((S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)phosphinic acid | 864682-69-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ((S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)phosphinic acid
• 英文别名: [(3S)-4-methoxy-4-oxo-3-(phenylmethoxycarbonylamino)butyl]phosphinic acid
• CAS: 864682-69-9
• 化学式: C₁₃H₁₈NO₆P
• 分子量: 315.263
• InChiKey: SCIHCYPVHVTBOU-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  21
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ((S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)phosphinic acid 在 三氟化硼乙醚 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 methyl [(3S)-3-(N-benzyloxycarbonyl)amino-3-methoxycarbonylpropyl][(3-nitrophenyl)(N-benzylamino)methyl]phosphinate
  参考文献：
  名称：

  Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites

  摘要：

  A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an L-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu(4) subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.

  DOI：

  10.1021/acs.jmedchem.7b01438
• 作为产物：
  描述：

  methyl (2S)-2-(benzyloxycarbonylamino)-4-bromobutanoate 在 吡啶 、 sodium tetrahydroborate 、 次磷酸铵 、 三乙基硼 、 双氧水 、 氧气 作用下， 以 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 ((S)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)phosphinic acid
  参考文献：
  名称：

  对应于谷氨酰胺-γ-谷氨酸的膦酸磷酸肽的立体选择性合成及其掺入有效的多聚-γ-谷氨酰合成酶抑制剂

  摘要：

  将H 3 PO 2自由基加到N- / C-保护的乙烯基甘氨酸中可得到相应的H-次膦酸，产率极高。将非亲核性H-次膦酸转化为亲核性的P III物种RP（OTMS）2，该物质以两种方法用于含有伪肽的目标次膦酸。开发了一种新的方法，可导致RP（OTMS）2与未活化的亲电试剂（包括无环均烯丙基溴）的反应获得优异的收率。然而，途中目标假肽，RP（OTMS）的阿尔布蜀夫反应2与环状高烯丙基溴，（ř）-3-（溴甲基）-环戊-1-烯导致重排的烯丙基次膦酸而不是所需的均烯丙基衍生物，即假定的谷氨酸替代物。将RP（OTMS）2共轭添加到含有手性助剂的α-亚甲基戊二酸酯中只会导致适度的非对映选择性。通过快速色谱纯化提供假肽的两种非对映异构体的保护衍生物。整体脱保护后，（S）-H-Glu-γ-[Ψ（P（O）（OH）（CH 2））]-（S）-Glu-OH与（S）-H-Glu-γ偶联-[Ψ（P（O）（OH）（CH 2

  DOI：

  10.1021/jo0507439

文献信息

• [EN] HYPOPHOSPHOROUS ACID DERIVATIVES HAVING ANTIHYPERALGIC ACTIVITY AND BIOLOGICAL APPLICATIONS THEREOF<br/>[FR] DÉRIVÉS DE L'ACIDE HYPOPHOSPHOREUX AYANT UNE ACTIVITÉ ANTIHYPERALGIQUE ET LEURS APPLICATIONS BIOLOGIQUES
  申请人：UNIV PARIS DESCARTES

  公开号：WO2012156931A1

  公开（公告）日：2012-11-22

  The invention relates to hypophosphorous acid derivatives of formula (I) wherein - X is H or OH, - R represents one or several radicals R1-R5, identical or different, two of R1-R5 optionally occupying the same position on the phenyl group, one to four of R1-R5 being H and the others being selected in the group comprising - 0-(CH2)n-COOH; - S-(CH2)n-COOH; -NH-(CH2)n-COOH; - 0-(CH,R') -COOH; -O- (CH2)n-OH; OR', -R' being a C1 -C3 alkyl radical;-OH; --COOH; halogen, particularly -F, - CI, -Br, -I, -CF3; -OCF3; -N02; -CH=CH-COOH; - -(CH2)n-COOH; O - (CH2)n- P03H2; O - (CF2)n- P03H2; O - (CH2)n- S03H; O - (CH2)n- CONHOH; O - (CH2)n-tetrazol; O - (CH2)n-hydroxyisoxazol - n = 1 to 5, preferably 1-3; said hypophosrous acid derivatives being diastereoisomers or enantiomers.

