JP2006515854A - ヒト腫瘍発現ccxckr2の阻害剤 - Google Patents
ヒト腫瘍発現ccxckr2の阻害剤 Download PDFInfo
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- JP2006515854A JP2006515854A JP2004563974A JP2004563974A JP2006515854A JP 2006515854 A JP2006515854 A JP 2006515854A JP 2004563974 A JP2004563974 A JP 2004563974A JP 2004563974 A JP2004563974 A JP 2004563974A JP 2006515854 A JP2006515854 A JP 2006515854A
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- unsubstituted
- substituted
- mmol
- methyl
- modulator
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 52
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 35
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 18
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- 150000002431 hydrogen Chemical class 0.000 claims description 16
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- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 11
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- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 6
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 26
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 24
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- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 16
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- 238000000746 purification Methods 0.000 description 13
- UGYPXRGQGNLWOF-UHFFFAOYSA-N 1-(ethyliminomethylideneamino)-n,n-dimethylpropan-1-amine Chemical compound CCN=C=NC(CC)N(C)C UGYPXRGQGNLWOF-UHFFFAOYSA-N 0.000 description 12
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 12
- 0 CC(CN(CC1NCCC1)C(c1cc(*)c(*)c(*)c1)=O)=*c1ccc(*)cc1* Chemical compound CC(CN(CC1NCCC1)C(c1cc(*)c(*)c(*)c1)=O)=*c1ccc(*)cc1* 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
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- FQRAPYDQGAABAT-UHFFFAOYSA-N 7-methoxy-2,2-dimethyl-1,3-benzodioxole-5-carboxylic acid Chemical compound COC1=CC(C(O)=O)=CC2=C1OC(C)(C)O2 FQRAPYDQGAABAT-UHFFFAOYSA-N 0.000 description 11
- 206010006187 Breast cancer Diseases 0.000 description 11
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
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- 241000699670 Mus sp. Species 0.000 description 10
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- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 9
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
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- QEZBOPWZULAPBJ-UHFFFAOYSA-N 4-(difluoromethoxy)-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1OC(F)F QEZBOPWZULAPBJ-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
