CN1315945A - 抗高血压药物的硝酸盐 - Google Patents

抗高血压药物的硝酸盐 Download PDF

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CN1315945A
CN1315945A CN99807516A CN99807516A CN1315945A CN 1315945 A CN1315945 A CN 1315945A CN 99807516 A CN99807516 A CN 99807516A CN 99807516 A CN99807516 A CN 99807516A CN 1315945 A CN1315945 A CN 1315945A
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methyl
dihydro
residue
phenyl
same
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P·德尔索尔达托
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Nicox SA
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Nicox SA
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/12—Antihypertensives
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    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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    • 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
    • C07C215/22—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 the carbon skeleton being unsaturated
    • C07C215/28—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 the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—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 the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
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    • 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
    • C07C215/22—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 the carbon skeleton being unsaturated
    • C07C215/28—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 the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/38—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 the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
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    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/36—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C255/43—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • 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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
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Abstract

具有抗高血压活性的药用硝酸盐。

Description

抗高血压药物的硝酸盐
本发明涉及可用于治疗和预防高血压的化合物及它们的组合物。更准确地说是涉及所述抗高血压药物系统和局部使用特别是用于心血管区域的用途。更准确地说，本发明涉及新的具有改进疗效的化合物。
在高血压的治疗中使用的先有技术已知化合物的疗效有限。通常将所述抗高血压药物联合其它对血管系统具有医疗活性的药物来进行高血压的治疗，其中所述血管活性药物例如钙拮抗剂、利尿药、β-阻断剂、ACE抑制剂。例如当单独使用时，血管紧张素的抗高血压拮抗剂(如氯沙坦)、钙拮抗剂(如二氢吡啶)、利尿药(例如噻嗪衍生物)、直接和间接的血管扩张剂(如长压定、扎普司特)不能确保治疗成功。
另外，必须指出，一些抗高血压药对呼吸器官引起副作用，如支气管缩小、呼吸困难。例如用于治疗心绞痛和心律不齐的抗高血压药(如噻吗洛尔和心得安)造成所述副作用。
其它抗高血压药通过抑制磷酸二酯酶引起血管舒张并引起各器官(胃肠、心血管、眼等)的副作用，例如见Sildenafil和扎普司特。
我们认为，需要治疗作用改善的抗高血压活性组合物，该组合物在高血压的病理学治疗中可用于系统性和局部性应用，特别是心血管区域。另外，特别需要具有β-阻断或抗磷酸二酯酶作用、较低副作用的抗高血压药。
本申请人出乎预料并令人惊奇地发现，在高血压病理学治疗中能够系统和局部使用(特别是心血管区域)的化合物和药用组合物，它们具有改善的医疗作用并且没有已知抗高血压药的副作用。
本发明的一个目的就是，提供具有抗高血压活性的硝酸盐化合物或其药用组合物，它们可系统和局部使用，特别是用于心血管区域，所述化合物的特征是含有至少一个能够成盐的反应基团，所述化合物可选自如下类型：(A1b)类：RA1=-O与RⅢ A1自由价，以便与5位的碳原子形成酮基，RA1与RⅠ A1和式(A1b)化合物中杂环上的4及5位碳原子、RⅣ A1和RⅢ A1自由价形成含有-COOH基团的6个碳原子的芳环：RⅠ A1=H,Cl；RⅠ A1与RA1、RⅣ A1、RⅢ A1和式(A1b)杂环上的4及5位碳原子形成含有一个-COOH基团的芳环(Ⅸc)，RⅠ A1与RⅣ A1和式(A1b)杂环上的4位碳原子形成下面的5个碳原子的饱和环：RⅡ A1=-(CH2)3-CH3,-O-CH2-CH3；RⅢ A1=H，自由价，RⅢ A1自由价与RⅣ A1自由价在式(A1b)中杂环上的4位和5位碳原子之间形成一个双键，RⅢ A1与RⅣ A1、RⅠ A1和式(A1b)中杂环上的4及5位碳原子形成含有一个-COOH基团的芳环(Ⅸc)；RⅣ A1=自由价，RⅣ A1与RⅠ A1一起和式(A1b)中杂环上的4位碳原子形成5个碳原子的饱和环(Ⅸd)，RⅣ A1与RⅢ A1、RⅠ A1一起和式(A1b)杂环上的4及5位碳原子形成含有一个-COOH基团的芳环(Ⅸc)，RⅣ A1与RⅢ A1皆自由价在式(A1b)中杂环上的4位和5位碳原子之间形成一个双键；(A1c)类：
Figure A9980751600222
称为缬沙坦；(A2)类：
该类的前体为下列化合物：1(2H)-2,3-二氮杂萘酮腙(肼苯哒嗪)；6-(1-哌啶基)-2,4-嘧啶二胺3-氧化物(长压定)；1-[[3-(4,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑[4,3-d]嘧啶-5-基)-4-etoxy苯基]磺酰基-4-甲基-哌嗪(Sildenafil),2-(2-丙氧基苯基)-8-氮杂嘌呤-6-酮(扎普司特)；(A3)类：
Figure A9980751600231
RⅠ B1与RⅡ B1彼此相同或不同地为H、CH3，
Figure A9980751600241
在式(XId)中t=0、1。在式(Ⅺe)中YB1可为：
Figure A9980751600242
在式(Ⅺf)中Z=H、-OCH3；在式(A3)中：XB1=-O-,-S-；n和m彼此相同或不同，为0、1；-CH2-CH(OH)-CH2-NH-CH(CH3)2(Ⅺr),在式(Ⅺp)中：S1=H、CN、OCH3、CH3、-CH2-CH3、-O-CH2-CONH-CH3、-COCH3、-CO-(CH2)2-CH3、-O-CH2-CH=CH2、-CH2-CH=CH2、环戊基或
Figure A9980751600262
S2=H、CH3、Cl、-SOCH3、-CONH2；S1与S2和同一基团(Ⅺp)中C6芳环的2及3位碳原子形成如下所示的环：
Figure A9980751600271
其中：[(*)原子连接式ⅪpⅦ中的芳环]B=-CH2-、-NH-、-CH=CH-、(*)-CO-CH2-；A=-O-、(*)-CH2-CH(OH)-、(*)-O-CH2-、(*)-S-CH2-、-CH2-CH2-、-CH2-,A为一个叔碳原子而同时W1为自由价以便在A和1′位碳原子之间形成一个双键-CH=CH-,在5元环(ⅪpⅦ)中A为含有一个取代基的叔碳原子，以便与1′位碳原子及与W1或W2基团中的一个(另外一个基团为自由价)形成下式所示的6个碳原子的芳环：
Figure A9980751600272
W1=H、自由价，当W1为自由价而A为如前定义的叔碳原子时，在A和1′位碳原子之间形成一个双键，W1与W2、1′位碳原子一起和取代基A形成一个具有6个碳原子的芳环；W2=自由价、H、OH、-CH3、-ONO2、与W1=自由价一起和1′位碳原子形成一个酮基的-O,W2与W1、1′位碳原子一起和取代基A形成一个具有6个碳原子的芳环；S3=H、F、Cl、OH、NO2、-CH2-CO-NH2、-(CH2)2-OCH3、-NH-COCH3、-CH2-O-CH2-CH2-O-CH(CH3)2、-CH2-CH2-COOCH3、-NH-CO-N(C2H5)2、-NH-CO-(CH2)2-CH3、-NH-SO2-CH3、-NH-CO-NH-环己基、-CH2-CH2-O-CH2-环丙基；S4=H、Cl、-CH2-CH2-，-CH2-CH2-与同一基团(Ⅺp)中芳环的1位及6位碳原子一起和式(A3)的XB1(等于氧)形成下式环，同时m=n=1和RⅦB1自由价：