  该发明涉及式(I)的次磷酸衍生物，其中- X为H或OH，- R代表一个或几个基团R1-R5，相同或不同，R1-R5中的两个可以选择占据苯基上的同一位置，R1-R5中的一到四个为H，其余的选择自-0-(CH2)n-COOH；-S-(CH2)n-COOH；-NH-(CH2)n-COOH；-0-(CH,R')-COOH；-O-(CH2)n-OH；OR'，其中-R'为C1-C3烷基基团；-OH；-COOH；卤素，特别是-F，-Cl，-Br，-I，-CF3；-OCF3；-NO2；-CH=CH-COOH；-(CH2)n-COOH；O-(CH2)n-P03H2；O-(CF2)n-P03H2；O-(CH2)n-S03H；O-(CH2)n-CONHOH；O-(CH2)n-四唑；O-(CH2)n-羟基异噁唑-n=1至5，优选1-3；所述的次磷酸衍生物为对映异构体或对映体。
• Determination of the absolute configuration of phosphinic analogues of glutamate
  作者：Bruno Commare、Delphine Rigault、Isabelle A. Lemasson、Patrick Deschamps、Alain Tomas、Pascal Roussel、Isabelle Brabet、Cyril Goudet、Jean-Philippe Pin、Frédéric R. Leroux、Françoise Colobert、Francine C. Acher

  DOI：10.1039/c4ob01960a

  日期：——

  promising in vivo activity. However, so far all were synthesized and tested as a mixture of two diastereomers whose absolute and relative configurations are not known. In this study, the stereomers were separated on a Crownpack CR(+) column and their absolute configuration was assessed by means of a diastereoselective synthesis. Both separated L-stereomers activated the mGlu4 receptor with EC50's of 0.72

  已证明一系列次膦谷氨酸衍生物（例如LSP1-2111）是促代谢型谷氨酸（mGlu）受体的有效激动剂，并显示出有希望的体内活性。但是，到目前为止，所有化合物都是作为两种非对映异构体的混合物进行合成和测试的，其绝对和相对构型尚不清楚。在这项研究中，在Crownpack CR（+）色谱柱上分离了立体异构体，并通过非对映选择性合成评估了它们的绝对构型。两种分离的L-立体异构体分别激活（1S，1'S）-和（1S，1'R）-LSP1-2111的mGlu4受体，EC50为0.72和4.4μM。
• Hypophosphorous Acid Derivatives and their Therapeutical Applications
  申请人：Acher Francine

  公开号：US20090170813A1

  公开（公告）日：2009-07-02

  Hypophosphorous acid derivatives having Formula (I) wherein .M is a [C(R3,R4)]n1-C(E,COOR1,N(H,Z)) group, or an optionally substituted Ar—CH(COOR1,N(H,Z)) group, or an a, β, or a β, g-cyclic amino acid; .R 1 is H or R, R being an hydroxy or a carboxy protecting group; .Z is H or an amino protecting group R′, benzyl oxycarbonyl, benzyl or benzyl substituted; .E is H or a C1-C3 alkyl, aryl, an hydrophobic group; .R 2 is selected in the group comprising: D-CH(R 6 )—C—(R 7 ,R 8 ), (R 11 ,R 12 )CH—C(R 9 ,R 10 ), D-CH(OH), D-[C(R 13 ,R 14 )] n3 —, C[(R 15 ,R 16 ,R 17 )] n4 , D-CH 2 , (R 18 )CH═C(R 19 ), D-(M 1 ) n6 —CO, Formula (II), PO(OH) 2 —CH 2 or (PO(OH) 2 —CH 2 ), (COOH—CH 2 )—CH 2 , with -D=H, OH, OR, (CH 2 ) n2 OH, (CH 2 ) n1 OR, COOH, COOR, (CH 2 ) n2 COOH, (CH 2 ) n1 COOR, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 1 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 ) n2 -alkyl, (COOH,NH 2 )—(CH 2 ) u1 -cyclopropyl-(CH 2 ) u2 —, CO—NH-alkyl, Ar, (CH 2 ) n2 —Ar, CO—NH—Ar; —R 3 to R 19 being H, OH, OR, (CH 2 ) n2 OH, (CH 2 ) n1 OR, COOH, COOR, (CH 2 ) n2 COOH, (CH 2 ) n1 COOR, C 1 -C 3 alkyl, cycloalkyl, (CH 2 )n1-alkyl, aryl, (CH 2 )n1-aryl, halogen, CF 3 , SO 3 H, (CH 2 ) x PO 3 H 2 , with x=0, 1 or 2, B(OH) 2 , Formula (III), NO 2 , SO 2 NH 2 , SO 2 NHR; SR, S(O)R, SO 2 R, benzyl; -M 1 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, 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 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, said hypophosphorous acid derivatives being diasteroisomers or enantiomers. Application as drugs.