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Abstract
Description
本出願は、2002年12月20日に出願された米国特許仮出願第60/434912号および2003年10月30日に米国特許仮出願60/516151号による優先権を主張する。それら優先出願の開示は、そのまま参照により本願明細書に援用される。
本発明は、CCXCKR2受容体に結合する新規の化合と小分子モジュレーターを含有する組成物とを対象とする。一般には、新規化合物は、構造(I)を有する:
一態様では、新規の化合物は、構造(II)を有する:
別の態様では、組成物は、本発明のモジュレーターおよび薬学的に許容できる担体を含む。
別の態様では、癌を治療する方法を開示する。
本発明の化合物、組成物、方法(method)および方法(process)を記載する場合、他に記載のない限り、次の用語は、以下のように定義される。
「化合物」とは、特定の分子のことをいい、それにはその鏡像異性体、ジアステレオマー、多形およびその塩を含む。
「シクロアルキル」とは、単一の環または縮合環を有する一価の飽和炭素環炭化水素基のことをいう。他に定義が無ければ、このようなシクロアルキル基は典型的には、3から10個の炭素原子を含有する。代表的なシクロアルキル基には例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなどが含まれる。
「ヘテロ原子」とは、窒素、酸素、ケイ素または硫黄のことをいう。
「薬学的に許容できる塩」とは、哺乳動物などの患者に投与するために許容される塩のことをいう(例えば、所定の投薬計画で許容できる哺乳類安全性を有する塩)。このような塩は、本願明細書に記載の化合物に存在する特定の置換基に応じて、薬学的に許容できる無機または有機塩基ならびに薬学的に許容できる無機または有機酸に由来してよい。本発明の化合物が、相対的に酸性の官能基を有する場合には、そのまま、または適切な不活性溶剤中で、このような化合物の中性の形態と十分な量の所望の塩基とを接触させることにより、塩基付加塩を得ることができる。薬学的に許容できる無機塩基に由来する塩には、アルミニウム、アンモニウム、カルシウム、銅、第二鉄、第一鉄、リチウム、マグネシウム、第二マンガン、第一マンガン、カリウム、ナトリウム、亜鉛塩などが含まれる。薬学的に許容できる有機塩基に由来する塩には、置換アミン、環式アミン、天然に生じるアミンなど、例えば、アルギニン、ベタイン、カフェイン、コリン、N,N’−ジベンジルエチレンジアミン、ジエチルアミン、2−ジエチルアミノエタノール、2−ジメチルアミノエタノール、エタノールアミン、エチレンジアミン、N−エチルモルホリン、N−エチルピペリジン、グルカミン、グルコサミン、ヒスチジン、ヒドラバミン、イソプロピルアミン、リジン、メチルグルカミン、モルホリン、ピペラジン、ピペリジン、ポリアミン樹脂、プロカイン、プリン、テオブロミン、トリエチルアミン、トリメチルアミン、トリプロピルアミン、トロメタミンなどを含む、1級、2級、3級および4級アミンの塩が含まれる。本発明の化合物が相対的に塩基性の官能基を含有する場合には、そのまま、または適切な不活性溶剤中で、このような化合物の中性の形態と十分な量の所望の酸とを接触させることにより、酸付加塩を得ることができる。薬学的に許容できる酸に由来する塩には、酢酸、アスコルビン酸、ベンゼンスルホン酸、安息香酸、ショウノウスルホン酸、クエン酸、エタンスルホン酸、フマル酸、グルコン酸、グルコロン(glucoronic)酸、グルタミン酸、馬尿酸、臭化水素酸、塩酸、イセチオン酸、乳酸、ラクトバイオ酸(lactobionic)、マレイン酸、リンゴ酸、マンデル酸、メタンスルホン酸、粘液酸、ナフタレンスルホン酸、ニコチン酸、硝酸、パモ酸、パントテン酸、リン酸、コハク酸、硫酸、酒石酸、p−トルエンスルホン酸塩などが含まれる。
本発明は、癌を治療する際に使用するためのモジュレーターを提供する。これらの化合物は、CCXCKR2受容体と結合することにより、SDF−1およびI−TACのモジュレーターとして役立てることができる。モジュレーター(I)はさらに、他のケモカイン受容体に対するモジュレーターとして役立てることができる。ペプチドのケモカインファミリーは、配列相同性をベースにして、保存システインモチーフ上での多様性の存在により定義される。Schall(1996年)Cytokine 3:165−183;およびOppenheim et al.(1991年)Annu.Rev.Immunol.9:617−648。ケモカインは、幅広い細胞型において炎症促進性活性から増殖調節活性にわたる幅広いin vitroおよびin vivo機能を示す。今日までに、いくつかのケモカイン受容体が記載されている。例えば、Neote et al.(1993年)Cell 72:415−425;Ponath et al.(1996年)J.Exp.Med.183:2437−2448;およびPower et al.(1995年)J.Biol.Chem.270:19495−19500を参照のこと。
mは、1から5の整数であり;
Yはそれぞれ独立に、水素、ハロゲン、−CN、−NO2、−OH、−OR’、−C(O)R’、−CO2R’、−O(CO)R’、−C(O)NR’R”、−OC(O)NR’R”、−SR’、−SOR’、−SO2R’、−SO2NR’R”、−NR’R”、−NR’C(O)R”、−NR’C(O)2R”、−NR’SO2R”、−NR’(CO)NR”R’”、未置換または置換C1〜C8アルキル、未置換または置換C2〜C8アルケニル、未置換または置換C2〜C8アルキニル、未置換または置換C3〜C8シクロアルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択され;
