CN1332943C - 硫取代的磺酰基氨基羧酸n－芳基酰胺,其制备方法、用途以及含有该化合物的药物制剂 - Google Patents

硫取代的磺酰基氨基羧酸n－芳基酰胺,其制备方法、用途以及含有该化合物的药物制剂 Download PDF

Info

Publication number
CN1332943C
CN1332943C CNB998082953A CN99808295A CN1332943C CN 1332943 C CN1332943 C CN 1332943C CN B998082953 A CNB998082953 A CN B998082953A CN 99808295 A CN99808295 A CN 99808295A CN 1332943 C CN1332943 C CN 1332943C
Authority
CN
China
Prior art keywords
alkyl
phenyl
chloro
group
ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB998082953A
Other languages
English (en)
Other versions
CN1308606A (zh
Inventor
U·辛德勒
K·肖纳芬格
H·斯托贝尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Aventis Pharma Deutschland GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19830430A external-priority patent/DE19830430A1/de
Priority claimed from DE19903126A external-priority patent/DE19903126A1/de
Application filed by Aventis Pharma Deutschland GmbH filed Critical Aventis Pharma Deutschland GmbH
Publication of CN1308606A publication Critical patent/CN1308606A/zh
Application granted granted Critical
Publication of CN1332943C publication Critical patent/CN1332943C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/58—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/02—Thiocyanates
    • C07C331/12—Thiocyanates having sulfur atoms of thiocyanate groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 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
    • C07D211/54—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/38—Nitrogen atoms
    • C07D231/42—Benzene-sulfonamido pyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • 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
    • C07D233/66—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 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
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/14—Nitrogen atoms
    • C07D261/16—Benzene-sulfonamido isoxazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/22—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 with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Psychiatry (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

本发明涉及式(Ⅰ)化合物，其中A1、A2、R1、R2、R3、X和n如权利要求中所定义，该化合物是用于治疗和预防疾病例如心血管疾病如高血压、心绞痛、心功能不足、血栓形成或动脉粥样硬化的有价值的药物活性化合物。式(Ⅰ)化合物可以调节体内环鸟苷酸(cGMP)的产生，可用于治疗和预防与cGMP平衡紊乱有关的疾病。本发明还涉及式(Ⅰ)化合物的制备方法、其用于治疗和预防上述疾病以及在制备用于该目的的药物中的用途，以及含有式(Ⅰ)化合物的药物制剂。

