JP6272897B2 - Cxcr7アンタゴニスト - Google Patents
Cxcr7アンタゴニスト Download PDFInfo
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- JP6272897B2 JP6272897B2 JP2015545194A JP2015545194A JP6272897B2 JP 6272897 B2 JP6272897 B2 JP 6272897B2 JP 2015545194 A JP2015545194 A JP 2015545194A JP 2015545194 A JP2015545194 A JP 2015545194A JP 6272897 B2 JP6272897 B2 JP 6272897B2
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- pyrazin
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- PRDKWTLIYNMIFH-ZDUSSCGKSA-N tert-butyl n-[(3s)-1-(8-methylpyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl]carbamate Chemical compound C12=C(C)C=CN2C=CN=C1N1CC[C@H](NC(=O)OC(C)(C)C)C1 PRDKWTLIYNMIFH-ZDUSSCGKSA-N 0.000 description 1
- OKXMGVHRDZMSHD-NSHDSACASA-N tert-butyl n-[(3s)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)CCN1C1=NC=CN2C1=NC=C2 OKXMGVHRDZMSHD-NSHDSACASA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- UXHMGTYELGTNSJ-UHFFFAOYSA-N triazole-1-carboxamide Chemical compound NC(=O)N1C=CN=N1 UXHMGTYELGTNSJ-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000004066 vascular targeting agent Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/715—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons
- G01N2333/7158—Assays involving receptors, cell surface antigens or cell surface determinants for cytokines; for lymphokines; for interferons for chemokines
Description
本出願は、2012年11月29日に提出された米国特許仮出願第61/731,463号に対する優先権の利益を主張し、その内容は参照により全体が本明細書に組み込まれる。
該当事項なし
以下に添付される。
用語「アルキル」(alkyl)とは、それ自体で又は別の置換基の一部として、特に断らない限り、指定される炭素原子を有する直鎖又は枝分れ鎖の炭化水素基を意味する(すなわち、C1-8は、1〜8個の炭素を意味する)。アルキル基の例としては、メチル、エチル、n-プロピル、イソプロピル、n−ブチル、t-ブチル、イソブチル、sec−ブチル、n-ペンチル、n−ヘキシル、n-ヘプチル、n-オクチル、及び同様のものを挙げることができる。用語「アルケニル」(alkenyl)とは、1又は2以上の二重結合を有する不飽和アルキル基を言及する。同様に、用語「アルキニル」(alkynyl)とは、1又は2以上の三重結合を有する不飽和アルキル基を言及する。そのような不飽和アルキル基の例としては、ビニル、2−プロペニル、クロチル、2−イソペンテニル、2−(ブタジエニル)、2、4−ペンタジエニル、3−(1、4−ペンタジエニル)、エチニル、1− 及び 3−プロピニル、 3−ブチニル、及び高級同族体及び異性体を挙げることができる。用語「シクロアルキル」(cycloalkyl)とは、示される数の環原子(例えば、C3-6シクロアルキル)を有し、そして十分に飽和されているか、又は環頂点間にわずか1つの二重結合を有する炭化水素環を言及する。「シクロアルキル」はまた、二環式及び多環式炭化水素環、例えばビシクロ[2.2.1]ヘプタン、ビシクロ[2.2.2]オクタン、等を意味する。用語「シクロアルケニル」(cycloalkenyl)とは、環頂点間に少なくとも1つの二重結合を有するシクロアルキル基を意味する。シクロアルケニルの例としては、シクロペンテニル及びシクロヘキセニルを挙げることができる。用語「スピロシクロアルキル」(spirocycloalkyl)とは、単一の環頂点が分子の2つの他の非水素部分に結合されているシクロアルキル基を意味する。