DE2462752C2 - - Google Patents

Info

Publication number
DE2462752C2
DE2462752C2 DE2462752A DE2462752A DE2462752C2 DE 2462752 C2 DE2462752 C2 DE 2462752C2 DE 2462752 A DE2462752 A DE 2462752A DE 2462752 A DE2462752 A DE 2462752A DE 2462752 C2 DE2462752 C2 DE 2462752C2
Authority
DE
Germany
Prior art keywords
general formula
carbon atoms
hydrogen
compounds
acid derivatives
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 - Lifetime
Application number
DE2462752A
Other languages
German (de)
Inventor
Dieter Dr. 6233 Kelkheim De Bormann
Wulf Dr. 6232 Neuenhain De Merkel
Roman Dr. 6230 Frankfurt De Muschaweck
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.)
Hoechst AG
Original Assignee
Hoechst AG
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
Application filed by Hoechst AG filed Critical Hoechst AG
Priority to DE2462752A priority Critical patent/DE2462752C2/de
Priority claimed from DE2419970A external-priority patent/DE2419970C3/en
Application granted granted Critical
Publication of DE2462752C2 publication Critical patent/DE2462752C2/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two 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
    • C07D207/325—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 two 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 with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • C07D207/06—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 radicals, containing only hydrogen and carbon atoms, 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
    • C07D207/02—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
    • 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
    • C07D207/02—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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two 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
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • 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
    • C07D207/44—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 three double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D207/44—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 three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—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 three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—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 three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—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 three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by 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
    • 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
    • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—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 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 directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • 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
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C07D265/33—Two oxygen atoms, in positions 3 and 5
    • 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
    • C07D295/04—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 substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Die Erfindung betrifft den Gegenstand der Ansprüche.The invention relates to the subject matter of the claims.

Bei dem erfindungsgemäßen Verfahren nach a. ist es überraschend, daß es gelingt, Sulfamoylbenzoesäurederivate der allgemeinen Formel II durch Borwasserstoffe oder komplexe Borhydride in Gegenwart von Lewis-Säuren zu reduzieren, ohne daß die anderen Gruppen im Molekül geändert werden. Bei dieser Verfahrensweise werden die Endprodukte in ausgezeichneten Ausbeuten erhalten.In the method according to a. is it Surprisingly, it is possible to use sulfamoylbenzoic acid derivatives of the general formula II by hydrocarbons or complex borohydrides in the presence of Lewis acids reduce without the other groups in the molecule be changed. With this procedure, the End products obtained in excellent yields.

Die erfindungsgemäß eingesetzten Sulfamoylbenzoesäurederivate der allgemeinen Formel II sind nach verschiedenen Verfahren zugänglich. Beispielsweise erhält man die 3-Imido-5-sulfamoyl-benzoesäurederivate der allgemeinen Formel II (Z = O) aus den literaturbekannten 3-Amino-5-sulfamoylbenzoesäurederivaten der allgemeinen Formel VII, in der die Reste R¹ bis R³ und X die angegebenen Bedeutungen haben, indem man diese Aminoverbindungen mit zur Imidbildung befähigten Dicarbonsäurederivaten der allgemeinen Formel VIII, in der A die angegebene Bedeutung hat, Z für O steht und L eine abspaltbare Gruppe, vorzugsweise ein Halogen, eine Trialkylammoniumgruppe oder den Rest OR′ eines aktivierten Esters bedeutet, umsetzt. Für diese Acylierungsreaktion sind Hydroxy-, Amino- und/oder Mercaptogruppen in anderen Stellungen des Moleküls durch übliche Schutzgruppen zu blockieren. The used according to the invention Sulfamoylbenzoic acid derivatives of the general formula II are accessible by various methods. For example the 3-imido-5-sulfamoyl-benzoic acid derivatives are obtained general formula II (Z = O) from the literature 3-Amino-5-sulfamoylbenzoic acid derivatives of the general Formula VII, in which the radicals R¹ to R³ and X are the have the meanings given by this Amino compounds capable of imide formation Dicarboxylic acid derivatives of the general formula VIII, in which A has the meaning given, Z stands for O and L one cleavable group, preferably a halogen, a Trialkylammoniumgruppe or the rest OR 'of an activated Esters means implements. For this acylation reaction are hydroxy, amino and / or mercapto groups in others Positions of the molecule through usual protective groups To block.  

Dicarbonsäuren, die sich in ihre Dicarbonsäurehalogenide überführen lassen, sind beispielsweise Bernsteinsäure, Methylbernsteinsäure, 2,3-Dimethylbernsteinsäure oder Brombernsteinsäure. Die Umsetzung dieser Dicarbonsäurederivate mit den Aminoverbindungen der allgemeinen Formel VII erfolgt unter den Bedingungen der bekannten Schotten-Raumann-Reaktion.Dicarboxylic acids, which can be found in their dicarboxylic acid halides are transferred, for example, succinic acid, Methyl succinic acid, 2,3-dimethyl succinic acid or Bromosuccinic acid. Implementation of this Dicarboxylic acid derivatives with the amino compounds of general formula VII takes place under the conditions of well-known Schotten-Raumann reaction.

Es lassen sich auch die Anhydride dieser Dicarbonsäuren einsetzen. Die in vielen Fällen sich primär bildenden Carbonsäurederivate der allgemeinen Formel IX gehen unter Wasserabspaltung direkt in die Imidoverbindungen (II) über.The anhydrides of these dicarboxylic acids can also be used deploy. In many cases, those that form primarily Carboxylic acid derivatives of the general formula IX are lost Splitting of water directly into the imido compounds (II).

Die Umsetzung läßt sich dünnschichtchromatographisch leicht verfolgen. Je nach Wahl der Reaktionsbedingungen, insbesondere beim Erhitzen der Reaktionsmischung auf Temperaturen von 150 bis 250°C erhält man die ringgeschlossenen Produkte in hoher Ausbeute. Vorteilhaft wird das Anhydrid in einem größeren Überschuß eingesetzt, etwa im 2- bis 3fachen Überschuß und die Reaktion in Abwesenheit eines Lösungsmittels durchgeführt.The reaction can be carried out easily by thin layer chromatography follow. Depending on the choice of reaction conditions, especially when heating the reaction mixture Temperatures of 150 to 250 ° C are obtained ring-closed products in high yield.  The anhydride is advantageous in a larger excess used, approximately in a 2 to 3-fold excess and the Reaction carried out in the absence of a solvent.

Die nach dem erfindungsgemäßen Verfahren ebenfalls einsetzbaren Amidoverbindungen der allgemeinen Formel II, in der Z für zwei Wasserstoffatome steht, sind nach verschiedenen Verfahren zugänglich, beispielsweise aus den Aminoverbindungen der allgemeinen Formel VII durch Umsetzung mit ω-substituierten Buttersäurederivaten der allgemeinen Formel VIII, in der Z für zwei Wasserstoffatome steht, gemäß den Bedingungen der Schotten-Baumann-Reaktion und anschließender Cyclisierung der entstehenden Amidoverbindungen der Formel XI The amido compounds of the general formula II, in which Z represents two hydrogen atoms, which can likewise be used by the process according to the invention, are accessible by various processes, for example from the amino compounds of the general formula VII by reaction with ω- substituted butyric acid derivatives of the general formula VIII, in which Z represents two hydrogen atoms, according to the conditions of the Schotten-Baumann reaction and subsequent cyclization of the resulting amido compounds of the formula XI

unter Abspaltung von H-L.splitting off H-L.