Description

硫取代的磺酰基氨基羧酸N-芳基酰胺， 其制备方法、用途以及含有该化合物的药物制剂
本发明涉及式I的化合物
Figure C9980829500091
其中A1、A2、R1、R2、R3、X和n如下文所定义，该化合物是用于治疗和预防疾病例如心血管疾病如高血压、心绞痛、心功能不足、血栓形成或动脉粥样硬化的有价值的药物活性化合物。式I化合物可以调节体内环鸟苷酸(cGMP)的产生，可用于治疗和预防与cGMP平衡紊乱有关的疾病。本发明还涉及式I化合物的制备方法、其用于治疗和预防上述疾病的用途及其在制备用于该目的的药物中的用途，以及含有式I化合物的药物制剂。
cGMP是一种重要的细胞内信使，它通过调节cGMP依赖型蛋白激酶，磷酸二酯酶和离子通道而引发多种不同的作用。例如，松弛平滑肌、抑制血小板激活和抑制平滑肌细胞的增殖及白细胞的粘着。cGMP由颗粒状和可溶性鸟苷酸环化酶在受到各种细胞外和细胞内的刺激时产生。对于颗粒状鸟苷酸环化酶，刺激主要由肽信使引起，例如心房肽或脑钠尿肽。可溶性鸟苷酸环化酶(sGC)是胞质异源二聚体血红素蛋白，它主要由一族由酶催化形成的低分子量的因子进行调控。最重要的刺激物是一氧化氮(NO)或与其密切相关的物质。其它因子如一氧化碳或羟基的功能还不很清楚。目前认为，NO与血红素结合形成五配位的血红素-亚硝酰配合物是通过NO激活的激活机制。所伴随的以基础状态与铁结合的组氨酸的释放将酶转变成活性构象。
活性的可溶性鸟苷酸环化酶由一个α亚单位和一个β亚单位组成。已发现了多种亚单位亚型，它们彼此在序列、组织特异性分布以及在不同的发育阶段表达方面存在差异。α1和β1亚型主要在脑和肺内表达，而β2主要出现在肝和肾中。α2亚型存在于人类胎儿的脑中。从人脑中分离出了称为α3和β3的亚单位，它们与α1和β1是同源的。最近的研究发现了α2i亚单位，其在催化结构域中含有插入片段。所有亚单位在催化结构域区域显示高度的同源性。据推测，酶在每个异源二聚体中含有一个血红素，其通过β1-Cys-78和/或β1-His-105结合并且是调节中心的一部分。
在病理条件下，鸟苷酸环化酶活化因子的形成可能会减少，或者它们的降解会由于自由基的增加而加速。所造成的sGC激活的下降会通过cGMP-介导的细胞应答的减弱而导致例如血压升高、血小板激活或细胞增殖和细胞粘着的增加。结果导致出现内皮功能障碍、动脉粥样硬化、高血压、稳定或不稳定心绞痛、血栓形成、心肌梗塞、中风或勃起功能障碍。对sGC的药理学刺激能够会使cGMP的产生正常化，因此可以治疗和/或预防所述疾病。
为了对sGC进行药理学刺激，迄今为止所使用的几乎全部是其活性是基于中间体NO释放的化合物，例如有机硝酸酯。该治疗的缺点是出现耐受性和活性的降低，因此需要更高的剂量。
Vesely在一系列出版物中描述了各种不通过NO释放起作用的sGC刺激剂。但是，这些化合物中大部分是激素、植物激素、维生素或天然化合物如蜥蜴毒，它们仅对溶胞产物中的cGMP形成有很弱的作用(D.L.Vesely，《欧洲临床研究杂志》(Eur.J.Clin.Invest)15(1985)258；D.L.Vesely，《生物化学生物物理学研究通讯》(Biochem.Biophys.Res.Comm.)88(1979)1244)。Ignarro等(《药理学进展》(Adv.Pharmacol.)26(1994)35)证实了通过原卟啉IX刺激不含血红素的鸟苷酸环化酶。Pettibone等(《欧洲药理学杂志》(Eur.J.Pharmacol.)116(1985)307)描述了碘化二苯六氟磷酸盐的抗高血压作用，并将其归因于对sGC的刺激作用。根据Yu等的描述(《英国药理学杂志》(Brit.J.Pharmacol.)114(1995)1587)，对离体大鼠主动脉具有松弛作用的异甘草根亭配基也可以激活sGC。Ko等(《血液》(Blood)84(1994)4226)、Yu等(《生物化学杂志》(Biochem.J.)306(1995)787)和Wu等(《英国药理学杂志》(Brit.J.Pharmacol.)116(1995)1973)证实了1-苄基-3-(5-羟基甲基-2呋喃基)吲唑的sGC刺激活性，并证实了其抗增殖和抑制血小板形成的作用。EP-A-908456和DE-A-19744027中描述了具有sGC刺激活性的吡唑和稠合的吡唑类化合物。
在文献中记载了一系列在N-芳基上带有硫取代基的2-磺酰基氨基苯甲酸N-芳基酰胺类化合物。这些在N-芳基通常还带有其它易被氧化的取代基例如两个彼此处于对位的羟基(在该情况下可以看作是氢醌衍生物)的化合物是制备照相用材料的辅料(参见，例如化学文摘119，105757；120，41858；123，70224或126，257007)。如果考虑孤立的结构单元，则这些已知化合物中的N-芳基相当于式I中当A1表示在2位和5位带有羟基(或氧取代基)的1，4-亚苯基并且n是0时的基团R1-S(O)n-A1。英国专利公开号876526(化学文摘56，15432e)公开了可用于保护羊毛防止蠹虫的3，5-二氯-2-甲基磺酰基氨基苯甲酸N-(5-氯-2-(4-氯苯基巯基)-苯基)-酰胺。GB-A-876526所包含的化合物相当于同时满足如下条件的式I化合物：其中含有带有基团C(＝X)-NH-和NH-SO2R2的碳原子的环A1与R3基团合在一起是带有1-4个选自氯和溴的卤原子的苯环，R2是(C1-C4)-烷基，X是氧并且基团R1-S(O)n-A1-是被卤素和/或三氟甲基取代的并且还可以被甲基或(C1-C4)-烷氧基取代的苯基巯基苯基基团(＝苯硫基苯基-)，并且卤原子和三氟甲基的总数大于2。没有公开这些已知的2-磺酰基氨基苯甲酸N-芳基酰胺类化合物的药理学活性。
令人惊奇的是，我们发现本发明的化合物对鸟苷酸环化酶有很强的激活作用，因此可用于治疗和预防与低cGMP水平有关的疾病。
因此，本发明涉及式I化合物
Figure C9980829500121
其中
A1是选自亚苯基、亚萘基和亚杂芳基的二价基团，它们均可以被一个或多个相同或不同的取代基所取代，所述取代基选自卤素、(C1-C5)-烷基、苯基、甲苯基、CF3、NO2、OH、-O-(C1-C5)-烷基、-O-(C2-C4)-烷基-O-(C1-C3)-烷基、(C1-C2)-亚烷基二氧基、NH2、-NH-(C1-C3)-烷基-N((C1-C3)-烷基)2、-NH-CHO、-NH-CO-(C1-C5)-烷基、-CN、-CO-NH2、-CO-NH-(C1-C3)-烷基、-CO-N((C1-C3)-烷基)2、-CO-OH、-CO-O-(C1-C5)-烷基、杂环基、CHO、-CO-(C1-C5)-烷基、-S(O)n-(C1-C4)-烷基、-S(O)n-苯基和-S(O)n-甲苯基；
含有带有基团C(＝X)-NH-和NH-SO2R2的碳原子的环A2是苯环、萘环、饱和或部分不饱和的3-7元碳环、饱和或部分不饱和或芳香性的含有一个或多个选自N、O和S的环杂原子的5-7元单环杂环、或饱和或部分不饱和或芳香性的含有一个或多个选自N、O和S的环杂原子的8-10元二环杂环；
R1是芳基、杂环基或(C1-C18)-烷基，其可以被一个或多个相同或不同的R4基团所取代，或者，如果基团R1-S(O)n-中的n是2，则R1还可以是NR5R6或者，如果基团R1-S(O)n-中的n是0，则R1还可以是-CN；R2是芳基、杂环基、NR5R6或(C1-C10)-烷基，其可以被一个或多个相同或不同的R4基团所取代；
R3表示一个或多个相同或不同的选自氢、卤素、CF3、OH、O-(C1-C7)-烷基、-O-(C2-C4)-烷基-O-(C1-C7)-烷基、-O-芳基、(C1-C2)-亚烷基二氧基、NO2、-CN、NR7R8、-CO-NR7R8、-CO-OH、-CO-O-(C1-C5)-烷基、杂环基、-S(O)n-(C1-C5)-烷基和(C1-C5)-烷基的基团，其可以被一个或多个相同或不同的R4基团所取代；
R4是氟、OH、O-(C1-C10)-烷基、-O-(C2-C4)-烷基-O-(C1-C7)-烷基、-O-芳基、-CN、NR7R8、-CO-NH2、-CO-NH-(C1-C3)-烷基、-CO-N((C1-C3)-烷基)2、-CO-OH、-CO-O-(C1-C5)-烷基、杂环基或氧代；
R5是氢、(C1-C10)-烷基，其可以被一个或多个相同或不同的取代基R4和/或被芳基取代，或者是芳基、杂环基、-CO-NR7R8、-CO-芳基或其中的烷基部分可以被一个或多个相同或不同的R4基团所取代的-CO-(C1-C10)-烷基；
R6与R5相互独立地具有R5所给出的含义之一，或者R5和R6与它们所结合的氮原子合在一起形成5-8元饱和或部分不饱和的环，所述的环中除了带有基团R5和R6的氮原子外，还可以含有一个或多个选自N、O和S的其它环杂原子，并且该环可以被一个或多个相同或不同的取代基所取代，所述取代基选自氟、(C1-C5)-烷基、羟基-(C1-C3)-烷基-、-(C1-C3)-烷基-O-(C1-C4)-烷基、芳基、CF3、OH、-O-(C1-C7)-烷基、-O-芳基、O-(C2-C4)-烷基-O-(C1-C7)-烷基、(C2-C3)-亚烷基二氧基、NR7R8、-CN、-CO-NH2、-CO-NH-(C1-C3)-烷基、-CO-N((C1-C3)-烷基)2、-CO-OH、-CO-O-(C1-C5)-烷基、CHO、-CO-(C1-C5)-烷基、-S(O)n-(C1-C4)-烷基、-S(O)n-NH2、-S(O)n-NH-(C1-C3)-烷基、-S(O)n-N((C1-C3)-烷基)2、氧代、-(CH2)m-NH2、(CH2)m-NH-(C1-C4)-烷基和-(CH2)m-N((C1-C4)-烷基)2，其中，在取代基-(CH2)m-N((C1-C4)-烷基)2中，两个烷基可以通过单键连接，然后与携带它们的氮原子合在一起形成5-7元环，该环除氮原子和碳原子外，还可含有氧原子、硫原子或基团NR5作为环原子；
R7是氢或可被一个或多个相同或不同的取代基取代的(C1-C7)-烷基，所述取代基选自OH、-O-(C1-C5)-烷基、NH2，-NH-(C1-C4)-烷基和-N((C1-C4)-烷基)2，其中，在取代基N((C1-C4)-烷基)2中，两个烷基可以通过单键连接，然后与携带它们的氮原子合在一起形成5-7元环，该环除氮原子和碳原子外，还可含有氧原子、硫原子或基团NR5作为环原子；
R8与R7相互独立地具有R7所给出的含义之一，或者是-CO-(C1-C4)-烷基；
芳基是苯基、萘基或杂芳基，它们均可以被一个或多个相同或不同的取代基所取代，所述取代基选自卤素、(C1-C5)-烷基、苯基、甲苯基、CF3、-O-CF3、NO2、OH、-O-(C1-C5)-烷基、O-(C2-C4)-烷基-O-(C1-C3)-烷基、(C1-C2)-亚烷基二氧基、NH2、-NH-(C1-C3)-烷基、-N((C1-C3)-烷基)2、-NH-CHO、-NH-CO-(C1-C5)-烷基、-CN、-CO-NH2、-CO-NH-(C1-C3)-烷基、-CO-N((C1-C3)-烷基)2、-CO-OH、-CO-O(C1-C5)-烷基、杂环基、CHO、-CO-(C1-C5)-烷基、-S(O)n-(C1-C4)-烷基、-S(O)n-苯基和-S(O)n-甲苯基；
杂芳基和亚杂芳基是含有一个或多个选自N、O和S的环杂原子的5或6元单环芳香族杂环或8至10元二环芳香族杂环的基团；
杂环基是含有一个或多个选自N、O和S的环杂原子的5至11元饱和或部分不饱和的单环或多环杂环的基团，其可以被一个或多个相同或不同的取代基所取代，所述取代基选自氟、(C1-C5)-烷基、OH、-O-(C1-C5)-烷基、-O-(C2-C4)-烷基-O-(C1-C3)-烷基、NH2、-NH-(C1-C3)-烷基、-N((C1-C3)-烷基)2、-CN、-CO-NH2、-CO-NH-(C1-C3)-烷基、-CO-N((C1-C3)-烷基)2、-CO-OH和-CO-O-(C1-C5)-烷基；
n是0、1或2；
m是2、3或4；
X是O或NH，或者X是通过单键与基团A1中的环碳原子连接的氮原子，所述环碳原子紧邻A1中带有基团-NH-C(＝X)-的碳原子，从而基团-NH-C(＝X)-与A1中带有该基团的碳原子合在一起形成稠合的咪唑环；其所有的立体异构体形式及其各种比例的混合物，以及它们的生理可接受的盐；
但是，其中不包括含带有基团C(＝X)-NH-和NH-SO2R2的碳原子的环A2是在3位和5位被氯取代的苯环，R2是甲基，X是氧同时R1-S(O)n-A1-是5-氯-2-(4-氯苯基巯基)-苯基的式I化合物。
如果基团或取代基可以在式I化合物中出现多次，例如R3、R4、R5、芳基、杂环基、烷基等或数字n和m，则它们可以彼此独立地具有给定的含义并且在每种情况下可以相同或不同。
烷基可以是直链或支链的。当它们是其它基团的一部分例如在烷氧基、烷氧基羰基或氨基中时，或者当它们被取代时，也是如此。烷基的例子是甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、这些基团的正异构体、异丙基、异丁基、异戊基、仲丁基、叔丁基、新戊基、3，3-二甲基丁基。术语烷基还包括不饱和的烷基，即含有一个或多个双键和/或一个或多个叁键的烷基，例如链烯基或链炔基。当然，不饱和的烷基含有至少两个碳原子。因此，碳原子数可以从1至给定的上限之间变化的特定烷基还包括碳原子数可以从2至给定的上限之间变化的不饱和烷基。所述基团的例子是乙烯基、1-丙烯基、2-丙烯基(烯丙基)、2-丁烯基、2-甲基-2-丙烯基、3-甲基-2-丁烯基、乙炔基、2-丙炔基(炔丙基)、2-丁炔基或3-丁炔基。此外，术语烷基还包括通过在烷基内进行内部关环形成环系的烷基基团，即，术语烷基还包括饱和及部分不饱和的环烷基和环烷基-烷基-基团(环烷基取代的烷基)。当然，单环环烷基基团含有至少3个碳原子。因此，碳原子数可以从1至给定的上限之间变化的特定烷基还包括碳原子数可以从3至给定的上限之间变化的单环环烷基和适宜的环烷基-烷基-基团。所述环烷基的例子是环丙基、环丁基、环戊基、环己基、环庚基和环辛基，这些环烷基均可以被一个或多个相同或不同的(C1-C4)-烷基、特别是甲基所取代。所述取代的环烷基的例子是4-甲基环己基、4-叔丁基环己基或2，3-二甲基环戊基。此外，若无另外说明，术语烷基还包括未取代的烷基基团以及被一个或多个，例如一个、两个、三个或四个相同或不同的芳基所取代的烷基。因此，术语烷基还包括芳烷基基团，例如芳基-(C1-C4)-烷基-例如苄基、苯乙基或二氢化茚基。在取代的烷基，例如芳烷基-、羟基烷基例如-(C1-C3)-烷基-OH或烷氧基烷基-例如(C1-C3)-烷基-O-(C1-C4)-烷基中，取代基可以位于任何适宜的位置。
代表环A2的饱和或部分不饱和的3至7元碳环可以从单环的母系统如环丙烷，环丁烷、环戊烷、环己烷或环庚烷衍生得到。如果碳环是不饱和的，它可以含有例如一个双键，或者在5元环、6元环或7元环的情况下，可以含有两个双键，这两个双键可以是孤立的也可以是共轭的。双键可以存在于相对于基团C(＝X)-NH-和NH-SO2-R2而言的任何位置，例如，双键还可以存在于带有这两个基团的两个环碳原子之间。
若无另外说明，苯基、萘基和杂环基团(例如杂芳基)可以是未取代的或带有一个或多个，例如一个、两个、三个或四个相同或不同的取代基，所述取代基可以位于任何适宜的位置。若无另外说明，在这些基团中可以存在例如作为芳基取代基所定义的那些取代基。可以存在于芳基中的一组优选的取代基包括卤素、(C1-C5)-烷基、苯基、甲苯基、CF3、NO2、OH、-O-(C1-C5)-烷基、-O-(C2-C4)-烷基-O-(C1-C3)-烷基、(C1-C2)-亚烷基二氧基、NH2、-NH(C1-C3)-烷基、-N((C1-C3)-烷基)2、-NH-CHO、-NH-CO-(C1-C5)-烷基、-CN、-CO-NH2、-CO-NH-(C1-C3)-烷基、-CO-N((C1-C3)-烷基)2、-CO-OH、CO-O-(C1-C5)-烷基、杂环基、CHO、-CO-(C1-C5)-烷基、-S(O)n-(C1-C4)-烷基、-S(O)n-苯基和-S(O)n-甲苯基。如果式I化合物中存在硝基作为取代基，则在分子中总共可以存在最多两个硝基。如果在芳基例如苯基和/或杂环基团中存在苯基、苯氧基、苄基或苄氧基作为取代基，则这些取代基中的苯环也可以是未取代的或被一个或多个，例如一个、两个、三个或四个相同或不同的基团所取代，例如被选自(C1-C4)-烷基、卤素、羟基、(C1-C4)-烷氧基、三氟甲基、氰基、羟基羰基、((C1-C4)-烷氧基)羰基、氨基羰基、硝基、氨基、(C1-C4)-烷基氨基、二-((C1-C4)-烷基)氨基和((C1-C4-烷基)羰基氨基的基团所取代。
在单取代的苯基中，取代基可以位于2-位、3-位或4-位，在二取代的苯基中，取代基可以位于2，3-位、2，4-位、2，5-位、2，6-位、3，4-位或3，5-位。在三取代的苯基中，取代基可以位于2，3，4-位、2，3，5-位、2，3，6-位、2，4，5-位、2，4，6-位或3，4，5-位。甲苯基(＝甲基苯基)可以是2-甲苯基、3-甲苯基或4-甲苯基。萘基可以是1-萘基或2-萘基。在单取代的1-萘基中，取代基可以位于2-位、3-位、4-位、5-位、6-位、7-位或8-位，在单取代的2-萘基中，取代基可以位于1-位、3-位、4-位、5-位、6-位、7-位或8-位。
上文中及如下关于一价基团的解释同样适用于二价基团亚苯基、亚萘基和亚杂芳基。二价基团用来和相邻基团连接的游离价键可以存在于任何环碳原子上。对于亚苯基，它们可以位于1，2-位-(邻-亚苯基)、1，3-位(间-亚苯基)或1，4-位(对-亚苯基)。对于亚萘基，游离价键可以位于1，2-位(＝1，2-亚萘基)或1，3-位、1，4-位、1，5-位、1，6-位、1，7-位、1，8-位，2，3-位、2，6-位或2，7-位。对于含有一个杂原子的5元芳环，例如噻吩或呋喃，两个游离价键可以位于2，3-位、2，4-位、2，5-位或3，4-位。从吡啶衍生的二价基团可以是2，3-、2，4-、2，5-、2，6-、3，4-或3，5-亚吡啶基。对于不对称的二价基团，本发明包括所有的位置异构体，即，例如，对于2，3-亚吡啶基，包括一个相邻的基团位于2-位而另一个相邻的基团位于3-位的化合物以及一个相邻的基团位于3-位而另一个相邻的基团位于2-位的化合物。
代表环A2以及由两个与氮原子结合的基团同该氮原子一起形成的环的杂芳基、亚杂芳基、杂环基团、杂环优选来自含有一个、两个、三个或四个相同或不同的环杂原子的杂环，更优选来自含有一个、两个或三个、特别是一个或两个相同或不同的杂原子的杂环。若无另外说明，杂环可以是单环或多环的，例如单环、二环或三环的。优选它们是单环或二环的。优选5元环、6元环或7元环。可以衍生式I化合物中出现的基团的单环和二环杂环系统的例子是吡咯、呋喃、噻吩、咪唑、吡唑、1，2，3-三唑、1，2，4-三唑、1，3-间二氧杂环戊烯、1，3-唑(＝唑)、1，2-唑(＝异唑)、1，3-噻唑(＝噻唑)、1，2-噻唑(＝异噻唑)、四唑、吡啶、哒嗪、嘧啶、吡嗪、吡喃、噻喃、1，4-二烯、1，2-嗪、1，3-嗪、1，4-嗪、1，2-噻嗪、1，3-噻嗪、1，4-噻嗪、1，2，3-三嗪、1，2，4-三嗪、1，3，5-三嗪、1，2，4，5-四嗪、吖庚因、1，2-二氮杂、1，3-二氮杂、1，4-二氮杂、1，3-氧杂吖庚因(oxazepine)、1，3-硫杂吖庚因(thiazepine)、吲哚、苯并噻吩、苯并呋喃、苯并噻唑、苯并咪唑、喹啉、异喹啉、噌啉、喹唑啉、喹喔啉、酞嗪、噻吩并噻吩、1，8-萘啶和其它的萘啶、蝶啶或吩噻嗪，它们均可以是饱和的形式(全氢化的形式)或部分不饱和的形式(例如二氢形式或四氢形式)或最大不饱和的形式，主要各种形式是已知的并且是稳定的即可。因此，适宜的杂环还包括，例如饱和的杂环吡咯烷、哌啶、哌嗪、吗啉和硫代吗啉。杂环基团的饱和度表现在其各自的定义上。不饱和的杂环可以在环系内含有例如一个、两个或三个双键。5元环和6元环还可以是芳香性的。
从这些杂环衍生的基团可以通过任何适宜的碳原子连接。可以在环氮原子上带有氢原子或取代基的氮杂环如吡咯、咪唑、吡咯烷、吗啉、哌嗪等，还可以通过环氮原子连接，特别是当所述的杂环基团是与碳原子结合时。例如，噻吩基可以以2-噻吩基或3-噻吩基存在，呋喃基以2-呋喃基或3-呋喃基存在，吡啶基以2-吡啶基、3-吡啶基或4-吡啶基存在，哌啶基以1-哌啶基(＝哌啶子基)、2-哌啶基、3-哌啶基或4-哌啶基存在，(硫代)吗啉基以2-(硫代)吗啉基、3-(硫代)吗啉基或4-(硫代)吗啉基(＝硫代吗啉代基团)存在。从1，3-噻唑或咪唑衍生的通过碳原子连接的基团可以通过2-位、4-位或5-位连接。
若无另外说明，杂环基团可以是未取代的或带有一个或多个，例如一个、两个、三个或四个相同或不同的取代基。杂环中的取代基可以位于任何适宜的位置，例如在2-噻吩基或2-呋喃基中位于3-位和/或4-位和/或5-位，在3-噻吩基或3-呋喃基中位于2-位和/或4-位和/或5-位，在2-吡啶基中位于3-位和/或4-位和/或5-位和/或6-位，在3-吡啶基中位于2-位和/或4-位和/或5-位和/或6-位，在4-吡啶基中位于2-位和/或3-位和/或5-位和/或6-位。若无另外说明，在杂环基团中可以存在例如在芳基的定义中所给出的那些取代基作为取代基，在饱和或部分不饱和的杂环中，还可以存在氧代基团或硫代基团作为取代基。杂环上的取代基以及碳环上的取代基还可以形成环，即，可以稠合(或增环)其它环的环系，从而还可以存在例如环戊二烯并稠合的、环己二烯并(cyclohexa)稠合的或苯并稠合的环。杂环中可被取代的环氮原子上的适宜取代基是，例如未取代的(C1-C5)-烷基和芳基-取代的烷基、芳基、酰基如-CO-(C1-C5)-烷基或磺酰基如-SO2-(C1-C5)-烷基。适宜的氮杂环还可以以N-氧化物或含有从生理可接受的酸衍生的抗衡离子的季铵盐的形式存在。例如，吡啶基团可以以吡啶-N-氧化物的形式存在。
卤素是氟、氯、溴或碘，优选氟或氯。
对本发明没有任何限定的意思，在式Ia、Ib、Ic、Id、Ie、If、Ig和Ih中给出了其中式I中的A2具有特定含义的本发明化合物的例子。式Ia、Ib、Ic、Id、Ie、If、Ig和Ih中的A1、R1、R2、R3、X和n如以上式I中所定义，式Ib中的数值k是1、2、3、4或5，尤其是3或4。
Figure C9980829500201
在式Ia中所描述的带有基团C(＝X)-NH-和-NHSO2R2的苯环上，存在4个可以携带R3基团的位置。因此，式Ia化合物可以带有4个R3基团，根据R3的定义，这4个R3基团可以彼此独立地是氢或具有除氢之外的含义，即，在式Ia化合物中，式Ia中所描述的苯环可以是未取代的或者可以带有一个、两个、三个或四个相同或不同的取代基，所述取代基选自卤素、CF3、OH、-O-(C1-C7)-烷基、-O-(C2-C4)-烷基-O-(C1-C7)-烷基、-O-芳基、(C1-C2)-亚烷基二氧基、NO2、-CN、NR7R8、-CO-NR7R8、-CO-OH、-CO-O-(C1-C5)-烷基、杂环基、-S(O)n-(C1-C5)-烷基和(C1-C5)-烷基，其可以被一个或多个相同或不同的R4基团取代。这些说明同样适用于Ib至Ih的化合物。
式Ii表示的是其中X是通过单键与基团A1中的环碳原子连接的氮原子的式I化合物，其中，所述环碳原子紧邻A1中带有基团-NH-C(＝X)-的碳原子，从而基团-NH-C(＝X)-与A1中携带该基团的碳原子一起形成了稠合的咪唑环。
Figure C9980829500211
式Ii中的A2、R1、R2、R3和n如以上式I中所定义。从基团A1通过与代表X的氮原子之间形成键所形成的、并且在环中含有式Ii中所描述的带有稠合咪唑环的氮原子的两个碳原子的环A3是苯环、萘环或杂芳族环，其中，对于这些环，以上关于A1的说明同样适用。
本发明包括式I化合物的所有立体异构体形式。式I化合物中所存在的不对称中心可以是可以彼此独立地具有S构型或R构型。本发明包括所有可能的对映体和非对映体以及各种比例的两种或多种立体异构体的混合物，例如对映体和/或非对映体的混合物。因此，本发明的对映体包括对映体纯的形式(包括左旋和右旋的对映体)、外消旋体的形式以及两种对映体以各种比例形成的混合物的形式。对于顺/反异构现象，本发明包括顺式形式和反式形式以及这些形式以各种比例形成的混合物。如需要，可以通过用常规方法例如色谱法或结晶法分离混合物、通过在合成中使用立体化学单一的原料或者通过立体选择性合成来制备单独的立体异构体。在分离立体异构体之前可以选择性地进行衍生化。立体异构体混合物的分离可以在式I化合物的阶段进行，也可以在合成过程的中间体阶段进行。本发明还包括式I化合物的所有互变异构体形式。
如果式I化合物含有一个或多个酸性或碱性的基团，则本发明还包括相应的生理或毒理学可接受的盐，特别是可药用的盐。因此，含有酸性基团的式I化合物可以在这些基团上以例如碱金属盐、碱土金属盐或铵盐的形式存在和使用。所述盐的例子是钠盐、钾盐、钙盐、镁盐或与氨或有机胺如乙胺、乙醇胺、三乙醇胺或氨基酸形成的盐。含有一个或多个碱性基团、即可以被质子化的基团的式I化合物可以以其与无机酸或有机酸的酸加成盐的形式存在和使用，例如与盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸等形成的盐。如果式I化合物在分子中同时含有酸性和碱性基团，则除了所述的盐形式外，本发明还包括内盐或内铵盐(两性离子)。盐可以通过本领域技术人员已知的常规方法从式I化合物制得，例如，通过与有机或无机酸或碱在溶剂或分散剂中混合，或者通过与其它的盐进行阴离子交换或阳离子交换制得。本发明还包括由于生理相容性低而不能直接用于药物但可以用作例如化学反应的中间体或用于制备生理可接受盐的式I化合物所有的盐。
本发明还包括式I化合物的所有溶剂化物，例如水合物或与醇的加合物，以及式I化合物的衍生物，例如酯、酰胺、前药和活性代谢物。
A1优选是亚苯基或5元或6元的亚杂芳基，更优选亚苯基，其中，所有这些基团均可以是未取代的或者按照以上的描述被取代。如果A1是取代的，即，如果它带有一个或多个除基团R1-S(O)n之外的其它取代基，则它优选被一个或两个相同或不同的上述取代基所取代。优选代表A1的亚苯基是未取代的，即，除了基团R1-S(O)n和C(＝X)-NH外，它带有4个氢原子。基团R1-S(O)n优选连接在A1中不直接与带有基团C(＝X)-NH的碳原子相邻的碳原子上。如果A1是亚苯基，基团R1-S(O)n特别优选位于带有基团C(＝X)-NH的碳原子的间位或对位，更优选位于对位。
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2优选是芳香族环，更优选苯环或噻吩环，特别优选苯环，其中，所有这些环均可以是未取代的或被一个或多个不是氢的R3基团所取代。
R1优选是(C1-C7)-烷基、NR5R6或芳基，更优选NR5R6、苯基或5元或6元的杂芳基，特别优选NR5R6，其中，所有这些基团均可以是未取代的或按照所描述的被取代，并且，如上所述，如果基团R1-S(O)n-中的n是2，R1可以是NR5R6。
R2优选是芳基，更优选苯基或5-元或6-元杂芳基，特别优选苯基或含有一个或两个相同或不同的选自N、O和S的杂原子的单环5元或6元芳族杂环的基团，例如苯基、噻吩基、吡唑基、咪唑基、异唑基、噻唑基、吡啶基等，特别是苯基或2-噻吩基，其中，所有这些基团均可以是未取代的或按照所描述的被取代。优选代表R2的芳基是取代的。如果代表R2的芳基是取代的，它优选被一个、两个或三个，特别是被一个或两个相同或不同的取代基所取代。代表R2的芳基中的取代基优选是选自卤素、CF3、-O-CF3、NO2、-CN、(C1-C4)-烷基和-O-(C1-C4)-烷基的取代基，更优选选自F、Cl、Br、CF3、-O-CF3、NO2、-CN、CH3和-OCH3的取代基。特别优选代表R2的取代的芳基是被Cl取代的，例如被一个或两个、特别是一个氯原子取代的。
