WO2018233326A1 - 有机物盐形式的硫化氢供体及其制备方法 - Google Patents

有机物盐形式的硫化氢供体及其制备方法 Download PDF

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WO2018233326A1
WO2018233326A1 PCT/CN2018/079115 CN2018079115W WO2018233326A1 WO 2018233326 A1 WO2018233326 A1 WO 2018233326A1 CN 2018079115 W CN2018079115 W CN 2018079115W WO 2018233326 A1 WO2018233326 A1 WO 2018233326A1
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hydrogen sulfide
compound
organic
salt
donor
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郑虎
翁玲玲
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成都市考恩斯科技有限责任公司
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    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new form of hydrogen sulfide donor which may have research and/or medicinal value.
  • H 2 S hydrogen sulfide
  • the hydrogen sulfide has a molecular weight of 34, a boiling point of -63.33 ° C, 1.13 times heavier than air, a gas at normal temperature, and an odor of 0.02 to 0.13 ppm in the air. It can dissolve 0.5g in 100ml water at 10 °C, only dissolve 0.3g at 20 °C, the pH value of the solution is 4.5, PKa17.04, PHa211.96, and alkali metals such as Na, K, Ca, etc. Or NH 3 forms a stable salt.
  • H 2 S is an endogenous molecular gas in living organisms, it has attracted extensive attention like NO and CO, and has become a hot topic and frontier topic in world scientific research.
  • the research field mainly includes the mechanism of H 2 S formation in vivo, molecular biology research of H 2 S in vivo, including the molecular regulation mechanism of cells, the correlation between H 2 S and major diseases and its molecular mechanism, and the supply of hydrogen sulfide. Body research to develop its medical value.
  • H 2 S present in the body can pass at least three of thiosulfate r-lyase (CSE), cystathionine ⁇ -synthase (CBS) and 3-thiopyruvate transferase (3-MST).
  • CSE thiosulfate r-lyase
  • CBS cystathionine ⁇ -synthase
  • 3-thiopyruvate transferase 3-thiopyruvate transferase transferase
  • the enzyme is naturally produced in the body by using a sulfur-containing amino acid such as L-cysteine as a substrate, and can also be produced by spontaneous reaction of red blood cells such as glucose and sulfur with reduced glutathione (GSH).
  • GSH reduced glutathione
  • H 2 S donors such as Na 2 S, NaHS, CaS
  • organic H 2 S donors such as sulfur-containing organic compounds
  • organically synthesized H 2 S donors such as sulfhydryl-containing aspirin, thiol-containing ibuprofen, and the like.
  • molecular chemical studies such as their chemical structure, pharmacological activity on cell biology, effects on enzymes, and gene expression, have become more extensive and deeper (Philip K. Moore, Chemistry Biochemistry and Pharmacology of Hydrogen Sulfide). , Springer International Publishing, Switzerland 2015).
  • the present invention will provide a new form of hydrogen sulfide (H 2 S) donor which may have research and/or drug development value, ie a hydrogen sulfide donor in the form of an organic salt, and further provide its corresponding Preparation.
  • H 2 S hydrogen sulfide
  • the hydrogen sulfide donor in the form of an organic salt according to the present invention is a salt structural material formed of an organic compound having a basic structure and hydrogen sulfide (H 2 S). Since hydrogen sulfide is an acidic component, it is necessary to have a corresponding basic structure in the organic compound molecule capable of forming a salt with it, and the stronger the basicity, the higher the stability of the formed salt. In general, the organic compound having a basic structure having a pH of ⁇ 9.5 in a 1 mol/L concentration solution, and the donor in the form of a salt formed by hydrogen sulfide, generally have sufficient stability. .
  • organic compounds having a basic structure contain an N element in a molecular structure or a compound having an N group, including an aliphatic compound in an open-chain form, a monocyclic or polycyclic form, a compound having an aromatic ring and/or a heterocyclic structure, etc.
  • R or R 1 - R 4 in each structure may be a C 1-3 alkane or an olefin, respectively, and X may be a group containing O, S, N, respectively.
  • n 1 ⁇ 2).
  • it may include, but is not limited to, the compounds listed below.
  • the hydrogen sulfide donor of the present invention is a salt structure formed of an organic compound having a basic structure and hydrogen sulfide, it may have the same as an inorganic hydrogen sulfide donor such as sodium sulfide or sodium hydrosulfide, in a living body or a human body.
  • an inorganic hydrogen sulfide donor such as sodium sulfide or sodium hydrosulfide
  • hydrogen sulfide can be easily and quickly released and released without the need for other forms of organic hydrogen sulfide donors as reported now, and even in the body, it is necessary to participate in complex physiology by means of different enzymes. / Biochemical reaction to release hydrogen sulfide.