スピロシクロアルキル置換基は、アルキレン鎖の2つの炭素原子(典型的には、アルキレン鎖の末端)が分子の残りにおける同じ炭素原子に結合されている置換基である。用語「ヘテロシクロアルキル」(heterocycloalkyl)とは、N、O及びSから選択された1〜5個のヘテロ原子を含むシクロアルキル基を言及し、ここで窒素及び硫黄原子は任意には酸化され、そして窒素原子は任意には、四級化される。ヘテロシクロアルキルは、単環式、二環式又は多環式環系であり得る。ヘテロシクロアルキル基の非制限的例としては、ピロリジン、イミダゾリジン、ピラゾリジン、ブチロラクタム、バレロラクタム、イミダゾリジノン、ヒダントイン、ジオキソラン、フタルイミド、ピペリジン、1,4 - ジオキサン、モルホリン、チオモルホリン、チオモルホリン-S-オキシド、チオモルホリン-S、S-オキシド、ピペラジン、ピラン、ピリドン、3 - ピロリン、チオピラン、ピロン、テトラヒドロフラン、テトラヒドロチオフェン、キヌクリジン、及び同様のものを挙げることができる。ヘテロシクロアルキル基は、環炭素又はヘテロ原子を介して分子の残部に結合され得る。
本発明の化合物は、CXCR7受容体へのリガンドの結合を阻害でき、そして種々の疾患、例えば癌、特に固形腫瘍癌及びリンパ腫の治療に有用である。さらに最近、CXCR7へのリガンド結合の阻害は、動物モデルにおける関節リウマチの重症度を低めることが認められている。
A.化合物
1つの態様によれば、本発明は、下記式(I)
(i)単環式又は縮合二環式アリール及びヘテロアリール(ここで、前記へテロアリール基はN、O及びSから選択された1〜4個のヘテロ原子を環員として有し、そして前記アリール及びヘテロアリール基は任意には、1〜5個のR5置換基により置換される);
(ii)シクロアルカン及びヘテロシクロアルカンから成る群から選択された、単環式の4−、5−、6−又は7員の環(ここで前記へテロシクロアルカン環は、N、O及びSから選択された1〜3個のヘテロを環員として有し、そして各前記単環式Z環は任意には、1〜3個のR5置換基により置換される)から選択された群を表す。
(A)1つの実施態様の基によれば、Zは、N,O及びSから選択された環員として1−3個のヘテロ原子を有する、単環式又は縮合二環式へテロアリールであり;そして前記へテロアリール基は任意には、1〜5個のR5置換基により置換される。
(E)さらに別の実施態様の基によれば、式Iの化合物は、Zが下記式:
式Iaの選択された実施態様は、上記(A)〜(E)で同定された、Zについての各実施態様を含む。
(F)環頂点としてXa、Xb及びXcを有する二環式部分は、下記:
式Iaの別の特定の基の実施態様によれば、
(G)環頂点としてXa、Xb及びXcを有する二環式部分は、下記:
式Iaのさらに別の特定の基の実施態様によれば、
(H)環頂点としてXa、Xb及びXcを有する二環式部分は、下記:
式Iaの1つの特定の基の実施態様によれば、
(I)環頂点としてXa、Xb及びXcを有する二環式部分は、下記:
式Iaの別の特定の基の実施態様によれば、
(J)環頂点としてXa、Xb及びXcを有する二環式部分は、下記
特定の選択された実施態様によれば、式Iaの化合物、及び(F)、(G)、(H)、(I)及び(J)として同定される実施態様は、Zが上記(A)〜(E)として同定される実施態様から選択される化合物、特にZが任意に置換されたアリール、ヘテロアリール、シクロアルキル又はヘテロシクロアルキル環から選択された1つのR5基により、及び任意には、ハロゲン、C1-4アルキル、C1-4ハロアルキル及びCH2CNから選択される2つまでの追加のR5基により置換された5員のヘテロアリール基であるそれらの化合物である。
さらなる別の特定の基の実施態様によれば、式I又はIa、及び(F)、(G)、(H)、(I)及び(J)として同定される実施態様を参照して、Zは、下記:
1つの特定の基の実施態様によれば、化合物は、下記式:
(A)〜(J)で提供される実施態様、及び組み合せである実施態様(例えば、(A)及び(F);(B)及び(G);(A)及び(H)、及び同様のもの)の何れか内で、さらに他の選択された実施態様が存在する:
(a)ここで、下付文字nは0であり;
(b)ここで、nは0であり、そしてR1はH又はメチルであり;
(c)ここで、nは0であり、そしてR1はH又はメチルであり、そしてR2はH又はC1-8アルキルであり、そしてR3は水素であり;
(d)ここで、nは0であり、そして各R2及びR3は水素であり;
(e)ここで、nは0であり、各R2は水素であり、そしてR3は、メチル、エチル、−CONH2及び−CH2OHから成る群から選択され;
(f)ここで、各R2は水素である。
本発明の特定化合物は、本明細書の実施例部分に記載されるような方法論に従って調製され得る。さらに、本発明の化合物の調製において有用である特定の中間体化合物の合成がまた記載されている。
上記に提供される化合物の他に、ヒト及び動物においてCXCR7活性を調節するための組成物は典型的には、医薬的担体又は希釈剤を含むであろう。
