JP2005531486A - 新規のデプシペプチドおよびこれを調製するためのプロセス - Google Patents
新規のデプシペプチドおよびこれを調製するためのプロセス Download PDFInfo
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- JP2005531486A JP2005531486A JP2003519096A JP2003519096A JP2005531486A JP 2005531486 A JP2005531486 A JP 2005531486A JP 2003519096 A JP2003519096 A JP 2003519096A JP 2003519096 A JP2003519096 A JP 2003519096A JP 2005531486 A JP2005531486 A JP 2005531486A
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- 238000004519 manufacturing process Methods 0.000 title claims description 7
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 title abstract description 18
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- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
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Abstract
Description
本出願は、本明細書中でその全体が参考として援用される、2001年8月6日に出願された米国特許出願番号60/310,313の利益を主張する。
本発明は、新規のデプシペプチド化合物に関する。本発明はまた、これらの化合物の薬学的組成物、および抗菌剤としてこれらの化合物を使用する方法に関する。本発明はまた、これらの新規のデプシペプチド化合物およびこれらの化合物を生成する際に使用される中間体を生成する方法に関する。
グラム陽性感染(耐性細菌により引き起こされるものを含む)の発生の急速な増加は、新規のクラスの抗生物質の開発の新たな興味の口火となっている。有用な抗生物質としての能力を示している化合物のクラスは、環状デプシペプチドである。環状デプシペプチドの著名なメンバーは、例えば、以下に記載される、A−21978Cリポペプチドである:米国特許第RE 32,333号;同第RE 32,455号;同第RE 32,311号;同第RE 32,310号;同第4,482,487号;同第4,537,717号;および同第5,912,226号、および国際特許出願公開WO01/44272;WO01/44274;およびWO01/44271。さらに、米国特許第4,994,270号;同第5,039,789号;および同第5,028,590号に記載される、A54145クラスの化合物はまた、抗菌活性を保有することが示されている。
既存の抗生物質が示している見込みにもかかわらず、新規の抗生物質の必要性が続いている。多くの病原体は、一般的に用いられる抗生物質に繰返し曝露されている。この曝露は、広範な範囲の抗生物質に対して耐性である、種々の抗菌株の選択をもたらす。耐性機構により引き起こされる、抗生物質の能力および効力の損失は、抗生物質を無効にし、そして、結果として、実際に処置不可能である、いくつかの生命の危険を脅かす感染を導き得る。新規の抗生物質が市場に現れると、病原体は、これらの新規の薬物に対する耐性を生じ得るか、または耐性を媒介し得、出現するこれらの株と闘うために、新規の抗菌性薬剤の潮流の必要性が実際上生じる。さらに、殺菌活性を示す化合物は、現在の静菌化合物を超える利点を与える。従って、新規の抗菌性薬剤は、「天然の」病原体のみならず、中間の薬物耐性病原体および薬物耐性病原体もまた処置するために有用であることが予想される。なぜならば、この病原体は、この新規の抗菌性薬剤には、これまで決して曝露されていないからである。新規の抗菌性薬剤は、異なる型の病原体に対して異なる有効性を示し得る。
(a)Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b)各R1およびR6は、独立して、ヒドリドまたはメチルであり;
(c)R2は、メチルまたは−CH2CH2CH2R8であり;
(d)R3は、メチルまたは−CH2CH2CH2CH2R9であり;
(e)R4は、ヒドリドまたはメトキシであり;
(f)R5は、ヒドロキシまたはカルボキシアミノであり;
(g)R7、R8およびR9の各々は、独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノ、またはホスホンアミノであり;
(h)但し、
(1)R2が、−CH2CH2CH2R8であり、R7が、以下のもの:
R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、イミノアミノ、またはホスホンアミノであり;
(2)R2が、メチルであり、R7が、以下のもの:
R11およびR12は、ヒドリド、C6−C18非置換アルカノイル、C8−C18非置換アルケノイル、C8−C18非置換アルキル、またはC8−C18選択的置換アルキル;あるいは、R11およびR12は、共に、C8−C18アルキリデニルである。
(定義)
用語「活性化基」は、カルボニル基に隣接する場合に、このカルボニル基を活性化して、求核アミンにより攻撃し、活性化基の消失およびアミド結合の形成を生じる基を表す。活性化基の例は、アリールオキシ、アシルオキシ、イミダゾリル、
ここで、Rx2は、ヒドリド、アルキル、アリール、シクロアルキル、ヘテロアリールまたはヘテロシクリルから選択され、そしてRx3は、アルキル、アリール、シクロアルキル、ヘテロアリールまたはヘテロシクリルから選択される。
ここで、Rx5、Rx7およびRx8の各々は、ヒドリド基、アルキル基、アリール基、シクロアルキル基、ヘテロアリール基またはヘテロシクリル基から独立して選択され;Rx6は、アルキル基、アリール基、シクロアリール基、ヘテロアリール基またはヘテロシクリル基から選択される。
ここで、Rx9およびRx11の各々は、ヒドリド基、アルキル基、シクロアルキル基、アリール基、ヘテロアリール基またはヘテロシクリル基から独立して選択され;そしてRx10は、アルキル基、シクロアルキル基、アリール基、ヘテロアリール基またはヘテロシクリル基から選択される。
ここで、Rx12は、ヒドリド、アルキル、アリール、シクロアルキル、ヘテロアリールまたはヘテロシクリルから選択され;Rx13およびRx14の各々は、アルキル、アルコキシ、アリール、アリールオキシ、シクロアルキル、ヘテロアリールおよびヘテロシクリルから独立して選択される。
ここで、Rx15は、ヒドリド基、アルキル基、シクロアルキル基、アリール基、ヘテロアリール基またはヘテロシクリル基から選択され;そしてRx16が、アルキル基、シクロアルキル基、アリール基、ヘテロアリール基またはヘテロシクリル基から選択される。
ここで、Rx17は、ヒドリド基、アルキル基、アリール基、シクロアルキル基、ヘテロアリール基またはヘテロシクリル基から選択され;そしてここで、Rx18は、アルキル基、アリール基、シクロアルキル基、ヘテロアリール基またはヘテロシクリル基から選択される。
ここで、Rx19およびRx20の各々は、ヒドリド基、アルキル基、アリール基、シクロアルキル基、ヘテロアリール基またはヘテロシクリル基から独立して選択され;Rx21は、アルキル基、アリール基、シクロアルキル基、ヘテロアリール基、またはヘテロシクリル基から選択される。
ここで、Rx21およびRx22の各々は、ヒドリド基、アルキル基、アリール基、シクロアルキル基、ヘテロアリール基またはヘテロシクリル基から独立して選択され;そしてRx23は、アルキル基、アリール基、シクロアルキル基、ヘテロアリール基、またはヘテロシクリル基から選択される。
1つの局面では、本発明は、以下の式Iの化合物:
(a)Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b)各R1およびR6は、独立して、ヒドリドまたはメチルであり;
(c)R2は、メチルまたは−CH2CH2CH2R8であり;
(d)R3は、メチルまたは−CH2CH2CH2CH2R9であり;
(e)R4は、ヒドリドまたはメトキシであり;
(f)R5は、ヒドロキシまたはカルボキシアミノであり;
(g)R7、R8およびR9の各々は、独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノ、またはホスホンアミノであり;
(h)但し
(1)R2が、−CH2CH2CH2R8であり、R7が、以下:
R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノ、およびホスホンアミノであり;
(2)R2が、メチルであり、R7が、以下:
R11およびR12の各々は、ヒドリド、C6−C18非置換アルカノイル、C8−C18非置換アルケノイル、C8−C18非置換アルキル、またはC8−C18選択置換アルキルであるか;あるいは、R11およびR12は、共に、C8−C18アルキリデニルである。
ここで、Raa、Raa2およびRaa3の各々は、独立して、アミノ酸側鎖であり、そしてR13は、アミノ、一置換アミノ、二置換アミノ、アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノ、またはホスホンアミノである。
(式IIの化合物)
(式IIIの化合物)
本発明はまた、式Iの化合物の調製のための中間体として特に有用である、以下の式IVの化合物:
(a)Rは、2−ブチル、イソプロプルまたは2−(2’−アミノフェナシル)であり;
(b)R1およびR6の各々は、独立して、ヒドリドまたはメチルであり;
(c)R4は、ヒドリドまたはメトキシであり;
(d)R5は、ヒドロキシまたはカルボキシアミノであり;