代表A2的环可以是未取代的或按照以上的描述被取代。当它们未被取代时，它们仅带有是氢的R3基团。当它们是取代的时，它们带有一个或多个不是氢的R3基团。那些没带有不是氢的R3基团的取代基位置带有氢原子。如果环A2带有一个或多个不是氢的R3基团，则优选其带有一个或两个这样的R3基团，特别是一个这样的R3基团。不是氢的R3基团优选位于环A2中不直接与基团C(＝X)-NH和R2-SO2-NH相邻的位置。如果A2是饱和或部分不饱和的碳环，不是氢的R3基团优选是(C1-C4)-烷基，特别是甲基。如果A2是芳香族环，尤其当A2是苯环时，不是氢的R3基团优选是(C1-C3)-烷基、卤素、(C1-C3)-烷氧基或CF3，更优选甲基、氯或甲氧基。如果A2是芳香族环、特别是苯环时，特别优选环上带有一个氯原子或两个甲氧基作为取代基，即，存在一个是氯的R3基团或者存在两个是甲氧基的R3基团，苯环上的其它位置带有氢原子。如果A2是苯环，则不是氢的R3基团优选是位于4位和/或5位(相对于1位的C(＝X)-NH和2位的基团R2-SO-NH而言)。
如果基团被一个或多个R4基团所取代，则优选其被一个、两个或三个，特别是一个或两个相同或不同的R4基团所取代。R4优选是羟基、(C1-C4)-烷氧基、二-((C1-C4)-烷基)氨基或杂芳基。
R5和R6优选彼此独立地是氢、(C1-C9)-烷基、(C1-C4)-烷基-O-(C1-C3)-烷基-或5或6元的芳基，或者与带有R5和R6的氮原子一起形成5至7-元的杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另外一个选自N、O和S的环杂原子，并且所述杂环可以被一个或多个，例如一个、两个、三个或四个相同或不同的选自(C1-C3)-烷基、羟基-(C1-C3)-烷基-、5-元或6-元芳基、氨基甲酰基、羟基和氧代的基团所取代。特别优选R5和R6与带有这些基团的的氮原子一起形成5元、6元或7元的杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另外一个选自N、O和S的环杂原子，并且可以被一个或多个，例如一个、两个、三个或四个相同或不同的选自(C1-C3)-烷基、羟基-(C1-C3)-烷基-、5-元或6-元芳基、氨基甲酰基、羟基和氧代的基团，特别是(C1-C3)-烷基例如甲基所取代。优选由基团R5和R6与带有这些基团的氮原子一起形成的杂环是饱和的。
特别优选由基团R5和R6与带有这些基团的氮原子一起形成的杂环是从吗啉、硫代吗啉、1，1-二氧代-硫代吗啉、1-氧代-硫代吗啉、二烷基吗啉如二甲基吗啉、2，6-二甲基吗啉、顺-2，6-二甲基吗啉、3，5-二甲基吗啉、顺-3，5-二甲基吗啉、1-(嘧啶-2-基)-哌嗪、哌啶-4-甲酰胺、1-(2-羟基乙基)-哌嗪、1-甲基哌嗪、1-乙基哌嗪、1-芳基哌嗪、哌嗪-1-甲酸乙酯、哌啶、2-甲基哌啶、2，6-二甲基哌啶、顺-2，6-二甲基哌啶、3，5-二甲基哌啶、顺-3，5-二甲基哌啶、4-羟基哌啶、4-氧代哌啶或其缩酮如1，4-二氧杂-8-氮杂-螺[4.5]癸烷、四氢吡啶、四氢嘧啶、1-甲基高哌嗪、噻唑烷、吡咯啉、吡咯烷、3-羟基吡咯烷、1，2，3，4-四氢异喹啉或2，3-二氢-1H-异吲哚衍生得到的，其中，这些环是通过环氮原子连接，或者，对于哌嗪衍生物，通过未取代的环氮原子连接。更优选由基团R5和R6与带有这些基团的氮原子一起形成的杂环是从吗啉、硫代吗啉、1，1-二氧代-硫代吗啉、1-氧代-硫代吗啉、2，6-二甲基吗啉、顺-2，6-二甲基吗啉、3，5-二甲基吗啉、顺-3，5-二甲基吗啉、1-(嘧啶-2-基)-哌嗪、哌啶-4-甲酰胺、1，2，3，4-四氢异喹啉或2，3-二氢-1H-异吲哚衍生得到的，更优选是从吗啉、2，6-二甲基吗啉或顺-2，6-二甲基吗啉衍生得到的，特别是从吗啉或顺-2，6-二甲基吗啉衍生得到的，其中，这些环是通过环氮原子连接，或者，对于哌嗪衍生物，通过未取代的环氮原子连接。
R7优选是氢、(C1-C3)-烷基、((C1-C4)-烷基)2N-(C1-C3)-烷基或(C1-C4)-烷基-O-(C1-C3)-烷基-。
R8优选是氢、(C1-C3)-烷基或乙酰基。
芳基优选是苯基或杂芳基，特别是苯基或5元或6元杂芳基。若无另外说明，优选的芳基上的取代基是卤素、CF3、(C1-C3)-烷基、氰基、硝基和(C1-C3)-烷氧基，更优选的取代基是CF3、氯、甲基和甲氧基。
杂芳基和亚杂芳基优选是单环的5元或6元芳香族杂环的基团，特别是从杂芳族噻吩、吡唑、噻唑、唑、异唑、吡啶、嘧啶、哒嗪和四唑衍生的基团。
杂环基团优选是从饱和的杂环衍生的基团，更优选是从单环的5元或6元饱和杂环衍生物的基团，特别是从吡咯烷、哌啶、N-烷基哌嗪、吗啉、二烷基吗啉、硫代吗啉或四氢呋喃衍生的基团。此外，以上关于优选的由基团R5和R6与带有这些基团的氮原子一起形成的杂环的说明相应地适用于通过环氮原子连接的杂环基团。
如果基团S(O)n与氮原子结合，则其中的数字n优选是1或2，更优选2。基团R1-S(O)n中的数字n优选是0或2，特别优选2。
X优选是O或通过单键与基团A1中的环碳原子连接的氮原子，其中，所述环碳原子紧邻A1中带有基团-NH-C(＝X)-的碳原子，从而基团-NH-C(＝X)-与A1中带有该基团的碳原子合在一起形成稠合的咪唑环。特别优选X是O。
优选的式I化合物是其中一个或多个所包含的基团具有优选的含义的化合物，所有优选的取代基定义的组合均包括在本发明的范围内。同样，对于所有优选的式I化合物，本发明包括所有的立体异构体形式及其各种比例的混合物，以及它们的生理可接受的盐。优选的化合物还包括其中的一个或多个基团具有优选含义的式Ia、Ib、Ic、Id、Ie、If、Ig和Ih化合物、其所有的立体异构体形式及其各种比例的混合物，以及它们的生理可接受的盐。
一组特别优选的化合物包括，例如，如下的式I化合物，其中A1是亚苯基或亚杂芳基，其中，这些基团可以是未取代的或被一个或多个相同或不同的选自卤素、(C1-C4)-烷基、CF3、-O-(C1-C4)-烷基和-CN的取代基所取代；
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2是芳香族环；
R1是可以被一个或多个相同或不同的R4基团所取代的(C1-C7)-烷基或者是芳基，或者，如果基团R1-S(O)n-中的n是2，还可以是NR5R6；
R2是芳基；
R3表示一个或多个相同或不同的选自氢、卤素、CF3、OH、O-(C1-C4)-烷基、-O-(C2-C4)-烷基-O-(C1-C4)-烷基、-O-芳基、NO2、-CN、NR7R8、-CO-NR7R8、-CO-OH、-CO-O-(C1-C4)-烷基、杂环基、-S(O)n-(C1-C4)-烷基和(C1-C4)-烷基的基团，其可以被一个或多个相同或不同的R4基团所取代；
R4是氟、OH、-O-(C1-C10)-烷基、-O-(C2-C4)-烷基-O-(C1-C7)-烷基、-O-芳基、-CN、NR7R8、-CO-NH2、-CO-NH-(C1-C3)-烷基、-CO-N((C1-C3)-烷基)2、-CO-OH、-CO-O-(C1-C4)-烷基、杂环基或氧代；
R5和R6彼此独立地是氢、(C1-C9)-烷基、(C1-C4)-烷基-O-(C1-C3)-烷基-或芳基，或者与带有R5和R6的氮原子合在一起形成5-7元杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自N、O和S的环杂原子，并且该杂环可以被一个或多个相同或不同的选自(C1-C3)-烷基、羟基-(C1-C3)-烷基-、芳基、氨基甲酰基、羟基和氧代的基团所取代；
R7是氢、(C1-C3)-烷基、((C1-C4)-烷基)2N-(C1-C3)-烷基-或(C1-C4)-烷基-O-(C1-C3)-烷基-；
R8是氢、(C1-C3)-烷基或乙酰基；
芳基是苯基或杂芳基，它们均可以被一个或多个相同或不同的取代基所取代，所述取代基选自卤素、(C1-C4)-烷基、苯基、CF3、NO2、-O-(C1-C4)-烷基、(C1-C2)-亚烷基二氧基、NH2、-NH-CO-(C1-C4)-烷基、-CN、-CO-NH2、-CO-OH和-CO-O-(C1-C4)-烷基；
杂芳基和亚杂芳基是含有一个或多个相同或不同的选自N、O和S的环杂原子的5或6元单环芳香族杂环的基团；
杂环基是含有一个或多个相同或不同的选自N、O和S的环杂原子的5或6元饱和单环杂环的基团，其可以被一个或多个相同或不同的选自氟、(C1-C4)-烷基、OH、-O-(C1-C4)-烷基、NH2、-CN、-CO-NH2、-CO-OH和-CO-O-(C1-C4)-烷基的取代基所取代；
n是0、1或2；
X是O；
其所有的立体异构体形式及其各种比例的混合物，以及它们的生理可接受的盐。
一组更优选的化合物包括，例如，如下的式I化合物，其中A1是亚苯基，它可以是未取代的或被一个或多个相同或不同的选自卤素、(C1-C4)-烷基、CF3、-O-(C1-C4)-烷基和-CN的取代基所取代；含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2是苯环；
R1是NR5R6；
R2是芳基；
R3表示一个或多个相同或不同的选自氢、卤素、CF3、-O-(C1-C4)-烷基、-CN和(C1-C4)-烷基的基团；
R5和R6与带有R5和R6的氮原子合在一起形成5或6元的饱和杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自N、O和S的环杂原子，并且该杂环可以被一个或多个相同或不同的选自(C1-C3)-烷基、羟基-(C1-C3)-烷基-、芳基、氨基甲酰基、羟基和氧代的基团所取代；
芳基是苯基或含有一个或多个相同或不同的选自N、O和S的环杂原子的5或6元杂芳基，它们均可以被一个或多个相同或不同的选自卤素、(C1-C4)-烷基、CF3、NO2、-O-(C1-C4)-烷基、-NH-CO-(C1-C4)-烷基和-CN的取代基所取代；
n是2；
X是O；
其所有的立体异构体形式及其各种比例的混合物，以及它们的生理可接受的盐。
一组极为优选的化合物包括，例如，如下的式I化合物，其中A1是未取代的二价亚苯基基团；
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2是苯环；
R1是NR5R6；
R2是芳基；
R3表示一个或多个相同或不同的选自氢、卤素、-O-(C1-C4)-烷基和(C1-C4)-烷基的基团；
R5和R6与带有R5和R6的氮原子合在一起形成饱和的6元杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自N、O和S的环杂原子，并且该杂环可以被一个或多个相同或不同的选自(C1-C3)-烷基、芳基、氧代和氨基甲酰基的基团所取代；
芳基是苯基或含有一个或多个相同或不同的选自N、O和S的环杂原子的5或6元杂芳基，它们均可以被一个或多个相同或不同的选自卤素、(C1-C4)-烷基、CF3和-O-(C1-C4)-烷基的取代基所取代；
n是2；
X是O；
其所有的立体异构体形式及其各种比例的混合物，以及它们的生理可接受的盐。
一组最为优选的化合物包括，例如，如下的式I化合物，其中A1是未取代的二价1，4-亚苯基基团；
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2与基团R3合在一起是带有一个或两个选自氯和甲氧基的取代基的苯环；
R1是NR5R6；
R2是被一个或两个氯原子取代的苯基或噻吩基；
R5和R6与带有R5和R6的氮原子合在一起形成饱和的6元杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自O和S的环杂原子，并且该杂环是未取代的或被一个或两个甲基所取代；
n是2；
X是氧；
其所有的立体异构体形式及其各种比例的混合物，以及它们的生理可接受的盐。
本发明还涉及制备式I化合物的方法，该方法如下所述并且通过该方法可以制得本发明的化合物。根据反应方案1，本发明的化合物可以通过例如，首先将式II的氨基羧酸与式R2-SO2-Cl的磺酰氯或磺酸酐在碱的存在下在溶剂例如水、吡啶或醚中反应制得。适宜的碱是无机碱如碳酸钠或有机碱如吡啶或三乙胺。然后可以将得到的式III的磺酰基氨基甲酸通过例如与氯化试剂如五氯化磷、三氯氧磷或亚硫酰氯在惰性溶剂中反应进行活化，生成式IV的酰氯，然后将其与芳基胺反应。式III化合物中的羧酸基团的活化还可以通过不同的方式来进行，例如，通过本领域技术人员熟知的在肽化学中形成酰胺键的多种方法之一来进行，例如，转变成混合酸酐或活泼酯或使用碳二亚胺如二环己基碳二亚胺。
活化的磺酰基氨基甲酸与芳基胺的反应优选在惰性溶剂如吡啶、四氢呋喃或甲苯中、在含或不含惰性辅助碱如叔胺或吡啶的存在下进行。如果在与活化羧酸的反应中所用的芳基胺已经含有所需的取代基R1-S(O)n，则反应可以直接形成最终的式I化合物。基团R1-S(O)n中的n是1或2的式I化合物还可以通过将活化的羧酸与式R1-S-A1-NH2的巯基取代的芳基胺反应然后将式V化合物中的巯基在常规条件下，例如用过氧化物如过氧化氢或过酸如3-氯过苯甲酸或单过氧苯二甲酸在溶剂如二氯甲烷或丙酮中氧化制得。还可以首先将活化的羧酸与式A1-NH2的芳基胺反应。然后可以将形成的式VI的反应产物在常规条件下氯磺化并将氯磺酰基在常规条件下转变成基团R1-SO2，例如与适宜的胺直接反应或在溶剂如N-甲基吡咯烷酮、二甲基甲酰胺、甲苯或乙醚中反应，反应中可以选择性地存在辅助碱。采用类似的方式，可以将活化的羧酸与式F-SO2-A1-NH2的氟磺酰基芳基胺反应，所得到的式VII的氟磺酰基中间体可以在常规条件下转变成本发明的式I化合物。
反应方案1
Figure C9980829500311
本发明的式I化合物还可以通过将活化的磺酰基氨基羧酸，例如反应方案1中所示的式IV的酰氯与在硫原子上未被取代的式H2N-A1-SH的巯基芳基胺反应制得。然后可以将得到的式VIII的产物在亲核取代反应中在硫原子上用烷基卤化物或芳基卤化物或其它的活泼化合物在常规条件下烷基化或芳基化，然后，如需要，将硫进行氧化得到以上在式V化合物中所描述的亚砜或砜(参见反应方案2)。
反应方案2
式I化合物还可以通过，例如首先将适宜取代的式IX的硝基羧酸通过转变成相应的式X的酰氯或通过其它方法活化，然后将其与式R1-S(O)n-A1-NH2的取代的芳基胺按照与以上描述类似的方法反应制得(参见反应方案3)。在此，也可以使用式F-SO2-A1-NH2的氟磺酰基芳基胺作为芳基胺，在所得到的式XI的N-(氟磺酰基芳基)-甲酰胺中，可以将氟磺酰基在常规条件下，例如用式HNR5R6的胺转变成本发明的R1-SO2基团。
反应方案3
在将得到的式XII的硝基中间体中的硝基还原成氨基之前，可以利用硝基对环A2的活化作用将适宜的基团R3如卤原子通过与亲核试剂如胺反应用不同的基团R3所代替。将硝基还原生成氨基可以通过，例如在贵金属催化剂或者优选在阮内镍的存在下在溶剂例如乙醇、冰乙酸或氯化氢的乙醇溶液中催化氢化来完成，或者通过用贱金属如锌、锡或铁在酸存在下还原来完成。还原还可以用例如氯化锡(II)或通过与连二亚硫酸钠反应、优选在甲醇、四氢呋喃和水的混合溶剂中反应来完成。式XIII还原产物中氨基的磺酰化可以用活泼的磺酸衍生物按照与上述反应类似的方法进行，例如与磺酰氯在吡啶中反应，最后生成式I的化合物。
其中X是通过单键与基团A1中的环碳原子连接的氮原子并且所述的环碳原子紧邻A1中带有基团-NH-C(＝X)-的碳原子的式I化合物，即Ii的苯并咪唑衍生物，可以通过例如将按照以上反应方案1的描述制得的活化的磺酰基氨基羧酸衍生物，例如IV的酰氯(或者，与反应方案3类似，为硝基甲酸衍生物)与1，2-二氨基芳烃在脱水剂如亚硫酰氯或五氯化磷的存在下反应制得(参见反应方案4)。反应通常在惰性溶剂例如烃如甲苯或二甲苯中进行。1，2-二氨基芳烃可以已经含有最终的基团R1-S(O)n或其前体基团例如基团R1-S。然后可以按照以上描述进行随后的步骤，例如在硫原子上的反应。正因为如此，可以使用未取代的1，2-二氨基芳烃并可以将得到的式XIV的产物用例如氯磺酸进行氯磺化，然后可以将得到的磺酰氯通过例如与适宜的胺反应转变成含有基团R1-SO2的最终化合物。
反应方案4
Figure C9980829500351
合成式I化合物的所有反应均是本领域技术人员熟知的，并且可以按照文献中描述的方法或与其类似的方法在常规条件下进行，参见例如Houben-Weyl，《有机化学方法》(Methods of OrganicChemistry)，Thieme-Veriag，Stuttgart，或《有机反应》(OrganicReactions)，John Wiley & Sons，New York。为了避免在合成式I化合物的过程中发生副反应，可能需要根据具体情况通过引入保护基对功能基进行暂时性的封闭然后在合成的后期将其脱保护，或者以前体基团的形式引入功能基并在后来的反应步骤中将其转变成所需的功能基。适于具体情况的合成策略以及保护基和前体基团是本领域技术人员已知的。如需要，可将式I的化合物通过常规的纯化方法例如重结晶或色谱法纯化。制备式I化合物的原料化合物是可购买到的或者可以按照文献中描述的方法或与其类似的方法制得。
本发明的式I化合物可以通过激活可溶性鸟苷酸环化酶(sGC)来增加cGMP浓度，因此，它们可用于治疗和预防与cGMP水平偏低或下降有关的或由此引起的疾病，或者用于治疗或预防需要增加cGMP水平的疾病。式I化合物对sGC的激活可以通过例如以下描述的活性试验来证实。
可用式I化合物治疗和预防的与cGMP水平偏低有关或者需要增加cGMP水平的疾病或病症是，例如，心血管疾病，例如内皮功能障碍、心脏舒张功能障碍、动脉粥样硬化、高血压、稳定和不稳定心绞痛、血栓形成、再狭窄、心肌梗塞、中风、心功能不足或肺压力过高，或勃起功能障碍、支气管哮喘、慢性肾机能不全和糖尿病。式I化合物还可用于治疗肝硬化以及用于改善有限的记忆行为或学习能力。
式I化合物及其生理可接受的盐可以单独地、以混合物的形式或以药物制剂的形式作为药物向动物、优选哺乳动物、特别是人给药。因此，本发明还涉及式I化合物及其生理可接受的盐用作药物、其用于激活可溶性鸟苷酸环化酶、使紊乱的cGMP平衡正常化的用途，特别是其用于治疗和预防上述症状的用途及其在制备用于这些目的的药物中的用途。此外，本发明还涉及含有有效量的至少一种式I化合物和/或其生理可接受的盐作为活性成分以及常规的可药用载体、即一种或多种可药用载体物质和/或添加剂的药物制剂(或药物组合物)。本发明还涉及那些本身是已知的并且被从以上定义的本发明的式I化合物中排除了的式I化合物及其生理可接受的盐作为可溶性鸟苷酸环化酶的激活剂。因此，本文中所有关于药理学作用以及式I化合物用途的描述均适用于其中含有带有基团C(＝X)-NH-和NH-SO2R2的碳原子的环A2是在3位和5位被氯取代的苯环，R2是甲基，X是氧同时R1-S(O)n-A1-是5-氯-2-(4-氯苯基巯基)-苯基的式I化合物及其生理可接受的盐。因此，本发明的目的是，例如，所述化合物及其生理可接受的盐用作药物、含有有效量的所述化合物和/或其生理可接受的盐作为活性成分以及常规的可药用载体的药物制剂、所述化合物和/或其生理可接受的盐用于治疗或预防上述症状的用途及其在制备用于这些目的的药物中的用途。
本发明的药物可以以例如丸剂、片剂、包衣片剂、糖包衣片剂、颗粒剂、硬和软明胶胶囊、水、醇或油溶液、糖浆、乳剂或混悬剂的形式口服给药，或以栓剂的形式直肠给药。还可以进行胃肠外给药，例如以注射溶液或输注液的形式皮下、肌肉内或静脉内给药。其它适宜的给药形式是，例如，以软膏、酊剂、喷雾剂或经皮治疗系统的形式经皮或局部给药，或者以鼻喷雾剂或气雾剂混合物的形式吸入给药，或者以例如微胶囊、植入物或棒剂的形式给药。优选的给药方式取决于例如所治疗的疾病及其严重程度。
式I的活性化合物和/或其生理可接受盐在药物制剂中的量通常为每剂0.2至500mg，优选1至200mg，但根据药物制剂的类型，该含量还可以更高。药物制剂通常含有0.5至90％(重量)的式I化合物和/或其生理可接受的盐。药物制剂的制备可以通过已知的方式进行。为此，可将一种或多种式I化合物和/或其生理可接受的盐与一种或多种固体或液体药物载体物质和/或添加剂(或辅剂)混合，如需要，可与其它具有治疗或预防作用的药物活性化合物混合，制成适宜的给药或剂量形式，然后将其用作人用或兽用的药物。
生产丸剂、片剂、糖包衣片剂和硬明胶胶囊时，可以使用例如乳糖、淀粉如玉米淀粉或淀粉衍生物、滑石、硬脂酸或其盐等。用于软明胶胶囊和栓剂的载体是，例如脂肪、蜡、半固体和液体的多元醇、天然或硬化油等。用于制备溶液剂例如注射用溶液、乳液或糖浆的适宜载体是，例如水、生理盐水、醇如乙醇、甘油、多元醇、蔗糖、转化糖、葡萄糖、甘露醇、植物油等。还可以将式I化合物及其生理可接受的盐冷冻干燥并将得到的冷冻干燥物用于例如制备注射或输液用的制剂。用于微胶囊、植入物或棒剂的适宜载体是，例如乙醇酸和乳酸的共聚物。
除活性化合物和载体外，药物制剂还可以含有常规的添加剂，例如填料、崩解剂、粘合剂、润滑剂、湿润剂、稳定剂、乳化剂、分散剂、防腐剂、甜味剂、着色剂、矫味剂、香料、增稠剂、稀释剂、缓冲物质、溶剂、增溶剂、用来达到缓释效果的试剂、用于调节渗透压的盐、包衣剂和抗氧剂。
式I的活性化合物和/或其生理可接受盐的给药剂量取决于个体的情况，通常需要根据个体情况进行调节以达到最佳的效果。因此，它取决于所治疗疾病的性质和严重程度以及所治疗的人或动物的性别、年龄、体重和个体反应、所用化合物的效力和作用持续时间、治疗是急性的、慢性的还是预防性的、或者除了式I化合物外是否还施用其它的活性化合物。通常，约0.01至100mg/kg、优选0.1至10mg/kg、特别是0.3至5mg/kg(均为mg/kg体重)的每日剂量适合于向体重约为75kg的成人给药以达到所需的效果。每日剂量可以单次给药，或者，特别是当给药量较大时，可分成多次，例如两次、三次或四次给药。在某些情况下，根据个体的反应，可能需要超出给定每日剂量的上限或下限。
式I化合物主要通过与酶的血红素结合袋结合来激活可溶性鸟苷酸环化酶。根据该特点，除了可在人用或兽用药中用作药物活性化合物外，还可将其在需要这种对鸟苷酸环化酶的作用的生物化学研究中用作科研工具或助剂，并且还可将其用于诊断目的，例如用于细胞样品或组织样品的体外诊断。如上所述，式I化合物及其盐还可用作制备其它药物活性化合物的中间体。
以下式I化合物及其制备中间体的例子用来非限定性地说明本发明。
实施例
1.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酸
将33.71g(0.32mol)碳酸钠溶于250ml水并升温至60℃。向溶液中加入25.00g(0.13mol)2-氨基-4，5-二甲氧基-苯甲酸，然后在15分钟内向该溶液中分批加入29.55g(0.14mol)4-氯-苯磺酰氯。将混合物冷却并抽滤后，将残余物加入1％碳酸氢钠溶液中，将溶液过滤，加入1N盐酸使产物析出沉淀。得到25.90g(55％)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酸，熔点(m.p.)212-214℃。
按照类似方法制得：
2.)5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酸；M.p.：210℃
3.)5-氯-2-(3，4-二氯-苯基磺酰基氨基)-苯甲酸
5.)2-(4-氯-苯基磺酰基氨基)-环戊烷甲酸；M.p.：147℃
6.)2-(4-氯-苯基磺酰基氨基)-5-甲基-苯甲酸；M.p.：201℃
7.)3-(4-氯-苯基磺酰基氨基)-噻吩-2-甲酸；M.p.：180℃
8.)3-(4-氯-苯基磺酰基氨基)-吡唑-4-甲酸；油
9.)2-(4-氯-苯基磺酰基氨基)-吡啶-3-甲酸；M.p.：分解(分解)＞360℃
10.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰氯
将25.90g(0.07mol)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酸与75ml甲苯混合，加入17.30g(0.08mol)五氯化磷并将混合物于40-45℃下搅拌2.5小时。然后将混合物真空浓缩至其体积的一半，将沉淀出的产物抽滤并用少量甲苯洗涤。得到25.30g(93％)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰氯，熔点175-177℃。
按照类似的方法制得：
11.)5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰氯；M.p.：127℃
12.)5-氯-2-(3，4-二氯-苯基磺酰基氨基)-苯甲酰氯；M.p.：117℃
13.)2-(4-氯-苯基磺酰基氨基)-环戊烷甲酰氯；M.p.：107℃
14.)2-(4-氯-苯基磺酰基氨基)-5-甲基-苯甲酰氯；M.p.：114℃
15.)3-(4-氯-苯基磺酰基氨基)-噻吩-2-甲酰氯；M.p.：122
16.)3-(4-氯-苯基磺酰基氨基)-吡唑-4-甲酰氯；M.p.：260℃(分解)
17.)2-(4-氯-苯基磺酰基氨基)-吡啶-3-甲酰氯
18.)4-((2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰基)-氨基)-苯磺酰氟
将10.00g(25.6mmol)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰氯与300ml甲苯混合，加入4.49g(25.6mmol)4-氨基苯磺酰氟并将混合物加热回流4小时。冷却后，抽滤出固体沉淀并用甲苯洗涤。得到11.71g(87％)熔点为216-219℃的标题化合物。
按照类似的方法制得：
19.)4-((5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰基)-氨基)-苯磺酰氟；M.p.：242℃
20.)N-(4-氨基磺酰基-苯基)-5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰胺；M.p.：260℃
21.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-((4-(4-硝基-苯基)-巯基)-苯基)-苯甲酰胺；M.p.：255℃
22.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(苯基巯基)-苯基)-苯甲酰胺；M.p.：169℃
23.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-甲基巯基-苯基)-苯甲酰胺；M.p.：220℃
24.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-甲基-苯并噻唑-5-基)-苯甲酰胺；M.p.：251℃
25.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(3-二乙基氨基-2-羟基-丙基-巯基)-苯基)-苯甲酰胺；M.p.：102℃
