D 2 0): 8 21.85, 21.18 (d, J=96.0 Hz), 36.83 (d, J=76.7 Hz), 51.85, 170.33, 170.70. Mass (ESI): 226.1 (M-1). [a] 0 +14.8' (c 0.1, H 2 0). (3S)-3-[((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbony)propyl)(hydroxy)phosphinyl]-3 trifluoromethylpropanoic Acid Ethyl Ester (27). The compound was prepared from 5 (0.8mmol) and ethyl 4,4,4-trifluorocrotonate (504mg, 3mmol) by following the procedure described for preparation of compound 15 (64% yield). 'H NMR (CD 3 0D): 6 1.24 (m, 3H), 2.02 (m, 4H), 2.87 (m, 3H), 3.74 (s, 3H), 4.17 (q, J=6.8 Hz, 2H), 4.24 (m, 1H), 5.12 (s, 2H), 7.36 (m, 5H). 31 p NMR (CD 3 0D): 6 43.24. (3S)-3-[((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl]-3-trifluoromethypropanoic Acid (28). The removal of the protecting groups in compound 27 was accomplished using the same procedure as that used for compound 16 to afford 28. Compound 27 was purified by Dowex AG50x4 column (quantitative yield). 'H NMR (D 2 0): 6 1.81 (m, 2H), 2.17 (m, 2H), 2.79 (m, 2H), 3.15 (m, 1H), 4.07 (m, 1H). " P NMR (D20): 6 43.93, 46.21. Scheme 5 0 0 0 OH H 0 + o H a 2 OH 0 1-2 HNy 0 / b 5 0 O O H2 H O III OH C I -OH po H NH 2 - HNYa 31 30 0 Reagents and conditions: (a) CH 2
CI
2 , BSA, 15h; (b) LiOH, EtOH, 12h; (c) 4N HC1, 75*C, 4h 30 (3S)-4-[((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl]-4 hydroxy-3-methyl-2-butenoic Acid Ethyl Ester (29). The compound was prepared from 5 (0.8mmol) and ethyl-3-methyl-4oxocrotonate (426mg, 3mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD30D): 8 1.26 (m, 3H), 2.16 (m, 7H), 3.74 (s, 3H), 4.19 (m, 3H), 4.48 (d, J= 13.69 Hz, 1H), 5.12 (s, 2H), 5.86 (in, 1H), 7.36 (m, 5H). 3 P NMR (CD30D): 5 49.0. 3 C NMR (CD 3 0D): 8 13.96, 17.65, 22.63 (d, J= 89.68 Hz), 24.15, 52.17, 54.76, 60.73, 66.92, 74.05 (d, J= 101.52 Hz), 117.03, 127.98, 128.23, 128.68, 137.07, 155.87, 172.09, 172.81.
(
3 S)-4-[((3-(N-Benzyloxycarbonyl)amino-3-carboxy)propyl)(hydroxy)phosphinyl]-4 hydroxy-3-methyl-2-butenoic Acid (30). Compound 29 (472mg) was dissolved in 10 ml of ethanol and 10 ml of water. Lithium hydroxide (144mg, 6mmol) in 5 ml water was added to the solution, which was stirred at room temperature for 12h. Following removal of ethanol under vacuo, the resulting solution pH was adjusted to 1. Then extracted with ethyl acetate twice. The organic layer was washed with brine and dried with anhydrous MgSO 4 , and the solvent was evaporated in vacuo (66% yield over two steps). 1H NMR (CD 3 0D): 8 1.88 (in, 7H), 4.21 (in, 1H), 4.39 (d, J= 12.1 Hz, 1H), 5.11 (s, 2H), 5.93 (m, 1H), 7.39 (m, 5H). 31 P NMR (CD 3 0D): 8 49.4. (3S)-4-[((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl]-4-hydroxy-3-methyl-2 butenoic Acid (31). The removal of the benzyloxy carbonyl group was accomplished by adding 4N HCl (5ml) to the compound 30 (140 mg). The resulting solution was stirred at 75 0 C for 4h and cooled to room temperature. Volatile organic byproducts and water were removed under vacuo. The compound 31 was purified by anion exchange AGlx4 column using the procedure described for compound 10. Compound 31 was eluted with 0.3M HCOOH (quantitative yield). 'H NMR (D 2 0): 8 1.86 (in, 2H), 2.16 (m, 5H), 4.10 (m, 1H), 4.43 (d, J= 13.34 Hz, 1H), 5.99 (d, J= 3.85 Hz, 1H). 1 3 C NMR (D 2 0): 8 17.2, 22.40 (d, J= 100.23 Hz), 23.19, 53.5, 75.25 (d, J= 106.91 Hz), 116.35, 157.19, 170.54, 171.79. 31 P NMR
(D
2 0): 8 53.14.
31 Scheme 6 0 00 H "" ;0 0 H HN 50O HO OH
NH
2 NH O H OH OH OH 33-34 (3S)-2-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -hydroxymethylcyclopropane-1-carboxylic Acid Ethyl Ester (32). The compound was prepared from 5 (0.8mmol) and trans ethyl 2-formyl-1-cyclopropanecarboxylate (426mg, 3mmol) by following the procedure described for preparation of compound 15 (55% yield). 'H NMR (CD 3 0D) : 5 1.19 (m, 511), 1.96 (m, 6H), 3.40 (m, 0.51H), 3.67 (m, 0.5H), 3.73 (s, 3H), 4.12 (m, 2H), 4.29 (m, 1H), 5.11 (s, 2H), 7.37 (m, 5H). 31 P NMR (CD 3 0D) : 5 50.53. (3S)-2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyllcyclopropane-1 carboxylic Acid (33). The removal of the protecting groups in compound 27 was accomplished using the same procedure as that used for compound 16 to afford 33 and 34 (1:1, quantitative yield). The mixture (26mg) of the isomers 33 and 34 was separated by Dowex 50x4 (HW, 200 400 mesh, 44x2.2cm, water elution) chromatography. Diastereoisomers 33 and 34 were separated in fractions 9-14 (4.4mg) and 33-37 (3.1mg) respectively. 33: 'H NMR (D20): 8 1.12 (m, 1H), 1.25 (m, 1H), 1.80 (m, 4H), 2.13 (m, 2H), 3.40 (m, 1H), 3.96 (m, 1H). 31 P NMR
(D
2 0): 5 51.50. 34: 'H NMR (D 2 0): 8 1.14 (m, 1H); 1.34 (m, 1H); 1.82 (m, 4H); 2.15 (m, 2H); 3.15 (m, 111); 4.00 (m, 1H). 3P NMR (D2O): S 51.50. "C NMR (D20): 8 13.32 (d, J=78.49 Hz), 18.37 (d, J=42.77 Hz), 22.63 (d, J=79.30 Hz), 23.23 (d, J=78.93 Hz), 23.26, 53.94, 70.56 (d, J=109.05 Hz), 72.31 (d, J=1 12.07 Hz), 172.47, 178.52.
Scheme 7 0 0I 0 0 H~A H + O=a )o0" HN o +O< ". OH Y! 'H N o35OO 36 0 b 0 0 i OH P
NH
2 OOH 36 Reagents and conditions: (a) CH 2 Cl 2 , BSA, 15h; (b) 6N HC, reflux (3S)-4-[((3-(N-Benzyloxycarbonyl)amino-3 methoxycarbonyl)propyl)(hydroxy)phosphinylI furanone (35). The compound was prepared from 5 (0.8mmol) and 2-(5H)-furanone (252mg, 3mmol) by following the procedure described for preparation of compound 15 (75% yield). 'H NMR (CD 3 0D): 8 1.88 (m, 2H), 2.15 (m, 2H), 2.73 (m, 2H), 3.01 (m, 1H), 3.76 (s, 3H), 4.36 (m, 1H), 4.51 (m, 2H), 5.13 (s, 2H), 7.36 (m, 5H). "P NMR (CD30D): 8 49.2. "C NMR (CD 3 0D): 6 24.05, 24.69 (d, J= 80.81), 28.63, 34.51(d, J= 96.66), 51.93, 54.90, 66.82, 67.71, 127.91, 128.13, 128.55, 137.12, 157.64, 172.76, 177.27 (d, J= 9.94). (3S)-4-[((3-amino-3-carboxy)propyl)(hydroxy)phosphinyllfuranone (36). The removal of the protecting groups in compound 35 was accomplished using the same procedure as that used for compound 16 and purified by Dowex AG50x4 column to afford 36 (quantitative yield). 'H NMR (D 2 0): 8 1.72 (m, 2H), 2.15 (m, 2H), 2.80 (m, 3H), 4.10 (d, J= 6.4 Hz, 1H), 4.42 (m, 1H), 4.61 (m, 1H). "P NMR (D 2 0): 8 51.21. "C NMR (D 2 0): 8 23.19, 24.45 (d, J=93.71 Hz), 29.47, 34.86 (d, J=96.14 Hz), 54.2, 69.44, 172.03, 180.73 (d, J= 10.2).
33 Scheme 8 0 0 0~ HN O 5 0 C O O FCP p O2 H Y == OH 37 0 39 0 b d 30 0 O H 0 O H OH)" " O OHO O OH
F
3 C PP F2C NH HO I NH 2 6 2 H OH 02N 38 40 Reagents and conditions: (a) 3-nitro-4-(trifluoromethyl)benzaldehyde, CH 2 C1 2 , BSA, 15h; (b) 6N HC1, reflux; (c) 4-formylmethyl benzoate, CH 2 C1 2 , BSA, 15h; (d) 6N HC1, reflux (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -hydroxymethyl]-6-trifluoromethyl-1-nitrobenzene (37). 37 was prepared from 5 (0.8mmol) and 3-nitro-4-(trifluoromethyl)benzaldehyde (657mg, 3mmol) by following the procedure described for preparation of compound 15. 1H NMR (CD 3 0D): 8 2.04 (m, 4H), 3.75 (s, 31H), 4.33 (m, 1H), 5.15 (s, 2H), 6.21 (m, 1H), 7.36 (m, 5H), 8.15 (m, 3H). "P NMR (CD 3 0D): 8 48.14. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-6-trifluoromethyl-1 nitrobenzene (38). The removal of the protecting groups in compound 37 was accomplished using the same procedure as that used compound 16 and purified by Dowex AG5Ox4 column 34 to afford 38. 'H NMR (D 2 0): 8 1.75 (m, 2H), 2.10 (m, 2H), 4.01 (m, 1H), 5.97 (d, J= 10.95 Hz, 1H), 8.02 (m, 2H); 8.35 (s, 1H). 3 'P NMR (D 2 0): 6 48.25. (3S)-4{(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -hydroxymethyllbenzoic Acid Methyl Ester (39). 39 was prepared from 5 (0.8mmol) and methyl 4 formylbenzoate (492mg, 3mmol) by using the procedure described for preparation of compound 15. 1H NMR (CD 3 0D): 5 2.03 (m, 4H), 3.73 (s, 3H), 3.92 (s, 3H), 4.29 (in, 1H), 5.21 (s, 2H), 5.47 (in, 1H), 7.37 (in, 5H), 7.65 (in, 2H), 8.03 (m, 2H). 3 'P NMR (D 2 0): 8 48.81. 13C NMR (CD 3 0D): 8 23.39 (d, J= 91.57 Hz), 24.12, 51.82, 66.88, 72.16 (d, J= 108.61 Hz), 127.41, 127.86, 128.13, 128.60, 129.34, 129.66, 137.06, 143.48, 157.65, 167.53, 172.78. (3S)-4-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyllbenzoic Acid (40). The removal of the protecting groups in compound 39 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 40. 1H NMR (D 2 0): 6 1.65 (in, 2H), 1.94 (in, 2H), 3.94 (in, 1H), 4.90 (d, J=10.4 Hz, 1H), 7.48 (d, J=7.19 Hz, 2H), 7.93 (d, J=8.22 Hz, 2H). 3 'P NMR (D 2 0): 6 49.89. "C NMR
(D
2 0): 6 22.71 (d, J=90.3 Hz), 23.70, 54.52, 73.44 (d, J=104.96 Hz), 127.34, 129.21, 130.00, 144.38, 170.89, 172.73. Scheme 9 0 0 H-P-H + OH HN 50% aqueous O (2S)-2-(N-Benzyloxycarbonyl)amino-4-[(hydroxy)phosphinyl]butanoic Acid Methyl Ester (5). A mixture of hypophosphorous acid (660mg, 5mmol, 50% aqueous), Z-L-vinyl glycine methyl ester (250mg, 1mmol) and a,a'-azoisobutyronitrile (AIBN, 8.1mg, 0.05mmol) in methanol (1ml) was refluxed at 80 0 C for 5 h. Then the methanol was evaporated under vacuum and the residue was extracted with ethyl acetate, dried over MgS04. The organic layer was evaporated under vacuum and purified by Silica gel chromatography
(CH
2
C
2 :MeOH, 1:0 to 9:1) to afford 5 (90% yield); 'H NMR (CD 3 0D): 8 1.98 (in, 4H), 3.72 J= 92 Hz), 52.2, 54.7, 66.9, 128.0, 128.3, 128.7, 137.2, 157.5, 172.7. 3 'P NMR (CD30D): 8 35.3. Scheme 10 0 O OH HN O 50 O 00 Oi O OO 41 0 3 0 b d HN 0HN 0 OH OH 41 0 43 0 0 00O HO ,11 HO- OH OH OH H NH 2 HO H NH2 42 44 Reagents and conditions: (a) diethylvinylphosphonate, CH 2 Gl 2 , BSA, 15h; (b) 8N HC, reflux; (c) triethyl-4 phosphonocrotonate, CH 2
CI
2 , BSA, 15h; (d) 8N HC, reflux (3S)-2-[((3-(N-Benzyloxycarbonyl)amino-3 methoxycarbonyl)propyl)(hydroxy)phosphinyl] ethylphosphonate Diethyl Ester (41). The compound was prepared from 5 (0.8mmol) and diethylvinylphosphonate (492mg, 3mmol) by using the procedure described for preparation of compound 15 (87.8% yield). 'H NMR (CD 3 0D): 8 1.29 (m, 6H), 1.99 (m, 8H), 3.73 (s, 3H), 4.14 (m, 4H), 4.31 (m, 1H), 5.12 (s, 2H), 7.37 (m, 5H). 3 'P NMR (CD 3 0D): 8 32.57 (d, J=65.87 Hz), 52.31 (d, J=65.59 Hz). MS (ESI): m/z 480.1 (M+1).
36 (3S)-3-[((3-Amino-3-carboxy)propyl)(hydroxy)phosphinylethylphosphonate (42). The removal of the protecting groups in compound 21 was accomplished following the same procedure as that followed for compound 16 and purified by anion exchange AG1x4 column using the procedurce as described for compound 10. The compound 42 was eluted with 0.8 L.OM HCOOH (quantitative yield). 'H NMR (D 2 0) : 8 1.75 (in, 6H), 2.00 (in, 2H), 3.97 (t, J=5.79 Hz, 1H). "P NMR (D 2 0): 8 38.21 (d, J=65.00 Hz), 61.99 (d, J=65.13 Hz). MS (ESI): m/z 276.1 (M+1).