Als Beispiele für derartige Carbonsäurederivate der allgemeinen Formel VIII seien genannt: w-Chlorbuttersäurechlorid, ω-Brombuttersäurechlorid, ω-Brombuttersäurephenylester, Chlorid des Trimethylammoniumbuttersäurechlorids.Examples of such carboxylic acid derivatives of the general formula VIII are: w- chlorobutyric acid chloride, ω- bromobutyric acid chloride, ω- bromobutyric acid phenyl ester, chloride of trimethylammonium butyric acid chloride.

Die zur Abspaltung der Gruppierung H-L benötigten Basen sind bevorzugt tertiäre organische Basen wie Pyridin, Triethylamin oder N,N-Dimethylanilin, die in stöchiometrischer Menge oder in größerem Überschuß, z. B. gleichzeitig als Lösungsmittel eingesetzt werden.The bases required to split off the H-L group are preferably tertiary organic bases such as pyridine, Triethylamine or N, N-dimethylaniline, which in stoichiometric amount or in large excess, e.g. B. can be used simultaneously as a solvent.

Bei der erfindungsgemäßen Reduktion können die Amido- bzw. Imidoderivate als freie Säuren oder in Form ihrer die Reduktion nicht behindernden Salze, wie beispielsweise die Alkali- oder Erdalkalisalze eingesetzt werden.In the reduction according to the invention, the amido or Imido derivatives as free acids or in the form of their Reduction of non-interfering salts, such as the Alkali or alkaline earth salts are used.

Um besonders reine Umsetzungsprodukte in hoher Ausbeute zu erhalten, ist es vorteilhaft, die 5-Sulfamoylbenzoesäureester zur Reduktion einzusetzen.To particularly pure reaction products in high yield receive, it is advantageous to Use 5-sulfamoylbenzoic acid ester for reduction.

Die Ester lassen sich nach literaturbekannten Verfahren aus den Säuren herstellen. Als Ester kommen insbesondere in Betracht die Niedrigalkylester mit 1 bis 5 Kohlenstoffatomen, wie der Methyl-, Ethyl-, Propyl-, Butyl- oder n-Pentylester, sowie der t-Butylester. The esters can be removed by methods known from the literature the acids. In particular, esters come in Consider the lower alkyl esters with 1 to 5 Carbon atoms, such as methyl, ethyl, propyl, butyl or n-pentyl ester, and the t-butyl ester.  

Als Reduktionsmittel kommen verschiedene Borhydride, wie z. B. das Diboran in Betracht. Sie können unter entsprechenden Schutzmaßnahmen, wie z. B. die Verwendung von Stickstoff als Inertgas, in die Reaktionsmischung eingeführt werden. Für die Reaktionsführung ist es einfacher, die Borwasserstoffe, wie z. B. Diboran, in Lösungsmitteln aufzunehmen und die Lösung zur Reduktion zu verwenden. Als Lösungsmittel eignen sich besonders Ether, z. B. Tetrahydrofuran oder Diethylenglykoldimethylether. Die Anwesenheit von Lewis-Säuren fördert im allgemeinen die spezifische Reduktion.Various borohydrides, such as e.g. B. the diborane into consideration. You can go to appropriate protective measures such. B. the use of Nitrogen as an inert gas, in the reaction mixture be introduced. It is for reaction management easier to remove the hydrogen boride such. B. Diboran, in Absorb solvents and the solution for reduction use. Particularly suitable solvents are ethers, e.g. B. tetrahydrofuran or diethylene glycol dimethyl ether. The The presence of Lewis acids generally promotes that specific reduction.

Man erzielt die gleiche Reduktion der Verbindungen der allgemeinen Formel II, wenn man komplexe Borhydride oder Borwasserstoffe in Gegenwart von Lewis-Säuren einwirken läßt.The same reduction in the number of compounds is achieved general formula II if you have complex borohydrides or Hydrogens can act in the presence of Lewis acids.

Die bei dieser Reduktionsmethode eingesetzten komplexen Hydride des Bors sind z. B. die Alkaliboranate, wie Lithiumborhydrid, Natriumborhydrid oder Kaliumborhydrid oder die Erdalkaliboranate, wie Calciumborhydrid, aber auch Zinkborhydrid oder Aluminiumborhydrid. Diese Borhydride reduzieren bei Zugabe von Lewis-Säuren die in den eingesetzten Molekülen vorhandenen Amid- bzw. Imidgruppen, ohne die Carbonsäureesterfunktion wesentlich anzugreifen.The complex used in this reduction method Boron hydrides are e.g. B. the alkali boranates, such as Lithium borohydride, sodium borohydride or potassium borohydride or the alkaline earth boronates, such as calcium borohydride, but also Zinc borohydride or aluminum borohydride. These borohydrides reduce the addition of Lewis acids in the existing amide or imide groups used molecules, without significantly attacking the carboxylic acid ester function.

Als Lewis-Säuren im Sinne der Erfindung gelten besonders Aluminiumchlorid, Titantetrachlorid, Zinntetrachlorid, Kobalt-II-chlorid, Eisen-III-chlorid, Quecksilber-I-chlorid, Zinkchlorid und Bortrifluorid und seine Addukte, wie beispielsweise Bortrifluoridetherat. Hierbei besteht die Möglichkeit, daß bei der Umsetzung des Bortrifluoridetherats z. B. mit Natriumborhydrid Diboran in situ entstehen kann (vgl. Fieser, Fieser: Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, Vol. 1, S. 199). Lewis acids in the sense of the invention are particularly considered Aluminum chloride, titanium tetrachloride, tin tetrachloride, Cobalt-II-chloride, iron-III-chloride, Mercury-I-chloride, zinc chloride and boron trifluoride and its adducts, such as boron trifluoride etherate. There is a possibility that when implementing the Boron trifluoride etherate e.g. B. with sodium borohydride diborane in can arise in situ (see Fieser, Fieser: Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, Vol. 1, p. 199).  

Zur Erzielung eines besonders hohen Umsatzes und besonders reiner Endprodukte ist es vorteilhaft, die Lewis-Säure zusammen mit den Verbindungen der allgemeinen Formel II vorzulegen und Borwasserstoff oder das komplexe Borhydrid einzutragen.To achieve a particularly high turnover and particularly pure end products it is advantageous to use the Lewis acid together with the compounds of general formula II submit and boron hydrogen or the complex borohydride to be entered.

Besonders günstig ist es, die Lewis-Säure im Überschuß und das komplexe Borhydrid oder die Borwasserstoffe in mindestens stöchiometrischer Menge, bezogen auf die reduzierende Amidgruppe, einzusetzen.It is particularly favorable to use the Lewis acid in excess and the complex borohydride or the hydrocarbons in at least stoichiometric amount, based on the reducing amide group to use.

So erzielt man günstige Ergebnisse, wenn man beispielsweise beim Titanchlorid die dreifache stöchiometrische Menge an NaBH₄ hinzufügt, während bei Verwendung von Bortrifluoridetherat das komplexe Borhydrid oder der Borwasserstoff in stöchiometrischer Menge bezogen auf die jeweils zu reduzierende Anzahl von Amidgruppen eingesetzt werden kann.So you get good results if you for example three times as much with titanium chloride adds stoichiometric amount of NaBH₄ while at Using boron trifluoride etherate the complex borohydride or the boron hydrogen in a stoichiometric amount to the number of amide groups to be reduced in each case can be used.