Figure A9980751600281
S4为叔碳原子，它与基团(Ⅺp)中芳环的1位及6位碳原子一起和式(A3)的以下部分：碳原子-|C|n-(n=1)、基团XB1(等于氧)(m=1)以及RⅦ B1和RⅥ B1自由价，形成下式环：RⅥ B1=H、自由价；RⅦ B1=H、自由价；属于该类的其它化合物如下：2-羟基-5-[1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基]苯甲酰胺(拉贝洛尔)、1-(4-氨基6,7-二甲氧基-2-喹唑啉基)-4-[(四氢-2-呋喃基)羰基]哌嗪(特拉唑嗪)、1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-(2-呋喃基羰基)哌嗪(哌唑嗪)；(A4)类：
属于该类的各组化合物如下：(A4a)：
β-[(2-甲基丙氧基)甲基]-N-苯基-N-(苯甲基)-1-吡咯烷乙胺(双苯吡乙胺)、(2S-顺式)-3-(乙酰氧基)-8-氯-5-[2-(二甲氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫代氮杂(thiazepin)-4(5H)-酮(克仑硫)、(2S-顺式)-3-(乙酰氧基)-5-[2-(二甲氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫代氮杂-4(5H)-酮(地尔硫)、γ-苯基-N-(1-苯基乙基)苯丙胺(芬地林)、α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲氨基]丙基]-3,4,5-三甲氧基-α-(1-甲基乙基)-苯乙腈(戈洛帕米)、(1S-顺式)甲氧基乙酸2-[2[[3-(1H-苯并咪唑-2-基)丙基]甲氨基]乙基]-6-氟-1,2,3,4-四氢-1-(1-甲基乙基)-2-萘酯(Mibefradil)、N-(1-甲基-2-苯乙基)-γ-苯基苯丙胺(双苯丙胺)、(R)-2-[2-[3-[[2-(1,3-苯并间二氧杂环戊烯-5-基氧基)乙基]甲氨基]丙氧基]-5-甲氧基苯基]-4-甲基-2H-1,4-苯并噻嗪-3(4H)-酮(司莫地尔)、N-(1,1-二甲基乙基)-α-甲基-γ-苯基苯丙胺(双苯丁胺)、α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)-苯乙腈(戊脉胺)；(A4b)：
2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二羧酸3-乙酯5-甲酯(氨氯地平)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲酯2-氧代丙酯(阿雷地平)、[S-(R*,R*)]-1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯1-(苯基甲基)-3-吡咯烷基酯(巴尼地平)、(R*,R*)-±-1,4-氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯1-(苯基甲基)-3-哌啶酯(贝尼地平)、(E)-±-1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-甲氧基乙酯3-苯基-2-丙烯酯(西尼地平)、5-(5,5-二甲基-1,3,2-dioxaphosphorinane-2-基)-1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3-吡啶羧酸2-[苯基(苯甲基)氨基]乙酯对氧化物(p-oxide)(依福地平)、±-4-(1,3-苯并间二氧杂环戊烯-4-基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸2-[[(4-氟苯基)甲基]甲氨基]乙酯1-甲基乙酯(依高地平)、4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸乙酯甲酯(非洛地平)、4-(4-苯并呋咱基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸5-甲酯3-(1-甲基)乙酯(伊拉地平)、(E)-4-[2-[3-(1,1-二甲基乙氧基)-3-氧代-1-丙烯基]苯基]-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸二乙酯(拉西地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-[(3,3-二苯基-丙基)甲氨基]-1,1-二甲基乙酯甲酯(乐卡地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-[4-(二苯基甲基)-1-哌嗪基]乙酯甲酯(马尼地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯2-[甲基(苯甲基)氨基]乙酯(尼卡地平)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸二甲酯(硝苯吡啶)、2-氰基-1,4-二氢-6-甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸3-甲酯5-(1-甲基乙基)酯(尼伐地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-甲氧基乙酯1-甲基乙酯(硝苯吡酯)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲酯2-甲基丙酯(尼索地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸乙酯甲酯(尼群地平)；(A4c)：
1-(二苯基甲基)-4-(3-苯基-2-丙烯基)哌嗪(肉桂苯哌嗪)、(E)-1-[双(4-氟苯基)甲基]-4-(3-苯基-2-丙烯基)哌嗪(氟桂利嗪)、4-[4,4-双(4-氟苯基)丁基]-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺(利多氟嗪)、1-[双(4-氟苯基)甲基]-4-[(2,3,4-三甲氧基苯基)甲基]哌嗪(洛美利嗪)；(A4d)：
N,N-二甲基-3-[[1-(苯基甲基)-环庚基]氧基]-1-丙胺(苄环烷)、1-[2-[2-(二乙基氨基)乙氧基]苯基]-3-苯基-1-丙酮(乙胺苯丙酮)、3,4-二甲氧基-N-甲基-N-[3-[4-[[2-(1-甲基乙基)-1-中氮茚基]磺酰基]苯氧基]丙基]苯乙胺(泛托法隆)；(A7)类：
属于该类的各组化合物如下：(A7a)：
6-氯-3,4-二氢-3-[(2-丙烯基硫代基)甲基]-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(烯硫噻二嗪)、3,4-二氢-3-(苯基甲基)-6-三氟甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(苄氟噻嗪)、6-氯-3-[[(苯基甲基)硫代基]甲基]-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(苄硫噻嗪)、6-氯-3,4-二氢-3-(苯基甲基)-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(苄氢氯噻嗪)、6-氯-3,4-二氢-3-(2-甲基丙基)-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(异丁噻嗪)、6-氯-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(氯噻嗪)、2-氯-5-(2,3-二氢-1-羟基-3-氧代-1H-异吲哚-1-基)苯磺胺(氯噻酮)、6-氯-3-(环戊基甲基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(环戊氯噻嗪)、3-双环[2.2.1]-庚-5-烯-2-基-6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(环己氯噻嗪)、6-氯-3,4-二氢-3-[[(2,2,2-三氟乙基)硫代基]甲基]-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(氟硫噻嗪)、6-氯-3-乙基-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(乙噻嗪)、7-氯-1,2,3,4-四氢-4-氧代-2-苯基-6-喹唑啉磺胺(苯喹唑酮)、3-(氨基磺酰基)-4-氯N-(2,3-二氢-2-甲基-1H-吲哚-1-基)苯甲酰胺(吲哒帕胺)、6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氢氯噻嗪)、3,4-二氢-6-三氟甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氢氟噻嗪)、6-氯-3-(氯甲基)-3,4-二氢-2-甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(甲氯噻嗪)、3,4-二氢-6-甲基-2H-1-苯并硫代吡喃-7-磺胺1,1-二氧化物(Methycrane)、7-氯-1,2,3,4-四氢-2-甲基-3-(2-甲基苯基)-4-氧代-6-喹唑啉磺胺(甲苯喹唑酮)、6-氯-3-[(4-氟苯基)甲基]-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氟噻嗪)、6-氯-3,4-二氢-2-甲基-3-[[(2,2,2-三氟乙基)硫代基]甲基]2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(多噻嗪)、7-氯-2-乙基-1,2,3,4-四氢-4-氧代-6-喹唑啉磺胺(喹乙唑酮)、6-氯-3,4-二氢-3-三氯甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(四氯甲噻嗪)、6-氯-3-(二氯甲基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(三氯噻嗪)；(A7b)：