(
3
S)-
2
-[(((
3 -(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -methyl]-2-(diethylphosphonomethy)-propanoic Acid Ethyl Ester (43). The compound was prepared from 5 (0.8mmol) and triethyl-4-phosphonocrotonate (750mg, 3mmol) by a procedure similar to that for the preparation of compound 15 (83.8% yield). IH NMR
(CD
3 0D): 8 1.28 (in, 9H), 2.19 (in, 6H), 2.81 (in, 3H), 3.73 (s, 3H), 4.12 (in, 6H), 4.32 (in, 1H), 5.12 (s, 2H), 7.37 (m, 5H). 31 P NMR (CD 3 0D): 8 31.29 (d, J=57.26 Hz), 53.97 (d, J=57.27 Hz). MS (ESI): m/z 566.1 (M+1).
(
3
S)-
2
-[(((
3 -(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -methyl]-2-(phosphonomethy)-propanoic Acid (44). The removal of the protecting groups in compound 43 was accomplished using the same procedure as that used compound 16 and purified by anion exchange AG1x4 column using the procedurce as described for compound 10. The compound 44 was eluted with 1.0-1.3M HCOOH (quantitative yield). 'H NMR
(D
2 0): 8 1.62 (m, 3H), 1.86 (m, 3H), 2.26 (in, 1H), 2.41 (in, 1H), 2.47 (in, 1H), 3.85 (in, 1H). "P NMR (D 2 0): 8 37.51 (d, J=50.72 Hz), 63.67 (d, J=50.67 Hz). "C NMR (CD 3 0D): 8 22.20 (d, J=91.35 Hz), 22.47, 25.11 (d, J=136.71 Hz), 29.72 (d, J=92.69 Hz), 33.38, 52.98, 171.12, 175.30 (d, J=8.05 Hz).
37 Scheme 11 0 0 II 0 H-P H H HNYO"' 5OO 50 0 0 b0d O O AHO - I HN PI HN O OH HO0 OH 0= " 1 0 47 0 0 0 0 OH H O OH I NH 2 0H NHH OH OH 46 48 Reagents and conditions: (a) methyl-3-(bromomethyl)benzoate, CH 2 Cl 2 , BSA, 15h; (b) 6N HClI, reflux; (c) methyl-4-iodobutyrate, CH 2 Cl 2 , BSA, 15h; (d) 6N HCI, reflux (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl) -methyl]benzoic Acid Methyl Ester (45). The compound was prepared from 5 (0.8mmol) and methyl-3-(bromomethyl)-benzoate (687mg, 3mmol) by using the procedure described for preparation of compound 15 (72.2% yield). 'H NMR (CD 3 0D): 6 1.98 (m, 4H), 3.23 (d, J=15.04 Hz, 2H), 3.69 (s, 3H), 3.86 (s, 3H), 4.31 (m, 1H), 5.09 (s, 2H), 7.33 (m, 5H), 7.43 (m, 2H), 7.94 (m, 2H). 31 P NMR (CD 3 0D): 6 50.20. 13 C NMR (D 2 O): 6 24.35, 24.62 (d, J=93.22 Hz), 36.18, (d, J=88.71 Hz), 52.00, 54.93, 66.91, 128.02, 128.24, 128.68, 128.95, 130.63, 131.21, 133.19 (d, J=7.48 Hz), 134.93, 137.11, 157.50, 172.75, 174.39. MS (ESI): m/z 464.1 (M+1).
(3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-methyllbenzoic Acid (46). The removal of the protecting groups in compound 45 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AGSOx4 column to afford 46 (quantitative yield). 1H NMR (D 2 0): 8 1.60 (m, 2H), 2.00 (m, 2H), 3.08 (d, J=16.78 Hz, 2H), 3.93 (t, J=6.02 Hz, 1H), 7.39 (in, 2H), 7.76 (m, 2H). 31 P NMR (D 2 0): 3 54.66. 13 C NMR (D 2 0): 8 23.42, 24.38 (d, J=91.69 Hz), 37.21 (d, J=85.97 Hz), 53.80 (d, J=14.83 Hz), 128.24, 129.34, 130,24, 130.86, 133.98 (d, J=7.67 Hz), 135.11, 170.68, 172.20. MS (ESI): m/z 302.1 (M+1). (3S)-4-[((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy)phosphinyl butanoic Acid Methyl Ester (47). The compound was prepared from 5 (0.8mmol) and methyl 4-iodobutyrate (684mg, 3mmol) by using the procedure described for preparation of compound 15 (64.6% yield). 'H NMR (CD 3 0D): 8 2.14 (m, 10H), 3.68 (s, 3H), 3.74 (s, 3H), 4.34 (in, 1H), 5.12 (s, 2H), 7.36 (m, 5H). 3 'P NMR (CD 3 0D): 8 55.43. MS (ESI): m/z 416.1 (M+1). (3S)-4-[((3-Amino-3-carboxy)propyl)(hydroxy)phosphinyl]butanoic Acid (48). The removal of the protecting groups in compound 47 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 48 (quantitative yield). 'H NMR (D 2 0): 8 1.71 (in, 6H), 2.08 (m, 2H), 2.44 (in, 2H), 3.93 (t, J=5.98 Hz, 1H). 31 P NMR (D 2 0): 5 58.80. MS (ESI): m/z 254.1 (M+1).
Scheme 12 0 0~~ H-P ' H H HN O 5 0 c 0 0 OHO O H 3 O OH HO /--" HOP^' 6Hi HNYO - HO W HNY "' 0 2 N 61 0 0 2 N 63 0 b d O 0
PNH
2 - NH 2 \ HOOOH 0 2 N 0 2 N 62 64 aReagents and conditions: (a) 4-hydroxy-3-nitrobenzaldehyde, CH 2 C1 2 , BSA, 15h; (b) 6N HCl, 100*C, 5h; (c) 5-nitrovanillin, CH 2 C1 2 , BSA, 15h; (d) 6N HCI, 1 00*C , 5h. (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy) phosphinyl)-hydroxymethyl]-6-hydroxy-1-nitrobenzene (61). 61 was prepared from 5 (0.8mmol) and 4-hydroxy-3-nitrobenzaldehyde (401mg, 2.4mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 OD): S 2.02 (m, 4H), 3.74 (s, 3H), 4.33 (m, 1H), 5.02(d, J= 8.60 Hz, 1H), 5.09 (s, 2H), 7.13 (d, J= 8.54 Hz, 1H), 7.31 (m, 5H), 7.61 (d, J= 8.76 Hz, 1H), 8.08 (s, IH). "P NMR (CD 3 0D): 8 48.76. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethy]-6-hydroxy 1-nitrobenzene (62). The removal of the protecting groups in compound 61 was accomplished using the same procedure as that used compound 16 and purified by Dowex AG50x4 column to afford 62. 'H NMR (D 2 0): 8 1.78 (m, 2H), 2.05 (m, 2H), 3.98 (m, 1H), 4.80 (d, J= 8.56 Hz, 1H), 7.06 (d, J= 8.66 Hz, 1H); 7.57 (d, J= 8.63 Hz, 1H), 8.02 (s, 1H). 1 3 C NMR (D 2 0): 8 22.59 (d, J= 88.4 Hz), 23.61, 53.98 (d, J= 14.72 Hz), 71.75 (d, J= 107.37 Hz), 119.99, 123.70, 130.83, 134.31, 136.83, 153.28, 172.36. (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy) phosphinyl)-hydroxymethyl]-5-metboxy-6-hydroxy-1-nitrobenzene (63). 63 was prepared from 5 (0.8mmol) and 5-nitrovanillin (473mg, 2.4mmol) by using the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 2.12 (m, 4H), 3.73 (s, 3H), 3.92 (s, 3H), 4.32 (in, 1H), 5.08 (s, 214), 5.33 (m, 1H), 7.53 (in, 7H). 31 P NMR (CD 3 0D): 6 49.29. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethy1-5-methoxy 6-hydroxy-1-nitrobenzene (64). The removal of the protecting groups in compound 63 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 64. 1H NMR (D20) : 8 1.74 (m, 2H), 2.03 (M, 2H), 3.83 (s, 3H), 4.02 (m, 1H), 7.23 (s, 1H), 7.59 (s, 1H). "P NMR (D20): 8 50.03. 1 3 C NMR (D 2 0): 6 22.63 (d, J= 90.45 Hz), 23.68, 54.16 (d, J= 12.65 Hz), 56.91, 72.10 (d, J= 109.9 Hz), 114.43, 116.81, 129.99, 134.24, 143.91, 149.30, 172.56. MS (ESI) m/z: 365.1 (M+1).
0 O H-P HN O H 0 c OH OH OH6 O 0 0~ 0 CI H H HNH
O
2 N H 0 2 N OH 66 067 _:)OH OH?' SOH PiOH - NH 2 0 "' ' NH2 OH OH 0 2 N 0 2 N 66 68 'Reagents and conditions: (a) 4-chloro-3-nitrobenzaldehyde, CH 2 C1 2 , BSA, 15h; (b) 6N HCI, 100 0 C, 5h; (c) 4 morpholino-3-nitrobenzaldehyde, CH 2
CI
2 , BSA, 15h; (d) 6N HC, reflux, 5h. (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy) phosphinyl)-hydroxymethyl]-6-chloro-1-nitrobenzene (65). 65 was prepared from 5 (0.8mmol) and 4-chloro-3-nitrobenzaldehyde (445mg, 2.4mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 2.03 (in, 4H), 3.73 (s, 3H), 4.31 (m, 1H), 5.11 (s, 2H), 5.25 (d, J= 7.0 Hz, 1H), 7.34 (in, 5H), 7.65 (m, 2H), 8.07 (s, 1H). 31 P NMR (CD 3 0D): 8 46.26. (3S)-3-[(((3-amino-3-earboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl]-6-chloro-1 nitrobenzene (66). The removal of the protecting groups in compound 65 was accomplished using the same procedure as that used compound 16 and purified by Dowex AG50x4 column to afford 66. 'H NMR (D 2 0): 8 1.73 (m, 2H), 2.12 (m, 2H), 4.02 (in, 1H), 4.91 (d, J= 9.91 Hz, 1H), 7.60 (in, 2H); 7.98 (s, 1H). 3 P NMR (D 2 0): 8 49.02. 1 3 C NMR (D 2 0): 8 22.66 (d, J= 87.3 Hz), 23.55, 53.92 (d, J= 14.03 Hz), 72.00 (d, J= 106.4 Hz), 124.30, 125.79, 132.12, 132.56, 139.37, 147.39, 172.27. MS (ESI) m/z: 353.1 (M+1). (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy) phosphinyl)-hydroxymethyl]-6-morpholino-1-nitrobenzene (67). 67 was prepared from 5 (0.8mmol) and 4-morpholino-3-nitrobenzaldehyde (566mg, 2.4mmol) by using the procedure described for preparation of compound 15. 1H NMR (CD 3 0D): 8 2.05 (m, 411), 3.07 (m, 4H), 3.74 (s, 3H), 3.80 (m, 4H), 4.27 (m, 1H), 4.96 (d, J= 9.18 Hz, 1H), 5.12 (s, 2H), 7.30 (m, 6H), 7.67 (d, J= 8.49 Hz, IH), 7.91 (s, 1H). "P NMR (CD 3 0D): 8 45.98. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl]-6 morpholino-1-nitro benzene (68). The removal of the protecting groups in compound 67 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 68. 'H NMR (D 2 0): 5 1.64 (m, 2H), 2.05 (m, 2H), 3.03 (in, 4H), 3.73 (in, 1H), 3.81 (m, 4H), 4.79(d, J= 8.81 Hz, 1H), 7.27 (d, J= 8.54 Hz, 1H), 7.61 (d, J= 8.36 Hz, 1H), 7.91 (s, 1H). 3 'P NMR (D 2 0): 5 48.06. 1 3 C NMR (D 2 0): 6 23.13 (d, J= 90.9 Hz), 24.04, 52.06, 55.72, 66.88, 72.20 (d, J= 106.9 Hz), 121.29, 125.03, 133.60, 133.71, 142.22, 145.25, 174.46.
43 Scheme 14 00 0 OH H-PO-~ -a 0 2 N HN O a O2N H HN O 6 O NO 2 0 69 0 OH b iiO2NOH -~---- 0c 2 N / P~ N I NH2 OH
NO
2 70 aReagents and conditions (a) 2,4-dinitrobenzaldehyde, CH 2 C1 2 , BSA, 15h; (b) 6N HCI, 100*C , 5h
(
3
S)-
4
-[(((
3 -(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl)(hydroxy) phosphinyl)-hydroxymethyll-1,3-dinitrobenzene (69). The compound (69) was prepared from 5 (0.8mmol) and 4-methoxy-3-nitrobenzaldehyde (470 mg, 2.4mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 2.02 (in, 4H), 3.74 (s, 3H), 4.32 (in, 1H), 5.10 (s, 2H), 6.18 (in, 1H), 7.33 (in, 5H), 8.41 (in, 2H), 8.76 (d, J=8.39 Hz, 1H). 31 P NMR (CD 3 0D): 8 47.96.
(
3
S)-
4 -[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl]-1,3 dinitrobenzene (70). The removal of the protecting groups in compound 69 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 70. 'H NMR (D 2 0): 8 1.80 (m, 2H), 2.04 (in, 2H), 4.02 (in, 1H), 6.02 (d, J=1 1.15 Hz, 1H), 7.93 (d, J=8.70 Hz, 1H), 8.32 (s, 1H), 8.65 (d, J=7.33 Hz, 1H). 3 'P NMR (D 2 0): 8 54.37.
44 Scheme 15 0 OO 6 0 HOH HNyO 50O c OH OH OH OH 2 49 0 2 N 51 0 b d OHO 0HOH OH F _ P NH H OH 2 H 3 C - I NH 2 0 2 N 50 0 2 N 52 aReagents and conditions: (a) 3-nitro-4-(fluoro)benzaldehyde, CH 2
CI
2 , BSA, 15h; (b) 6N HC, reflux; (c) 3 nitro-4-(methyl)benzaldehyde, CH 2
C
2 , BSA, 15h; (d) 6N HCI, reflux (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3 methoxycarbonyl)propyl)(hydroxy)phosphinyl)-hydroxymethyl]-6-fluoro-l nitrobenzene (49). 49 was prepared from 5 (0.8mmol) and 3-nitro-4-(fluoro)benzaldehyde (507.3mg, 3mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 5 2.16 (m, 4H), 3.75 (s, 3H), 4.34 (m, 1H), 5.12 (s, 2H), 5.49 (d, J= 7.11 Hz, 1H), 7.39 (m, 6H), 7.86 (m, 1H), 8.26 (m, 1H). MP NMR (CD 3 0D): 8 47.99. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-6-fluoro-l-nitrobenzene (50). The removal of the protecting groups in compound 49 was accomplished using the same 45 procedure as that used compound 16 and purified by Dowex AG50x4 column to afford 50. 'H NMR (D 2 0): 6 1.75 (m, 2H), 2.11 (m, 2H), 4.00 (in, 1H), 4.89 (d, J= 9.02 Hz, IH), 7.35 (m, 1H), 7.70 (m, 1H), 8.09 (d, J= 6.84 Hz, 1H). "P NMR (D 2 0): 8 49.37. (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3 methoxycarbonyl)propyl)(hydroxy)phosphinyl) -hydroxymethyl]-6-methyl-1-nitrobenzene (51). The compound was prepared from 5 (0.8mmol) and 3-nitro-4-(methyl)benzaldehyde (495.5mg, 3mmol) by using the procedure described for preparation of compound 15. 1 H NMR (CD 3 0D): 8 2.14 (in, 4H), 2.55 (s, 3H), 3.74 (s, 3H), 4.32 (in, 1H), 5.12 (s, 2H), 5.46 (d, J= 7.54 Hz, 1H), 7.37 (in, 6H), 7.70 (d, J= 7.75 Hz, 1H), 8.13 (s, 1H). 31 P NMR (CD 3 0D): 6 48.69.
