CN1360502A - 多巴胺d3受体配体在生产肾功能紊乱治疗药物中的应用 - Google Patents
多巴胺d3受体配体在生产肾功能紊乱治疗药物中的应用 Download PDFInfo
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- CN1360502A CN1360502A CN00809977A CN00809977A CN1360502A CN 1360502 A CN1360502 A CN 1360502A CN 00809977 A CN00809977 A CN 00809977A CN 00809977 A CN00809977 A CN 00809977A CN 1360502 A CN1360502 A CN 1360502A
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- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 239000000442 dopamine 2 receptor blocking agent Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- UBLXEEBHYISRFM-UHFFFAOYSA-M folin's reagent Chemical compound [Na+].C1=CC=C2C(S(=O)(=O)[O-])=CC(=O)C(=O)C2=C1 UBLXEEBHYISRFM-UHFFFAOYSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 210000000585 glomerular basement membrane Anatomy 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- NOWPYQNOYJQXPV-UHFFFAOYSA-N n-methyl-1h-1,2,4-triazol-5-amine Chemical compound CNC=1N=CNN=1 NOWPYQNOYJQXPV-UHFFFAOYSA-N 0.000 description 1
- 210000000885 nephron Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- ZJLMKPKYJBQJNH-UHFFFAOYSA-N propane-1,3-dithiol Chemical compound SCCCS ZJLMKPKYJBQJNH-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 238000006891 umpolung reaction Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- A61K31/47—Quinolines; Isoquinolines
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Abstract
本发明涉及多巴胺D3受体配体在生产治疗肾功能紊乱的药物中的应用。
Description
本发明涉及选择性多巴胺D3受体配体在生产肾功能紊乱治疗药物中的应用。
受体配体优选为受体拮抗剂。
本发明特别涉及用于治疗肾小球超滤(glomerular hyperfiltration)意义上的肾小球滤过率异常性肾功能紊乱的药物。
有证据表明,多巴胺D3受体在肾脏、尤其是肾单位中表达(参见D.P.O’Connell等,Hypertension,1998,32,886)。
DE-A 4223921一般性介绍了多巴胺受体拮抗剂在治疗肾功能进行性恶化中的应用,但是没有指明多巴胺受体拮抗剂的具体亚型。
G.Luippold等在Naunyn-Schmiedeberg’s Arch.Pharmacol(1998)358:690-693中介绍了在没有病理生理学变化的纯人工功能状态下,研究特定的D2和D3受体拮抗剂对肾脏血液动力学和排泄功能的影向。
L.D.Asico等(J.Clin.Invest.,Vol.102(1998),493-498)介绍,阻断D3受体使肾素产生以及肾性钠潴留增加,因而导致肾素依赖性高血压。