  • organic compound having a basic structure which can form a salt with hydrogen sulfide in terms of its intervention or influence on the physiological processes of the organism (especially the human body), it may include the physiological activity related to the organism and/or A compound which is affected by pharmacological activity, and which does not have any physiological activity and/or pharmacological activity to an organism, and which does not have an adverse effect, can also be accepted as a so-called "neutral compound".
  • neutral compound the donor which forms a salt structure with hydrogen sulfide enters the organism and dissociates, and the only part which can produce an active action is hydrogen sulfide, and thus such hydrogen sulfide is supplied.
  • hydrogen sulfide is formed by forming a salt with the basic organic compound capable of having physiological and/or pharmacological activity corresponding to the living body, particularly to the human body.
  • the purpose and effect of the body to coordinate or complement each other, and/or the respective adverse effects can be mutually restricted or offset, not only can be used for the study of hydrogen sulfide, but also can be directly applied.
  • the above-mentioned basic organic compound containing an N element or having an N group may include a compound having one of structures such as anthracene, anthraquinone, an anthracene or an amine in the structure, such as
  • the basic organic compound containing an N element or having an N group may include, but is not limited to, a basic amino acid compound such as arginine, methionine, cystine, cysteine or the like.
  • the basic organic compound containing an N element or having an N group may further include an alkaloid compound with or without physiological/pharmacological activity which has been reported and/or used.
  • the compound which is currently the preferred focus may be a base type compound which has been studied as a therapeutic drug form for a disease which is closely related to hydrogen sulfide.
  • a base type compound which has been studied as a therapeutic drug form for a disease which is closely related to hydrogen sulfide.
  • metformin or similar excellent drugs for the treatment of diabetes which are made into hydrogen sulfide salts to become drug-hydrogen sulfide donor compounds, thereby facilitating the formation of dual acting targets or synergistic effects.
  • the present invention A common preparation method of a hydrogen sulfide donor in the form of an organic salt, dissolved in water or other good solvent of the raw material compound, formed into a salt by hydrogen sulfide gas, and subjected to a conventional post-treatment method such as precipitation, filtration, concentration or recrystallization. After separation from the reaction solvent, the target compound in a solid form can be obtained.
  • hydrogen sulfide salts such as arginine hydrogen sulfide, guanethidine, clonidine, morpholinium, phenacetam, cimetidine, and the like can be prepared by this method. get.
  • alkaloids such as berberine and yellow vine can also be made into hydrogen sulfide by this method.
  • a conventional non-pharmaceutical basic compound such as an anthraquinone compound can be used as a hydrogen sulfide salt after extensively exploring, researching, and understanding the properties of a hydrogen sulfide salt.
  • the common or commercially available forms are mostly stable salt compounds such as hydrochlorides, sulfates, carbonates and the like.
  • a corresponding alkaline reagent such as sodium hydroxide, barium hydroxide or silver ammonia depending on the form of the salt, or Under strong alkaline conditions such as sodium ethoxide or sodium methoxide, or treated with a strong alkaline or weakly basic ion exchange resin to obtain the free base, then directly pass hydrogen sulfide gas or hydrogen sulfide water. Or a solution such as ethanol to convert it into a salt of hydrogen sulfide.
  • the reaction temperature can be generally carried out in the range of -10 to 50 °C. After the reactants are filtered or concentrated by vacuum drying or the like, a hydrogen sulfide salt-like product can be obtained.
  • Figure 1 is a schematic diagram showing the metabolic process of sulfur-containing amino acids in the body as shown in the prior studies.
  • Metformin hydrochloride 1.65 g (10 mmol) was dissolved in 10 ml of water at room temperature, and 5 ml of a 2 mol/L sodium hydroxide aqueous solution was added thereto, and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure of water to give a white solid. A strong basic white solid metformin free base was obtained.
  • the crude product has a melting point of 90-100 ° C, and the product has a melting point of 110-112 ° C after recrystallization.
  • the sample moisture content is 11.58%.
  • the content of the reducing substance by the iodometric method was 88.2%.
  • the structure is:
  • Example 7 L-arginine hydrogen sulfide salt (C 6 H 14 N 4 O 2 .H 2 S, MW: 208.28)
  • the sample moisture content was 12.9%.
  • the content of the reducing substance by the iodometric method was 69.2%.
  • the structure is:
  • Example 8 Morpholine biguanide hydrogen sulfide salt (C 6 H 13 N 5 OH 2 S, MW: 205.28)
  • the sample moisture content was 16.26%.
  • the content of the reducing substance by the iodometric method was 76.3%.
  • the structure is:
  • the sample moisture content was 3.72%.
  • the content of the reducing substance by the iodometric method was 85.5%.
  • the structure is:
  • the sample moisture content was 5.36%.
  • the content of the reducing substance by the iodometric method was 86.2%.
  • the structure is:
  • the sample moisture content is 3.58%
  • the content of the reducing substance by the iodometric method was 90.2%.