(
3
S)-
3
-[(((
3 -amino-3-carboxy)propyl)(hydroxy)phosphinyl)-6-methyl-1-nitrobenzene (52). The removal of the protecting groups in compound 51 was accomplished using the same procedure as that used compound 16 and purified by Dowex AG50x4 column to afford 52. 'H NMR (D 2 0): 6 1.61 (m, 2H), 2.03 (m, 2H), 2.47 (s, 3H), 3.68 (in, 1H), 4.81 (d, J= 8.89 Hz, 1H), 7.36 (d, J= 7.92 Hz, 1H), 7.54 (d, J= 7.78 Hz, 1H), 7.96 (s, 1H). 31 P NMR (D 2 0): 8 47.99.
Scheme 16 0 0 H + F3- I F3C HN OH \_- - H OH 5 0 53 O b 500 F3 0 OH
F
3 C NH 2 OH 54 aReagents and conditions: (a) CH 2 Cl 2 , BSA, 15h; (b) 6N HC1I, reflux (3S)-4-[(((3-(N-Benzyloxycarbonyl)amino-3 methoxycarbonyl)propyl)(hydroxy)phosphinyl) -hydroxymethyl1-trifluoromethylbenzene (53). The compound was prepared from 5 (0.8mmol) and 4-(trifluoromethyl)benzaldehyde (522.4mg, 3mmol) by a procedure similar to that for the preparation of compound 15. 'H NMR (CD 3 0D): 6 2.13 (in, 4H), 3.72 (s, 3H), 4.32 (m, 1H), 5.11 (m, 311), 7.35 (m, 5H), 7.72 (m, 4H). 3 P NMR (CD 3 0D): 8 48.75. (3S)-4-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-1-trifluoromethylbenzene (54). The removal of the protecting groups in compound 53 was accomplished using the same procedure as that used compound 16 and purified by Dowex AG50x4 column to afford 54. 1 H NMR (D20): 6 1.65 (m, 2H), 1.94 (m, 2H), 3.94 (in, 1H), 4.89 (d, J= 9.99 Hz, 1H), 7.50 (d, J= 7.94 Hz, 2H), 7.64 (d, J= 7.93 Hz, 2H). MP NMR (D 2 0): 8 50.59.
Scheme 17 0 0H0 0 O0 0 OH HP HNOa HN 0 OH 0 02 - 0OH 0 OH 0 OH
NH
2 OH 0 2 N 56 aReagents and conditions: (a) CH 2 C1 2 , BSA, 15h; (b) 6N HCI, reflux (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxyearbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 3-nitrobenzene (55). The compound was prepared from 5 (0.8mmol) and 3-nitrobenzaldehyde (453mg, 3mmol) by using the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 2.15 (m, 4H), 3.73 (s, 3H), 4.31 (m, 1H), 5.12 (s, 2H), 5.16 (m, 1H), 7.34 (m, 5H), 7.61 (in, 1H), 7.91 (m, 1H), 8.16 (m, 1H), 8.42 (s, 1H). "P NMR (CD 3 0D): 6 48.40. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 3-nitroben zene (56). The removal of the protecting groups in compound 55 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 56 (quantitative yield). 'H NMR (D 2 O): 6 1.72 (m, 2H), 2.09 (m, 2H), 4.01 (in, 11), 4.94 (d, J=9.57 Hz, 1H), 7.53 (t, J=7.99 Hz, 1H), 7.74 (d, J=7.53 Hz, 1H), 8.09 (d, J=8.17 Hz, 1H), 8.20 (s, 1H). 3 'P NMR (D 2 0): 8 49.69.
48 Scheme 18 0 OH H 0H0 0 HP
H
3 CO/ HN 0 OH O
NO
2 OH H 5
OCH
3 0 2 N 57 0 b 0 OH 0 OH
H
3 CO P
NH
2 0 2 N 58 aReagents and conditions: (a) CH 2 C12, BSA, 15h; (b) 6N HC1, 100 0 C, 5h
(
3
S)-
3
-[(((
3 -(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 3-nitro-4-methoxybenzene (57). The compound was prepared from 5 (0.8mmol) and 4-methoxy-3-nitrobenzaldehyde (543 mg, 3mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 5 2.10 (in, 4H), 3.73 (s, 3H), 3.92 (s, 3H), 4.31 (in, 1H), 5.02 (d, J=8.49 Hz, 1H), 5.12 (s, 2H), 7.22 (d, J=8.63 Hz, 1H), 7.35 (in, 5H), 7.72 (d, J=8.3 Hz, 1H), 8.01 (s, 1H). 31 P NMR (CD 3 0D): 6 48.73.
(
3
S)-
3 -[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 3-nitro-4 methoxybenzene (58). The removal of the protecting groups in compound 57 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 58. 'H NMR (D 2 0): 8 1.73 (in, 2H), 2.09 (in, 2H), 3.91 (s, 3H), 4.00 (m, 1H), 4.83 (d, J=8.67 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.78 Hz, 1H), 7.93 (s, 1H). 3 P NMR (D 2 0): 8 50.13.
Scheme 19 O 0 SH HP + H-P-H 0 0 H oM0U M 0 O 50% aqueous b O 0 0 0 O OH d EtOOC O O
H
3 COCHN HN OH Og OH 59 60 aReagents and conditions: (a) AIBN, CH 3 0H , reflux at 80 0 C, 5h; (b) dibromoethane, reflux at 120'C, 5h; (c) CH(OEt) 3 , reflux at 140*C; (d) diethylacetamidomalonate, K 2
CO
3 , tetrabutylammonium bromide in THF, reflux ; (e) 8N HCI, reflux, 15h 5-[((3-(N-Acetyl)amino)-3-(bisethoxycarbonyl)propyl)(ethoxy)phosphinyljpentanoic Acid Ethyl Ester (59). A mixture of hypophosphorous acid (3.3g, 25mmol, 50% aqueous), diethylallylmalonate (1mg, 5mmol) and ac,a'-azoisobutyronitrile (AIBN, 41mg, 0.25mmol) in methanol (2ml) was refluxed at 80'C for 5 h. Then the methanol was evaporated under vacuum and the residue was extracted with ethyl acetate, dried over MgSO 4 . The organic layer was evaporated under vacuum. Then the crude product (1.338g) was mixed with dibromoethane (2.4ml, 28mmol) and hexamethydisilazane (2.96ml, 14mmol) was heated at 120'C for 9h. The formed trimethylbromosilane and excess dibromoethane were removed under vacuum. Then 50 ml of aqueous ethanol (1:1) were added dropwise to the residue and refluxed for 0.5 h. Then the solvent was removed under vacuum and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and the solvent was removed under vacuum.
50 The crude product (270mg) was treated with 40ml of triethyl orthoformate, and the mixture was refluxed with a Dean-Stark trap to remove ethanol and ethyl formate. Excess of triethylorthoformate was removed under vacuum. The crude product (200mg) was mixed with diethylacetamidomalonate (174mg, 0.8mmol), potassium carbonate (221mg, 1.6mmol) and tetrabutylammonium bromide (13mg, 0.04mmol) in THF (1ml). The reaction mixture was refluxed with stirring for 15 h. The residue was extracted with chloroform, washed with water, dried over MgSO 4 and the solvent was removed in vacuum to give 59. 1H NMR
(CD
3 0D): 8 1.21 (m, 12H), 2.01 (m, 15H), 4.20 (m, 8H). 31 P NMR (D 2 0): 6 59.0. 5-[((3-Amino-3-carboxy)propyl)(hydroxy)phosphinylpentanoic Acid (60). 190mg of 59 was treated with 2 ml of 8N HCl and refluxed for 15 h. The reaction mixture was concentrated under vacuum and the residue was purified using Dowex AG50x4 cation exchange resin column (H+, 20-50 mesh, 24x1.7 cm, water elution). The fractions which gave positive color reaction with ninhydrine were combined and evaporated under vacuum to give 60. 'H NMR (D 2 0): 6 1.66 (m, 8H), 2.09 (m, 2H), 2.06 (m, 2H), 2.38 (t, J=7.2 Hz, 2H), 3.94 (t, J= 5.93 Hz, 1H). 3 'P NMR (D 2 0): 6 60.58.
Scheme 20a 0 O H-P raO OH 5 0 O O OH 11 0 HOH 0 C0, 02N OH OH 0 71 0 040CH3 73 O b d
O
2 N- OH 2 O
NH
2 72 07
CH
3 7 aReagents and conditions: (a) 4-nitrobenzaldehyde, CH 2 C1 2 , BSA, 20h; (b) 6N HCl, reflux, 5h; (c) 4 methylsulphonyl benzaldehyde, CH 2 Cl 2 , BSA, 15h; (d) 6N HCI, reflux, 3h (3S)-4-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] nitrobenzene (71). The compound was prepared from 5 (0.8mmol) and 4-nitrobenzaldehyde (302mg, 2mmol) by using the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 1.98 (in, 4H), 3.73 (s, 3H), 4.32 (m, 1H), 5.12 (s, 2H), 5.19 (d, J=12.56 Hz, 1H), 7.33 (in, 5H), 7.71 (m, 2H), 8.19 (d, J=8.32 Hz, 2H). ' 1 P NMR
(CD
3 0D): 8 48.26. (3S)-4-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] nitrobenzene (72). The removal of the protecting groups in compound 71 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 72 (quantitative yield). 1 H NMR (D 2 0): 8 1.72 (in, 2H), 2.11 (m, 52 2H), 4.02 (m, 1H), 4.97 (d, J=10.8 Hz, 1H), 7.58 (d, J=7.43 Hz, 2H), 8.18 (d, J=8.64 Hz, 2H). 31 P NMR (D 2 0): 8 49.43. 13C NMR (D 2 0): 6 22.79 (d, J=98.03 Hz), 23.57, 54.02, 73.05 (d, J=104.90 Hz), 123.89, 127.98, 146.45, 147.40, 172.27. Mass (ESI): 319.1 (M+1). (3S)-4-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] methylsulphonylbenzene (73). The compound was prepared from 5 (0.8mmol) and 4-methylsulphonylbenzaldehyde (276mg, 1.5mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 6 2.03 (m, 4H), 3.11 (s, 3H), 3.72 (s, 3H), 4.32 (m, 1H), 5.12 (s, 2H), 5.14 (d, J=7.12 Hz, 1H), 7.35 (m, 5H), 7.76 (d, J=7.31 Hz, 2H), 7.96 (d, J=8.17 Hz, 2H). 31 P NMR (CD 3 0D): 6 48.37. 1 3 C NMR
(CD
3 0D): 6 22.10 (d, J=91.02 Hz), 24.19, 43.65, 52.20, 55.01, 66.95, 71.87 (d, J=108.88 Hz), 127.28, 128.01, 128.28, 128.72, 137.10, 140.17, 144.50, 157.61, 172.86.
(
3
S)-
4
-[(((
3 -amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethylI methylsulpho nylbenzene (74). The removal of the protecting groups in compound 73 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 74 (quantitative yield). 'H NMR (D 2 0): 6 1.69 (m, 2H), 2.07 (m, 2H), 3.16 (s, 3H), 3.99 (m, 111), 4.93 (d, J=10.63 Hz, 1H), 7.59 (d, J=8.31 Hz, 211), 7.84 (d, J=8.33 Hz, 211). 3 'P NMR (D 2 0): 6 49.72. 1 3 C NMR (D20): 8 21.69 (d, J=88.19 Hz), 22.87, 43.66, 53.21, 71.92 (d, J=107.75 Hz), 127.54, 128.26, 138.65, 143.91, 171.42.
Scheme 21a 0 OH 5 0 O O 0 2 N O H O H H 2H b d -HNY"" o 0 HN 0 O 2 NHH O H 0 2 N OH 0 2 N OH 75N 0 7 02N OH OH 9" ;OH 0 OH I NH2 P, NH OH OH NH 0 2 N OH 0 2 N OH 76 78 aReagents and conditions : (a) 3,5-dinitrosalicylaldehyde, CH 2 C1 2 , BSA, 15h; (b) 6N HCl, reflux, 3h; (c) 2 hydroxy 3-nitrobenzaldehyde, CH 2
CI
2 , BSA, 15h; (d) 6N HCI, reflux, 3h (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 2-hydroxy-1,5-dinitrobenzene (75). The compound was prepared from 5 (0.8mmol) and 3,5-dinitrosalicylaldehyde (424mg, 2mmol) by using the procedure described for preparation of compound 15. 'H NMR (CD30D): 8 2.04 (in, 4H), 3.75 (s, 3H), 4.29 (m, 1H), 5.07 (s, 2H), 5.55 (d, J=10.45 Hz, 1H), 7.31 (m, 5H), 8.64 (m, 1H), 8.88 (m, 1H). "P NMR (CD 3 0D): 8 48.38. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 2-hydroxy 1,5-dinitrobenzene (76). The removal of the protecting groups in compound 75 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 76 (quantitative yield). 'H NMR (D 2 0): 8 1.84 (in, 2H), 2.18 (m, 2H), 4.04 (m, 1H), 5.37 (d, J=8.28 Hz, 1H), 8.57 (s, 1H), 8.93 (s, 1H). MP NMR 54
(D
2 0): 8 49.52. "C NMR (D 2 0): 8 23.39 (d, J=98.75 Hz), 23.65, 54.3, 67.2 (d, J=106.3 Hz), 121.67, 129.67, 132.29, 134.48, 139.74, 156.2, 172.39. Mass (ESI): 381.1 (M+1). (3S)- 3 -[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 2-hydroxy-nitrobenzene (77). The compound was prepared from 5 (0.8mmol) and 2-hydroxy-3-nitrobenzaldehyde (334mg, 2mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 6 1.96 (m, 4H), 3.73 (s, 3H), 4.29 (m, 1H), 5.12 (s, 2H), 5.55 (d, J=7.89 Hz, IH), 7.08 (t, J=8.05 Hz, 1H), 7.33 (m, 5H), 7.95 (d, J=7.45 Hz, 1H), 8.06 (d, J=8.36 Hz, 1H). "P NMR (CD 3 0D): 8 48.74. 1 3 C NMR
(CD
3 0D): 6 21.76 (d, J=88.40 Hz), 24.20, 52.09, 55.04, 65.25 (d, J=1 11.58 Hz), 66.87, 119.89, 124.68, 127.88, 128.13, 128.58, 129.45, 134.32, 136.57, 137.07, 151.83, 157.62, 172.82.