いかなる特定の理論に縛られることを所望しないが、本発明の化合物及び組成物は、CXCR7受容体へのSDF−1及び/又はI−TACの結合を阻害することにより治療効果を提供すると思われる。従って、本発明の化合物及び組成物は、CXCR7受容体へのSDF−1及び/又はI−TACの結合の阻害が治療効果を提供する哺乳類における疾患又は障害の治療又は予防に使用され得る。
(a)肥満症の脂肪組織切除及び治療。Koloninら、Nature Medicine 10(6):625‐632(2004)を参照のこと;
(b)子癇前症の治療。Levineら、N.Engl.J.Med.350(7):
672‐683(204);Maynardら、J.Clin.Invest.111(5): 649‐658(2003)を参照のこと;及び
(c)心臓血管疾患の治療。例えば、Marchら、Am.J.Physiol.Heart Circ.Physiol.287:H458‐H463(2004);Rehmanら、Circulation 109:1292‐1298(2004)を参照のこと。
より特定には、本発明はまた、癌の治療法も提供する。癌の好ましい治療法は、治療的有効量の前述の化合物(又はその塩)を、癌患者に、癌を治療するのに十分な期間、投与することを包含する。
さらに、本発明の化合物及び組成物は、炎症の治療のために有用であり、そして本発明の化合物による癌又は炎症の治療の前、後又は同時に、治療を必要とする治療上有用な他の化合物及び組成物と組み合わされ得る。従って、組み合わせ方法及び組成物はまた、興味ある状態又は疾患、例えば炎症性又は自己免疫障害、状態及び疾患、例えば炎症性腸疾患、関節リウマチ、変形性関節症、乾癬性関節炎、多関節性関節炎、多発性硬化症、アレルギー性疾患、乾癬、アトピー性皮膚炎および喘息、及び上記に示されるそれらの病状を予防し、そして治療するための本発明の部分でもある。
さらに、本発明の化合物及び組成物は、国際公開第05/000333号(そのすべてが参照により本明細書に組み込まれる)に記載のような方法及びプロトコルに従って、任意には、本発明の化合物を用いて、前駆体/幹細胞を動員するために、及び従って、前駆体/幹細胞動員が、有効であるか又は所望される障害又は状態を治療するか又は改善するために有用である。改善され得るか、又は他方では、有益である状態は、例えば造血障害、例えば再生不良性貧血、白血病、薬物−誘発性貧血、及び化学療法又は放射線治療法からの造血欠陥を包含する。さらに、本発明の化合物及び組成物は、免疫抑制治療の間、及びそれに続いて、移植の成功の強化に、及びより効果的な創傷治療及び細菌感染の治療をもたらすことに使用され得る。さらに、本発明の化合物及び組成物は、国際公開第05/000333号(そのすべてが参照により本明細書に組み込まれる)に記載のような方法及びプロトコルに従って、任意には、本発明の化合物を用いて、前駆体/幹細胞を動員するために、及び従って、前駆体/幹細胞動員が、有効であるか又は所望される障害又は状態を治療するか又は改善するために有用である。改善され得るか、又は他方では、有益である状態は、例えば造血障害、例えば再生不良性貧血、白血病、薬物−誘発性貧血、及び化学療法又は放射線治療法からの造血欠陥を包含する。さらに、本発明の化合物及び組成物は、免疫抑制治療の間、及びそれに続いて、移植の成功の強化に、及びより効果的な創傷治療及び細菌感染の治療をもたらすことに使用され得る。任意には、本発明の化合物の投与に続いて、及び前駆体/幹細胞動員に続いて、動員された細胞を含む血液が集められ、そして任意には、動員された細胞が精製され、そして任意には、拡張され、そして所望により、同じ個人又は第2の個人(例えば、適合ドナー)中に再導入される。
またさらに、本発明の化合物及び組成物は、CXCR7に関連する疾患及び障害の診断のために有用である。特に、本発明の化合物は、標識された形(例えば、放射性標識された)で調製され得、そして例えば癌の診断のために使用され得る。CXCR7(例えば、アンタゴニスト又はアゴニスト)に結合する本発明の標識された化合物は、哺乳類対象におけるCXCR7のレベルを決定するために使用され得る。いくつかの実施態様によれば、CXCR7モジュレーターが、癌を有する対象に投与される。いくつかの実施態様によれば、標識された化合物は、進行性癌、例えば癌腫、神経膠腫、中皮腫、黒色腫、リンパ腫、白血病(急性リンパ性白血病を含む)、腺癌、乳癌、卵巣癌、子宮頸癌、神経膠芽腫、白血病、リンパ腫、前立腺癌、及びバーキットリンパ腫、頭頸部癌、結腸癌、結腸直腸癌、非小細胞肺癌、小細胞肺癌、食道癌、胃癌、膵臓癌、肝胆道癌、胆嚢癌、小腸癌、直腸癌、腎臓癌、腎癌、膀胱癌、前立腺癌、陰茎癌、尿道癌、精巣癌、子宮頸癌、膣癌、子宮癌、卵巣癌、甲状腺癌、副甲状腺癌、副腎癌、膵臓内分泌癌、カルチノイド癌、骨肉腫、皮膚癌、網膜芽細胞腫、ホジキンリンパ腫、非ホジキンリンパ腫(追加の癌については、CANCER:PRINCIPLES AND PRACTICE (DeVita、V.Tらeds 1997)を参照のこと); 並びに脳及び神経機能障害、例えばアルツハイマー病、多発性硬化症及び脱髄疾患; 高血圧性障害、例えば肺動脈性肺高血圧症; 腎臓機能障害; 腎機能障害; リウマチ性関節炎; 同種移植の拒絶反応;アテローム性動脈硬化症(及び上昇したコレステロールレベル); 喘息;糸球体腎炎;接触性皮膚炎; 炎症性腸疾患;大腸炎;乾癬;再灌流障害; 並びに本明細書に記載される他の障害及び疾患を検出するために投与される。いくつかの実施態様によれば、対象は、カポジ肉腫、多中心性キャッスルマン病又はAIDS関連原発性滲出液リンパ腫を有さない。CXCR7はしばしば、癌細胞において発現されるが、しかし非癌細胞においては発現されないので、典型的には、CXCR7のアンタゴニストを、癌を有する危険性のある対象に投与することが所望される。