3,7-二氢-1,3-二甲基-7-(4-吗啉基甲基)-1H-嘌呤-2,6-二酮(7-吗啉甲茶碱)、3,7-二氢-1-(2-羟基丙基)-3,7-二甲基-1H-嘌呤-2,6-二酮(羟丙可可碱)、3,7-二氢-3,7-二甲基-1H-嘌呤-2,6-二酮(可可碱)；(A7c)：
6-氨基-3-乙基-1-(2-丙烯基)-2,4-(1H,3H)-嘧啶二酮(氨乙烯丙尿嘧啶)、6-氨基-3-甲基-1-(2-甲基-2-丙烯基)-2,4-(1H,3H)-嘧啶二酮(阿米美啶)；(A7d)：
N-苯基-1,3,5-三嗪-2,4-二胺(阿马诺嗪)、3,5-二氨基-N-(氨基亚氨基甲基)-6-氯吡嗪甲酰胺(阿米洛利)、N-(4-氯苯基)-1,3,5-三嗪-2,4-二胺(氯苯三嗪胺)、[3-甲基-4-氧代-5-(1-哌啶基)-2-噻唑烷亚基]乙酸乙酯(乙氧唑啉)、6-肼基-3-哒嗪甲酰胺(肼氨羰哒嗪)、5-氨基-2[1-(3,4-二氯苯基)乙基]-2,4-二氢-3H-吡唑-3-酮(氯苄唑胺)、2-(2,2-二环己基乙基)哌啶(环己哌啶)、6-苯基-2,4,7-蝶啶三胺(氨苯蝶啶)、3-(氨基磺酰基)-5-丁氨基-4-苯氧基苯甲酸(丁苯氧酸)、5-(氨基磺酰基)-4-氯-2-[(2-呋喃基甲基)氨基]苯甲酸(呋喃苯胺酸)、N-[[(1-甲基乙基)氨基]碳酰基]-4-[(3-甲基苯基)氨基]-3-吡啶磺胺(胺吡磺异丙脲)；(A8)类：阿朴吗啡
在(A1b)类中优选的化合物如下：当XA1=(Ⅸa),RA1=CH2OH,RⅠ A1=Cl,RⅢ A1=RⅣ A1=自由价(与式(A1b)中杂环上的4和5位碳原子形成-CH=CH-双键)，RⅡ A1=-(CH2)3-CH3时，则所述优选化合物为氯沙坦残基；与在氯沙坦中一样，但是RA1=-O和RⅢ A1自由价，以便与式(A1b)中杂环上的5位碳原子形成一个酮基，RⅠ A1与RⅣ A1一起和杂环上的4位碳原子形成具有5个碳原子的饱和环(Ⅸd)，则所述优选化合物为Irbesartan残基；与在氯沙坦中一样，但是RⅡ A1=-O-CH2-CH3、RA1与RⅠ A1一起和RⅣ A1与RⅢ A1为自由价的杂环上的4和5位碳原子形成含有-COOH基团的芳香基(Ⅸc)，则所述优选化合物为Candesartan残基；与在氯沙坦中一样，但是XA1=-COOH、RA1=(Ⅸb)、RⅠ A1=H、RⅣ A1与RⅢ A1自由价在式(A1b)中杂环上的4和5位碳原子之间形成一个双键，则所述优选化合物为Eprosartan残基。
A2类的优选化合物如下：1-[[3-(4,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑[4,3-d]-嘧啶-5基)-4-乙氧基苯基]磺酰基-4-甲基-哌嗪(Sildenafil)、2-(2-丙氧基苯基)-8-氮杂嘌呤-6-酮(扎普司特)。
(A3)类的优选化合物如下：当RⅠ B1=H,RⅡ B1和RⅢ B1=CH3,RⅤ B1=H,RⅥ B1=RⅦ B1=H,m=n=1,XB1=-O-,RⅣ B1=(XIp)(其中S1=S2=S4=H,S3=-CH2-CONH2)时，则为阿替洛尔残基；与在阿替洛尔中一样，但是RⅣ B1=(Ⅺs)时，则为苯呋洛尔残基；与在阿替洛尔中一样，但是S3=S2=S4=H、S1=-CH2-CH=CH2时，则为阿普洛尔残基；与在阿替洛尔中一样，但是S1=COCH3、S3=-NH-CO-(CH2)2-CH3、S2=S4=H时，则为醋丁洛尔残基；与在阿替洛尔中一样，但是S3=-CH2-CH2-O-CH2-环丙基时，则为倍他洛尔残基；与在阿替洛尔中一样，但是S3=-CH2-O-CH2-CH2-O-CH(CH3)2时，则为比索洛尔残基；如在阿普洛尔中一样，但是S1=(ⅪpⅡ)和RⅠ B1=CH3时，则为布非洛尔残基；如在布非洛尔中一样，但是S1=-CN时，则为布尼洛尔残基；如在布非洛尔中一样，但是S1=H、S4=Cl、S2=CH3时，则为氯甲苯心安残基；如在布非洛尔中一样，但是S1=-CO-(CH2)2-CH3、S3=F时，则为丁非洛尔残基；如在阿替洛尔中一样，但是RⅣ B1=(ⅪpⅧ)，其中B=-NH-时，则为卡拉洛尔残基；如在布非洛尔中一样，但是RⅣ B1=(ⅪpⅦ)，其中A=-CH2-CH2-、B=-NH-、W2=-O,W2与W1自由价一起和1′位碳原子形成一个酮基时，则为卡替洛尔残基；如在布非洛尔中一样，但是S3=-NH-CO-N(C2H5)2、S1=-CO-CH3时，则为二乙脲心安残基；如在布非洛尔中一样，但是S1=-O-CH2-CONH-CH3时，则为塞他洛尔残基；如在氯甲苯心安中一样，但是S2=Cl时，则为氯拉洛尔残基；如在阿替洛尔中一样，但是S3=-CH2-CH2-COOCH3时，则为艾司洛尔残基；如在阿替洛尔中一样，但是RⅣ B1=(Xiu)时，则为茚诺洛尔残基；如在卡替洛尔中一样，但是在RⅣ B1=(ⅪpⅦ)中A=-CH2-、B=-CO-CH2-、W1=W2=H时，则为左布诺洛尔残基；如在卡替洛尔中一样，但是RⅠ B1=H并且在RⅣ B1=(ⅪpⅦ)中A为一个叔碳原子和W1自由价，以至在A和(ⅪpⅦ)中的1′位碳原子之间形成一个-CH=CH-双键，W2=CH3时，则为甲吲洛尔残基；在阿替洛尔中，如果S3=-(CH2)2-OCH3，则美托洛尔残基；在卡替洛尔中，如果在RⅣ B1=(ⅪpⅦ)中A=-CH2-CH(OH)-、B=-CH2-、W2=OH、W1=H，则为纳多洛尔残基；在阿替洛尔中，如果S3=NO2，则为硝苯洛尔残基；在甲吲洛尔中，如果在RⅣ B1=(ⅪpⅦ)中A=-O-CH2-、B=-CH2-、W2=-ONO2、W1=H，则为尼普地洛残基；在阿普洛尔中，如果S1=-O-CH2-CH=CH2，则为氧烯洛尔残基；在布非洛尔中，如果S1=环戊基，则为环戊丁心安残基；在甲吲洛尔中，如果W2=H，则为吲哚洛尔残基；在阿替洛尔中，如果S3=-NH-COCH3，则为普拉洛尔残基；在布非洛尔中，如果S1=H、S3=-NH-CO-NH-环己基，则为他林洛尔残基；在尼普地洛中，如果RⅠ B1=CH3、A=-S-CH2-而W2=H，则为特他洛尔残基；在特他洛尔中，如果RⅣ B1=(Ⅺn)，则为替利洛尔残基；在布非洛尔中，如果RⅣ B1=(Ⅺo)，则为噻吗洛尔残基；在布非洛尔中，如果S1=S2=CH3，则为希苯洛尔残基；在希苯洛尔中，如果RⅠ B1=S1=H，则为托利洛尔残基；在托利洛尔中，如果RⅡ B1=H而RⅢ B1=(XIa)，则为贝凡洛尔残基；在卡拉洛尔中，如果RⅡ B1=H而RⅢ B1=(Ⅺb)、卡维地洛残基；当在式(A3)中RⅠ B1=RⅡ B1=RⅢ B1=CH3、RⅤ B1=(Ⅺh)、n=m=1、RⅥ B1=RⅦ B1=H、XB1=-O-、RⅣ B1=(Ⅺg)时，则为波吲洛尔残基；在布非洛尔中，如果RⅣ B1=(XIt)，则为布库洛尔残基；当在式(A3)中m=n=0而RⅣ B1=(Ⅺz)、RⅠ B1=RⅡ B1=RⅢ B1=CH3、RⅤ B1=H时，则为丁呋洛尔残基；在阿替洛尔中，如果RⅢ B1=(Ⅺe)，其中YB1=H、n=m=0,RⅣ B1=(Ⅺi)时，则为布替君残基；在布替君中，如果RⅢ B1=(Ⅺe)，其中YB1=(Ⅺf),(Ⅺf)中Z=H,RⅣ B1=(Ⅺp)，其中S3=OH及S2=CONH2、S1=S4=H，则为地来洛尔残基；在贝凡洛尔中，如果S2=H、S1=CN、RⅢ B1=(Ⅺc)，则为依泮洛尔残基；在布替君中，如果RⅢ B1=CH3,RⅣ B1=(Ⅺm)，其中萘基通过2位的碳原子连接到带有-ORⅣ B1取代基的碳原子上时，则为丙萘洛尔残基；在丙萘洛尔中，如果m=1和XB1=-O-，而RⅣ B1为通过1位的碳原子连接XB1的萘基(Ⅺm)，则为普萘洛尔基团；在丙萘洛尔中，如果RⅣ B1=(Ⅺp)，其中S1=S2=S4=H并且S3=-NH-SO2-CH3，则为索他洛尔残基；在地来洛尔中，如果S2=SOCH3，并且在另一芳环(式Ⅺf)的对位Z=-OCH3，则为磺苄心安残基；当在式(A3)中RⅠ B1=RⅡ B1=H、RⅢ B1=其中t=1的(Ⅺd)、RⅤ B1=H、n=m=0、RⅣ B1=其中t=0的(Ⅺd)，则为奈必洛尔残基；2-羟基-5-[1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基]苯甲酰胺(柳胺心定)、1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢-2-呋喃基)碳酰基]哌嗪(特拉唑嗪)、1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-(2-呋喃基碳酰基)哌嗪(哌唑嗪)、苯甲腈、2-[2-羟基-3-[[2-(1H-吲哚-3-基)-1,1-二甲基乙基]氨基]丙氧基(苄腈吲心安)。
在(A4)类中优选的化合物如下：(A4a)：
(2S-顺式)-3-乙酰氧基-5-[2-(二甲基氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫代氮杂-4(5H)-酮(地尔硫)、α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)-苯乙腈(戊脉胺)；(A4b)：
2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二羧酸3-乙酯5-甲酯(氨氯地平)、4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸乙酯甲酯(非洛地平)、4-(4-苯并呋咱基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸5-甲酯3-(1-甲基)乙酯(伊拉地平)、乐卡地平、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯2[甲基(苯甲基)氨基]乙酯(硝吡胺甲酯)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸二甲酯(硝苯吡啶)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-甲氧基乙酯1-甲基乙酯(硝苯吡酯)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲酯2-甲基丙酯(尼索地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸乙酯甲酯(硝吡乙甲酯)；(A4c)：
