CN1326441A - 4-芳酰基-哌啶-ccr-3受体拮抗剂ⅲ - Google Patents
4-芳酰基-哌啶-ccr-3受体拮抗剂ⅲ Download PDFInfo
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- CN1326441A CN1326441A CN99813178A CN99813178A CN1326441A CN 1326441 A CN1326441 A CN 1326441A CN 99813178 A CN99813178 A CN 99813178A CN 99813178 A CN99813178 A CN 99813178A CN 1326441 A CN1326441 A CN 1326441A
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- Prior art keywords
- phenyl
- amino
- compound
- alkyl
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- 229940044551 receptor antagonist Drugs 0.000 title abstract description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- 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]
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及作为CCR-3受体拮抗剂的某些化学式(Ⅰ)的哌啶季盐,含有它们的药物组合物,其应用方法,及制备这些化合物的方法。
Description
本发明涉及某些作为CCR-3受体拮抗剂的4-芳酰基哌啶衍生物,含有这些衍生物的药物组合物,其应用方法,及制备这些化合物的方法。
组织嗜酸粒细胞增多是许多病理现象,例如哮喘,鼻炎,湿疹和寄生物感染病的特征(见Bousquet,J.等,N.Eng.,J.Med.,323:1033-1039(1990)和Kay,A.B.和Corrigan.C.J.,Br.Med.Bull.,48:51-64(1992))。发生哮喘时,嗜酸细胞积聚并被活化,导致对支气管上皮细胞的破坏,和对缩肌介质的过强响应。已知化学增活现象,例如RANTES,eotaxin和MCP-3可活化嗜酸细胞(见Baggiolini,M.和Dahinden,C.A.,Immunol.Today.,15:127-133(1994),Rot,A.M.等,J.Exp.Med.176,1489-1495(1992)和Ponath.P.D.等,J.Clin.Invest.,97卷,#3,604-612(1996))。然而,与还引起其它白细胞类型迁移的RANTES和MCP-3不同,eotaxin选择趋化嗜酸细胞(见Griffith-Johnson,D.A等,Biochem.Biophy.Res.Commun.,197:1167(1993)和Jose,P.J.等,Biochem.Biophy.Res.Commun.,207,788(1994))。无论是采取皮内或腹膜内注射,或气雾剂吸入的方式,在eotaxin给药的地方都可以观察到特殊的嗜酸细胞积聚现象((见Griffith-Johnson,D.A.等,Biochem.Biophy.Res.Commun.,197:1167(1993);Jose,P.J.等,J.Exp.Med.,179,881-887(1994);Rothenberg,M.E.等,J.Exp.Med.,181,1211(1995)和Ponath.P.D.,J.Clin.invest.,97卷,#3,604-612(1996))。
糖皮质激素,例如地塞米松,甲基强的松龙和氢化可的松,已被用于治疗多种与嗜酸细胞有关的疾病,包括支气管哮喘(见R.P.Schleimer等,Am.Rev.Respir.Dis.,141,559(1990))。据信,糖皮质激素抑制了在这些疾病中IL-5,IL-3调节的嗜酸细胞幸存者。然而,长期使用糖皮质激素会产生副作用,例如青光眼,骨质疏松症和患者发育延缓现象(见Hanania N.A.等,J.Allergy and Clin Immunol.,96卷,571-579(1995)和Saha M.T.等,ActaPaediatrica,86卷,#2,138-142(1997))。因此需要一种治疗与嗜酸细胞有关的疾病的可作为选择之一的方法,而不会引起这些不希望的副作用。
最近,CCR-3受体被认为是嗜酸细胞用于对eotaxin,RANTES和MCP-3响应的主要趋化因子受体。当被植入老鼠的前β淋巴瘤线内时,CCR-3结合到eotaxin,RANTES和MCP-3上,并且赋予eotaxin,RANTES和MCP-3对这些细胞的趋向性响应(见Ponath.P.D.等,J.Exp.Med.,183,2437-2448(1996))。CCR-3受体固定在嗜酸细胞,T-细胞(亚型Th-2),嗜碱细胞和肥大细胞的表面,并对eotaxin有高度选择性。研究表明,用抗-CCR-3 mAb对嗜酸细胞进行预处理,可完全抑制嗜酸细胞对eotaxin,RANTES和MCP-3的趋化作用((见Heath H.等,J.Clin.invest.,99卷,#2,178-184(1997))。
使CCR-3受体结合RANTES,MCP-3和eotaxin的能力受阻,并由此阻止嗜酸细胞的补充,可治疗嗜酸细胞作为媒介的炎症。
因此,本发明涉及新型的4-芳酰基哌啶类似物,其可抑制eotaxin与CCR-3受体的结合,从而提供一种治疗嗜酸细胞引发的疾病,例如哮喘的方法。
Ar1和Ar2彼此独立地为芳基或杂芳基;
R和R1彼此独立地为氢或烷基;
R2为3~6个碳原子的烷基,杂烷基,芳基,芳烷基,杂芳基,杂芳烷基,
杂环烷基,-(亚烷基)-C(O)-Z,其中Z为烷基,卤代烷基,烷氧基,
卤代烷氧基,羟基,氨基,单取代或双取代氨基,芳基,芳烷基,
芳氧基,芳烷氧基,杂芳基,杂芳氧基,或杂芳烷氧基;
X选自下列基团:
(a)-C(O)N(R3)-;
(b)-N(R4)C(O)N(R3)-;
(c)-N(R4)C(S)N(R3)-;
(d)-SO2N(R3)-;或
(e)-N(R4)SO2N(R3)-;
其中:
R3和R4彼此独立地为氢,烷基,芳烷基,杂芳烷基,杂环烷基,
杂烷基,或-(亚烷基)-C(O)-Z,其中Z为烷基,卤代烷基,烷氧基,
卤代烷氧基,羟基,氨基,单取代或双取代氨基,芳基,芳烷基,
芳氧基,芳烷氧基,杂芳基,杂芳氧基或杂芳烷氧基;和
Y为单键或具有1~3个碳原子的亚烷基;及
前体药物,单独的异构体,异构体混合物,及其适合药用的盐。
第二方面,本发明提供药物组合物,该组合物含有治疗有效量的化学式(Ⅰ)的化合物或其适合药用的盐,及适合药用的赋形剂。
第三方面,本发明提供一种通过服用CCR-3受体拮抗剂,包括服用治疗有效量的化学式(Ⅰ)的化合物或其适合药用的盐,来治疗哺乳动物疾病的方法。所述疾病包括例如哮喘的呼吸疾病。
第四方面,本发明提供一种制备化学式(Ⅰ)的化合物的方法。
除非特别指出,在说明书和权利要求书中使用的下列术语的含义如下:
“烷基”是指含有1~6个碳原子的线性饱和单价烃基,或含有3~6个碳原子的支化的饱和单价烃基,例如甲基,乙基,丙基,2-丙基,戊基等。
“烯基”是指含有2~6个碳原子的线性不饱和单价烃基,或含有3~6个碳原子的支化的不饱和单价烃基,例如乙烯基,丙烯基,2-丙烯基,戊烯基等。
“亚烷基”是指含有1~6个碳原子的线性饱和二价烃基,或含有3~6个碳原子的支化的饱和二价烃基,例如亚甲基,亚乙基,亚丙基,2-甲基亚丙基,亚戊基等。
“酰氧基”是指-OC(O)R基,其中R为烷基或任选取代的苯基,例如乙酰氧基,苯甲酰氧基等。
“卤素”是指氟,氯,溴或碘,优选氟和氯。
“卤代烷基”是指被一个或多个相同或不同的卤原子取代的烷基,例如-CH2Cl,-CF3,-CH2CF3,-CH2CCl3等。
“环烷基”是指含有3~6个环碳原子的饱和的单价环状烃基,例如环丙基,环己基等。
“单取代的氨基”是指-NHR基,其中R为烷基,杂烷基,卤代烷基,或任选取代的苯基,例如甲基氨基,(1-甲基乙基)氨基,苯基氨基等。
“双取代的氨基”是指-NRR′基,其中R和R′各自独立地为烷基,杂烷基,卤代烷基,或任选取代的苯基。典型的实例包括二甲基氨基,甲基乙基氨基,二(1-甲基乙基)-氨基等,但不仅限于此。
“芳基”是指含有6~10个环原子的单价单环或双环芳香烃基,并且各自独立地被一个或多个取代基任选取代,优选一个,两个或三个取代基,所述取代基选自烷基,卤代烷基,烯基,杂烷基,卤素,氰基,硝基,酰氧基,烷氧基,任选取代的苯基,杂芳基,杂芳烷基,氨基,单取代的氨基,双取代的氨基,-OR[其中R为氢,卤代烷基,任选取代的苯基,杂芳基或杂芳烷基],-S(O)nR([其中n为0~2的整数,并且R为氢,烷基,卤代烷基,任选取代的苯基,杂芳基,杂芳烷基,氨基,单取代或双取代氨基),-NRSO2R′(其中R为氢或烷基,并且R′为烷基,氨基,单取代或双取代氨基),-NHC(O)R(其中R为氢,烷基,杂烷基,卤代烷基或任选取代的苯基),-C(O)R(其中R为氢,烷基,杂烷基,卤代烷基或任选取代的苯基),-COOR(其中R为氢,烷基,任选取代的苯基,杂芳基或杂芳烷基),-(亚烷基)COOR(其中R为氢,烷基,任选取代的苯基,杂芳基或杂芳烷基),亚甲基二氧基,1,2-亚乙基二氧基,-CONR′R″或-(亚烷基)CONR′R″(其中R′和R″各自独立地选自氢,烷基,卤代烷基,任选取代的苯基,杂芳基和杂芳烷基)。更具体而言,术语芳基包括但不局限于苯基,1-萘基,2-萘基,及其衍生物。
“任选取代的苯基”是指独立地被一个,两个或三个取代基任选取代的苯基,所述取代基选自烷基,卤代烷基,卤素,硝基,氰基,-OR(其中R为氢或烷基),-NRR′(其中R和R′彼此独立地为氢或烷基),-COOR(其中R为氢或烷基)或-CONR′R″(其中R′和R″独立地选自氢或烷基)。