Für die Durchführung der Reduktion ist es ohne Belang, ob die zu reduzierenden Substanzen als Imidoverbindungen der allgemeinen Formel II (Z = O) oder als Amidoverbindungen (Z = 2 H) eingesetzt werden. Die Imidoverbindungen gehen überraschenderweise in einer Eintopfreaktion direkt in die Sulfamoylbenzoesäurederivate der allgemeinen Formel I über. Die Reduktion wird in einem Lösungsmittel durchgeführt. Als Lösungsmittel kommen beispielsweise in Betracht Ether wie Tetrahydrofuran oder Diethylenglykoldimethylether (Diglyme). Das Lösungsmittel, in dem die Reduktion durchgeführt wird, kann das gleiche sein wie das, in dem der Borwasserstoff gelöst ist, kann aber auch davon abweichen.For the implementation of the reduction it is irrelevant whether the substances to be reduced as imido compounds of general formula II (Z = O) or as amido compounds (Z = 2 H) be used. The imido connections go surprisingly in a one-pot reaction directly into the Sulfamoylbenzoic acid derivatives of the general formula I above. The reduction is carried out in a solvent. As Solvents are suitable, for example, ethers such as Tetrahydrofuran or diethylene glycol dimethyl ether (Diglyme). The solvent in which the reduction performed can be the same as that in which the boron hydrogen is dissolved, but it can also differ.

Die Reduktion kann in einem weiten Temperaturbereich durchgeführt werden. Die Reduktion kann bei Raumtemperatur oder wenig erhöhter Temperatur durchgeführt werden. Nimmt man etwas längere Reduktionszeiten in Kauf, so läßt sich die Reduktion auch in der Kälte durchführen. Die Reduktionsdauer hängt von den eingesetzten Reaktionskomponenten und der gewählten Temperatur ab.The reduction can be in a wide temperature range be performed. The reduction can be at room temperature or slightly elevated temperature. Takes  if you buy somewhat longer reduction times, you can carry out the reduction even in the cold. The Reduction time depends on the used Reaction components and the selected temperature.

Eine bevorzugte Ausführungsform des erfindungsgemäßen Verfahrens besteht darin, die 5-Sulfamoylbenzoesäurederivate der allgemeinen Formel II in einem inerten Lösungsmittel zusammen mit der Lewis-Säure vorzulegen und eine Lösung von Borwasserstoff oder des komplexen Borhydrids, gegebenenfalls einer Suspension des komplexen Borhydrids, in dem gleichen oder einem anderen Lösungsmittel bei Raumtemperatur zuzugeben und kurze Zeit nachrühren. Das komplexe Borhydrid kann auch in fester Form direkt zugefügt werden. Zur Beschleunigung der Umsetzung kann man die Reaktion gegebenenfalls auch bei höherer Temperatur durchführen oder nach Ende der Zugabe des Reduktionsmittels etwa eine Stunde auf 50 bis 80° erwärmen.A preferred embodiment of the invention The procedure is to 5-sulfamoylbenzoic acid derivatives of the general formula II in an inert solvent together with the Lewis acid to submit and a solution of hydrogen boride or complex borohydride, optionally a suspension of complex borohydrides, in the same or a different one Add solvent at room temperature and briefly stir. The complex borohydride can also be in solid form be added directly. To speed up implementation if necessary, the reaction can also be carried out at higher Perform temperature or after the addition of Warm the reducing agent at 50 to 80 ° for about an hour.

Eine andere Ausführungsform besteht darin, die zu reduzierende Substanz zusammen mit dem komplexen Borhydrid vorzulegen und bei Raumtemperatur die Lewis-Säure zuzugeben. Als komplexes Borhydrid kommt insbesondere das Natriumborhydrid zur Anwendung. Auch hier kann es von Vorteil sein, zur Erzielung eines rascheren Umsatzes nach Ende der Zugabe der Lewis-Säure etwa 1 Stunde auf 50 bis 80° zu erwärmen. Der Reaktionsverlauf kann mit Hilfe der Dünnschichtchromatographie am Auftreten der intensiven hellblauen Fluoreszenz (im Bereich von 366 nm) der entstandenen Verbindungen der Formel I kontrolliert werden. Another embodiment is that reducing substance together with the complex borohydride and the Lewis acid at room temperature to admit. This comes in particular as a complex borohydride Sodium borohydride for use. Again, it can be from Be advantageous to achieve faster sales after Add Lewis acid to 50 to about 1 hour To heat 80 °. The course of the reaction can be determined using the Thin layer chromatography at the occurrence of intense light blue fluorescence (in the range of 366 nm) of resulting compounds of formula I are controlled.  

Die Isolierung der Endprodukte kann auf verschiedenen Wegen erfolgen. Eine bevorzugte Aufarbeitungsmethode besteht darin, die Lösung des Reaktionsproduktes durch Zugabe von Wasser und geringen Mengen einer Säure von etwa noch vorhandenem Reduktionsmittel zu befreien und anschließend die erhaltenen 5-Sulfamoylbenzoesäureester durch Zugabe eines Nichtlösungsmittels auszufällen. Bei Verwendung von Diethylenglykoldimethylether eignet sich als Nichtlösungsmittel besonders Wasser. Die entstandenen 5-Sulfamoylbenzoesäureester der allgemeinen Formel I kristallisieren meist in hoher Reinheit nahezu quantitativ aus.The isolation of the end products can be done in several ways respectively. A preferred work-up method exists therein, the solution of the reaction product by adding Water and small amounts of an acid of about still free existing reducing agent and then the 5-sulfamoylbenzoic acid esters obtained by addition of a non-solvent. When using Diethylene glycol dimethyl ether is suitable as Non-solvent, especially water. The resulting 5-Sulfamoylbenzoic acid ester of the general formula I crystallize mostly in high purity, almost quantitatively.

Gegebenenfalls ist es notwendig, vorhandene durch Schutzgruppen geschützte Substituenten im Rest X der Sulfamoylbenzoesäurederivate der allgemeinen Formel I anschließend wieder in Freiheit zu setzen. Beispielsweise erhält man die p-Hydroxy-gruppe durch Verseifung der entsprechenden Acetate.It may be necessary to go through existing ones Protecting groups protected substituents in radical X of Sulfamoylbenzoic acid derivatives of the general formula I then set free again. For example the p-hydroxy group is obtained by saponification of the corresponding acetates.

Man kann auch die 5-Sulfamoylbenzoesäuren der allgemeinen Formel I direkt erhalten, indem man die Reaktionsmischung nach Zerstörung des überschüssigen Reduktionsmittels teilweise einengt, verdünnte Base zufügt und gegebenenfalls kurze Zeit erwärmt. Als Base dient z. B. Natronlauge. Die 5-Sulfamoylbenzoesäuren der allgemeinen Formel I lassen sich hierbei direkt in Form ihrer Salze isolieren. Durch Ansäuern werden die freien Säuren erhalten. Durch den glatten Verlauf der Bildung der 3-Imido- bzw. 3-Amido-5-sulfamoylbenzoesäurederivate der allgemeinen Formel II werden die neuen 5-Sulfamoylbenzoesäurederivate der allgemeinen Formel I nach der Verfahrensweise a. in hoher Reinheit und hoher Raum-Zeit-Ausbeute erhalten. You can also the 5-sulfamoylbenzoic acids of the general Formula I obtained directly by using the reaction mixture after destruction of the excess reducing agent partially concentrated, add dilute base and if necessary warmed up for a short time. As a base z. B. caustic soda. The 5-Sulfamoylbenzoic acids of the general formula I can be used here isolate directly in the form of their salts. By acidifying get the free acids. Due to the smooth course of the Formation of the 3-imido or 3-Amido-5-sulfamoylbenzoic acid derivatives of the general Formula II will be the new 5-sulfamoylbenzoic acid derivatives of general formula I according to procedure a. in high purity and high space-time yield obtained.  