R’、R”およびR’”はそれぞれ独立に、水素、ハロゲン、未置換または置換C1〜C8アルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルであり;
nは、0、1、2または3であり;
Zは、−CHR1R2−、−OR1または−NR1R2であり;
R1およびR2はそれぞれ独立に、アルキルまたは水素であるか、またはZはR1およびR2と組み合わさって、少なくとも1個の窒素および0から3個の追加のヘテロ原子を含む未置換または置換の5から8員環の環を形成し;
R6は、アルキル、水素またはハロゲンであり;
R3、R4およびR5はそれぞれ独立に、水素、ハロゲン、−CN、−NO2、−OH、−OR’、−C(O)R’、−CO2R’、−O(CO)R’、−C(O)NR’R”、−OC(O)NR’R”、−SR’、−SOR’、−SO2R’、−SO2NR’R”、−NR’R”、−NR’C(O)R”、−NR’C(O)2R”、−NR’SO2R”、−NR’(CO)NR”R’”、未置換または置換C1〜C8アルキル、未置換または置換C2〜C8アルケニル、未置換または置換C2〜C8アルキニル、未置換または置換C3〜C8シクロアルキルおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択されるか;または
R3、R4およびR5のうちのいずれか2個は、それらが置換している原子と共に、3から10員環の置換または未置換ヘテロシクリルを形成している]。
次の化合物は知られているが、CCXCKR2モジュレーターとしては知られていない:
あるいは、本発明のモジュレーター(I)は次の但書の1つ以上を有してもよい:
Zが−NR1R2であり、R1およびR2がZと共にモルホリニルを形成する場合、nは、3であり、R3、R4およびR5の少なくとも1個は、ヒドロキシ基、アルコキシまたはアリールオキシである;または
nが1であり、Zが−CHR1R2である場合、組み合わさったR1およびR2は、−CH2CH2NCH2CH2−ではない;または
nが3であり、Zが−NR1R2である場合、組み合わさったR1およびR2は−CHNCHCH−ではない;または
R1がR2と共に−CH(CH3)(CH2)4−である場合、Zは、−CH−である;または
R5がt−ブチルである場合、R3は水素である;または
R4およびR5が一緒になって5員環の環を形成する場合、フェニル環に結合している原子の少なくとも1個は、炭素である;
n=1であり、Zがアルキル−CHR1R2であり、ここで、R1およびR2がそれぞれメチルである場合、R3とR5のいずれもアルキルであってはならず;あるいはR3、R4またはR5はそれぞれ、同時に水素であってはならない;
もしくは、R4はメチルであってはならない。
R6は好ましくは、水素、ハロゲンまたはC1〜C8アルキルであり、さらに好ましくはメチルである。
好ましい一態様では、Zは、−CHR1R2であり、ここで、R1およびR2はZと一緒になって、ハロゲン、−CN、−NO2、−OH、−OR’、−C(O)R’、−CO2R’、−O(CO)R’、−C(O)NR’R”、−OC(O)NR’R”、−SR’、−SOR’、−SO2R’、−SO2NR’R”、−NR’R”、−NR’C(O)R”、−NR’C(O)2R”、−NR’SO2R”、−NR’(CO)NR”R”、未置換または置換C1〜C8アルキル、未置換または置換C2〜C8アルケニル、未置換または置換C2〜C8アルキニル、未置換または置換C3〜C8シクロアルキル、未置換または置換C6〜C10アリール、未置換または置換5から10員環のヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択される0から3個の置換基を有するC3〜C10シクロアルキルを形成する。
R7は、水素、−C(O)R’、−CO2R’、−C(O)NR’R”、−SO2R’、未置換または置換C1〜C10アルキル、未置換または置換C1〜C8アルコキシル(例えば、−CH2−CH2OCH2−CH2−OCH3のようなC1〜C10アルコキシルアルコキシルを含む)、未置換または置換C2〜C10アルケニル、未置換または置換C2〜C10アルキニル、未置換または置換C3〜C10シクロアルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択される]。
mは好ましくは、0、1または2である。
存在する場合、Yは好ましくは、ハロゲンである。
ここで、
Yはそれぞれ独立に、水素またはハロゲンであり;
R3、R4およびR5はそれぞれ独立に、水素、ハロゲンおよび−OR’からなる群から選択されるか;またはR3、R4およびR5のうちのいずれか2個は、それらが置換している原子と共に、3から10員環の未置換または置換ヘテロシクリルを形成し;R7は、水素、−C(O)R’、−CO2R’、−C(O)NR’R”、−SO2R’、未置換または置換C1〜C10アルキル、未置換または置換C1〜C8アルコキシルアルコキシル(例えば、−CH2−OCH2OCH3などのC1〜C10アルコキシルアルコキシルを含む)、未置換または置換C2〜C10アルケニル、未置換または置換C2〜C10アルキニル、未置換または置換C3〜C10シクロアルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択される。
本発明の活性化合物を合成するために、当業者に知られている多くの合成方法を使用することができるが、一般的な合成方法を、下記のスキームIに示す。
特許請求の範囲に記載の活性化合物(またはその塩)を投与するための医薬組成物は、投与単位形態で提供してよく、そして薬剤分野で知られているいずれかの方法で調製してもよい。好ましい方法は、1種または複数の活性化合物またはその塩と、1種または複数の副成分を含む1種または複数の担体とを組み合わせるステップを含む。