某些疾病发生肾小球毛细管硬化,由此引起肾小球滤过率异常,所述疾病例如糖尿病、高血压、感染性或非感染性肾小球肾炎、上行性泌尿道感染、镰状细胞性贫血或在单侧肾切除手术后的代偿性巴大。
几乎所有肾小球肾炎患者以及1/3以上的糖尿病患者发生肾功能进行性恶化。
肾小球硬化引起的肾功能紊乱也称为糖尿病性肾病,其组织学特征为弥漫性肾小球毛细血管壁增厚和肾小球膜改变,其原因是基底膜样物质或球状纤维蛋白沉积。因此发生超滤意义上的肾小球过滤异常。
肾小球肾炎同样如此,肾小球基底膜变化导致肾小球滤过率异常。
本发明目的就是找到某些药物,使得能够针对性治疗上述疾病的肾功能紊乱。
由此发现了本文开始阐述的应用。
基本上所有与多巴胺D3受体有亲和力的化合物都是其合适的受体配体,优选与多巴胺D3受体的亲和力比与另一多巴胺受体大10倍的化合物。
合适的化合物有例如下列文献中述及的选择性多巴胺D3受体配体:WO95/04713介绍的2-氨基茚满类(2-aminoindans)、WO95/30658公开的苯并咪唑类、EP-A286516和Bioorg.Med.Chem.Lett.1997,7,881公开的2-氨基四氢化萘类,以及WO 94/21608,WO 96/30333,Bioorg.Med.Chem.Lett.1996,6,6403或J.Med.Chem.,1996,39,4233公开的化合物。
此外,四氢异喹啉衍生物类也是合适的多巴胺D3受体配体,例如WO 97/43262、WO 98/51671、WO 98/50363、WO 98/49145、WO98/50364或WO 98/06699文献介绍的四氢异喹啉衍生物类,WO97/17326或WO 97/47602公开的化合物也同样合适。
WO 97/34884、Bioorg.Med.Chem.Lett.1997,7,2403、EP-A779584、WO 98/18798或WO 96/02520、WO 96/02519、WO 96/02249、WO 96/02246、WO 97/00106和WO 98/04138文献述及的化合物同样适合。
通式I的化合物及其与生理学上可耐受的酸的盐
L-D-E (I)其中L是
具有1、2或3个杂原子的5-或6-元芳香族杂单环体系L1,所
其中L可以任选包含1、2、3或4个取代基,所述取代基彼此
独立地选自OR1、任选被OH、OC1-C6-烷基、苯基或如CF3或CHF2
的卤素取代的C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C3-C8-环烷
基、卤素、CN、CONR1R2、CO2R1、NO2、NR1R2、SR1、SO2R1、
SO2NR1R2、OSO2R1、Ax1或任选被C1-C6-烷基、OC1-C6-烷基或
卤素取代的苯氧基、或C1-C6-烷酰基或苯甲酰基;其中Ax1为苯基、萘基或含有1-4个选自O、S和N的杂原子的5-或6-
元芳香杂环,其中Ax1可以任选包含1、2、3或4个取代基,
所述取代基彼此独立地选自任选被OH、OC1-C6-烷基、卤素或
苯基取代的C1-C6-烷基、C1-C6-烷氧基、C2-C6-烯基、C2-C6-炔基、
C3-C6-环烷基、卤素、CN、COOR1、NR1R2、NO2、SR1、SO2R2、
SO2NR1R2或任选被C1-C6-烷基、OC1-C6-烷基、NR2R2、CN、CF3、
CHF2或卤素取代的苯基,并且上述芳香杂环可以任选与苯环稠
合;
R1为H、C3-C6-环烷基或C1-C6-烷基,后者任选被OH、OC1-C6-
烷基、苯基或卤素如CF3或CHF2取代;
基团R2可以是相同或不同基团,具有就R1指出的相同含义或
为COR1或CO2R1;
R3为Ax1、OR1、R1、C2-C6-烯基、C2-C6-炔基、Hal、CN、CONR1R1、
COOR1、NO2、NR1R1、SR1、OSO2R1、SO2R1,
R4至R6彼此独立为H、C1-C6-烷基、OR1、CN、NR2R2、SR1、
CF3;
R7为H、C1-C6-烷基、C3-C6-环烷基或苯基;假如L为L2,则D为CONR7-C3-C10-亚烷基基团;或者假如L为5-
或6-元芳香族单杂环体系L1,则D为C4-C10-亚烷基基团或C3-
C10-亚烷基基团,它包含至少一个选自-CH2-、O、S、NR1、C3-C6-
环烷基、CO、CONR1的基团Z、一个双键以及一个三键,其中
R1定义同前,E为一个式(E1)或(E2)的基团,而
(E1)为B-G,其中B为
含有1个或2个氮杂原子的6-、7-或8-元饱和环,其中氮杂原