26.)4-((5-氯-2-(3，4-二氯-苯基磺酰基氨基)-苯甲酰基)-氨基)-苯磺酰氟；M.p.：232℃
27.)4-(2-(4-氯-苯基磺酰基氨基)-环戊烷羰基氨基)-苯磺酰氟；M.p.：211℃
28.)4-((2-(4-氯-苯基磺酰基氨基)-5-甲基-苯甲酰基)-氨基)-苯磺酰氟；M.p.：224℃
29.)4-((3-(4-氯-苯基磺酰基氨基)-噻吩-2-羰基)-氨基)-苯磺酰氟；M.p.：255℃
30.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-巯基-苯基)-苯甲酰胺；M.p.：202℃
31.)4-((3-(4-氯-苯基磺酰基氨基)-吡唑-4-羰基)-氨基)-苯磺酰氟；M.p.：251℃
32.)3-((5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰基)-氨基)-苯磺酰氟；M.p.：224℃
33.)4-(2-(4-氯-苯基磺酰基氨基)-吡啶-3-羰基)-氨基)-苯磺酰氟；M.p.：263-265℃
34.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-甲基-5-(硫代吗啉-4-磺酰基)-噻唑-2-基)-苯甲酰胺；M.p.：265-267℃
35.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-甲基巯基-苯基)-苯甲酰胺
36.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(3-甲基巯基-苯基)-苯甲酰胺
37.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(5-甲基-异唑-3-基-氨磺酰基)-苯基)-苯甲酰胺
38.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(4-硝基-苯基磺酰基)-苯基)-苯甲酰胺
39.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(5-乙基磺酰基-2-羟基-苯基)-苯甲酰胺
40.)N-(3-丁基氨磺酰基-苯基)-5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰胺
41.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-硝基-5-丙基巯基-苯基)-苯甲酰胺
42.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-氰硫基-苯基)-苯甲酰胺
43.)N-(4-乙酰基氨磺酰基-苯基)-5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰胺
44.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-苯基巯基-苯基)-苯甲酰胺
45.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-氯-5-(2-氰基-乙基氨磺酰基)-苯基)-苯甲酰胺
46.)N-(5-丁基氨磺酰基-2-甲氧基-苯基)-5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰胺
47.)N-(4-苯甲酰基氨磺酰基-苯基)-5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰胺
48.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-氯-4-甲基磺酰基苯基)-苯甲酰胺
49.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(十六烷基磺酰基)-苯基)-苯甲酰胺
50.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(丁基氨基羰基氨基磺酰基)-苯基)-苯甲酰胺
51.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-氨磺酰基-苯基)-苯甲酰胺
52.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(2-甲基巯基-5-三氟甲基-苯基)-苯甲酰胺
53.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(3-甲基磺酰基-苯基)-苯甲酰胺
54.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(3-(2-羟基-乙基磺酰基)-苯基)-苯甲酰胺
55.)(4-(5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰基氨基)-苯基巯基)-乙酸
56.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(3，4-二甲基-异唑-5-基氨磺酰基)-苯基)-苯甲酰胺
57.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(噻唑-2-基氨磺酰基)-苯基)-苯甲酰胺
58.)5-氯-2-(3，4-二氯-苯基磺酰基氨基)-N-(4-乙基巯基-苯基)-苯甲酰胺；M.p.：171℃
59.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺
将500mg(0.95mmol)4-((2-(4-氯-苯基磺酰基氨基)4，5-二甲氧基-苯甲酰基)-氨基)-苯磺酰氟溶于1ml硫代吗啉并加热至90℃30分钟。为了进行分离，将混合物倒在50ml冰/1N盐酸上，抽滤出沉淀，在真空干燥器内用五氧化磷干燥，然后用己烷/乙酸乙酯重结晶得到378mg(65％)熔点为241℃的标题化合物。
按照类似的方法制得：
60.)2-(4-氯-苯基磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-吡啶-3-甲酰胺；M.p.：256-258℃
61.)N-(4-(4-氨基甲酰基-哌啶-1-磺酰基)-苯基)-2-(4-氯-苯基磺酰基氨基)-吡啶-3-甲酰胺；M.p.：273-276℃
62.)2-(4-氯-苯基磺酰基氨基)-N-(4-(哌啶-1-磺酰基)-苯基)-吡啶-3-甲酰胺；M.p.：180-183℃
63.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(硫代吗啉-4-磺酰基)苯基)-苯甲酰胺；M.p.：246℃
64.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(4-甲基-哌嗪-1-磺酰基)-苯基)-苯甲酰胺；M.p.：219℃
65.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(2，6-二甲基-吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：259℃
66.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：251℃
67.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(4-羟基-哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：255℃
68.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(1，4-二氧杂-8-氮杂-螺[4.5]癸烷-8-磺酰基)-苯基)-苯甲酰胺；M.p.：256℃
69.)5-氯-2-(3，4-二氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：253℃
70.)5-氯-2-(3，4-二氯-苯基磺酰基氨基)-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：222℃
71.)5-氯-2-(3，4-二氯-苯基磺酰基氨基)-N-(4-(4-甲基-哌嗪-1-磺酰基)-苯基)-苯甲酰胺；M.p.：246℃
72.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：172℃
73.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(4-(2-羟基-乙基)-哌嗪-1-磺酰基)-苯基)-苯甲酰胺；M.p.：277℃
74.)2-(4-氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-环戊烷甲酰胺；M.p.：180℃
75.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-二乙基氨磺酰基-苯基)-苯甲酰胺；M.p.：226℃
76.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：240℃
77.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(2-甲氧基-乙基氨磺酰基)-苯基)-苯甲酰胺；M.p.：209℃
78.)2-(4-氯-苯基磺酰基氨基)-5-甲基-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：203℃
79.)3-(4-氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-噻吩-2-甲酰胺；M.p.：220℃
80.)3-(4-氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-1H-吡唑-4-甲酰胺；油
81.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(3-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：238℃
82.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(3-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：202℃
83.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(3-(4-甲基-哌嗪-1-磺酰基)-苯基)-苯甲酰胺盐酸盐；M.p.：245℃
84.)3-(4-氯-苯基磺酰基氨基)-N-(4-(硫代吗啉-4-磺酰基)-苯基)-噻吩-2-甲酰胺；M.p.：229℃
85.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：228℃
86.)2-(4-氯-苯基磺酰基氨基)-5-甲基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：234℃
87.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(4-甲基-哌嗪-1-磺酰基)-苯基)-苯甲酰胺；M.p.：172℃
88.)2-(4-氯-苯基磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：208℃
89.)2-(4-氯-苯基磺酰基氨基)-N-(4-(4-羟基-哌啶-1-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：244℃
90.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(哌啶-3-磺酰基)-苯基)-苯甲酰胺；M.p.：258℃
91.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(噻唑烷-3-磺酰基)-苯基)-苯甲酰胺；M.p.：261℃
92.)2-(4-氯-苯基磺酰基氨基)-N-(4-(2，5-二氢-1H-吡咯-1-磺酰基)苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：262℃
93.)2-(4-氯-苯基磺酰基氨基)-N-(4-(1，2，3，6-四氢-吡啶-1-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：252℃
94.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(2-甲基-哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：227℃
95.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(哌嗪-1-磺酰基)苯基)-苯甲酰胺；M.p.：243℃
96.)4-(4-(2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰基氨基)-苯基磺酰基)-哌嗪-1-甲酸乙酯；M.p.：245℃
97.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(4-甲基-哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：267℃
98.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(4-甲基-全氢-[1，4]二氮杂-1-磺酰基)-苯基)-苯甲酰胺；M.p.：274℃
99.)2-(4-氯-苯基磺酰基氨基)-N-(4-(4-乙基-哌嗪-1-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：191℃
100.)2-(4-氯-苯基磺酰基氨基)-N-(4-((2-二甲基氨基-乙基)-乙基-氨磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：分解＞119℃
101.)2-(4-氯-苯基磺酰基氨基)-N-(4-(1，4，5，6-四氢-嘧啶-1-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：分解＞237℃
102.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(4-(嘧啶-2-基)-哌嗪-1-磺酰基)-苯基)-苯甲酰胺；M.p.：分解＞194℃
103.)2-(4-氯-苯基磺酰基氨基)-N-(4-(4-(4-氯-苯基)-哌嗪-1-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：分解＞243℃
104.)2-(4-氯-苯基磺酰基氨基)-N-(4-(二氢茚-1-基氨磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：161℃
105.)2-(4-氯-苯基磺酰基氨基)-N-(4-((2-(1H-吲哚-3-基)-乙基)-甲基-氨磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：182℃
106.)1-(4-((2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰基)-氨基)-苯基磺酰基)-哌啶-4-甲酰胺；M.p.：252℃
107.)2-(4-氯-苯基磺酰基氨基)-N-(4-环丙基氨磺酰基-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：222℃
108.)2-(4-氯-苯基磺酰基氨基)-N-(4-(3-羟基-吡咯烷-1-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺；M.p.：272℃
109.)N-(4-(烯丙基-环己基-氨磺酰基)-苯基)-2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰胺；M.p.：182℃
110.)1-(4-((2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-苯甲酰基)-氨基)-苯基磺酰基)-吡咯烷-2-甲酸；M.p.：240℃(烧结)
111.)5-氯-2-硝基-苯甲酰氯
将100.00g(0.50mol)5-氯-2-硝基苯甲酸与72.20g(0.61mol)亚硫酰氯混合并将混合物加热回流2小时。真空蒸除过量的亚硫酰氯。得到106.50g(约98％)油状的5-氯-2-硝基-苯甲酰氯粗品。
按照类似的方法制得：
112.)5-甲基-2-硝基-苯甲酰氯；油
113.)4-(5-氯-2-硝基-苯甲酰基氨基)-苯磺酰氟
86.00g(0.39mol)5-氯-2-硝基-苯甲酰氯溶于300ml甲苯，滴加62.00g(0.35mol)4-氨基苯磺酰氟的溶液，然后将混合物加热回流4小时。冷却后，真空浓缩至其原体积的一半，冷却，然后抽滤出固体沉淀。得到121.60g(86％)熔点为182-184℃的标题化合物。
按照类似方法制得：
114.)4-(5-甲基-2-硝基-苯甲酰基氨基)-苯磺酰氟；M.p.：179℃
115.)5-氯-N-(4-乙基巯基-苯基)-2-硝基-苯甲酰胺
116.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-硝基-苯甲酰胺
将120.00g(0.33mol)4-(5-氯-2-硝基-苯甲酰基氨基)-苯磺酰氟、29.10g(0.33mol)吗啉和33.85g(0.33mol)三乙胺在1200ml甲苯中于60℃搅拌2天。抽滤出固体沉淀并用丙酮/正己烷重结晶。得到102.10g(71％)熔点为243-245℃的标题化合物。
按照类似方法制得：
117.)5-氯-2-硝基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：120℃
118.)5-甲基-N-(4-(吗啉-4磺酰基)-苯基)-2-硝基-苯甲酰胺；M.p.：249℃
119.)N-(4-(吗啉-4-磺酰基)-苯基)-5-(吗啉-4-基)-2-硝基-苯甲酰胺
将20.00g(0.56mol)4-(5-氯-2-硝基-苯甲酰基氨基)-苯磺酰氟在48.5g(0.557mol)吗啉中加热回流1小时。然后将混合物冷却，倒在冰/盐酸上然后抽滤。得到26.0g(98％)熔点为252℃的标题化合物。
120.)2-氨基-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺
将11.10g(26.1mmol)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-硝基-苯甲酰胺溶于440ml四氢呋喃/甲醇(1∶1)，然后滴加27.23g(156.4mmol)连二亚硫酸钠的330ml水溶液。室温搅拌1小时后，用旋转蒸发仪蒸除有机溶剂，抽滤出产物沉淀，用二氯甲烷/甲醇(9∶1)进行硅胶色谱纯化。得到5.68g(55％)熔点为229-231℃的标题化合物。
按照类似方法制得：
121.)2-氨基-5-氯-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：177℃
122.)2-氨基-N-(4-(吗啉-4-磺酰基)-苯基)-5-(吗啉-4-基)-苯甲酰胺；M.p.：228℃
123.)2-氨基-5-氯-N-(4-乙基磺酰基-苯基)-苯甲酰胺；M.p.：159-161℃
124.)5-氯-2-(5-氯-1，3-二甲基-1H-吡唑-4-磺酰基-氨基)-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺
将250mg(0.60mmol)2-氨基-5-氯-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺溶于10ml无水吡啶，然后在0℃下滴加195mg(0.85mmol)5-氯-1，3-二甲基-1H-吡唑-磺酰氯的5ml吡啶溶液。2小时后，将混合物倒在冰上，抽滤出固体沉淀并用二氯甲烷/甲醇(98∶2)通过硅胶色谱纯化。得到250mg(69％)熔点为215-216℃的标题化合物。
按照类似方法制得：
125.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(4-甲基-苯基磺酰基氨基)-苯甲酰胺；M.p.：214℃
126.)5-氯-2-(3，4-二甲氧基-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：245℃
127.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(4-三氟甲氧基-苯基磺酰基氨基)-苯甲酰胺；M.p.：195℃
128.)2-((4-乙酰基氨基-苯基)-磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：198℃
129.)5-氯-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)苯基)-苯甲酰胺；M.p.：112℃
130.)5-氯-2-(5-氯-1，3-二甲基-吡唑-4-磺酰基-氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：161℃
131.)5-氯-2-((1-甲基-咪唑-4-磺酰基)-氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：141℃
132.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(吡啶-3-磺酰基氨基)苯甲酰胺；M.p.：222℃
133.)2-(4-苯甲酰氧基-苯基磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：245℃
134.)5-氯-2-(乙基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：274-276℃
135.)2-((2-乙酰氨基-4-甲基-噻唑-5-磺酰基)-氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：257℃
136.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(噻吩-2-磺酰基氨基)-苯甲酰胺；M.p.：216℃
137.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(4-三氟甲基-苯基磺酰基氨基)-苯甲酰胺；M.p.：264℃
138.)2-(4-溴-苯基磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：232
139.)2-(3，5-二-三氟甲基-苯基磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：209℃
140.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(4-硝基-苯基磺酰基氨基)-苯甲酰胺；M.p.：239℃
141.)5-氯-2-(4-氰基-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：238℃
142.)5-氯-2-(4-甲基磺酰基-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：181℃
143.)5-氯-2-(4-异丙基-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：105℃
144.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-((2-苯基-乙烯基)-磺酰基氨基)-苯甲酰胺；M.p.：278℃
145.)5-氯-2-(4，5-二溴-噻吩-2-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：232℃
146.)5-氯-2-(4-氟-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：245℃
147.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(5-苯基磺酰基-噻吩-2-磺酰基氨基)-苯甲酰胺；M.p.：103℃
148.)5-氯-2-(3-氯-4-甲氧基-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：274℃
149.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(喹啉-8-磺酰基氨基)苯甲酰胺；M.p.：262℃
150.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(2，4，6-三甲基-苯基磺酰基氨基)-苯甲酰胺；M.p.：240℃
151.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(3-硝基-苯基磺酰基氨基)-苯甲酰胺；M.p.：220℃
152.)5-氯-2-(4-甲氧基-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：269℃
153.)5-氯-2-甲基磺酰基氨基-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：248℃
154.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-苯基甲基磺酰基氨基-苯甲酰胺；M.p.：106℃
155.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(2，2，2-三氟-乙基磺酰基氨基)-苯甲酰胺；M.p.：208℃
156.)2-(丁基-磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：102℃
157.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(3-三氟甲基-苯基磺酰基氨基)-苯甲酰胺；M.p.：212℃