(e)R15は、ヒドリド、
ここで:R18は、アミノまたはヒドロキシであり;R19は、ヒドリドまたはヒドロキシであり;そしてR20は、カルボキシアミノまたはカルボキシメチルであり、
(f)R16は、メチルまたは−CH2CH2CH2R21であり;
(g)R17は、メチルまたは−CH2CH2CH2CH2R22であり;
R21およびR22の各々は、独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノ、またはホスホンアミノである。
本発明は、式Iの化合物、またはその塩を含む薬学的組成物または薬学的処方物を提供する。
(1.半合成プロセス)
R2およびR3の少なくとも1つが、メチル以外であり、R8およびR9が、それぞれ独立してNH2である、式Iの化合物の調製のためのプロセス。
R2およびR3の少なくとも1つが、メチル以外であり、R8およびR9が、それぞれ独立してNH2である式Iの化合物について、本発明の1つの局面によれば、このプロセスは以下の工程を包含する:
(a)式XIのデプシペプチド誘導体あるいはこれらの塩を提供する工程であって、
(b)式XIの化合物の遊離アミノ基を保護基で保護し、保護されたデプシペプチド化合物を得る工程;
(c)(b)で得られた保護化デプシペプチド化合物を脱アシル剤で処理し、末端アミノ化合物を得る工程;
(d)(c)で得られた末端アミノ化合物のトリプトファンアミノ酸残基を除去し、デストリプトファン化合物を得る工程;
(e)(d)で得られたデストリプトファン化合物の末端アミノ酸残基を除去し、デスジペプチド化合物を得る工程;
(f)(e)で得られたデスジペプチド化合物の末端アミノ酸残基を除去し、デプシペプチドコア化合物を得る工程;
(g)(f)のデプシペプチドコア化合物を、修飾剤で処理する工程;および
(h)保護された式Iの化合物から保護基を除去し、式Iaの化合物を得る工程。
(手順B)
R2およびR3の少なくとも1つがメチル以外であり、R8およびR9の各々がNH2以外である、式Iの化合物について、本発明の別の局面に従うプロセスは、以下のさらなる工程を包含する:
(i)手順Aの工程(h)の式Iの遊離アミノ化合物を、修飾剤で処理し、式Iの化合物を得る工程。
R2およびR3の少なくとも1つがメチル以外であり、R8およびR9の各々がNH2以外である、式Iの化合物を調製するための代替の手順は、以下の工程を包含する:
(a)式XI
(b)式XIの化合物の遊離アミノ基を修飾剤で処理し、ブロックされたデプシペプチド化合物を得る工程であって、ここでこの修飾剤は、形成されたブロックされたデプシペプチド化合物が、工程(c)、(d)、(e)、(f)および(g)に対して安定であるように選択される、工程;
(c)(b)で得られたブロックされたデプシペプチド化合物を、脱アシル剤で処理し、末端アミノ化合物を得る工程;
(d)(c)で得られた末端アミノ化合物のトリプトファンアミノ酸残基を除去し、デストリプトファン化合物を得る工程;
(e)(d)で得られたデストリプトファン化合物の末端アミノ酸残基を除去して、デスジペプチド化合物を得る工程;
(f)(e)で得られたデスジペプチド化合物の末端アミノ酸残基を除去して、デプシペプチドコア化合物を得る工程;
(g)(f)のデプシペプチドコア化合物を修飾剤で処理する工程。
上記を参照のこと)。
R7が
同様に、式Iの化合物および式Iaの化合物を、スキームVIIIに記載されるように化合物XIVから調製し得るか、スキームIXに記載されるように化合物XXVIによって調製され得る;ここで、R7は以下の式
同様に、式Iの化合物および式Iaの化合物を、スキームXに記載されるように化合物XVから調製し得るか、スキームXIに記載されるように化合物XXVIIによって調製され得る;ここで、R7は以下の式
(デプシペプチド化合物の固体支持体合成)
本発明の代替の実施形態において、式Iのデプシペプチド化合物を、固体支持体上で合成し得る(スキームXII、スキームXIIIおよびスキームXV)。
本発明の化合物はまた、組換え方法によって調製され得る。このプロセスにおいて、ダプトマイシン(daptomycin)の改変非リボソームペプチドシンセターゼを、式Iの化合物を生成し得る細胞へと導入し、そして細胞を培養して、式Iの化合物を形成する。ダプトマイシンの非リボソームペプチドシンセターゼならびにこれらのシンセターゼの改変は、報告されている(国際特許出願番号02/059,322を参照のこと)。
(ペプチド樹脂化合物23の合成)
(化合物29の合成)
(化合物33の合成)
(化合物34の合成)
(化合物39の合成)
(化合物41の合成)
(化合物45の合成)
(化合物47の合成)
(化合物50の合成)
(化合物53の合成)
(化合物57の合成)
(トリプトファンを除去するためのエドマン分解:化合物70の調製)
(脱アスパラギン(desasparagine)化合物72の調製)
(コア化合物74の調製)
(生物学的活性)