“杂芳基”是指含有5~10个环原子的单价单环或双环芳基,含有1个,两个,或三个选自N,O,或S的环杂原子,其余的环原子为C。所述芳基独立地被1个或多个取代基任选取代,优选被1个或两个取代基任选取代,所述取代基选自烷基,卤代烷基,杂烷基,卤素,氰基,硝基,酰氧基,任选取代的苯基,氨基,单取代或双取代氨基,-OR[其中R为氢,烷基,卤代烷基,或任选取代的苯基],-S(O)nR[其中n为0~2的整数,R为氢,烷基,卤代烷基,任选取代的苯基,氨基,单取代或双取代的氨基],-NHC(O)R(其中R为氢,烷基,杂烷基,卤代烷基或任选取代的苯基),-C(O)R(其中R为氢,烷基,杂烷基,卤代烷基或任选取代的苯基),-COOR(其中R为氢,烷基,或任选取代的苯基),-(亚烷基)-COOR(其中R为氢,烷基或任选取代的苯基),亚甲基二氧基,1,2-亚乙基二氧基,-CONR′R″或-(亚烷基)-CONR′R″(其中R′和R″各自独立地选自氢,烷基,卤代烷基,或任选取代的苯基)。更具体而言,术语杂芳基包括但不仅限于:吡啶基,吡咯基,噻吩基,吡唑基,噻唑基,咪唑基,嘧啶基,噻二唑基,吲哚基,咔唑基,氮杂吲哚基,苯并呋喃基,苯并三唑基,苯并异噁唑基,嘌呤基,喹啉基,苯并吡喃基,及其衍生物。
“杂环”或“杂环基”是指含有3~8个环原子的饱和或不饱和环基,其中有一个或两个环原子是选自N,O,或S(O)n(其中n为0~2的整数)的杂原子。所述杂环可以独立地被一个,两个或三个取代基任选取代,所述取代基选自烷基,卤代烷基,芳基,芳烷基,杂芳基,杂芳烷基,卤素,氰基,酰基,氨基,单取代的氨基,双取代的氨基,-COOR(其中R为氢或烷基),-XR(其中X为O或S(O)n,其中n为0~2的整数,并且R为氢,烷基,卤代烷基,环烷基,芳烷基,芳基,杂芳基或杂芳烷基)或-CONR′R″(其中R′和R″各自独立地选自氢或烷基)。典型的实例包括但不仅限于:四氢吡喃基,哌啶子基,哌嗪基,吗啉代,1-(4-氯代苯基)哌啶子基等。
“杂烷基”是指如上所定义的烷基,环烷基,或环烷基烷基,带有含有选自N,O,S(O)n(其中n为0~2的整数)的杂原子的取代基。典型的取代基包括-NRaRb,-ORa或-S(O)nRc,其中n为0~2的整数,R2为氢,烷基,卤代烷基,任选取代的苯基,吡啶基,-COR(其中R为烷基或烷氧基)或氨基烷基,Rb为氢,烷基,-SO2R(其中R为烷基或羟烷基),-SO2NRR′(其中R和R′彼此独立地为氢或烷基),-CONR′R″(其中R′和R″各自独立地选自氢或烷基),Rc为氢,烷基,任选取代的苯基,氨基,单取代或双取代的氨基。典型实例包括但不仅限于:2-甲氧基乙基,2-羟基乙基,3-羟基丙基,2-氨基乙基,3-氨基丙基,2-甲基氨基乙基,2-二甲基氨基乙基,苄氧基甲基等。
“羟基烷基”是指被一个或两个羟基取代的,含有2~6个碳原子的线性单价烃基或含有三或六个碳原子的支化的单价烃基,前提是如果存在两个羟基,它们不在同一个碳原子上。典型实例包括但不仅限于:2-羟基乙基,2-羟基丙基,3-羟基丙基,1-(羟基甲基)-2-甲基丙基,2-羟基丁基,3-羟基丁基,4-羟基丁基,2,3-二羟基丙基,1-(羟基甲基)-2-羟基乙基,2,3-二羟基丁基,3,4-二羟基丁基和2-(羟基甲基)-3-羟基丙基,优选2-羟基乙基,2,3-二羟基丙基,和1-(羟基甲基)-2-羟基乙基。
“氨基烷基”是指如上所定义的烷基,带有一个或两个氨基,例如,2-氨基乙基,2-氨基丙基,3-氨基丙基,1-(氨基甲基)-2-甲基丙基等。
“芳烷基”是指-RaRb基团,其中Ra为如上所定义的亚烷基,Rb为如上所定义的芳基,例如,苄基,苯乙基,3-(3-氯代苯基)-2-甲基戊基等。
“杂芳烷基”是指-RaRb基团,其中Ra为如上所定义的亚烷基,Rb为如上所定义的杂芳基,例如,吡啶-3-基甲基,3-(苯并呋喃-2-基)丙基等。
“杂环烷基”是指-RaRb基团,其中Ra为如上所定义的亚烷基,Rb为如上所定义的杂环基,例如,四氢吡喃-2-基甲基,4-甲基哌嗪-1-基乙基等。
“烷氧基”,“卤代烷氧基”,“芳氧基”,“杂芳氧基”,“芳烷氧基”或“杂芳烷氧基”是指-OR基团,其中R分别为如上所定义的烷基,卤代烷基,芳基,杂芳基,芳烷基,或杂芳烷基,例如,甲氧基,苯氧基,吡啶-2-基氧基,苄氧基等。
“任选的”或“任选地”是指随后描述的事件或情况可以发生,但不是必需发生,并且该描述中包括其中的事件或情况发生的实例,和其中的事件或情况没有发生的实例。例如,被烷基任选单取代或双取代的杂环基,是指烷基可以存在,但不是必需存在,并且该描述包括其中杂环基被烷基单取代或双取代的情形,和杂环基没有被烷基取代的情形。
术语“异构体”是指分子式相同,而特性不同,或其原子联接顺序不同,或其原子在空间的排列不同的化合物。原子在空间的排列不同的异构体称为“立体异构体”。彼此不为镜像的立体异构体称为“非对映异构体”,而彼此为非重叠镜像的立体异构体称为“对映体”。当化合物具有一个不对称中心时,例如,当碳原子与四个不同的基团相连时,有可能形成一对对映体。对映体可用其不对称中心的绝对构型表征,并且用Cahn和PrelogR-和S-顺序规则描述,或由其中的分子使偏振光平面旋转的方式进行表征,并指定为右旋或左旋(即,分别指定为(+)或(-)异构体)。手性化合物可以以单一的对映体形式或对映体混合物的形式存在。含有等比例的对映体的混合物,称作“外消旋混合物”。
本发明的化合物可以具有一个或多个不对称中心;因此制备来出的这样的化合物可以是单一的(R)-或(S)-立体异构体或其混合物。例如,如果在化学式(Ⅰ)的化合物中R1和R2取代基不同,那么它们所连接的碳原子为不对称中心,并且化学式(Ⅰ)的化合物可以以(R)-或(S)-立体异构体的形式存在。除非另外指出,在说明书和权利要求中对特定化合物的描述或命名,意味着既包括单一的对映体,也包括其混合物,该混合物可以是外消旋的或不是外消旋的。立体化学的测定方法和立体异构体的分离方法,在本领域中是众所周知的(见Advanced Organic Chemistry,第四版,J.March,JohnWiley and Sons,New York,1992,第四章)。
“适合药用的赋形剂”是指在制备药物组合物中有用的赋形剂,其通常是安全的,无毒的,并且既不是生物学方面也不是其它方面所不希望存在的,包括既适合兽类使用,也适合人类药用的赋形剂。在说明书和权利要求书中使用的“适合药用的赋形剂”,既包括一种,也包括一种以上的这种赋形剂。
“适合药用的抗衡离子”是指带有与其相伴的物质相反电荷的离子,并且其是适合药用的。典型的实例包括但不仅限于:氯化物,溴化物,碘化物,甲基磺酸盐,对甲苯磺酸盐,三氟乙酸盐,乙酸盐等。
化合物的“适合药用的盐”是指一种盐,它是适合药用的,并且具有所需要的母体化合物的药理学活性。这些盐包括:
(1)酸加成盐,是与无机酸,例如盐酸,氢溴酸,硫酸,硝酸,磷酸等形成的;或是与有机酸,例如乙酸,丙酸,己酸,环戊基丙酸,乙醇酸,丙酮酸,乳酸,丙二酸,琥珀酸,苹果酸,马来酸,富马酸,酒石酸,柠檬酸,苯甲酸,3-(4-羟基苯甲酰基)-苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,1,2-二磺酸乙烷,2-羟基乙磺酸,苯磺酸,4-氯代苯磺酸,2-萘磺酸,4-甲苯磺酸,樟脑磺酸,4-甲基二环[2.2.2]八-2-烯-1-羧酸,葡庚糖酸,4,4′-亚甲基双(3-羟基-2-烯-1-羧酸),3-苯基丙酸,三甲基乙酸,三级丁基乙酸,月桂基硫酸,葡糖酸,谷氨酸,羟基萘甲酸,水杨酸,硬脂酸,粘康酸等形成的;或
(2)当在母体化合物中存在酸性质子时,用金属离子,例如碱金属离子,碱土金属离子,或铝离子取代所形成的盐;或用有机碱,例如乙醇胺,二乙醇胺,三乙醇胺,tromethamine,N-甲基葡糖胺等与其配位所形成的盐。
“离去基团”的含义如通常在有机合成化学中所使用的那样,即能被亲核试剂取代的原子或基团,包括卤素,烷基磺酰氧基,芳基磺酰氧基,酯,或氨基,例如氯,溴,碘,甲磺酰氧基,甲苯磺酰氧基,三氟代磺酰氧基,甲氧基,N,O-二甲基羟基-氨基等。
“前体药物”是指任何一种这样的化合物,当这种前体药物被患病的哺乳动物服用时,其在动物体内释放出有活性的化学式(Ⅰ)的母体药物。化学式(Ⅰ)的化合物的前体药物,可以通过对化学式(Ⅰ)的化合物中存在的官能团进行修饰来制备,所述的修饰部分可以在体内被切断而释放出母体化合物。前体药物包括化学式(Ⅰ)的化合物,其中化合物(Ⅰ)中的羟基,巯基或氨基可连接到任何在体内可断裂以分别再生成自由羟基,氨基,或巯基的基团上。前体药物的实例包括但不仅限于:化学式(Ⅰ)的化合物中羟基官能团的酯(例如,乙酸酯,甲酸酯,和苯甲酸酯衍生物),氨基甲酸酯(例如,N,N-二甲基氨基羰基)等。
疾病的“治疗”(treating or treatment)包括:
(1)预防疾病,即,使易受疾病感染,或倾向于转向疾病,但还没有经历或显示疾病症状的哺乳动物的疾病临床症状不再发展,
(2)抑制疾病,即,抑制或减轻疾病或其临床症状的发展,或
(3)缓解疾病,即,使疾病或其临床症状消退。
“治疗有效量”是指,当给哺乳动物服用以治疗疾病时,足以达到治疗疾病目的的化合物的量。“治疗有效量”依化合物,疾病及其患病的程度,和接受治疗的哺乳动物的年龄,体重等而变化。
本申请所使用的命名法一般是基于IUPAC推荐的方法,例如,
化学式(Ⅰ)的化合物,其中R和R1为氢,R2为2-丙基,Ar1为3,4,5-三甲氧基苯基,Ar2为3,4-二氯代苯基,Y为单键,并且X为-NHCONH-,命名为1-{1-[4-(3,4-二氯代苯甲酰基)哌啶-1-基甲基]-2-甲基丙基}-3-(3,4,5-三甲氧基苯基)脲。
化学式(I)的化合物,其中R和R1为氢,R2为2-丙基,Ar1为4-甲氧基苯基,Ar2为3,4-二氯代苯基,Y为单键,并且X为-CONH-,命名为N-{1-[4-(3,4-二氯代苯甲酰基)哌啶-1-基甲基]-2-甲基丙基}-4-甲氧基苯甲酰胺。本发明的典型化合物如下:Ⅰ.其中R=R1=氢;Y=单键;X=-C(O)NH-,并且其它基团定义如下的典型的化学式(Ⅰ)的化合物是:
Ⅱ.其中R=R1=氢;Y=单键;X=-NHC(O)NH-,并且其它基团定义如下的典型的化学式(Ⅰ)的化合物是:
CPD# | *C上的立体化学 | Ar1 | R2 | Ar2 | 质谱m/e | 熔点℃ |