158.)2-(4-溴-2，5-二氯-噻吩-3-磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：267℃
159.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(2-三氟甲基-苯基磺酰基氨基)-苯甲酰胺；M.p.：234℃
160.)5-氯-2-(3-氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：206℃
161.)2-(4-溴-2-甲氧基-苯基磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M-p.：260℃
162.)5-氯-2-(2，6-二氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：244℃
163.)5-氯-2-(2-氰基-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：200℃
164.)2-(4-丁氧基-苯基磺酰基氨基)-5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：225℃
165.)5-氯-2-(7，7-二甲基-2-氧代-二环[2.2.1]庚烷-1-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：120℃
166.)5-氯-2-(3-氟-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：204℃
167.)2-(4-氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-5-(吗啉-4-基)-苯甲酰胺；M.p.：264℃
168.)5-氯-N-(4-乙基磺酰基-苯基)-2-(4-甲基-苯基磺酰基氨基)-苯甲酰胺；M.p.：188-192℃
169.)5-氯-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-乙基磺酰基-苯基)-苯甲酰胺；M.p.：195-197℃
170.)5-氯-2-(4-氯-3-硝基-苯基磺酰基氨基)-N-(4-乙基磺酰基-苯基)-苯甲酰胺；M.p.：196-198℃
171.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-乙基磺酰基-苯基)-苯甲酰胺；M.p.：180-185℃
172.)5-氯-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-乙基磺酰基-苯基)-苯甲酰胺；M.p.：分解＞249℃
173.)5-氯-2-乙基磺酰基氨基-N-(4-乙基磺酰基-苯基)-苯甲酰胺；M.p.：103℃
174.)4-氯-N-(2-(1H-苯并咪唑-2-基)-4-氯-苯基)-苯磺酰胺
将1.00g(2.7mmol)5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰氯和296mg(2.7mmol)邻苯二胺在150ml甲苯中加热回流1小时。抽滤出少量固体，然后将滤液蒸发。将残余物加入50ml甲苯中，加入600mg亚硫酰氯并将混合物再次加热回流10小时。冷却，然后抽滤出固体沉淀。得到280mg(25％)熔点为225-228℃的标题化合物。
175.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(1，1-二氧代-硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺
和
176.)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(1-氧代-硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺
将500mg(0.82mmol)2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺的50ml丙酮溶液冷却至0℃。加入371mg(1.23mmol)57％间氯过苯甲酸的20ml丙酮溶液，然后将混合物室温搅拌过夜。为了进行分离，将其倒入水/冰中，然后抽滤出沉淀。将得到的两种产物的混合物用二氯甲烷/甲醇(97∶3)通过硅胶色谱分离。
按照类似方法制得：
177.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(1，1-二氧代-硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：182℃
178.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(1-氧代-硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：233℃
179.)5-氯-2-(3，4-二氯-苯基磺酰基氨基)-N-(4-乙基磺酰基-苯基)-苯甲酰胺；M.p.：240℃
180.)5-氯-N-(4-乙基磺酰基-苯基)-2-硝基-苯甲酰胺
181.)4-氯-N-(4-氯-2-(6-(吗啉-4-磺酰基)-1H-苯并咪唑-2-基)-苯基)-苯磺酰胺
将200mg(0.5mmol)4-氯-N-(2-(1H-苯并咪唑-2-基)-4-氯-苯基)-苯磺酰胺于0℃下加入到1ml氯磺酸中并于60℃加热30分钟。随后，将混合物倒入水/冰中，抽滤出固体，干燥，然后在0℃下加入到1ml吗啉中。室温搅拌1小时后，将混合物倒入冰/盐酸中并用乙酸乙酯萃取。将萃取液蒸发并将残余物用己烷/乙酸乙酯(1∶1)通过硅胶色谱纯化。得到20mg(7％)熔点为225-228℃的标题化合物。
1H-NMR(D6-DMSO)：δ(ppm)＝2.9(m，4H，吗啉-H)，3.6(m，4H，吗啉-H)，7.5(dd，4H，亚苯基-H)，7.4-8.2(m，6H，苯并-H，苯基-H)
182.)5-氯-N-(4-(吗啉-4-磺酰基)-苯基)-2-(2-(吡咯烷-1-基)-乙基磺酰基氨基)-苯甲酰胺
该化合物用2-氯-乙磺酰氯制备。将分离出的1-(2-(4-氯-2-(4-(吗啉-4-磺酰基)-苯基氨基甲酰基)-苯基氨磺酰基)-乙基)-吡啶氯化物中间体与吡咯烷反应得到标题化合物。
1H-NMR(D6-DMSO)：δ(ppm)＝1.8(m，4H，吡咯烷-H)，2.65(m，4H，吡咯烷-H)，3.0(m，4H，吗啉-H)，3.1(t，2H，亚乙基-H)，3.35(t，2H，亚乙基-H)，3.75(m，4H，吗啉-H)，7.50(dd，1H，H-4)，7.7(d，1H，H-3)，7.75(dd，1H，H-6)，7.85(“dd”，4H，亚苯基-H)
183.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-异丙基巯基-苯基)-苯甲酰胺
将1.00g(2.21mmol)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-巯基-苯基)-苯甲酰胺溶于25ml二甲基甲酰胺然后加入0.25g(2.21mmol)叔丁醇钾。将混合物室温搅拌15分钟，然后滴加0.27g(2.21mmol)异丙基溴化物并将混合物于60℃加热8小时。为了进行分离，将其倒入水中并用乙酸乙酯萃取。将合并的萃取液蒸发并将残余物用己烷/乙酸乙酯(3∶1)通过硅胶色谱纯化。得到420mg(39％)熔点为168-169℃的标题化合物。
按照类似方法制得：
184.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-氰基甲基巯基苯基)-苯甲酰胺；M.p.：104℃
185.)(4-((5-氯-2-(4-氯-苯基磺酰基氨基)-苯甲酰基)-氨基)-苯基巯基)-乙酸乙酯；M.p.：133℃
186.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(2-(吗啉-4-基)-乙基巯基)-苯基)-苯甲酰胺；M.p.：95℃
187.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(2-(2-甲氧基-乙氧基)-乙基巯基)-苯基)-苯甲酰胺；油
188.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(丙-2-炔基)-巯基-苯基)-苯甲酰胺；M.p.：185℃
189.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-异丙基巯基-苯基)-苯甲酰胺；M.p.：169℃
190.)5-氯-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺钠盐
将0.48g细碎的氢氧化钠和7g 5-氯-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺的混合物在250ml乙醇中通过短时间加热制成溶液。然后将混合物真空蒸发，加入50ml水并将其再次真空蒸发至干。将该过程重复两次。将得到的产物于50℃真空干燥。M.p.：343℃(分解)
按照与以上类似的方法，制得如下实施例的化合物：
191.)4，5-二甲氧基-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(N-甲基-N-(吡啶-3-基-甲基)-氨基磺酰基)-苯基)-苯甲酰胺盐酸盐；M.p.：214℃
192.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-3-甲基-苯基)-苯甲酰胺；M.p.：192℃
193.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-3-甲基-苯基)-苯甲酰胺；M.p.：254℃
194.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(3，5-二甲基-哌啶-1-磺酰基)-3-甲基-苯基)-苯甲酰胺；M.p.：242
195.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(哌啶-1-磺酰基)-3-甲基-苯基)-苯甲酰胺；M.p.：189℃
196.)4，5-二甲氧基-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(N-甲基-N-(吡啶-3-基-甲基)-氨基磺酰基)-苯基)-苯甲酰胺；M.p.：213℃
197.)4，5-二甲氧基-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(N-(吡啶-3-基-甲基)-氨基磺酰基)-苯基)-苯甲酰胺；M.p.：216℃
198.)5-氯-2-(2，4-二甲基-噻唑-5-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：190℃
199.)4，5-二甲氧基-2-(4-氯-苯基磺酰基氨基)-N-(4-(3，5-二甲基-哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：249℃(分解)
200.)2-(4-氯-苯基磺酰基氨基)-N-(4-(N-甲基-N-(吡啶-3-基-甲基)-氨基磺酰基)-苯基)-苯甲酰胺；树脂
201.)3，4-二甲氧基-2-(4-氯-苯基磺酰基氨基)-N-(4-(N-甲基-N-(吡啶-3-基-甲基)-氨基磺酰基)-苯基)-苯甲酰胺；M.p.：241℃
202.)5-溴-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-3-甲基-苯基)-苯甲酰胺；M.p.：249℃
203.)5-溴-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：244℃
204.)5-溴-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：197℃
205.)4，5-二甲氧基-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(1，2，3，4-四氢-异喹啉-2-磺酰基)-苯基)-苯甲酰胺；M.p.：213℃
206.)4，5-二甲氧基-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：232℃
207.)4，5-二甲氧基-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(顺-2，6-二甲基-哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：213℃
208.)5-氯-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(1，2，3，4-四氢-异喹啉-2-磺酰基)-苯基)-苯甲酰胺；M.p.：260℃
209.)5-氯-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(N-甲基-N-(吡啶-3-基-甲基)-氨基磺酰基)-苯基)-苯甲酰胺；M.p.：65℃(烧结)
210.)6-甲基-2-(4-氯-苯基磺酰基氨基)-N-(4-(全氢吖庚因-1-磺酰基)-苯基)-苯甲酰胺；M.p.：151℃
211.)6-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(吡咯烷-1-磺酰基)-苯基)-苯甲酰胺；M.p.：217℃
212.)6-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(4-羟基丁基氨基)-磺酰基)-苯基)-苯甲酰胺；树脂
213.)5-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(N-乙基-N-(吡啶-4-基-甲基)-氨基磺酰基)-苯基)-苯甲酰胺；树脂
214.)2-(4-氯-苯基磺酰基氨基)-N-(4-硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：209℃
215.)3-甲基-2-(4-氯-苯基磺酰基氨基)-N-(4-(N-甲基-N-(2-(吡啶-2-基)-乙基)-氨基磺酰基)-苯基)-苯甲酰胺；M.p.：193℃
216.)4，5-二氟-2-(4-氯-苯基磺酰基氨基)-N-(4-(4-氨基羰基-哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：227℃
217.)4，5-二氟-2-(4-氯-苯基磺酰基氨基)-N-(4-(4-(2-羟基乙基)-哌嗪-1-磺酰基)-苯基)-苯甲酰胺；树脂
218.)5-氯-4-甲氧基-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；油
219.)5-氯-4-甲氧基-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-1-磺酰基)-苯基)-苯甲酰胺；M.p.：89℃
220.)5-氯-4-甲氧基-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(N-吡啶-3-基)-N-甲基-氨基磺酰基)-苯基)-苯甲酰胺；M.p.：135℃
221.)4，5-二甲氧基-2-(4-氯-苯基磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-苯甲酰胺钠盐；M.p.：330℃(分解)
222.)5-氯-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：230℃
223.)5-氯-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(3，5-二甲基哌啶-1-磺酰基)-苯基)-苯甲酰胺；M.p.：61℃
224.)5-氯-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：286℃
225.)5-氯-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-苯基磺酰基)-苯基)-苯甲酰胺；M.p.：227℃
226.)4-氯-2-(4-氯-苯基磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-苯甲酰胺；M.p.：103℃
药理学研究
1)可溶性鸟苷酸环化酶的激活
本发明化合物对催化三磷酸鸟苷(GTP)向环鸟苷酸(cGMP)和焦磷酸转变的可溶性鸟苷酸环化酶(sGC)的激活通过来自Amersham的酶免疫试验(EIA)来测量。为此，将待测试的物质首先与sGC一起在微滴度板中保温，然后测定所形成的cGMP的量。
所用的sGC从牛肺中分离(参见《酶学方法》(Methods inEnzymology)，195卷，377页)。试验溶液(每孔100μl)含有50m三乙醇胺(TEA)缓冲液(pH7.5)、3mM MgCl2、3mM还原的谷胱甘肽(GSH)、0.1mM GTP、1mM 3-异丁基-1-甲基黄嘌呤(IBMX)、适当稀释的酶溶液和待测试物质或溶剂(对照实验)。将待测试的物质溶于二甲亚砜(DMSO)，然后将溶液用DMSO/水稀释，从而使待测试物质在测试溶液中的最终浓度c具有表中给定的数值。测试溶液中的DMSO浓度为5％(v/v)。通过加入sGC引发反应。将反应混合物在37℃保温15至20分钟，然后通过用冰冷却并加入终止试剂(50mM EDTA，pH8.0)停止反应。取出50μl等分试样并用Amersham cGMP-EIA试剂盒的乙酰化方案测定cGMP含量。在微滴度板读数器中测定样品在450nm(参考波长620nm)的吸收值。用在相同测试条件下获得的标准曲线确定cGMP浓度。试验物质对sGC的激活用在对照实验(用溶剂代替测试物质)中测得的基础酶活性的n倍刺激来表示(用公式n倍刺激＝[cGMP]试验物质/[cGMP]对照来计算)。
测得如下结果：
化合物               浓度          n-倍刺激
(实施例号)           [μm]
23                   50            14.7
59                   50            34.8
63                   50            33.9
64                   50            23.9
65                   50            24.6
66                   50            33
67                   50            29.6
68                   50            12.1
69                   50            28.3
70                   50            25.1
71                   50            13.4
72                   50            27
73                   50            16.5
75                   50            5.1
76                   50            10.6
77                   50            5.9
79                   50            15.4
84                   50            23.7
86                   50            32.9
87                   50            12.5
88                   50            24.4
89                   50            11.6
124                  50            31.2
129                  50            8.6
化合物              浓度           n-倍刺激
(实施例号)          [μm]
130                 50             35.3
132                 50             9.9
134                 50             7.2
136                 50             24.2
137                 50             4.6
139                 50             21.9
145                 50             8
146                 50             10.2
148                 50             15.5
150                 50             15.3
151                 50             19.9
155                 50             7.8
156                 50             7.8
157                 50             4.6
175                 50             21.1
176                 50             13.9
191                 10             27.5
192                 10             26.7
193                 10             31.1
194                 5              20.0
195                 10             16.2
196                 10             21.9
206                 50             19.3
208                 10             23.1
209                 10             28.5
222                 10             29.5
223                 10             27.1
224                 50             27.8
化合物             浓度          n-倍刺激
(实施例号)         [μm]
225                10            13.4
226                25            3.3
2)大鼠主动脉的松弛
为了进行该试验，将血压正常的雄性Wistar-Kyoto大鼠通过向颈部注射空气处死。通过中间胸骨切开术打开腹腔和胸腔。随后取出下行主动脉，除去结缔组织并分成8个长度约为4mm的环。将镊子的尖端插入其中4个环的腔内。通过小心地将环在镊子尖端旋转除去内皮。将所有8个主动脉环(4个有内皮，4个没有内皮)悬挂在37℃恒温的器官浴(Schuler-Organbad；Hugo Sachs Elektronik)中以测定等长收缩状况。将环在1g的静息张力下在碳酸化的(95％O2；5％CO2)pH7.4的Krebs-Henseleit溶液(组成：Na+144.0mM；K+5.9mM；Cl-126.9mM；Ca2+1.6mM；Mg2+1.2mM；H2PO4 -1.2mM；SO4 2-1.2mM；HCO3 -25.0mM；D-葡萄糖11.1mM)中校准30分钟。此外，还向Krebs-Henseleit溶液中加入1μmol/l的消炎痛以抑制前列腺素的生物合成。然后通过加入苯福林(在溶液中的浓度为1μM)使环预收缩，然后通过加入乙酰胆碱(在溶液中的浓度为1μM)测试内皮依赖性的松弛或内皮功能的丧失。经过30分钟的清洗期后，通过加入苯福林(1μM)使环再次预收缩，然后通过施用累积剂量的式I的试验物质来测定它的松弛作用。通过常规方法对数据进行评估。所给出的是抑制收缩达50％的浓度IC50(50％松弛)。
得到如下结果：
化合物                                      IC50
(实施例号)
59                无内皮的环                0.27μM
59                有内皮的环                0.52μM
88      无内皮的环    0.29μM
88      有内皮的环    0.67μM
129     无内皮的环    0.31μM
129     有内皮的环    0.46μM
3)对猪血液动力学的影响
将三只猪(德国当地品种)麻醉(氯胺酮20mg/kg i.m.，Methomidate 8mg/kg i.p.，赛拉嗪2.5mg/kg i.m.和戊巴比妥25mg/kg静脉内快速浓注，0.16mg/kg/分钟)。进行气管插管并用空气对动物进行人工呼吸。加入氧气以保持血气参数在正常范围内。为了通过Statham 23Db血压传感器记录血压(BP；BP(s)＝收缩压，BP(d)＝舒张压)，在右股动脉插入导管。用插入到右心室内的Millar PC 350导管“尖端测压计”测定左心室压(LVP)、左心室舒张末期压(LVEDP)、收缩力(dP/dt)和心率(HR)。经过30分钟的血液动力参数稳定期后，将试验物质用导管以指定的剂量加入到暴露的十二指肠内。通过常规方法对测得的数据进行评估。所给出的是起始值以及各参数最大变化(＝最大效应)的平均值和标准偏差(M±SEM)。
得到如下结果：
实施例88的化合物(剂量10mg/kg i.d.)
参数   起始值     最大改变 作用持续时间(分钟)
BP(s)(mm Hg)   123±26     -23±6 ＞180
BP(d)(mm Hg)   83±24     -20±8 ＞180
LVEDP(mm Hg)   4±0.6     -1.3±0.3 ＞180
dP/dtmax(mm Hg/秒))   1800±289     -633±33 ＞180
HR(次/分)   98±2     -8±2 ＞180