  • the structure is:
  • Example 12 Famotidine Hydrogen Sulfide (C 8 H 15 N 7 O 2 S 3 .H 2 S, MW: 371.53)
  • the sample moisture content was 4.62%.
  • the content of the reducing substance by the iodometric method was 93.7%.
  • the structure is:
  • the mixture was mixed with 100 mL of tetrahydrofuran at room temperature, and then added dropwise to a reaction flask filled with hydrogen sulfide gas at room temperature. After reacting for 12 hours at room temperature, the mixture was frozen at 0-5 ° C, and a solid was precipitated, and filtered to obtain a white solid 3.6. g, the target compound is collected.
  • the sample moisture content was 3.93%.
  • the content of the reducing substance was determined by iodometric method to be 92.6%.
  • the structure is:
  • the sample moisture content was 2.72%.
  • the content of the reducing substance by the iodometric method was 93.3%.
  • the structure is:
  • the sample moisture content was 6.52%.
  • the content of the reducing substance by the iodometric method was 91.9%.
  • the structure is:
  • the sample moisture content was 3.37%.
  • the content of the reducing substance by the iodometric method was 95.2%.
  • the structure is:
  • Example 17 1,8-diazabicycloundec-7-ene (DBU) hydrogen sulfide salt (C 9 H 16 N 2 .H 2 S, MW: 186.32)
  • the sample moisture content was 18.33%.
  • the content of the reducing substance was determined by iodometric method to be 62.6%.
  • the structure is:
  • Example 18 4-Dimethylaminopyridine (DMAP) hydrogen sulfide salt (C 7 H 10 N 2 .H 2 S, MW: 156.25)
  • the sample moisture content was 5.62%.
  • the content of the reducing substance by the iodometric method was 85.9%.
  • the structure is:
  • the sample moisture content was 2.98%.
  • the content of the reducing substance was determined by iodometric method to be 92.9%.
  • the structure is:
  • the sample moisture content was 3.65%.
  • the content of the reducing substance by the iodometric method was 93.7%.
  • the structure is:
  • the present invention provides a hydrogen sulfide (H 2 S) donor in the form of a new structural form that can be of research and/or pharmaceutical development value, i.e., a hydrogen sulfide donor in the form of an organic salt, and further provides a corresponding method of preparation.