1 | (RS) | 3,4-亚甲基二氧基苯基 | 2-丙基 | 3,4-二氯代苯基 | 491 | |
2 | (RS) | 4-甲基苯基 | 2-丙基 | 3,4-二氯代苯基 | 461 | 110-118 |
3 | (RS) | 4-甲氧基苯基 | 2-丙基 | 3,4-二氯代苯基 | 477 | |
4 | (RS) | 4-乙烯基苯基 | 2-丙基 | 4-氟代苯基 | 422 | |
5 | (RS) | 5-甲基噻吩-2-基 | 2-丙基 | 3,4-二氯代苯基 | 467 | |
6 | (RS) | 喹啉-3-基 | 2-丙基 | 3,4-二氯代苯基 | 498 | |
7 | (RS) | 4-乙酰基苯基 | 2-丙基 | 3,4-二氯代苯基 | 489 | |
8 | (RS) | 3,4-二氟代苯基 | 2-丙基 | 3,4-二氯代苯基 | 483 | |
9 | (RS) | 苯并呋喃-2-基 | 2-丙基 | 3,4-二氯代苯基 | 487 | |
10 | (RS) | 4-甲氧基苯基 | 2-丙基 | 4-氟代苯基 | 426 | |
11 | (RS) | 3,4-亚甲基二氧基苯基 | 2-丙基 | 4-氟代苯基 | 440 |
CPD# | *C上的立体化学 | Ar1 | R2 | Ar2 | 质谱m/e | 熔点℃ |
12 | (RS) | 4-乙酰基苯基 | 2-丙基 | 4-氟代苯基 | 438 | |
13 | (RS) | 3,4-二氟代苯基 | 2-丙基 | 4-氟代苯基 | 432 | |
14 | (RS) | 4-羟甲基苯基 | 2-丙基 | 4-氟代苯基 | 426 | |
15 | (RS) | 4-二甲基氨基苯基 | 2-丙基 | 4-氟代苯基 | 439 | |
16 | (RS) | 3,4-二甲基苯基 | 2-丙基 | 4-氟代苯基 | 424 | |
17 | (RS) | 4-甲基磺酰基苯基 | 2-丙基 | 4-氟代苯基 | ||
18 | (RS) | 喹啉-3-基 | 2-丙基 | 4-氟代苯基 | 447 | |
19 | (RS) | 4-甲基苯基 | 2-丙基 | 4-氟代苯基 | 123-128 | |
20 | (RS) | 4-三氟甲基苯基 | 2-丙基 | 4-氟代苯基 | 464 | |
21 | (RS) | 5-甲基噻吩-2-基 | 2-丙基 | 4-氟代苯基 | 416 | |
22 | (RS) | 苯并呋喃-2-基 | 2-丙基 | 4-氟代苯基 | 436 | |
23 | (RS) | 3-氨基-4-甲基苯基 | 2-丙基 | 4-氟代苯基 | 425 | |
24 | (RS) | 3-氟-4-甲基苯基 | 2-丙基 | 4-氟代苯基 | 428 | |
25 | (RS) | 吡啶-2-基 | 2-丙基 | 4-氟代苯基 | 397 | |
26 | (RS) | 3-溴代吡啶-5-基 | 2-丙基 | 4-氟代苯基 | ||
27 | (RS) | 4-氯代苯基 | 2-丙基 | 4-氟代苯基 | 125-135 | |
28 | (RS) | 4-甲基磺酰基苯基 | 2-丙基 | 3,4-二氯代苯基 | 525 | |
29 | (RS) | 3-氨基-4-甲基苯基 | 2-丙基 | 3,4-二氯代苯基 | 476 | |
30 | (RS) | 4-二甲基氨基苯基 | 2-丙基 | 3,4-二氯代苯基 | 490 | |
31 | (RS) | 吡啶-2-基 | 2-丙基 | 3,4-二氯代苯基 | 448 |
CPD# | *C上的立体化学 | Ar1 | R2 | Ar2 | 质谱m/e |
1 | (RS) | 3,4,5-三甲氧基苯基 | 2-丙基 | 3,4-二氯代苯基 | 552 |
2 | (RS) | 3,5-二甲氧基苯基 | 2-丙基 | 3,4-二氯代苯基 | 522 |
3 | (RS) | 3-甲氧基苯基 | 2-丙基 | 3,4-二氯代苯基 | 492 |
4 | (RS) | 2,5-二甲氧基苯基 | 2-丙基 | 3,4-二氯代苯基 | 522 |
5 | (RS) | 3-乙酰基苯基 | 2-丙基 | 3,4-二氯代苯基 | 504 |
6 | (RS) | 3-甲氧基苯基 | 2-丙基 | 4-氟代苯基 | 441 |
7 | (RS) | 2,5-二甲氧基苯基 | 2-丙基 | 4-氟代苯基 | 471 |
8 | (RS) | 3-乙酰基苯基 | 2-丙基 | 4-氟代苯基 | 453 |
9 | (RS) | 3,5-二甲氧基苯基 | 2-丙基 | 4-氟代苯基 | |
10 | (RS) | 3,4,5-三甲氧基苯基 | 2-丙基 | 4-氟代苯基 | 501 |
11 | (RS) | 3,4,5-三甲氧基苯基 | 2-丙基 | 苯基 | 483 |
R,R1为氢。(A)在优选的化合物组中,较优选的化合物组是这样一些化合物,其中:
(a)X为-C(O)NH-;并且
R2为含有3或4个碳原子的支化的亚烷基链,优选2-丙基或2,2-
二甲基乙基,或
(b)X为-C(O)NH-;并且
R2为杂烷基,优选1-羟基乙基,2-羟基乙基,或3-羟基丙基。
在这些优选和较优选的化合物组中,更优选的化合物组是这样一些化合物,其中:
(ⅰ) Y为单键;或
(ⅱ)Y为含有1个或2个碳原子的亚烷基链,优选亚甲基。
在这些优选,较优选和更优选的化合物组中,特别优选的化合物组是这样一些化合物,其中:
Ar1为杂芳基或芳基环,优选吡啶-2-基,吡啶-3-基,喹啉-3-基或5-甲基噻吩-2-基环,或被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,-COR(其中R为烷基),-SO2R(其中R为烷基,氨基,或单取代或双取代的氨基),亚甲基二氧基,羟基,卤素,酰基氨基,氨基,单取代或双取代氨基,-CONR′R″,-(亚烷基)-CONR′R″(其中R′和R″为氢或烷基),-COOR,-(亚烷基)-COOR(其中R为氢或烷基),或-NRSO2R′(其中R为氢或烷基,并且R′为烷基,氨基,单取代或双取代的氨基),更优选被1个,2个或3个取代基任选取代的苯环,所述取代基选自甲基,甲氧基,氟,氯,二甲基氨基,乙酰基,羟基,氨基,亚甲基二氧基,-SO2Me,2-乙酰基氨基乙基,2-[(R)-氨基-3-甲基丁酰基氨基]乙基,2-氨基乙基,氨基甲基,羟甲基,氨基羰基,-COOH,羧甲基,甲氧基羰基甲基,氨基羰基甲基,二甲基氨基羰基甲基,乙酰基氨基甲基,甲基磺酰基氨基,甲基磺酰基氨基甲基,二甲基氨基磺酰基氨基甲基,或二甲基氨基,最优选苯基,4-氯代苯基,3,4-二氟代苯基,4-甲基苯基,4-甲氧基苯基,4-羟基苯基,4-二甲基氨基苯基,4-氨基羰基苯基,4-二甲基氨基羰基苯基,4-乙酰基苯基,4-乙酰基氨基苯基,3,4-亚甲基二氧基苯基,4-甲基磺酰基苯基,4-[(2-乙酰基氨基)乙基]苯基,4-{2-[(R)-氨基-3-甲基丁酰基氨基]乙基}苯基,4-(2-氨基乙基)苯基,4-(氨基甲基)苯基,4-(羟甲基)苯基,2,5-二甲氧基苯基,3,5-二甲氧基苯基,3,4-二甲氧基苯基,3,4,5-三甲氧基苯基,4-氨基羰基甲基苯基,4-乙酰基氨基甲基苯基,4-甲基磺酰基氨基苯基,4-甲基磺酰基氨基甲基苯基,或4-氨基苯基;并且
Ar2为杂芳基或芳基环,优选1-乙酰基吲哚-3-基,3-甲基苯并噻吩-2-基,5-硝基噻吩-3-基,或被1个,2个,或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的氨基,更优选被1个或2个选自甲基,甲氧基,氯,氟,三氟甲基,或硝基的取代基取代的苯环,最优选4-氟代苯基,4-硝基苯基,4-三氟甲基苯基,4-氯代苯基,3,4-二氟代苯基,2,3-二氯代苯基,3-甲基-4-硝基苯基,3-氯-4-氟苯基,或3,4-二氯代苯基。(B)在组(Ⅰ)的化合物中,另一组更优选的化合物这样一些化合物,其中:
(a)X为-NHC(O)N(R3)-,其中R3为氢,烷基,或杂烷基,优选氢,甲基,2-羟基乙基,2-氨基乙基,或3-羟基丙基;并且
R2为含有3或4个碳原子的支化的亚烷基链,优选2-丙基或2,2-二甲基乙基;或
(b)X为-NHC(O)N(R3)-,其中R3为氢,烷基或杂烷基,优选氢,甲基,2-羟基乙基,2-氨基乙基,或3-羟基丙基;并且
R2为杂烷基,优选1-羟基乙基,2-羟基乙基,或3-羟基丙基。
在这些优选和较优选的化合物组中,更优选的化合物组是这样一些化合物,其中:
Y为单键。
在这些优选,较优选和更优选的化合物组中,特别优选的化合物组是这样一些化合物,其中:
Ar1为杂芳基或芳基环,优选吡啶-2-基,吡啶-3-基,喹啉-3-基或5-甲基噻吩-2-基环,或被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,-COR(其中R为烷基),-SO2R(其中R为烷基,氨基,或单取代或双取代的氨基),亚甲基二氧基,羟基,卤素,酰基氨基,氨基,单取代或双取代氨基,-CONR′R″,-(亚烷基)-CONR′R″(其中R′和R″为氢或烷基),-COOR,-(亚烷基)-COOR(其中R为氢或烷基),或-NRSO2R′(其中R为氢或烷基,并且R′为烷基,氨基,单取代或双取代的氨基),更优选被1个,2个或3个取代基任选取代的苯环,所述取代基选自甲基,甲氧基,氟,氯,二甲基氨基,乙酰基,乙酰氨基,羟基,氨基,亚甲基二氧基,-SO2Me,2-乙酰基氨基乙基,2-[(R)-氨基-3-甲基丁酰基氨基]乙基,2-氨基乙基,氨基甲基,羟甲基,氨基羰基,-COOH,羧甲基,甲氧基羰基甲基,氨基羰基甲基,二甲基氨基羰基甲基,乙酰基氨基甲基,甲基磺酰基氨基,甲基磺酰基氨基甲基,二甲基氨基磺酰基氨基甲基,或二甲基氨基,最优选苯基,3-甲氧基苯基,3-甲基磺酰基苯基,3-二甲基氨基苯基,3-乙酰基氨基苯基,3-乙酰基苯基,3-[(2-乙酰基氨基)乙基]苯基,3-氨基羰基苯基,3-羧基苯基,2,5-二甲氧基苯基,3,5-二甲氧基苯基,3,4-二甲氧基苯基,3,4,5-三甲氧基苯基,3-氨基羰基甲基苯基,3-乙酰基氨基甲基苯基,3-羧基甲基苯基,3-甲基磺酰基氨基苯基,3-甲基磺酰基氨基甲基苯基,或3-氨基苯基;并且
