CN112367989A - 噻吩并嘧啶的葡甲胺盐 - Google Patents
噻吩并嘧啶的葡甲胺盐 Download PDFInfo
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- CN112367989A CN112367989A CN201980026565.8A CN201980026565A CN112367989A CN 112367989 A CN112367989 A CN 112367989A CN 201980026565 A CN201980026565 A CN 201980026565A CN 112367989 A CN112367989 A CN 112367989A
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- Prior art keywords
- salt
- alkyl
- stereoisomer
- tautomer
- hydrate
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 title claims description 36
- 206010019280 Heart failures Diseases 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 17
- 241000124008 Mammalia Species 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 150000004682 monohydrates Chemical class 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
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- 125000001424 substituent group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
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- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 208000038002 heart failure with reduced ejection fraction Diseases 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
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- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical class C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 12
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- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 4
- HXGDTGSAIMULJN-UHFFFAOYSA-N acetnaphthylene Natural products C1=CC(C=C2)=C3C2=CC=CC3=C1 HXGDTGSAIMULJN-UHFFFAOYSA-N 0.000 description 4
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 4
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- BAVDEDVBIHTHJQ-UVJOBNTFSA-N (2s)-1-[(2s)-6-amino-2-[[(1s)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid;hydrate Chemical compound O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 BAVDEDVBIHTHJQ-UVJOBNTFSA-N 0.000 description 3
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101001117256 Drosophila melanogaster High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A Proteins 0.000 description 3
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 description 3
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- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
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Images
Classifications
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Description
技术领域
本发明涉及用于治疗或预防心力衰竭的噻吩并嘧啶葡甲胺盐。
背景技术
心力衰竭是一个全球性问题,影响着全球3800万患者,是65岁或65岁以上的住院患者中最常见的诊断,折磨着600万以上的美国人。心力衰竭的5年生存率比大多数癌症都差,在美国,每年的心力衰竭护理费用估计超过300亿美元。Braunwald,Lancet,385,812-24(2015)。