  • the hydrogen sulfide donor of the invention has simple structure, simple and convenient preparation method, and can obtain different forms of hydrogen sulfide donor according to research and development requirements, and the process of dissociating and providing hydrogen sulfide in the body is simple and quick after entering the living body. And effective, without the need for any enzymes or other complex conditions, has great application prospects and value.

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Abstract

有机物盐形式的硫化氢供体及其制备方法。所述的硫化氢供体是由具有碱性结构的有机化合物与硫化氢形成的盐类结构。该硫化氢供体的结构简单，制备方法简便易行，并且可以根据研究和开发的需要得到不同形式的硫化氢供体，进入生物体后，在体内离解和提供硫化氢的过程简单、快捷和有效，无需有任何酶或其它复杂条件的要求，具有极大的应用前景和价值。

Description

有机物盐形式的硫化氢供体及其制备方法 技术领域
本发明涉及一种可具有研究和/或药用价值的新形式硫化氢供体。
背景技术
众所周知,硫化氢(H 2S)因其恶臭、高毒、被列为有毒气体而认为毫无医药用途。但近十多年来对其在体内生物***中影响生理病理过程的了解，惊人地发现内源性的H 2S具有广泛的生物学效应，具有很大的医学潜力。
硫化氢分子量34，沸点-63.33℃，比空气重1.13倍，常温下为气体，空气中含0.02～0.13ppm就可闻出其臭味。其在10℃时的100ml水中可溶解0.5g，20℃时只能溶解0.3g，溶液的pH值为4.5，PKa17.04，PHa211.96，与Na，K，Ca等碱金属，碱土金属能或NH 3形成稳定的盐。
自从发现H 2S是生物体内的内源性分子气体之后，其与NO、CO一样已引起了广泛的重视，成为了世界科学研究的热点和前沿课题。研究领域主要包括体内H 2S形成的机制，H 2S在体内的分子生物学研究，包括对细胞的分子调控机制，H 2S与重大疾病的相关性及其分子机制，以及对硫化氢供体的研究，以开发其医学价值。
研究发现，存在于体内的H 2S，至少可以通过硫代硫酸r裂解酶(CSE)，胱硫醚β-合成酶(CBS)和3-硫基丙酮酸转移酶(3-MST)等三种酶，将如L-半胱氨酸等含硫氨基酸作为底物在体内自然产生，也可通过如葡萄糖和硫并有还原型谷胱甘肽(GSH)的红细胞自发反应产生。替内含硫氨基酸的代谢过程如图1所示。
对H 2S的体内生物调控方面的研究，目前特别关注的是其与哮喘，动脉粥样硬化和糖尿病，高血压等疾病的关系。近期在H 2S与肿瘤学方面的关系也引起了许多重视，主要靶点是与H 2S有关联的酶或基因水平的表达。
如有报道(Qiangian Sun et al.Hypertension,2016,67(3)541-9)，人体摄入过量的盐可以导致高血压的产生。因而，世界卫生组织建议健康人群每日食盐摄入量应在6g以下。研究发现，同时在体内引入H 2S供体如牛磺酸，在体内使形成外源性H 2S则可以作为机体产生因盐导致的高血压的内源性防御体系，因为在高血压发生过程中发。高血压前期人群 血浆中H 2S水平显著降低。
已有研究表明，使用无机H 2S供体包括如Na 2S、(NH 4) 2S等，在动物脑缺血，血流量、血液流变学等研究中都表现出有意义的结果(Yu Zhao et al Design,Synthesis and Cardioprotective Effect of N-Mercapto-Based Hydrogen Sulfide Donors J.of Med，chem(2015,58(18):7501-7511))。
作为硫化氢的供体，目前已有报道的有三类，包括无机H 2S供体如Na 2S，NaHS，CaS；有机H 2S供体，如含硫的有机化合物；有机合成的H 2S供体，如含巯基的阿司匹林，含巯基的布洛芬等。包括对它们的化学结构，药理活性对细胞生物调控，对酶的影响，与基因表达等分子生物学研究个，都已愈来愈广泛和深入(Philip K.Moore，Chemistry Biochemistry and Pharmacology of Hydrogen Sulfide，Springer International Publishing，Switzerland 2015)。
发明内容
鉴于此，本发明将提供一种可具有研究和/或药物开发价值的新结构形式的硫化氢(H 2S)供体，即有机物盐形式的硫化氢供体，并进一步提供了其相应的制备方法。