Die für die Verfahrensweise b. benötigten 5-Halogensulfonylbenzoesäurederivate der allgemeinen Formel III erhält man auf verschiedenen Wegen, beispielsweise aus den Aminobenzoesäurederivaten der allgemeinen Formel XIIThe procedure for b. required 5-halosulfonylbenzoic acid derivatives of the general formula III can be obtained in various ways, for example from the aminobenzoic acid derivatives of the general formula XII

entsprechend der nach Meerwein bekannten Reaktionsfolge, in der in J. pr. /2/152, 251 (1939) bzw. DBP 8 59 461 beschriebenen Weise. according to the reaction sequence known from Meerwein, in the in J. pr. / 2/152, 251 (1939) or DBP 8 59 461 described way.  

Die Halogensulfonylbenzoesäurederivate weden in an sich bekannter Weise mit Aminen der allgemeinen FormelThe halosulfonylbenzoic acid derivatives are inherently known manner with amines of the general formula

zu den Endprodukten der allgemeinen Formel I umgesetzt. Die Aminobenzoesäurederivate der allgemeinen Formel XII erhält man auf verschiedenen Wegen, z. B. aus den literaturbekannten Aminonitrobenzoesäurederivaten der allgemeinen Formel XIII nach dem Reaktionsschemaimplemented to the end products of general formula I. The aminobenzoic acid derivatives of the general formula XII can be obtained in different ways, e.g. B. from the known aminonitrobenzoic acid derivatives of general formula XIII according to the reaction scheme

indem man die Verbindungen mit Carbonsäurederivaten der allgemeinen Formel VIII wie oben beschrieben umsetzt und anschließend die entstandenen Verbindungen der allgemeinen Formel XIV mit Borwasserstoffen bzw. Borwasserstoffen oder komplexen Borhydriden in Gegenwart von Lewis-Säuren zu den Nitrobenzoesäureestern XV reduziert. Anschließend wird die Nitrogruppe reduziert, vorteilhaft durch katalytische Hydrierung in Gegenwart von Raney-Nickel, oder durch sonstige übliche Reduktionsmethoden. by the compounds with carboxylic acid derivatives of general formula VIII as described above and then the resulting connections of the general Formula XIV with hydrocarbons or hydrocarbons or complex borohydrides in the presence of Lewis acids Nitrobenzoic acid esters XV reduced. Then the Reduced nitro group, advantageous through catalytic Hydrogenation in the presence of Raney nickel, or by other usual reduction methods.  

Bei der Reduktion der 3-Amido- bzw. 3-Imidoverbindungen der allgemeinen Formel XIV lassen sich die gleichen Bedingungen anwenden wie bei der Verfahrensweise a. beschrieben.When reducing the 3-amido or 3-imido compounds of general formula XIV, the same conditions apply as for procedure a. described.

Es ist überraschend, daß die Reduktion mit Borwasserstoffen bzw. Borwasserstoffen und komplexen Borhydriden in Gegenwart von Lewis-Säuren auch hier an der Amid- bzw. Imidgruppe erfolgt, ohne daß andere funktionelle Gruppen nennenswert angegriffen werden.It is surprising that the reduction with hydrogen boride or borohydrides and complex borohydrides in Presence of Lewis acids here also on the amide or Imide group takes place without other functional groups be attacked significantly.

Die nach der Verfahrensweise c. eingesetzten Verbindungen der allgemeinen Formel IV sind auf verschiedenen Wegen zugänglich.The procedure c. used connections The general formula IV are in different ways accessible.

Beispielsweise erhält man die Verbindungen, in der B in der allgemeinen Formel IV für eine CH₂OH steht, aus den Carbonsäurederivaten der allgemeinen Formel I durch überschüssiges Reduktionsmittel.For example, one obtains the compounds in which B in the general formula IV represents a CH₂OH, from the Carboxylic acid derivatives of the general formula I by excess reducing agent.

Diese Reaktion kann als Nebenreaktion beobachtet werden, wenn man die Imido- bzw. Amidoderivate der allgemeinen Formel II nach Verfahrensweise a. mit überschüssigem Reduktionsmittel bei erhöhter Temperatur reduziert. Nach dem erfindungsgemäßen Verfahren gelingt es, die zu weit reduzierten Verbindungen der allgemeinen Formel IV in die eigentlich gewünschten Verbindungen der allgemeinen Formel I durch Behandlung mit Oxydationsmitteln zurückzuverwandeln. Als Oxydationsmittel eignet sich vor allem Kaliumpermanganat in alkalischer, wäßriger Lösung. Nach der Abtrennung des ausgefallenen Braunsteins lassen sich die Carbonsäuren der allgemeinen Formel I (R³ = H) beim Ansäuern isolieren.This reaction can be observed as a side reaction if you take the imido or amido derivatives of the general Formula II according to procedure a. with excess Reducing agent reduced at elevated temperature. To the method according to the invention succeeds in overly reduced compounds of general formula IV in the actually desired compounds of the general formula I by treatment with oxidizing agents convert back. Suitable as an oxidizing agent all potassium permanganate in alkaline, aqueous solution. Leave after separating the brown stone the carboxylic acids of the general formula I (R³ = H) isolate when acidifying.

Die Verbindungen der allgemeinen Formel IV, in der B für eine CH₂OH-Gruppe steht, lassen sich auch leicht in solche überführen, in denen B für eine CH₂-Halogengruppe steht, beispielsweise beim Erhitzen der Methylolverbindung mit Thionylchlorid. Derartige Halogenmethylderivate lassen sich nach dem Verfahren von Sommelet (Überblick Organic Reactions 8, 197 (1954) in die Aldehyde überführen, die leicht zu den Endprodukten der allgemeinen Formel I weiteroxydiert oder durch Reduktion mit Hydroxylamin in üblicher Weise in die Oxime und diese durch Wasserabspaltung beim Erwärmen mit Acetanhydrid in die Nitrile überführt werden können.The compounds of general formula IV, in which B for is a CH₂OH group, can be easily in such  transfer in which B represents a CH₂-halogen group, for example when heating the methylol compound Thionyl chloride. Such halomethyl derivatives can be using the Sommelet process (Overview Organic Reactions 8, 197 (1954) in the aldehydes that easy to the end products of general formula I. further oxidized or by reduction with hydroxylamine in usual in the oximes and this through Elimination of water when heating with acetic anhydride in the Nitriles can be transferred.