特定の理論に結びつけられることは望まないが、本発明の組成物は、CCXCKR2受容体へのSDF−1および/またはI−TACの結合を阻害する方法を提供すると考えられる。SDF−1は、ヒトなどの哺乳動物での癌細胞の発生または伝播を妨害するためのターゲットもたらすことが知られている。下記の実施例24から26に示されているように、CCXCKR2受容体へのI−TACの結合の阻害により、血管が新生した腫瘍の形成が妨げられる。前記組成物と、CCXCKR2受容体を発現する癌細胞とを接触させることにより、さもないと癌細胞のきっかけとなる侵襲性応答を低減することができる。したがって、さらに本発明は、癌、特に充実性腫瘍癌、さらに特には、乳癌を予防および/または治療する際に有用である方法を対象としている。
さらに本発明は、癌を治療する方法を提供する。癌を治療する好ましい方法は、癌を治療するのに十分な時間、治療的に有効な量の1種または複数の前記化合物(またはその塩)を癌患者に投与することを含む。
塩酸1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド0.48g(2.4mmol)を乾燥テトラヒドロフラン20mlに加えた。この攪拌溶液に、乾燥トリエチルアミン0.23ml(2.4mmol)を加えた。約15分後に、3,4,5−トリメトキシ安息香酸0.52g(2.4mmol)を加えた。窒素下に室温で、反応混合物を1時間攪拌した。次いで、1−ヒドロキシベンゾトリアゾール0.24g(1.76mmol)を加え、さらに30分後に、(2−メチル−3−フェニル−アリル)−[2−(1−メチル−ピロリジン−2−イル)−エチル]−アミン0.42g(1.6mmol)を加えた。室温で一晩攪拌した後に、水5mlで反応をクエンチし、酢酸エチル20mlで抽出した。合わせた有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、真空下に濃縮した。9:1のジクロロメタン/メタノールを用いてシリカゲルから溶離することにより、混合物を精製すると、無色のオイル0.38gが得られた。収率:53%。
LC−MSD、C26H32N2O3F2についてのm/z[M+H]+:459.1、[M+2H]+:460.1、[M+3H]:461.2。
LC−MSD、C28H36N2O4についてのm/z[M+H]+:465.2、[M+2H]+:466.2。
[実施例40]
[実施例44]
LC−MSD、C31H42N2O3についてのm/z[M+H]+:491.3:[M+2H]:492.3、[M+3H]:493.3。
[実施例51]
[実施例53]
[実施例54]
[実施例57]
20分で20から95%のアセトニトリル勾配を使用する分析C18HPLCで、18.00分で溶離しする。
LC−MSD、C34H44N2O4F4についてのm/z[M+H]+:583.2、[M+2H]:584.2、[M+3H]:585.2。
[実施例60]
LC−MSD、C32H42N2O4F2についてのm/z[M+H]+:527.2、[M+2H]:528.2、[M+3H]:529.2。
LC−MSD、C31H36N2O3F6についてのm/z[M+H]+:599.2、[M+2H]:600.2、[M+3H]:601.2。
[実施例62]
LC−MSD、C33H42N2O4F2についてのm/z[M+H]+:569.2、[M+2H]:570.2、[M+3H]:571.2。
[実施例63]
LC−MSD、C31H38N2O3F4についてのm/z[M+H]+:563.2、[M+2H]:564.2、[M+3H]:565.2。
[実施例64]
LC−MSD、C31H38N2O3F4についてのm/z[M+H]+:563.2、[M+2H]:564.2、[M+3H]:565.2。
[実施例65]
LC−MSD、C33H40N2O3F6についてのm/z[M+H]+:627.2、[M+2H]:628.2、[M+3H]:629.2。
LC−MSD、C31H40N2O3についてのm/z[M+H]+:489.2、[M+2H]:490.2、[M+3H]:491.2。
LC−MSD、C31H42N2O3についてのm/z[M+H]+:491.2、[M+2H]:492.2、[M+3H]:493.2。
LC−MSD、C33H46N2O3についてのm/z[M+H]+:519.3、[M+2H]:520.3、[M+3H]:521.3。
LC−MSD、C33H44N2O3についてのm/z[M+H]+:533.3、[M+2H]:534.3、[M+3H]:535.3。
LC−MSD、C33H40N2O3F2についてのm/z[M+H]+:527.2、[M+2H]:528.2、[M+3H]:529.2。
LC−MSD、C33H40N2O3F2についてのm/z[M+H]+:527.2、[M+2H]:528.2、[M+3H]:529.2。
[実施例74]
LC−MSD、C33H42N2O4F2についてのm/z[M+H]+:569.2、[M+2H]:570.2、[M+3H]:571.2。
LC−MSD、C29H34N2O3F2についてのm/z[M+H]+:497.2、[M+2H]:498.2、[M+3H]:499.2。
LC−MSD、C30H40N2O3についてのm/z[M+H]+:477.2、[M+2H]:478.2、[M+3H]:479.2。
[実施例77]
LC−MSD、C30H38N2O4についてのm/z[M+H]+:491.2、[M+2H]:492.2、[M+3H]:493.2。
LC−MSD、C28H34N2O3F2についてのm/z[M+H]+:485.2、[M+2H]:486.2、[M+3H]:487.2。
LC−MSD、C28H36N2O3についてのm/z[M+H]+:449.2、[M+2H]:450.2、[M+3H]:451.2。