本发明所述的有机物盐形式的硫化氢供体，是由具有碱性结构的有机化合物与硫化氢(H 2S)所形成的盐类结构物质。由于硫化氢是一种酸性成分，因此能与其成盐的有机化合物分子中需具有相应的碱性结构，且碱性越强，所形成的盐的稳定性越高。一般情况下，在1mol/L浓度溶液中的pH值≥9.5的所述具有碱性结构的有机化合物，与硫化氢所形成的盐结构形式的所述供体，通常都可以具有足够的稳定性。
众所周知，所述具有碱性结构的有机化合物，绝大多数都是在分子结构中含有N元素或者是具有含N基团的化合物，包括开链形式、单环或多环形式的脂肪族化合物、具有芳香环和/或杂环结构的化合物等(各结构中的R或R 1-R 4分别可为C 1-3的烷烃或烯烃，X分别可为含O，S，N的基团，n＝1～2)。例如，可包括但不限于下述所列举的化合物。
Figure PCTCN2018079115-appb-000001
由于本发明的硫化氢供体是由具有碱性结构的有机化合物与硫化氢所形成的盐结构的物质，可具有与硫化钠、硫氢化钠等无机硫化氢供体一样，在生物体或人体的体液中的溶解过程中，可以使硫化氢方便、快捷地游离和释放出来，而无需如现已有报道的其它形式的有机硫化氢供体，在体内甚至必需借助不同酶参与下经复杂生理/生化反应才能将硫化氢释放出来。
在上述可与硫化氢成盐的具有碱性结构的有机化合物中，就其对生物体(特别是人体)的生理过程的干预或影响而言，可以包括能对生物体产生相关生理活性和/或药理活性影响的化合物，以及虽然对生物体并不具有任何生理活性和/或药理活性，同时也不会产生不利后果，因而也可以为生物体接受的所谓“中性化合物”。对于后者的所谓“中性化合物”而言，其与硫化氢形成盐结构的供体进入生物体并离解后，能产生活性作用的部分唯有硫化氢一种，因而此类的硫化氢供体虽也不排除也可用于对药物的开发，但其更大的应用优势，是在可排除其它因素影响的情况下对硫化氢的相关生理/药理作用的研究。而根据对硫化氢的相关生理/药理作用的研究和了解，选择与能对生物体、特别是对人体具有相应生理和/或药理活性的所述碱性有机化合物成盐所形成的硫化氢供体，以达到使其有利的作用能相互配合或互补，和/或对各自的不利作用能相互制约或抵消的目的和效果，则不仅同样可用于对硫化氢作用的研究，还可以直接应用于药物的开发。
具体而言，上述可以选择的所述含有N元素或具有含N基团的碱性有机化合物中，可以包括结构中具有胍类、脒类、肼类或胺类等结构之一的化合物，如所述的含有N元素或具有含N基团的碱性有机化合物可以包括但不限于如精氨酸、蛋氨酸、胱氨酸、半胱氨酸等在内的碱性氨基酸类化合物。
此外，所述的含有N元素或具有含N基团的碱性有机化合物，还可以包括已有报道和/或使用的具有或不具有生理/药理活性的生物碱类化合物。
在上述可以用来作为硫化氢供体的各类有机碱类化合物中，目前作为优选重点的化合物，可以是有研究表明对与硫化氢关系密切的现有疾病的治疗药物形式的碱基型化合物，包括但不限于如二甲双胍或类似的用于治疗糖尿病的优秀药物，将其制成硫化氢盐而成为药物-硫化氢供体化合物，从而有利于形成双重作用靶点或协同作用。
由于硫化氢是一种在水中有一定的溶解性的酸性气态物，而且所述能与硫化氢成盐的具有碱性结构有机化合物在水中通常也具有一定的溶解性，因此本发明所述的有机物盐形式的硫化氢供体的通常制备方法，溶于水或其它该原料化合物的良溶剂中，通入硫化氢气体成盐后，经沉淀、过滤、浓缩或重结晶等相应常规后处理方式与反应溶剂分离后，即可以得到固体形式的目标化合物。这些都已是本领域所熟知的常规成盐反应及盐类化合物的制备方法和过程。例如，包括如精氨酸硫化氢盐，胍乙啶，可乐定，吗啉胍，苯乙福明，西咪替丁等常用药物型碱基化合物的硫化氢盐等，都可以用此方法制备得到。此外，也可以用此方法将黄连素，黄藤素等生物碱制成硫化氢盐。对于如，肼类化合物等目前的非药物类碱性化合物，将其制备成为硫化氢盐后，也可以作为深入探索、研究和了解硫化氢盐的性质使用。
对于稳定性不高或很不稳定的某些游离碱等碱性化合物，其常见或市售的形式多为其盐酸盐、硫酸盐、碳酸盐等稳定的盐类化合物。为此，制备其相应的硫化氢盐化合物的另一种可选择的便捷方式是，可根据其盐的不同形式，通过氢氧化钠，氢氧化钡，银氨等相应的碱性试剂，或是在如乙醇钠，甲醇钠等强碱性条件下，或者是用强碱性或弱碱性离子交换树脂处理，得到其游离碱后，再直接通入硫化氢气体，或是用硫化氢的水或乙醇等溶液，使其转换成硫化氢的盐。反应温度一般在-10～50℃范围内都可以进行。反应物后经过滤，或用低温真空干燥等方式浓缩后，即可得到硫化氢盐类产物。
以下结合由附图所示实施例的具体实施方式，对本发明上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明上述技 术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均应包括在本发明的范围内。
附图说明
图1是现有研究表明的体内含硫氨基酸的代谢过程示意图。
具体实施方式
实施例1  胍游离碱的制备(1)
室温下向装有无水氯化钙(或其它适当干燥剂)干燥管的1000毫升茄形瓶中，加入500毫升无水乙醇，批加入剪好的金属钠2.53g(110mmol)，待全溶后得到乙醇钠溶液。向乙醇钠溶液中分次加入二甲双胍盐酸盐18.10g(110mmol)，即有大量白色固体悬浮，加完后加热至60℃反应1小时后，冷至室温过滤，得白色固体6.0g，五氧化二磷干燥器干燥后得白色固体13.88克粗品。将粗品5克用丙酮超声促溶脱盐，滤液浓缩干得白色固体二甲双胍游离碱。熔点108-110℃