Die Überführung der Produkte der allgemeinen Formel IV in die Endprodukte der allgemeinen Formel I erfolgt je nach der Art des Substituenten B. Steht B für eine CH₂OH-Gruppe, eine CH₂OCOCH₃- oder CH=O-Gruppe, so werden die Endprodukte, wie bereits beschrieben, durch Oxydation erhalten. Steht B für eine Nitrilgruppe, so bilden sich bei der alkalischen Hydrolyse die Amide, die anschließend z. B. durch weitere Hydrolyse in die freien Carbonsäuren überführt werden können. Oder man erhält durch Umsetzung mit alkoholischer Salzsäure aus den Nitrilen die Iminoester, die durch Hydrolyse in die Esterverbindungen, gewünschtenfalls auch in die entsprechenden Carbonsäuren überführt werden können.The transfer of the products of the general formula IV into the end products of the general formula I depend on the nature of the substituent B. B is a CH₂OH group, a CH₂OCOCH₃ or CH = O group, so the End products, as already described, by oxidation receive. If B stands for a nitrile group, then form the alkaline hydrolysis the amides, which subsequently z. B. by further hydrolysis into the free carboxylic acids can be transferred. Or you get through implementation with alcoholic hydrochloric acid from the nitriles Imino esters, which by hydrolysis into the ester compounds, if desired also in the corresponding carboxylic acids can be transferred.

Die nach Verfahrensweise d. eingesetzten Sulfamoylbenzoesäurederivate der allgemeinen Formel V sind auf verschiedenen Wegen zugänglich, beispielsweise aus den Sulfamoylbenzoesäurederivaten der allgemeinen Formel XIAccording to procedure d. used Sulfamoylbenzoic acid derivatives of the general formula V are accessible in various ways, for example from the Sulfamoylbenzoic acid derivatives of the general formula XI

durch Reduktion der Amidgruppen mit Borwasserstoffen oder Borwasserstoffen bzw. komplexen Borhydriden in Gegenwart von Lewis-Säuren in der bereits beschriebenen Weise. Bei dieser Reduktion ist es überraschend, daß die Amidgruppe reduziert wird, ohne daß die Leavinggruppe L beeinflußt wird.by reducing the amide groups with hydrocarbons or Hydrogen boron or complex borohydrides in the presence of Lewis acids in the manner already described. At this Reduction it is surprising that the amide group reduces without influencing the leaving group L.

Die Cyclisierung der Verbindungen der allgemeinen Formel V unter Abspaltung von HL kann unter basischen oder sauren Bedingungen geschehen. Steht L beispielsweise für Halogenatom, vorzugsweise für Chlor oder Brom, so erfolgt die Abspaltung von HL entsprechend Ber. dtsch. chem. Ges. 42, 3427 (1909) (Überblick Chem. Rev. 63, 55 (1963) beim Erwärmen der Verbindung in konzentrierter Schwefelsäure auf Temperaturen von 80 bis 120°C. Dabei werden anschließend die gewünschten Endprodukte durch Eintragen der Reaktionsmischung in Eis erhalten. Hierbei entstehen die freien Carbonsäuren der allgemeinen Formel I (R³ = H). Steht L für eine Trialkylammoniumgruppe, so erfolgt die Cyclisierung beim Erwärmen mit organischen Basen unter Abspaltung von Trialkylamin und HX. Als Basen, die bei der Abspaltung verwendet werden können, seien Triethylamin, N,N-Dimethylanilin oder auch Alkaliacetat genannt. The cyclization of the compounds of the general formula V with the elimination of HL under basic or acidic Conditions happen. For example, L stands for Halogen atom, preferably for chlorine or bromine, is carried out the splitting off of HL according to Ber. German chem. Ges. 42, 3427 (1909) (overview Chem. Rev. 63, 55 (1963) at Warm up the compound in concentrated sulfuric acid Temperatures from 80 to 120 ° C. Thereafter, the desired end products by entering the Obtain reaction mixture in ice. This creates the free carboxylic acids of general formula I (R³ = H). If L stands for a trialkylammonium group, then the Cyclization when heated with organic bases under Elimination of trialkylamine and HX. As bases that at Cleavage can be used are triethylamine, N, N-dimethylaniline or also called alkali acetate.  

Die anschließende Cyclisierung erfolgt in literaturbekannter Weise, z. B. nach dem Verfahren von Wurtz durch Umsetzung der Verbindungen der allgemeinen Formel VI mit metallischem Natrium oder durch Einwirkung von Zn auf die siedende alkoholische Lösung, wie in J. prakt. Chem. [2] 36, 300 (1887) beschrieben. Diese Methode eignet sich besonders für die Herstellung 5-gliedriger Ringe in 3-Stellung der Verbindung der allgemeinen Formel I.The subsequent cyclization takes place in known in the literature, e.g. B. by the Wurtz method by reacting the compounds of the general formula VI with metallic sodium or by the action of Zn the boiling alcoholic solution as described in J. Prakt. Chem. [2] 36, 300 (1887). This method is suitable especially for the production of 5-membered rings in 3-position of the compound of general formula I.

Im Anschluß an die unter a. bis e. aufgeführten Verfahrensweisen können freie Carbonsäuren der allgemeinen Formel I in üblicher Weise in die Ester überführt werden. Hierfür werden Alkohole der allgemeinen Formel R³OH bzw. deren funktionsfähige Derivate verwendet oder die Veresterung in anderer, literaturbekannter Weise durchgeführt. Umgekehrt können zunächst erhaltene Carbonsäureester der allgemeinen Formel I in die entsprechenden freien Carbonsäuren überführt werden. Hierfür kommt insbesondere Hydrolyse oder in geeigneten Fällen auch Hydrogenolyse oder sonstige Eliminierungsreaktionen in Frage. So lassen sich die Alkylester durch alkalische Hydrolyse spalten. Following the under a. to e. listed Procedures can free carboxylic acids general formula I. be converted into the esters in a conventional manner. For this purpose alcohols of the general formula R³OH or their functional derivatives used or the Esterification in a different way known from the literature carried out. Conversely, initially received Carboxylic acid esters of the general formula I in the corresponding free carboxylic acids are transferred. This comes in particular hydrolysis or in suitable Cases also hydrogenolysis or other Elimination reactions in question. So they can be Split the alkyl ester by alkaline hydrolysis.  

Die freien Carbonsäuren können durch Umsetzung mit entsprechenden Basen wie Alkali-, Erdalkali- oder Ammonium-hydroxyden oder -carbonaten in ihre pharmazeutisch verträglichen Salze überführt werden. Schließlich ist es möglich, die erfindungsgemäßen Verbindungen der allgemeinen Formel I dadurch zu erhalten, daß in letzter Reaktionsstufe eine der üblichen Schutzgruppen für die Hydroxy-, Amino- oder Mercapto-Gruppen freigesetzt werden, wobei beispielsweise acylierte Hydroxygruppen oder Aminogruppen in üblicher Weise hydrolysiert werden. Die Schutzgruppen von Hydroxy-, Amino- oder Mercaptogruppen sind insbesondere bei der Herstellung der Ausgangsstoffe der allgemeinen Formel II erforderlich, um eine Acylierung mit Carbonsäurederivaten der allgemeinen Formel VIII an den unerwünschten Stellen zu vermeiden. In diesem Falle wird die erfindungsgemäße Reduktion nach Verfahrensweise a. oft mit den geschützten Hydroxy-, Amino- oder Mercaptoverbindungen durchgeführt und erst im Anschluß an die Reduktion die Abspaltung der Schutzgruppe, wie oben beschrieben, vorgenommen. Jedoch auch bei den anderen Verfahrensweisen kann es zweckmäßig sein, reaktionsfähige Substituenten zu blockieren, welche in der letzten Reaktionsstufe abgespalten werden.The free carboxylic acids can be reacted with corresponding bases such as alkali, alkaline earth or Ammonium hydroxides or carbonates in their pharmaceutical tolerated salts are transferred. After all it is possible, the compounds of the general invention Formula I obtained in that in the last reaction stage one of the usual protecting groups for the hydroxy, amino or mercapto groups are released, wherein for example acylated hydroxyl groups or amino groups be hydrolyzed in the usual way. The protection groups of hydroxyl, amino or mercapto groups are in particular in the manufacture of the starting materials of the general Formula II required to use acylation Carboxylic acid derivatives of the general formula VIII to the to avoid unwanted spots. In this case the inventive reduction according to procedure a. often with the protected hydroxy, amino or Mercapto connections carried out and only after the reduction, the deprotection, as above described, made. But also with the others Procedures may be appropriate to be reactive To block substituents in the last Reaction stage are split off.