(a)放射性標識された又は検出可能形の式Iの化合物を、そのようなイメ−ジングの必要な対象に投与し;そして
(b)前記化合物が前記対象において濃縮される場合を決定するために、前記化合物を検出することを含んで成る、腫瘍、器官又は組織をイメ−ジングするための方法を提供する。
(a)高められたレベルのCXCR7を有する疑いのあるサンプルと、放射性標識された又は検出可能形の式Iの化合物とを接触させ;
(b)前記サンプルに存在するCXCR7のレベルを決定するために、前記サンプルに存在するCXCR7に結合される化合物のレベルを決定し;そして
(c)高レベルのCXCR7が前記サンプルに存在するかどうかを決定するために、工程(b)で決定されたレベルと、対照サンプルとを比較することを含んで成る、サンプル中のCXCR7の上昇レベルの検出方法を提供する。
CXCR7の阻害剤は、単独で、又は1又は2以上の他の薬物と共に供給され得る。可能な併用パターンは、例えば追加の抗血管新生因子及び/又は化学療法剤(例えば、細胞毒性剤)又は放射線,癌ワクチン、免疫調節剤、抗血管剤,シグナル伝達阻害剤、抗増殖剤、又はアポトーシス誘導剤を包含することができる。
次の実施例は、本発明を例示するために提供されるが、しかし本発明の範囲を制限するものではない。
実施例114:(S)−1−フェニル−N−(1−(ピロロ[1,2−a]ピラジン−1−イル)ピロリジン−3−イル)−1H−1,2,4−トリアゾ−ル−3−カルボキサミドの合成
下記表における化合物を、上記のようにして調製した。特性データ(NMR)が、個々のために提供される。
上記に記載される化合物がCXCR7に結合するケモカインのために有用なモジュレーターであることを実証するために、化合物をインビトロでスクリーンし、複数濃度でCXCR7受容体からSDF−1を置換するそれらの能力を決定した。化合物を、IC50値、試薬及び細胞の決定(下記参照のこと)に詳細されるように、125I−標識されたSDF−1ケモカインの存在下でCXCR7受容体を発現する細胞(例えば、MCF細胞、又はCXCR7を発現するようトランスフェクトされた細胞)と組み合わせた。次に、複数濃度でCXCR7受容体部位から、標識されたケモカインを置換する化合物の能力を、スクリーニング工程により決定した。
試薬及び細胞。125Iにより標識されたSDF−1を、Perkin‐Elmer Life Sciences,Inc.(Boston,MA)から購入した。MCF−7(腺癌;乳腺)細胞系を、American Type Culture Collection (ATCC,Manassas,VA)から入手し、そして5%CO2/空気混合物下で、加熱インキュベーターにおいて37℃で、10%ウシ胎児血清(FBC)(Hyclone Logan,UT)及びウシインスリン(0.01mg/ml)(St.Louis,MO)により補充されたDMEM(Mediatech,Herndon,VA)において培養した。CXCR7をトランスフェクトされたMDA−MB−435Sを、下記のようにして生成した。MDA−BM−435Sヒト乳癌系を、ATCCから購入し、そしてDMEM/10%FBS培養において培養した。CXCR7(別名、CCXCKR2、hRDC1)をコードする遺伝子の完全なコード配列を、μMACs mRNA 単離キット (Miltenyi Biotec,Auburn, CA)を用いて、MCF−7細胞から単離した。DNA汚染を、RNeasyカラム(Qiagen,Inc.,Valencia,CA)を介してDNase消化により除去し、そしてcDNAを、GeneAmp RNA PCR Core Kit (Applied Biosystems,Foster City,CA)を用いて生成した。cDNAサンプルのPCRを、Taq PCR Master Mix キット (Qiagen,Inc.)、及び5’及び3’NotI部位を有するhRDC1プライマー(HRDC1F 5’−GAATGCGGCCGCTATGGATCTGCATCTCTTCGACT−3’、hRDC1R 5’−GAATGCGGCCGCTCATTTGGTGCTCTGCTCCAAG−3’)を用いて実施した。NotIにより消化されたPCR生成物を、Not1消化されたpcDNA3.1(+)(Invitrogen,Carlsbad,CA)中に連結し、そして確認される配向及び配列についてスクリーンした。次に、プラスミドDNAを、Maxiprep (Qiagen,Inc.)により、一晩の細菌培養物から単離した。プラスミドDNA(10μg)を、MDA−MB−435s細胞に付加し、そして細胞を、Gene Pulser (Biorad laboratories,Hercules,CA)によりエレクトロポレートした(0.22kV、960uF)。48時間のエレクトロポレーションの後、細胞を、選択培地(600μg/mlのG418)に移した。