Ar2为杂芳基或芳基环,优选1-乙酰基吲哚-3-基,3-甲基苯并噻吩-2-基,5-硝基噻吩-3-基,或被1个,2个,或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的氨基,更优选被1个或2个选自甲基,甲氧基,氯,氟,三氟甲基,或硝基的取代基取代的苯环,最优选4-氟代苯基,3,4-二氟代苯基,4-硝基苯基,4-三氟甲基苯基,4-氯代苯基,2,3-二氯代苯基,3-甲基-4-硝基苯基,3-氯-4-氟苯基,或3,4-二氯代苯基。
或另外指出,下列本发明物质是优选的,即(C)化学式Ⅰ的化合物,其中R2为含有3或4个碳原子的支化烷基。1.C的化合物,其中:
R和R1为氢;并且
X为-C(O)N(R3)-,其中R3为氢,烷基或杂烷基。2. 1.的化合物,其中:
Ar1为杂芳环;并且Ar2为芳环。3. 1.的化合物,其中:
Ar1和AR2为芳基。4. 2.的化合物,其中:
X为-C(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。5. 4.的化合物,其中:
Ar1为吡啶-2-基,吡啶-3-基,喹啉-3-基,或5-甲基噻吩-2-基;并
且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的
氨基。6. 5.的化合物,其中:
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基,或4-氟代
苯基。7. 3.的化合物,其中:
X为-C(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。8. 7.的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
烷基,杂烷基,烷氧基,-COR(其中R为烷基),-SO2R(其中R为烷基,
氨基,或单取代或双取代的氨基),亚甲基二氧基,羟基,卤素,酰基
氨基,氨基,单取代或双取代氨基,-CONR′R″,-(亚烷基)-CONR′R″(其
中R′和R″为氢或烷基),-COOR,-(亚烷基)-COOR(其中R为氢或烷
基),或-NRSO2R′(其中R为氢或烷基,并且R′为烷基,氨基,单取代或
双取代的氨基);并且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的
氨基。9. 8.的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
甲基,甲氧基,氟,氯,二甲基氨基,乙酰基,羟基,氨基,亚甲基二
氧基,-SO2Me,2-乙酰基氨基乙基,2-[(R)-氨基-3-甲基丁酰基氨基]乙基,
2-氨基乙基,氨基甲基,羟基甲基,氨基羰基,二甲基氨基羰基,
-COOH,羧甲基,甲氧基羰基甲基,氨基羰基甲基,二甲基氨基羰基甲
基,乙酰基氨基甲基,甲基磺酰基氨基,甲基磺酰基氨基甲基,二甲
基氨基磺酰基氨基甲基,或二甲基氨基;并且
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基或4-氟代
苯基。10. 9.的化合物,其中:
Ar1为苯基,4-氯代苯基,3,4-二氟代苯基,4-甲基苯基,4-甲氧基苯
基,4-羟基苯基,4-二甲基氨基苯基,4-氨基羰基苯基,4-二甲基氨基羰
基苯基,4-乙酰基苯基,4-乙酰基氨基苯基,3,4-亚甲基二氧基苯基,4-
甲基磺酰基苯基,4-[(2-乙酰基氨基)乙基]苯基,4-{2-[(R)-氨基-3-甲基
丁酰基氨基]乙基}苯基,4-(2-氨基乙基)苯基,4-(氨基甲基)苯基,4-(羟
基甲基)苯基,2,5-二甲氧基苯基,3,5-二甲氧基苯基,3,4-二甲氧基苯基,
3,4,5-三甲氧基苯基,4-氨基羰基甲基苯基,4-乙酰基氨基甲基苯基,4-
甲基磺酰基氨基苯基,4-甲基磺酰基氨基甲基苯基,或4-氨基苯基。11.C的化合物,其中:
R和R1为氢;并且
X为-NHC(O)N(R3)-,其中R3为氢,烷基或杂烷基。12. 11.的化合物,其中:
Ar1为杂芳基环;并且
Ar2为芳基环。13. 11.的化合物,其中:Ar1和Ar2为芳基。14. 12.的化合物,其中:
X为-NHC(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。15. 14.的化合物,其中:
Ar1为吡啶-2-基,吡啶-3-基,喹啉-3-基,或5-甲基噻吩-2-基;并
且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的氨基。16. 15.的化合物,其中:
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基,或4-氟代
苯基。17. 13.的化合物,其中:
X为-NHC(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。18. 17.的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
烷基,杂烷基,烷氧基,-COR(其中R为烷基),-SO2R(其中R为烷基,氨
基,或单取代或双取代的氨基),亚甲基二氧基,羟基,卤素,酰基氨
基,氨基,单取代或双取代氨基,-CONR′R″,-(亚烷基)-CONR′R″(其
中R′和R″为氢或烷基),-COOR,-(亚烷基)-COOR(其中R为氢或烷
基),或-NRSO2R′(其中R为氢或烷基,并且R′为烷基,氨基,单取代
或双取代的氨基);并且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的
氨基。19. 18.的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自
甲基,甲氧基,氟,氯,二甲基氨基,乙酰基,乙酰基氨基,羟基,氨
基,亚甲基二氧基,-SO2Me,2-乙酰基氨基乙基,2-[(R)-氨基-3-甲基丁
酰基氨基]乙基,2-氨基乙基,氨基甲基,羟基甲基,氨基羰基,二甲
基氨基羰基,-COOH,羧甲基,甲氧基羰基甲基,氨基羰基甲基,二甲
基氨基羰基甲基,乙酰基氨基甲基,甲基磺酰基氨基,甲基磺酰基氨
基甲基,二甲基氨基磺酰基氨基甲基,或二甲基氨基;并且
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基,或4-氟
代苯基。20. 19.的化合物,其中:
Ar1最优选为苯基,3-甲氧基苯基,3-甲基磺酰基苯基,3-二甲基氨
基苯基,3-乙酰基氨基苯基,3-乙酰基苯基,3-[(2-乙酰基氨基)乙基]苯
基,3-氨基羰基苯基,4-二甲基氨基羰基苯基,3-羧基苯基,2,5-二甲氧
基苯基,3,5-二甲氧基苯基,3,4-二甲氧基苯基,3,4,5-三甲氧基苯基,3-
氨基羰基甲基苯基,3-乙酰基氨基甲基苯基,3-羧基甲基苯基,3-甲基
磺酰基氨基苯基,3-甲基磺酰基氨基甲基苯基,或3-氨基苯基。
本发明的化合物,可采用本领域技术人员已知的很多方法来制备。优选的方法包括下面公开的总的合成步骤,但不仅限于此。
在制备这些化合物时所用的起始原料和试剂,或者可以从供应商,例如Aldrich Chemical Co.(Milwaukee,Wisconsin,美国),Bachem(Torrance,California,美国),Emka-Chemie,或Sigma(St.Louis,Missouri,美国)处购得,或者可以用本领域技术人员已知的方法,按照参考文献例如Fieser andFieser′s Reagents for Organic Synthesis,1-15卷(John Wiley and Sons,1991);Rodd′s Chemistry of Carbon Compounds,1-5卷和补充卷(Elsevier SciencePublishers,1989),Organic Reactions,1-40卷(John Wiley and Sons,1991),March′s Advanced Organic Chemistry,(John Wiley and Sons,1992),和Larock′s Comprehensive Organic Transformations(VCH Publishers Inc.,1989)列出的步骤来制备。这些流程图只是举例说明可以合成本发明化合物的一些方法,对这些流程图的各种修改都是可以的,并且建议本领域的技术人员参照本发明中公开的内容进行各种修改。
如果需要,可以使用常规的技术分离和纯化反应的起始原料和中间产物,所用的技术包括过滤,蒸馏,结晶,色谱法等,但不仅限于此。这些原料可以用常规的方式来表征,包括物理常数和光谱数据。化学式(Ⅰ)的化合物的制备
按照如下流程图A所示的方法,制备化学式(Ⅰ)的化合物,其中R,R1,R2,X,Y,Ar1和Ar2的定义与发明综述中的定义相同。
通常,化学式3的化合物由两步反应制备,首先将化学式1的4-芳酰基哌啶转化成化学式3的N-保护的氨基烷基衍生物,然后用如下详述的的方法脱除3的氨基保护基。
在室温,于还原氨化反应条件下,即在合适的还原剂(例如,氰基硼氢化钠,三乙酰氧基硼氢化钠等),及有有机酸或没有有机酸(例如,冰醋酸,三氟乙酸等)存在的条件下,使化学式1的化合物与化学式2的醛反应,制备化学式3的N-保护的氨基烷基衍生物[此处PG为氨基保护基(例如,叔丁氧羰基(BOC),苄氧基羰基(CBZ),苄基等)]。对于该反应,合适的溶剂为卤代烃(例如,1,2-二氯乙烷,氯仿等)。
4-芳酰基哌啶1,例如4-(4-氟代苯甲酰基)哌啶,是可商购的。4-(3,4-二氯代苯甲酰基)哌啶可以采用Boswell等,J.Med.Chem.21,136,(1977)中公开的方法制备。也可以采用本领域熟知的方法,通过脱除叔丁氧基羰基,由N-叔丁氧基羰基-4-哌啶酮来制备化合物1,N-叔丁氧基羰基-4-哌啶酮的合成方法公开于下面的流程F中。
通过使用如DIBAL-H_的合适的还原剂,将酯基还原成醛基,很容易由相应的N-保护的天然或非天然α-氨基酸酯制备化学式2的醛。可选择地,可用氧化N-保护的α-氨基醇,例如缬氨醇中醇基的方法来制备化学式2的醛。