Nach dem erfindungsgemäßen Verfahren lassen sich eine Vielzahl hochwirksamer Pharmazeutika, insbesondere Diuretika und Saluretika herstellen, von denen im folgenden einige erwähnt sein sollen.According to the method of the invention Variety of highly effective pharmaceuticals, especially Manufacture diuretics and saluretics, of which the following some should be mentioned.

3-N-Pyrrolidino-4-p-chlorphenoxy-5-sulfamoylbenzoesäure; Fp. 253-4°C
3-N-Pyrrolidino-4-(3′,5′-dimethylphenoxy)-5-sulfamoylbenzoesäure; Fp. 246-8°C
3-N-Pyrrolidino-4-(4′-hydroxyphenoxy)-5-sulfamoylbenzoesäure; Fp. 271-273°C
3-N-Pyrrolidino-4-benzyl-5-sulfamoylbenzoesäure; Fp. 263-238°C
3-N-Pyrrolidino-4-phenylthio-5-sulfamoylbenzoesäure; Fp. 238-239°C3-N-pyrrolidino-4-p-chlorophenoxy-5-sulfamoylbenzoic acid; Mp 253-4 ° C
3-N-pyrrolidino-4- (3 ′, 5′-dimethylphenoxy) -5-sulfamoylbenzoic acid; Mp 246-8 ° C
3-N-pyrrolidino-4- (4'-hydroxyphenoxy) -5-sulfamoylbenzoic acid; Mp 271-273 ° C
3-N-pyrrolidino-4-benzyl-5-sulfamoylbenzoic acid; Mp 263-238 ° C
3-N-pyrrolidino-4-phenylthio-5-sulfamoylbenzoic acid; Mp 238-239 ° C

In der vorstehenden Aufzählung der erfindungsgemäßen Verbindung kann z. B. bei jeder Verbindung auch anstelle des Wortteils "5-sulfamoyl-" der folgende Wortteil eingesetzt werden:In the above list of the invention Connection can e.g. B. with each connection instead of Word part "5-sulfamoyl-" the following word part used will:

5-N-methylsulfamoyl
5-N,N-dimethylsulfamoyl.5-N-methylsulfamoyl
5-N, N-dimethylsulfamoyl.

Die vorstehende Aufzeichnung enthält die substituierten Benzoesäuren der allgemeinen Formel I. Es kommen z. B. auch sämtliche vorgenannten Verfahrensprodukte in Frage, in denen anstelle des Wortendes "-benzoesäure" die folgenden Wortendungen enthalten sind:The above record contains the substituted ones Benzoic acids of the general formula I. Belly all aforementioned process products in question, in which instead of the word "-benzoic acid" the following Word endings are included:

-benzoesäuremethylester
-benzoesäureethylester
-benzoesäure-tert.-butylester.-benzoic acid methyl ester
-benzoic acid ethyl ester
-benzoic acid tert-butyl ester.

Die erfindungsgemäßen Sulfamoylbenzoesäurederivate der allgemeinen Formel I sowie deren pharmazeutisch verträgliche Salze sind hochwirksame Diuretika und Saluretika, die als Pharmazeutika in der Human- und Veterinärmedizin eingesetzt werden können.The sulfamoylbenzoic acid derivatives according to the invention general formula I and their pharmaceutical tolerable salts are highly effective diuretics and Saluretics used as pharmaceuticals in human and Veterinary medicine can be used.

Die erfindungsgemäßen Verbindungen werden in Dosierungen von 0,5 bis 100 ml in Kapseln, Dragees, Tabletten oder Lösungen mit verschiedenen Zusätzen enteral z. B. oral mit der Sonde oder parenteral (Injektion in das Gefäßsystem, z. B. intravenös oder auch Injektion in die Muskulatur oder unter die Haut) verabfolgt. Sie eignen sich zur Behandlung von Ödemkrankheiten, wie kardiale, renale oder hepatisch bedingter Ödeme und anderer derartiger auf Störungen des Wasser- und Elektrolyt-Haushalts zurückzuführenden Erscheinungen.The compounds of the invention are in doses from 0.5 to 100 ml in capsules, coated tablets, tablets or Solutions with various additives enteral z. B. orally with the probe or parenterally (injection into the vascular system, e.g. B. intravenously or injection into the muscles or  under the skin). They are suitable for treatment edema diseases such as cardiac, renal or hepatic conditional edema and other such disorders of the Water and electrolyte budget traceable Apparitions.

BeispieleExamples Herstellung von 3-N(3-Methylpyrrolidino-4-phenoxy-5- sulfamoylbenzoesäure-methylester und weiteren ZwischenproduktenPreparation of 3-N (3-methylpyrrolidino-4-phenoxy-5- methyl sulfamoylbenzoate and others Intermediate products a) 3-Nitro-4-phenoxy-5-sulfamoyl-benzoesäure-methylestera) 3-Nitro-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester

34 g (∼ 0,1 Mol) 3-Nitro-4-phenoxy-5-sulfamoylbenzoesäure werden in 150 ml Methanol gelöst und zum Sieden erhitzt. Dann tropft man langsam 5,4 ml H₂SO₄ konz. hinzu und läßt 10 Stunden unter Rückfluß erhitzen. Beim Abkühlen kristallisiert der 3-Nitro-4-phenoxy-5- sulfamoyl-benzoesäure-methylester aus. Er kann aus Methanol/Aceton umkristallisiert werden.
Fp. 181-182°C; Ausbeute: 25,9 g (73,1%)34 g (∼ 0.1 mol) of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid are dissolved in 150 ml of methanol and heated to boiling. Then slowly 5.4 ml of H₂SO₄ conc. added and allowed to reflux for 10 hours. On cooling, the 3-nitro-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester crystallizes out. It can be recrystallized from methanol / acetone.
Mp 181-182 ° C; Yield: 25.9 g (73.1%)

b) 3-Amino-4-phenoxy-5-sulfamoyl-benzoesäure-methylesterb) 3-Amino-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester

35 g (∼ 0,1 Mol) 3-Nitro-4-phenoxy-5- sulfamoylbenzoesäure-methylester werden in 150 ml Methanol suspendiert und mit Raney-Nickel (5-10%) im Autoklaven bei 40-50° und 100 atü hydriert. Die ausgefallene Aminoverbindung wird auf dem Dampfbad durch Zugabe von Aceton in Lösung gebracht und vom Raney-Nickel filtriert.35 g (∼ 0.1 mol) 3-nitro-4-phenoxy-5- Methyl sulfamoylbenzoate are dissolved in 150 ml Methanol suspended and with Raney nickel (5-10%) in Autoclaves are hydrogenated at 40-50 ° and 100 atm. The precipitated amino compound is through on the steam bath Addition of acetone brought into solution and from Raney nickel filtered.