LC−MSD、C28H32N2O3F4についてのm/z[M+H]+:527.2、[M+2H]:528.2、[M+3H]:529.2。
LC−MSD、C27H36N2O4についてのm/z[M+H]+:453.3。
LC−MSD、C35H44N2O4についてのm/z[M+H]+:557.7。
[実施例92]
LC−MSD、C32H42N2O4についてのm/z[M+H]+:519.2、[M+2H]:520.2、[M+3H]:521.2。
[実施例98]
試験
前記化合物がSDF−1およびI−TACケモカインのための有用なモジュレーターであることを証明するために、化合物をin vitroでスクリーニングして、CCXCKR2受容体からSDF−1および/またはI−TACを追い出す能力を複数の濃度で決定した。「IC50値、試薬および細胞の決定」(下記参照)に詳述されているように、125I標識化ケモカインの存在下に、化合物を、CCXCKR2受容体を発現する乳腺細胞と組み合わせた。複数の濃度において化合物が標識化ケモカインをCCXCKR2受容体サイトから追い出す能力を、スクリーニングプロセスで決定した。
<試薬および細胞>
125I標識されているSDF−1は、Perkin−Elmer Life Sciences,Inc.(Boston,MA)から購入した。MCF−7(腺癌:乳腺)細胞系は、American Type Culture Collection(Manassas,VA)から得て、10%の胎児ウシ血清(FBS)(HyClone Logan,UT)およびウシインスリン(0.01mg/mL)(Sigma,St.Louis,MO)を補足されたDMEM(Mediatech,Herndon,VA)中、37℃で、加湿インキュベーター中、5%CO2/空気混合物下に培養した。
ターゲット化合物を試験して、MCF−7細胞上のCCXCKR2サイトに結合するその能力を測定した。Dairaghi DJ,et al.,HHV8−encoded vMIP−I selectively engages chemokine receptor CCR5.Agonist and antagonist profiles of viral chemokines.,J.Biol.Chem.1999年7月30日;274(31):21569−74およびGosling J.et al.,Cutting edge:identification of a novel chemokine receptor that binds dendritic cell−and T cell−active chemokines including ELC,SLC,and TECK.,J.Immunol.2000年3月15日;164(6):2851−6に記載されているような濾過プロトコルを使用する効率最大化放射リガンド結合を使用した。
小分子量の化合物による、乳癌で発現されるCCXCKR2のアンタゴニズムは、in vitroでの細胞増殖を阻害した。in vitroで処置された細胞は、未処置の対照に比較して長期にわたって低い細胞増殖を示した。
in vitro静的接着アッセイを使用して、細胞の接着およびその後の所定の組織への移出を含む白血球遊走の事象をモデリングする。血管内皮細胞の単分子膜を、表面上で増殖させ、CCXCKR2を発現する細胞を蛍光染料で標識して、目に見えるようにした。実験により、内皮層に接着しているCCXCKR2発現細胞が存在すると、CCXCKR2が発現されなかった対照群と比較して、付加的なCCXCKR2発現細胞の接着が促進されることが判明した。加えて、CCXCKR2モジュレーターを加えると、ビヒクル処置された対照群に比較して、接着が阻害された。
免疫不全症マウスに、CCXCKR2を発現するヒトB細胞リンパ腫細胞を注射した。CCXCKR2モジュレーターでこれらのマウスを処置すると、血管新生腫瘍を生じさせる能力が阻害された。研究の1つでは、CCXCKR2アンタゴニストで処置された17匹のマウスのうち1匹だけが、被包化された血管新生腫瘍を生じ、他方で、ビヒクル対照群の17匹のマウスのうち11匹が、被包化された血管新生腫瘍を生じた。
免疫不全症マウスに、ヒト乳癌を注射した。腫瘍の測定を週に3回行い、腫瘍容量を決定した。CCXCKR2モジュレーターで処理されたマウスは、ビヒクル対照群のマウスと比較して低い腫瘍容量を示した。
Claims (38)
- 構造(I)のモジュレーターまたはその塩:
mは、1から5の整数であり;
Yはそれぞれ独立に、水素、ハロゲン、−CN、−NO2、−OH、−OR’、−C(O)R’、−CO2R’、−O(CO)R’、−C(O)NR’R”、−OC(O)NR’R”、−SR’、−SOR’、−SO2R’、−SO2NR’R”、−NR’R”、−NR’C(O)R”、−NR’C(O)2R”、−NR’SO2R”、−NR’(CO)NR”R’”、未置換または置換C1〜C8アルキル、未置換または置換C2〜C8アルケニル、未置換または置換C2〜C8アルキニル、未置換または置換C3〜C8シクロアルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択され;
R’、R”およびR’”はそれぞれ独立に、水素、ハロゲン、未置換または置換C1〜C8アルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルであり;
nは、0、1、2または3であり;
Zは、−CHR1R2−、−OR1または−NR1R2であり;
R1およびR2はそれぞれ独立に、置換もしくは未置換アルキルまたは水素であるか、あるいは、ZはR1およびR2と組み合わさって少なくとも1個の窒素および0から3個の追加のヘテロ原子を含む置換または未置換の5から8員環を形成し;
R6は、アルキル、水素またはハロゲンであり;そして