a)破壊的関節炎症のウサギモデル
ウサギLPS研究を、Podolinら、J.Immunol.169(11):6435‐6444(2002)に記載のようにして、実質的に実施した。雌のニュージーランドウサギ(約2kg)を、LPS(10ng)により両膝の関節内処理した。目的の化合物、例えば、1.016(1%メトセルで処方された)又はビヒクル(1%メトセル)を、2度(関節内LPS注入の2時間前、及び関節LPS注入の4時間後)、5ml/kgの用量体積で経口投与した。LPS注入の16時間後、膝を洗浄し、そして細胞計算を行った。治療の有益な効果を、膝関節の炎症滑液にリクルートされる炎症性細胞の数の低下により決定した。目的の化合物による治療は、リクルートされた炎症性細胞の有意な低下をもたらした。
17日の進行性II型コラーゲン関節炎研究を行い、関節炎誘発された臨床学的足首の腫脹に対する目的の化合物の効果を評価する。ラットコラーゲン関節炎は、多数の抗−関節炎剤の前臨床試験のために広く使用されて来た多発性関節炎の実験モデルである(Trenthamら、J.Exp.Med.146(3):857‐868 (1977),Bendeleら、Toxicologic Pathol.27:134‐142 (1999),Bendeleら、Arthritis Rheum.42:498‐506 (1999)を参照のこと)。このモデルの特徴は、堅固で容易に測定できる多関節炎症、パンヌス形成に関連する顕著な軟骨破壊、及び軽度〜中程度の骨吸収及び骨膜骨増殖の信頼できる発症及び進行である。
創傷治癒研究において、ICR由来の雄マウス(24±2g)を使用する。試験期間中、動物を単独で個別のケージに収容する。ヘキソバルビタール(90mg/kg、IP)麻酔下で各動物の肩及び背部を剃り毛する。鋭いパンチ(ID 12mm)を適応し、皮筋層及び接着組織を包含する皮膚を除去する。試験化合物又はビヒクルを、毎日1回10日間連続して、皮膚損傷後にすぐに、それぞれ局部投与する。陽性対照、例えばA2アデノシン受容体アゴニスト(CGS−21680;10μg/マウス)を、実験の間、毎日、局部投与することができる。透明なプラスチックシート状にトレースされる創傷領域を、1,3,5,7,9及び11日目、Image Analyzer (Life Science Resources Vista,Version 3.0)の使用により測定する。創傷の%閉鎖率を計算し、そして創傷半閉鎖時間(CT50)を決定し、そしてGraph‐Pad Prism (Graph Pad Software)を用いて、線状回帰により分析する。片側スチューデント検定を、各測定時点で試験されたグループとビヒクルグループとの間の比較のために適用することができる。差異は、P<0.05レベルで統計学的有意であると思われる。
動物における多くの腫瘍モデルは、当業界において知られており、そして本発明の化合物を評価するために使用され得る。例えば、肺癌異種移植片研究において、A549腫瘍断片(30〜40mg)を、ヌードマウスの皮下空間に移植する。腫瘍を、約150mgのサイズ(100〜200mg)になるまで、増殖させ、この時点で、マウスを研究に登録し、そして治療を開始する。マウスを、目的の化合物又はビヒクル対照により治療する。メルファラン(melphalan)が、陽性対照(9mpk/用量、ip投与、Q4Dx3)として包含され得る。腫瘍を、カリパスにより週2度、二次元的に測定し、そして長楕円形状についての式(a×b2/2)(ここで、aは長い方の寸法であり、そしてbは短い方の寸法である)を用いて、及び単位密度(1mm3=1mg)を仮定して、腫瘍質量に転換する。体重をまた、週2度、測定し、化合物投与の何れかの悪影響を評価する。抗腫瘍活性を、ビークル処理された対照グループに比較して処理されたグループの腫瘍増殖の遅延により評価する。
齧歯動物EAEは、再発性寛解及び進行性MSの治療のための多数の剤の前臨床試験のために広く使用されて来た多発性硬化症(MS)の実験モデルである。このモデルの特徴は、堅固で容易に測定できる尾及び手足の麻酔、神経炎症、神経抗原に対応しての著しい脱髄の信頼できる発症及び進行である。
動物における多くの腫瘍モデルは、当該技術分野において周知であり、そして目的の化合物を評価するために使用され得る。例えば、マウスグリア芽腫モデルにおいて、1×106固のU251MG細胞を、ヌードマウスの脳内に、定位注射により注入する。20日後、腫瘍を、1−15Gyの放射線により照射する。照射に続いて、マウスを、化合物又はビークル対照により処理し(皮下、腹腔内、経口、非経口又は他の経路による)、そして腫瘍を進行させる。腫瘍増殖及び/又は死亡率を、研究の残りの間、モニターする。腫瘍を、カリパスにより週2度、二次元的に測定し、そして長楕円形状についての式(a×b2/2)(ここで、aは長い方の寸法であり、そしてbは短い方の寸法である)を用いて、及び単位密度(1mm3=1mg)を仮定して、腫瘍質量に転換する。体重をまた、週2度、測定し、化合物投与の何れかの悪影響を評価する。抗腫瘍活性を、ビヒクル処理された対照グループに比較して処理されたグループの腫瘍増殖の遅延により評価する。