通常,α-氨基酸酯也可商购获得。例如,丙氨酸甲酯,丝氨酸甲酯,缬氨酸乙酯是可商购的。其它的α-氨基酸酯可用本领域熟知的方法,通过α-氨基酸的酯化来制备。天然和非天然的氨基酸,都可由供应商如Aldrich和Bachem处商购获得。非天然的氨基酸的实例包括,高丝氨酸,高半光氨酸,N-α-甲基精氨酸,正亮氨酸,N-甲基异亮氨酸,苯基甘氨酸,羟脯氨酸,焦谷氨酸,鸟氨酸,2-氨基异丁酸,2-氨基丁酸,β-环己基丙氨酸,3-(1-萘基)丙氨酸,3-(2-萘基)丙氨酸,瓜氨酸,2-哌啶酸,哌嗪酸,4-氯代苯基丙氨酸,4-氟代苯基丙氨酸和肌氨酸。
通过脱除氨基保护基,N-保护的氨基烷基衍生物3转化成化学式4的化合物。所采用的条件取决于保护基的性质。例如,如果保护基是叔丁氧基羰基,可在酸性水解反应条件下脱除该基团,而如果保护基为苄基,则在催化氢化反应条件下脱除。
如果需要,可以使用烷基化试剂R3L,其中L为在烷基化反应条件下可离去的基团,例如卤素,甲苯磺酸酯,甲磺酸酯,将其中R3为氢的化学式4的化合物烷基化,制备相应的其中R3不为氢的化学式4的化合物。
然后,按照本领域熟知的方法,将化学式4的化合物转化成化学式(Ⅰ)的化合物。部分方法公开如下。1.按照如下流程B所示的方法,制备其中X为-C(O)N(R3)-,并且Y和Ar1最广泛的定义如上的化学式(Ⅰ)的化合物:
其中X为氨基的化学式(Ⅰ)的化合物的制备,可以采用下列两种方法之一:(ⅰ)使化学式4的化合物,与酰基化试剂Ar1-Y-C(O)L反应,其中L为在酰基化反应条件下可离去的基团,例如卤素(特别是Cl或Br)或咪唑基(imidazolide)。该反应的合适的溶剂包括非质子传递溶剂(例如,二氯甲烷,四氢呋喃,二氧杂环己烷等)。当使用酰卤作为酰基化试剂时,该反应是在非亲核有机碱(例如三乙胺或吡啶,优选吡啶)存在下进行的;(ⅱ)加热化学式4的化合物与酸酐。该反应的合适溶剂为四氢呋喃,二氧杂环己烷等。2.按照如下流程C所示的方法,制备其中X为-N(R4)C(O)N(R3)-,-N(R4)C(S)N(R3)-,并且Y和Ar1最广泛的定义如上的化学式(Ⅰ)的化合物:
流程C
其中X为脲/硫脲基的化学式(Ⅰ)的化合物的制备,可以采用如下三种方法之一:(ⅰ)使化学式4的化合物与诸如羰基二咪唑/硫羰基二咪唑的活化剂反应,随后用一级或二级胺对咪唑基进行亲核取代。合适的溶剂包括极性有机溶剂(例如四氢呋喃,二氧杂环己烷等);(ⅱ)使化学式4的化合物与氨基甲酰基/氨基硫羰基卤化物反应。该反应是在非亲核有机碱存在下进行的。该反应的合适溶剂是二氯甲烷,1,2-二氯乙烷,四氢呋喃或吡啶;(ⅲ)在非质子有机溶剂(例如苯,四氢呋喃,二甲基甲酰胺等)中,使化学式4的化合物与异氰酸酯/异硫氰酸酯反应。3.按照如下流程D所示的方法,制备其中X为
-SO2N(R3)-的化学式(Ⅰ)的化合物:
流程D
采用在流程B的方法(ⅰ)中公开的反应条件,使化学式4的化合物与磺酰基卤化物反应,可制备其中X为亚磺酰氨基的化学式(Ⅰ)的化合物。磺酰基卤化物可商购,或者可以采用例如在(1)Langer,R.F.;Can.J.Chem.,61,1583-1592,(1983);(2)Aveta,R.等;Gazetta Chimica Italiana,116,649-652,(1986);(3)King,J.F.和Hillhouse,J.H.;Can.J.Chem.;54,498,(1976);和(4)Szymonifka,M,J.和Heck,J.V.;Tet.Lett.;30,2869-2872,(1989)中公开的方法制备。4.按照如下流程E所示方法,制备其中X为-N(R4)SO2N(R3)-的化学式(Ⅰ)的化合物:
采用在流程B的方法(ⅰ)中公开的反应条件,使化学式4的化合物与氨磺酰基卤化物反应,可制备其中X为硫酰胺基的化学式(Ⅰ)的化合物。氨磺酰基卤化物可商购,或者可以采用例如在Graf,R;德国专利,931225(1952)和Catt,J.D.和Matler,W.L;J.Org.Chem.,39,566-568,(1974)中公开的方法制备。
可选择地,可用如下流程F所示的方法来制备化学式(Ⅰ)的化合物,其中R,R1,R2,X,Y,Ar1和Ar2最广泛的定义如上:
流程F
在合适的碱,例如正丁基锂存在下,用Boc-保护的化学式5的哌啶酮与化学式为Br-(Ph)3P+-CH2Ar2的Wittig试剂进行缩合,制备化学式6的亚烷基中间产物。用硼烷处理6,随后在Brown,Garg,J.Am.Chem.Soc.83,2951(1961)公开的反应条件下,用例如铬酸的氧化剂氧化得到的烷基硼烷,给出化学式7的Boc-保护的4-芳酰基哌啶。使用合适的酸,例如三氟乙酸处理,随后用碱处理,脱除Boc-保护基,生成相应的4-芳酰基哌啶。通过与乙二醇反应,将4-芳酰基哌啶中的酮基以环缩酮的形式保护起来,制得化学式8的化合物,随后用下面公开的方法(a)或(b),将8转化成化学式(Ⅰ)的化合物。方法(a):
使8与化学式9的化合物反应,来制备化学式10的氨基烷基哌啶,其中PG为氨基保护基[(例如,叔丁氧基羰基(BOC),苄氧基羰基(CBZ),苄基等)],并且Z为醛,酮(X=-C(O)R,其中R为烷基),羧基或羧基的反应衍生物,例如酰卤。
制备10时使用的反应条件,取决于Z基团的性质。如果Z为醛基或酮基,该反应是在还原氨化的反应条件进行的,即在合适的还原剂(例如氰基硼氢化钠,三乙酰氧基硼氢化钠等)和有机酸(例如冰醋酸,三氟乙酸等)存在下,在室温下进行。该反应的合适溶剂为卤代烃(例如,1,2-二氯乙烷,氯仿等)。如果Z为羧基,该反应是在合适的偶合剂[例如,N,N-二环己基碳化二亚胺,1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺等]存在下,在合适的有机溶剂(例如,二氯甲烷,四氢呋喃等)中进行,给出酰胺中间体。脱去氨基保护基,随后用合适的还原剂(例如,乙硼烷,氢化铝锂等),在醚类有机溶剂,例如乙醚或四氢呋喃中还原酰胺中间体,得到化学式10的化合物。如果Z为酸衍生物,例如酰氯,该反应是在合适的碱例如三乙胺,吡啶存在下,在有机溶剂(例如,二氯甲烷,二氯乙烷,N,N-二甲基甲酰胺等)中进行的,得到酰胺中间体,随后按照如上公开的方法,将该中间体还原成化合物10。
通常,化学式9的化合物可商购获得,或可用有机化学领域熟知的方法制备。部分这样的方法的实例列举并详细公开如下。
化学式9的醛(Z为-CHO),可以很容易地由相应的其中Z为羧基的化学式9的天然或非天然α-氨基酸制备。首先用本领域熟知的方法制备相应的酯,随后用合适的还原剂,例如DIBAL-H_将酯基还原成醛基。可选择地,通过用合适的氧化剂氧化羟基,可由N-保护的α-氨基醇来制备化学式9的醛(Z为-CHO)。
通过将化学式9的α-氨基酸转化成Weinreb酰胺,随后用其中R为烷基的化学式RMgBr的Grignard试剂处理,可由化学式9的N-保护的α-氨基酸制备化学式9的酮。可选择地,可通过相应的化学式9的醛(Z为-CHO)与Grignard试剂进行烷基化反应,随后用合适的氧化剂,例如高锰酸钾等氧化得到的醇,来制备化学式9的酮。
通过在合适的有机溶剂,例如二氯甲烷等中,用合适的氯化试剂(例如,草酰氯,亚硫酰氯等)氯化羧基,可由相应的化学式9的酸(Z为-COOH),制备其中Z为酸衍生物,例如酰氯的化学式9的化合物。
将10中的缩酮基水解,可得到化学式4的化合物,该化合物采用如上的流程A-E的方法,可转化成化学式(Ⅰ)的化合物。方法(b):
可选择地,在还原氨化反应条件下,用化学式8的化合物与其中X,Y和Ar1最广泛的定义如上的化学式11的醛进行缩合反应,得到化学式12的化合物,随后用合适的酸,例如盐酸等将缩酮基水解,可制备化学式(Ⅰ)的化合物。
化学式11的化合物的制备,可以由可商购的α-氨基醇出发,按照如上流程B-E所示方法进行反应,然后使用合适的氧化剂,例如氯铬酸吡啶鎓盐,将醇基氧化成醛基。
本发明的化合物是CCR-3受体拮抗剂,因此它们能抑制由于化学增活现象,例如RANTES,eotaxin和MCP-3引起的嗜酸细胞,T细胞,嗜碱细胞和肥大细胞的补充。本发明的化合物,通常比其中R1和R2为氢的相应的哌啶类似物更有效。因此,本发明的化合物和含有它们的组合物,在治疗嗜酸细胞引发的疾病,例如哺乳动物,特别是人的哮喘,鼻炎,湿疹和寄生物传染病中是有效的。
可以通过体外试验,例如在实施例5,6和7中较详细描述的配体结合和趋化性试验,来测试本发明化合物的CCR-3拮抗活性。也可以通过在实施例8中有较详细描述的Balb/c试验老鼠卵清蛋白诱导哮喘试验,在体内测试本发明化合物的CCR-3拮抗活性。
通常,可以采用任何可接受的服用具有相似药理作用的制剂的方式,服用治疗有效量的本发明化合物。本发明化合物即活性成分的实际给药量,取决于众多因素,例如需要治疗的疾病的严重性,患者的年龄和健康状况,所用化合物的效能,给药路线和形式,及其它因素等。
化学式(Ⅰ)的化合物的治疗有效量的范围,约为每天每千克受体体重0.05~20mg;优选约为0.1~10mg/kg/day。因此,对于体重70kg的人,服用的剂量范围最优选约为7mg~0.7g/day。
通常,本发明的化合物将以药物组合物的形式,采取下列任意一条路线服用:口服,系统给药(例如,经皮,鼻内或以栓剂的形式给药),或肠胃外(例如,肌肉,静脉内或皮下)给药。优选的给药方式是口服,采用方便的日用量服法,其可依据病痛程度进行调节。组合物可采取片剂,丸剂,胶囊,半固体,粉末,持续释放的制剂,溶液,悬浮液,酏剂,气雾剂,或任何其它适合的组合物的形式。
配方的选择取决于各种因素,例如药物的服用方式(例如对于口服,优选药片,药丸或胶囊形式的制剂)和药物本身的生物药效率。最近,基于通过增加表面积,即降低颗粒大小可以提高生物药效率的原理,特别为具有较差的生物药效率的药物开发出制药配方。例如,在美国专利4,107,288中,公开了颗粒大小为10~1,000nm的制药配方,其中活性原料负载在大分子的交联基体上。美国专利5,145,684中公开了一种药物制剂的生产,其中在表面改性剂存在下,将药物研磨成极小的颗粒(平均颗粒大小为400nm),然后将其分散到液体介质中,得到显示出极高生物药效率的药物制剂。