(
3
S)-
3 -[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 2-hydroxy nitrobenzene (78). The removal of the protecting groups in compound 77 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 78 (quantitative yield). 'H NMR (D 2 0): 6 1.83 (m, 2H), 2.12 (m, 2H), 4.08 (m, IH), 5.34 (d, J=7.74 Hz, 1H), 7.06 (t, J=8.14 Hz, 1H), 7.78 (d, J=7.59 Hz, 1H), 8.03 (d, J=8.50 Hz, 1H). 31 P NMR (D 2 0): 6 50.72. 1 3 C NMR (D 2 0): 8 23.19 (d, J=89.51 Hz), 23.58, 53.91, 66.31 (d, J=108.25 Hz), 120.45, 125.17, 129.22, 134.59, 136.51, 151.51, 172.41.
55 Scheme 22a 0 0 O H-P HN O 6H O 0c F OHO OHOH O O 0 F P PHNN - OH I O H N F F 0 0 2 N 81 0 0 82 F F OHO 0H0 OH OH I_ NH 2
-N
2 OH O'H F F 0 2 N 80 82 aReagents and conditions: (a) pentafluoro benzaldehyde, CH 2 Cl 2 , BSA, 15h; (b) 6N HC1, reflux, 3h; (c) 2 hydroxy 5-nitrobenzaldehyde,
CH
2 C1 2 , BSA, 15h; (d) 6N HCl, reflux, 3h (3S)-1-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyll 2,3,4,5,6-pentafluorobenzene (79). The compound was prepared from 5 (0.8mmol) and pentafluoro benzaldehyde (392mg, 2mmol) by using the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 2.16 (in, 4H), 3.76 (s, 3H), 4.32 (m, 1H), 5.12 (s, 2H), 5.34 (d, J=11.02 Hz, 1H), 7.33 (m, 5H). MP NMR (CD 3 0D): 6 47.51. (3S)-1-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 2,3,4,5,6 penta fluorobenzene (80). The removal of the protecting groups in compound 79 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 80 (quantitative yield). 'H NMR (D 2 0): 8 1.86 (m, 2H), 56 2.13 (m, 2H), 4.07 (m, 1H), 5.18 (d, J=10.68 Hz, 1H). "P NMR (D 2 0): 8 47.78. Mass (ESI): 364.1 (M+l). (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 4-hydroxy-nitrobenzene (81). The compound was prepared from 5 (0.8mmol) and 2-hydroxy-5-nitrobenzaldehyde (334mg, 2mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 2.05 (in, 4H), 3.72 (s, 3H), 4.30 (in, 1H), 5.12 (s, 2H), 5.45 (d, J=7.41 Hz, 1H), 6.96 (d, J=8.95 Hz, IH), 7.30 (m, 5H), 8.07 (in, 1H), 8.47 (s, 1H). 3 P NMR (CD 3 0D): 6 49.56. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 4-hydroxy nitrobenzene (82). The removal of the protecting groups in compound 81 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 82 (quantitative yield). 'H NMR (D 2 0): 8 1.83 (in, 2H), 2.09 (in, 2H), 3.98 (in, 1H), 5.10 (d, J=8.22 Hz, 1H), 6.83 (d, J=9.01 Hz, 1H), 7.91 (d, J=8.93 Hz, 1H), 8.16 (s, 1H). 3 PNMR (D 2 0): 6 51.73. "C NMR (D 2 0): 8 20.90 (d, =76.74 Hz), 21.51, 51.95 (d, J=13.02 Hz), 65.72 (d, J=108.25 Hz), 114.91, 122.96, 123.66, 124.20, 138.82, 158.63, 170.29. Mass (ESI): 335.1 (M+1).
57 Scheme 23a 0 O II 0
H-P
OH HNYO 5 0 a c OH O O, <- If, - ~~HNYO-, Pi 0 OH S OH HN 0 2 N 83 0 0 2 N 85 0 b d OH O 9,, OH OH PH NH,
NH
2 0 OH P\SOH 0 2 N 84 0 2 N 86 aReagents and conditions: (a) 5-nitro-2-furaldehyde, CH 2 C1 2 , BSA, 18h; (b) 6N HCI, 90*C , 3h; (c) 5-nitro-2 thiophenecarboxaldehyde, CH 2 Cl 2 , BSA, 15h; (d) 6N HCl, 90*C, 3h (3S)-2-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 5-nitrofuran (83). The compound was prepared from 5 (0.8mmol) and 5-nitro-2-furaldehyde (282mg, 2mmol) by using the procedure described for preparation of compound 15. 1 H NMR (CD 3 0D): 8 2.07 (m, 4H), 3.73 (s, 3H), 4.32 (m, 1H), 5.08 (d, J=15.98 Hz, 1H), 5.11 (s, 2H), 6.80 (m, 1H), 7.38 (m, 6H). 3 'P NMR (CD 3 0D): S 46.14. (3S)-2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl 5 nitrofuran (84). The removal of the protecting groups in compound 83 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 84 (quantitative yield). 1H NMR (D 2 0): 8 1.86 (m, 2H), 2.19 (m, 2H), 4.12 (m, 1H), 4.95 (d, J=1 1.96 Hz, 1H), 6.73 (m, 1H), 7.50 (d, J=3.69 Hz, 1H). 3 1 P NMR
(D
2 0): 6 48.16. Mass (ESI): 307.1 (M+1).
58 (3S)-2-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 5-nitrothiophene (85). The compound was prepared from 5 (0.8mmol) and 5-nitro-2-thiophenecarboxaldehyde (314mg, 2mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD30D): 8 2.08 (in, 4H), 3.72 (s, 3H), 4.30 (in, 1H), 5.10 (in, 3H), 7.12 (in, 111), 7.34 (in, 5H), 7.89 (in, 1H). 31 P NMR
(CD
3 0D): 6 46.65. (3S)-2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 5-nitrothio phene (86). The removal of the protecting groups in compound 85 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 86 (quantitative yield). 1H NMR (D 2 0): 8 1.78 (in, 2H), 2.14 (in, 2H), 4.02 (in, 1H), 5.08 (d, J=1 1.11 Hz, 1H), 7.06 (in, 11), 7.94 (d, J=4.30 Hz, 1H). 31 P NMR
(D
2 0): 8 46.82. 1 3 C NMR (D 2 0): S 22.83 (d, J=93.34 Hz), 23.70, 53.89, 70.19 (d, J=106.74 Hz), 124.93, 130.71, 150.24, 153.80, 172.35. Mass (ESI): 323.1 (M-1).
59 Scheme 24" 0 O O O H-P HN O 50 ~c O O OH HN O H HN 0 0 OH O O H
F
3 C 87 0 0 OH OH
NO
2 OH0 OH 0 II-\ .If, OH OH NH 2 PH 0- OH NH
F
3 C 88NO 2 88 90 aReagents and conditions : (a) 5-trifluoromethyl-2-furaldehyde, CH 2 C1 2 , BSA, 15h; (b) 6N HCI, 90*C, 3h ; (c) 2,6-dinitrobenzaldehyde, CH 2 C1 2 , BSA, 15h; (d) 6N HC1, 90 0 C, 3h (3S)-2-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyll 5-trifluoromethylfuran (87). The compound was prepared from 5 (0.8mmol) and 5-trifluoromethyl-2-furaldehyde (328mg, 2mmol) by using the procedure described for preparation of compound 15. 1 H NMR (CD 3 0D): a 2.01 (m, 4H), 3.72 (s, 3H), 4.32 (m, 1H), 5.03 (d, J=11.24 Hz, 1H), 5.12 (s, 2H), 6.70 (m, 1H), 6.94 (m, 1H), 7.32 (m, 5H). 3 P NMR (CD 3 0D): 8 46.79. (3S)-2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 5 trifluorome thylfuran (88). The removal of the protecting groups in compound 87 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 88 (quantitative yield). 1H NMR (D 2 0): 8 1.82 (m, 2H), 60 2.18 (in, 2H), 4.07 (in, 1H), 4.85 (d, J=11.59 Hz, 1H), 6.53 (in, 1H), 6.59 (in, 1H). "P NMR
(D
2 0): 8 48.29. "C NMR (D 2 0): 8 23.11 (d, J=91.21 Hz), 23.41, 53.82 (d, J=13.90 Hz), 67.16 (d, J=109.70 Hz), 110.80, 113.74, 115.53 (q, J=266.26 Hz), 141.40 (q, J=43.59 Hz), 154.59, 172.09. (3S)-2-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 1,3-dinitrobenzene (89). The compound was prepared from 5 (0.8mmol) and 2,6-dinitrobenzaldehyde (392mg, 2mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 6 1.96 (in, 4H), 3.72 (s, 3H), 4.32 (in, 1H), 5.11 (s, 2H), 6.27 (d, J=16.15 Hz, 1H), 7.34 (in, 5H), 7.64 (in, 1H), 7.97 (d, J=7.86 Hz, 2H). "P NMR (CD 3 0D): 6 48.69. (3S)-2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl 1,3-dinitro benzene (90). The removal of the protecting groups in compound 89was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 90 (quantitative yield). 'H NMR (D 2 0): 6 1.87 (m, 2H), 2.12 (m, 2H), 4.03 (in, 1H), 5.96 (d, J=1 1.57 Hz, 1H), 7.64 (t, J=7.97, 1H), 8.01 (d, J=6.70 Hz, 2H). "P NMR (D 2 0): 6 48.28. 1 3 C NMR (D 2 0): 6 23.80, 24.55 (d, J=93.91 Hz), 54.29, 69.17 (d, J=100.70 Hz), 128.81, 129.65, 149.49, 172.54. Mass (ESI): 364.1(M+1).
61 Scheme 25a HO 0 HO H O 0 OO b N + H 0. H-P HNYO"
CF
3 - CF 3 / CF 3 OH
NO
2
NO
2
NO
2 5 0 91 92 c O 0 OH dN OO __ d ___ _HN 0 O
NH
2 ' / OH 0 2 N / OH 0 2 N 0
CF
3 93
CF
3 4 aReagents and conditions: (a) BH 3 , THF, 2h; (b) (CICO) 2 , DMSO, TEA, CH 2 C1 2 ; (c) CH 2 C1 2 , BSA, 0.5h; (d) 6N HCI, 90*C, 3h 3-trifluoromethyl-4-nitrobenzyl alcohol (91). To a stirred solution of 3-trifluoromethyl-4 nitrobenzoic acid (3g) in 15 ml of tetrahydrofuran at 0*C was added 1 M BH 3 /THF (64 ml) dropwise under argon. This reaction mixture was allowed to stir at room temperature for 2h and quenched by saturated NaHCO 3 . The solution was extracted with dichloromethane and then evaporated the organic layer to dryness in vacuo. The crude residue was purified on silica gel using cyclohexane:ethylacetate (90:10 to 60:40, gradient) as the eluent to afford 1.76 g of 91. 'H NMR (CD 3 0D): 6 4.80 (s, 2H), 7.78 (d, J=8.33 Hz, 1H), 4.91 (in, 2H). 3-trifluoromethyl-4-nitrobenzaldehyde (92). Dichloromethane (7 ml) was cooled to -78*C in round bottom flak with septum under argon. Oxalyl chloride (0.49 ml) was added in one portion. Dimethyl sulfoxide (0.67ml) in dichloromethane (3.5ml) was added dropwise over lh. 3-trifluoromethyl-4-nitrobenzyl alcohol 91 (1.04g) in dichloromethane (7ml) was added dropwise over lh. The reaction mixture was stirred at -78*C for 45min. Triethylamine (2.6ml) was added over 45 min. TLC analysis indicated the reaction was complete. The reaction was quenched with 1 M aqueous potassium hydrogensulfate (50ml).the organic layer was washed with saturated NaHCO 3 (50ml), water (50ml), and brine (50ml). The organic layer was dried over magnesium sulphate, and concentrated in vacuo to afford the desired aldehyde 92. 'H NMR (CDCl 3 ): 8 8.05 (d, J=8.2 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.36 (s, 1H), 10.18 (s, 1H).