動物における多くの腫瘍モデルは、当該技術分野において周知であり、そして目的の化合物を評価するために使用され得る。例えば、ラットC6モデルにおいて、1×106固のC6細胞を、Sprague‐Dawleyラットの脳内に、定位注射により注入する。7日後、腫瘍を、5−20Gyの放射線により照射する。照射に続いて、ラットを、化合物又はビヒクル対照により処理し(皮下、腹腔内、経口、非経口又は他の経路による)、そして腫瘍を進行させる。動物を、死亡まで、又は20%以上の体重の低下まで追跡するか、又は適切な規制及び基準に従って、腫瘍誘導性神経障害、例えば発作及び不動性のために除いた。化合物活性を、生存性のカプラン・マイヤー分析により決定し、そして表1における化合物1.090は、ビークル処理された対照グループに比較して、処理されたグループの腫瘍増殖の遅延により評価されるように、強い抗腫瘍活性を有した。
動物における肺機能不全及び高血圧症の多くのモデルは、当該技術分野において周知であり、そして本発明の化合物を評価するために使用され得る。たとえば、慢性低酸素誘導性高血圧症モデルにおいて、新生マウス(FVB/NJ)を、2週間、基準気圧の正常酸素(ルームエアコン(RA))、又は低酸素(HA)(FiO2=0.12)にランダムに暴露する。1週間のRA又はHAの後、マウスを、生後7日目から14日目まで、ビークル又は目的の化合物の毎日の皮下注射により処理する。肺高血圧症の程度を、右心室収縮期圧(RVSP)を測定することにより決定することができる。手短には、開胸を実施し、そして圧力変換器(Gould Instruments,OH)を連結された25ゲージ針を、右心室に挿入し、そしてRSVPを記録する。RVSP測定のすぐ後、マウスを屠殺し、心臓を取り出し、そして解剖する。右心室肥大(RVH)を、右心室/左心室+隔壁(RV/LV+S)の比率により評価する。RSVP及びRVHの測定値改善は、候補化合物が治療能力を有することを示唆する。
最初に、上記スクリーニング方法の何れかにより興味あるものとして同定された化合物をさらに、インビボで見掛け活性を検証するために試験することができる。好ましくは、そのような研究は、適切な動物モデルにより行われる。そのような方法の基本的形式は、ヒトのための疾患モデルとして役立つ動物への、初期スクリーニングの間、同定されたリード化合物の投与、及び次に、疾患(例えば、癌、心筋梗塞、創傷治療、炎症性疾患、又はCXCR7に関連するための疾患)が実際、変更され、そして/又は疾患又は状態が改善されるかどうかの決定を包含する。検証研究に使用される動物モデルは一般的に、何れの種類の動物でもあり得る。適切な動物の特定の例としては、霊長類、マウス、ラット及びゼブラフィッシュを挙げることができるが、但しそれらだけには限定されない。
配列番号1 CXCR7コード配列
ATGGATCTGCATCTCTTCGACTACTCAGAGCCAGGGAACTTCTCGGACATCAGCTGGCCATGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCGGCAGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTATCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGCTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTCTCAGAGACGGAGTACTCTGCCTTGGAGCAGAGCACCAAATGA
配列番号2 CXCR7アミノ酸配列
MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFSINLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDTYYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVSETEYSALEQSTK
配列番号3 CXCR7.2コード配列
ATGGATCTGCACCTCTTCGACTACGCCGAGCCAGGCAACTTCTCGGACATCAGCTGGCCATGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCAGCGGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTATCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGCTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTGTCGGAGACGGAGTACTCCGCCTTGGAGCAAAACGCCAAGTGA
配列番号4 CXCR7.2アミノ酸配列
MDLHLFDYAEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFSINLFSGIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDTYYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVSETEYSALEQNAK
配列番号5 CXCR7.3コード配列
ATGGATCTGCATCTCTTCGACTACTCAGAGCCAGGGAACTTCTCGGACATCAGCTGGCCATGCAACAGCAGCGACTGCATCGTGGTGGACACGGTGATGTGTCCCAACATGCCCAACAAAAGCGTCCTGCTCTACACGCTCTCCTTCATTTACATTTTCATCTTCGTCATCGGCATGATTGCCAACTCCGTGGTGGTCTGGGTGAATATCCAGGCCAAGACCACAGGCTATGACACGCACTGCTACATCTTGAACCTGGCCATTGCCGACCTGTGGGTTGTCCTCACCATCCCAGTCTGGGTGGTCAGTCTCGTGCAGCACAACCAGTGGCCCATGGGCGAGCTCACGTGCAAAGTCACACACCTCATCTTCTCCATCAACCTCTTCGGCAGCATTTTCTTCCTCACGTGCATGAGCGTGGACCGCTACCTCTCCATCACCTACTTCACCAACACCCCCAGCAGCAGGAAGAAGATGGTACGCCGTGTCGTCTGCATCCTGGTGTGGCTGCTGGCCTTCTGCGTGTCTCTGCCTGACACCTACTACCTGAAGACCGTCACGTCTGCGTCCAACAATGAGACCTACTGCCGGTCCTTCTACCCCGAGCACAGCATCAAGGAGTGGCTGATCGGCATGGAGCTGGTCTCCGTTGTCTTGGGCTTTGCCGTTCCCTTCTCCATTGTCGCTGTCTTCTACTTCCTGCTGGCCAGAGCCATCTCGGCGTCCAGTGACCAGGAGAAGCACAGCAGCCGGAAGATCATCTTCTCCTACGTGGTGGTCTTCCTTGTCTGCTGGTTGCCCTACCACGTGGCGGTGCTGCTGGACATCTTCTCCATCCTGCACTACATCCCTTTCACCTGCCGGCTGGAGCACGCCCTCTTCACGGCCCTGCATGTCACACAGTGCCTGTCGCTGGTGCACTGCTGCGTCAACCCTGTCCTCTACAGCTTCATCAATCGCAACTACAGGTACGAGCTGATGAAGGCCTTCATCTTCAAGTACTCGGCCAAAACAGGGCTCACCAAGCTCATCGATGCCTCCAGAGTCTCAGAGACGGAGTACTCTGCCTTGGAGCAGAGCACCAAATGA
Claims (31)
- 下記式(I):
各環頂点Xa、Xb及びXcは、N、NH、N(R2)、O、CH及びC(R2)から成る群から独立して選択され;
下付き文字nは、0、1又は2であり;
Zは、以下:
(i)単環式又は縮合二環式アリール及びヘテロアリール(ここで、前記へテロアリール基はN、O及びSから選択される1〜4個のヘテロ原子を環員として有し、そして前記アリール及びヘテロアリール基は任意には、1〜5個のR5置換基により置換される);
(ii)シクロアルカン及びヘテロシクロアルカンから成る群から選択される、単環式の4−、5−、6−又は7員の環(ここで前記へテロシクロアルカン環は、N、O及びSから選択される1〜3個のヘテロを環員として有し、そして各前記単環式Z環は任意には、1〜3個のR5置換基により置換される)から成る群から選択され;
R1は、H及びC1-8アルキルから成る群から選択されるメンバーであり、ここで前記アルキル部分は任意には、ハロゲン、−NRaRb、−ORa、−CO2Ra及び−CONRaRbで置換される;
各R2は、H、ハロゲン、CN、C1-8アルキル、C1-8ハロアルキル、C1-8ヒドロキシアルキル、−ORa、−CO2Ra、−X−C02Ra、−NRaRb、−CONRaRb及び−X−CONRaRbから成る群から独立して選択され;
R3は、H、C1-8アルキル、C1-8ハロアルキル、C1-8ヒドロキシアルキル、−CO2Ra、−X−CO2Ra、−CONRaRb及び−X−CONRaRbから成る群から選択されるメンバーであり;
各R4は、存在する場合、C1-8アルキル、C1-8ハロアルキル、C1-8ヒドロキシアルキル、−ORa、−CO2Ra、−X−C02Ra、−NRaRb、−CONRaRb 及び−X−CONRaRbから成る群から独立して選択されるメンバーであり;
各R5は、ハロゲン、CN、−X−CN、C1-8アルキル、C3-8シクロアルキル、C3-8シクロアルケニル、C3-5スピロシクロアルキル、C2-8アルケニル、C2-8アルキニル、C1-8ハロアルキル、C1-8ヒドロキシアルキル、−ORa、−CO2Ra、−X−CO2Ra、−NRaRb、−CONRaRb、−X−CONRaRb、アリール、5− 又は 6−員のヘテロアリール、及び3−、4−、5−又は6−員の複素環から成る群から独立して選択されるメンバーであり、ここでヘテロアリール及び複素環式環の環頂点として存在するヘテロ原子は、N、O及びSから選択され、そしてR5のアリール、ヘテロアリール及び複素環部分はさらに任意には、1〜3個のRaで置換され;