1H NMR(400MHz,D 2O):δ2.87(s,6H)；
13C NMR(100MHz,D 2O):δ37.14(2C),158.44,161.55。结构为：
Figure PCTCN2018079115-appb-000002
实施例2  胍游离碱的制备(2)
室温下将二甲双胍盐酸盐1.65g(10mmol)溶于10毫升水中，加入5毫升2mol/L氢氧化钠水溶液，室温下搅拌1小时，减压浓缩除去水，得到的白色固体，用丙酮脱盐，得到强碱性白色固体二甲双胍游离碱。粗品熔点90-100℃，重结晶后产物熔点110-112℃。
实施例3  胍游离碱的制备(3)
50℃搅拌下向二甲双胍盐酸盐16.6g(100mmol)的异丙醇(70毫升)悬浮液加入氢氧化钾5.88g(105mmol)，维持50℃反应两小时后，冷至室温过滤，滤饼用异丙醇和丙酮洗涤，洗液和滤液合并浓缩，将所得固体用丙酮脱盐，得到强碱性白色固体二甲双胍游离碱。熔点110-112℃。
实施例4  胍游离碱的制备(4)
室温下将氧化银460mg(2mmol)剧烈搅拌下悬浮于8毫升蒸馏水中，滴加入9.5毫升10倍稀释的浓氨水，待反应液澄清后，向该新制备好的银氨溶液([Ag(NH 3) 2] +OH -)中加入二甲双胍盐酸盐660mg(4mmol)，即产生大量白色沉淀，室温下继续搅拌30分钟后过滤，滤液减压浓缩干后，所得到产物。
实施例5  胍游离碱的制备(5)
室温下将硫酸胍1.21g(10mmol)溶于10毫升蒸馏水中，加入新配置的氢氧化钡水溶液5mL(2mol/L)，室温下搅拌30分钟后，减压旋干水得到浅黄色油状物，室温放置过夜后固化，得到目标化合物。
13C NMR(100MHz,D 2O):δ160.98,162.45。
实施例6  1,1-二甲基双胍硫化氢盐(C 4H 11N 5.H 2S,MW:163.24)
取实施例1～4之一的1,1,-二甲基双胍26g(0.2mol)与100mL水混匀，在保持2℃条件下加入含有6.8g硫化氢的水溶液100ml，混合均匀，将此混合液进行冰冻干燥24h后，得白色固体32g，收集即得目标化合物。
1H NMR(400MHz,D 2O):δ3.01(s,6H)；
13C NMR(100MHz,D 2O):δ37.45(2C)，158.39,160.15。
元素分析结果：for C 4H 15N 5OS；Cacld(计算值)：C 29.43％,H 8.03％,N 42.90％,S 19.64％；
Found(测定值)：C 28.16％,H 8.36％,N 41.39％,S 17.46％。
样品含水量为11.58％，
碘量法滴定还原性物质含量为88.2％。结构为：
Figure PCTCN2018079115-appb-000003
实施例7  L-精氨酸硫化氢盐(C 6H 14N 4O 2.H 2S,MW:208.28)
取L-精氨酸一水合物38.4g(0.2mol)，与100mL水混匀，保持为25℃通入硫化氢气体0.5h，然后将此混合液冰冻干燥24h后，得白色固体44g，收集即得产品。
1H NMR(400MHz,D 2O):δ1.54-1.74(m,4H)，3.17(t,J＝6.7Hz,2H)，3.43(t,J＝6.0Hz,1H)；
13C NMR(100MHz,D 2O):δ24.44，31.58，40.73，54.94，156.70，179.27。
样品含水量为12.9％。
碘量法滴定还原性物质含量为69.2％。结构为：
Figure PCTCN2018079115-appb-000004
实施例8  吗啉双胍硫化氢盐(C 6H 13N 5O.H 2S,MW:205.28)
取吗啉双胍34.2g(0.2mol)，与100mL水混匀，保持为25℃通入硫化氢气体0.5h后，将此混合液于50℃旋蒸除去水，得白色固体46g，收集即得目标化合物。
1H NMR(400MHz,D 2O):δ3.35(t，J＝4.0Hz,1H),3.46(t,J＝4.0Hz,2H),3.67(t,J＝4.0Hz,1H),3.71(t,J＝4.0Hz,2H)；
13C NMR(100MHz,D 2O):δ45.08,65.99,158.86,160.33；
元素分析结果：for C 6H 15N 5OS，Cacld：C 35.11％,H 7.37％,N 34.12％,S 15.62％；
Found：C 29.31％,H 8.36％,N 27.29％,S 12.46％。
样品含水量为16.26％。
碘量法滴定还原性物质含量为76.3％。结构为：
Figure PCTCN2018079115-appb-000005
实施例9  对胍基苯甲酸硫化氢盐(C 8H 9N 3O 2.H 2S,MW:213.26)
取对胍基苯甲酸35.8g(0.2mol)，与100mL无水乙醇混匀，保持为10℃通入硫化氢气体1h后，将此混合液于45℃旋蒸除去溶剂，得白色固体41g，收集即得目标化合物。
元素分析结果：for C 8H 11N 3O 2S，Cacld：C 45.06％,H 5.20％,N 19.70％,S 15.04％；
Found：C 38.99％,H 5.56％,N 17.29％,S 13.03％。
样品含水量为3.72％。
碘量法滴定还原性物质含量为85.5％。结构为：
Figure PCTCN2018079115-appb-000006
实施例10  氰基胍硫化氢盐(C 2H 4N 4.H 2S,MW:118.16)