所述组合物通常包括与至少一种适合药用的赋形剂相结合的化学式(Ⅰ)的化合物。可接受的赋形剂为无毒的,助吸收的,并且对化学式(Ⅰ)的化合物的治疗效果没有副作用。这样的赋形剂可以是任何固体,液体,半固体的形式,或在气雾剂组合物的情况下,为气态赋形剂,这些赋形剂通常是本领域的技术人员可以得到的。
固体药物赋形剂包括淀粉,纤维素,滑石,葡萄糖,乳糖,蔗糖,凝胶,麦芽,大米,面粉,白垩,硅胶,硬脂酸镁,硬脂酸钠,单硬脂酸甘油酯,氯化钠,干脱脂乳等。液体和半固体赋形剂可以选自甘油,1,2-丙二醇,水,乙醇和各种油类,包括石油,动物油,植物油,或合成得到的油,例如花生油,大豆油,矿物油,芝麻油等。特别对于可注射溶液来说,优选的液体载体包括水,盐水,葡萄糖水溶液和乙二醇。
可使用压缩气体,将本发明的化合物以气雾剂的形式分散。适合该目的的惰性气体有氮气,二氧化碳等。
其它合适的药用赋形剂及其制剂公开于Remington′s PharmaceuticalSciences,E.W.Martin编辑(Mack Publishing Company,18th ed.,1990)。
所述化合物在制剂中的含量,可以在本领域技术人员所采用的范围内变化。典型地,基于重量百分比(wt%),所述制剂可含有基于制剂总量的约0.01~99.99wt%的化学式(Ⅰ)的化合物,其余为一种或多种适合药用的赋形剂。优选地,该化合物的含量为约1~80wt%。含有化学式(Ⅰ)的化合物的典型药物配方公开于实施例4。
实施例
用三乙酰氧基硼氢化钠(1.36g,6.4mmol),处理4-(3,4-二氯代苯甲酰基)哌啶(1.28g,4.96mmol)(见Boswell等,J.Med.Chem.,21,136,(1977))和DL-N-BOC-Valinal(1.33g,6.6mmol)(见Stanfield等,J.Org.Chem.,46(23),4797,(1981))在二氯甲烷(150ml)中的混合物。该反应混合物在氮气下搅拌1天,然后直接通过衬硅胶的过滤器过滤纯化,用己烷和乙酸乙酯洗提。除去有机物,将得到的油状物(2.1g)溶解在二氯甲烷(22ml)中,并用三氟乙酸(8ml)处理。在氮气下搅拌1h后,抽真空除去溶剂。残余物用碳酸氢钠水溶液处理至碱性,并用氯仿萃取产品。有机层用硫酸镁干燥,过滤并浓缩,得到[1-(2-氨基-3-甲基丁基)哌啶-4-基]-(3,4-二氯代苯基)甲酮(1.47g)油状物。步骤2
用三甲氧基苯基异氰酸酯(30mg)处理[1-(2-氨基-3-甲基丁基)哌啶-4-基]-(3,4-二氯代苯基)甲酮(30mg)的二氯甲烷(3ml)溶液,并加入三乙胺(1ml,0.3M的二氯甲烷溶液),该反应混合物在室温搅拌过夜。加入聚苯乙烯三胺树脂(约0.5g,3.5mmol/g),以捕获过量的异氰酸酯,并再搅拌2h。过滤出树脂,并浓缩滤液。用柱色谱纯化,得到1-{1-[4-(3,4-二氯代苯甲酰基)哌啶-1-基甲基]-2-甲基丙基}-3-(3,4,5-三甲氧基苯基)脲(27.5mg)。
用4-甲氧基苯甲酰氯(30mg)处理[1-(2-氨基-3-甲基丁基)哌啶-4-基]-(3,4-二氯代苯基)甲酮(30mg)的二氯甲烷(3ml)溶液。然后加入三乙胺(1ml,0.3M的二氯甲烷溶液),该反应混合物在室温搅拌过夜。加入聚苯乙烯三胺树脂(约0.5g,3.5mmol/g),以捕获过量的酰氯,并再继续搅拌2h。过滤出树脂,并浓缩滤液。用柱色谱纯化,得到N-{1-[4-(3,4-二氯代苯甲酰基)哌啶-1-基甲基]-2-甲基丙基}-4-甲氧基苯甲酰胺(34.8mg)。
在氩气氛下,向冰冷却的3,4-二氯代苄基三苯基鏻溴化物(54g,108mmol)(通过在65℃,在THF中,将等摩尔的3,4-二氯代溴化苄和三苯基磷搅拌过夜制备)的干燥的THF(500ml)悬浮液中,缓慢加入正丁基锂(43.2ml,2M的戊烷溶液,108mmol)。15分钟后,使该反应混合物升温到室温,并再搅拌2h。加入1-叔丁氧基羰基-4-哌啶酮(21.42g,108mmol),并继续搅拌过夜。加入己烷(2L),搅拌该反应物,然后过滤。抽真空浓缩滤液,得到41.8g橙色胶状物。采用0.5kg闪蒸级硅胶进行柱色谱,用70%的二氯甲烷/己烷到100%二氯甲烷的梯度淋洗液洗提,随后用1%的甲醇/二氯甲烷到5%的甲醇/二氯甲烷的梯度淋洗液洗提,得到1-(叔丁氧基羰基)-4-(3,4-二氯代苯亚甲基)哌啶(29g)浅棕褐色油状物。步骤2
在氩气氛下,向室温下的1-(叔丁氧基羰基)-4-(3,4-二氯代苯亚甲基)哌啶(6.4g,18.7mmol)的干燥的THF(100ml)溶液中,加入乙硼烷(22.4ml,1M的THF溶液,22.4mmol),并将该反应混合物搅拌3h。缓慢滴加入水(20ml),以破坏掉过量的乙硼烷。抽真空除去四氢呋喃,并加入乙醚(200ml)。将该反应混合物在冰浴中冷却,并以一定的速度滴加入Jones试剂(取18.6g水合重铬酸钠,14ml浓硫酸,并加入足够的水,以得到93ml溶液),使反应温度维持在25℃左右。该橙色溶液在室温搅拌2h。分离出有机层,水层用乙醚萃取两遍。合并后的有机层用稀的碳酸钾水溶液洗涤两遍,用无水硫酸镁干燥,并除去有机物。该反应混合物粗品,用闪蒸级硅胶进行减压色谱,用10%的乙酸乙酯/己烷到15%的乙酸乙酯/己烷的梯度淋洗液洗提,得到4-(3,4-二氯代苯甲酰基)哌啶-1-羧酸叔丁酯(3.8g,10.6mmol)。步骤3
向室温下的4-(3,4-二氯代苯甲酰基)哌啶-1-羧酸叔丁酯(3.8g,10.6mmol)的二氯乙烷(100ml)溶液中,加入三氟乙酸(25ml),并搅拌该溶液1h。除去有机物后,加入乙酸乙酯(200ml),得到的溶液用1N氢氧化钠水溶液碱化。分离出乙酸乙酯层,用硫酸镁干燥并浓缩,得到4-(3,4-二氯代苯甲酰基)哌啶(2.73g)白色固体。步骤4
将4-(3,4-二氯代苯甲酰基)哌啶(1.0g,3.9mmol),1,2-亚乙基二醇(0.65ml,11.6mmol),一水合对甲苯磺酸(1.48g,7.8mmol),和甲苯(100ml)的混合物,经过Dean-Stark分水器回流4h。浓缩后,残余物中加入乙酸乙酯和稀的碳酸氢钠水溶液搅拌。分离出有机层,用硫酸镁干燥,并抽真空浓缩,得到4-[2-(3,4-二氯代苯基)-[1,3]二氧戊环-2-基]哌啶(0.6g,1.99mmol)。步骤5
将二异丙基乙基胺(17.4ml,134mmol)加入到(DL)-缬氨醇(9.85g,95mmol)的二氯甲烷(100ml)溶液中。将该反应混合物冷却到0℃,用对甲基苯甲酰氯(12.8ml,91mmol)的二氯甲烷(50ml)溶液处理,然后加热到室温。搅拌3h后,加入过量的氢氧化钠水溶液,并将反应物转移到分液漏斗中。分离出有机层,水层用一份二氯甲烷洗涤。合并后的有机层用水和盐水洗涤,用硫酸镁干燥,并抽真空浓缩。色谱分离,用25%乙酸乙酯的己烷溶液洗提,随后用50%乙酸乙酯的己烷溶液洗提,得到N-对甲基苯甲酰基缬氨醇(18.04g)。步骤6
在惰性气氛下,在搅拌下,将二甲亚砜(2.2ml,31mmol)用注射器缓慢地加入到-78℃的草酰氯(15ml,171mmol)的二氯甲烷(35ml)溶液中。10分钟后,加入N-对甲基苯甲酰基缬氨醇(6.0g,29mmol)的二氯甲烷(50ml)溶液,并再搅拌15分钟。加入三乙胺(6ml,389mmol),并将反应物加热到室温。1.5h后,用50%乙酸乙酯的己烷溶液稀释该反应物,并用水和盐水洗涤。用衬硅胶的过滤器过滤,随后除去溶剂,得到固体残余物。色谱分离,用20%乙酸乙酯的己烷溶液洗提,随后用33%乙酸乙酯的己烷溶液洗提,得到N-对甲基苯甲酰基缬氨醛(3.6g)固体,将在步骤7中使用。步骤7
在氩气氛下,将4-[2-(3,4-二氯代苯基)-[1,3]二氧戊环-2-基]哌啶(0.21g,0.7mmol),N-对甲基苯甲酰基缬氨醛(0.17g,0.764 mmol),三乙酸基硼氢化钠(0.22g,1.04mmol)的二氯甲烷(20ml)溶液搅拌过夜。反应混合物浓缩后,残余物加入乙酸乙酯和稀的碳酸钾水溶液搅拌。分离出有机层,水层用乙酸乙酯萃取。合并后的有机层用硫酸镁干燥,并抽真空浓缩。粗品用闪蒸级硅胶进行减压色谱,用1%甲醇/二氯甲烷(含1%氨)为淋洗液,得到N-(1-{4-[2-(3,4-二氯代苯基)-[1,3]二氧戊环-2-基]哌啶-1-基甲基}-2-甲基丙基)-4-甲基苯甲酰胺(0.187g,0.366mmoles).步骤8
将N-(1-{4-[2-(3,4-二氯代苯基)-[1,3]二氧戊环-2-基]哌啶-1-基甲基}-2-甲基丙基)-4-甲基苯甲酰胺(0.4g,0.791mmol),HCl水溶液(10ml,6N),和乙腈(10ml)的混合物回流2h。将该反应混合物浓缩后,残余物加入乙酸乙酯和水搅拌。加入氢氧化钠溶液(6N),直到水层的PH值为8。分离出有机层,水层用乙酸乙酯萃取。合并后的有机层用硫酸镁干燥,并浓缩,得到N-{1-[4-(3,4-二氯代苯甲酰基)-哌啶-1-基甲基]-2-甲基丙基}-4-甲基苯甲酰胺,通过向游离碱的乙醚溶液中加入2mol过量的HCl乙醚溶液(1M),该产品可转化成盐酸盐。
实施例4
下面是含有化学式(Ⅰ)的化合物的典型药物配方。
药片配方
密切混合下列成分,并压成有单一记号的药片。成分 每个药片中的量,mg本发明的化合物 400玉米淀粉 50Croscarmellose sodium 25乳糖 120硬脂酸镁 5
胶囊配方
密切混合下列成分,并装入到硬壳凝胶胶囊中。成分 每个胶囊中的量,mg本发明的化合物 200乳糖,喷雾干燥 148硬脂酸镁 2
悬浮液配方
混合下列成分,制成适合口服的悬浮液。成分 数量本发明的化合物 1.0g富马酸 0.5g氯化钠 2.0g甲基paraben 0.15g丙基paraben 0.05g砂糖 25.5g山梨糖醇(70%溶液) 12.85gVeegum K(Vanderbilt公司) 1.0g调味品 0.035ml着色剂 0.5mg蒸馏水 足够的量以补足到100ml
注射配方
混合下列成分,以制成注射制剂。成分 数量本发明的化合物 0.2g乙酸钠缓冲溶液,0.4M 2.0mlHCl(1N)或NaOH(1N) 足够的量以调节至合适的PH值水(蒸馏过的,消过毒的) 足够的量以补足到20ml
局部用药配方