各Ra及びRbは、水素、ヒドロキシル、ハロゲン、シアノ、C1-8アルキル、C1-8アルコキシ、C1-8ハロアルキル、C3-6シクロアルキル、C3-6シクロアルキルアルキル、アミノ、C1-8アルキルアミノ、ジC1-8アルキルアミノ、カルボキサミド、カルボキシC1-4アルキルエステル、カルボン酸、及び−SO2−C1-8アルキルから成る群から独立して選択され;
各Xは、C1-4アルキレン結合基又は式−(CH2)mO(CH2)p−(式中、下付文字m及びpは0〜5の整数であり、そしてm+pは0〜6である)を有する結合基であり、ここでXのメチレン部分のいずれかは、1又は2個のメチル基で任意に置換される]
を有する化合物、その医薬的に許容できる塩、水和物、又は同位体的に富化された若しくは鏡像異性体的に富化された化合物。 - Zが、N、O及びSから選択される1〜3個のヘテロ原子を環員として有する、単環式又は縮合二環式へテロアリールであり;そして前記へテロアリール基が、任意には、1〜5個のR5置換基で置換される、請求項1に記載の化合物。
- Zが、イミダゾール、ピラゾール、1,2,3‐トリアゾール、1,2,4‐トリアゾール、テトラゾール、チアゾール、オキサゾール、オキサジアゾール、ピリミジン、ピラジン、ピリダジン、及びキナゾリンから成る群から選択される単環式又は縮合二環式へテロアリールであり、個々が任意には、1〜2個のR5置換基で置換される、請求項1に記載の化合物。
- nが0である、請求項2に記載の化合物。
- R1がHである、請求項4に記載の化合物。
- 各R2が、H及びC1-4アルキルから成る群から独立して選択される、請求項1に記載の化合物。
- R3が、H、CH2OH及びC(O)NH2から成る群から選択される、請求項1に記載の化合物。
- Zが、任意に置換されたアリール、ヘテロアリール、シクロアルキル又はヘテロシクロアルキル環から選択される1つのR5基で、及び任意には、ハロゲン、C1-4アルキル、C1-4ハロアルキル及びCH2CNから選択される2個までの追加のR5基で置換される5員のヘテロアリール基である、請求項8に記載の化合物。
- Raが、水素、ハロゲン、シアノ、C1-8アルキル及び−SO2−C1-8アルキルから成る群から選択される、請求項13に記載の化合物。
- R2が、H及びC1-4アルキルから成る群から選択される、請求項13に記載の化合物。
- Raが、水素、ハロゲン、シアノ、C1-8アルキル及び−SO2−C1-8アルキルから成る群から選択され;そしてR2が、H及びC1-4アルキルから成る群から選択される、請求項13に記載の化合物。
- 請求項1に記載の化合物、及び医薬的に許容できる賦形剤を含む医薬組成物。
- 請求項17〜19のいずれか1項に記載の化合物を含む、請求項20に記載の医薬組成物。
- 哺乳類における疾患又は障害を処置するための、請求項20又は21に記載の医薬組成物。
- 前記疾患又は障害が、癌、炎症及び神経又は前駆/幹細胞障害から成る群から選択される、請求項22に記載の医薬組成物。
- 前記癌が、頭頸部癌である、請求項23に記載の医薬組成物。
- 前記癌が、神経膠芽腫である、請求項23に記載の医薬組成物。
- CXCR7受容体へのケモカインI‐TAC又はSDF‐1の結合を阻害するための医薬組成物であって、前記医薬組成物が請求項1に記載の化合物を含有し、前記阻害が、前記医薬組成物と、CXCR7受容体を発現する細胞とを、前記CXCR7受容体への前記ケモカインの結合を阻害するのに十分な時間、接触させることを含む、医薬組成物。
- 前記化合物が、請求項17〜19のいずれか1項に記載の化合物である、請求項26に記載の医薬組成物。
- 腫瘍、器官又は組織をイメージングするための組成物であって、前記組成物が放射性標識された又は検出可能な形態の請求項1〜19のいずれか一項に記載の化合物を含有し、前記イメージングが、以下の工程:
(a)前記組成物を、そのようなイメージングの必要な対象に投与し;そして
(b)前記化合物を検出して、前記化合物が前記対象において濃縮される場所を決定する
ことを含む、組成物。 - 前記化合物が放射性標識される、請求項28に記載の組成物。
- サンプル中の上昇したCXCR7のレベルの検出のための組成物であって、前記組成物が放射性標識された又は検出可能な形態の請求項1〜19のいずれか一項に記載の化合物を含有し、前記検出が、以下の工程:
(a)上昇したCXCR7のレベルを有する疑いのあるサンプルと、前記組成物とを接触させ;
(b)前記サンプルに存在するCXCR7に結合される化合物のレベルを決定して、
前記サンプルに存在するCXCR7のレベルを決定し;そして
(c)工程(b)で決定されたレベルと対照サンプルとを比較して、上昇したCXCR7のレベルが前記サンプルに存在するかどうかを決定する
ことを含む、組成物。 - 前記化合物が放射性標識される、請求項30に記載の組成物。
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