(E)-1-[双(4-氟苯基)甲基]-4-(3-苯基-2-丙烯基)哌嗪(氟桂利嗪)。
在(A7)类中优选的化合物如下：(A7a)：
6-氯-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(氯噻嗪)、2-氯-5-(2,3-二氢-1-羟基-3-氧代-1H-异吲哚-1-基)苯磺胺(氯噻酮)、6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氢氯噻嗪)、3-(氨基磺酰基)-4-氯-N-(2,3-二氢-2-甲基-1H-吲哚-1-基)苯甲酰胺(吲哒帕胺)、7-氯-1,2,3,4-四氢-2-甲基-3-(2-甲基苯基)-4-氧代-6-喹唑啉磺胺(甲苯喹唑酮)、7-氯-2-乙基-1,2,3,4-四氢-4-氧代-6-喹唑啉磺胺(喹乙唑酮)；(A7d)：
3,5-二氨基-N-(氨基亚氨基甲基)-6-氯吡嗪甲酰胺(阿米洛利)、6-苯基-2,4,7-蝶啶三胺(氨苯蝶啶)、3-(氨基磺酰基)-5-丁氨基-4-苯氧基苯甲酸(丁苯氧酸)、5-(氨基磺酰基)-4-氯-2-[(2-呋喃基甲基)氨基]苯甲酸(呋喃苯胺酸)、N-[[(1-甲基乙基)氨基]碳酰基]-4-[(3-甲基苯基)氨基]-3-吡啶磺胺(胺吡磺异丙脲)；
按照本发明的特别优选的化合物如下：
A1b)类：氯沙坦；
A2)类：Sildenafil、扎普司特；
A3)类：阿替洛尔、拉贝洛尔、噻吗洛尔、哌唑嗪、特拉唑嗪、普萘洛尔；
A4)类：尼卡地平、硝苯地平、尼莫地平；
A7)类：氯噻嗪、阿米洛利、呋塞米。
按照通过引用结合到本文中的“The Merck Index 12aEd.”(1996)中描述的方法制备属于上述类型的盐的前体。在DE专利2,162,096中描述了扎普司特的制备方法。在G.B．专利2,001,633中描述了布新洛尔的制备方法。
在按照本发明的组合物中也可以使用属于上述类型化合物的异构体。异构体的实例有顺式、反式、旋光异构体D型和L型或外消旋物、对映体。通常某种异构体较其它异构体具有较高的活性，例如D型较L型高或反之亦然。
属于所述类型的化合物的盐至少含有1摩尔硝酸根离子/1摩尔化合物。硝酸根离子和前体摩尔数比优选为单元式的。当该分子中存在其碱性足以成盐的其它氨基时可获得较高摩尔比的盐。
按照本领域熟知的技术，将本发明的盐与常规的赋形剂一起制成相应的药用组合物，例如见“Remington’s Pharmaceutical Sciences15aEd.”卷。
本发明的盐在它们的药用组合物中的用量是相同的，并且通常低于上述类型其前体用量。
按照下列方法之一获得本发明的盐：
当将要成盐的物质是可溶解于有机溶剂中的一种游离碱或相应盐时，其中所述有机溶剂为优选不含羟基的有机溶剂如乙腈、乙酸乙酯、四氢呋喃等，通过将该物质溶解在溶剂中制备所述的盐，其浓度最好等于或高于10％w/v，加入对应于化合物中存在的可成盐的氨基摩尔量的浓硝酸。最好用相同的溶剂稀释硝酸。最好在加成期间和之后将该混合物冷却到20℃-0℃的温度范围内。通过过滤回收该产物并用所述溶剂洗涤。
相反，当该物质不是十分易溶或者说在上述溶剂中它是作为一种并不十分易溶的盐获得时，可使用与羟基化溶剂的相应混合物。该类溶剂的实例有甲醇、乙醇和水。在加入硝酸后，用一种非极性溶剂稀释所得的混合物可以加速沉淀。
当用盐酸使原料成盐时，可以在该化合物溶液中直接加入硝酸银制备硝酸盐。过滤氯化银后，浓缩该溶液并冷却以便回收硝酸盐。
当原料为一种盐时，可以通过用钠或钾的碳酸氢盐或碳酸盐的饱和溶液或用氢氧化钠或钾的稀溶液处理该盐以便释放出对应的碱。然后用适宜的有机溶剂(例如卤化溶剂、酯、醚)提取该游离碱，并脱水。蒸发有机溶剂，然后按照前面的制备方法进行，将该游离碱溶解于乙腈或上述其它熔剂中。
按照以本申请人的名义在欧洲专利759,899中描述的方法(通过引用结合到本文中)，制备在分子中由连接桥键合有一个-ONO2基团的前述类型的前体，也可以得到硝酸盐。
举出下列实施例仅仅是为了说明目的而它们并不是限制本发明。
实施例1噻吗洛尔硝酸盐的制备
向碳酸氢钠的饱和水溶液(100ml)中加入噻吗洛尔马来酸盐(7g)。用乙酸乙酯(300ml)提取该混合物。用硫酸钠使有机层干燥并在真空下蒸发，得到对应的噻吗洛尔碱(4.9g)，将其溶解于乙腈(25ml)中。用冰冷却该溶液，再用65％硝酸溶液(1.08ml)的乙腈(5ml)溶液处理，在冷却下搅拌30分钟后，用乙醚(100ml)处理，得到一种固体，过滤、用乙醚洗涤并在真空下干燥。得到4.6g噻吗洛尔硝酸盐，m.p.m.p.115-116℃。1H-NMR(D2O)ppm:4.34(1H,m),3.76(4H,t),3.39(4H,t),3.23(2H,m),3.04(2H,m),1.29(9H,s)。元素分析(C13H25N5O6S)：计算值(％)C41.15    H6.64    N18.46    S8.45实测值(％)C41.24    H6.61    N18.38    S8.31
实施例2普萘洛尔硝酸盐的制备
向碳酸氢钠的饱和水溶液(70ml)中加入普萘洛尔盐酸盐(5g)。用乙酸乙酯(250ml)提取该混合物。用硫酸钠使有机层干燥并在真空下蒸发,得到对应的普萘洛尔碱(4.2g)，将其溶解于乙腈/四氢呋喃5/2(70ml)中。用冰冷却该溶液并用65％硝酸溶液(1.13ml)的乙腈(10ml)溶液处理，在冷却下搅拌30分钟后，用乙醚(50ml)处理，得到一种固体，过滤并用乙醚洗涤，在真空下干燥。得到5.1g普萘洛尔硝酸盐，m.p.127-130℃。1H-NMR(D2O)ppm:8.15(1H,m),7.80(1H,m),7.48-7.32(4H,m),6.86(1H,d),4.32(1H,m),4.13(2H,d),3.36(1H,m),3.22(2H,d),1.24(6H,d)。元素分析(C16H22N2O5)：计算值(％)    C59.62    H6.88    N8.69实测值(％)    C59.99    H6.97    N8.65
实施例3Sildenafil硝酸盐的制备
用溶解于乙腈(10ml)中的65％硝酸(1.13ml)处理Sildenafil(7.7g,16.3mmol)的乙腈(100ml)和四氢呋喃(40ml)溶液。在+4℃30分钟后，通过在减压下蒸发，浓缩该混合物至少量体积并缓慢地加入乙醚(100ml)。过滤形成的沉淀、用乙醚洗涤并在真空下干燥。得到一种白色的无定形固体(6.5g)。元素分析(C22H31N7O7S)：计算值(％)C49.15    H5.81    N18.24    S5.96实测值(％)C49.34    H5.75    N18.38    S6.00
实施例4缬沙坦硝酸盐的制备
将缬沙坦(3.48g,8mmol)溶解于乙腈(30ml)和四氢呋喃(10ml)的混合物中得到缬沙坦溶液。在冷却下，加入用乙腈稀释的硝酸(将2.7ml65％的硝酸加入乙腈中使终体积为10ml，取该溶液2ml)。30分钟后，在相同的温度(+4℃)下，缓慢地加入乙醚(100ml)。过滤形成的沉淀、用乙醚洗涤并在真空下干燥。得到一种白色的无定形固体(3.1g)。元素分析(C24H30N6O6)：
计算值(％) C57.82  H6.07  N16.86
实测值(％) C58.02  H6.02  N16.77
实施例5肼苯哒嗪硝酸盐的制备
将盐酸肼苯哒嗪(3g)加入到碳酸钾水溶液(50ml)中。用乙酸乙酯(80ml)提取该溶液。用水洗涤有机相、用硫酸钠干燥并在真空下蒸发。将残余物(1g,6.25mmol)溶解于乙腈(30ml)和甲醇(20ml)的混合物中。将其冷却至+4℃并且加入65％硝酸(0.6g,6.24mmol)的乙腈(10ml)溶液。形成一种白色沉淀，过滤并在真空下干燥(1g,m.p.237-243℃)。元素分析(C8H9N5O3)：计算值(％)    C43.05    H4.06    N31.38实测值(％)    C43.32    H4.03    N31.22
实施例6硝吡胺甲酯硝酸盐的制备
在避光下，用硝酸银(0.33g,0.194mmol)处理盐酸硝吡胺甲酯(0.1g,0.194mmol)的乙腈(20ml)溶液。在室温下，持续搅拌30分钟，形成一种白色固体沉淀。过滤该固体，减压下浓缩滤液至一半体积，将其冷却至+40℃并用乙醇处理。过滤沉淀并干燥。得到一种黄色的固体(0.05g,m.p.193-198℃)。元素分析(C26H30N4O9)：计算值(％)    C57.56    H5.57    N10.33实测值(％)    C57.44    H5.63    N10.44实施例7戊脉安硝酸盐的制备
在避光下，用硝酸银(1.19g,7mmol)处理盐酸戊脉安(3.44g,7mmol)在乙腈(50ml)和四氢呋喃(15ml)混合物中的溶液。在室温下，持续搅拌一小时。缓慢地形成沉淀并在沉淀完全后过滤。将滤液浓缩至一半体积，冷却至+4℃并过滤形成的沉淀。干燥后，得到一种白色的无定形固体(2.8g)。元素分析(C27H39N3O7)：计算值(％)    C62.65    H7.59    N8.12实测值(％)    C62.48    H7.68    N8.11
实施例8阿米洛利硝酸盐的制备
在避光下，用硝酸银(1.28g,7.5mmol)处理盐酸阿米洛利(2g,7.5mmol)的甲醇(100ml)溶液。迅速地形成沉淀。在搅拌下，将其在室温放置30分钟。最后过滤固体并在减压下浓缩该溶液至一半体积。用乙醚(50ml)处理上述溶液并在+40℃冷却后，过滤得到的固体。干燥后分离得到一种固体(0.8g,mp.＞280℃)。元素分析(C6H9ClN8O4)：计算值(％)C24.63    H3.10    N38.29    Cl12.11实测值(％)C24.75    H3.03    N38.19    Cl12.24
实施例9普萘洛尔、普萘洛尔硝酸盐、噻吗洛尔和噻吗洛尔硝酸盐对豚鼠的实验性支气管狭窄的作用研究
将化合物以10mg/kg的剂量和相应的载体经腹膜内途径给予豚鼠(每组6只)，连续给药三天。
按照Del Soldato等J.Pharmacol.Methods 52791981的方法准备动物。45分钟后，给动物静脉注射0.1ml的辣椒硷溶液(1μg/kg)。通过连接到多道描记器系统上的Konzetl设备测量辣椒硷给药前后的潮气量变化，可按照前述参考资料描述的方法校正设备。
在表Ⅰ中报告了受试化合物及其相应的硝酸盐对由注射辣椒硷诱导的豚鼠实验性支气管狭窄的作用。
                        表Ⅰ
    处理     支气管狭窄效应(％)