用下列成分制备局部用药制剂。成分 量,g本发明的化合物 10Span60 2TWEEN_60 2矿物油 5凡士林 10甲基paraben 0.15丙基paraben 0.05BHA(丁基化羟基茴香醚) 0.01水 足够的量以补足到100
除了水以外,上述所有成分,都在搅拌下混合并加热到60-70C。然后在剧烈搅拌下,加入足够量的60℃的水,使配料乳化,然后向其中加入足够的水至100g。
栓剂配方
通过将本发明的化合物与Witepsol_H-15(饱和植物脂肪酸的甘油三酯;Riches-Nelson公司,纽约)混合,制备总重量为2.5g的栓剂,组成如下:本发明的化合物 500mgWitepsol_H-15 余量
实施例5CCR-3受体结合试验—体外
用本发明化合物抑制125I-eotaxin与CCR-3L1.2感染的细胞结合的能力,确定本发明化合物的CCR-3拮抗活性,CCR-3L1.2感染的细胞购自LeukoSite(Cambridge,MA)。
该试验是在Costar96孔聚丙烯圆底盘中进行的。将试验化合物溶解在DMSO中,然后用粘合缓冲溶液(50mM HEPES,1mM CaCl2,5mMMgCl2,0.5%牛血清白蛋白,0.02%叠氮化钠,pH7.24)稀释,使得最终的DMSO浓度为2%。将25μl的试验溶液或只含有DMSO的缓冲液(对照样),加入到每个孔中,随后加入25μl125I-eotaxin(100pmol)(NEX314,NewEngland Nuclear,Boston,MA)和含有1.5×105个CCR-3L1.2感染的细胞的25μl粘合缓冲溶液。最后反应物的体积为75μl。
该反应混合物在室温孵化1h后,使用聚乙烯亚胺处理过的PackardUnifilter GF/C滤板(Packard,Chicago,Ⅱ.)过滤反应混合物,以终止反应。滤器用含有10mm HEPES和0.5M氯化钠的冰冷的洗涤缓冲液(pH7.2)洗4遍,并在65℃干燥约10分钟。向每个孔中加入25μl Microscint-20TM闪光液体(Packard),并用Packard TopCoutTM测定在过滤器上保留的放射性。
在本试验中,本发明的化合物是有活性的。
在表Ⅰ和Ⅱ中化合物的IC50值(能使125I-eotaxin对CCR-3L1.2感染细胞的结合减少50%所要求的试验化合物的浓度)在0.6~10μm之间。
实施例6Eotaxin调节的CCR-3L1.2感染细胞趋化性的抑制--体外试验
采用稍加改动的Ponath,P.D.等,1996,“Cloning ofthe Human EosinophilChemoattractant,Eotaxin”,J.Clin.invest.,97:604-612公开的方法,通过测量对Eotaxin调节的CCR-3L1.2感染细胞趋化性的抑制作用,可以确定本发明化合物的CCR-3拮抗活性。该试验是在24孔趋化性板(CollaborativeBiomedical Products)中进行的。CCR-3L1.2感染细胞,指定为10E6,在含有RPMI1640,10%HycloneTM胎牛血清,5.5%×10-5 2-巯基乙醇和G418(0.8mg/ml)的培养介质中生长。在试验前18~24h,用正丁酸处理感染细胞,使最终的浓度为5mM/l×106细胞/ml,分离,并在含有等比例的RPMI1640和M199及0.5%BSA的试验介质中,重新形成1×107细胞/ml的悬浮液。
将浓度为1mg/ml的人eotaxin的PBS(Gibco#14190-029)悬浮液,加入到底室,最后的浓度为100nm。将具有3微米孔的BiocoatTM Transwell培养物插入物(Costar公司,Cambridge MA),插入到每个孔中,并向顶室加入L1.2细胞(1×106),最后的体积为100μl。向顶室和底室都加入试验化合物的DMSO溶液,使最后的DMSO的体积为0.5%。该试验与两个对照样系列同时进行。正的对照样在顶室含有细胞,而不含试验化合物,在底室只含有eotaxin。负的对照样在顶室含有细胞,而不含试验化合物,在底室即没有eotaxin,也没有试验化合物。该板在37℃孵化。4h后,从孔中取出插入物,并从底室用吸液管吸出500μl细胞悬浮液到1.2ml Cluster管(Costar)中,并在FACS上对其记数30秒,计算出迁移到底室的细胞的数量。
在本试验中,本发明的化合物显示出活性。
实施例7Eotaxin调节的人体嗜酸细胞趋化性的抑制--体外试验
采用稍加改动的Carr,M.W.等,Proc.Natl.Acad.Sci. USA,91:3652-3656(1994)公开的方法,评价本发明的化合物抑制Eotaxin调节的人体嗜酸细胞趋化性的能力。使用24孔趋化板(Collaborative Biomedical Products)进行试验。采用PCT申请,公开号WO96/22371中公开的方法,从血液中分离出嗜酸细胞。使用的内皮细胞为内皮细胞系ECV304,得自欧洲动物细胞培养物收藏中心(Porton Down,Salisbury,英国)。内皮细胞是在具有3μm孔的,直径为6.5mm的Biocoat_ Transwell组织培养插入物(Costar公司,Cambridge MA)中培养的。ECV304细胞的培养基由M199,10%牛胎血清,L-谷氨酰胺和抗生素组成。试验介质是由等比例的RPMI1640和M199,及0.5%BSA组成。在试验前24h,将2×105个ECV304细胞涂到24孔趋化板的每个插入物上,并在37℃孵化。将稀释在试验介质中的20nM eotaxin加入到底室。在底室的最后体积为600μl。将内皮细胞涂敷的组织培养插入物,插入到每个孔中。将悬浮在100μl试验缓冲溶液中的106个嗜酸细胞,加入到顶室。向顶室和底室都加入溶解在DMSO中的试验化合物,使最后在每个孔中的DMSO体积为0.5%。该试验是与两个对照样系列同时进行的。正的对照样在顶室含有细胞,在底室含有eotaxin。负的对照样在顶室含有细胞,在底室只含有试验缓冲液。该板在37℃,5%CO2/95%空气的气氛下孵化1~1.5h。
用血细胞流量记数仪计算迁移到底室的细胞数量。将500μl细胞悬浮液从底室取出,放入试管中,通过30秒时间周期内获得的数量,可得到相对的细胞数量。
在本试验中,本发明的化合物显示出活性。
实施例8存卵清蛋白敏化的balb/c老鼠体内CCR-3拮抗剂对嗜酸细胞趋化性的抑制--体内试验
通过测定在用气雾剂激发抗原后,本发明化合物对嗜酸细胞在卵清蛋白(OA)-敏化的balb/c老鼠BAL液体内积聚的抑制作用,可以确定本发明化合物的CCR-3拮抗活性。简单地说,就是在第1天和第14天,用OA(10μg,在0.2ml氢氧化铝溶液中)在腹膜内对体重为20~25g的雄性balb/c老鼠进行敏化。1周后,将老鼠分成10组。试验化合物或赋形剂(正的对照组)被服用。1h后,将老鼠放于树脂玻璃箱中,并暴露于PARISTARTM喷雾器喷出的OA气雾剂中20分钟。没有被敏化或激发的老鼠作为负对照组。经过24或72h后,将老鼠麻痹(氨基甲酸乙酯,约lg/kg,腹膜内),插入气管套管(PE60管),将肺部用0.3ml PBS灌洗4次。将Bal液体转移到塑料管中,并冰冻保存。使用血细胞计数器和/或Coulter CounterTM,测定20μl BAL液体中的白细胞总量。在用改性的Wright′s染剂(Diff-QuickTM)染色的Cytospin标本上,用光显微镜法,采用标准的形态学标准,测定差示的白细胞数量。
在本试验中,本发明的化合物被认为是有活性的。
为了达到清楚和明白的目的,通过举例说明和实施例的方式,部分详细地公开了前述发明。很明显,对于本领域的技术人员而言,在附加的权利要求所限定的范围内,可以进行改变或修改。因此,应该明白,上面的说明书是为了说明,而不是为了限制。因此,确定本发明的范围,不应参照上述说明书,而应该参照下面附加的权利要求书,及所有这些权利要求的等效物。
在本申请中引用的所有专利,专利申请和出版物,为各种目的,其所有内容同样地结合在此作为参考,即使各个专利,专利申请和出版物是分别提到的。
Claims (29)
Ar1和Ar2彼此独立地为芳基或杂芳基;
R和R1彼此独立地为氢或烷基;
R2为3~6个碳原子的烷基,杂烷基,芳基,芳烷基,杂芳基,杂芳烷基,
杂环烷基,-(亚烷基)-C(O)-Z,其中Z为烷基,卤代烷基,烷氧基,
卤代烷氧基,羟基,氨基,单取代或双取代氨基,芳基,芳烷基,
芳氧基,芳烷氧基,杂芳基,杂芳氧基,或杂芳烷氧基;
X选自下列基团:
(a)-C(O)N(R3)-;
(b)-N(R4)C(O)N(R3)-;
(c)-N(R4)C(S)N(R3)-;
(d)-SO2N(R3)-;或
(f)-N(R4)SO2N(R3)-;
其中:
R3和R4彼此独立地为氢,烷基,芳烷基,杂芳烷基,杂环烷基,
杂烷基,或-(亚烷基)-C(O)-Z,其中Z为烷基,卤代烷基,烷氧基,
卤代烷氧基,羟基,氨基,单取代或双取代氨基,芳基,芳烷基,
芳氧基,芳烷氧基,杂芳基,杂芳氧基或杂芳烷氧基;并且
Y为单键或具有1~3个碳原子的亚烷基;及其
前体药物,单独的异构体,异构体混合物,和适合药用的盐。
2.权利要求1的化合物,其中R2为具有3或4个碳原子的支化的烷基。
3.权利要求2的化合物,其中:
R和R1为氢;并且
X为-C(O)N(R3)-,其中R3为氢,烷基或杂烷基。
4.权利要求3的化合物,其中:
Ar1为杂芳环;并且
Ar2为芳环。
5.权利要求3的化合物,其中:
Ar1和Ar2为芳基。
6.权利要求4的化合物,其中:
X为-C(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。
7.权利要求6的化合物,其中:
Ar1为吡啶-2-基,吡啶-3-基,喹啉-3-基或5-甲基噻吩-2-基;并且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的氨基。
8.权利要求7的化合物,其中
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基或4-氟代苯基。
9.权利要求5的化合物,其中:
X为-C(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。