Claims (21)

1.式I化合物
Figure C998082950002C1
其中
A1是选自亚苯基二价基团或噻唑二价基团，它们均可以被一个或多个相同或不同的(C1-C5)烷基取代基所取代；
含有带有基团C(＝X)-NH-和NH-SO2R2的碳原子的环A2是苯环、饱和或部分不饱和的3-7元碳环、噻吩环、吡唑环或吡啶环；
R1是苯基、或(C1-C7)-烷基，其可以被一个或多个相同或不同的R4基团所取代，或者，如果基团R1-S(O)n-中的n是2，则R1还可以是NR5R6；
R2是芳基、或(C1-C10)-烷基，其可以被一个或多个相同或不同的R4基团所取代；
R3表示一个或多个相同或不同的选自氢、卤素、-O-(C1-C7)-烷基、和(C1-C5)-烷基的基团；
R4是氟、OH、-O-(C1-C10)-烷基、-O-(C2-C4)-烷基-O-(C1-C7)-烷基、-CN、NR7R8、-CO-O-(C1-C5)-烷基或吗啉基；
R5是氢、(C1-C10)-烷基，其可以被一个或多个相同或不同的取代基R4或被吲哚基或被吡啶基取代；
R6是氢或(C1-C10)烷基，或者R5和R6与它们所结合的氮原子合在一起形成5-8元饱和或部分不饱和的环，所述的环中除了带有基团R5和R6的氮原子外，还可以含有一个或两个选自N、O和S的其它环杂原子，并且该环可以被一个或多个相同或不同的取代基所取代，所述取代基选自(C1-C5)-烷基、羟基-(C1-C3)-烷基-、嘧啶、OH、-CO-NH2、氧代和被氯选择性取代的苯基；
R7是氢或(C1-C7)-烷基；
R8是氢或(C1-C7)-烷基；
所述芳基是苯基或杂芳基，它们均可以被一个或多个相同或不同的取代基所取代，所述取代基选自卤素、(C1-C5)-烷基、CF3、-O-CF3、NO2、OH、-O-(C1-C5)-烷基、-NH-CO-(C1-C5)-烷基、-CN、-S(O)n-(C1-C4)-烷基和-S(O)n-苯基；仅在这里n为2；
所述杂芳基是各自含有一个或多个选自N、O和S的环杂原子的5或6元单环芳香族杂环或10元二环芳香族杂环的基团；
n是0、1或2；
X是0，或者X是通过单键与基团A1中的环碳原子连接的氮原子，所述环碳原子紧邻A1中带有基团-NH-C(＝X)-的碳原子，从而基团-NH-C(＝X)-与A1中带有该基团的碳原子合在一起形成稠合的咪唑环；
其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
2.权利要求1所述的式I化合物，其中A1是亚苯基，其中，该基团可以是未取代的或取代的，其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
3.权利要求1或2所述的式I化合物，其中，含有带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2是苯环，其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
4.权利要求1或2所述的式I化合物，其中X是氧，其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
5.权利要求1或2所述的式I化合物，其中R2是未取代或取代的芳基，其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
6.权利要求1或2所述的式I化合物，其中R1是(C1-C7)-烷基或苯基，其中，这些基团可以是未取代或取代的，其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
7.权利要求1或2所述的式I化合物，其中R1是NR5R6，其中的R5和R6彼此独立地是氢或(C1-C9)-烷基，或者R5和R6与它们所结合的氮原子合在一起形成5至7元的杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另外一个选自N、O和S的环杂原子，并且所述环可以被一个或两个相同或不同的选自(C1-C3)-烷基、羟基-(C1-C3)-烷基-和苯基的取代基所取代，其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
8.权利要求1所述的式I化合物，其中
A1是亚苯基或噻唑二价基团，其中，这些基团可以是未取代的或被一个或多个相同或不同的选自(C1-C4)-烷基的取代基所取代；
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2是苯环；
R1是可以被一个或多个相同或不同的R4基团所取代的(C1-C7)-烷基或苯基，或者，如果基团R1-S(O)n-中的n是2，则R1还可以是NR5R6；
R2是芳基；
R3表示一个或多个相同或不同的选自氢、卤素、-O-(C1-C4)-烷基、(C1-C4)-烷基的基团；
R4是氟、OH、-O-(C1-C10)-烷基、-O-(C2-C4)-烷基-O-(C1-C7)-烷基、-CN、NR7R8、-CO-O-(C1-C4)-烷基或吗啉基；
R5和R6彼此独立地是氢或(C1-C9)-烷基，或者R5和R6与它们所结合的氮原子合在一起形成5-7元杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自N、O和S的环杂原子，并且该杂环可以被一个或两个相同或不同的选自(C1-C3)-烷基、羟基-(C1-C3)-烷基-、苯基的基团所取代；
R7是氢或(C1-C3)-烷基；
R8是氢或(C1-C3)-烷基；
其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
9.权利要求1或2所述的式I化合物，其中
A1是亚苯基，它可以是未取代的或被一个或多个相同或不同的选自(C1-C4)-烷基的取代基所取代；
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2是苯环；
R1是NR5R6；
R2是芳基；
R3表示一个或多个相同或不同的选自氢、卤素、-O-(C1-C4)-烷基、和(C1-C4)-烷基的基团；
R5和R6与它们所结合的氮原子合在一起形成5或6元的饱和杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自N、O和S的环杂原子，并且该杂环可以被一个或两个相同或不同的选自(C1-C3)-烷基、羟基-(C1-C3)-烷基-、苯基的基团所取代；
n是2；
X是0；
其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
10.权利要求1或2所述的式I化合物，其中
A1是未取代的二价亚苯基基团；
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2是苯环；
R1是NR5R6；
R2是芳基；
R3表示一个或多个相同或不同的选自氢、卤素、-O-(C1-C4)-烷基和(C1-C4)-烷基的基团；
R5和R6与它们所结合的氮原子合在一起形成饱和的6元杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自N、O和S的环杂原子，并且该杂环可以被一个或多个相同或不同的选自(C1-C3)-烷基、苯基的基团所取代；
n是2；
X是0；
其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
11.权利要求1或2所述的式I化合物，其中
A1是未取代的二价1，4-亚苯基基团；
含有两个带有基团R2-SO2-NH和C(＝X)-NH-的碳原子的环A2与基团R3合在一起是被一个或两个相同或不同的选自氯和甲氧基所取代的取代基的苯环；
R1是NR5R6；
R2是被一个或两个氯原子取代的苯基或噻吩基；
R5和R6与它们所结合的氮原子合在一起形成饱和的6元杂环，所述杂环除了带有基团R5和R6的氮原子外，还可以含有另一个选自O和S的环杂原子，并且该杂环是未取代的或被一个或两个甲基所取代；
n是2；
X是氧；
其所有的立体异构体形式及其各种比例的混合物，或它们的生理可接受的盐。
12.权利要求1或2所述的式I化合物，其中所述的盐为钠盐。
13.根据权利要求1所述的式I化合物，其为2-(4-氯-苯基磺酰基氨基)-4，5-二甲氧基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺或其生理可接受的盐。
14.根据权利要求1所述的式I化合物，其为2-(4-氯-苯基磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-4，5-二甲氧基-苯甲酰胺或其生理可接受的盐。
15.根据权利要求1所述的式I化合物，其为5-氯-2-(5-氯-噻吩-2-磺酰基氨基)-N-(4-(吗啉-4-磺酰基)-苯基)-苯甲酰胺或其生理可接受的盐。
16.根据权利要求1所述的式I化合物，其为5-氯-2-(3，5-二甲基-异唑-4-磺酰基氨基)-N-(4-(顺-2，6-二甲基-吗啉-4-磺酰基)-苯基)-苯甲酰胺或其生理可接受的盐。
17.权利要求1-16中的任一项所述的式I化合物的制备方法，该方法包括，将式II的环状氨基羧酸化合物转变成式III的磺酰基氨基羧酸化合物，然后将式III化合物转变成式I化合物，
或者，将式IX的环状硝基羧酸化合物转变成式XII的硝基甲酰胺化合物，然后通过将硝基还原成氨基并将氨基磺酰化将式XII化合物转变成式I化合物，
其中，在式I、II、III、IX和XII的化合物中，基团A1、A2、R1、R2、R3、X和n具有权利要求1至11所给出的含义，或者，其中的基团或功能基还可以以被保护的形式或前体基团的形式存在。
18.药物制剂，其含有一种或多种权利要求1-16中任一项所述的式I化合物和/或其生理可接受的盐以及可药用的载体。
19.权利要求1-16中任一项所述的式I化合物和/或其生理可接受的盐用于制备用作可溶性鸟苷酸环化酶的激活剂的药物的用途。
20.权利要求1-16中任一项所述的式I化合物和/或其生理可接受的盐用于制备药物的用途，所述药物用于治疗或预防心血管疾病、勃起功能障碍、支气管哮喘、慢性肾机能不全、糖尿病或肝硬化，或用于改善有限的记忆行为或学习能力。
21.权利要求20的用途，其中所述心血管疾病包括内皮功能障碍、心脏舒张功能障碍、动脉粥样硬化、高血压、心绞痛、血栓形成、再狭窄、心肌梗塞、中风、心功能不全和肺压力过高。
CNB998082953A 1998-07-08 1999-06-25 硫取代的磺酰基氨基羧酸n－芳基酰胺,其制备方法、用途以及含有该化合物的药物制剂 Expired - Fee Related CN1332943C (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19830430A DE19830430A1 (de) 1998-07-08 1998-07-08 Schwefelsubstituierte Sulfonylamino-carbonsäure-N-arylamide, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate
DE19903126A DE19903126A1 (de) 1999-01-27 1999-01-27 Schwefelsubstituierte Sulfonylamino-carbonsäure-N-arylamide, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate
DE19830430.7 1999-01-27
DE19903126.6 1999-01-27