62 (3S)-4-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyl] 2-trifluoromethyl-1-nitrobenzene (93). The compound was prepared from 5 (0.8mmol) and 3- trifluoromethyl-4-nitrobenzaldehyde (394mg, 1.8mmol) by following the procedure described for preparation of compound 15. 'H NMR (CD 3 0D): 8 2.05 (m, 4H), 3.74 (s, 3H), 4.32 (m, 1H), 5.11 (s, 2H), 5.18 (d, J=10.39 Hz, 1H), 7.34 (m, 5H), 8.01 (in, 3H). 31 P NMR (CD 3 0D): 8 47.70. (3S)-4-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl 2-trifluoro methyl-1-nitrobenzene (94). The removal of the protecting groups in compound 93 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG5Ox4 column to afford 94 (quantitative yield). 'H NMR (D 2 0): 8 1.79 (m, 2H), 2.14 (m, 2H), 4.03 (in, 1H), 5.02 (d, J=10.85 Hz, 1H), 7.82 (d, J=8.42 Hz, 1H), 7.94 (s, 1H), 8.02 (d, J=8.43 Hz, 1H). 3 'P NMR (D 2 0): 8 48.33. Mass (ESI): 387.1 (M+1). Scheme 26a HO H 0 0 0 a + H 4 b 0 2 N
NO
2 0 2 N -NO 2 OH H N3-o 95 5 0 O0 0 H 0 2 N O p c 0 2 N O OH H I~i NH 2 H HN OM H S O H 0~ N 0 2 9 7O
NO
2 96 NO 2 97 aReagents and conditions: (a) (C1CO) 2 , DMSO, TEA, CH 2
CI
2 ; (b) CH 2 Cl 2 , BSA, 0.5h; (c) 6N HCI, 90*C, 3h 3,5-dinitrobenzaldehyde (95). The title compound was obtained from 3,5-dinitrobenzyl alcohol as yellow solid in a similar manner for the preparation of 92. 'H NMR (CDCl 3 ): 6 9.04 (s, 2H), 9.22 (s, IH), 10.25 (s, 1H). (3S)-3-[(((3-(N-Benzyloxycarbonyl)amino-3-methoxycarbonyl)propyl) (hydroxy) phos phinyl)-hydroxymethyll 1,5-dinitrobenzene (96). The compound was prepared from 5 (0.8mmol) and 3,5-dinitrobenzaldehyde (392mg, 2mmol) by using the procedure described 63 for preparation of compound 15. 'H NMR (CD 3 0D): 8 1.99 (m, 4H), 3.75 (s, 3H), 4.32 (m, 1H), 5.10 (s, 2H), 5.29 (d, J=9.43 Hz, 1H), 7.32 (m, 5H), 8.72 (s, 2H), 8.88 (s, 1H). 3 P NMR
(CD
3 0D): 8 47.71. 1 3 C NMR (CD 3 0D): S 22.28 (d, J=92.43 Hz), 24.10, 52.19, 54.96, 66.92, 70.65 (d, J=108.91 Hz), 117.79, 127.30, 127.86, 128.15, 128.59, 136.98, 143.01, 148.60, 157.60, 172.83. (3S)-3-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-hydroxymethyl] 1,5 dinitrobenz ene (97). The removal of the protecting groups in compound 96 was accomplished following the same procedure as that followed for compound 16 and purified by Dowex AG50x4 column to afford 97 (quantitative yield). 'H NMR (D 2 0): S 1.78 (m, 2H), 2.14 (m, 2H), 4.05 (m, 1H), 5.08 (d, J=10.04 Hz, 1H), 8.58 (s, 2H), 8.91 (s, 1H). "P NMR
(D
2 0): 8 48.29. "C NMR (D 2 0): 8 22.81 (d, J=91.46 Hz), 23.54, 53.84, 71.99 (d, J=104.79 Hz), 118.30, 127.49, 143.41, 148.37, 172.17. Mass (ESI): 364.0 (M+1). Example 2: Sythesis of substituted benzaldehydes A) Preparation of nitro-benzaldehydes from nitro-benzoic acids or nitro-benzyl alcohols 1) Reduction (step 1) - oxidation (step 2)
CO
2 H
CH
2 OH CHO red oxyd
NO
2 rNO 2
.NO
2 Reduction step: a) BH3-SMe2 (Aulenta JOC 05; Campbell TLO3) b) BH3, THF (Campbell TL03; Liou JMC04; Parlow JMC03) Oxidation step: a) PDC (Liou JMC04) b) PCC (Aulenta JOC05; Campbell TL03) c) oxidizing polymer (Sorg Angew 01) d) Swern (Campbell 03; Parlow JMC03) 2) one step reduction i) TMSC ii) DiBAL-H (Chandrasekhar TL98) 64 This procedure was applied to the following alcohols or acids:
CH
2 OH OH 02N
NO
2 1
CH
3
NO
2
NO
2 B) Substitutions of nitro-benzaldehydes 1) substitution with benzofurazans CHO CHO F + O O
NO
2
NO
2 0): :N OH R 0 N R= NO 2 or SO 2
NH
2 R benzofurazan 2) substitution with sulfonyl chlorides CHO SO 2 CI CHO K2C03 ref1 Carr OL2004 +
NO
2 acetone reflux 24h NO 2 ref2 LinJMC1991 OH TsO other sulfonylchlorides can be used, for example S0 2 CI S0 2 CI S0 2 CI S0 2 CI S02CI
-OCF
3 -N0 2
-CF
3 N o-, in-, p- avaible o-, in-, p- avaible 0-, m-, p at SIAL at SIAL avaible at SIAL dansyl
N,
65 The following phosphinates can be synthesized using the aldehydes described above C0 2 H oCO 2 H HO , P O" HHO NH 2 HO P\ NH 2 P OH OH
INO
2
NO
2
NO
2
NO
2 OH H CO 2 H CO 2 H HO P\ NH NH 2 HOONHH NH 2 'OH
N
2
~NNO
2 0 C0 TsO S0 2 -0 R N / R R= N0 2 or SO 2
NH
2
N
66 Example 3: Experimental of hypophosphorous acid derivatives according to Method B Scheme 27 0
(H
3
C)
3 SiOP b (H 3
C)
3 SiOP
(H
3
C)
3 SiO' (H 3
C)
3 SIO' c 0 00 0 0 + B d OH 2a 2b e EtOOC0 0 EtOIC->P^ A o- f OC_,-, ICI 2 H
H
3 COCHN HOOC10 NH 2 09 OH 3 4 Reagents and conditions: (a) reflux at 1204C; (b) ethyl acrylate, 504C, 2h; (c) dibromoethane, reflux at 120*C, 5h; (d) CH(OEt) 3 , reflux at 140*C; (e) diethylacetamidomalonate, K 2 C0 3 , tetrabutylammonium bromide in THF, reflux; (f) 8N HC1, reflux, 15h 3-[(2-Bromoethyl)(ethoxy)phosphinyl)]propanoic Acid Ethyl Ester (1). A mixture of ammonium hypophosphite (4g, 48mmol) and hexamethydisilazane (7.73g, 48mmol) was heated at 120*C for one hour under argon. After the mixture was cooled to 0*C, ethyl acrylate (4.8g, 48mmol) was carefully added dropwise and the resulting mixture was stirred at 504C for 2h. Then the mixture was cooled to room temperature, dibromoethane (20ml) was added and stirred for 5h at 120*C. The formed trimethylbromosilane and excess dibromoethane were removed under vacuum. Then 50 ml of aqueous ethanol (1:1) were added dropwise to the residue and refluxed for 0.5 h. Then the solvent was removed under vacuum and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and the solvent was removed in vacuum to give 1 (5.42g, 41.4%). 1H NMR (CD 3 0D): 8 1.25 (t, J= 7.1 Hz, 3H), 2.06 (m, 2H), 2.42 (m, 2H), 2.61 (m, 2H), 2.61 (m, 2H), 4.14 (q, J= 7.1 Hz, 2H). "P NMR (CD 3 0D): 8 49.5.
67 3-[Ethoxy(vinyl)phosphinyl]propanoic Acid Ethyl Ester (2). 5.42g of 1 (19.9mmol) were treated with 40ml of triethyl orthoformate, and the mixture was refluxed with a Dean-Stark trap to remove ethanol and ethyl formate. Excess of triethylorthoformate was removed in vacuo to give 2a+2b ([39.5:60.5], 5.91g).2b: 'H NMR (CD 3 0D): 8 1.27 (m, 6H), 2.18 (m, 2H), 2.57 (m, 2H), 4.10 (m, 4H), 6.36 (m, 3H). 31 P NMR (CD 3 0D): 8 44.9. 3-[((3-(N-Acetyl)amino)-3-(bisethoxycarbonyl)propyl)(ethoxy)phosphinyllpropanoic Acid Ethyl Ester (3). Compound 2 (500mg, 0.9:lmmol[a:b]) was mixed with diethylacetamidomalonate (453mg, 2.1mmol), potassium carbonate (573mg, 4.2mmol) and tetrabutylammonium bromide (32.2mg, 0.lmmol) in THF (2ml). The reaction mixture was refluxed with stirring for 15 h. The residue was extracted with chloroform, washed with water, dried over MgSO 4 and the solvent was removed in vacuum to give 3 (564mg, 67.9%). The residue was purified by column chromatography (Silica gel 60, EtOAc/MeOH, 1:0 to 8:2) to afford 3 (507mg). 'H NMR (CD 3 0D): 8 1.31 (in, 12H), 1.75 (in, 2H), 2.05 (s, 3H), 2.16 (m, 2H), 2.59 (m, 4H), 4.17 (in, 8H). 1 3 C NMR (CD 3 0D): 8 13.5, 16.1, 21.6, 22.4 (d, J= 101 Hz), 22.9 (d, J= 93 Hz), 25.8, 26.7, 60.5, 61.1, 62.7, 66.8 (d, J= 17 Hz), 167.6, 171.4, 172.5 (d, J= 14 Hz). "P NMR (CD 3 0D): 6 58.1. 3-[((3-Amino-3-carboxy)propyl)(hydroxy)phosphinyl]propanoic Acid (4). 210mg of 4 (0.48mmol) was treated with 2 ml of 8N HCl and refluxed for 15 h. The reaction mixture was concentrated under vacuum and the residue was purified using Dowex AG5Ox4 cation exchange resin column (H*, 20-50 mesh, 24x1.7 cm, water elution). The fractions which gave positive color reaction with ninhydrine were combined and evaporated under vacuum to give 5 (95mg, 82.8%). 'H NMR (D 2 0): 6 1.66 (m, 2H), 1.85 (m, 2H), 2.06 (m, 2H), 2.51 (m, 2H), 3.96 (t, J= 5.7 Hz, 1H). 3 C NMR (D 2 0): 6 23.5, 24.3 (d, J= 91 Hz), 25.0 (d, J= 91 Hz), 27.3, 54.1 (d, J= 15 Hz), 172.6, 177.5 (d, J= 15 Hz). 3 'P NMR (D 2 0): 6 57.4. MS (ESI): m/z 238.1 (M-1). Anal. (C 7 H1 4
NO
6 P. 0.25H20) C, H, N.
68 Scheme 28 0
(H
3
C)
3 SiO'PH b (H 3
C)
3 Sio'P100
(H
3
C)
3 SiO (H3C) c O O o O OH 9a 9b 0 EtOOC O HOOC C0 2 H EtOOC1- OP f HOOC O CO2
H
3 COCHN NH 2 OH 10 11 Reagents and conditions: (a) reflux at 1200C; (b) diethyl maleate, 50*C, 2h; (c) dibromoethane, reflux at 1200C; (d) CH(OEt) 3 , reflux at 1400C; (e) diethylacetamidomalonate, K 2 C0 3 , tetrabutylammonium bromide in THF, reflux; (f) 8N HCI, reflux 2-[((2-Bromoethyl)(hydroxy)-phosphinyl)methyllbutane-1,4-dioic Acid Ethyl Ester (8). The compound was prepared from diethyl maleate by a procedure similar to that for the preparation of compound 1 (oily liquid, 1.21g, 35% yied); IH NMR (CD 3 0D): 6 1.26 (m, 6H), 2.58 (m, 2H), 2.91 (m, 2H), 3.50 (m, 1H), 3.66 (m, 2H), 4.20 (m, 4H). "P NMR (CD 3 0D): 8 41.9. 2-[(((3-(N-Acetyl)amino)-3-(bisethoxycarbonyl)propyl)(ethoxy)phosphinyl)methyllbutane-1,4 dioic Acid Ethyl Ester (10). Compound 8 was esterified by triethylorthoacetate by a procedure similar to that for the preparation of compound 2 (oily liquid, 1.36g); "P NMR (CD 3 0D): 6 37.8, 48.1 (9a and 9b). The residue (1g) was used for the next step procedure similar to that of compound 3 without further purification. (77.1% yield over two steps); '1H NMR (CD 3 0D): 8 69 1.33 (m, 15H), 1.88 (m, 2H), 2.07 (s, 3H), 2.57 (in, 2H), 2.92 (m, 2H), 3.56 (m, 1H), 4.22 (m, 10H). "P NMR (CD 3 OD): 8 51.7.52.2 (1:1). MS (ESI): m/z 508.1 (M-1). 2-[(((3-amino-3-carboxy)propyl)(hydroxy)phosphinyl)-methyllbutane-1,4-dioic Acid (11). The removal of the protecting groups in compound 10 (186mg, 0.37mmol) was accomplished using the same procedure as that used for compound 4 to afford 11. The residue was purified by anion exchange chromatography. The residue was dissolved in freshly boiled and cooled water (0.2L), then pH adjusted to 9-10, and the solution deposited on a AG1x4 resin (HCOO~, 200-400 mesh, 8.5x1 cm). The resin was washed with boiled water and the compound 10 was eluted with 0.72-0.73 M HCOOH (83mg, 80% yied). 1H NMR (D 2 0): 8 1.78 (in, 2H), 2.14 (in, 2H), 2.81 (in, 2H), 3.18 (in, 1H), 4.05 (t, J= 5.9 Hz, 1H). "C NMR
(D
2 0): 6 23.4, 24.7 (d, J= 96 Hz), 30.9, 45.0 (d, J= 77 Hz), 53.7 (d, J= 15 Hz), 172.0, 174.4, 176.2 (d, J= 15 Hz). "P NMR (D 2 0): 6 46.5. Scheme 29 0
(H
3
C)
3 SiO'PH b (H 3
C)
3 SiO,
(H
3
C)
3 iO' (H 3
C)
3 SiO c 0 0
H
2 N OH e NH O d NH O :r P OH~ P 0 --- HO OH O OH HOOC OH 14 13 12 Reagents and conditions: (a) reflux at 120*C; (b) ethyl acrylate, 50 0 C, 2h; (c) acetamidoacrylic acid, 60*C, 4h; (d) 2N HCI, MeOH, 80 0 C, 0.5h; (e) 8N HCI, reflux 3-[(((2-(N-Acetyl)amino)-2-carboxy)propyl)(hydroxy)phosphinyllpropanoic Acid Ethyl Ester (12). A mixture of ammonium hypophosphite (498mg, 6mmol) and hexamethydisilazane (966g, 6mmol) was heated at 120 0 C for one hour under argon. After the 70 mixture was cooled to 0 0 C, ethyl acrylate (350mg, 3.5mmol) was carefully added dropwise and the resulting mixture was stirred at 50*C for 2h. Then the mixture was cooled to room temperature, acetamidoacrylic acid (387mg, 3mmol) was added and stirred for 5h at 65 0 C. A sample was taken from the reaction mixture and treated with one drop of 2N HCl and
CD
3 0D. 'H NMR (CD 3 0D): 8 1.28 (t, J= 7.1 Hz, 3H), 2.02 (s, 3H), 2.12 (m, 2H), 2.36 (m, 2H), 2.62 (m, 2H), 4.18 (q, J= 7.1 Hz, 2H), 4.72 (i, 1H). 3 P NMR (CD 3 0D): 8 48.7. 3-[(((2-(N-Acetyl)amino)-2-methoxycarbonyl)propyl)(hydroxy)phosphinyl]propanoic Acid Methyl Ester (13). 10 ml of 2N HCI was added dropwise to the above residue and extracted with ethylacetate. The aqueous part was evaporated to dryness, then 50 ml of methanol were added and the solvent was removed at 50*C under vacuum to afford 13 (645mg, 73% yield over three steps). 'H NMR (CD 3 0D): 8 2.08 (s, 3H), 2.14 (in, 2H), 2.43 (m, 2H), 2.65 (in, 2H), 3.71 (s, 3H), 3.76 (s, 3H), 4.80 (m, 1H). 31 P NMR (CD 3 0D): 8 51.8. 3
-[((
2 -amino-2-carboxy)propyl)(hydroxy)phosphinyljpropanoic Acid (14). The removal of the protecting groups in compound 13 (525mg, 1.78mmol) was accomplished following the same procedure as that followed for compound 4 to afford 14. Compound 14 was purified by a Dowex AG50x4 column as described earlier (quantitative yied). H NMR (D 2 0): 6 1.93 (m, 2H), 2.06 (in, 1H), 2.32 (m, IH), 2.56 (in, 2H), 4.19 (in, 1H). "C NMR (D 2 0): 8 25.3 (d, J= 96 Hz), 27.3, 29.4 (d, J= 86 Hz), 49.3, 172.0, 177.3. 3 P NMR (D 2 0): 8 52.0. MS (ESI): m/z 224.1 (M-1). Example 4: Synthesis of Oxophosphonates The a-hydroxyphosphinates described above may be oxidized to a-oxophosphinates usind PDC (pyridinium dichromate) (see P. Vayron et al. Chem. Eur. J. 2000, 6, 1050) HO 0 CO2R oxidation 00 D-alkyl,aryl P-M NHZ, D-alkyl,aryl O -M CHZ OH NZ PDC OH NH 71 Example 5: Synthesis of Sulfonates Sulfides were oxidized to sulfones using oxone. Examples are given below. R0 2 C OH 1) oxone
NO
2 2) deprotection H NOO ZHN OH H 2 N' P ~ N0 2
O
2 OH 1) oxone RC \NO 2) deprotection
HO
2 C OH HO 0 b Example 6: Separation of a-hydroxyphosphinate diastereoisomers Substituted hydroxymethyl phosphinates as 22, 24, etc. are mixtures of diastereoisomers. They were separed by HPLC using a reverse phase column (see for example Liu et al. J.Organometal. Chem. 2002, 646, 212) or a chiral anion exchange column (Chiralpack QD AX (Daicel), see Lammerhofer et al. Tetrahedron Asym. 2003, 14, 2557). Separation of 50 and 56 was achieved on a Crownpack column (Daicel).