式Iの化合物を、全ての試験を37℃で実施したことを除いて、National Committee for Clinical Laboratory Standards(NCCLS文献 M7−A5、20巻、2号、2000)によって記載される標準的な手順に従って、生物のパネルに対する抗菌活性について、試験した。化合物を、100%ジメチルスルホキシドに溶解し、微生物増殖培地中の最終反応濃度(0.1μg/mL〜100μg/mL)まで希釈した。全ての場合において、細胞とともにインキュベートするジメチルスルホキシドの最終濃度は、1%以下である。最少阻害濃度(MIC)を計算するために、2倍希釈の化合物を、100μlの最終容量の培地(50mg/L Ca+を補充したMueller−Hintonブロス)に5×104の細菌細胞を含むマイクロタイタープレートのウェルに添加した。市販のプレート読み取り機を使用して、細菌細胞の光学濃度(OD)(これは、細菌細胞の増殖(growth)および増殖(proliferation)を測定する)を測定した。MIC値を、試験生物の増殖を阻害する最低の化合物濃度と定義する。本発明の代表的な化合物のMIC(μg/ml)値を表IIIに列挙する。
「++」は、その化合物が、それぞれ1μg/mlまたは1mg/kgより大きい、それぞれMIC(μg/ml)またはED50を有するが、10μg/mlまたは10mg/kgのED50以下であることを示し;そして
「+」は、その化合物が、10μg/mlより大きいMIC(μg/ml)または10mg/kgより大きいED50を有することを示す。
(インビボ活性)
マウス防御試験は、インビボでの試験化合物の有効性を測定するための工業規格である[このモデルの例として、J.J.Clementら、Antimicrobial Agents and Chemotherapy,38(5),1071−1078,(1994)を参照のこと]。以下に例示するように、この試験を、細菌に対する本発明の化合物のインビボでの有効性を実証するために使用する。
Claims (30)
- 以下の式:
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は、独立して、ヒドリドまたはメチルであり;
(c) R2はメチルまたは−CH2CH2CH2R8であり;
(d) R3はメチルまたは−CH2CH2CH2CH2R9であり;
(e) R4はヒドリドまたはメトキシであり;
(f) R5はヒドロキシまたはカルボキシアミノであり;
(g) R7、R8およびR9の各々は独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノであり;
(h) 但し、
(1) R2が−CH2CH2CH2R8である場合、R7は以下:
(2)R2がメチルである場合、R7は以下:
組成物。 - 請求項1に記載の組成物であって、Rが2−(2’−アミノフェナシル)であり;R1およびR4の各々がヒドリドであり;R2が−CH2CH2CH2R8であり;R3およびR6の各々がメチルであり;そしてR5がヒドロキシルである、組成物。
- 請求項1に記載の組成物であって、Rが2−ブチルまたはイソプロピルであり;R1およびR2の各々がメチルであり;R3が−CH2CH2CH2CH2R9であり;R4がメトキシであり;そしてR5がカルボキシアミノである、組成物。
- 請求項4に記載の組成物であって、Rが2−(2’−アミノフェナシル)であり;R1およびR4の各々がヒドリドであり;R2が−CH2CH2CH2R8であり;R3およびR6の各々がメチルであり;そしてR5がヒドロキシルである、組成物。
- 請求項4に記載の組成物であって、Rが2−ブチルまたはイソプロピルであり;R1およびR2の各々がメチルであり;R3が−CH2CH2CH2CH2R9であり;R4がメトキシであり、そしてR5がカルボキシアミノである、組成物。
- 以下の式:
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は独立して、ヒドリドまたはメチルであり;
(c) R4は、ヒドリドまたはメトキシであり;
(d) R5は、ヒドロキシまたはカルボキシアミノであり;
(e) R15は、ヒドリド、
ここで:R18がアミノまたはヒドロキシであり;R19がヒドリドまたはヒロドキシであり;そしてR20がカルボキシアミノまたはカルボキシメチルであり;
(f) R16がメチルまたは−CH2CH2CH2R21であり;
(g) R17がメチルまたは−CH2CH2CH2CH2R22であり;
ここで、R21およびR22の各々が、独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノである、
組成物。 - R21およびR22の各々が、独立して、−NHR23であり、ここでR23がアミノ保護基である、請求項7に記載の組成物。
- 以下の式:
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は、独立して、ヒドリドまたはメチルであり;
(c) R2はメチルまたは−CH2CH2CH2R8であり;
(d) R3はメチルまたは−CH2CH2CH2CH2R9であり;
(e) R4はヒドリドまたはメトキシであり;
(f) R5はヒドロキシまたはカルボキシアミノであり;