在美国,每年约有1百万例心力衰竭住院。在美国约有570万成年人患有心力衰竭,而发展为心力衰竭的人中约有一半在诊断后的5年内死亡。疾病控制中心心力衰竭情况说明书,http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm。
在射血分数降低的心力衰竭(HFrEF)(也称为收缩期HF)中,心肌无法充分收缩,因此将较少的富氧血液喷射到循环中。患有这种疾病的患者在超声心动图上的左心室射血分数低于正常水平。射血分数保留的心力衰竭(HFpEF)是第二种心力衰竭,目前尚无任何疗法,因此尤其成问题。HFpEF至少构成所有心力衰竭病例的一半。运动不耐症、肺部充血和疲劳是明显的HFpEF症状,并导致不良的生活质量。
心力衰竭的医疗保健包括多种非药物、药物和侵入性策略,以治疗和预防进一步恶化。磷酸二酯酶9(PDE9)抑制剂先前已作为用于治疗疾病的潜在疗法进行过研究,所述疾病例如为过度活动的膀胱综合征、尿频、尿失禁、与前列腺增生相关的排尿困难、尿路结石、阿尔茨海默氏病、慢性阻塞性肺疾病、心肌梗塞、血栓形成、糖尿病等。参见例如美国专利号8,293,754。
最近发现,抑制PDE9的噻吩并嘧啶化合物在心血管疾病的治疗中、尤其是在HF的预防性治疗中显示出有前景的结果。参见国际公开号WO2018/009899。尽管噻吩并嘧啶化合物显示出有前景的抑制作用,但由于游离酸的缘故,化合物本身具有低溶解性。类似地,噻吩并嘧啶羧酸的钠盐和钾盐之类的形式也已经证明了具有较差的理化性质。参见U.S.8,293,754(公开了噻吩并嘧啶羧酸的实施例)。例如,钠盐和钾盐表现出许多问题,例如固体形式不稳定性、高吸湿性、多种多晶型物和高残留溶剂保留率。为了开发用于治疗HF的药物制剂而鉴定合适形式的噻吩并嘧啶类的需求仍未被满足。
发明内容
本发明的一个方面包括式(I)所示的噻吩并嘧啶化合物的葡甲胺盐
或其立体异构体、互变异构体或水合物,
其中:
R1是氢、(C1-C6)烷基、(C1-C6)烷氧基或含有1~6个卤素原子的(C1-C6)卤代烷基;
R2是氢、(C1-C6)烷基、[(C1-C6)亚烷基]芳基或氨基;
R3是氢、(C1-C6)烷基、(C2-C6)烯基、[(C1-C6)亚烷基]N(R4)(R5)、[(C1-C6)亚烷基]S(R4)或-X-Y,或者R2和R3与它们所连接的原子一起形成杂环基;
R4和R5独立地是H或(C1-C6)烷基;
X是化学键、-CH2-、-CH(OH)-、-CH(C6H5)-、-CO-、-CH2CH2-、-CH2CO-、-COCH2-、S、O或NH;
Y是环烷基、杂环基、芳基或杂芳基;
Z是S或O;
n是0,1,2,3或4;
其中任何烷基、亚烷基、环烷基、杂环基、杂芳基或芳基任选地被选自OH、CN、卤素、(C1-C6)烷基、O(C1-C6)烷基、(C2-C6)烯基、卤代烷基、氨基、氧代基和硝基的1、2或3个基团取代。
在一个方面,R1是(C1-C6)烷基。在另一方面,R1是甲基。
在一个方面,R2是氢。
在一个方面,R3是-X-Y。
在一个方面,X是-CH2-且Y是芳基。在另一方面,X是-CH2-且Y是被一个或多个为Cl的卤素原子取代的(C1-C6)芳基。在另一方面,X是-CH2-且Y是被一个或多个为Cl的卤素原子取代的苯基。
在一个方面,Z是氧。
在一个方面,n为0。
在本发明的一个方面,式(I)的葡甲胺盐选自:
在另一方面,式(I)的葡甲胺盐选自:
2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
2-(3-氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
5-甲基-4-氧代-2-(3-三氟甲基苄基)-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
2-(3-氯-4-氟苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
2-(5-氯-2-氟苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
2-(环戊-1-烯基甲基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
4-氧代-2-(噻吩-2-基甲基)-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
2-苄基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
2-(3-氯苄基)-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐;
4-氧代-2-(3-三氟甲基苄基)-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐。
在另一方面,式(I)的葡甲胺盐是:
在本发明的一个方面,式(I)的葡甲胺盐是结晶固体。
在本发明的另一方面,式(I)的结晶葡甲胺盐是一水合物。
在本发明的另一方面,式(I)的结晶葡甲胺盐是无水的。
在本发明的另一方面,式(I)的结晶葡甲胺盐是一水合物,具有在2Θ角数值为约5.24、约7.53、约11.40、约11.62、约15.04、约16.77、约17.58、约19.54、约22.18、约23.33、约24.38、约25.90和约28.67±0.2处有特征峰的粉末X射线衍射图。
在本发明的一个实施方式中,式(I)的结晶葡甲胺盐是一水合物,具有在2Θ角数值为约5.24、约7.53、约11.40、约15.04、约16.77、约17.58、约19.54、约22.18、约25.90和约28.67±0.2处有特征峰的粉末X射线衍射图。