72 Example 7: Cyclic phosphinate synthesis Scheme 30 OH O AIBN H-P-H + RO2C CO2R'
RO
2 C CO 2 R' OH 800C, 5h BSA 50% aqueous RT OC. ,OH R=R'=Et,Me leq NaOH O ,OH P _ _ _ _ _ _ H02C ,a C02R' or R2 0R HO2C CO 2 R' R=benzyl R'=Et,Me H 2 /Pd RO 2 C CO 2 R' 1) RCOCI or oxalyl chloride 2) NaBH4 lequiv 3) Swern oxydation x OH 1) Strecker reaction 0, H X OH /2) HCI 8N reflux H OHC CO 2 R' - HO 2 C CO 2 H
H
2 N The glutaric a, y-dimethylene diester was prepared according to Basavaiah et al. J. Org. Chem. 2002, 67, 7135 C02R DABCO
CO
2 R' + Br -""f RO 2 C CO 2 R' Substitutions were introduced in the starting glutaric a, y-dimethylene diester according to Saxena et al. Synlett 2003, 10, 1439. POH
RO
2 C CO 2 R' , ,, HO 2 C CO 2 H R" H 2 N R" Example 8: Derivatives with an cc, p cyclic aminoacid group OH tBuO 2 C NHBoc tBuO 2 C NHBoc OH OBn Lit CBr 4 /PPh 3 > OH Br R-(+) 71 72 tBuO 2 C NHBoc TMSO, 72 , H3PO2 + BSA 'OPH 72 TMSO HO-P=O H tBuO 2 C NHBoc H BSA, DCHO HO-P=O D OH 74 Example 9: Synthesis of a-alkyl vinylglycine Hydroxyalkylation of imidazolidinones and oxazolidinones (5, 6) derived from methionine with acetaldehyde cleanly afforded a single diastereoisomer but hydrolysis only lead to side products. However the reaction was successful with alkyl substitution: the imidazolidinone derived from methionine was converted to the vinylglycine derivative by oxidation and subsequent pyrolysis of the sulfoxide. Deprotonation of this compound followed by reaction with alkyl halides as electrophiles, cleanly afforded ct-alkyl vinyl imidazolidinone which was subsequently hydrolysed (6N HCl, 100*C) to the corresponding a-alkylated vinylglycines (Scheme 31). These compounds can be also obtained by first a-alkylation of imidazolidinones derived from methionine, and then oxidation and subsequent pyrolysis of the sulfoxide (8) (scheme 32). In this latter case diastereoisomeric excess are higher. 1) H202/AcOH 1) LDA \ EX de% N O 2) xylene, A N 2) EX N 6N HC, A HO Mel N EtN>I 90 NN N .EH2N 'IE AllylBr 7 Bz Bz Bz' BenzylBr 87 Scheme 31 74 N O ) LDA \N ) H22cOH \ 6NH, HEX de % 2) EX N 0 2) xylene, A N .
0 6N HOIA HO o EX de Bz/ N BN e 9
S
Scheme 32 Milder hydrolysis conditions are required with oxazolidinones intermediates. This approach was used by Acton and Jones starting with D-Methionine (9). The ratio of diastereoisomeric alkyl oxazolidinone was only 88:12 and the major cis isomer could only be purified by RP HPLC. Alkylation yield was only about 50%. 1) NaOH N 0 2 Na EtOH/H20 CbzCI, -20*C 0 D-Met -CN 2) PhCHO Dean-Stark 5- Cbz 5 KHMDS allyll -78*C :All NaOH/THFH - N --- N :\Al Cbz' Cbz H 88:12 purification RP HPLC Scheme 33 A similar methodology was recently used by Annedi et al.(10) for the synthesis of a alkylhomoserine and could be used for a-alkylvinylglycine preparation (Scheme 34). 1) 1N NaOH -N CO 2 Na MeOCOCI D-Met N~ ___ 2) tBuCHO pentane Dean-Stark s_ MeO 2 C 86:14 NaHMDS inseparable mixture EX 1) Me30BF4 -78*C 2) NaHCO3 reflux HO o N: ,,E MeO 2 C H 2 N
S
inseparable mixture ' H E=allyl, 2-Me-allyl '' ' HO
H
2 N Scheme 34 L-a-benzyl vinyl glycine may be obtained from D-Phe according to the procedure described by Cheng et al (11) (Scheme 35). A similar synthesis was carried out starting with N protected phenylglycine (12). 1) KHMDS 2) ethylene oxyde
BF
3 .OEt 2 o 3) BF3.OEt2 0 Cbz-L-Phe /)\ OW e -Cb bz O=\Me 'O de>98% NaOH/THF HO Meo CbzN Cbz OH Cbz-D-a-benzylvinylglycine methyl ester Scheme 35 The bis-lactim methodology developed by Sch6llkopf has been also used for the preparation of substituted L-vinylalanine (6, 13) (Scheme 36). OMe 1) nBuLi OMe 1) SOCI2, Pyr N - 2) MeCOR> N )OH 2) HCI, MeOH MeO 0 - N R" H 2 N R" eOMe R"=H,Me,Phe Scheme 36 Other synthesis are reviewed and described in (6). One possible synthesis for Cbz-L-a-alkylvinylglycine methyl ester is the following: 1) KHMDS 0 b tBF3.OEt 0 O 2) EX Cbz Cb' OMe S 1) NaOHITHF Me 1) H 2 0 2 /AcOH 2) HCI/MeOH 2) xylene, A CbzNH E CbzNH
E
76 Example 10: Pharmacological results Agonist activity of the compounds was tested on HEK293 cells transiently transfected with rat mGlu4 expressing plasmid pRKG4 and chimeric G-protein Gqi9 by electroporation, as described by Gomeza, J. et al, Mol. Pharmacol; 1996, 50, 923-930. Cells were plated in 96-well culture plates and labeled overnight with [ 3 H]myoinositol. The day after, cells were washed three times with Krebs buffer, incubated for 10 min with LiCl 5mM, and then incubated for 30 min in the absence (basal) or in the presence of the indicated compounds at InM up to 1000pM. The total amount of [ 3 H]phosphatidylinositol accumulated in the cells was determined after Dowex purification as previously by Goudet C, et al, Prod. Nati. Acad. Sci. USA 2004, 101, 378-383. The response dosis curves were adjusted by using equatrier y =[(Yma-y min)/(1+(x/EC)")]+ymin where EC 50 is the concentration necessary for obtaining half of the maximal effect and n is Hill coefficient. Results obtained with (3R)-PCEP and (3RS)-PCEP concerning the mGlu4, mGlu6, mGlu7 and mGlu8 receptors of group III are given in Table 1 and figures 1A-IE. Table 1 Compounds EC 50 mGlu4 piM EC 60 mGlu6 pM ECso mGlu7 pM EC 50 mGlu8 pM (3R)-PCEP 24.2 7.6 (3) 99.± 9.0 (3) > 1000 58.2 ± 8.8 (2) (3SR)-PCEP 6.6 2.8 (2) 33.1 ±10 4 (2) > 1000 24.2 ±9.0 (2) 77 Results obtained with other compounds according to the invention are given in Table 2 Table 2 mGlu4 Patent Lab structure EC 5 o Reference R6f6rence pM (n) 4 CS42 HO 2 C 0 RS 1CO 7.1 (5)
H
2 N 2 2 OH (3RS)-PCEP R 24.2 (3) 7 CS80 6.4 (5)
H
2 C C He 2 2 OH (+)-(3S)-PCEP CS2.071 11 CS68 HO 2 C CO 2 H 59.0 (5) C
CO
2 H
H
2 N OH 14 CS102 0 y inactive at H02C CO2H 100 MC02
H
2 N 2 OH (1) (2RS)-ECEP 26 CS128 HO 2 C O 3.8 (2)
H
2 N CO 2 H OH 19 CS134 H02C 0 28.7 (2) H2
CO
2 H OH CO 2
H
78 60 CS117 HO 2 C 0 inactive at
H
2 N C 100plM OH 3 1 C S 1 7 1 H 0 2 C N 0 2
H
2 N, - C0 2 H 100 tM OH Me(1) 24 CS155 H0 2 0 OH 20.8 (5)
H
2 NIH C0 2 H 22 CS173 HO 2 C 0 OH CO 2 H inactive at H 100p M OH 33-34 CS158 HO 2 C OH 5.1 (2) H2 CO 2 H IOH isomer 2 (see below) 33-34 CS159 HO 2 C O OH 12.9(2)
H
2 N
CO
2 H partial OH isomer 1 (see below) (containing <7% isomer2) 36 CS172 11.5 (2) H02C 0 0 partial
H
2 NO
OH
79 16OS18 10% max at H0 2 C 00.
2 H 100 giM(1) 28 CS19I H0 2 C 0o F 60% max at C0 2 H
H
2 N," P 100 Lm (1) 38 CS2.012 H0 2 C \0OH
H
2 N P.2(9) OH F 40 CS2.014 H0 2 C OH 3. 3 OHr p'' a
CO
2 H 42 CS2.024 H0 2 C 040% max at I -~ PO H 100 FLM (1) 44 CS2.029
PH
2 33% max at H0 2 C oC0 2 H 100 gtM (1) II 48 CS2.042
H
2 C 80% max at 100 4M(1) 80 50 CS2.080 OH HN N02 52 CS2.086 OH HON02
H
2
NO
2 1.69(5) OH C H 3 54 CS2.088 OH H2rP' 22.2(3)
HC
2 N 56 CS2.093 H0 2 C 0OH PNO2 0.63 (14) H6 C 0NO 2 2 O H 62 CS2.109 2p
NO
2 2.00(4) OH OH 58 CS2.101 1 ' NO 2 2.89 (3) H~wov -- pOCH 3 66 CS2.118H0C0O 11'- I NO 2 2.74(2)
OH
81 64 CS2.111 OH HON02
HNO
2 1.50(4) OH OH
OCH
3 68 CS2123 H 2 C OH >100(3) IH 3O 0 70 CS2.127 1.00 (4) H0 2 C 0OH NO 2
H
2 Ni
NO
2 72 CS2.147 OH 0.93 (2) OHH NO 2 74 CS2.153 O
HO
2 C OH OH2)
H
2 N NO OH 76 CS2.15 H0 2 C 0 OH OH 2.3 () H2NO 2
H
2 NOH 1
NO
82 78 CS2.163 HOH N 15.2 (2) 82OS217170 H1 NO2 H2N F OH 86 CS3.12 OH 1.17(4) 11 NO 2
H
2 Ne pN 8OH 90 CS2.176 OH 0N 2 1.96 (4)
H
2 N N OH 0 2 N 80 C82.166 H0 2 C0 OH F 5.19 (4) F
H
2 Ne p OH FF F 86C302 H0 2 C oOH 0.310 (4) OH 84 CS3.003 H0C0OH 0076 H20 0 OH /NO 97 CS3.030 H0 2 C 0OH 0.81 (3)
H
2 N? OH NO0 2 83 94 CS3.035 OH 0.305 (2) HN P -"-a CF3 OH
NO
2 88 CS3.051 OH 1.98(2) H N
CF
3 OH / CS158 and CS159 (33-34) are each a mixture of diastereoisomers. O H N2HH H0 2 C H02 QHT if R R + H 2 Nw, ~
H
2 N
CO
2 H
HHNCO
2 H, OH OH H0COH HO C OH II R R+ i s HO 2 ' 0HHIC0 2 H OH U Antagonist activity of the compounds was tested on HEK293 cells transiently transfected with rat mGlu4 expressing plasmid pRKG4 and chimeric G-protein Gqi9 by electroporation, as described in (14) Cells were plated in 96-well culture plates and labeled overnight with [3H]myoinositol. The day after, cells were washed three times with Krebs buffer, incubated for 10 min with LiCi 5mM, then pre-incubated for 5 min in the presence of the compounds at from 1 nM up to 1000 pM tested as an antagonist, and then incubated for 30 min in the presence or the absence of the agonist (L-AP4 from 0.1 to 100 p.M, depending on the receptor tested mGlu4(L-AP4 300nM), mGlu6, mGlu7, mGlu8). Incubation was stopped by replacing the stimulation buffer by a solution of formic acid 0.1 M. The total amount of [3H]phosphatidylinositol accumulated in the cells was determined after Dowex purification as previously described in (15).
84 The response dosis curves were adjusted by using equatrier y =[(Ymax-y min)/(1+(x/EC50)n)]+ymin where IC50 is the concentration necessary for obtaining half of the maximal inhibitory effect and n is Hill coefficient. The derivatives of the invention with antagonist properties are particularly useful for treating pathologies such as ADHD (Attention Deficit and Hyperactivity Disorder) and the so-called affective pathologies such as nervous breakdown and/or bipolar disorders (depressions followed by over excitation) and psychotic syndromes.