(g) R7、R8およびR9の各々は独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノであり;
(h) 但し、
(1) R2が−CH2CH2CH2R8である場合、R7は以下:
ここで、R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、イミノアミノまたはホスホンアミノであり;
(2)R2がメチルである場合、R7は以下:
ここで、R11およびR12の各々は、ヒドリド、C6〜C18非置換アルカノイル、C8〜C18非置換アルケノイル、C8〜C18非置換アルキル、もしくはC8〜C18選択置換アルキルであるか;または代替的に、R11およびR12は一緒になってC8〜C18アルキリデニルである、
組成物。 - 請求項10に記載の組成物であって、Rが2−(2’−アミノフェナシル)であり;R1およびR4の各々がヒドリドであり;R2が−CH2CH2CH2R8であり;R3およびR6の各々がメチルであり;そしてR5がヒドロキシルである、組成物。
- 請求項10に記載の組成物であって、Rが2−ブチルまたはイソプロピルであり;R1およびR2の各々がメチルであり;R3が−CH2CH2CH2CH2R9であり;R4がメトキシであり;そしてR5がカルボキシアミノである、組成物。
- 被験体において細菌感染を処置する方法であって、該方法が、治療有効量の請求項1に記載の組成物を、被験体に投与する工程を包含する、方法。
- 以下の式I:
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は独立して、ヒドリドまたはメチルであり;
(c) R2は、メチルまたは−CH2CH2CH2R8であり;
(d) R3は、メチルまたは−CH2CH2CH2CH2R9であり;
(e) R4は、ヒドリドまたはメトキシであり;
(f) R5は、ヒドロキシまたはカルボキシアミノであり;
(g) R7、R8およびR9の各々は独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノであり;
(h) 但し、
(1) R2が−CH2CH2CH2R8である場合、R7は以下:
ここで、R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、イミノアミノまたはホスホンアミノであり;
(2)R2がメチルである場合、R7は以下:
ここで、R11およびR12の各々は、ヒドリド、C6〜C18非置換アルカノイル、C8〜C18非置換アルケノイル、C8〜C18非置換アルキル、もしくはC8〜C18選択置換アルキルであるか;または代替的に、R11およびR12は一緒になってC8〜C18アルキリデニルであり;
該プロセスが、以下の式XVII:
ここで、R28がメチルまたは−CH2CH2CH2NHPあり;R29がメチルまたは−CH2CH2CH2CH2NHPで−であり;そしてPはアミノ酸保護基であり;但し、R28またはR29の少なくとも1つがメチル以外のものである、
プロセス。 - 以下の式I:
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は独立して、ヒドリドまたはメチルであり;
(c) R2は、メチルまたは−CH2CH2CH2R8であり;
(d) R3は、メチルまたは−CH2CH2CH2CH2R9であり;
(e) R4は、ヒドリドまたはメトキシであり;
(f) R5は、ヒドロキシまたはカルボキシアミノであり;
(g) R7、R8およびR9の各々は独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノであり;
(h) 但し、
(1) R2が−CH2CH2CH2R8である場合、R7は以下:
ここで、R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、イミノアミノまたはホスホンアミノであり;
(2)R2がメチルである場合、R7は以下:
該プロセスが、以下の式Ia
ここで、R2aがメチルまたは−CH2CH2CH2NH2あり;そしてR3aがメチルまたは−CH2CH2CH2CH2NH2であり;但し、R2aおよびR3aのうちの少なくとも一方はメチル以外のものである;
プロセス。 - 以下の式I:
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は独立して、ヒドリドまたはメチルであり;
(c) R2は、メチルまたは−CH2CH2CH2R8であり;
(d) R3は、メチルまたは−CH2CH2CH2CH2R9であり;
(e) R4は、ヒドリドまたはメトキシであり;
(f) R5は、ヒドロキシまたはカルボキシアミノであり;
(g) R7、R8およびR9の各々は独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノであり;
(h) 但し、
(1) R2が−CH2CH2CH2R8である場合、R7は以下:
ここで、R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、イミノアミノまたはホスホンアミノであり;