在本发明的另一实施方式中,式(I)的结晶葡甲胺盐是一水合物,具有在2Θ角数值为约5.24、约7.53、约11.40、约15.04、约19.54、约22.18和约25.90±0.2处有特征峰的粉末X射线衍射图。
在本发明的另一实施方式中,式(I)的结晶葡甲胺盐是一水合物,具有在2Θ角数值为约7.53、约11.40、约19.54和约25.90±0.2处有特征峰的粉末X射线衍射图。
在本发明的另一方面,式(I)的结晶葡甲胺盐是无水的,具有在2Θ角数值为约7.21、约11.23、约13.36、约20.19、约24.92和约27.33±0.2处有特征峰的粉末X射线衍射图。
在本发明的一个实施方式中,式(I)的结晶葡甲胺盐是无水的,具有在2Θ角数值为约7.21、约13.36、约24.92和约27.33±0.2处有特征峰的粉末X射线衍射图。
本发明的另一方面包括将式I的噻吩并嘧啶化合物的葡甲胺盐给予哺乳动物,例如患有或易患心力衰竭的哺乳动物。
附图说明
图1显示2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸的葡甲胺盐一水合物的XRPD图。
图2显示2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸的无水葡甲胺盐的XRPD图。
具体实施方式
定义
除非另有说明,本文中所用的如下术语和短语具有下述含义。
“氨基”指:-NH2取代基。
“羧基”指:-CO2H取代基。
“羰基”指:-C(O)-、-(CO)-或-C(=O)-基团。本说明书中,所有表示法可互换使用。
“氰基”指:-C≡N取代基。
“乙酰基”指:-C(O)CH3取代基。
“羟基(Hydroxy)”或“羟基(hydroxyl)”指:-OH取代基。
“氧代”指:=O取代基。
“硫代”或“巯基”指:-SH取代基。
“烷基”指:饱和、直链或支化的烃链基团,其仅由碳和氢原子组成,具有一至十二个碳原子(C1-C12烷基)、一至八个碳原子(C1-C8烷基)或一至六个碳原子(C1-C6烷基),并且其通过单键与分子的剩余部分相连。示例性的烷基基团包括:甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)、3-甲基己基、2-甲基己基等。
“低级烷基”与上述烷基的含义相同,但具有一至四个碳原子(C1-C4烷基)。
“烯基”指:不饱和烷基基团,其具有至少一个双键和二至十二个碳原子(C2-C12烯基)、二至八个碳原子(C2-C8烯基)或二至六个碳原子(C2-C6烯基),并且其通过单键与分子的剩余部分相连,例如,乙烯基,丙烯基,丁烯基,戊烯基,己烯基等。
“炔基”指:不饱和烷基基团,其具有至少一个三键,和二至十二个碳原子(C2-C12炔基)、二至十个碳原子(C2-C10炔基)、二至八个碳原子(C2-C8炔基)或二至六个碳原子(C2-C6炔基),并且其通过单键与分子的剩余部分相连,例如,乙炔基,丙炔基,丁炔基,戊炔基,己炔基等。
“亚烷基”或“亚烷基链”指:直链或支化的二价烃(烷基)链,其将分子的剩余部分与原子团基团相连,分别仅由碳和氢组成。亚烷基可具有一至十二个碳原子,例如,亚甲基,亚乙基,亚丙基,亚正丁基等。亚烷基链通过单键或双键连接至分子的剩余部分。亚烷基链与分子的剩余部分的连接点可通过一个碳或该链中的任何两个碳。“任选取代的亚烷基”指:亚烷基或取代的亚烷基。
“烷氧基”指:式-ORa的基团,其中,Ra是具有如上定义的指示数量的碳原子的烷基。烷氧基基团的示例包括但不限于:-O-甲基(甲氧基),-O-乙基(乙氧基),-O-丙基(丙氧基),-O-异丙基(异丙氧基)等。
“芳基”或“芳基基团”指:包含氢、6-18个碳原子和至少一个芳环的烃环系基团。示例性的芳基是包含氢和6-9个碳原子和至少一个芳环的烃环系基团;包含氢和9-12个碳原子和至少一个芳环的烃环系基团;包含氢和12-15个碳原子和至少一个芳环的烃环系基团;或包含氢和15-18个碳原子和至少一个芳环的烃环系基团。出于本发明目的,芳基基团可以是单环、双环、三环或四环环系,其可包括稠合或桥接环系。芳基基团包括但不限于,源自如下构成的芳基基团:醋蒽烯(aceanthrylene)、苊烯(acenaphthylene)、荧蒽(acephenanthrylene)、蒽、薁、苯、(chrysene)、荧蒽、芴、不对称引达省(as-indacene)、对称引达省(s-indacene)、茚满、茚、萘、非那烯、菲、七曜烯(pleiadene)、芘,和苯并菲(triphenylene)。“任选取代的芳基”指:芳基基团或取代的芳基基团。
“环烷基”或“环烷基环”指:稳定的非芳族单环或多环烃基团,其仅由碳和氢原子组成,其可包括稠合或桥接环系,具有三至十五个碳原子,优选具有三至十个碳原子,三至九个碳原子,三至八个碳原子,三至七个碳原子,三至六个碳原子,三至五个碳原子,具有四个碳原子的环,或具有三个碳原子的环。环烷基环可以是饱和或不饱和的,并且通过单键与分子的剩余部分相连。单环基团包括,例如,环丙基、环丁基、环戊基、环己基、环庚基和环辛基。多环基团包括,例如,金刚烷基、冰片基、十氢萘基、7,7-二甲基-二环[2.2.1]庚基等。
“稠合”指:本文中所述的任何环结构,其与本发明化合物中已有的环结构稠合。当稠合环是杂环基环或杂芳基环时,成为稠合杂环基环或稠合杂芳基环的部分的已有环结构上的任何碳原子可被氮原子替代。
“卤代”或“卤素”指:溴代(溴)、氯代(氯)、氟代(氟)或碘代(碘)。
“卤代烷基”指:如本文中定义的,具有指示数量的碳原子的烷基基团,其中所述烷基基团的一个或多个氢原子被卤素取代(卤代基团),如上定义。卤素原子可以相同或不同。示例性的卤代烷基有:三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1,2-二氟乙基、3-溴-2-氟丙基、1,2-二溴乙基等。