    载体噻吗洛尔噻吗洛尔硝酸盐普萘洛尔普萘洛尔硝酸盐     10018894280110
实施例10Sildenafil硝酸盐与Sildenafil的药理活性比较
将受试化合物用生理溶液给予。对照组仅用载体(生理溶液)处理。
用实验性的前列腺输出管(deferent vessel)狭窄模型测定Sildenafil硝酸盐的血管舒张活性，该模型是在按照Ribeiro等，Hypertension,20,298,1992描述的方法用NW-硝基-L-精氨酸甲酯(L-NAME)处理的大鼠，通过用次最大的电刺激(D.A.Taylor等,J.Pharmacol.Exp.Ther.224,40-45 1983)诱导产生。Wistar成年雄性大鼠(235-284g)饮用L-NAME浓度为60-70mg/100ml的饮用水6周，日剂量大约为60mg/kg。通过皮下途径分别给予受试动物日剂量为10mg/kg的Sildenafil硝酸盐、Sildenafil或载体5天。在最后处理后一小时，处死受试动物并切除输出管的前列腺部分，将其浸泡在37℃的生理溶液中，并用跨壁刺激(最大刺激的95％,0.2Hz)使其收缩。
由于加入10-6M浓度的受试物质，在5分钟内引起神经原性收缩反应的减少，将其作为血管舒张活性的量度。
                      表Ⅱ
    处理     对血管收缩的作用(％)
    载体Sildenafil.HNO3Sildenafil     1002568
正如表中显示，硝酸盐的肌舒张活性大于其前体对照化合物。
也研究了对海绵体动脉和人海绵体(cavemosum corpora)的舒张作用(在外围水平的血管舒张作用)。该研究采用了R.G.Hempelmann等，在European Journal of Pharmacology 276,277-280(1995)中描述的技术，使用了来自于进行外科手术的病人的可勃起的组织。将海绵体动脉与周围结缔组织分离并清洗。得到约2mm长的组织节段并将其安装在一个肌动描记设备上。
在记录下实验性的直径/张力曲线后，将样本的直径调节到在100mmHg跨腔压(transluminal pressure)下所能达到的直径的90％；在稳定大约60分钟后，用3×10-6M肾上腺素使其收缩。15分钟后，加入10-6M剂量的各受试化合物并记录舒张百分率。结果见表Ⅲ。
按照相同的方案在分离的3×3×5mm海绵体组织条上进行第二系列的实验，在5-10mN张力下，将分离的组织条等体积地悬浮在分离器官的池中。结果见表Ⅳ。
                        表Ⅲ
处理 对分离的预先用肾上腺素收缩的人海绵体动脉的舒张作用(n=5)(舒张％)
 Sildenafil 10-6MSIN-1 10-6MSildenafil.HNO3 10-6M     25±436±761±3
                      表Ⅳ
处理 对分离的预先用肾上腺素收缩的人海绵体组织的舒张作用(n=4)(舒张％)
 Sildenafil 10-6MSIN-1 10-6MSildenafil.HNO3 10-6M     42±633±468±7
在上述两个实验模型中，对由肾上腺素引起收缩作用用Sildenafil和SIN-1氮氧化物供体处理后，舒张作用是明显的。按照本发明的衍生物已经显示具有比前体Sildenafil和SIN-1更高的药理活性。
实施例11氯沙坦硝酸盐与氯沙坦的抗高血压和抗血管收缩的活性比较研究
受试化合物用生理溶液给予。对照组仅用载体(生理溶液)处理。
采用两个实验模型分析了氯沙坦硝酸盐对动脉性高血压的抑制作用，该两种实验模型为由L-NAME诱导的动脉性高血压(参见前述实施例)及由血管紧张素Ⅱ引起的肌收缩。在第一个实验中，Wistar成年雄性大鼠(235-284g)饮用L-NAME浓度为60-70mg/100ml的饮用水6周，日剂量大约为60mg/kg。通过皮下途径分别给予受试动物日剂量为10mg/kg的氯沙坦硝酸盐、氯沙坦或载体5天。在最后处理后一小时，按照Zatz,Lab.Anim Sci.,42,198,1990描述的方法，由尾部测量系统动脉压。
在第二个实验(由血管紧张素Ⅱ引起收缩)中，采用P.C.Wong等在Hypertension,13,489-497,1989中描述的方法。将从豚鼠(300-350g)分离的回肠段浸泡在分别含有血管紧张素Ⅱ(10mcg/ml)、血管紧张素Ⅱ+10-6M的氯沙坦硝酸盐及血管紧张素Ⅱ+10-6M的氯沙坦的生理溶液中。结果见表Ⅴ。
                    表Ⅴ
处理 平均动脉压(mmHg) 对平滑肌系统收缩的作用％(n=5)
载体氯沙坦.HNO3氯沙坦     170±7115±4153±5     1001233
从表中可以看出，所述硝酸盐对由L-NAME引起的高血压比该前驱参比化合物具有更大的抑制作用。因为所述两个产品都能抑制血管紧张素Ⅱ引起的收缩，因此它们都具有有效的肌舒张活性，但是按照本发明的化合物显示出更高的功效。
实施例12米诺地尔硝酸盐与米诺地尔的抗高血压活性及血管舒张活性比较的研究
将受试化合物用生理溶液给予。对照组仅用载体(生理溶液)处理。
采用两个实验模型测定了米诺地尔硝酸盐对动脉性高血压的抑制作用，该两种实验模型为由L-NAME诱导的动脉性高血压(见实施例10)及由电刺激引起的血管收缩。在第一个药理实验中，按照在实施例11的药理实验中的描述用L-NAME处理受试大鼠。在第二个实验中，如前所述，采用Taylor(见实施例10)所描述的方法。取出分离的大鼠(200-220g)输送管的前列腺部分并将其浸泡在37℃的生理溶液中，然后用跨壁刺激(最大刺激的95％,0.2Hz)使其收缩。
在加入10-6M浓度的受试化合物后5分钟之内测定的神经原性收缩反应减少，将其用来表示血管舒张活性。
                            表Ⅵ
处理 平均动脉压(mmHg) 对血管收缩的作用％(n=5)
载体米诺地尔硝酸盐米诺地尔     170±7110±6132±6     100518
正如表Ⅵ所示，米诺地尔硝酸盐对由L-NAME引起的高血压的抑制作用大于其参比化合物。至于血管舒张活性，这两种产品对电刺激引起的血管收缩皆有有效的抑制作用。
实施例13噻吗洛尔硝酸盐与噻吗洛尔的抗高血压活性和β-肾上腺素活性的比较研究
采用的两种实验模型为由L-NAME诱导的动脉性高血压和由异丙肾上腺素引起的正性肌力。
在前一个实验中，按照实施例11描述的实验模型研究抗高血压活性。
在后一个实验中，采用Grodzinski等在Arch.Int.Phramacodyn.,191,133-141,1971中描述的方法。将取自豚鼠(300-350g)的左心房样本保养在钙离子浓度低于1/3的32℃生理溶液中并用异丙肾上腺素(10mcg/ml)刺激。在监测下加入10-6M浓度的受试化合物后，以正性肌力作用(心房肌肉收缩增强)的降低用来表示β-肾上腺素活性。
                      表Ⅶ
处理 平均动脉压(mmHg) 正性肌力作用％(n=5)
载体噻吗洛尔硝酸盐噻吗洛尔     170±7108±8144±5     1001332
正如表Ⅶ所示，噻吗洛尔硝酸盐对由L-NAME引起的高血压的抑制作用大于噻吗洛尔。至于肾上腺素活性，这两种产品对由异丙肾上腺素引起的正性肌力作用皆有有效的抑制作用，但是按照本发明的化合物显示出更高的功效。
实施例14硝吡胺甲酯硝酸盐与硝吡胺甲酯的抗高血压活性和钙拮抗活性的比较研究
采用的两种实验模型为由L-NAME诱导的动脉性高血压和由氯化钙引起的肌肉收缩。
在前一个实验中，按照实施例11描述的实验模型研究抗高血压活性。
在后一个实验中，采用的实验模型是由氯化钙引起的回肠收缩，按照M.J.Spedding,J.Pharmacology 83,211-220,1984所描述的方法进行。将取自豚鼠(300-350g)的回肠段保养在不含钙离子的37℃生理溶液中，然后加入氯化钙(终浓度为20mcg/ml)刺激。加入10-6M浓度的各受试化合物后，以回肠收缩减少测定钙拮抗活性。
                        表Ⅷ
处理 平均动脉压(mmHg) 挛缩作用％(n=5)
载体     170±7     100
硝吡胺甲酯硝酸盐     108±3     8
硝吡胺甲酯     122±6     25
正如表中所示，所述硝酸盐对由L-NAME引起的高血压的抑制作用大于其前体硝吡胺甲酯。至于钙拮抗活性，即使是在不同的程度上，所述两种化合物在抑制依赖于钙的挛缩作用中皆是有效的。
实施例15阿米洛利硝酸盐与阿米洛利对大鼠的抗高血压活性和利尿活性的比较研究
用下列实验模型测定阿米洛利的药理活性类型，所述实验模型为由L-NAME引起的动脉性高血压和利尿作用。
在前一个实验中，按照实施例11描述的实验模型研究抗高血压活性。
在后一个实验中，按照W.L.Lipschwitz等在J.Pharmacol.Exp.Ther.,79,97-100,1943中描述的方法研究利尿作用。3组，每组6只大鼠(200-220g)，将其关在代谢笼中饮用蒸馏水(25ml/kg，口服)。然后经皮下分别给每组注射阿米洛利硝酸盐(10mg/kg)、阿米洛利(10mg/kg)或载体。收集给药后6小时内的尿液体积，以ml计量。以收集的尿液体积对用载体处理的对照组的尿液体积计算的百分率表示利尿作用。
                      表Ⅸ
处理 平均动脉压(mmHg) 利尿作用％(n=5)
载体阿米洛利硝酸盐阿米洛利     170±7110±7158±7     100215220
正如表Ⅸ所示，阿米洛利硝酸盐对由L-NAME引起的高血压的抑制作用明显强于阿米洛利的抑制作用。至于血管舒张活性，所述的两个化合物显示相似的利尿活性。
实施例16Sildenafil硝酸盐和扎普司特硝酸盐的急性毒性研究
将所述的两种产品以2％羧甲基纤维素的悬浮液给药。
通过经口给药方法，逐渐增加给予受试鼠(每组10只)的受试化合物剂量评价上述盐的急性毒性。每组给予一个剂量。
持续观察受试动物14天，评价致死发生率和任何毒性症状。
甚至在给予50mg/kg的剂量后也未观察到明显的毒性征兆。所有的受试动物皆存活。
实施例17Sildenafil硝酸盐和扎普司特硝酸盐与它们的前体对胃毒性的比较研究
将5组Sprague-Dawley雄性大鼠(n=10)禁食24小时。然后分别用Sildenafil、扎普司特及所述药物的相关硝酸盐经腹膜内处理4组受试动物。一组不作任何处理并作为对照组。30分钟后给予(OS)受试动物1ml的50％乙醇水溶液。
1小时后处死受试动物。取出胃部并肉眼检查胃组织。由一个不知道受试鼠在处死前受到何种处理的研究人员进行该检查。按照Gretzer等(Br.J.Pharmacol.123,927,1998)的描述，检查是否存在损伤。