(2)R2がメチルである場合、R7は以下:
該プロセスが、以下の式XXVIII
ここで、R37がメチルまたは−CH2CH2CH2R8であり;そしてR38がメチルまたは−CH2CH2CH2CH2R9であり;但し、R37およびR38のうちの少なくとも一方はメチル以外のものであり、そしてさらに但し、R8およびR9の各々がアミノ以外のものである;
プロセス。 - 以下の式XXXII:
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は独立して、ヒドリドまたはメチルであり;
(c) R4は、ヒドリドまたはメトキシであり;
(d) R5は、ヒドロキシまたはカルボキシアミノであり;
(e) R18は、アミノまたはヒドロキシであり;
(f) R19は、ヒドリドまたはヒドロキシであり;
(g) R20は、カルボキシアミノまたはカルボキシメチルであり;
(h) R28は、メチルまたは−CH2CH2CH2NHPであり;
(i) R29は、メチルまたは−CH2CH2CH2CH2NHPであり;
(j) Pは、アミノ保護基であり;
(k) R39は独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノであり;
(l) 但し、
(1) R2が−CH2CH2CH2R8である場合、R7は以下:
ここで、R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、イミノアミノまたはホスホンアミノであり;
(2)R2がメチルである場合、R7は以下:
該プロセスが、以下の式XIV
プロセス。 - 以下の式XXXIV
(a) Rは、2−ブチル、イソプロピルまたは2−(2’−アミノフェナシル)であり;
(b) R1およびR6の各々は独立して、ヒドリドまたはメチルであり;
(c) R4は、ヒドリドまたはメトキシであり;
(d) R5は、ヒドロキシまたはカルボキシアミノであり;
(e) R18は、アミノまたはヒドロキシであり;
(f) R19は、ヒドリドまたはヒドロキシであり;
(g) R28は、メチルまたは−CH2CH2CH2NHPであり;
(h) R29は、メチルまたは−CH2CH2CH2CH2NHPであり;
(i) Pは、アミノ保護基であり;
(j) R39は独立して、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、チオウレイド、イミノアミノまたはホスホンアミノであり;
(k) 但し、
(1) R2が−CH2CH2CH2R8である場合、R7は以下:
ここで、R10は、アミノ、一置換アミノ、二置換アミノ、アシルアミノ、ウレイド、グアニジノ、カルバモイル、スルホンアミノ、チオアシルアミノ、イミノアミノまたはホスホンアミノであり;
(2)R2がメチルである場合、R7は以下:
該プロセスが、以下の式XV
プロセス。
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2002
- 2002-08-06 NZ NZ531493A patent/NZ531493A/xx not_active IP Right Cessation
- 2002-08-06 BR BRPI0211761-4A patent/BR0211761A/pt not_active IP Right Cessation
- 2002-08-06 CA CA002456323A patent/CA2456323A1/en not_active Abandoned
- 2002-08-06 EP EP02761255A patent/EP1423414A4/en not_active Withdrawn
- 2002-08-06 AT AT02789158T patent/ATE430160T1/de not_active IP Right Cessation
- 2002-08-06 KR KR10-2004-7001758A patent/KR20040022233A/ko not_active Application Discontinuation
- 2002-08-06 RU RU2004106630/04A patent/RU2348647C2/ru not_active IP Right Cessation
- 2002-08-06 AU AU2002353775A patent/AU2002353775A1/en not_active Abandoned
- 2002-08-06 JP JP2003519096A patent/JP2005531486A/ja active Pending
- 2002-08-06 WO PCT/US2002/025106 patent/WO2003017924A2/en not_active Application Discontinuation
- 2002-08-06 IL IL16017102A patent/IL160171A0/xx unknown