子位于1,4-位或1,5-位,而该环与1位的基团D以及4-或5-位
苯基、吡啶基、嘧啶基或三嗪基,其中G可任选包含1-4个取
代基,这些取代基彼此独立地选自OR1、烷基、C2-C6-烯基、C2-C6-
炔基、烷氧基烷基、卤代烷基、卤素、CN、CO2R1、NO2、SO2R1、
NR1R2、SO2NR1R2、SR1、5-或6-元芳香碳环或非芳香碳环以及
含有1个或2个选自O、S以及N的杂原子的5-或6-元芳香杂
环或非芳香杂环,其中所述碳环或杂环任选被C1-C6-烷基、苯
基、苯氧基、卤素、OC1-C6-烷基、OH、NO2或CF3取代,其中
G可任选与上述定义类型的碳环或杂环稠合;(E2)为一个E2a至E2d的基团其中X3为CH2或CH2CH2;R11为H、任选被OH、OC1-C6-烷基、苯基或卤素取代的C1-C6-
烷基、C3-C6-环烷基、任选卤代(1个或2个卤素原子)C2-C6-
烯基或C2-C6炔基;R8、R9以及R10彼此独立地选自H、任选被OH、OC1-C6-烷基、
C1-C6-烷硫基、卤素或苯基任选取代的C1-C6-烷基、OH、
C1-C6-烷氧基、SH、C1-C6-烷硫基、C2-C6-烯基、C2-C6-炔
基、卤素、CN、NO2、SO2R1、OSO2R1、SO2NR1R1、NHSO2R1、
NR1R2、5-或6-元芳香碳环或非芳香碳环以及含有1个或2
个彼此独立地选自O、S以及N的杂原子的5-或6-元芳香
杂环或非芳香杂环,其中所述碳环或杂环可含有1或2个
彼此独立地选自C1-C6-烷基、苯基、苯氧基、卤素、C1-C6-
烷氧基、OH、NO2、CF3和CHF2的取代基,并且R8、R9
和R10取代基中的两个取代基与其键合的苯环碳原子一起可
形成与所述苯环稠合的苯基、环戊基或环己基环。
在本发明中,下列表述具有以下含义:
烷基(包括如烷氧基、烷基氨基等基团中的烷基)为1-6个碳原子、尤其是1-4碳原子的直链或支链烷基。烷基基团可含有一个或多个彼此独立地选自OH、OC1-C6-烷基、卤素或苯基的取代基。
烷基实例有甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。
环烷基特指C3-C6-环烷基,例如环丙基、环丁基、环戊基以及环己基。
亚烷基为直链或支链基团。假如D不含基团Z,则D包含4-10个碳原子、优选4-8个碳原子。那么L与基团E之间的链至少含有4个碳原子。假如一个上述基团包含Z,则D包含3-10个碳原子、优选3-8个碳原子。
亚烷基可任选包含一个上述D定义中说明的Z基团。正如上述双键或三键一样,基团Z可以位于基团D任何需要位置或1或2位的亚烷基链中(由基团L可知)。优选基团CONR1和COO的排列使得在各种情况下羰基面接基团L1。
特别优选D如同式I中一样代表各种化合物,其中D为-Z-C3-C6-亚烷基,特别是-Z-CH2CH2CH2-、-ZCH2CH2CH2CH2-、-Z-CH2CH=CHCH2-、-Z-CH2C(CH3)=CHCH2-、-Z-CH2-C(=CH2)CH2-、-Z-CH2CH(CH3)CH2-或线性-Z-C7-C10-亚烷基。在这种情况下Z也可以是CH2而优选CH2、O,尤其优选S。
卤素通常为F、Cl、Br或I,优选F或Cl。
卤代烷基可包含一个或多个卤素原子,优选包含1、2、3或4个卤素原子,它们可以位于一个或多个碳原子上,优选位于α-或ω-位。尤其优选CF3、CHF2、CF2Cl或CH2F。
酰基优选HCO或C1-C6-烷基-CO,尤其优选乙酰基。假如L被取代,取代基也可以位于杂原子N上。
COOR1、NR1R2、SR1、SO2R1,R4至R6彼此独立为H、C1-C6-烷基、OR1、CN、NR2R2、SR1、CF3,R7为H、C1-C6-烷基或C3-C6-环烷基,M为N或CH。
Ax1优选为下式取代基其中R4至R6同以上说明的含义,而R7优选为C1-C4-烷基。
CHF2,R4至R6为H、C1-C6-烷基、OR1、NR2R2,而R7为H、C1-C6-烷基。Ax1尤其优选为尤其优选所指示的苯基、吡嗪基、噻唑基以及吡咯基,其中R4、R5以及R7同上述定义。
按照一个实施方案,本发明涉及这样的式I化合物的应用:其中E为上述基团(E2)而L和D同上定义,那么L优选为L1a特别优选E为E2b或E2c,在E2b中X3优选为CH2CH2,在E2c中
X3优选为CH2,则L尤其优选在3位携带取代基Ax1以及在4
位携带基团R7的1,2,4-(4H)-三唑。假如E为基团E2b、E2c或E2d,则D优选为C4-C10-亚烷基或C3-C10-