“杂环基”,“杂环”,或“杂环环”指:稳定的3-18元饱和或不饱和基团,其由二至十二个碳原子和选自氮、氧和硫的一至六个杂原子,例如,一至五个杂原子、一至四个杂原子、一至三个杂原子,或一至二个杂原子组成。示例性的杂环包括但不限于:稳定的3-15元饱和或不饱和基团、稳定的3-12元饱和或不饱和基团、稳定的3-9元饱和或不饱和基团、稳定的8元饱和或不饱和基团、稳定的7元饱和或不饱和基团、稳定的6元饱和或不饱和基团,或稳定的5元饱和或不饱和基团。
除非说明书中另有特定说明,杂环基基团可以是单环、双环、三环或四环环系,其可包括稠合或桥接环系;并且,所述杂环基基团中的氮、碳或硫原子可以任选地被氧化;氮原子可任选地季铵化;并且杂环基基团可部分或完全饱和。非芳族杂环基基团的示例包括但不限于,氮杂环丁烷基(azetidinyl)、二氧戊环基、噻吩基[1,3]二噻烷基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、哌嗪基、4-哌啶酮基、吡咯烷基、吡唑烷基、奎宁环基、噻唑烷基、四氢呋喃基、硫杂环丁基(thietanyl)、三噻烷基(trithianyl)、四氢吡喃基、硫代吗啉基、硫杂吗啉基、1-氧代-硫代吗啉基,和1,1-二氧代-硫代吗啉基。杂环基包括本文定义的杂芳基,并且芳族杂环基的示例列于下文中的杂芳基的定义中。
“杂芳基”指:5-14元环系基团,其包含氢原子、一至十三个碳原子、选自氮、氧和硫的一至六个杂原子,和至少一个芳环。出于本发明目的,杂芳基基团可以是稳定的5-12元环、稳定的5-10元环、稳定的5-9元环、稳定的5-8元环、稳定的5-7元环,或稳定的6元环,其包含至少1个杂原子、至少2个杂原子、至少3个杂原子、至少4个杂原子、至少5个杂原子或至少6个杂原子。杂芳基可以是单环、双环、三环或四环环系,其可包括稠合或桥接环系;并且,杂芳基基团中的氮、碳或硫原子可任选地被氧化;氮原子可任选地季铵化。杂原子可以是芳族或非芳族环的成员,限制条件是该杂芳基中的至少一个环是芳族的。示例包括但不限于,氮杂基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并二噁茂基、苯并呋喃基、苯并氧氮茂基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧杂环庚三烯基(benzo[b][1,4]dioxepinyl)、1,4-苯并二噁烷基、苯并萘并呋喃基、苯并噁唑基、苯并二噁茂基、苯并二噁英基、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并硫代苯基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、噌啉基、二苯并呋喃基、二苯并硫代苯基、呋喃基、呋喃酮基、异噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、异喹啉基、吲嗪基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂基、噁唑基、环氧乙烷基、1-氧吡啶基、1-氧嘧啶基、1-氧吡嗪基、1-氧哒嗪基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、奎宁环基、异喹啉基、四氢喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基,和硫代苯基(即,噻吩基)。
“葡甲胺”指结构:
也称为(2R,3R,4R,5S)-6-(甲基氨基)己烷-1,2,3,4,5-五醇。
“亚砜”指:-S(O)-基团,其中硫原子共价连接至两个碳原子。
“砜”指:-S(O)2-或-(SO2)-基团,其中,六价硫通过双键连接至各两个氧原子,并且通过单个共价键进一步连接至两个碳原子。
本发明化合物可以多种异构形式,以及一种或多种互变异构形式存在,包括两种单一互变异构体,和互变异构体的混合物。术语"异构体"意在涵盖本发明化合物的全部异构形式,包括所述化合物的互变异构形式。
本文所述的一些化合物可具有不对称中心,并因此以不同的对映和非对映异构形式存在。本发明化合物可以是光学异构体或非对映异构体的形式。因此,本发明涵盖本发明的化合物和它们如本文所述的以其光学异构体、非对映异构体及其混合物,包括外消旋混合物的形式的应用。本发明化合物的光学异构体可通过已知技术获得,例如不对称合成、手性色谱法,或通过利用光学活性拆分剂对立体异构体进行化学分离。
除非另有指示,"立体异构体"指,化合物的一种立体异构体,其基本不含该化合物的另一种立体异构体。因此,具有手性中心的立体异构纯化合物基本不含该化合物的相反对映异构体。具有两个手性中心的立体异构纯的化合物基本不含该化合物的其它非对映异构体。典型的立体异构纯的化合物包含大于约80重量%的该化合物的一种立体异构体和小于约20重量%的该化合物的另一种立体异构体,例如,大于约90重量%的该化合物的一种立体异构体和小于约10重量%的该化合物的另一种立体异构体,或大于约95重量%的该化合物的一种立体异构体和小于约5重量%的该化合物的另一种立体异构体,或大于约97重量%的该化合物的一种立体异构体和小于约3重量%的该化合物的另一种立体异构体。
如果在描述的结构和对该结构给定的名称之间存在差异,则以描述的结构为准。此外,若结构或结构的部分的立体化学未用例如粗或虚线指示,则该结构或结构的部分应被理解为涵盖其全部立体异构体。然而,在其中存在多于一个手性中心的一些情况中,结构和名称单一对映异构体的形式表示,以助于描述相关的立体化学。有机合成领域的技术人员应知晓用制备所述化合物的单一对映异构体的方法制备它们的情况。
在本说明书中,术语“互变异构体”或“互变异构形式”指,通过低能垒可相互转化的不同能量的结构异构体。例如,质子互变异构体(也称为质子型互变异构体)包括经由质子迁移的相互转化,例如酮-烯醇和亚胺-烯胺异构化。价互变异构体包括经由一些键合电子的重组的相互转化。
本发明的互变异构体的示例如下:
术语"治疗"、"处理"和"疗法"指:减轻或根除疾病或与疾病相关的症状。在某些实施方式中,此类术语指:通过给予一种或多种预防或治疗剂至患有疾病的患者,使该疾病的扩散或恶化最小化。本发明的内容中,术语"治疗"、"处理"和"疗法"也指:
(i)预防所述疾病或病症在哺乳动物中发生,具体是在所述哺乳动物倾向于患上该病症但尚未诊断患有该病症时;
(ii)抑制该疾病或病症,即阻止其发展;
(iii)减轻该疾病或病症,即,使该疾病或病症消退;或
(iv)减轻由该疾病或病症所致的症状,即,减轻痛苦但不解决潜在的疾病或病症。本文中所用术语“疾病”和“病症”可互换使用,或可不同,其中具体的疾病或病症可不具有已知的致病物(从而病因尚不知晓),因此其尚未被视作疾病而仅仅是作用不希望的病症或综合征,其中由临床医师或多或少地鉴定出了具体的一组症状。
术语"有效量"指:在对于疾病的治疗或预防中足以提供治疗或预防益处或延缓疾病相关症状或使之最小化的一定量的本发明化合物或其它活性成分。此外,关于本发明化合物的治疗有效量指:一定量的治疗剂,其单独或与其它疗法联合,能在疾病的治疗或预防中提供治疗益处。在联合本发明化合物使用时,所述术语可涵盖这样的量,其改善全体治疗,降低或避免疾病症状或病因,或者增强其它治疗剂疗效或增强与其它治疗剂的协同作用。
术语"调节"、"调控"等指:化合物增加或减少例如磷酸二酯酶9(PDE9)的功能或活性的能力。"调节"及其各种形式意在涵盖抑制、拮抗、部分拮抗、活化、激动和/或部分激动与cGMP水平相关的活性。PDE9抑制剂是结合至、部分或完全阻断刺激、降低、防止、延迟活化、灭活、降低敏感性或下调信号转导的化合物。化合物调节激酶活性的能力可在酶测定法或细胞型测定法中证实。
"患者"或"对象"包括动物,例如人、奶牛、马、绵羊、羔羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或豚鼠。该动物可以是哺乳动物,例如非灵长类和灵长类(例如,猴子和人类)。在一个实施方式中,患者是人,例如,人类婴儿、孩童、青少年或成人。
治疗应用
在某些方面,所治疗的哺乳动物正患有或曾经患有心力衰竭。哺乳动物也可以患有或曾经患有充血性心力衰竭。哺乳动物也可以患有或曾经患有心源性休克。
在特定的实施方式中,所治疗的哺乳动物患有或易患心血管疾病或病症,包括心脏肥大、射血分数保留的心力衰竭(HfpEF)、射血分数降低(收缩功能降低)的心力衰竭(HFrEF)、舒张功能降低、适应不良性肥大、收缩功能保留的心力衰竭、舒张性心力衰竭、高血压性心脏病、主动脉瓣狭窄、肥厚型心肌病和/或缺血后心脏重塑。
在一个优选方面,选择患有或曾经患有心力衰竭的哺乳动物进行心力衰竭治疗,并且将本文所公开的化合物的盐给予所选哺乳动物。哺乳动物可以被鉴别为表现出具有低心输出量和/或低每搏输出量的充血性心力衰竭疾病。
在优选方面,所治疗的哺乳动物是人。
噻吩并嘧啶盐可以与一种或多种其它不同的用于治疗心力衰竭的药剂联合给药。
还提供了试剂盒,其适当地可以包含本文所公开的噻吩并嘧啶盐和使用噻吩并嘧啶盐来治疗心力衰竭的说明书。这些说明通常采用书面形式,例如位于药品说明书(package insert)或产品标签上。
本文所公开的噻吩并嘧啶盐的使用可提供测得的环状GMP水平的增加,例如相对于对照(来自用本文所公开的噻吩并嘧啶盐治疗之前的对象的血液或尿液样品),对象的血液或尿液样品中测得的环状GMP值有20、30、40、50、80或100%或更多的增加。
本文所公开的一种或多种噻吩并嘧啶盐所给予的对象合适地是哺乳动物,或者特别是人。在一些实施方式中,治疗心力衰竭的方法可以进一步包括选择患有或易患心力衰竭的对象,包括曾经患有或容易患有急性心源性休克的充血性心力衰竭的对象。
在其它实施方式中,治疗心力衰竭的方法可以进一步包括以下步骤:选择患有或易患心脏肥大、射血分数保留的心力衰竭(HfpEF)、射血分数降低(收缩功能降低)的心力衰竭(HFrEF)、舒张功能降低、适应不良性肥大、收缩功能保留的心力衰竭、舒张性心力衰竭、高血压性心脏病、主动脉瓣狭窄、肥厚型心肌病和/或缺血后心脏重塑的对象。
在一些实施方式中,本文所公开的一种或多种噻吩并嘧啶盐可以与一种或多种其它不同的心力衰竭治疗剂联合给药。用于联合给药的示例性药剂包括血管紧张素转换酶(ACE)抑制剂,例如卡托普利(Capoten)、依那普利(Vasotec)、福辛普利(Monopril)、利诺普利(Prinivil、Zestril)、培哚普利(Aceon)、奎那普利(Accupril)、雷米普利(Altace)和群多普利(Mavik);血管紧张素II受体阻滞剂(或抑制剂),例如坎地沙坦(Atacand)、氯沙坦(Cozaar)和缬沙坦(Diovan);单独或组合的脑啡肽酶抑制剂,例如血管紧张素受体脑啡肽抑制剂(ARNI)组合、如沙比特利/缬沙坦(Entresto),If通道阻滞剂(或抑制剂)、如伊伐布雷定(Corlanor);β受体阻滞剂,例如比索洛尔(Zebeta)、琥珀酸美托洛尔(Toprol XL)、卡维地洛(Coreg)和卡维地洛CR(Coreg CR)Toprol XL;醛固酮拮抗剂,例如螺内酯(Aldactone)和依普利酮(Inspra);肼屈嗪和硝酸异山梨酯;利尿剂,例如呋塞米(Lasix)、布美他尼(Bumex)、托拉塞米(Demadex)、氯噻嗪(Diuril)、阿米洛利(Midamor)、氯噻酮(Hygroton)、氢氯噻嗪(Esidrix、Hydrodiuril)、吲达帕胺(Lozol)、美托拉宗(Zaroxolyn)和氨苯蝶啶(Dyrenium);抗凝剂(血液稀释剂);和/或降低胆固醇的药物(他汀类)。
本文所公开的噻吩并嘧啶盐的治疗有效剂量可以在相当宽的范围内变化,并且可以调整或选择以提供足够水平的活性剂或维持所需的效果。可能需要考虑的因素包括疾病状态的严重程度,对象的总体健康状况,对象的年龄、体重和性别,饮食,给药的时间和频率,药物组合,反应敏感性和对治疗的耐受性/响应。合适的有效剂量可以在每天0.01至5或10mg/kg的范围内,尽管也可以适当地使用超出该范围的剂量。
盐的治疗有效剂量可以通过多种给药途径给予对象。尽管也可以将其它给药方案用作肠胃外、舌下或经植入的储库,但是通常优选口服或局部给药。在一些实施方式中,可以将盐配制成用于给药目的的胶囊,片剂,凝胶,粉剂,液剂,悬浮剂或乳剂。