结果见表Ⅹ。在表中，将一组中出现胃损伤的受试鼠数量按照发生率(％)表示为胃毒性。
                                  表Ⅹ
处理 游离碱药物mg/kg/i.p. 胃毒性(％发生率)
对照SildenafilSildenafil.HNO3扎普司特扎普司特硝酸盐 10101010     50100209030
正如表中所示，在用Sildenafil或扎普司特处理的受试大鼠组中，胃的病理学恶化超过了对照组。所述药物相应硝酸盐的胃毒性低于对照组。
实施例18哌克昔林硝酸盐的制备
将65％的硝酸(0.75ml)加入在0℃下冷却的哌克昔林(3.02g,10.9mmol)的乙腈和甲醇(10ml)溶液中。
在0℃、磁力搅拌下，保存所得的溶液30分钟，然后在室温下再保存30分钟。在减压下蒸发溶剂并将粗制物悬浮在乙醚中，然后过滤。
获得产物(3.09g)，一种熔点等于151-155℃的白色固体。元素分析：
        C          H          N计算值    67.00％    10.65％    8.26％实测值    67.05％    10.79％    8.40％实施例19阿朴吗啡硝酸盐的制备
将硝酸银(2.72g,16mmol)加入到阿朴吗啡盐酸盐(5g,16mmol)的乙腈(70ml)溶液中。在氮气氛下、黑暗中，搅拌该混合物30分钟。滤去氯化银并用乙醚稀释滤液。形成沉淀并过滤，用乙醚洗涤并在真空下干燥。得到4.3g产物。C、H、N分析计算值(％)    C61.81    H5.49    N8.48实测值(％)    C61.84    H5.45    N8.51
实施例20扎普司特硝酸盐的制备
在0℃下将0.5ml 65％硝酸/乙腈(2.7ml/7.3ml)溶液加入扎普司特(0.5g,1.84mmol)的乙腈(10ml)的溶液中，在避光、氮气氛下搅拌所获得的混合物30分钟。然后用乙醚稀释溶液，过滤形成的沉淀，用乙醚洗涤并真空干燥(0.4g)。C、H、N分析计算值(％)    C46.71    H4.22    N25.14实测值(％)    C46.68    H4.26    N25.11

Claims (16)

1．选自下列类型化合物的硝酸盐：(A1b)类：
Figure A9980751600021
；RA1=-O与RⅢ A1自由价，以便与5位的碳原子形成酮基，RA1与RⅠ A1一起和式(A1b)化合物中杂环上的4及5位碳原子、RⅣ A1和RⅢ A1自由价形成含有-COOH基团的6个碳原子的芳环：
Figure A9980751600022
RⅠ A1=H、Cl；RⅠ A1与RA1、RⅣ A1、RⅢ A1和式(A1b)杂环上的4及5位碳原子形成含有一个-COOH基团的芳环(Ⅸc)，RⅠ A1与RⅣ A1和式(A1b)杂环上的4位碳原子形成下面的5个碳原子的饱和环：RⅡ A1=-(CH2)3-CH3、-O-CH2-CH3；RⅢ A1=H，自由价，RⅢ A1自由价与RⅣ A1自由价在式(A1b)中杂环上的4位和5位碳原子之间形成一个双键，RⅢ A1与RⅣ A1、RⅠ A1和式(A1b)中杂环上的4及5位碳原子形成含有一个-COOH基团的芳环(Ⅸc)；RⅣ A1=自由价，RⅣ A1与RⅠ A1一起和式(A1b)中杂环上的4位碳原子形成5个碳原子的饱和环(Ⅸd)，RⅣ A1与RⅢ A1、RⅠ A1一起和式(A1b)杂环上的4及5位碳原子形成含有一个-COOH基团的芳环(Ⅸc)，RⅣ A1与RⅢ A1皆自由价在式(A1b)中杂环上的4位和5位碳原子之间形成一个双键；(A1c)类：(A1c)类前体称为缬沙坦；(A2)类：
1(2H)-2,3-二氮杂萘酮腙(肼苯哒嗪)；6-(1-哌啶基)-2,4-嘧啶二胺3-氧化物(长压定)；1-[[3-(4,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑[4,3-d]嘧啶-5-基)-4-etoxy苯基]磺酰基-4-甲基-哌嗪(Sildenafil),2-(2-丙氧基苯基)-8-氮杂嘌呤-6-酮(扎普司特)；(A3)类：RⅠ B1与RⅡ B1彼此相同或不同地为H、CH3，
Figure A9980751600051
在式(Ⅺd)中t=0、1。在式(Ⅺe)中YB1可为：
Figure A9980751600052
在式(Ⅺf)中Z=H、-OCH3；在式(A3)中：XB1=-O-,-S-；n和m彼此相同或不同，为0、1；
Figure A9980751600061
-CH2-CH(OH)-CH2-NH-CH(CH3)2(Ⅺr),在式(Ⅺp)中：S1=H、CN、OCH3、CH3、-CH2-CH3、-O-CH2-CONH-CH3、-COCH3、-CO-(CH2)2-CH3、-O-CH2-CH=CH2、-CH2-CH=CH2、环戊基或
Figure A9980751600072
S2=H、CH3、Cl、-SOCH3、-CONH2；S1与S2一起和相同基团(Ⅺp)中C6芳环的2及3位碳原子形成如下所示的环：
Figure A9980751600081
其中：[(*)原子连接式ⅪpⅦ中的芳环]B=-CH2-、-NH-、-CH=CH-、(*)-CO-CH2-；A=-O-、(*)-CH2-CH(OH)-、(*)-O-CH2-、(*)-S-CH2-、-CH2-CH2-、-CH2-,A为一个叔碳原子而同时W1为自由价以便在A和1′位碳原子之间形成一个双键-CH=CH-，在5元环(ⅪpⅦ)中A为含有一个取代基的叔碳原子，以便与1′位碳原子及与W1或W2基团中的一个(另外一个基团为自由价)形成下式所示的6个碳原子的芳环：
Figure A9980751600082
W1=H、自由价，当W1为自由价而A为如前定义的叔碳原子时，在A和1′位碳原子之间形成一个双键；W1与W2、1′位碳原子一起和取代基A形成一个具有6个碳原子的芳环；W2=自由价、H、OH、-CH3、-ONO2、与W1=自由价一起和1′位碳原子形成一个酮基的-O,W2与W1、1′位碳原子一起和取代基A形成一个具有6个碳原子的芳环；S3=H、F、Cl、OH、NO2、-CH2-CO-NH2、-(CH2)2-OCH3、-NH-COCH3、-CH2-O-CH2-CH2-O-CH(CH3)2、-CH2-CH2-COOCH3、-NH-CO-N(C2H5)2、-NH-CO-(CH2)2-CH3、-NH-SO2-CH3、-NH-CO-NH-[环己基]、-CH2-CH2-O-CH2-[环丙基]；S4=H、Cl、-CH2-CH2-,-CH2-CH2-与同一基团(XIp)中芳环的1位及6位碳原子一起和式(A3)的XB1(等于氧)形成下式环，同时m=n=1和RⅦ B1自由价S4为叔碳原子，它与基团(Ⅺp)中芳环的1位及6位碳原子一起和式(A3)的以下部分：碳原子-|C|n-(n=1)、基团XB1(等于氧)(m=1)以及RⅦ B1和RⅥ B1自由价，形成下式环：
Figure A9980751600092
RⅥ B1=H、自由价；RⅦ B1=H、自由价；以及除所述化合物之外还包括下列化合物：2-羟基-5-[1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基]苯甲酰胺(拉贝洛尔)、1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢-2-呋喃基)羰基]哌嗪(特拉唑嗪)、1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-(2-呋喃基羰基)哌嗪(哌唑嗪)、苄腈、2-[2-羟基-3-[[2-(2-(1H-吲哚-3基)-1,1-二甲基乙基]氨基]]丙氧基](布新洛尔)；(A4)类：(A4a)：
β-[(2-甲基丙氧基)甲基]-N-苯基-N-(苯甲基)-1-吡咯烷乙胺(双苯吡乙胺)、(2S-顿式)-3-(乙酰氧基)-8-氯-5-[2-(二甲氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫代氮杂(thiazepin)-4(5H)-酮(克仑硫)、(2S-顺式)-3-(乙酰氧基)-5-[2-(二甲氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫代氮杂-4(5H)-酮(地尔硫)、γ-苯基-N-(1-苯基乙基)苯丙胺(芬地林)、α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲氨基]丙基]-3,4,5-三甲氧基-α-(1-甲基乙基)-苯乙腈(戈洛帕米)、(1S-顺式)甲氧基乙酸2-[2[[3-(1H-苯并咪唑-2-基)丙基]甲氨基]乙基]-6-氟-1,2,3,4-四氢-1-(1-甲基乙基)-2-萘酯(Mibefradil)、N-(1-甲基-2-苯乙基)-γ-苯基苯丙胺(双苯丙胺)、(R)-2-[2-[3-[[2-(1,3-苯并间二氧杂环戊烯-5-基氧基)乙基]甲氨基]丙氧基]-5-甲氧基苯基]-4-甲基-2H-1,4-苯并噻嗪-3(4H)-酮(司莫地尔)、N-(1,1-二甲基乙基)-α-甲基-γ-苯基苯丙胺(双苯丁胺)、α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)-苯乙腈(戊脉胺)；(A4b)：