  含有Formula (I)的次磷酸衍生物，其中.M是[C(R3,R4)]n1-C(E,COOR1,N(H,Z))基团，或者是一个可选择取代的Ar—CH(COOR1,N(H,Z))基团，或者是α，β或αβ，γ-环氨基酸；.R1是H或R，R是一个羟基或羧基保护基团；.Z是H或氨基保护基团R′，苄氧羰基，苄基或苄基取代；.E是H或C1-C3烷基，芳基，疏水基团；.R2是从以下群体中选择的：D-CH(R6)—C—(R7,R8)，(R11,R12)CH—C(R9,R10)，D-CH(OH)，D-[C(R13,R14)]n3—，C[(R15,R16,R17)]n4，D-CH2，(R18)CH═C(R19)，D-(M1)n6—CO，Formula (II)，PO(OH)2—CH2或(PO(OH)2—CH2)，(COOH—CH2)—CH2，其中-D=H，OH，OR，(CH2)n2OH，(CH2)n1OR，COOH，COOR，(CH2)n2COOH，(CH2)n1COOR，SR，S(OR)，SO2R，NO2，杂环芳基，C1-C3烷基，环烷基，杂环烷基，(CH2)n2-烷基，(COOH,NH2)—(CH2)u1-环丙基-(CH2)u2—，CO—NH-烷基，Ar，(CH2)n2—Ar，CO—NH—Ar；—R3到R19为H，OH，OR，(CH2)n2OH，(CH2)n1OR，COOH，COOR，(CH2)n2COOH，(CH2)n1COOR，C1-C3烷基，环烷基，(CH2)n1-烷基，芳基，(CH2)n1-芳基，卤素，CF3，SO3H，(CH2)xPO3H2，其中x=0，1或2，B(OH)2，Formula (III)，NO2，SO2NH2，SO2NHR；SR，S(O)R，SO2R，苄基；-M1是一个烷基或芳基基团；-n1=1，2或3，n2=1，2或3，n3=0，1，2或3，n4=1，2或3，n5=1，2或3，n6=0或1，u1和u2，相同或不同=0，1或2，但Formula (I)不代表3-氨基，3-羧基-丙基-2′-羧基-乙磷酸的消旋体(3R,S)和对映体形式(3R)；3-氨基，3-羧基-丙基-4′羧基，2′羧基-丁酰磷酸；3-氨基，3-羧基-丙基-2′羧基-丁酰磷酸；3-氨基，3-羧基-丙基-3′氨基，3′羧基-丙基磷酸；和3-氨基，3-羧基丙基-7′氨基-2′，7′-二羧基庚基磷酸，所述的次磷酸衍生物为二对映异构体或对映体。用作药物的应用。
• [EN] DIASTEREOISOMERS OF HYPOPHOSPHOROUS ACID DERIVATIVES<br/>[FR] DIASTÉRÉOISOMÈRES DE DÉRIVÉS D'ACIDE HYPOPHOSPHOREUX
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2010106526A1

  公开（公告）日：2010-09-23

  The invention relates to the diastereoisomers of hypophosphorous acid derivatives, having formula (I), wherein the phenyl group is substituted by one or several atoms or groups, occupying one or several positions on the phenyl ring, and a method for the separation thereof.