亚烷基,后者包括至少一个选自O、S、CO或-CH2-的基团、一
个双键和一个三键。优选R8、R9和R10基团中至少一个基团为H。基团R8、R9和R10优选彼此独立地选自H、C1-C6-烷基、OH、C1-C6-
烷氧基、OSO2R1、C1-C6-烷硫基-C1-C6-烷基和卤素。尤其优选苯
基含有一个或两个取代基,也就是基团R8、R9和R10中的一个
或两个基团是C1-C6-烷基、OH、C1-C6-烷氧基或卤素。假如基团R8、R9和R10中一个基团为5-元或6-元杂环基团,则为例
如吡咯烷基、哌啶基、吗啡基、吡啶基、嘧啶基、三嗪基、吡
咯基、噻吩基或吡唑基,优选吡咯基、吡咯烷基、吡唑基或噻
吩基。假如R8、R9和R10的其中一个基团为碳环基团,则优选苯基、环戊
基或环己基。
述取代基特别位于间位和(或)对位。取代基优选彼此独立地选自
C1-C6-烷基、卤代烷基、NO2、特别是氯的卤素、苯基、吡咯基、
咪唑基、吡唑基、噻吩基、环戊基和环己基。假如其中一个取
代基为C1-C6-烷基,优选支链基团、特别是异丙基或叔丁基。G优选为任选取代的苯基、2-,3-,4-吡啶基或2-,4(6)-,5-嘧啶基。假如基团G的一个取代基是5-或6-元杂环,则为例如吡咯烷基、哌
啶基、吗啡基、吡啶基、嘧啶基、三嗪基、吡咯基、噻吩基、
噻唑基、咪唑基、噁唑基、异噁唑基、吡唑基或噻二唑基,优
选吡咯基、咪唑基、吡唑基或噻吩基。假如基团G的一个取代基是碳环基团,则优选为苯基、环戊基或环
己基。假如G与碳环基团稠合,则它特别为萘基、二氢萘基或四氢萘基。
尤其优选的式I化合物为以下这样的化合物:L选自而D为-Z-(CH2)3-或-Z-(CH2)4,E为B1-G,其中R3、R4、R7、Z、B1和G同以上定义。
本发明还包括式I化合物与生理学上可耐受的酸的酸加成盐。合适的生理学上可耐受的有机及无机酸有例如盐酸、氢溴酸、磷酸、硫酸、乙二酸、马来酸、富马酸、乳酸、酒石酸、己二酸或苯甲酸。Fortschritte der Arzneimittelforschung,[Advances in PharmaceuticalResearch],第10卷,第224ff页,Birkhuser Verlag,Basle andStuttgart,1996中介绍了其它可用酸。
式I化合物可含有一个或多个不对称中心。因此本发明不仅包括外消旋物,而且还包括相关的对映异构体和非对映异构体。本发明还包括其各自的互变异构体。
制备通式(I)化合物的方法是:a)使通式(II)的化合物
L-D-Y1 (II)
其中Y1为通常的离去基团如Hal、链烷磺酰氧基、芳基磺酰氧基
等,Z与上述定义一致,
与通式(III)的化合物反应
H-E (III);
或者b)使通式(IV)的化合物
L-D1-Z1H (IV)
其中Z1为O、NR1或S,D1为C1-C10-亚烷基或一个化学键,
与通式(V)的化合物反应
Y1-D2-E (V)
其中Y1与上述定义一致,D2为C1-C10-亚烷基,D1和D2一起含
有3到10个碳原子;或者c)使通式(VI)的化合物
L-Y1 (VI)
其中Y1与上述定义一致;
与通式(VII)的化合物反应
H-Z1-D-E (VII)
其中Z1与上述定义一致;
或者d)使式(VIII)的化合物NC-D-E (VIII)转化为式(IX)的化合物然后再将其与二羰基化物按已知方法进行反应;e)按照例如以下文献Albright,Tetrahedron,1983,39,3207或D.Seebach,Synthesis 1969,17和1979,19或H Stetter,Angew.Chem.Int.Ed.1976,15,639或Van Niel等,Tetrahedron 1989,45,7643Martin等,Synthesis 1979,633,介绍,用文献已知试剂如1,3-丙二硫醇、氰化钾/水、TMSCN(三甲基甲硅烷基氰化物)或氰化钾/吗啉,使式(X)化合物进行“极反转”(反转极性)获得产物(Xa)(例如1,3-丙烷二硫醇)然后用以下通式(XI)的化合物延长分子链
Y1-D3-E (XI)其中Y1的含义同上,D3为可含有基团Z的C3-C9-亚烷基,去保护或还原后,获得下式(Ia)化合物:
T-Z3-D2-E (Ia)其中Z3为CO或亚甲基,Z3和D2总计含有4-10个碳原子;或者g)利用类似的常规方法,例如Houben-Weyl“Methoden derOrganischen Chemie”[Methods of Organic Chemistryl,第四版,Thieme Verlag Stuttgart,Volume V/lb p.383 ff或Vol,v/1c p.575ff.中介绍的方法,将式(X)的化合物与通式(XII)化合物反应