R3、R4およびR5はそれぞれ独立に、水素、ハロゲン、−CN、−NO2、−OH、−OR’、−C(O)R’、−CO2R’、−O(CO)R’、−C(O)NR’R”、−OC(O)NR’R”、−SR’、−SOR’、−SO2R’、−SO2NR’R”、−NR’R”、−NR’C(O)R”、−NR’C(O)2R”、−NR’SO2R”、−NR’(CO)NR”R’”、未置換または置換C1〜C8アルキル、未置換または置換C2〜C8アルケニル、未置換または置換C2〜C8アルキニル、未置換または置換C3〜C8シクロアルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択されるか、あるいは、そこにおいてR3、R4およびR5のうちのいずれか2個は、それらが置換している原子と共に、3から10員環の置換または未置換ヘテロシクリルを形成している]。 - R6が水素である、請求項1に記載のモジュレーター。
- R6が置換または未置換C1〜C8アルキルである、請求項1に記載のモジュレーター。
- R6がハロゲンである、請求項1に記載のモジュレーター。
- R3、R4およびR5がそれぞれ独立に、水素、−OR’および置換または未置換C1〜C8アルキルからなる群から選択される、請求項1に記載のモジュレーター。
- R3、R4およびR5がそれぞれ独立に、−OR’および水素からなる群から選択される、請求項1に記載のモジュレーター。
- R3、R4およびR5がそれぞれ−OR’であり、ここで、R’は、置換C1〜C8アルキルである、請求項1に記載のモジュレーター。
- R4およびR5が、それらが置換している原子と共に、1から2個の酸素原子を含有する5から6員環の置換または未置換ヘテロシクリルを形成している、請求項1に記載のモジュレーター。
- ZがCHR1R2であり、ここで、R1およびR2はZと一緒になって、ハロゲン、−CN、−NO2、−OH、−OR’、−C(O)R’、−CO2R’、−O(CO)R’、−C(O)NR’R”、−OC(O)NR’R”、−SR’、−SOR’、−SO2R’、−SO2NR’R”、−NR’R”、−NR’C(O)R”、−NR’C(O)2R”、−NR’SO2R”、−NR’(CO)NR”R’”、未置換または置換C1〜C8アルキル、未置換または置換C2〜C8アルケニル、未置換または置換C2〜C8アルキニル、未置換または置換C3〜C8シクロアルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択される0から3個の置換基を有するC3〜C10シクロアルキルを形成する、請求項1に記載のモジュレーター。
- R1およびR2がZと一緒になって、ハロゲン、−OR、置換または未置換C1〜C8アルキル、置換または未置換C1〜C8アルケニル、置換または未置換C1〜C8アルキニル、置換または未置換C6〜C10アリール、5から10員環の置換または未置換ヘテロアリールからなる群から選択される0から3個の置換基を有する3から10員環のヘテロシクリルを形成する、請求項1に記載のモジュレーター。
- Zが−CHR1R2−である、請求項1に記載のモジュレーター。
- Zが−NR1R2−である、請求項1に記載のモジュレーター。
- R1およびR2と組み合わされたZが、置換または未置換モルホリニル、置換または未置換ピロリジニル、置換または未置換ピペリジニルおよび置換または未置換ピペラジニルからなる群から選択される、請求項1に記載のモジュレーター。
- R7が、置換または未置換C1〜C10アルキル、置換または未置換C1〜C10アルコキシ、置換または未置換アリールオキシあるいは置換または未置換C3〜C10シクロアルキルである、請求項1に記載のモジュレーター。
- nが1、2または3である、請求項1に記載のモジュレーター。
- mが1または2であり、Yがそれぞれハロゲンである、請求項1に記載のモジュレーター。
- mが0である、請求項1に記載のモジュレーター。
- 置換アルキル、置換アルケニル、置換アルキニルおよび置換シクロアルキルが、それぞれ独立に、ハロゲン、−OR’、−NR’R”、−SR’、−SiR’R”R’”、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R”、−OC(O)NR’R”、−NR”C(O)R’、−NR’−C(O)NR”R’”、−NR”C(O)2R’、−S(O)R’、−S(O)2R’、−S(O)2NR’R”、−NR’S(O)2R”、−CN、オキソ(=Oまたは−O−)または−NO2で1から3回置換されていてもよく、ここで、R’、R”およびR’”はそれぞれ独立に、水素、ハロゲン、未置換C1〜C8アルキル、未置換C3〜C6シクロアルキル、未置換C2〜C8アルケニル、未置換またはC2〜C8アルキニル、未置換アリール、未置換へテロアリール、未置換または置換へテロシクリルである、請求項1に記載のモジュレーター。
- 置換アリールおよび置換ヘテロアリールがそれぞれ独立に、ハロゲン、未置換または置換アルキル、未置換または置換アルケニル、未置換または置換アルキニル、未置換または置換シクロアルキル、−OR’、オキソ(=Oまたは−O)、−OC(O)R’、−NR’R”、−SR’、−R’、−CN、−NO2、−CO2R’、−CONR’R”、−C(O)R’、−OC(O)NR’R”、−NR”C(O)R’、−NR”C(O)2R’、−NR’−C(O)NR”R’”、−NH−C(NH2)=NH、−NR’C(NH2)=NH、−NH−C(NH2)=NR’、−S(O)R’、−S(O)2R’、−S(O)2NR’R”、−NR’S(O)2R”および−N3で1から3回置換されていてもよく、ここで、R’、R”およびR’”はそれぞれ独立に、水素、ハロゲン、未置換C1〜C8アルキル、未置換C3〜C6シクロアルキル、未置換C2〜C8アルケニル、未置換C2〜C8アルキニル、未置換または置換アリール、未置換へテロアリール、未置換へテロシクリルである、請求項1に記載のモジュレーター。