2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二羧酸3-乙酯5-甲酯(氨氯地平)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲酯2-氧代丙酯(阿雷地平)、[S-(R*,R*)]-1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯1-(苯基甲基)-3-吡咯烷基酯(巴尼地平)、(R*,R*)-±-1,4-二氢-2,6二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯1-(苯基甲基)-3-哌啶酯(贝尼地平)、(E)-±-1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-甲氧基乙酯3-苯基-2-丙烯酯(西尼地平)、5-(5,5-二甲基-1,3,2-dioxaphosphorinane-2-基)-1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3-吡啶羧酸2-[苯基(苯甲基)氨基]乙酯对氧化物(P-oxide)(依福地平)、±-4-(1,3-苯并间二氧杂环戊烯-4-基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸2-[[(4-氟苯基)甲基]甲氨基]乙酯1-甲基乙酯(依高地平)、4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸乙酯甲酯(非洛地平)、4-(4-苯并呋咱基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸5-甲酯3-(1-甲基)乙酯(伊拉地平)、(E)-4-[2-[3-(1,1-二甲基乙氧基)-3-氧代-1-丙烯基]苯基]-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸二乙酯(拉西地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-[(3,3-二苯基-丙基)甲氨基]-1,1-二甲基乙酯甲酯(乐卡地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-[4-(二苯基甲基)-1-哌嗪基]乙酯甲酯(马尼地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯2-[甲基(苯甲基)氨基]乙酯(尼卡地平)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸二甲酯(硝苯吡啶)、2-氰基-1,4-二氢-6-甲基-4-(3-硝基-苯基)-3,5-吡啶二羧酸3-甲酯5-(1-甲基乙基)酯(尼伐地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-甲氧基乙酯1-甲基乙酯(硝苯吡酯)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲酯2-甲基丙酯(尼索地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸乙酯甲酯(尼群地平)；(A4c)：
1-(二苯基甲基)-4-(3-苯基-2-丙烯基)哌嗪(肉桂苯哌嗪)、(E)-1[双(4-氟苯基)甲基]-4-(3-苯基-2-丙烯基)哌嗪(氟桂利嗪)、4-[4,4-双(4-氟苯基)丁基]-N-(2,6-二甲基苯基)-1-哌嗪乙酰胺(利多氟嗪)、1-[双(4-氟苯基)甲基]-4-[(2,3,4-三甲氧基苯基)甲基]哌嗪(洛美利嗪)；(A4d)：
N,N-二甲基-3-[[1-(苯基甲基)-环庚基]氧基]-1-丙胺(苄环烷)、1-[2-[2-(二乙基氨基)乙氧基]苯基]-3-苯基-1-丙酮(乙胺苯丙酮)、3,4-二甲氧基-N-甲基-N-[3-[4-[[2-(1-甲基乙基)-1-中氮茚基]磺酰基]苯氧基]丙基]苯乙胺(泛托法隆)；(A7)类：(A7a)：
6-氯-3,4-二氢-3-[(2-丙烯基硫代基)甲基]-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(烯硫噻二嗪)、3,4-二氢-3-(苯基甲基)-6-三氟甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(苄氟噻嗪)、6-氯-3-[[(苯基甲基)硫代基]甲基]-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(苄硫噻嗪)、6-氯-3,4-二氢-3-(苯基甲基)-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(苄氢氯噻嗪)、6-氯-3,4-二氢-3-(2-甲基丙基)-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(异丁噻嗪)、6-氯-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(氯噻嗪)、2-氯-5-(2,3-二氢-1-羟基-3-氧代-1H-异吲哚-1-基)苯磺胺(氯噻酮)、6-氯-3-(环戊基甲基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(环戊氯噻嗪)、3-双环[2.2.1]-庚-5-烯-2-基-6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(环己氯噻嗪)、6-氯-3,4-二氢-3-[[(2,2,2-三氟乙基)硫代基]甲基]-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(氟硫噻嗪)、6-氯-3-乙基-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(乙噻嗪)、7-氯-1,2,3,4-四氢-4-氧代-2-苯基-6-喹唑啉磺胺(苯喹唑酮)、3-(氨基磺酰基)-4-氯-N-(2,3-二氢-2-甲基-1H-吲哚-1-基)苯甲酰胺(吲哒帕胺)、6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氢氯噻嗪)、3,4-二氢-6-三氟甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氢氟噻嗪)、6-氯-3-(氯甲基)-3,4-二氢-2-甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(甲氯噻嗪)、3,4-二氢-6-甲基-2H-1-苯并硫代吡喃-7-磺胺1,1-二氧化物(Methycrane)、7-氯-1,2,3,4-四氢-2-甲基-3-(2-甲基苯基)-4-氧代-6-喹唑啉磺胺(甲苯喹唑酮)、6-氯-3-[(4-氟苯基)甲基]-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氟噻嗪)、6-氯-3,4-二氢-2-甲基-3-[[(2,2,2-三氟乙基)硫代基]甲基]-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(多噻嗪)、7-氯-2-乙基-1,2,3,4-四氢-4-氧代-6-喹唑啉磺胺(喹乙唑酮)、6-氯-3,4-二氢-3-三氯甲基-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(四氯甲噻嗪)、6-氯-3-(二氯甲基)-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(三氯噻嗪)；(A7b)：
3,7-二氢-1,3-二甲基-7-(4-吗啉基甲基)-1H-嘌呤-2,6-二酮(7-吗啉甲茶碱)、3,7-二氢-1-(2-羟基丙基)-3,7-二甲基-1H-嘌呤-2,6-二酮(羟丙可可碱)、3,7-二氢-3,7-二甲基-1H-嘌呤-2,6-二酮(可可碱)；(A7c)：
6-氨基-3-乙基-1-(2-丙烯基)-2,4-(1H,3H)-嘧啶二酮(氨乙烯丙尿嘧啶)、6-氨基-3-甲基-1-(2-甲基-2-丙烯基)-2,4-(1H,3H)-嘧啶二酮(阿米美啶)；(A7d)：
N-苯基-1,3,5-三嗪-2,4-二胺(阿马诺嗪)、3,5-二氨基-N-(氨基亚氨基甲基)-6-氯吡嗪甲酰胺(阿米洛利)、N-(4-氯苯基)-1,3,5-三嗪-2,4-二胺(氯苯三嗪胺)、[3-甲基-4-氧代-5-(1-哌啶基)-2-噻唑烷亚基]乙酸乙酯(乙氧唑啉)、6-肼基-3-哒嗪甲酰胺(肼氨羰哒嗪)、5-氨基-2[1-(3,4-二氯苯基)乙基]-2,4-二氢-3H-吡唑-3-酮(氯苄唑胺)、2-(2,2-二环己基乙基)哌啶(环己哌啶)、6-苯基-2,4,7-蝶啶三胺(氨苯蝶啶)、3-(氨基磺酰基)-5-丁氨基-4-苯氧基苯甲酸(丁苯氧酸)、5-(氨基磺酰基)-4-氯-2-[(2-呋喃基甲基)氨基]苯甲酸(呋喃苯胺酸)、N-[[(1-甲基乙基)氨基]碳酰基]-4-[(3-甲基苯基)氨基]-3-吡啶磺胺(胺吡磺异丙脲)；(A8)类：阿朴吗啡。
2．下列(A1b)类化合物的按照权利要求1的硝酸盐：当XA1=(Ⅸa),RA1=CH2OH,RⅠ A1=Cl,RⅢ A1=RⅣ A1=自由价(与式(A1b)中杂环上的4和5位碳原子形成-CH=CH-双键)，RⅡ A1=-(CH2)3-CH3时，则为氯沙坦残基；与在氯沙坦中一样，但是RA1=-O和RⅢ A1自由价，以便与式(A1b)中杂环上的5位碳原子形成一个酮基，RⅠ A1与RⅦ A1一起和杂环上的4位碳原子形成具有5个碳原子的饱和环(Ⅸd)时，则为Irbesartan残基；与在氯沙坦中一样，但是RⅡ A1=-O-CH2-CH3、RA1与RⅠ A1一起和RⅣ A1与RⅢ A1为自由价的杂环上的4和5位碳原子形成含有-COOH基团的芳香基(Ⅸc)时，则为Candesartan残基；与在氯沙坦中一样，但是XA1=-COOH、RA1=(IXb)、RⅠ A1=H、RⅣ A1与RⅢ A1自由价在式(A1b)中杂环上的4和5位碳原子之间形成一个双键时，则为Eprosartan残基。