Y3-D-E (XII)其中Y3为正膦或膦酸酯。
其中Y2为OH、OC1-C4-烷基、Cl,或者Y2与CO一起为活化酯基,
D4为可含有基团Z的C0-C9-亚烷基,
与式(XIV)化合物反应,
Z2-D-E (XIV)
其中Z2为OH或NR7。
式III化合物是制备式V、VII和VIII化合物的原料化合物。
式IIIa化合物
H-B-G (IIIa)可用例如J.A.Kiristy等,J.Med.Chem.1978,21,1303或C.B.Pollard,J.Am.Chem.Soc.1934,56,2199介绍的标准方法制备,或用下面的方法制备:a)使下述两种化合物按照已知方法进行反应:通式(XV)化合物HB3 (XV)其中B3为,Q为H或常规氨基保护基团如丁氧基羰基、苄基或甲基;通式(XVI)化合物Y4-G (XVI)其中Y4为B(OH)2、SnBu3、三氟甲磺酰氧基,或者与Y1的定义一致;或者b)根据例如S.Buchwald等,Angew.Chem.1995,107,1456或J.F.Hartweg等,Tertrahedron Lett 1995,36,3604或J.K..Stille等,Angew.Chem.1986,98,504或Pereyre M.等,“Tin in Organic Synthesis,Butterworth 1987中介绍的已知方法,使以下两种化合物进行反应:通式(XVII)化合物Q-B4 (XVII)其中B4为而Y4和Q与上述定义一致;以及通式(XVIII)化合物Y5-G (XVIII)其中如果Y4为卤素或三氟甲基磺酰氧基,则Y4为硼衍生物例如B(OH)2或含金属的离去基团,举例来说如SnR3(R=丁基或苯基)或卤化锌;或者如果Y4为硼衍生物例如B(OH)2或含金属的离去基团,举例来说如SnR3(R=丁基或苯基)或卤化锌,则Y5为卤素或三氟甲基磺酰氧基;或者c)将通式(XIX)的化合物与化合物M-G反应,其中M为一种金属,例如Li、MgY4,而Y6为溴、氯或碘。M-G可按照文献已知方法获得。B型化合物要么是已知的化合物,要么可以按照类似的已知方法制备,例如:1,4-和1,5-二氮杂环烷烃类:L.Brjeson等Acta Chem.Scand.1991,45,621Majahrzah et al Acta Pol.Pharm.,1975,32,1451,4-二氮杂环辛-6-烯类:W.Schroth等Z.Chem.1969,9,143
1-氮杂环辛酮类:
N.J.Leonard等J.Org.Chem.1 964,34,1066
1-氮杂环庚酮类:
A.Yokoo等Bull Chem.Soc.Jpn.1956,29,631。L与G型化合物要么是已知的化合物,要么可以根据例如下述文
献介绍的已知方法制备:A.R/.Katritzky,CW.Ree(编著)
“Comprehensive Heterocyclic Chemistry”,Pergamon Press,或
“The Chemisry of Heterocyclic Compounds”,J.Wiley&Sons
Inc.NY以及其中引用的参考文献或以上引用的专利文献。
制备通式(Ib)化合物
L1a-D-E2 (Ib)的方法是:a)在类似于例如J.Org.Chem.1986,50,1927或WO 92/20655介绍的文献已知方法的还原条件下,使通式(XX)化合物
与通式(XXIV)化合物反应
L1a-D-Z4H (XXIV)其中Z4为NR11,R11与上述定义一致。(XXIV)型化合物可如下合成:使式(II)化合物经Gabriel合成反应得到相应的胺(XXV)L-D-NH2 (XXV)然后将它先与R11连接(用相应的醛或在碱存在下的烷基化作用),
然后按照例如J.Org.Chem.1986,50,1927介绍的方法,与E2
进行还原性胺化作用。通式(XXV)化合物也可以如下获得:将式(II)化合物与叠氮化物如
叠氮化钠反应,然后按照例如H.Staudinger,Helv.Chim.Acta
1985,2,635或R.Carrie,Bull.Chem.Soc.Fr.1985,815介绍的
方法进行还原反应。式(XXII)和(XXIII)化合物要么是文献中已知的化合物,要么可以
用例如以下文献介绍的已知方法制备:
A.van Vliet等J.Med.Chem.1996,39,4233
M.Langlois Bioorg.Med.Chem.Lett.1993,3,2035
U.Hacksell J.Med, Chem.1993,36,4221
或WO 93/08799或WO 95/04713。假如E2为通式(XXVI)基团其中R8、R9、R10、X3的含义同上,则相应的胺可按照文献例如S.Smith等,Bioorg.Med.Chem.Lett.1998,8,2859;WO 97/47602或WO 920655或J.Med.Chem.1987,30,2111和2208中介绍的方法制备。式(IV)化合物要么是已知的化合物,要么可以根据例如以下文献介绍的已知方法制备:A.R.Katrizky,C.W.Rees(编著)“ComprehensiveHeterocycyclic Chemistry”,Pergamon Press,或“The Chemistry ofHeterocyclic Copounds”J.Wiley&sons Inc.NY以及其中引用的参考文献或S.Kubota等Chem.Pharm.Bull 1975,23,955或Vosilevskii等Izv.Akad.Nauk.SSSR Ser.Khim 1975,23,955。
下面的实施例用于描述本发明而非限制本发明。
实施例1
4’-乙酰基联苯基-4-羧酸N-(4-(4-(2-甲氧苯基)哌嗪-1-基)丁-1-基)酰胺
实施例2
噻吩基-2-羧酸N-(4-(4-(2,3-二氯代苯基)哌嗪-1-基)丁-1-基)酰胺
实施例3
3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)丁-2-基巯基)-4-甲基-5-甲氨基-1,2,4-(4H)-三唑
实施例4
3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)2-亚甲基丙-1-基-巯基)5-甲氨基-1,2,4-(4H)-三唑
实施例5
5-氨基-3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)高哌嗪-1-基)2-甲基-丁-2-烯-1-基巯基)-4-甲基-1,2,4-(4H)-三唑
实施例6
3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)丙-1-基巯基)-4-甲基-5-甲氨基-1,2,4-(4H)-三唑
实施例7
5-氨基-3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)2-甲基-丁-2-烯-1-基巯基)-4-甲基-1,2,4-(4H)-三唑
实施例8
5-氨基-3-(4-(4-(2-叔丁基-6-正丙基)嘧啶-4-基)哌嗪-1-基)2-甲基-丙-1-烯-1-基巯基)-4-甲基-1,2,4-(4H)-三唑
实施例9
5-氨基-3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)2-甲基-丁-2-基巯基)-4-甲基-1,2,4-(4H)-三唑
实施例10
2-(3-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)丙氧基-嘧啶-4-醇
实施例11
2-(3-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)丙基巯基嘧啶-4-醇的富马酸盐(fumarate)
实施例12
2-萘甲酸N-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)高哌嗪-1-基)丁-1-基酰胺
实施例13
5-氨基-3-(4-(4-(2-叔丁基-6-正丙基)嘧啶-4-基)哌嗪-1-基)-2-亚甲基基-丙-1-基巯基)-4-甲基-1,2,4-(4H)-三唑
实施例14
3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)丙-1-基巯基-5-(2,5-二甲基呋喃-3-基)4-甲基-1,2,4-(4H)-三唑
实施例15
(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)高哌嗪-1-基)丙-1-基巯基-4-甲基-5-(4-甲基吡唑-5-基)1,2,4-(4H)-三唑
实施例16