  该发明涉及具有式（I）的次磷酸衍生物的对映异构体，其中苯基被一个或多个原子或基团取代，占据苯环上的一个或多个位置，并提供了一种分离它们的方法。
• THIOPHOSPHI(O)NIC ACID DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
  申请人：Acher Francine

  公开号：US20100137258A1

  公开（公告）日：2010-06-03

  The invention relates to thiophosphi(o)nic acid derivatives having formula (I) wherein. M is a [C(R 3 ,R 4 )]n1-C(E,COOR 1 ,N(H,Z)) group, or an optionally substituted Ar—CH(COOR 1 ,N(H,Z)) group (Ar designating an aryl or an heteroaryl group), or an α, β cyclic aminoacid group such as, formula (II) or a β, &ggr;-cyclic aminoacid group such as, formula (III). 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 ) n1 -alkyl, (CH 2 ) n1 -aryl (or heteroaryl), such as a benzyl group, or a xanthyl, alkyl xanthyl or alkyl thioxanthyl group, or —(CH 2 ) n1 -cycloalkyl, —(CH 2 ) n —(CH 2 —Ar) 2 , a chromanyl group, particularly 4-methyl chromanyle, indanyle, tetrahydro naphtyl, particularly methyl-tetrahydronaphtyl; or M is OM′, wherein M′ is as above defined for M; R 2 is selected in the group comprising: D-CH(R 6 )—C—(R 7 ,R 8 )—(R 11 ,R 12 )CH—C(R 9 .R 10 )-D-CH(OH)-D-[C(R 13 ,R 14 )] n3 —C[(R 15 ,R 16 ,R 17 ] n4 -D-CH 2 —(R 18 )CH═C(R 19 )-D-(M 1 )n6-CO-D-C(R,R′)—O-D-O—, formula (IV), PO(OH) 2 —CH 2 or (PO(OH) 2 —CH 2 ), (COOH—CH 2 )—CH 2 — with -D=H, OH, OR, (CH 2 ) n2 OH, (CH 2 ) n1 OR, COOH, COOR, (CH 2 ) n2 COOH, (CH 2 ) n1 C00R, SR, S(OR), SO 2 R, NO 2 , heteroaryl, C 1 -C 3 alkyl, cycloalkyl, heterocycloalkyl, (CH 2 ) n2 -alkyl, (COOH, NH 2 )—(CH 2 ) u1 -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, —R 3 to R 19 , identical or different, being H, OH, OR, (CH 2 ) n2 OH, (CH 2 ) n1 OR, COOH, COOR, (CH 2 ) n2 COOH, (CH 2 ) n1 COOR, C 1 -C 3 alkyl, cycloalkyl, (CH 2 ) n1 -alkyl, aryl, (CH 2 ) n1 -aryl, halogen, CF 3 , SO 3 H, (CH 2 )XPO 3 H 2 , with x=0, 1 or 2, B(OH) 2 , formula (V), NO 2 , SO 2 NH 2 , SO 2 NHR; SR, S(O)R, SO 2 R, benzyl; one of R 11 or R 12 being COOR, COOH, (CH 2 ) n2 —COOH, (CH 2 ) n2 —COOR, PO 3 H 2 the other one being such as defined for R 9 and R 10 ;—one Of R 15 , R 16 and R 17 is COON 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;—n 1 =1, 2 or 3;—n 2 =1, 2 or 3,—n 3 =0, 1, 2 or 3 and—n 4 =1, 2 or 3;—n 5 =1, 2 or 3;—n 6 =0 or 1,—u 1 and u 2 , 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 ) n1 OH, (CH2) n1 OR, COOH, COOR, (CH 2 ) n1 C00H, (CH 2 ) n1 COOR, C 1 -C 3 alkyl, cycloalkyl, (CH 2 ) n1 -alkyl, aryl, (CH 2 ) n1 -aryl, halogen, CF 3 , SO 3 H, (CH 2 ) x PO 3 H 2 , with x=0, 1 or 2, B(OH) 2 , formula (V), NO 2 , SO 2 NH 2 , SO 2 NHR; SR, S(O)R, SO 2 R, benzyl; R being such as above defined.