如所讨论的,还提供了治疗组合物,其包括一种或多种本文所公开的盐,任选地包括药学上可接受的载体。
如本文所用,术语“药学上可接受的载体”是指药学上可接受的材料、组合物或载体,例如液体或固体填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或包封材料,参与将本发明中有用的化合物的盐携带或输送到对象内或者携带或输送给对象,从而使其可以执行其预期功能。通常,将此类构建体从一个器官或身体部分携带或输送到另一器官或身体部分。在与包括本发明中有用的盐在内的制剂的其它成分相容并且对患者无害方面,各载体必须是“可接受的”。可以用作药学上可接受的载体的材料的一些示例包括:糖,例如乳糖/葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如乙基纤维素、乙酸纤维素和羧甲基纤维素钠;粉末状胶黄芪;麦芽;明胶;滑石;赋形剂,例如可可脂和栓剂蜡;油,例如花生油,棉籽油,红花油,芝麻油,橄榄油,玉米油和大豆油;二醇,例如丙二醇;多元醇,例如甘油,山梨糖醇,甘露糖醇和聚乙二醇;酯,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;表面活性剂;海藻酸;无热原水;等渗盐水;林格氏溶液;乙醇;磷酸盐缓冲溶液;和药物制剂中使用的其它无毒相容性物质。
在一个优选方面,可以将盐配制成用于给药目的的胶囊,片剂,凝胶,粉剂,液剂,悬浮剂或乳剂;然而,给药方法可以无特别限制。
在一些实施方式中,治疗有效剂量的化合物的盐可以口服、肠胃外、口腔、舌下或通过植入式储库给药。
化合物的盐可以与给药说明书一同包括在试剂盒、容器、包装或分配器内。例如,试剂盒可以包含产品标签或书面药品说明书,其中记载用于治疗包括预防心力衰竭在内的组合物的用途。
本发明的优选的盐可以是通过体外试验确定的磷酸二酯酶9(PDE9)的强效抑制剂。
以下非限制性实施例是对本发明的说明。
实施例1
可以通过已知流程合成用于本发明方法和试剂盒的噻吩并嘧啶盐,所述流程包括Gotanda等的美国专利8,293,754中公开的那些流程。噻吩并嘧啶类可以通过母体噻吩环上的嘧啶核的环合或母体嘧啶环上的噻吩核的环合来合成。参见Abdel-Megid等,J.Pharm.Appl Chem.,2,No.3,103-127(2016)。
2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸(1)的合成。将1mmol的2,5-二甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯(2)、1mmol的碳酸钠、15mL的乙腈和1mL的合适的苄基氯的混合物合并,并在回流下加热过夜。真空除去挥发物,并将所得残余物通过硅胶上的柱色谱法纯化(用氯仿:甲醇=100∶1洗脱),得到45%的2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸乙酯(3)。
将所得的噻吩并嘧啶羧酸酯与3.4mL的1N氢氧化钠水溶液和2.2mL的乙醇合并,并在回流下加热2小时。冷却后,将反应液倒在冰上,用稀盐酸调至酸性,通过过滤回收随后沉淀的晶体。用水洗涤后,通过减压下的加热将晶体干燥,得到所要的羧酸(1)。(参见U.S.8,293,754,实施例1)
实施例2
2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐一水合物(4)的合成。将1.0当量份(450mg)的2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸(1)与14体积的纯乙醇和10%的葡甲胺水溶液合并,形成初始浆料。将合并的混合物在45℃下浆化,其中最初形成稀浆料。稀浆料逐渐转变成不可搅动的浆料。用额外体积的EtOH:水(8:2体积)稀释所得的浆料,其提供35-45体积的总溶剂体积。过滤浆料,用2份体积的EtOH:水(8:2体积)洗涤两次,得到所要的盐(4)。参见图1和表1。
表1.葡甲胺盐一水合物形式的XRPD峰表
实施例3
无水2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐(5)的合成。将1.0当量份(450mg)的2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸(1)与无水四氢呋喃(THF)和10%的葡甲胺水溶液(426.0μL)合并,形成几乎澄清的溶液。将合并的混合物在室温下浆化,逐渐转变成粘稠浆料。用额外体积的无水THF稀释所得的浆料,得到所要的无水盐(5)。参见图2和表2。
表2.葡甲胺盐无水晶体形式的XRPD峰表
实施例4
无水2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐“D型”(6)的合成。将1.0当量份(450mg)的2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸(1)与无水四氢呋喃(THF)和10%的葡甲胺水溶液(426.0μL)合并,形成几乎澄清的溶液。将合并的混合物在室温下浆化,逐渐转变成粘稠浆料。用额外体积的乙醇/水(8:2体积/体积%)稀释所得的浆料,以提供一水合盐(4)。该一水合盐也称为“水合物”,将其加热至170℃并在170℃下保持30分钟,然后冷却至室温(20-23℃),得到脱水盐(6),记作“D型”。参见表3。
表3.无水羧酸葡甲胺盐“D型”的XRPD
实施例5
无水2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸葡甲胺盐“O型”(7)的合成。将1.0当量份(450mg)的2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸(1)与DMSO:乙腈(1:1体积/体积)溶剂体系和10%的葡甲胺水溶液合并,其通过“急冷”而迅速形成溶剂化物形式的晶体。回收所得的晶体,在大气中干燥,得到“O型”的所要的无水盐(7)。参见表4。