- 置換へテロシクリルが、ハロゲン、未置換または置換アルキル、未置換または置換アルケニル、未置換または置換アルキニル、未置換または置換シクロアルキル、−OR’、オキソ(=Oまたは−O)、−OC(O)R’、−NR’R”、−SR’、−R’、−CN、−NO2、−OC(O)NR’R”、−NR”C(O)R’、−NR”C(O)2R’、−NR’−C(O)NR”R’”、−NH−C(NH2)=NH、−NR’C(NH2)=NH、−NH−C(NH2)=NR’、−S(O)R’、−S(O)2NR’R”、−NR’S(O)2R”および−N3で1から3回置換されていてもよく、ここで、R’、R”およびR’”はそれぞれ独立に、水素、ハロゲン、未置換C1〜C8アルキル、未置換またはC3〜C6シクロアルキル、未置換C2〜C8アルケニル、未置換C2〜C8アルキニル、未置換アリール、未置換へテロアリール、未置換へテロシクリルである、請求項1に記載のモジュレーター。
- 構造(II)を有するモジュレーター:
n=0〜4;
Yはそれぞれ独立に、水素またはハロゲンであり;
R3、R4およびR5はそれぞれ独立に、R3、R4およびR5はそれぞれ独立に、水素、ハロゲンおよび−OR’からなる群から選択されるか;または
R3、R4およびR5のうちのいずれか2個は、それらが置換している原子と共に、3から10員環の未置換または置換ヘテロシクリルを形成し;および
R7は、水素、−C(O)R’、−CO2R’、−C(O)NR’R”、−SO2R’、未置換または置換C1〜C8アルキル(場合によって、C1〜C8アルコキシアルキルオキシ、CH2CH2OCH2CH2OMe)アルキル、未置換または置換C2〜C8アルケニル、未置換または置換C2〜C8アルキニル、未置換または置換C3〜C8シクロアルキル、未置換または置換C6〜C10アリール、5から10員環の未置換または置換ヘテロアリールおよび3から10員環の未置換または置換ヘテロシクリルからなる群から選択される]。 - R7がC1〜C8アルコキシアルキルオキシである、請求項27に記載のモジュレーター。
- nが1である、請求項27に記載のモジュレーター。
- 請求項1に記載のモジュレーターおよび薬学的に許容できる担体を含む医薬組成物。
- 請求項27に記載のモジュレーターおよび薬学的に許容できる担体を含む医薬組成物。
- 請求項2830に記載のモジュレーターおよび薬学的に許容できる担体を含む医薬組成物。
- CCXCKR2受容体へのケモカインI−TACおよび/またはSDF−1の結合を阻害する方法であって、CCXCKR2受容体へのそれらケモカインの結合を阻害するのに十分な時間、請求項3234に記載の組成物とCCXCKR2受容体を発現する細胞とを接触させることを含む方法。
- CCXCKR2受容体へのケモカインI−TACおよび/またはSDF−1の結合を阻害する方法であって、CCXCKR2受容体へのそれらケモカインの結合を阻害するのに十分な時間、請求項1に記載のモジュレーターとCCXCKR2受容体を発現する細胞とを接触させることを含む方法。
- 癌を治療するのに十分な時間、治療的に有効な量の請求項3234に記載の組成物を癌患者に投与することを含む、癌を治療する方法。
- 癌を治療するのに十分な時間、治療的に有効な量の請求項1に記載のモジュレーターを癌患者に投与することを含む、癌を治療する方法。
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US43491202P | 2002-12-20 | 2002-12-20 | |
US60/434,912 | 2002-12-20 | ||
US51615103P | 2003-10-30 | 2003-10-30 | |
US60/516,151 | 2003-10-30 | ||
PCT/US2003/041024 WO2004058705A2 (en) | 2002-12-20 | 2003-12-22 | Inhibitors of the binding of chemokines i-tac or sdf-1 to the ccxckr2 receptor |
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JP2006515854A true JP2006515854A (ja) | 2006-06-08 |
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US (2) | US7649011B2 (ja) |
EP (1) | EP1606251B1 (ja) |
JP (1) | JP4870357B2 (ja) |
KR (1) | KR101061352B1 (ja) |
CN (1) | CN1747929B (ja) |
AT (1) | ATE427933T1 (ja) |
AU (1) | AU2003300293B8 (ja) |
CA (1) | CA2511242C (ja) |
DE (1) | DE60327106D1 (ja) |
ES (1) | ES2323528T3 (ja) |
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- 2003-12-22 DE DE60327106T patent/DE60327106D1/de not_active Expired - Lifetime
- 2003-12-22 EP EP03814334A patent/EP1606251B1/en not_active Expired - Lifetime
- 2003-12-22 CN CN2003801097644A patent/CN1747929B/zh not_active Expired - Lifetime