3．下列(A3)类化合物的按照权利要求1的硝酸盐：当RⅠ B1=H,RⅡ B1和RⅢ B1=CH3,RⅤ B1=H,RⅥ B1=RⅦ B1=H,m=n=1,XB1=-O-,RⅣ R1=(Ⅺp)(其中S1=S2=S4=H,S3=-CH2-CONH2)时，则为阿替洛尔残基；与在阿替洛尔中一样，但是RⅣ B1=(Ⅺs)时，则为苯呋洛尔残基；与在阿替洛尔中一样，但是S3=S2=S4=H、S1=-CH2-CH=CH2时，则为阿普洛尔残基；与在阿替洛尔中一样，但是S1=COCH3、S3=-NH-CO-(CH2)2-CH3、S2=S4=H时，则为醋丁洛尔残基；与在阿替洛尔中一样，但是S3=-CH2-CH2-O-CH2-环丙基时，则为倍他洛尔残基；与在阿替洛尔中一样，但是S3=-CH2-O-CH2-CH2-O-CH(CH3)2时，则为比索洛尔残基；与在阿普洛尔中一样，但是S1=(ⅪpⅡ)和RⅠ B1=CH3时，则为布非洛尔残基；与在布非洛尔中一样，但是S1=-CN时，则为布尼洛尔残基；与在布非洛尔中一样，但是S1=H、S4=Cl、S2=CH3时，则为氯甲苯心安残基；与在布非洛尔中一样，但是S1=-CO-(CH2)2-CH3、S3=F时，则为丁非洛尔残基；与在阿替洛尔中一样，但是RⅣ B1=(ⅪpⅧ)，其中B=-NH-时，则为卡拉洛尔残基；与在布非洛尔中一样，但是RⅣ B1=(ⅪpⅦ)，其中A=-CH2-CH2-、B=-NH-、W2=-O,W2与W1自由价一起和1′位碳原子形成一个酮基时，则为卡替洛尔残基；与在布非洛尔中一样，但是S3=-NH-CO-N(C2H5)2、S1=-CO-CH3时，则为二乙脲心安残基；与在布非洛尔中一样，但是S1=-O-CH2-CONH-CH3时，则为塞他洛尔残基；与在氯甲苯心安中一样，但是S2=Cl时，则为氯拉洛尔残基；与在阿替洛尔中一样，但是S3=-CH2-CH2-COOCH3时，则为艾司洛尔残基；与在阿替洛尔中一样，但是RⅣ B1=(Xiu)时，则为茚诺洛尔残基；与在卡替洛尔中一样，但是在RⅣ B1=(ⅪpⅦ)中A=-CH2-、B=-CO-CH2-、W1=W2=H时，则为左布诺洛尔残基；与在卡替洛尔中一样，但是RⅠ B1=H并且在RⅣ B1=(ⅪpⅦ)中A为一个叔碳原子和W1自由价，以至在A和(ⅪpⅦ)中的1′位碳原子之间形成一个-CH=CH-双键，W2=CH3时，则为甲吲洛尔残基；与在阿替洛尔中一样，但是S3＝-(CH2)2-OCH3时，则为美托洛尔残基；与在卡替洛尔中一样，但是在RⅣ B1=(ⅪpⅦ)中A=-CH2-CH(OH)-、B=-CH2-、W2=OH、W1=H时，则为纳多洛尔残基；与在阿替洛尔中一样，但是S3=NO2时，则为硝苯洛尔残基；与在甲吲洛尔中一样，但是在RⅣ B1=(ⅪpⅦ)中A=-O-CH2-、B=-CH2-、W2=-ONO2、W1=H时，则为尼普地洛残基；与在阿普洛尔中一样，但是S1=-O-CH2-CH=CH2时，则为氧烯洛尔残基；与在布非洛尔中一样，但是S1=环戊基时，则为环戊丁心安残基；与在甲吲洛尔中一样，但是W2=H时，则为吲哚洛尔残基；与在阿替洛尔中一样，但是S3=-NH-COCH3时，则为普拉洛尔残基；与在布非洛尔中一样，但是S1=H、S3=-NH-CO-NH-环己基时，则为他林洛尔残基；与在尼普地洛中一样，但是RⅠ B1=CH3、A=-S-CH2-而W2=H时，则为特他洛尔残基；与在特他洛尔中一样，但是RⅣ B1=(XIn)时，则为替利洛尔残基；与在布非洛尔中一样，但是RⅣ B1=(XIo)时，则为噻吗洛尔残基；与在布非洛尔中一样，但是S1=S2=CH3时，则为希苯洛尔残基；与在希苯洛尔中一样，但是RⅠ B1=S1=H时，则为托利洛尔残基；与在托利洛尔中一样，但是RⅡ B1=H而RⅢ B1=(Ⅺa)时，则为贝凡洛尔残基；与在卡拉洛尔中一样，但是RⅡ B1=H而RⅢ B1=(Ⅺb)时，则为卡维地洛残基；当在式(A3)中RⅠ B1=RⅡ B1=RⅢ B1=CH3、RⅤ B1=(XIh)、n=m=1、RⅥ B1=RⅦ B1=H、XB1=-O-、RⅣ B1=(Ⅺg)时，则为波吲洛尔残基；与在布非洛尔中一样，但是RⅣ B1=(XIt)时，则为布库洛尔残基；当在式(A3)中m=n=0而RⅣ B1=(Ⅺz)、RⅠ B1=RⅡ B1=RⅢ B1=CH3、RⅤ B1=H时，则为丁呋洛尔残基；与在阿替洛尔中一样，但是RⅢ B1=(XIe)，其中YB1=H、n=m=0,RⅣ B1=(Ⅺi)时，则为布替君残基；与在布替君中一样，但是RⅢ B1=(XIe)，其中YB1=(Ⅺf),(Ⅺf)中Z=H,RⅣ B1=(Ⅺg)，其中S3=OH及S2=CONH2、S1=S4=H时，则为地来洛尔残基；与在贝凡洛尔中一样，但是S2=H、S1=CN、RⅢ B1=(XIc)时，则为依泮洛尔残基；与在布替君中一样，但是RⅢ B1=CH3,RⅣ B1=(XIm)，其中所述萘基通过2位的碳原子连接到带有-ORⅣ B1取代基的碳原子上时，则为丙萘洛尔残基；与在丙萘洛尔中一样，但是m=1和XB1=-O-，而RⅣ B1为通过1位的碳原子连接XB1的萘基(Ⅺm)时，则为普萘洛尔残基；与在丙萘洛尔中一样，但是RⅣ B1=(Ⅺp)，其中S1=S2=S4=H并且S3=-NH-SO2-CH3时，则为索他洛尔残基；与在地来洛尔中一样，但是S2=-SOCH3，并且在另一芳环(式Ⅺf)的对位Z=-OCH3时，则为磺苄心安残基；当在式(A3)中RⅠ B1=RⅡ B1=H、RⅢ B1=其中t=1的(Ⅺd)、RⅤ B1=H、n=m=0、RⅣ B1=其中t=0的(Ⅺd)时，则为奈必洛尔残基；2-羟基-5-[1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基]苯甲酰胺(柳胺心定)、1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢-2-呋喃基)碳酰基]哌嗪(特拉唑嗪)、1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)-4-(2-呋喃基碳酰基)哌嗪(哌唑嗪)。
4．下列(A4)类化合物的按照权利要求1的硝酸盐：(A4a)：
(2S-顺式)-3-乙酰氧基-5-[2-(二甲基氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-1,5-苯并硫代氮杂-4(5H)-酮(地尔硫)、α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)-苯乙腈(戊脉胺)；(A4b)：
2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二-氢-6-甲基-3,5-吡啶二羧酸3-乙酯5-甲酯(氨氯地平)、4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸乙酯甲酯(非洛地平)、4-(4-苯并呋咱基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸5-甲酯3-(1-甲基)乙酯(伊拉地平)、乐卡地平、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸甲酯2[甲基(苯甲基)氨基]乙酯(硝吡胺甲酯)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸二甲酯(硝苯吡啶)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸2-甲氧基乙酯1-甲基乙酯(硝苯吡酯)、1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-3,5-吡啶二羧酸甲酯2-甲基丙酯(尼索地平)、1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸乙酯甲酯(硝吡乙甲酯)；(A4c)：
(E)-1-[双(4-氟苯基)甲基]-4-(3-苯基-2-丙烯基)哌嗪(氟桂利嗪)。
5．下列(A7)类化合物的按照权利要求1的硝酸盐：(A7a)：
6-氯-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(氯噻嗪)、2-氯-5-(2,3-二氢-1-羟基-3-氧代-1H-异吲哚-1-基)苯磺胺(氯噻酮)、6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物(双氢氯噻嗪)、3-(氨基磺酰基)-4-氯-N-(2,3-二氢-2-甲基-1H-吲哚-1-基)苯甲酰胺(吲哒帕胺)、7-氯-1,2,3,4-四氢-2-甲基-3-(2-甲基苯基)-4-氧代-6-喹唑啉磺胺(甲苯喹唑酮)、7-氯-2-乙基-1,2,3,4-四氢-4-氧代-6-喹唑啉磺胺(喹乙唑酮)；(A7d)：
3,5-二氨基-N-(氨基亚氨基甲基)-6-氯吡嗪甲酰胺(阿米洛利)、6-苯基-2,4,7-蝶啶三胺(氨苯蝶啶)、3-(氨基磺酰基)-5-丁氨基-4-苯氧基苯甲酸(丁苯氧酸)、5-(氨基磺酰基)-4-氯-2-[(2-呋喃基甲基)氨基]苯甲酸(呋喃苯胺酸)、N-[[(1-甲基乙基)氨基]碳酰基]-4-[(3-甲基苯基)氨基]-3-吡啶磺胺(胺吡磺异丙脲)。
6．下列化合物的按照权利要求1-5的硝酸盐：
A1b)类：氯沙坦；
A2)类：Sildenafil、扎普司特；
A3)类：阿替洛尔、拉贝洛尔、噻吗洛尔、哌唑嗪、特拉唑嗪、普萘洛尔；
A4)类：尼卡地平、硝苯地平、尼莫地平；
A7)类：氯噻嗪、阿米洛利、呋塞米。
7．含有一种或多种所述化合物的异构体的按照权利要求1-6的硝酸盐。
8．按照权利要求1-7的盐，其中所述化合物的盐至少含有一个摩尔量的硝酸根离子/化合物。
9．按照权利要求1-8的硝酸盐的药用组合物。
10．按照权利要求1-9的硝酸盐和药用组合物作为药物的用途。
11．按照权利要求10的盐和药用组合物在制备治疗高血压的药物中的用途。
12．按照权利要求11的盐和药用组合物用于制备心血管药物的用途。
13．按照权利要求1-8的硝酸盐的制备方法，其中当使用所述需要成盐的物质是可溶于不含羟基的有机溶剂的游离碱或相应的盐时，通过将所述物质以等于或高于10％w/v的浓度溶解在所述溶剂中，加入相当于化合物中存在的可成盐的氨基基团摩尔量的浓硝酸，在加入期间和之后将该混合物冷却在20℃-0℃的温度范围内冷却并通过过滤回收该产物，从而制备所述盐。
14．按照权利要求13的方法，其中当所述物质不是十分易溶或者在上述溶剂中它是作为一种并不十分易溶的盐使用时，可使用与羟基化溶剂的相应混合物，在加入硝酸后，用一种非极性溶剂稀释由此获得的混合物以加速沉淀。
15．按照权利要求13-14的方法，其中当用盐酸使原料成盐时，可以在该化合物溶液中直接加入硝酸银制备所述硝酸盐，过滤氯化银后，浓缩该溶液并冷却以便回收硝酸盐。
16．制备按照权利要求1-8的硝酸盐的方法，其中当原料为一种盐时，可以通过用钠或钾的碳酸氢盐或碳酸盐的饱和溶液或用氢氧化钠或氢氧化钾的稀溶液处理该盐以便释放出对应的碱，然后用适宜的有机溶剂提取所述碱并采用在权利要求13或14中指出的制备所述硝酸盐的方法。
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ITMI981408A1 (it) 1999-12-19
HUP0102719A3 (en) 2002-11-28
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US20040147575A1 (en) 2004-07-29
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US6645965B1 (en) 2003-11-11
HUP0102719A2 (hu) 2001-12-28
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EP1087953B1 (en) 2004-11-17
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