4-甲基-5-苯基-1,2,4-(4H)-三唑-3-羧酸N-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)高哌嗪-1-基)丁-1-基-酰胺
实施例17
5-氨基-2-(8-(4-(3-氰基苯基)哌嗪-1-基)辛基-1-基-巯基)-1,3,4-噻二唑
实施例18
2-(3-(5-(3-三氟甲基苯基)-1,5-二氮芳辛-1-基)-丙基-巯基)嘧啶-4-醇
实施例19
3-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)-丁-1-基嘧啶-4-醇
实施例20
4-甲氧基苯甲酸N-(4-(4-(2-叔丁基-6-三氟甲基)-嘧啶-4-基)高哌嗪-1-基)丁-1-基酰胺
实施例21
1-苯并噻吩-2-羧酸N-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)哌嗪-1-基)丁-1-基酰胺
实施例22
5-甲氧基苯并呋喃-2-羧酸N-(4-(4-(2-叔丁基-6-三氟甲基)嘧啶-4-基)高哌嗪-1-基)丁-1-基酰胺
实施例23
(E)-N-({2-[(7-氰基-3,4-二氢-2(1H)-异喹啉基)甲基]-环丙基}甲基)-3-(1H-吲哚-5-基)-2-丙烯酰胺
实施例24
三氟甲磺酸2-(4-{[(E)-3-(1H-吲哚-5-基)-2-丙烯酰基]氨基}丁基)-1,2,3,4-四氢-7-异喹啉酯
令人惊奇的是,使用这种多巴胺D3受体配体制备的控制肾功能失调的药物,特别能够改善过滤功能性病理生理学失调。
用糖尿病性肾病实验动物模型研究了多巴胺D3受体拮抗剂的作用。给予大鼠链脲菌素而产生糖尿病,在14天内出现显著肾小球超滤。假如用多巴胺D3受体拮抗剂亚慢性地治疗以该方法诱发产生糖尿病的大鼠,则不会发生糖尿病性超滤。
多巴胺D3受体配体还可以与其它活性化合物组合用于生产治疗上述综合征的药物。ACE抑制剂如群多普利和AT1拮抗剂如氯沙坦尤其适合这种组合。此外,也可以与钙拮抗剂或β-阻滞剂组合。方法
将60mg/kg溶解于柠檬酸盐缓冲液(21mg柠檬酸/ml重蒸馏水)的链脲菌素腹膜内注射入180-200g体重的雄性Sprague-Dawley大鼠体内。如果24小时后晚上静脉血葡萄糖浓度至少为180mg/dl,则认为成功诱发了糖尿病。糖尿病大鼠的血糖值为350-450mg/dl。因此没有必要进行胰岛素替代治疗。实验大鼠体重每天增加约5g。将相同量的柠檬酸缓冲溶液经腹膜注射入非糖尿病的时间对照大鼠体(CON)内。它们的血糖值为90-1120mg/dl。
在确定成功诱发糖尿病后,使大鼠在标准笼内适应标准饲料(Altromin 1320),自来水任意饮用。经不同的药物治疗(通过饮水给药),形成下面四组实验:
CON(1) 没有外加治疗措施的非糖尿病动物(时间对照)
DM-VHC(2) 没有外加治疗措施的糖尿病动物(糖尿病对照)
DM-SUL(3) 用舒必利治疗的糖尿病动物(25ml/kg/d)
DM-D3(4) 用D3-A治疗的糖尿病动物(D3-A:根据实例(7)的D3受体拮抗剂(5mg/kg/d);D3-A2:根据实例(11)的D3受体拮抗剂)。
记录每天吸收的液体量。每三天检测一次实验动物的体重及血糖浓度。在十二天后,将实验动物置于代谢笼进行二十四小时尿液收集。根据Lowry介绍的标准方法测定尿液中的蛋白质浓度。为此,使样品与1M的NaOH温育后,用福林氏试剂(苯酚-Ciocalteu’s)引发颜色反应,用光度计测定颜色强度。用白蛋白特异性放射免疫测定(RIA)测定尿液白蛋白浓度。应用Biermann的试剂盒(KHAD2:白蛋白放射免疫测定),它用抗人类血清白蛋白的多克隆抗体(山羊)和125I-标记的人类血清白蛋白作为示踪剂。14-16天后,用硫喷妥钠(80mg/kg)麻醉实验动物并用聚乙烯导尿管进行颈静脉、颈动脉以及膀胱插管。通过3H-菊粉肾脏廓清率测定肾小球滤过率(GFR)。此外在实验期间记录其平均动脉血压(MAP)和心率(HR)。在廓清率实验结束时,切除肾脏并进行组织病理学检查。实验结果
对清醒动物收集的二十四小时尿液进行检测,如果与时间对照大鼠相比,没有治疗的糖尿病动物尿液存在显著蛋白尿(proteinuria)(133与46mg/d)和更显著的白蛋白尿(albuminuria)(118与23μg/d),说明其肾小球过滤屏障受损。用舒必利治疗的糖尿病动物中,这种病理性白蛋白尿只有轻微降低(101μg/d)而蛋白尿甚至进一步加重(178mg/d)。与此相反,用根据实例7的D3-A治疗的糖尿病动物,不但蛋白尿减轻(113mg/d),而且完全抑制了白蛋白尿,只有18μg/d。