表4.无水羧酸葡甲胺盐“O型”的XRPD
实施例6
2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸精氨酸盐(8)的合成。将1.0当量份(450mg)的2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸(1)与乙醇:水(8:2体积/体积)溶剂体系和1.1当量份的L-精氨酸合并。将合并的混合物在室温下浆化,逐渐转变成粘稠浆料。用额外体积的乙醇/水(8:2体积/体积%)稀释所得的浆料(总共35-40体积)。回收晶体并干燥,得到所要的精氨酸盐(8)。
实施例7
2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸赖氨酸盐(9)的合成。将1.0当量份(450mg)的2-(3,4-二氯苄基)-5-甲基-4-氧代-3,4-二氢噻吩并[2,3-d]嘧啶-6-羧酸(1)与乙醇:水(8:2体积/体积)溶剂体系和1.1当量份的L-赖氨酸合并。将合并的混合物在室温下浆化,逐渐转变成粘稠浆料。用额外体积的乙醇/水(8:2体积/体积%)稀释所得的浆料。回收晶体并干燥,得到所要的赖氨酸盐(9)。
实施例8
初步研究确定噻吩并嘧啶羧酸是PDE9抑制剂,可用于治疗或预防HF。然而,已证明羧酸形式的化合物几乎完全不溶于任何药学上可接受的制剂。在进一步的研究中,钾盐被确定为制剂的候选物,因为它是可溶的,在临床前毒理学研究中提供高暴露量,并且相对容易扩大规模。然而,钠盐和钾盐形式的噻吩并嘧啶表现出许多难以克服的挑战,例如固体形式不稳定性、高吸湿性、多种多晶型物和高残留溶剂保留率。出乎意料的是,噻吩并嘧啶化合物的一水合物结晶葡甲胺盐为药物制剂提供了所需的性质,如表5所示。
表5.噻吩并嘧啶羧酸(1)的结晶盐
如表5所示,与L-精氨酸(8)、L-赖氨酸(9)和钾盐相比,葡甲胺盐(4)表现出低吸湿性和形状稳定性。
实施例9:狗的药代动力学研究
使用健康的狗来研究不同的盐候选物,以评估每种候选物的药代动力学特性。采用了六个处理组:
N=4个动物/组制剂
1-4组 K+、L-精氨酸、L-赖氨酸、葡甲胺以胶囊内粉末形式给药
5组 羧酸形式在含54mM NaOH的80%丙二醇(PG)/20%水中的溶液
6组 K+盐在0.5%甲基纤维素(MC)中的溶液
将动物禁食过夜,可自由饮水。在给药前30分钟给予五肽胃泌素(PG)(6μg/kg,IM)。给药后4小时恢复进食。
盐候选物、游离酸和对照的平均血浆浓度-时间曲线提供了以下结果:
表6.药代动力学特性
在表6中,葡甲胺盐(4)表现出优异的药代动力学特性,同时保留了表5中所示的优异形式和稳定性。数据表明,以胶囊内粉末(PIC)形式给药的葡糖胺盐提供了分别与以溶液形式给药的游离酸和钾盐相当的暴露量。就AUC最后、Cmax和Tmax值而言,葡甲胺盐(4)的结果优于L-精氨酸(8)、L-赖氨酸(9)和钾盐(PIC)的结果。类似地,一水合葡甲胺盐的AUC最后显示出与游离酸相当的消除速率。因此,药代动力学数据证明了,一水合葡甲胺盐优于其它盐衍生物,并且具有与游离酸相当的生物利用度。
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Claims (20)
1.具有以下结构的式(I)的盐:
或其立体异构体、互变异构体或水合物,
其中:
R1是氢、(C1-C6)烷基、(C1-C6)烷氧基或含有1~6个卤素原子的(C1-C6)卤代烷基;
R2是氢、(C1-C6)烷基、[(C1-C6)亚烷基]芳基或氨基;
R3是氢、(C1-C6)烷基、(C2-C6)烯基、[(C1-C6)亚烷基]N(R4)(R5)、[(C1-C6)亚烷基]S(R4)或–X-Y,或者R2和R3与它们所连接的原子一起形成杂环基;
R4和R5独立地是H或(C1-C6)烷基;
X是化学键、–CH2–、–CH(OH)–、–CH(C6H5)–、–CO–、–CH2CH2–、–CH2CO–、–COCH2–、S、O或NH;
Y是环烷基、杂环基、芳基或杂芳基;
Z是S或O;
n是0,1,2,3或4;
其中任何烷基、亚烷基、环烷基、杂环基、杂芳基或芳基任选地被选自OH、CN、卤素、(C1-C6)烷基、O(C1-C6)烷基、(C2-C6)烯基、卤代烷基、氨基、氧代基和硝基的1、2或3个基团取代。
2.如权利要求1所述的盐或其立体异构体、互变异构体或水合物,其中R1是(C1-C6)烷基,R2是–H,且R3是–X-Y。
3.如权利要求2所述的盐或其立体异构体、互变异构体或水合物,其中X是–CH2-且Y是芳基。
4.如权利要求3所述的盐或其立体异构体、互变异构体或水合物,其中X是–CH2-且Y是被一个或多个卤素原子取代的(C1-C6)芳基。
5.如权利要求2所述的盐或其立体异构体、互变异构体或水合物,其中Z是氧。
6.如权利要求1所述的盐或其立体异构体、互变异构体或水合物,其中n为0。
8.如权利要求1所述的盐或其立体异构体、互变异构体或水合物,其中式(I)的葡甲胺盐是结晶固体。
9.如权利要求8所述的盐或其立体异构体、互变异构体或水合物,其中式(I)的结晶固体是一水合物。
10.如权利要求8所述的盐,其中式(I)的结晶固体是无水的。
11.如权利要求9所述的盐,其中式(I)的结晶固体是一水合物,具有在2Θ角数值为约5.24、约7.53、约11.40、约11.62、约15.04、约16.77、约17.58、约19.54、约22.18、约23.33、约24.38、约25.90和约28.67±0.2处有特征峰的粉末X射线衍射图。
12.如权利要求9所述的盐,其中式(I)的结晶固体是一水合物,具有在2Θ角数值为约5.24、约7.53、约11.40、约15.04、约19.54、约22.18和约25.90±0.2处有特征峰的粉末X射线衍射图。