Beim Abkühlen kristallisiert der 3-Amino-4-phenoxy-5- sulfamoyl-benzoesäure-methylester sauber aus.
Fp. 179°C; Ausbeute: 24,1 g (75,4%) On cooling, the 3-amino-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester crystallizes cleanly.
Mp 179 ° C; Yield: 24.1 g (75.4%)

c) 3-N-(3-Methylsuccinimido)-4-phenoxy-sulfamoyl­ benzoesäure-methylesterc) 3-N- (3-methylsuccinimido) -4-phenoxysulfamoyl methyl benzoate

16 g 3-Amino-4-phenoxy-5-sulfamoyl-benzoesäuremethylester und 15 g 3-Methylbersteinsäureanhydrid werden mit etwas Diglyme im offenen Kolben zusammengeschmolzen und etwa 2,5 Stunden bei ca. 180°C gehalten. Bei Zugabe von Methanol kristallisiert der 3-N-(3-Methylsuccinimido)-4-phenoxy-5-sulfamoyl- benzoesäure-methylester aus.
Aus Glykolmonomethylether weiße Kristalle vom Fp. 272°C;  Ausbeute: 17 g (82%)16 g of 3-amino-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester and 15 g of 3-methylsuccinic anhydride are melted together with a little diglyme in an open flask and held at about 180 ° C. for about 2.5 hours. When methanol is added, the 3-N- (3-methylsuccinimido) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester crystallizes out.
White crystals of mp 272 ° C. from glycol monomethyl ether; Yield: 17 g (82%)

d) 3-N-(3-Methylpyrrolidino)-4-phenoxy-5-sulfamoyl- benzoesäure-methylesterd) 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoyl- methyl benzoate

17 g 3-N-(3-Methylsuccinimido)-4-phenoxy-5-sulfamoyl- benzoesäure-methylester werden in 150 ml Diglyme suspendiert. Dazu gibt man 11 ml BF₃-Etherat und tropft dann bei Eiskühlung eine Lösung von 3 g NaBH₄ in 150 ml Diglyme hinzu. Nach dem Zutropfen wird der entstandene 3-N-(3-Methylpyrrolidino)-4-phenoxy-5-sulfamoyl- benzoesäure-methylester mit Wasser ausgefällt;
weiße Kristalle aus Methanol vom Fp. 145°C; Ausbeute: 9,5 g (59,9%)17 g of 3-N- (3-methylsuccinimido) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester are suspended in 150 ml of diglyme. 11 ml of BF₃ etherate are added and then a solution of 3 g of NaBH₄ in 150 ml of diglyme is added dropwise while cooling with ice. After the dropwise addition, the 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester formed is precipitated with water;
white crystals of methanol, mp 145 ° C; Yield: 9.5 g (59.9%)

Beispiel 1Example 1 3-N-(3-Methylpyrrolidino)-4-phenoxy-5-sulfamoyl-benzoesäure3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoyl-benzoic acid

9 g 3-N-(3-Methylpyrrolidino)-4-phenoxy-5-sulfamoyl- benzoesäure-methylester werden in 1 n NaOH auf dem Wasserbad erwärmt, bis eine klare Lösung entstanden ist. Danach fällt man bei Raumtemperatur die 3-N-(3- Methylpyrrolidino)-4-phenoxy-5-sulfamoyl-benzoesäure mit 2 n HCl aus und kristallisiert sie aus CH₃OH/H₂O um;
weißgelbe Kristalle vom Fp. 206-208°C; Ausbeute: 7,3 g (84,1%)9 g of 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester are warmed in 1 N NaOH on a water bath until a clear solution has formed. Thereafter, the 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoyl-benzoic acid is precipitated with 2N HCl at room temperature and recrystallized from CH₃OH / H₂O;
white-yellow crystals of mp 206-208 ° C; Yield: 7.3 g (84.1%)

Claims (4)

1. 3-(1-Pyrrolidinyl)-5-sulfamoylbenzoesäurederivate der allgemeinen Formel I in der bedeuten:
R¹ und R², die gleich oder verschieden sind, Wasserstoff oder Alkyl mit 1 bis 4 Kohlenstoffatomen,
R³ Wasserstoff oder Alkyl mit 1 bis 6 Kohlenstoffatomen,
X eine der Gruppen -CH₂-R⁴, -O-R⁴ und -S-R⁴, worin
R⁴ für den Phenylrest steht, der mit Hal, OH, Alkyl mit 1 bis 4 Kohlenstoffatomen, oder Alkoxy mit 1 bis 3 Kohlenstoffatomen substituiert sein kann und
A Alkylen mit 2 Kohlenstoffatomen, das durch Alkyl mit 1 bis 4 C-Atomen substituiert sein kann,
wobei jedoch Verbindungen, in denen A die Gruppe -CH₂-CH₂ bedeutet, falls X Phenoxy- oder 4′-Methyl-phenoxy, R¹, R² Wasserstoff und R³ Wasserstoff oder Alkyl mit 1 bis 5 C-Atomen bedeuten, ausgenommen sind,
sowie deren pharmazeutisch verträgliche Salze mit Basen oder Säuren.1. 3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid derivatives of the general formula I in which mean:
R¹ and R², which are the same or different, are hydrogen or alkyl having 1 to 4 carbon atoms,
R³ is hydrogen or alkyl having 1 to 6 carbon atoms,
X is one of the groups -CH₂-R⁴, -O-R⁴ and -S-R⁴, wherein
R⁴ represents the phenyl radical, which can be substituted with Hal, OH, alkyl with 1 to 4 carbon atoms, or alkoxy with 1 to 3 carbon atoms and
A alkylene with 2 carbon atoms, which can be substituted by alkyl with 1 to 4 carbon atoms,
however, compounds in which A denotes the group —CH₂-CH₂ if X denotes phenoxy- or 4′-methylphenoxy, R¹, R² is hydrogen and R³ is hydrogen or alkyl having 1 to 5 carbon atoms are excluded,
as well as their pharmaceutically acceptable salts with bases or acids. 2. Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I in der die Reste R¹ bis R³, A und X die angegebenen Bedeutungen haben, dadurch gekennzeichnet, daß man
  • a. 3-substituierte Sulfamoylbenzoesäurederivate der allgemeinen Formel II in der die Reste R¹ bis R³, A und X die oben angegebenen Bedeutungen haben, wobei Hydroxy-, Amino- oder Mercaptogruppen gegebenenfalls durch übliche Schutzgruppen blockiert sind, und Z für zwei Wasserstoffatome oder ein Sauerstoffatom steht, durch Borwasserstoffe gegebenenfalls in Gegenwart von Lewis-Säuren, oder durch komplexe Borhydride in Gegenwart von Lewis-Säuren reduziert oder in an sich bekannter Weise
  • b. 5-Halogensulfonylbenzoesäurederivate der allgemeinen Formel III in der R³, A und X die angegebenen Bedeutungen haben und Hal für ein Halogenatom steht, mit Aminen der allgemeinen Formel worin R¹ und R² die angegebenen Bedeutungen haben, umsetzt oder
  • c. Sulfamoylverbindungen der allgemeinen Formel IV in der die Reste R¹ und R², A und X die angegebenen Bedeutungen haben und B für einen in eine Carbonsäure umwandelbaren Rest steht, durch Hydrolyse oder Oxydationsreaktionen in die 5-Sulfamoylbenzoesäuren der Formel mit R³ = H überführt oder
  • d. Sulfamoylbenzoesäurederivate der allgemeinen Formel V in der die Reste R¹ bis R³, A und X die angegebenen Bedeutungen haben und L für eine abspaltbare Gruppe steht, mit Säuren oder Basen zur Abspaltung von HL behandelt.
2. Process for the preparation of the compounds of general formula I. in which the radicals R¹ to R³, A and X have the meanings given, characterized in that
  • a. 3-substituted sulfamoylbenzoic acid derivatives of the general formula II in which the radicals R 1 to R 3, A and X have the meanings given above, where hydroxyl, amino or mercapto groups are optionally blocked by customary protective groups, and Z represents two hydrogen atoms or one oxygen atom, by hydrogen boron, if appropriate in the presence of Lewis Acids, or reduced by complex borohydrides in the presence of Lewis acids or in a manner known per se
  • b. 5-halosulfonylbenzoic acid derivatives of the general formula III in which R³, A and X have the meanings given and Hal represents a halogen atom, with amines of the general formula wherein R¹ and R² have the meanings given, implemented or
  • c. Sulfamoyl compounds of the general formula IV in which the radicals R¹ and R², A and X have the meanings given and B represents a radical which can be converted into a carboxylic acid, converted into the 5-sulfamoylbenzoic acids of the formula with R³ = H by hydrolysis or oxidation reactions or
  • d. Sulfamoylbenzoic acid derivatives of the general formula V in which the radicals R¹ to R³, A and X have the meanings given and L represents a cleavable group, treated with acids or bases for the elimination of HL.
3. Verbindungen der allgemeinen Formel II in der die Substituenten R¹ bis R³, A und X die in Anspruch 1 angegebene Bedeutung haben.3. Compounds of the general formula II in which the substituents R¹ to R³, A and X have the meaning given in claim 1. 4. Pharmazeutische Präparate, gekennzeichnet durch einen Gehalt an einer Verbindung gemäß Anspruch 1 zusammen mit den pharmazeutisch üblichen Hilfs- und Trägerstoffen.4. Pharmaceutical preparations, characterized by a Content of a compound according to claim 1 together with the usual pharmaceutical excipients and carriers.
DE2462752A 1974-04-25 1974-04-25 Expired - Lifetime DE2462752C2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE2462752A DE2462752C2 (en) 1974-04-25 1974-04-25