取氰基胍16.8g(0.2mol)与100mL无水乙醇混匀，保持为2℃时加入含有6.8g硫化氢的乙醇溶液100ml后，将此混合液于45℃旋蒸除去溶剂，得白色固体23g，收集即得目标化合物。
元素分析结果：for C 2H 6N 4S，Cacld：C 20.33％,H 5.12％,N 47.42％,S 27.14％；
Found：C 16.59％,H 5.59％,N 38.68％,S 22.14％。
样品含水量为5.36％。
碘量法滴定还原性物质含量为86.2％。结构为：
Figure PCTCN2018079115-appb-000007
实施例11  乙酸胍硫化氢盐(C 3H 7N 3O 2.H 2S,MW:151.19)
取乙酸胍23.4g(0.2mol)与100mL二氯甲烷混匀，在室温下滴入充满硫化氢气体的三颈瓶中，保持室温搅拌3h，有白色固体析出，过滤，真空干燥，得白色固体26g，即得目标化合物。
元素分析结果：for C 3H 9N 3O 2S，Cacld：C 23.83％,H 6.00％,N 27.79％,S 21.21％；
Found：C 20.68％,H 6.43％,N 24.26％,S 18.41％。
样品含水量为3.58％；
碘量法滴定还原性物质含量为90.2％。结构为：
Figure PCTCN2018079115-appb-000008
实施例12  法莫替丁硫化氢盐(C 8H 15N 7O 2S 3.H 2S,MW:371.53)
取法莫替丁6.74g(0.02mol)与100mL四氢呋喃混匀，在30℃时通入硫化氢气体2h后，将此混合液于40℃旋蒸除去溶剂，得白色固体7.3g，收集即得目标化合物。
元素分析结果：for C 8H 17N 7O 2S 4，Cacld：C 25.86％,H 4.61％,N 26.39％,S 34.52％；
Found：C 23.18％,H 5.03％,N 23.58％,S 30.85％。
样品含水量为4.62％。
碘量法滴定还原性物质含量为93.7％。结构为：
Figure PCTCN2018079115-appb-000009
实施例13  胍乙啶硫化氢盐(C 9H 21N 5.H 2S,MW:233.38)
取胍乙啶4.00g(0.02mol)与100mL四氢呋喃混匀，室温下滴入充满硫化氢气体的反应瓶中，室温反应12h后，置0-5℃冷冻后析出固体，过滤，得白色固体3.6g，收集即得目标化合物。
元素分析结果：for C 9H 23N 5S，Cacld：C 46.32％,H 9.93％,N 30.01％,S 13.74％；
Found：C 41.31％,H 10.93％,N 26.69％,S 12.22％。
样品含水量为3.93％。
碘量法滴定还原性物质含量为92.6％。结构为：
Figure PCTCN2018079115-appb-000010
实施例14  可乐定硫化氢盐(C 9H 9Cl 2N 3.H 2S,MW:264.17)
取可乐定4.58g(0.02mol)与50mL二氯甲烷混匀，在0℃时加入含有3.9g硫化氢的乙醇溶液50ml，保温反应2h后，置0-5℃冷冻后析出固体，过滤，得白色固体3.6g，收集即得目标化合物。
元素分析结果：for C 9H 11Cl 2N 3S，Cacld：C 40.92％,H 4.20％,Cl 26.84％,N 15.91％,S12.14％；
Found：C 37.16％,H 4.33％,Cl 24.34％,N 14.65％,S 11.02％。
样品含水量为2.72％。
碘量法滴定还原性物质含量为93.3％。结构为：
Figure PCTCN2018079115-appb-000011
实施例15  西咪替丁硫化氢盐(C 10H 16N 6S.H 2S,MW:286.42)
取西咪替丁5.04g(0.02mol)与50mL乙酸乙酯混匀，在0℃时加入含有3.9g硫化氢的乙酸乙酯溶液50ml，保温反应3h后，置0-5℃冷藏后析出固体，过滤，得白色固体2.9g，收集即得目标化合物。
元素分析结果：for C 10H 18N 6S 2，Cacld：C 41.93％,H 6.33％,N 29.34％,S 22.39％；
Found：C 36.11％,H 6.76％,N 25.51％,S 19.26％。
样品含水量为6.52％。
碘量法滴定还原性物质含量为91.9％。结构为：
Figure PCTCN2018079115-appb-000012
实施例16  胍氯酚硫化氢盐(C 9H 12Cl 2N 4O.H 2S,MW:297.20)
取胍氯酚5.25g(0.02mol)与100mL二氯甲烷混匀，保持为0℃通入干燥的硫化氢气体5h后，置0-5℃冷藏，析出固体，过滤，得白色固体2.6g，收集即得目标化合物。
元素分析结果：for C 9H 14Cl 2N 4OS，Cacld：C 36.37％,H 4.75％,Cl 23.86％,N 18.85％,S10.79％；
Found：C 33.36％,H 5.07％,Cl 21.93％,N 17.29％,S 9.92％。
样品含水量为3.37％。
碘量法滴定还原性物质含量为95.2％。结构为：
Figure PCTCN2018079115-appb-000013
实施例17  1,8-二氮杂二环十一碳-7-烯(DBU)硫化氢盐(C 9H 16N 2.H 2S,MW:186.32)