  本发明涉及具有以下式（I）的硫代磷酸衍生物，其中M是[C（R3，R4）]n1-C（E，COOR1，N（H，Z））基团，或者是一个可选择取代的Ar—CH（COOR1，N（H，Z））基团（Ar代表芳基或杂芳基），或者是α，β环氨基酸基团，如式（II）或β，γ-环氨基酸基团，如式（III）。R1是H或R，其中R是一个羟基或羧基保护基团，例如C1-C3烷基，Ar（代表芳基或杂芳基），Z是H或氨基保护基团R'，例如C1-C3烷基，C1-C3酰基，Boc，Fmoc，COOR，苄氧羰基，苄基或与Ar相关定义的苄基取代物；E是H或C1-C3烷基，芳基，疏水基团，如（CH2）n1-烷基，（CH2）n1-芳基（或杂芳基），如苄基，或者是黄色素基团，如（CH2）n1-环烷基，（CH2）n-（CH2—Ar）2，一环色基团，特别是4-甲基色基，茚基，四氢萘基，特别是甲基-四氢萘基；或者M是OM'，其中M'如上定义为M；R2在组中选择：D-CH（R6）—C—（R7，R8）—（R11，R12）CH—C（R9.R10）-D-CH（OH）-D-[C（R13，R14）]n3—C（R15，R16，R17）n4-D-CH2—（R18）CH═C（R19）-D-（M1）n6-CO-D-C（R，R'）—O-D-O—，式（IV），PO（OH）2—CH2或（PO（OH）2—CH2），（COOH—CH2）—CH2—，其中-D=H，OH，OR，（CH2）n2OH，（CH2）n1OR，COOH，COOR，（CH2）n2COOH，（CH2）n1C00R，SR，S（OR），SO2R，NO2，杂芳基，C1-C3烷基，环烷基，杂环烷基，（CH2）n2-烷基，（COOH，NH2）—（CH2）u1-环丙基-（CH2）u2—，CO—NH-烷基，Ar，（CH2）n2—Ar，CO—NH—Ar，其中R如上定义，Ar是可选择取代的芳基或杂芳基，—R3到R19，相同或不同，为H，OH，OR，（CH2）n2OH，（CH2）n1OR，COOH，COOR，（CH2）n2COOH，（CH2）n1COOR，C1-C3烷基，环烷基，（CH2）n1-烷基，芳基，（CH2）n1-芳基，卤素，CF3，SO3H，（CH2）XPO3H2，其中x=0，1或2，B（OH）2，式（V），NO2，SO2NH2，SO2NHR；SR，S（O）R，SO2R，苄基；其中R11或R12之一为COOR，COOH，（CH2）n2—COOH，（CH2）n2—COOR，PO3H2，另一个如R9和R10定义的；其中R15，R16和R17之一为COON或COOR，其他的相同或不同，如上定义；其中R18和R19之一为COOH或COOR，另一个如上定义；其中M1是一个烷基或芳基基团；n1=1，2或3；n2=1，2或3；n3=0，1，2或3；n4=1，2或3；n5=1，2或3；n6=0或1；u1和u2，相同或不同=0，1或2，Ar和烷基基团可选择在同一位置或不同位置上由一个或多个取代基取代，所述取代基选择自羟基，OR，（CH2）n1OH，（CH2）n1OR，COOH，COOR，（CH2）n1C00H，（CH2）n1COOR，C1-C3烷基，环烷基，（CH2）n1-烷基，芳基，（CH2）n1-芳基，卤素，CF3，SO3H，（CH2）xPO3H2，其中x=0，1或2，B（OH）2，式（V），NO2，SO2NH2，SO2NHR；SR，S（O）R，SO2R，苄基；R如上定义。