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2462752A DE2462752C2 (en) 1974-04-25 1974-04-25
DE2419970A DE2419970C3 (en) 1974-04-25 1974-04-25 3- <1-Pyrrolidinyl) -4-phenoxy-5sulfamoylbenzoic acid and process for its preparation

Publications (1)

Publication Number Publication Date
DE2462752C2 true DE2462752C2 (en) 1990-01-11

Family

ID=25767040

Family Applications (1)

Application Number Title Priority Date Filing Date
DE2462752A Expired - Lifetime DE2462752C2 (en) 1974-04-25 1974-04-25

Country Status (1)

Country Link
DE (1) DE2462752C2 (en)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NICHTS ERMITTELT *

Similar Documents

Publication Publication Date Title
DE2419970C3 (en) 3- &lt;1-Pyrrolidinyl) -4-phenoxy-5sulfamoylbenzoic acid and process for its preparation
DE1695139A1 (en) Process for the preparation of imidazole derivatives
DE2618999C2 (en) 1 - {[5- (4-Hydroxy-2H-1,2-benzothiazin-3-yl) -1,2.4-oxadiazol-3-yl] methyl} -ethanone-S, S-dioxide, process for their preparation as well Process for their further processing
DE2462752C2 (en)
DE2618978A1 (en) METHOD OF MANUFACTURING 1- CURVED CLAMP TO ANGULAR CLAMP TO 5- (4-HYDROXY-2H-1,2-BENZOTHIAZINE- 3-YL) -1,2,4-OXADIAZOL-3-YL ANGLE CLAMP TO METHYL COLLAR CLAMP -AETHANONE- S, S-DIOXIDE AND INTERMEDIATE PRODUCTS USED IN THE PROCESS
DE2029991C3 (en) 2-Hydroxy-5-aminobenzamides, processes for their preparation and pharmaceuticals containing these compounds
DE2518999A1 (en) Diuretic 3-sulphamoyl 5-alkylamino benzoic acids - from N-protected 4-halo 3-sulphamoyl benzoic acids
DE1803911C3 (en) Process for the preparation of 7-chloro-2-methylamino-5-phenyl-3H-1,4benzodiazepine-4-oxide
DE2331044A1 (en) DIPHENYLMETHANE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION
DE2462907C2 (en)
AT224116B (en) Process for the preparation of new, 4-substituted 1,2-diaryl-3,5-dioxo-pyrazolidines
DE1901167C3 (en) Substituted indoles, processes for their preparation and pharmaceutical compositions
DE2243112C3 (en) Process for the preparation of substituted aromatic compounds nitrated in the side chain
AT355009B (en) METHOD FOR PRODUCING NEW AMINO-ALKYLPHENOXYALKAN ACIDS, THEIR ESTERS AND SALTS
AT384221B (en) METHOD FOR PRODUCING NEW 3-SUBSTITUTED TETRAHYDRO-PYRROLO (1,2-A) PYRIMIDINE DERIVATIVES AND THEIR ACID ADDITIONAL AND QUATERNAUS SALTS
DE1620556C (en) 1 Cyclohexylbarbituric acid derivatives
DE2365469C3 (en) 18.10.72 Japan 103606-72 alpha-acylamino square bracket to alpha-alkyl (or -aryl) -thio square bracket to -carboxylic acid thlol ester and process for their preparation
AT308118B (en) Process for the production of new benzodiazepine derivatives and their salts
DE1670001C3 (en) Process for the preparation of indole-3-acetic acid derivatives
DE1695012C3 (en) N to the power of 1 - (6-Cyclopropyl-4-pyrimidinyl) sulfanilamides
DE1695381B2 (en) PHTHALAZINO SQUARE CLAMP ON 2.3-ANGLE BRACKET FOR PHTHALAZINE AND A METHOD FOR MAKING IT
DE1695135A1 (en) Process for the preparation of sulfonamides
WO1984000032A1 (en) Amino-oxy-(mercapto-alkyl)-benzenes, method for the preparation thereof and pharmaceutical products containing them
CH501624A (en) Anti-inflammatory anilino-nicotinic acid - derivs
DE2262830A1 (en) Oximinoaceto-ortho-toluidide prepn - from orthotoluidine hydrochloride, chloral hydrate and hydroxylammonium sulphate in presence of sodium sulphate and ethanol

Legal Events

Date Code Title Description
OI Miscellaneous see part 1
OI Miscellaneous see part 1
OD Request for examination
AC Divided out of

Ref country code: DE

Ref document number: 2419970

Format of ref document f/p: P

D2 Grant after examination
8364 No opposition during term of opposition