- 2003-12-22 US US10/743,281 patent/US7649011B2/en active Active
- 2003-12-22 CA CA002511242A patent/CA2511242C/en not_active Expired - Lifetime
- 2003-12-22 AT AT03814334T patent/ATE427933T1/de not_active IP Right Cessation
- 2003-12-22 WO PCT/US2003/041024 patent/WO2004058705A2/en active Application Filing
- 2003-12-22 KR KR1020057010949A patent/KR101061352B1/ko active IP Right Grant
- 2003-12-22 MX MXPA05006507A patent/MXPA05006507A/es active IP Right Grant
- 2003-12-22 AU AU2003300293A patent/AU2003300293B8/en not_active Expired
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2009
- 2009-12-11 US US12/636,212 patent/US20100144720A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001055107A2 (en) * | 2000-01-28 | 2001-08-02 | Melacure Therapeutics Ab | Aromatic amines and amides acting on the melanocortin receptors |
WO2002024649A1 (en) * | 2000-09-25 | 2002-03-28 | Actelion Pharmaceuticals Ltd | Substituted amino-aza-cycloalkanes useful against malaria |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007514651A (ja) * | 2003-10-30 | 2007-06-07 | ケモセントリックス インコーポレーティッド | ケモカイン受容体に関連する疾患および状態を検出および処置するための組成物および方法 |
JP4755107B2 (ja) * | 2003-10-30 | 2011-08-24 | ケモセントリックス インコーポレーティッド | ケモカイン受容体に関連する疾患および状態を検出および処置するための組成物および方法 |
JP2007520564A (ja) * | 2004-02-03 | 2007-07-26 | ケモセントリックス インコーポレーティッド | 血管新生を調節するための方法および組成物 |
JP4916889B2 (ja) * | 2004-02-03 | 2012-04-18 | ケモセントリックス インコーポレーティッド | 血管新生を調節するための方法および組成物 |
JP2016520120A (ja) * | 2013-05-30 | 2016-07-11 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | Cxcr7受容体調節剤 |
JP2017535618A (ja) * | 2014-12-01 | 2017-11-30 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | Cxcr7受容体調節剤 |
Also Published As
Publication number | Publication date |
---|---|
ATE427933T1 (de) | 2009-04-15 |
WO2004058705A2 (en) | 2004-07-15 |
DE60327106D1 (de) | 2009-05-20 |
CN1747929B (zh) | 2010-04-28 |
AU2003300293A1 (en) | 2004-07-22 |
US20100144720A1 (en) | 2010-06-10 |
CN1747929A (zh) | 2006-03-15 |
CA2511242C (en) | 2010-01-12 |
KR101061352B1 (ko) | 2011-08-31 |
WO2004058705A3 (en) | 2004-08-19 |
US20040171655A1 (en) | 2004-09-02 |
AU2003300293B2 (en) | 2009-12-17 |
EP1606251B1 (en) | 2009-04-08 |
US7649011B2 (en) | 2010-01-19 |
WO2004058705B1 (en) | 2004-09-30 |
JP4870357B2 (ja) | 2012-02-08 |
KR20050109920A (ko) | 2005-11-22 |
EP1606251A2 (en) | 2005-12-21 |
CA2511242A1 (en) | 2004-07-15 |
ES2323528T3 (es) | 2009-07-20 |
AU2003300293B8 (en) | 2010-01-14 |
MXPA05006507A (es) | 2006-02-17 |
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