- 2002-08-06 EP EP02789158A patent/EP1423137B1/en not_active Expired - Lifetime
- 2002-08-06 DE DE60232158T patent/DE60232158D1/de not_active Expired - Fee Related
- 2002-08-06 US US10/213,218 patent/US7262268B2/en not_active Expired - Fee Related
- 2002-08-06 CA CA002456761A patent/CA2456761A1/en not_active Abandoned
- 2002-08-06 US US10/213,389 patent/US20030083240A1/en not_active Abandoned
- 2002-08-06 CN CNB028174658A patent/CN100352836C/zh not_active Expired - Fee Related
- 2002-08-06 WO PCT/US2002/024896 patent/WO2003014147A1/en active Application Filing
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2004
- 2004-02-04 ZA ZA200400928A patent/ZA200400928B/en unknown
-
2006
- 2006-04-28 US US11/414,762 patent/US20060194714A1/en not_active Abandoned
- 2006-06-06 US US11/448,066 patent/US7335726B2/en not_active Expired - Fee Related
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2008
- 2008-01-30 US US12/022,470 patent/US20080119395A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012126753A (ja) * | 2008-04-21 | 2012-07-05 | Signum Biosciences Inc | 化合物、組成物およびそれらを作製する方法 |
JP2014217322A (ja) * | 2013-05-08 | 2014-11-20 | 株式会社ゲノム創薬研究所 | 固相レジンを用いた環状ペプチド化合物の製造方法 |
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RU2004106630A (ru) | 2005-06-27 |
EP1423137A4 (en) | 2005-11-30 |
WO2003017924A2 (en) | 2003-03-06 |
US20060223983A1 (en) | 2006-10-05 |
IL160171A0 (en) | 2004-07-25 |
US20080119395A1 (en) | 2008-05-22 |
US20030096948A1 (en) | 2003-05-22 |
AU2002353775A1 (en) | 2003-03-10 |
KR20040022233A (ko) | 2004-03-11 |
NZ531493A (en) | 2006-03-31 |
ATE430160T1 (de) | 2009-05-15 |
EP1423414A4 (en) | 2005-11-30 |
RU2348647C2 (ru) | 2009-03-10 |
CN100352836C (zh) | 2007-12-05 |
US7262268B2 (en) | 2007-08-28 |
US20060194714A1 (en) | 2006-08-31 |
EP1423414A1 (en) | 2004-06-02 |
CA2456761A1 (en) | 2003-02-20 |
BR0211761A (pt) | 2007-01-09 |
EP1423137B1 (en) | 2009-04-29 |
EP1423137A2 (en) | 2004-06-02 |
CN1551887A (zh) | 2004-12-01 |
US20030083240A1 (en) | 2003-05-01 |
WO2003017924A3 (en) | 2004-03-04 |
US7335726B2 (en) | 2008-02-26 |
CA2456323A1 (en) | 2003-03-06 |
DE60232158D1 (de) | 2009-06-10 |
WO2003014147A1 (en) | 2003-02-20 |
ZA200400928B (en) | 2005-05-04 |
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