10.权利要求9的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,-COR(其中R为烷基),-SO2R(其中R为烷基,氨基,或单取代或双取代的氨基),亚甲基二氧基,羟基,卤素,酰基氨基,氨基,单取代或双取代氨基,-CONR′R″,-(亚烷基)-CONR′R″(其中R′和R″为氢或烷基),-COOR,-(亚烷基)-COOR(其中R为氢或烷基),或-NRSO2R′(其中R为氢或烷基,并且R′为烷基,氨基,单取代或双取代氨基);并且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代氨基。
11.权利要求10的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自甲基,甲氧基,氟,氯,二甲基氨基,乙酰基,羟基,氨基,亚甲基二氧基,-SO2Me,2-乙酰基氨基乙基,2-[(R)-氨基-3-甲基丁酰基氨基]-乙基,2-氨基乙基,氨基甲基,羟甲基,氨基羰基,二甲基氨基羰基,-COOH,羧甲基,甲氧基羰基甲基,氨基羰基甲基,二甲基氨基羰基甲基,乙酰基氨基甲基,甲基磺酰基氨基,甲基磺酰基氨基甲基,二甲基氨基磺酰基氨基甲基,或二甲基氨基;并且
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基或4-氟代苯基。
12.权利要求11的化合物,其中Ar1为苯基,4-氯代苯基,3,4-二氟代苯基,4-甲基苯基,4-甲氧基苯基,4-羟基苯基,4-二甲基氨基苯基,4-氨基羰基苯基,4-二甲基氨基羰基苯基,4-乙酰基苯基,4-乙酰基氨基苯基,3,4-亚甲基二氧基苯基,4-甲基磺酰基苯基,4-[(2-乙酰基氨基)乙基]苯基,4-{2-[(R)-氨基-3-甲基丁酰基氨基]乙基}苯基,4-(2-氨基乙基)苯基,4-(氨基甲基)苯基,4-(羟甲基)苯基,2,5-二甲氧基苯基,3,5-二甲氧基苯基,3,4-二甲氧基苯基,3,4,5-三甲氧基苯基,4-氨基羰基甲基苯基,4-乙酰基氨基甲基苯基,4-甲基磺酰基氨基苯基,4-甲基磺酰基氨基甲基苯基,或4-氨基苯基。
13.权利要求2的化合物,其中:
R和R1为氢;并且
X为-NHC(O)N(R3)-,其中R3为氢,烷基或杂烷基。
14.权利要求13的化合物,其中:
Ar1为杂芳环;并且
Ar2为芳环。
15.权利要求13的化合物,其中:
Ar1和Ar2为芳基。
16.权利要求14的化合物,其中:
X为-NHC(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。
17.权利要求16的化合物,其中:
Ar1为吡啶-2-基,吡啶-3-基,喹啉-3-基或5-甲基噻吩-2-基;并且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代的氨基。
18.权利要求17的化合物,其中:
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基或4-氟代苯基。
19.权利要求15的化合物,其中:
X为-NHC(O)NH-;
Y为单键;并且
R2为2-丙基或2,2-二甲基乙基。
20.权利要求19的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,-COR(其中R为烷基),-SO2R(其中R为烷基,氨基,或单取代或双取代的氨基),亚甲基二氧基,羟基,卤素,酰基氨基,氨基,单取代或双取代氨基,-CONR′R″,-(亚烷基)-CONR′R″(其中R′和R″为氢或烷基),-COOR,-(亚烷基)-COOR(其中R为氢或烷基),或-NRSO2R′(其中R为氢或烷基,并且R′为烷基,氨基,单取代或双取代氨基);并且
Ar2为被1个,2个或3个取代基任选取代的苯环,所述取代基选自烷基,杂烷基,烷氧基,卤素,三氟甲基,硝基,或单取代或双取代氨基。
21.权利要求20的化合物,其中:
Ar1为被1个,2个或3个取代基任选取代的苯环,所述取代基选自甲基,甲氧基,氟,氯,二甲基氨基,乙酰基,乙酰基氨基,羟基,氨基,亚甲基二氧基,-SO2Me,2-乙酰基氨基乙基,2-[(R)-氨基-3-甲基丁酰基氨基]乙基,2-氨基乙基,氨基甲基,羟甲基,氨基羰基,二甲基氨基羰基,-COOH,羧甲基,甲氧基羰基甲基,氨基羰基甲基,二甲基氨基羰基甲基,乙酰基氨基甲基,甲基磺酰基氨基,甲基磺酰基氨基甲基,二甲基氨基磺酰基氨基甲基,或二甲基氨基;并且
Ar2为3,4-二氟代苯基,2,3-二氯代苯基,3,4-二氯代苯基或4-氟代苯基。
22.权利要求21的化合物,其中Ar1最优选为苯基,3-甲氧基苯基,3-甲基磺酰基苯基,3-二甲基氨基苯基,3-乙酰基氨基苯基,3-乙酰基苯基,3-[(2-乙酰基氨基)乙基]苯基,3-氨基羰基苯基,4-二甲基氨基羰基苯基,3-羧基苯基,2,5-二甲氧基苯基,3,5-二甲氧基苯基,3,4-二甲氧基苯基,3,4,5-三甲氧基苯基,3-氨基羰基甲基苯基,3-乙酰基氨基甲基苯基,3-羧基甲基苯基,3-甲基磺酰基氨基苯基,3-甲基磺酰基氨基甲基苯基,或3-氨基苯基。
23.一种药物组合物,包括治疗有效量的权利要求1~23中任何一个的化合物,及适合药用的赋形剂。
24.一种制备权利要求1的化合物的方法,它包括使其中R,R1,R2和Ar2如权利要求1中所定义的化学式(Ⅱ)的化合物:与(ⅰ)化学式为Ar1-Y-COL的酰基化试剂,其中L为在酰基化反应条件下可离去的基团,或化学式为(Ar1-Y-CO)2O的酸酐反应,得到化学式(Ⅰ)的化合物,其中X为-C(O)N(R3)-,其中R3为氢;或与(ⅱ)化学式为Ar1-Y-NH(R4)的胺,其中R4的定义如本发明概述所做的定义,在合适的偶合剂存在下反应,或化学式为Ar1-Y-N=C=O的异氰酸酯,或化学式为Ar1-Y-N(R4)-C(O)L的氨基甲酰卤反应,其中R4的定义如本发明概述所做的定义,并且L为在酰基化反应条件下的离去基团,得到化学式(Ⅰ)的化合物,其中X为-N(R4)CON(R3)-,其中R3为氢;或(ⅲ)化学式为Ar1-Y-NH(R4)的胺,其中R4的定义如本发明概述所做的定义,在合适的偶合剂存在下反应,或化学式为Ar1-Y-N=C=S的异硫氰酸酯,或化学式为Ar1-Y-N(R4)-C(S)L的硫代氨基甲酰卤反应,其中R4的定义如本发明概述所做的定义,并且L为离去基团,给出化学式(Ⅰ)的化合物,其中X为-N(R4)C(S)N(R3)-,其中R3为氢;或(ⅳ)化学式为Ar1-Y-SO2L或Ar1-Y-N(R4)-SO2L的磺酰化试剂反应,其中R4的定义如本发明概述所做的定义,并且L为在磺酰化反应条件下的离去基团,给出化学式(Ⅰ)的化合物,其中X分别为-SO2NR3-或-N(R4)SO2N(R3)-,其中R3为氢;和(ⅴ)任选地,将在上面的步骤(ⅰ)~(ⅳ)中制备的其中R3为氢的化学式(Ⅰ)的化合物,转化成其中R3不为氢的化学式(Ⅰ)的化合物;和(ⅵ)任选地,通过用酸处理,将在上面的步骤(ⅰ)~(ⅴ)中制备的化学式(Ⅰ)的化合物,转化成相应的酸加成盐。
25.按照权利要求22的方法制备的化合物。
26.用作治疗剂的权利要求1~22中任何一个的化合物。
27.一种治疗通过服用CCR-3拮抗剂可治疗的哺乳动物疾病,优选哮喘的方法,包括给哺乳动物服用治疗有效量的权利要求1的化合物。
28.权利要求1~22中任何一个所要求的化合物在制备药物中的应用,该药物包括权利要求1~22中任何一个所要求的化合物作为活性组分,该药物可用于治疗通过服用CCR-3拮抗剂可治疗的疾病,其中所述疾病特别优选为哮喘。
29.如此前所公开的本发明。
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CN111050558A (zh) * | 2017-09-13 | 2020-04-21 | 先正达参股股份有限公司 | 杀微生物的喹啉(硫代)羧酰胺衍生物 |
CN111093372A (zh) * | 2017-09-13 | 2020-05-01 | 先正达参股股份有限公司 | 杀微生物的喹啉(硫代)羧酰胺衍生物 |
CN111093372B (zh) * | 2017-09-13 | 2022-05-27 | 先正达参股股份有限公司 | 杀微生物的喹啉(硫代)羧酰胺衍生物 |
CN111050558B (zh) * | 2017-09-13 | 2022-05-27 | 先正达参股股份有限公司 | 杀微生物的喹啉(硫代)羧酰胺衍生物 |
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ITTO990990A1 (it) | 2001-05-16 |
CN1163484C (zh) | 2004-08-25 |
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JP3475177B2 (ja) | 2003-12-08 |
IT1307062B1 (it) | 2001-10-23 |
BR9915403A (pt) | 2001-08-14 |
ZA200103249B (en) | 2002-07-22 |
TR200101155T2 (tr) | 2001-09-21 |
DE69921351T2 (de) | 2006-03-09 |
PT1131291E (pt) | 2005-01-31 |
US6140344A (en) | 2000-10-31 |
GB2343891B (en) | 2001-05-30 |
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AU1045900A (en) | 2000-06-05 |
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AR029150A1 (es) | 2003-06-18 |
FR2785902A1 (fr) | 2000-05-19 |
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