舒必利和D3-A1的选择性见WO 96/02520实施例42介绍。
在廓清率研究中,与时间对照动物相比,未治疗糖尿病麻醉动物(2)的肾小球滤过率显著增加(1.10与0.83ml/min),说明存在糖尿病性肾小球超滤。舒必利和D3-A治疗的糖尿病动物((3)和(4)的糖尿病性超滤均得到了抑制,几乎为正常的GFR(分别为0.71和0.83ml/min)。
与健康的时间对照动物(1)相比,没有治疗的糖尿病动物(2)除了整个肾脏肥大性增大外,组织病理学研究显示其肾小球显著增大(表示为每20个显微镜检测区的平均值)。在用舒必利治疗的糖尿病动物(3)中也观察到类似的肾小球肥大,但是用D3-A1治疗的糖尿病动物(4)却没有这样的肾小球肥大。
成年非糖尿病大鼠的肾脏正常湿重为0.9±0.1g/100g体重。糖尿病大鼠(DM-VHC)的肾脏湿重为1.1±0.04g/100g体重,说明为初期肾脏肥大。用D3-A2治疗后,肾脏湿重恢复正常,为0.96±0.03g/100g体重。
总之,这些在糖尿病活体模型发现的数据显示:用多巴胺D2受体药理学抑制剂(舒必利)和多巴胺D3受体药理学抑制剂进行亚慢性治疗,使糖尿病性肾病病程中的肾脏血液动力变化显著减轻。
用D3-A2(30mg/kg体重/天)进行亚慢性治疗明显减轻肾小球超滤以及糖尿病性肾脏超灌注。肾脏初期肥大也显著减轻。
此外,对各治疗组进行比较表明,多巴胺D3受体拮抗剂D3-A1和D3-A2消除糖尿病性肾病发生的结构性减少性(eliminated)肾内变化,而多巴胺D2受体拮抗剂舒必利没有此作用。在功能上,这种区别还表现为多巴胺D3受体拮抗剂D3-A显著减少病理性蛋白质和白蛋白排泄,而多巴胺D2受体拮抗剂没有此作用,病理性蛋白质和白蛋白排泄被认为是肾功能受损加重的重要标志。总而言之,研究结果清楚表明,给予多巴胺D3受体拮抗剂例如D3-A可有利地治疗糖尿病性肾病。
Claims (10)
1.多巴胺D3受体配体在生产治疗肾功能紊乱的药物中的应用。
2.权利要求1要求保护的用途,其中所用的受体配体是多巴胺D3受体拮抗剂。
3.权利要求1要求保护的用途,该用途为用于生产治疗肾小球超滤性肾功能紊乱的药物的用途。
4.权利要求1或2要求保护的用途,该用途为用于生产治疗糖尿病引起的肾功能紊乱的药物的用途。
5.权利要求1或2要求保护的用途,该用途为用于生产治疗非肾性高血压引起的肾功能紊乱的药物的用途。
6.权利要求1或2要求保护的用途,该用途为用于生产治疗肾小球性肾炎引起的肾功能紊乱的药物的用途。
7.权利要求1或2要求保护的用途,该用途为用于生产治疗上行性泌尿道感染引起的肾功能紊乱的药物的用途。
8.权利要求1或2要求保护的用途,该用途为用于生产治疗镰状细胞性贫血引起的肾功能紊乱的药物的用途。
9.权利要求1或2要求保护的用途,该用途为用于生产治疗单侧肾切除手术后代偿性肥大引起的肾功能紊乱的药物的用途。
10.权利要求1或2要求保护的用途,该用途为用于生产治疗肾小球膜机能障碍引起的肾功能紊乱的药物的用途。
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PCT/EP2000/003865 WO2000067847A2 (de) | 1999-05-07 | 2000-04-28 | Verwendung von dopamin-d3-rezeptorliganden zur herstellung von arzneimittel für die behandlung von nierenfunktionsstörungen |
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WO2002078697A1 (en) * | 2001-03-29 | 2002-10-10 | Smithkline Beecham Corporation | Compounds and methods |
DE10131543A1 (de) * | 2001-06-29 | 2003-01-16 | Abbott Lab | Pyrimidinoxyalkylpiperazine und ihre therapeutische Verwendung |
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