85 References (1) Afzali-Ardakani, A.; Rapoport, H. L-Vinylglycine. J Org.Chem. 1980, 45, 4817 4820. (2) Olsen, J. A.; Severinsen, R.; Rasmussen, T. B.; Hentzer, M.; Givskov, M.; Nielsen, J. Synthesis of new 3- and 4-substituted analogues of acyl homoserine lactone quorum sensing autoinducers. Bioorg. Med. Chem. Lett. 2002, 12, 325-328. (3) Krol, W. J.; Mao, S. S.; Steele, D. L.; Townsend, C. A. Stereochemical correlation of proclavaminic acid and syntheses of erythro- and threo-L-p-hydroxyornithine from an improved vinylglycine synthon. J Org. Chem. 1991, 56, 728-731. (4) Berkowitz, D. B.; Charette, B. D.; Karukurichi, K. R.; McFadden, J. M. a-vinylic amino acids: occurrence, asymmetric synthesis, and biochemical mechanisms. Tetrahedron: Asymmetry 2006, 17, 869-882. (5) Cativiela, C.; Diaz-de-Villegas, M. D. Stereoselective synthesis of quaternary a-amino acids. Part 1: Acyclic compounds. Tetrahedron: Asymmetry 1998, 9, 3517-3599. (6) Berkowitz, D. B.; Chisowa, E.; McFadden, J. M. Stereocontrolled synthesis of quaternary B,y-unsaturated amino acids: chain extension of - and -a-(2 tributylstannyl)vinyl amino acids. Tetrahedron 2001, 57, 6329-6343. (7) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Addition of chiral glycine, methionine, and vinylglycine enolate derivatives to aldehydes and ketones in the preparation of enantiomerically pure -amino-hydroxy acids. Heiv. Chim.Acta 1987, 70, 237-261. (8) Weber, T.; Aeschimann, R.; Maetzke, T.; Seebach, D. Methionin als Vorlaufer zur enantioselektiven Synthese -verzweigter Vinylglycine und anderer Aminosauren. Helv.Chim.Acta 1986, 69, 1365-1377. (9) Acton, J. J.; Jones, A. B. Synthesis and derivatization of a versatile a-substituted lactam dipeptide isostere. Tetrahedron Lett. 1996, 37, 4319-4322. (10) Annedi, S. C.; Biabani, F.; Poduch, E.; Mannargudi, B. M.; Majumder, K.; Wei, L.; Khayat, R.; Tong, L.; Kotra, L. P. Engineering D-amino acid containing novel protease inhibitors using catalytic site architecture. Bioorg. Med Chem. 2006, 14, 214-236. (11) Cheng, H.; Keitz, P.; Jones, J. B. Design and synthesis of a conformationally restricted cysteine protease inhibitor. J Org. Chem. 1994, 59, 7671-7676. (12) Ma, D.; Zhu, W. Synthesis of (S)-a-cyclopropyl-4-phosphonophenylglycine. J. Org. Chem. 2001, 66, 348 - 350. (13) Groth, U.; Schllkopf, U.; Chiang, Y.-C. Asymmetric syntheses via heterocyclic intermediates; XIII1. Enantioselective synthesis of (R)-a-alkenylalanine methyl esters using L-valine as chiral auxiliary reagent. Synthesis 1982, 864-866. (14) Gomeza, J. et al, Mol. Pharmacol;1996, 50, 923-930. (15) Goudet C, et al, Prod.Natl. Acad. Sci. USA 2004, 101, 378-383.

Claims (30)

1. Hypophosphorous acid derivatives having formula (I) 0 11 R 2 -P-M OH wherein M is a [C(R 3 ,R 4 )],i - C(E,COORi, N(H, Z)) group, or an optionally substituted Ar-CH(COORI, N(H, Z)) group (Ar designating an arylene or an heteroarylene group), or an a, p cyclic aminoacid group of formula C(R 3 , R 4 )] C0 2 R 1 N(H, Z) R 1 is H or R, R being an hydroxy or a carboxy protecting group, such as Ci-C 3 alkyl, Ar (being aryl or heteroaryl), Z is H or an amino protecting group R', such as CI-C 3 alkyl, C-C 3 acyl, Boc, Fmoc, COOR; E is H or a Cl-C3 alkyl, aryl, an hydrophobic group such as (CH 2 )ni-alkyl, (CH 2 )ni -aryl (or heteroaryl), such as a benzyl group, or a xanthyl, alkyl xanthyl or alkyl thioxanthyl group, or -(CH 2 )ni-cycloalkyl, -(CH 2 )n-(CH 2 -Ar) 2 , a chromanyl group, particularly 4-methyl chromanyle, indanyle, tetrahydro naphtyl, particularly methyl-tetrahydronaphtyl; R 2 is selected in the group comprising: D-CH(R)- C-(R 7 , R8) D - CH(OH) D-CH 2 (R 18 )CH = C(Rig) D-(M1)n6-CO with - D = H, OH, OR, (CH 2 )n2OH, (CH 2 )nIOR, COOH, COOR, (CH 2 )n2COOH, (CH 2 )nICOOR, NO 2 , heteroaryl, Ci-C 3 alkyl, (CH 2 )n 2 -alkyl, CO-NH-alkyl, Ar, (CH 2 )n 2 -Ar, CO NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, - R 3 to R 1 9 , identical or different, being H, OH, OR, (CH 2 )n 2 OH, (CH 2 )niOR, COOH, COOR, (CH 2 )n 2 COOH, (CH 2 )nCOOR, CI-C 3 alkyl, cycloalkyl, (CH 2 )ni-alkyl, aryl, (CH 2 )ni- 87 N-N N 1 aryl, halogen, CF 3 , SO 3 H, (CH 2 )x P0 3 H 2 , with x = 0, 1 or 2, B(OH) 2 , , NO 2 , SO 2 NH 2 , SO 2 NHR; S(O)R, SO 2 R, benzyl; one of R, 1 or R 12 being COOR, COOH, (CH 2 )n 2 -COOH, (CH 2 )n 2 -COOR, P0 3 H 2 the other one being such as defined for R 9 and Rio; - one of R 15 , R 16 and R 17 is COOH or COOR, the others, identical or different, being such as above defined; - one of R 18 and R 19 is COOH or COOR, the other being such as above defined; - MI is an alkylene or arylene group; - n1= 1, 2 or 3; - n2= 1, 2 or 3, - n3= 0, 1,2 or 3 and - n4= 1, 2 or 3, except when R2= [C(R 5 , R16, R 17 )]n 4 , wherein n4=1; - n5= 1,2 or 3; - n6= 0 or 1, - ul and u2, identical or different = 0,1 or 2, Ar, and alkyl groups being optionally substituted by one or several substituents on a same position or on different positions, said substituents being selected in the group comprising: OH, OR, (CH 2 )nIOH, (CH 2 )nIOR, COOH, COOR, (CH 2 )nICOOH, (CH 2 )nCOOR, C 1 -C 3 alkyl, cycloalkyl, (CH 2 )ni-alkyl, aryl, (CH 2 )ni-aryl, halogen, CF 3 , SO 3 H, (CH 2 )x P0 3 H 2 , with x = 0, 1 N-N or 2, B(OH) 2 , , NO 2 , SO 2 NH 2 , SO 2 NHR; SR, S(O)R, SO 2 R, benzyl; R being such as above defined, said hypophosphorous acid derivatives being diasteroisomers or enantiomers; with the proviso that formula I does not represent the racemic (3R, S) and the enantiomeric form (3R) of 3 amino,3-carboxy-propyl-2'-carboxy-ethylphosphinic acid; 3 amino,3-carboxy-propyl 4'carboxy,2'carboxy-butanoylphosphinic acid; 3 amino,3-carboxy-propyl- 2'carboxy butanoylphosphinic acid; 3 amino,3-carboxy-propyl- 3'amino, 3'carboxy-propylylphosphinic acid; and 3 amino,3-carboxypropyl -7'amino-2', 7'-dicarboxyheptylphosphinic acid, (S)-2 amino-2- methyl -4 - (phenylphosphino)butanoic acid; with the proviso that 7701 en- 88 -when M is a [C(R 3 ,R 4 )]n - C(ECOOR 1 , N(H, Z)) group, wherein R 3 and R4 are both H, and E, R, and Z are H, and nl= 1 or 2 D is OR, (CH 2 )n2OH, (CH 2 )niOR, COOH, COOR, (CH 2 )n 2 COOH, (CH 2 )niCOOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 2 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 -alkyl, (COOH, NH 2 ) (CH 2 )ui-cyclopropyl-(CH 2 )u 2 -, CO-NH-alkyl, Ar, (CH 2 ) 1 a-Ar, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, -when M is a [C(R 3 ,R 4 )]n - C(E,COORI, N(H, Z)) group, wherein R 3 and R 4 are both H, and E, R, and Z are H, and D is H, OR, (CH 2 )n2OH, (CH 2 )niOR, COOH, COOR, R being different from CH 3 , (CH 2 )n 2 COOH, (CH 2 )njCOOR when nl=1 and R is H, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 -alkyl, (COOH, NH 2 )-(CH 2 )ui-cyclopropyl-(CH 2 )u 2 -, CO-NH-alkyl, Ar, with Ar being not phenyl, (CH 2 )n 2 -Ar, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, - when M is a [C(R 3 ,R 4 )].i - C(E,COOR 1 , N(H, Z)) group, with one of R 3 or R 4 is H and the other COOH, E, R, and Z are H and nl=3, D is OR, (CH 2 )n 2 OH, (CH 2 )niOR, COOR, (CH 2 )niCOOR, R being different from H with nl=1, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 -alkyl, (COOH, NH 2 )-(CH 2 )ui-cyclopropyl-(CH 2 )u2-, CO-NH-alkyl, Ar, with Ar being not phenyl, (CH 2 )n 2 -Ar, with Ar being not phenyl with n2=2, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, -when M is a [C(R 3 ,R4)]ni - C(E,COORI, N(H, Z)) group, wherein R 3 and R4 and Z are H, E is H, CH 3 or C 2 H 5 and nI is 2 or 3 D is H, OR, (CH 2 )n 2 OH, (CH 2 )n 1 OR, COOH, COOR, (CH 2 )n2COOH, (CH 2 )n]COOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 2 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 -alkyl, (COOH, NH 2 )-(CH 2 )ui-cyclopropyl-(CH2)u2-, CO-NH-alkyl, Ar, with Ar being not phenyl, (CH 2 )n 2 -Ar, with Ar being not phenyl when n2=2, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, - when M is a [C(R 3 ,R 4 )]ni - C(E,COOR 1 , N(H, Z)) group, wherein R 3 and R4 are both H, and E, Ri and Z are H, R 2 is not PO(OH) 2 -CH 2 when n2=2 - when M is a [C(R 3 ,R 4 )]ni - C(E,COOR 1 , N(H, Z)) group, wherein R 3 and R 4 are both H, and E, R, and Z are H, and nl=3 D is H, OR, (CH 2 )n 2 OH, (CH 2 ), 1 OR, COOH, COOR, (CH 2 ). 2 COOH, (CH 2 )n 1 COOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 1 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 -alkyl, (COOH, NH 2 )-(CH 2 )ui- 89 cyclopropyl-(CH 2 )u 2 -, CO-NH-alkyl, Ar, (CH 2 )n 2 -Ar, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, - when M is a [C(R 3 ,R 4 )] 1 i - C(E,COOR 1 , N(H, Z)) group, wherein R 3 , R 4 , E and Z = H and R, =CH3, D is H, OH, OR, (CH 2 )n 2 OH, (CH 2 )nIOR, COOH, COOR, R being not CI alkyl, (CH 2 )n 2 COOH, (CH 2 )niCOOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 1 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 alkyl, (COOH, NH 2 )-(CH 2 )ui-cyclopropyl-(CH 2 )u2-, CO-NH-alkyl, Ar, (CH 2 )n 2 -Ar, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group, - when M is a [C(R 3 ,R 4 )]ni - C(E,COORi, N(H, Z)) group, with R 3 , R 4 and E = H, Ri is CH 3 and Z is Cbz, when n1=2 D is OH, OR, (CH 2 )2OH, (CH 2 )nIOR, COOH, COOR, (CH 2 )n 2 COOH, (CH 2 )nICOOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 1 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 )n 2 -alkyl, (COOH, NH 2 )-(CH 2 )ui cyclopropyl-(CH 2 )u2-, CO-NH-alkyl, Ar, (CH 2 )n2-Ar, CO-NH-Ar, R being as above defined and Ar being an optionally substituted aryl or heteroaryl group. ''7 1 A4 -ti 90
2. The hypophosphorous acid derivatives of claim 1, having formula (II) 0 D-CH(R 6 )--C-(R 7 , R)-P-M OH (II) wherein the substituents are as above defined.
3. The hypophosphorous acid derivatives of claim 2, wherein D is Ar or a substituted Ar, especially a phenyl group having 1 to 5 substituents.
4. The hypophosphorous acid derivatives of claim 3, wherein the substituents are in ortho and/or meta and/or para positions and are selected in the group comprising OH, OR, (CH 2 )n 2 OH, (CH 2 )n 2 OR, COOH, COOR, (CH 2 )n 2 COOH, (CH 2 )n 2 COOR, Cl-C3 alkyl or cycloalkyl, (CH 2 )n 2 -alkyl, aryl, (CH 2 )n 2 -aryl, halogen, CF 3 , SO 3 H, P0 3 H 2 , B(OH) 2 alkylamino, N-N fluorescent group (dansyl, benzoyl dinitro 3, 5', , NO 2 , SO 2 NH 2 , S0 2 (NH,R) SR, S(O)R, SO 2 R, OCF 3 , heterocycle, heteroaryl, substituted such as above defined with respect to Ar.
5. The hypophosphorous acid derivatives of claim 1 having formula (III) 0 II (R 11 , R 12 )CH-C(R 9 , Rid)-P-M OH (III) wherein the substituents are as above defined.
6. The hypophosphorous acid derivatives of claim 5, wherein one of R 1 or R 1 2 is COOH. 91
7. The hypophosphorous acid derivatives of claim 1, having formula (IV) 0 D-CH(OH)-P-M OH (IV) wherein the substituents are as above defined.
8. The hypophosphorous acid derivatives of claim 7, wherein D is as above defined in claim 3 or 4 with respect to formula II.
9. The hypophosphorous acid derivatives of claim 1, having formula (V) - 0 D-- C(R, R 1)-- C 13 , R 1 4 ) P-M . n3 OH (V) wherein the substituents are as above defined, one of R 13 or R 14 representing OH.
10. The hypophosphorous acid derivatives of claim 9, wherein D is as above defined in claim 3 or 4 with respect to formula II.
11. The hypophosphorous acid derivatives of claim 1, having formula (VI) 0 C(R 15, R 16 , R 17 ) - p-M .n4 OH (VI) wherein the substituents are as above defined, n4 = 1.
12. The hypophosphorous acid derivatives of claim 11, wherein, in the first group of the chain, one or two of R 15 , R 16 or R 17 is COOH.
13. The hypophosphorous acid derivatives of claim 1, having formula (VII) '7"7904 Q Ir L 92 0 D-CH -P-M OH (VII) wherein the substituents are as above defined.
14. The hypophosphorous acid derivatives of claim 13, as above defined in claim 3 or 4 with respect to formula II.
15. The hypophosphorous acid derivatives of claims 2 to 14, wherein R 6 , R7, R8 are H, CI-C 3 alkyl, OH, CF 3 .
16. The hypophosphorous acid derivatives of claim 1, having formula (VIII) 0 II (R 1 8 )C H=C(R 9) -P- M OH (VIII) wherein the substituents are as above defined.
17. The hypophosphorous acid derivatives of claim 16, wherein R18 is COOH.
18. The hypophosphorous acid derivatives of claim 16 or 17, wherein Rig is H, Ci-C 3 alkyl, OH.
19. The hypophosphorous acid derivatives of claim 1, having formula LIX 0 D- Mj CO- P1 M OH (LIX) wherein the substituents are as above defined. '7'70Q 104 -1,r 93
20. The hypophosphorous acid derivatives of claim 19, wherein either n6= 0, or n6= 1 and Mi is an alkylene or an arylene group such as above defined.