13.如权利要求9所述的盐,其中式(I)的结晶固体是一水合物,具有在2Θ角数值为约7.53、约11.40、约19.54和约25.90±0.2处有特征峰的粉末X射线衍射图。
14.如权利要求9所述的盐,其中式(I)的结晶固体是一水合物,具有如图1所示的粉末X射线衍射图。
15.一种在有需要的哺乳动物中治疗或预防心血管疾病或病症的方法,包括给予所述哺乳动物治疗有效量的式(I)的化合物的盐:
或其立体异构体、互变异构体或水合物,
其中:
R1是氢、(C1-C6)烷基、(C1-C6)烷氧基或含有1~6个卤素原子的(C1-C6)卤代烷基;
R2是氢、(C1-C6)烷基、[(C1-C6)亚烷基]芳基或氨基;
R3是氢、(C1-C6)烷基、(C2-C6)烯基、[(C1-C6)亚烷基]N(R4)(R5)、[(C1-C6)亚烷基]S(R4)或–X-Y,或者R2和R3与它们所连接的原子一起形成杂环基;
R4和R5独立地是H或(C1-C6)烷基;
X是化学键、–CH2–、–CH(OH)–、–CH(C6H5)–、–CO–、–CH2CH2–、–CH2CO–、–COCH2–、S、O或NH;
Y是环烷基、杂环基、芳基或杂芳基;
Z是S或O;
n是0,1,2,3或4;
其中任何烷基、亚烷基、环烷基、杂环基、杂芳基或芳基任选地被选自OH、CN、卤素、(C1-C6)烷基、O(C1-C6)烷基、(C2-C6)烯基、卤代烷基、氨基、氧代基和硝基的1、2或3个基团取代。
18.如权利要求17所述的方法,其中所述葡甲胺盐或其立体异构体、互变异构体或水合物具有如图1所示的粉末X射线衍射图。
19.如权利要求15所述的方法,其中心血管疾病或病症是心脏肥大、心力衰竭、射血分数保留的心力衰竭(HfpEF)、射血分数降低(收缩功能降低)的心力衰竭(HFrEF)、舒张功能降低、适应不良性肥大、收缩功能保留的心力衰竭、舒张性心力衰竭、高血压性心脏病、主动脉瓣狭窄、肥厚型心肌病或缺血后心脏重塑。
20.如权利要求19所述的方法,其中心血管疾病或病症是心力衰竭。
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US201862658683P | 2018-04-17 | 2018-04-17 | |
US62/658,683 | 2018-04-17 | ||
PCT/US2019/027665 WO2019204298A1 (en) | 2018-04-17 | 2019-04-16 | Meglumine salts of thienopyrimidines |
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WO2018009899A1 (en) * | 2016-07-07 | 2018-01-11 | Cardurion Pharmaceuticals, Llc | Methods for treatment of heart failure |
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2019
- 2019-04-16 US US16/385,748 patent/US10822346B2/en active Active
- 2019-04-16 BR BR112020021153-2A patent/BR112020021153A2/pt not_active Application Discontinuation
- 2019-04-16 AU AU2019255233A patent/AU2019255233A1/en not_active Abandoned
- 2019-04-16 CN CN201980026565.8A patent/CN112367989A/zh active Pending
- 2019-04-16 MX MX2020010884A patent/MX2020010884A/es unknown
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US4377583A (en) * | 1981-08-21 | 1983-03-22 | Mead Johnson & Company | N-Methyl-D-glucamine salt of with 3,4-dihydro-5-methyl-6-(2-methylpropyl)-4-oxothieno[2,3-d]pyrimidine-2-carboxylic acid |
US20020010208A1 (en) * | 1996-05-22 | 2002-01-24 | Victor Shashoua | Dha-pharmaceutical agent conjugates of taxanes |
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WO2018009899A1 (en) * | 2016-07-07 | 2018-01-11 | Cardurion Pharmaceuticals, Llc | Methods for treatment of heart failure |
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AU2019255233A1 (en) | 2020-11-26 |
SG11202010161UA (en) | 2020-11-27 |
BR112020021153A2 (pt) | 2021-03-23 |
KR20210002541A (ko) | 2021-01-08 |
MX2020010884A (es) | 2021-02-26 |
PH12020551701A1 (en) | 2021-09-06 |
US10822346B2 (en) | 2020-11-03 |
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