取DBU30.4g(0.2mol)与100mL水混匀，保持为25℃加含有6.8g硫化氢的水溶液100ml并混合后，将混合液50℃旋蒸，得固体39g，收集即得目标化合物。
元素分析结果：for C 9H 18N 2S，Cacld：C 58.02％,H 9.74％,N 15.04％,S 17.21％；
Found：C 29.11％,H 11.67％,N 7.51％,S 8.56％。
样品含水量为18.33％。
碘量法滴定还原性物质含量为62.6％。结构为：
Figure PCTCN2018079115-appb-000014
实施例18  4-二甲氨基吡啶(DMAP)硫化氢盐(C 7H 10N 2.H 2S,MW:156.25)
取DMAP 24.4g(0.2mol)溶于100ml二氯甲烷中，在-5C°滴入充满硫化氢气体的三颈瓶中反应1.5h，反应液颜色逐渐变深，静置过夜后析出淡黄色固体，过滤，收集即得目标化合物8.6g。
元素分析结果：for C 7H 12N 2S，Cacld：C 53.81％,H 7.74％,N 17.93％,S 20.52％；
Found：C 43.82％,H 8.68％,N 14.61％,S 16.72％。
样品含水量为5.62％。
碘量法滴定还原性物质含量为85.9％。结构为：
Figure PCTCN2018079115-appb-000015
实施例19  哌嗪硫化氢盐(C 4H 10N 2.H 2S,MW:120.22)
取哌嗪17.2g(0.2mol)溶于100ml无水乙醇中，室温下通入干燥的硫化氢气体，立即有白色针状固体析出，搅拌5min，过滤，收集即得目标化合物2.9g。
元素分析结果：for C 4H 12N 2S，Cacld：C 39.96％,H 10.06％,N 23.30％,S 26.67％；
Found：C 36.02％,H 8.68％,N 20.91％,S 23.92％。
样品含水量为2.98％。
碘量法滴定还原性物质含量为92.9％。结构为：
Figure PCTCN2018079115-appb-000016
实施例20  色胺硫化氢盐(C 10H 12N 2.H 2S,MW:194.30)
取色胺3.2g(0.02mol)溶于30ml无水乙醇中，通入干燥的硫化氢气体，立即有白色固体析出，搅拌30min，过滤，收集即得目标化合物0.8g。
1H NMR(400MHz,D 2O):δ2.96(t，J＝9.0Hz,2H),3.11(t,J＝8.8Hz,2H),7.03(t,J＝4.0Hz,1H),7.08-7.13(m,2H),7.34(d,J＝4.0Hz,1H),7.49(d,J＝4.0Hz,1H)；
13C NMR(100MHz,D 2O):δ22.93,40.10,109.39,112.35,118.58,119.71,122.48,124.53,126.75,136.71；
元素分析结果：for C 10H 14N 2S，Cacld：C 61.82％,H 7.26％,N 14.42％,S 16.50％；
Found：C 55.82％,H 8.12％,N 13.02％,S 15.02％。
样品含水量为3.65％。
碘量法滴定还原性物质含量为93.7％。结构为：
Figure PCTCN2018079115-appb-000017
工业实用性
本发明提供了一种可具有研究和/或药物开发价值的新结构形式的硫化氢(H 2S)供体，即有机物盐形式的硫化氢供体，并进一步提供了其相应的制备方法。本发明硫化氢供体的结构简单，制备方法简便易行，并且可以根据研究和开发的需要得到不同形式的硫化氢供体，进入生物体后，在体内离解和提供硫化氢的过程简单、快捷和有效，无需有任何酶或其它复杂条件的要求，具有极大的应用前景和价值。

Claims (8)

  1. 有机物盐形式的硫化氢供体，其特征是由具有碱性结构的有机化合物与硫化氢形成的盐类结构。
  2. 如权利要求1所述的有机物盐形式的硫化氢供体，其特征是所述具有碱性结构的有机化合物为结构中含有N元素或是具有含N基团的化合物。
  3. 如权利要求1所述的有机物盐形式的硫化氢供体，其特征是所述具有碱性结构的有机化合物为具有生理和/或药理活性的药用化合物。
  4. 如权利要求2所述的有机物盐形式的硫化氢供体，其特征是所述具有碱性结构的有机化合物为具有胍类结构、脒类、肼类结构或胺类结构之一的化合物。
  5. 如权利要求2所述的有机物盐形式的硫化氢供体，其特征是所述具有碱性结构的有机化合物为包括精氨酸、蛋氨酸、胱氨酸、半胱氨酸在内的氨基酸类化合物。
  6. 如权利要求2所述的有机物盐形式的硫化氢供体，其特征是所述具有碱性结构的有机化合物为生物碱性类化合物。
  7. 权利要求1至6之一所述的有机物盐形式的硫化氢供体的制备方法，其特征是将所述具有碱性结构的有机化合物溶解于溶剂中，通入硫化氢气体成盐后，与反应溶剂分离，得到所述目标产物。
  8. 如权利要求7所述的有机物盐形式的硫化氢供体的制备方法，其特征是所述的具有碱性结构的有机化合物为非硫化氢盐的其它盐类化合物，在碱性条件下使其盐类化合物转化为游离碱形式后，通入硫化氢气体或者加入硫化氢的水或醇溶液，形成所述的硫化氢盐目标产物并分离得到。
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