21. The hypophosphorous acid derivatives of anyone of claims 1 to 20, wherein M is a [C(R 3 ,R 4 )]n 1 - C (E, COORI, N(H,Z))group.
22. The hypophosphorous acid derivatives of anyone of claims 1 to 20, wherein M is an arylene group or a substituted arylene group - Ar-CH (COORI, N (H, Z)), particularly a C 6 H 4 group or a substituted C 6 H 4 group, the substituents being as above defined with respect to formula I.
23. The hypophosphorous acid derivatives of anyone of claims 1 to 20, wherein M comprises a cyclic aminoacid group, particularly an a, P cyclic aminoacid group such as C(R 3 , R 4 )] C0 2 R 1 N(H, Z) or a P, y-cyclic aminoacid group such as C(E, COOR,, N(H, Z))
24. A process for preparing hypophosphorous acid derivatives of formula I 0 R 2 - P-M OH wherein the substituents are as above defined in anyone of claims 1 to 23, comprising - according to method A): al) treating a derivative of formula (IX) 94 O cH (IX) wherein the substituents and n1 are as above defined, with either trimethylsilylchloride (TMSCl) and triethylamine (Et 3 N), or N,O-(bis triethylsilyl)acetamide (BSA); a2) adding to the reaction product one of the following derivatives having, respectively, formula X: D-C(R 6 ) = C(R 7 , R8), or formula XI: (RI 1 ,R 12 )C= C(R 9 , RIO) formula XII: with n= 1 or 2 formula XIII: D - CH(=0) formula XIV: D- [C(R 13 , R 1 4 )]. 3 - Br formula XV: [C(R 15 , R 16 , RI 1 7 )] 4 - Br formula XVI: D - I formula XVII: (R 18 )CH = C(R 19 ) a3) treating the reaction product under acidic conditions or with catalysts to obtain the desired final product; a4) recovering the diastereoisomers or the enantiomer forms, a5) separating, if desired, diastereoisomers when obtained; - according to method B, said process comprises bl) treating a derivative of formula (XVIII) (R"SiO) 2 - P-H (XVIII) wherein R" is a C 1 -C 3 alkyl with either a derivative of formula (X) D - C (R 6 ) = C(R 7 , R8) T77OQ1OI eotr 95 (X) or with a derivative of formula (XI) (RI 1 ,R 12 )C= C(R 9 , Rio) (XI) wherein one of R 9 or RIO is COOalk, alk being a C 1 -C 3 alkyl b2) treating the condensation product with a dibromo derivative of formula (XIX) Br - [C(R 3 ,R 4 )]ni- Br (XIX) under reflux conditions; and adding HC(Oalk) 3 wherein alk is a Cl-C3 alkyl b3) treating the condensation product with a derivative of formula (XX) NH(Z)-CH(CO 2 R) 2 (XX) in the presence of K 2 C0 3 , BuO 4 NBr, under reflux conditions; b4) treating the condensation product under acidic conditions or with catalyts to obtain the final desired product; b5) recovering the diastereoisomers or the enantiomer forms, and b6) if desired, separating diastereoisomers, when obtained, into the enantiomers; or - alternatively, the reaction product obtained at step bl) is reacted, according to step b2i), with a derivative of formula (XXI) [(R 3 , R 4 )C],i= C (COORI, NH(Z)) (XXI) and, according to step b3i), the reaction product is treated under acidic conditions to give the final desired product - according to method C, said process comprises cl) reacting, as defined in step al), a derivative of formula (XXII) 0 H-P-Ar-T OH (XXII) I7'7n01I4MC -1 96 wherein Ar is as above defined and preferably an optionally substituted C 6 H 4 group and T represents a C 1 -C 3 alkyl group c2) carrying out reaction step a2) by using one of the derivatives of formula (X) to (XVII) c3) treating the reaction product with NBS, AiBN to have a bromo derivative with Ar substituted by T'-Br, with T'= CH 2 c4) reacting the bromo derivative thus obtained with (CH) 6 N 4 in an organic solvent, then AcOH/H 2 0 to obtain a cetone derivative with Ar substituted by -C=0, c5) treating cetone derivatives with KCN, NH 4 Cl and NH 4 0H to obtain aminocyano derivatives, with Ar substituted by -C (CN, NH 2 ) c6) treating under acidic conditions to obtain derivatives with Ar substituted by -C (COOR, NH 2 ), and c7) treating with catalysts to obtain the final desired product.
25. The process of claim 24, wherein - in method A, according to a preferred embodiment the use of derivatives of formula (X) D - C(R 6 ) = C(R 7 ,R 8 ) (X) with derivatives of formula (IX) results, in step a2), in intermediate derivatives of formula (XXIII) 0 D-CH(R 6 )-C(R 7 , R8)-- C(R3, R 4 )]-nCH(COOR,, NH(Z)) OH (XXIII) and, in step a3), in a final product of formula (XXIV) 0 D-CH(R 6 )-C(R 7 , R 4 )}-nCH(COOH, NH 2 ) OH (XXIV) the use of derivatives of formula (XI) or formula (XII) '7'1o I I 114ei 97 (R 1 ,R 12 )C= C(R9, Rio) (XI) or 0 (XII) results, in step a2), in intermediate derivatives of formula (XXV) 0 (Ril, R12)CH---(Rg, R1(3)C -- C(R 3, R4)] -CH(COORJ, NH(Z)) OH (XXV) and, in step a3), in a final product of formula (XXVI) 0 (R, 1 , R 12 )CH-(Rg, Rj)C- -[C(R 3 , R 4 )4yCH(COOH, NH 2 ) OH (XXVI) the use of derivatives of formula (XIII) D-CH (=0) (XIII) results, in step a2), in intermediate deriv atives of formula (XXVII) 0 D-6H(OH)- -C(R3, R 4 )]- CH(COOR,, NH(Z)) OH (XXVII) and, in step a3), in a final product of formula (XXVIII) 0 D-6H(OH)- - C(R3, R4) CH(COOH, NH 2 ) OH (XXVIII) the use of derivatives of formula (XIV) 98 D- [C(R 13 , R 14 )]. 3 - Br (XIV) results, in step a2), in intermediate derivatives of formula (XXIX) 0 D-C(R, R ) C(R 3 , R 4 )]-CH(COOR, NH(Z)) (XXIX) and, in step a3), in a final product of formula (XXX) 0 D-[C(Rl , R 14 )]- C(R 3 , R 4 ) ]-CH(COOH, NH 2 ) (XXX) the use of derivatives of formula (XV) [C(Ri 5 , R 16 , R 17 )]. 4 - Br (XV) with n4 = 1 results, in step a3), in intermediate derivatives of formula (XXXI) 0 C(R, R, R 7 ) P- [C(R 3 , R 4 )]-CH(COOR,, NH(Z)) O4 H (XXXI) with n4 = 1 and, in step a3), in a final product of formula (XXXII) 0 C(R, R 1 , R 1 ) P-[ C(R 3 , R 4 ) ]-CH(COOH, NH 2 ) O H (XXXII) the use of derivatives of formula (XVI) D-I (XVI) '770Q10 O1r 99 results, in step a2), in intermediate derivatives of formula (XXXIII) 0 D-CHi-[--C(R 3 , R 4 ) CH(COOR,, NH(Z)) H (XXXIII) and, in step a3), in a final product of formula (XXXIV) 0 11 D--CH2~ -[-C(R, R 4 ) -CH(COOH, NH 2 ) OH (XXXIV) the use of derivatives of formula (XVII) (Ri8)C=C(Rig) (XVII) results, in step a2), in intermediate derivatives of formula (XXXV) 0 11 (R 18 )-CH-C(R,,)-P- [C(R 3 , R 4 ) ]-CH(COOR,, NH(Z)) (XXXV) and, in step a3), in a final product of formula (XXXVI) 0 (R,)-CH--C(R,,)- [C(R 3 , R 4 )]-CH(COOH, NH 2 ) (XXXVI) the use of derivatives of formula (LIX) 0 D- M, CHOH-P- M-CH(COOH, NH 2 ) OH (LIX) '770Q I col, 100 wherein M, is as above defined with respect to M and results by oxidation in a product of formula (LXI) 0 D--M,, CO-P-M-CH(COOH, NH 2 ) OH (LXI).
26. The method of claim 24, wherein - in method B, the use, with derivatives of formula (XVIII), of derivatives of formula (X) D - C(R 6 ) = C(R 7 ,R 8 ) (X) results, in step bl), in intermediate derivatives of formula (XXXVII) D-C(R 6 )=C (R 7 ,Rs)-P-(OSiR") 2 (XXXVII) in step b2), in intermediate derivatives of formula (XXXVIII) 0 || D-CH(R 6 )-C(R 7 , R8)- C(R 3 , R4) Br OR" (XXXVIII) in step b3), in intermediate derivatives of formula (XXXIX) 0 NHZ D-CH(R )-C(Ry, R)- C(R 3 , R 4 )- C--CO 2 R R" CO2 R (XXXIX) and, in step b4), in a final product of formula (XXXX) '7'10 9 10 U, 101 0 D-CH(R 6 )-C(R 7 , R,)-P C(R 3 , R 4 ) CH(COOH, NH 2 ) OH (XXXX) the use, with derivatives of formula (XVIII), of derivatives of formula (XI) (R 1 ,R 12 )C= C(R 9 , Rio) (XI) results, in step b 1), in intermediate derivatives of formula (XXXXI) (RI 1 , R 1 2 )CH-C(R 9 , Rio)-P-(OSi R") 2 (XXXXI) in step b2), in intermediate derivatives of formula (XXXXII) 0 I I ________ (Ril, R 12 )CH-C(R, RJ)-P- C(R 3 , R 4 )] -Br OR (XXXXII) in step b3), in intermediate derivatives of formula (XXXXIII) O NHAc (R 1 , R )CH-C(R, Rio)- -[C(R, R 4 ) -- CO 2 R OH CO 2 R (XXXXIII) in step b4), in final products of formula (XXXXIV) 0 (R 11 , 12 )CH--C(Rg, Rlo)-P C(R 3 , R 4 )--CH(COOH, NH 2 ) OH (XXXXIV) or, alternatively, 102 the use with derivatives of formula (XXXXI) obtained according to step b 1) is reacted with a derivative of formula (XXXXV) [(R 3 , R 4 ) C],i=C (COOR, NH(Z) (XXXXV) giving intermediate derivatives of formula (XXXXVI) 0 (Ril, R 12 )CH-C(Rg, R 1 )-P C(R 3 , R 4 ) -- CH(COOR, NHZ) OH (XXXXVI) the treatment under acidic conditions giving the final product of formula (XXXXVII) 0 (Ril, R 12 )CH-P C(R 3 , R 4 ) -CH(COOH, NH 2 ) OH (XXXXVII)
27. The process of claim 24, wherein - in method C, the use, of a derivative of formula (XXII), 0 H-P-Ar-T OH (XXII) with a derivative of formula X: D-C(R 6 )= C(R 7 , R 8 ), or formula XI: (RI 1 ,R 1 2 )C= C(R 9 , Rio) formula XII: O formula XIII: D - CH(=0) formula XIV: D- [C(R 1 3 , R 14 )]n 3 - Br '7702 10 Genc 103 formula XV: [C(R 15 , R 16 , R 17 )]. 4 - Br formula XVI: D - I formula XVII: (Ri 8 )C = C(R 19 ) results in intermediate derivatives respectively having formulae (XXXXVIII) to (LIV) 0 || D-CH(Rd)-C-(R 7 , R)-P Ar-T OH (XXXXVIII) 0 II (R 1 1 , R 1 )CH-C(Rg, Rj)-P-Ar-T OH (XXXXIX) 0 11 D- CH(OH)-P-Ar-T OH (L) 0 II D C(R 13 , R 14 ) P-Ar-T ic n3 OH (LI) 0 || [(R1, R15' , R17 P-Ar-T n4 OH (LII) with n4 1 0 D-CHg-P-Ar-T OH (LIII) 104 0 II (Rl)CH=C(Rlg)-P-Ar-T OH (LIV)
28. The process of claim 24 or 25, wherein - in method A, the derivatives of formula IX 0 -C(R3, R 4 )1-CH(COORJ, NH(Z)) n1 CH (IX) are advantageously obtained by reacting hypophosphorous acid of formula (LV) 0 H-- H H (LV) with a derivative of formula (LVI) (R 3 , R 4 ). 1 C=CH-C(E,COORI, NH(Z)) (LVI) preferably Z-vinyl-glyOMe or a derivative thereof with E different from H, the reaction being advantageously carried out in the presence of AIBN by heating above 50 C - 100*C, preferably at about 80*C.
29. The process of claim 24 or 26, wherein - in method B, the derivatives of formula (XVIII) (R"SiO) 2 - P-H (XVIII) are obtained by reacting an hypophosphorous acid ammonium salt of formula (LVII) 0 II 0 NH4+ (LVII) - - 70 T IQ O 1,0 o 105 with hexamethyl disilazane of formula (LVIII) (alk 3 Si)-NH (LVIII) the reaction being carried under an inert gas, by heating above 1 00*C, particularly at about
120-C, or by reacting hypophosphorous acid with N, 0-(bis-triethylsilyl) acetamide (BSA) at room temperature. 30. The method of claim 24 or 27, wherein - in method C, the derivatives of formula (XXII) 0 H-P-Ar-T OH (XXII) are advantageously obtained by reacting a mixture of H 3 PO 2 , Ar-NH 2 , Ar-Br and a catalyst Pd(0) Ln (Ln = n ligands). 31. Hypophosphorous acid derivatives which are intermediates in the process of anyone of claims 24 to 30. 32. Pharmaceutical compositions comprising an effective amount of at least one of the hypophosphorous acid derivatives according to anyone of claims 1 to 23, in combination with a pharmaceutically acceptable carrier, said derivatives including the derivatives excluded from claim 1, except the case where R 2 is C 6 H 5 - or C 6 H 1 1 when M is (CO 2 H,CH 3 ,NH 2 ) CH (CH 2 )n with n= 2. 33. The pharmaceutical compositions according to claim 32, which are under a form suitable for an administration by the oral route, such as tablets, pills or capsules. 34. The pharmaceutical compositions of claim 33, comprising 1 to 100 mg of active ingredient per dose unit. '7'70211 L 106 35. The pharmaceutical compositions according to claim 32, which are under a form suitable for an administration by injection, such as injectable solutions for the intravenous, subcutaneous or intramuscular route. 36. The pharmaceutical compositions of claim 35, comprising 1 to 30 mg of active ingredient per dose unit. 37. The pharmaceutical compositions of anyone of claims 32 to 36 for treating convulsions, pain, drug addiction, anxiety disorders and neurodegenerative diseases. 38. Use of at least one of the hypophosphorous acid derivatives of anyone of claims 1 to 23 for preparing a drug for treating brain disorders, said derivatives including those excluded from claim 1. Centre National de la Recherche Scientifique (CNRS) Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON
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