Publications (2)

Publication Number Publication Date
CN1308606A CN1308606A (zh) 2001-08-15
CN1332943C true CN1332943C (zh) 2007-08-22

Family

ID=26047263

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB998082953A Expired - Fee Related CN1332943C (zh) 1998-07-08 1999-06-25 硫取代的磺酰基氨基羧酸n－芳基酰胺,其制备方法、用途以及含有该化合物的药物制剂

Country Status (24)

Country Link
US (5) US6335334B1 (zh)
EP (2) EP1095016B1 (zh)
JP (2) JP3786579B2 (zh)
KR (1) KR100720844B1 (zh)
CN (1) CN1332943C (zh)
AR (1) AR035306A1 (zh)
AT (1) ATE309206T1 (zh)
AU (1) AU761983B2 (zh)
BR (1) BR9911914B1 (zh)
CA (1) CA2336807C (zh)
CL (1) CL2004000031A1 (zh)
CZ (1) CZ302691B6 (zh)
DE (1) DE69928260T2 (zh)
DK (1) DK1095016T3 (zh)
ES (1) ES2251200T3 (zh)
HK (1) HK1038346A1 (zh)
HU (1) HU228111B1 (zh)
ID (1) ID26773A (zh)
MY (1) MY134696A (zh)
NO (1) NO327755B1 (zh)
PL (1) PL199236B1 (zh)
TR (1) TR200100147T2 (zh)
TW (1) TWI234558B (zh)
WO (1) WO2000002851A1 (zh)

Families Citing this family (118)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1332943C (zh) 1998-07-08 2007-08-22 萨诺费－阿文蒂斯德国有限公司 硫取代的磺酰基氨基羧酸n－芳基酰胺,其制备方法、用途以及含有该化合物的药物制剂
DE19830431A1 (de) 1998-07-08 2000-01-13 Hoechst Marion Roussel De Gmbh Sulfonylamino-carbonsäure-N-arylamide als Guanylatcyclase-Aktivatoren
GB9824579D0 (en) * 1998-11-10 1999-01-06 Novartis Ag Organic compounds
DE19944226A1 (de) 1999-09-15 2001-03-29 Aventis Pharma Gmbh Verfahren zum Nachweis von oxidierten Formen der löslichen Guanylatzyklase und Verfahren zum Screening nach Aktivatoren der löslichen Guanylatzyklase mit oxidiertem Hämeisen
KR100733752B1 (ko) * 1999-11-26 2007-06-29 시오노기세이야쿠가부시키가이샤 Ｎｐｙｙ５ 길항제
SE0001899D0 (sv) 2000-05-22 2000-05-22 Pharmacia & Upjohn Ab New compounds
GB2365426A (en) * 2000-08-01 2002-02-20 Pantherix Ltd Bactericidal benzamide derivatives
WO2002017897A2 (en) 2000-08-30 2002-03-07 Primecyte, Inc. Methods for treating tumors using sulfonyl compounds
EP1193267A1 (en) * 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active hydrophilic sulfonamide derivatives as inhibitors of protein JunKinases
EP1193268A1 (en) * 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active sulfonamide derivatives bearing both lipophilic and ionisable moieties as inhibitors of protein Junkinases
EP1193256A1 (en) * 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active benzsulfonamide derivatives as inhibitors of JNK proteins
AU2002213048A1 (en) * 2000-10-05 2002-04-15 Smith Kline Beecham Corporation Phosphate transport inhibitors
US6878714B2 (en) 2001-01-12 2005-04-12 Amgen Inc. Substituted alkylamine derivatives and methods of use
US6995162B2 (en) * 2001-01-12 2006-02-07 Amgen Inc. Substituted alkylamine derivatives and methods of use
US7102009B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted amine derivatives and methods of use
US7105682B2 (en) 2001-01-12 2006-09-12 Amgen Inc. Substituted amine derivatives and methods of use
US20030134836A1 (en) 2001-01-12 2003-07-17 Amgen Inc. Substituted arylamine derivatives and methods of use
DE10128331A1 (de) 2001-06-12 2002-12-19 Aventis Pharma Gmbh Anthranilsäureamide mit Heteroarylsulfonyl-Seitenkette, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltende pharmazeutische Zubereitungen
SE0102616D0 (sv) * 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
GB2378179A (en) * 2001-08-03 2003-02-05 Pantherix Ltd Aromatic sulfonamides and their use in treating bacterial diseases
ES2315430T3 (es) * 2001-10-04 2009-04-01 Smithkline Beecham Corporation Inhibidores de nf-kb.
CN1633428A (zh) * 2001-11-22 2005-06-29 比奥维特罗姆股份公司 11－β－羟基类固醇脱氢酶1型抑制剂
RS44304A (en) 2001-11-22 2007-06-04 Biovitrum Ab., Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
EA200400709A1 (ru) * 2001-11-22 2004-12-30 Биовитрум Аб Ингибиторы 11-бета-гидроксистероиддегидрогеназы типа 1
EP1532133A4 (en) * 2002-06-06 2006-11-15 Smithkline Beecham Corp NF-: B INHIBITORS
US7307088B2 (en) 2002-07-09 2007-12-11 Amgen Inc. Substituted anthranilic amide derivatives and methods of use
US20040157836A1 (en) * 2002-10-08 2004-08-12 Comess Kenneth M. Sulfonamides having antiangiogenic and anticancer activity
US7491718B2 (en) * 2002-10-08 2009-02-17 Abbott Laboratories Sulfonamides having antiangiogenic and anticancer activity
US20040068012A1 (en) * 2002-10-08 2004-04-08 Comess Kenneth M. Sulfonamides having antiangiogenic and anticancer activity
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7279576B2 (en) 2002-12-31 2007-10-09 Deciphera Pharmaceuticals, Llc Anti-cancer medicaments
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
SE0300092D0 (sv) * 2003-01-15 2003-01-15 Astrazeneca Ab Novel compounds
SE0300091D0 (sv) * 2003-01-15 2003-01-15 Astrazeneca Ab Novel compounds
US7288538B2 (en) * 2003-02-20 2007-10-30 Encysive Pharmaceuticals, Inc. Phenylenediamine urotensin-II receptor antagonists and CCR-9 antagonists
EP1610753A4 (en) * 2003-02-20 2007-07-04 Encysive Pharmaceuticals Inc UROTENSIN-II RECEPTOR ANTAGONISTS OF PHENYLENEDIAMINE AND ANTAGONISTS OF CCR-9
GB0318094D0 (en) * 2003-08-01 2003-09-03 Pfizer Ltd Novel combination
EP1663193B1 (en) * 2003-09-12 2012-04-04 Merck Serono SA Sulfonamide derivatives for the treatment of diabetes
GB0325291D0 (en) * 2003-10-29 2003-12-03 Pfizer Ltd Novel combination
DE102004009931A1 (de) * 2004-02-26 2005-09-15 Aventis Pharma Deutschland Gmbh Kv1.5-Blocker zur selektiven Steigerung der Vorhofkontraktilität und Behandlung der Herzinsuffizienz
US7262318B2 (en) * 2004-03-10 2007-08-28 Pfizer, Inc. Substituted heteroaryl- and phenylsulfamoyl compounds
NZ552284A (en) 2004-05-24 2010-01-29 Amgen Inc Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
DE102004047272A1 (de) * 2004-09-24 2006-04-06 Schering Ag Inhibitoren der löslichen Adenylatzyklase
EA200700555A1 (ru) * 2004-09-24 2007-10-26 Байер Шеринг Фарма Акциенгезельшафт Производные индола в качестве ингибиторов растворимой аденилатциклазы
DE102005000666B3 (de) * 2005-01-04 2006-10-05 Sanofi-Aventis Deutschland Gmbh Sulfonylpyrrolidine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DE102005031576A1 (de) * 2005-07-06 2007-01-25 Bayer Healthcare Ag Verwendung von Aktivatoren der löslichen Guanylatzyklase zur Behandlung von Reperfusionsschäden
DE102005047945A1 (de) * 2005-07-16 2007-01-18 Bayer Healthcare Ag Verwendung von Aktivatoren der löslichen Guanylatzyklase zur Behandlung von Raynaud Phänomenen
US20100016305A1 (en) * 2005-07-18 2010-01-21 Bayer Healthcare Ag novel use of activators and stimulators of soluble guanylate cyclase for the prevention or treatment of renal disorders
US8247556B2 (en) 2005-10-21 2012-08-21 Amgen Inc. Method for preparing 6-substituted-7-aza-indoles
AU2006316867A1 (en) 2005-11-22 2007-05-31 Amgen Inc. Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1
GB0526252D0 (en) * 2005-12-22 2006-02-01 Novartis Ag Organic compounds
US20070225284A1 (en) * 2006-03-23 2007-09-27 Bernd Buchmann Inhibitors of soluble adenylate cyclase
US9284278B2 (en) * 2007-02-14 2016-03-15 Basf Se Electroluminescent metal complex
DE102007026392A1 (de) 2007-06-06 2008-12-11 Bayer Healthcare Ag Lösungen für die Perfusion und Konservierung von Organen und Geweben
BRPI0815057B8 (pt) 2007-08-03 2021-05-25 Romark Laboratories Lc composto, composição farmacêutica, e, uso de um composto
ATE505454T1 (de) * 2007-09-20 2011-04-15 Amgen Inc 1-(4-(4-benzylbenzamid)-benzyl)-azetidin-3- carboxylsäurederivate und entsprechende verbindungen als s1p-rezeptor-modulatoren zur behandlung von immunerkrankungen
BRPI0817483A2 (pt) 2007-10-05 2016-07-26 Sanofi Aventis Deutschland uso de n-fenilamidas de ácido 2-sulfonilaminobenzoico substituídas por sulfonila no tratamento da dor
CA2720343A1 (en) 2008-04-04 2009-10-08 Takeda Pharmaceutical Company Limited Heterocyclic derivative and use thereof
CN102164987B (zh) * 2008-08-22 2015-07-08 诺沃梅尔公司 用于合成聚合物的催化剂和方法
MX2011007515A (es) * 2009-01-17 2011-08-12 Bayer Schering Pharma Ag Estimuladores de la sgc o activadores de la sgc en combinacion con inhibidores de la pde5 para el tratamiento de la disfuncion erectil.
PE20121118A1 (es) 2009-05-12 2012-09-05 Romark Lab Lc Compuestos de haloalquil heteroaril benzamida
EP2445349B1 (en) 2009-06-26 2022-02-09 Romark Laboratories, L.C. Compounds and methods for treating influenza
RS54336B1 (en) * 2010-02-05 2016-02-29 Adverio Pharma Gmbh SGC STIMULATORS OR SGC ACTIVATORS, ONLY FOR YOURSELF AND COMBINED WITH PDE5 INHIBITORS FOR CYST FIBROSIS TREATMENT
US20130178475A1 (en) 2010-03-17 2013-07-11 Ironwood Pharmaceuticals, Inc. sGC STIMULATORS
ES2549979T3 (es) 2010-05-26 2015-11-03 Adverio Pharma Gmbh El uso de estimuladores de la sGC, activadores de la sGC, solos y en combinaciones con inhibidores de la PDE5 para el tratamiento de esclerosis sistémica (EcS)
EP2585055A1 (de) 2010-06-25 2013-05-01 Bayer Intellectual Property GmbH Verwendung von stimulatoren und aktivatoren der löslichen guanylatzyklase zur behandlung von sichelzellanämie und konservierung von blutersatzstoffen
JP5860459B2 (ja) 2010-06-30 2016-02-16 アイアンウッド ファーマシューティカルズ インコーポレイテッド ｓＧＣ刺激薬
CN103402515B (zh) 2010-11-09 2017-05-17 铁木医药有限公司 sGC刺激剂
WO2013101830A1 (en) 2011-12-27 2013-07-04 Ironwood Pharmaceuticals, Inc. 2 - benzyl, 3 - (pyrimidin- 2 -yl) substituted pyrazoles useful as sgc stimulators
KR101475056B1 (ko) 2012-06-29 2014-12-22 동국대학교 산학협력단 설폰아미드계 화합물을 유효성분으로 포함하는 ｃ형 간염의 예방 또는 치료용 약학적 조성물
WO2014047111A1 (en) 2012-09-18 2014-03-27 Ironwood Pharmaceuticals, Inc. Sgc stimulators
EP2897953B8 (en) 2012-09-19 2019-06-26 Cyclerion Therapeutics, Inc. Sgc stimulators
ES2882258T3 (es) * 2012-12-21 2021-12-01 Mayo Found Medical Education & Res Métodos y materiales para tratar estenosis de la válvula aórtica calcificada
RS59981B1 (sr) 2013-03-15 2020-03-31 Cyclerion Therapeutics Inc Sgc stimulatori
US10265314B2 (en) 2013-07-25 2019-04-23 Bayer Pharma Aktiengesellschaft SGC stimulators in combination with additional treatment for the therapy of cystic fibrosis
JP2016540017A (ja) 2013-12-11 2016-12-22 アイアンウッド ファーマシューティカルズ インコーポレイテッド ｓＧＣ刺激物質
EP3094327A1 (en) 2014-01-13 2016-11-23 Ironwood Pharmaceuticals, Inc. USE OF sGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS
TW201625586A (zh) 2014-07-02 2016-07-16 諾華公司 環己烯－１－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
TW201625584A (zh) 2014-07-02 2016-07-16 諾華公司 茚滿及吲哚啉衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
TW201625601A (zh) 2014-07-02 2016-07-16 諾華公司 噻吩－２－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
EP2990403A1 (en) 2014-08-29 2016-03-02 Novartis Tiergesundheit AG Anthranilamides, sulfonamides and nitro analogues derived therefrom as anthelmintics
CN107406421A (zh) 2014-09-17 2017-11-28 铁木医药有限公司 sGC刺激物
AU2015317824A1 (en) 2014-09-17 2017-03-23 Cyclerion Therapeutics, Inc. Pyrazole derivatives as sGC stimulators
WO2016044445A2 (en) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. sGC STIMULATORS
TN2017000465A1 (en) 2015-05-06 2019-04-12 Bayer Pharma AG The use of sgc stimulators, sgc activators, alone and combinations with pde5 inhibitors for the treatment of digital ulcers (du) concomitant to systemic sclerosis (ssc)
HRP20201932T4 (hr) 2015-07-23 2024-02-16 Bayer Pharma Aktiengesellschaft Stimulatori / aktivatori topive gvanilat-ciklaze u kombinaciji s nep-inhibitorom i/ili angiotenzin aii-antagonistom i njihova uporaba
CN105111118B (zh) * 2015-08-14 2017-04-12 天津小新医药科技有限公司 L‑薄荷醇类p2y12受体拮抗剂、制备方法及其用途
CN105111119B (zh) * 2015-08-14 2017-04-12 天津小新医药科技有限公司 一类卤代苯l‑薄荷醇类p2y12受体拮抗剂及其用途
CN105085345B (zh) * 2015-08-14 2016-09-14 天津小新医药科技有限公司 含硝基的l-薄荷醇类p2y12受体拮抗剂及其用途
CN105152996B (zh) * 2015-08-14 2017-04-12 天津小新医药科技有限公司 一类l‑薄荷醇类p2y12受体拮抗剂及其用途
CN105085346B (zh) * 2015-08-14 2017-03-29 天津小新医药科技有限公司 含胺基的l-薄荷醇类p2y12受体拮抗剂及其用途
AU2016371762A1 (en) 2015-12-14 2018-06-21 Cyclerion Therapeutics, Inc. Use of sGC stimulators for the treatment of gastrointestinal sphincter dysfunction
KR20230074840A (ko) 2016-07-07 2023-05-31 사이클리온 테라퓨틱스, 인크. sGC 자극제의 고체 형태
AU2017291826B2 (en) 2016-07-07 2021-10-21 Cyclerion Therapeutics, Inc. Phosphorus prodrugs of sGC stimulators
KR20230124760A (ko) 2016-09-02 2023-08-25 사이클리온 테라퓨틱스, 인크. 융합된 비시클릭 sGC 자극제
US11331308B2 (en) 2016-10-11 2022-05-17 Bayer Pharma Aktiengesellschaft Combination containing sGC activators and mineralocorticoid receptor antagonists
AU2017356887B2 (en) 2016-11-08 2022-06-30 Cyclerion Therapeutics, Inc. sGC stimulators
EP3538096B1 (en) 2016-11-08 2024-02-28 Tisento Therapeutics Inc. Treatment of cns diseases with sgc stimulators
US20190381039A1 (en) 2016-12-13 2019-12-19 Cyclerion Therapeutics, Inc. USE OF sGC STIMULATORS FOR THE TREATMENT OF ESOPHAGEAL MOTILITY DISORDERS
WO2018153899A1 (de) 2017-02-22 2018-08-30 Bayer Pharma Aktiengesellschaft Selektive partielle adenosin a1 rezeptor-agonisten in kombination mit stimulatoren und/oder aktivatoren der löslichen guanylatcyclase (sgc)
WO2019081456A1 (en) 2017-10-24 2019-05-02 Bayer Aktiengesellschaft USE OF SGC ACTIVATORS AND STIMULATORS COMPRISING A BETA2 SUBUNIT
EP3498298A1 (en) 2017-12-15 2019-06-19 Bayer AG The use of sgc stimulators and sgc activators alone or in combination with pde5 inhibitors for the treatment of bone disorders including osteogenesis imperfecta (oi)
CN111712247B (zh) 2017-12-19 2024-02-09 塞科里昂医疗股份有限公司 sGC刺激剂
MX2023004858A (es) 2018-03-07 2023-11-24 Cyclerion Therapeutics Inc Formas cristalinas de un estimulante de la guanilil ciclasa soluble (sgc).
WO2019211081A1 (en) 2018-04-30 2019-11-07 Bayer Aktiengesellschaft The use of sgc activators and sgc stimulators for the treatment of cognitive impairment
CA3100096A1 (en) 2018-05-15 2019-11-21 Bayer Aktiengesellschaft 1,3-thiazol-2-yl substituted benzamides for the treatment of diseases associated with nerve fiber sensitization
US11508483B2 (en) 2018-05-30 2022-11-22 Adverio Pharma Gmbh Method of identifying a subgroup of patients suffering from dcSSc which benefits from a treatment with sGC stimulators and sGC activators in a higher degree than a control group
BR112021000358A2 (pt) 2018-07-11 2021-04-06 Cyclerion Therapeutics, Inc. Uso de estimulantes de sgc para o tratamento de distúrbios mitocondriais
CN113330030A (zh) 2019-01-17 2021-08-31 拜耳公司 确定受试者是否适于用可溶性鸟苷酸环化酶(sGC)的激动剂治疗的方法
WO2021195403A1 (en) 2020-03-26 2021-09-30 Cyclerion Therapeutics, Inc. Deuterated sgc stimulators
US20230128032A1 (en) 2020-03-31 2023-04-27 Curtails Llc Early Drug Interventions to Reduce COVID-19 Related Respiratory Distress, Need for Respirator Assist and Death
US20240207265A1 (en) 2021-04-20 2024-06-27 Tisento Therapeutics Inc. TREATMENT OF CNS DISEASES WITH sGC STIMULATORS
WO2022225903A1 (en) 2021-04-20 2022-10-27 Cyclerion Therapeutics, Inc. Sgc stimulators
US20240342187A1 (en) 2021-06-14 2024-10-17 Curtails Llc Use of nep inhibitors for the treatment of gastrointestinal sphincter disorders
WO2023018795A1 (en) 2021-08-11 2023-02-16 Curtails Llc Nep inhibitors for the treatment of laminitis
WO2023237577A1 (en) 2022-06-09 2023-12-14 Bayer Aktiengesellschaft Soluble guanylate cyclase activators for use in the treatment of heart failure with preserved ejection fraction in women
WO2024086179A1 (en) 2022-10-18 2024-04-25 Tisento Therapeutics, Inc. Pyrimidine sgc stimulators
WO2024086182A1 (en) 2022-10-18 2024-04-25 Tisento Therapeutics Inc. Treatment of mitochondrial diseases with sgc stimulators

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0908456A1 (de) * 1997-10-06 1999-04-14 Hoechst Marion Roussel Deutschland GmbH Pyrazol-Derivate, ihre Herstellung und ihre Verwendung in Arzneimitteln

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB876526A (en) * 1957-12-24 1961-09-06 Geigy Ag J R Process for the production of new aminobenzoic acid derivatives and their use in pest control
US3737316A (en) * 1971-08-31 1973-06-05 Eastman Kodak Co Two-equivalent sulfonamido couplers
FR2201083A1 (en) * 1972-09-28 1974-04-26 Ferlux 6-Phenyl pyrimidine-4-carboxylic acids - analgesics, vasodilators, cardiac stimulants and respiratory analeptics
JPH01206338A (ja) 1988-02-15 1989-08-18 Konica Corp ハロゲン化銀カラー写真感光材料
JPH04285955A (ja) 1991-03-14 1992-10-12 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料
JP2673061B2 (ja) 1991-07-23 1997-11-05 富士写真フイルム株式会社 ハロゲン化銀カラー写真感光材料
US6048897A (en) * 1993-06-15 2000-04-11 Brigham And Women's Hospital Lipoxin compounds and their use in treating cell proliferative disorders
JPH0756293A (ja) 1993-08-18 1995-03-03 Fuji Photo Film Co Ltd ハロゲン化銀写真感光材料
US6176874B1 (en) 1993-10-18 2001-01-23 Masschusetts Institute Of Technology Vascularized tissue regeneration matrices formed by solid free form fabrication techniques
JP3233642B2 (ja) 1995-04-04 2001-11-26 テキサス・バイオテクノロジー・コーポレイシヨン エンドセリンの活性を調整するチエニル−、フリル−、ピロリル−およびビフェニルスルホンアミドならびにその誘導体
JPH0943786A (ja) 1995-07-28 1997-02-14 Fuji Photo Film Co Ltd ハロゲン化銀カラー写真感光材料
IT1285454B1 (it) 1996-01-25 1998-06-08 Mario Ciucani Macchina perfezionata per la cucitura di articoli vari, in particolare articoli di pelle e similari
DE19705133A1 (de) 1997-02-11 1998-08-13 Hoechst Ag Sulfonamid-substituierte Verbindungen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
US6432994B1 (en) * 1997-04-28 2002-08-13 Texas Biotechnology Corporation Sulfonamides for treatment of endothelin-mediated disorders
US5783705A (en) * 1997-04-28 1998-07-21 Texas Biotechnology Corporation Process of preparing alkali metal salys of hydrophobic sulfonamides
DE19744027A1 (de) 1997-10-06 1999-04-08 Hoechst Marion Roussel De Gmbh Substituierte Pyrazolo[3,4-b]pyridine, ihre Herstellung und Verwendung in Arzneimitteln
DE19749453A1 (de) 1997-11-10 1999-05-12 Hoechst Marion Roussel De Gmbh Sulfonamid-substituierte anellierte 5-Ring-Verbindungen, ihre Verwendung als Medikament sowie sie enthaltende pharmazeutische Zubereitungen
DE19830431A1 (de) 1998-07-08 2000-01-13 Hoechst Marion Roussel De Gmbh Sulfonylamino-carbonsäure-N-arylamide als Guanylatcyclase-Aktivatoren
CN1332943C (zh) 1998-07-08 2007-08-22 萨诺费－阿文蒂斯德国有限公司 硫取代的磺酰基氨基羧酸n－芳基酰胺,其制备方法、用途以及含有该化合物的药物制剂
DE19834629A1 (de) * 1998-07-31 1998-12-03 Novartis Ag Herbizides Mittel
CA2341678C (en) * 1998-09-01 2009-10-13 Bristol-Myers Squibb Company Potassium channel inhibitors and method

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0908456A1 (de) * 1997-10-06 1999-04-14 Hoechst Marion Roussel Deutschland GmbH Pyrazol-Derivate, ihre Herstellung und ihre Verwendung in Arzneimitteln

Also Published As

Publication number Publication date
NO20010013L (no) 2001-03-01
AU4616099A (en) 2000-02-01
CA2336807C (en) 2010-04-13
US8106213B2 (en) 2012-01-31
CL2004000031A1 (es) 2005-04-22
US6335334B1 (en) 2002-01-01
AR035306A1 (es) 2004-05-12
DE69928260T2 (de) 2006-07-20
ID26773A (id) 2001-02-08
EP1614678A2 (en) 2006-01-11
PL199236B1 (pl) 2008-08-29
US20040186145A1 (en) 2004-09-23
US20080096936A1 (en) 2008-04-24
NO327755B1 (no) 2009-09-14
US7326789B2 (en) 2008-02-05
KR20010083091A (ko) 2001-08-31
BR9911914A (pt) 2001-03-27
DK1095016T3 (da) 2006-03-13
US20120108573A1 (en) 2012-05-03
US20020061887A1 (en) 2002-05-23
EP1095016A1 (en) 2001-05-02
TWI234558B (en) 2005-06-21
HU228111B1 (en) 2012-11-28
HUP0104905A2 (en) 2002-06-29
EP1614678A3 (en) 2006-03-22
CA2336807A1 (en) 2000-01-20
EP1095016B1 (en) 2005-11-09
WO2000002851A1 (en) 2000-01-20
CZ302691B6 (cs) 2011-09-07
CZ200151A3 (en) 2001-05-16
KR100720844B1 (ko) 2007-05-25
MY134696A (en) 2007-12-31
NO20010013D0 (no) 2001-01-02
PL345539A1 (en) 2001-12-17
JP3786579B2 (ja) 2006-06-14
CN1308606A (zh) 2001-08-15
US6881735B2 (en) 2005-04-19
HUP0104905A3 (en) 2005-04-28
BR9911914B1 (pt) 2010-10-19
JP4422670B2 (ja) 2010-02-24
TR200100147T2 (tr) 2001-05-21
DE69928260D1 (de) 2005-12-15
HK1038346A1 (en) 2002-03-15
ATE309206T1 (de) 2005-11-15
JP2006143737A (ja) 2006-06-08
EP1614678B1 (en) 2014-01-01
US8541410B2 (en) 2013-09-24
JP2002520309A (ja) 2002-07-09
ES2251200T3 (es) 2006-04-16
AU761983B2 (en) 2003-06-12

Similar Documents

Publication Publication Date Title
CN1332943C (zh) 硫取代的磺酰基氨基羧酸n－芳基酰胺,其制备方法、用途以及含有该化合物的药物制剂
RU2234497C2 (ru) Серозамещенные n-ариламиды сульфониламинокарбоновой кислоты, способ их получения (варианты), фармацевтическая композиция и способ лечения
AU2015226855C1 (en) Human plasma kallikrein inhibitors
CN1326519C (zh) 化合物及其降低激素－敏感性脂肪酶活性的用途
ES2326897T3 (es) Derivados de 3-aminoindazoles y su empleo para el tratamiento de enfermedades asociadas con cinasa dependiente del suero humano y del glucocorticoide (sgk).
TWI404715B (zh) 二芳基醚脲化合物
CN1906155B (zh) 异羟肟酸酯衍生物及其医药用途
AU760988B2 (en) Substituted 4-amino-2-aryl-pyrimidines, their production and use and pharmaceutical preparations containing same
TW201350479A (zh) Ｔｒｋ阻害化合物
MX2007016319A (es) Derivados de n-(piridin-2-il)-sulfonamida.
TW200944511A (en) Substituted 4-hydroxypyrimidine-5-carboxamides
JP2009514837A (ja) グルコキナーゼ調節物質としてのトリシクロ置換アミド
CZ2004627A3 (cs) Dibenzylaminové sloučeniny a jejich farmaceutické použití
TW200815412A (en) A pharmaceutical combination comprising 3-or 4-monosubstituted phenol and thiophenol derivatives
CN101448397A (zh) 选择性的苄胺衍生物和其作为胆固醇酯转运蛋白抑制剂的应用
TWI328005B (en) Heterocyclic methylsulfon derivatives
TW200526627A (en) New compounds
JP4422335B2 (ja) グアニル酸シクラーゼ活性化剤としてのスルホニルアミノカルボン酸ｎ−アリールアミド
DE60001414T2 (de) Pyrazinone thrombin hemmungsmittel
TW202140444A (zh) Ｐｈｄ抑制劑化合物、組成物及使用方法
TW202140442A (zh) Ｐｈｄ抑制劑化合物、組成物及使用方法
JP2001519826A (ja) 金属プロテイナーゼ阻害剤
CN101208299A (zh) 二芳基砜磺酰胺和其用途
TW201206918A (en) Chemical compounds
MXPA00012966A (es) N-arilamidas de acido sulfonilaminocarboxilico con sustitucion de azufre, su preparacion, su uso y preparaciones farmaceuticas que las contienen

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20070822

Termination date: 20170625