WO1994027996A1 - Derives de 1,2,5-thiadiazole, leur preparation et leur utilisation - Google Patents

Derives de 1,2,5-thiadiazole, leur preparation et leur utilisation Download PDF

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Publication number
WO1994027996A1
WO1994027996A1 PCT/DK1994/000198 DK9400198W WO9427996A1 WO 1994027996 A1 WO1994027996 A1 WO 1994027996A1 DK 9400198 W DK9400198 W DK 9400198W WO 9427996 A1 WO9427996 A1 WO 9427996A1
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WO
WIPO (PCT)
Prior art keywords
disorders
compound according
piperidino
fluoro
compound
Prior art date
Application number
PCT/DK1994/000198
Other languages
English (en)
Inventor
John Bondo Hansen
Frederik Christian GRØNVALD
Original Assignee
Novo Nordisk A/S
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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU69238/94A priority Critical patent/AU6923894A/en
Publication of WO1994027996A1 publication Critical patent/WO1994027996A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to 1 ,2,5-thiadiazole derivatives which are useful for treating CNS-system, cardiovascular system and/or gastrointestinal disorders, methods for preparing such compounds and pharmaceutical compositions containing them.
  • DA dopamine
  • clozapine some neuroleptics (e.g. clozapine) show an atypical profile: the compounds are not only beneficial in treating patients, who respond poorly to classical neuroleptic therapy, but the compounds are also relatively devoid of extrapyrimidal side effects (EPS) commonly seen with classical neuroleptics (Ereshefsky et al., Clin.Pharm 8, 691-709, 1989).
  • EPS extrapyrimidal side effects
  • the antipsychotic effect of clozapine and related compounds might be due to its blockade of not only DA-receptors (D-1 , D-2, D-3, D-4, D-5) but also 5HT-receptor subtypes (5HT 2 -, 5HT 3 -, 5HT 1C -, 5HT 1A -), NA- ⁇ receptors. histamine and possibly other receptors.
  • 5HT 2 -blockade may also be important (Meltzer, Schizphr. Bull. 17: 263-87, 1991) to counteract the socalled negative symptoms of psycho ⁇ sis (delusions and social withdrawal) which are otherwise difficult to treat with conventional neuroleptics.
  • the present invention relates to 1 ,2,5-thiadiazole deriva ⁇ tives of the general formula (I)
  • A is a straight or branched, saturated acyclic hydrocarbon of 2-6 carbon atoms
  • Y is CH or N
  • X is O, S, NH, NCH 3 . or CH 2 ;
  • R 1 is 1 ,2-benzisothiazol-3-yl, 1 ,2-benzisoxazol-3-yl, 1 H-indazol-3-yl, or 1-methyl-1H-indazol-3-yl, all of which may be substituted independently with halogen or C,_ 6 -alkyl in one, two, three or all of the 4-, 5-, 6- and 7-posi- tions; or
  • R 1 is 4-fluorobenzoyl or phenyl optionally substituted with halogen or C,_ 6 - alkyl;
  • R 2 is optionally substituted any I or heteroaryl
  • Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be sub ⁇ jected to further purification by recrystallization.
  • the invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof.
  • C ⁇ -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, n-pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.
  • aryl denotes a phenyl group which optionally carries one or more substituents selected from halogen, 1 ,3-dioxolanyl and 1 ,4-dioxanyl, such as 2,3-methyleneoxy- phenyl, 4-chlorophenyl, 4-fluorophenyl.
  • heteroaryl denotes an univalent aromatic heterocyclic 5- or 6-membered ring containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, such as pyridyl, pyrrolyl, thienyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, thiadia- zolyl, pyranyl, piperidyl, 1 ,4-dioxanyl, 1 ,3-dioxanyl, oxazinyl, thiazinyl, pipe- razinyl, pyrazinyl, pyrimidyl and pyrazinyl.
  • halogen means fluorine, chlorine, bromine and iodine.
  • R 1 is selected from benzisothia- zolyl, 6-fluoro-benzisoxazolyl, phenyl, 4-chlorophenyl, 4-fluorobenzoyl and 3,4-methy lenedioxyphenyl .
  • A is straight or branched C,. 6 -alkyl, preferably ethyl or propyl; and X is O or S.
  • R 2 is selected from phenyl, 2,3-methyleneoxyphenyl, thienyl and pyridyl.
  • Preferred compounds of the invention are:
  • the compounds of the present invention demonstrate high affinity for various receptor subtypes including the 5HT 2 -, the dopamine D and D 2 - receptors or a combination of these.
  • the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders.
  • the invention also relates to the use of the inventive com ⁇ pounds of formula (I) as medicaments useful for treating CNS-system, cardiovascular system and gastrointestinal disorders, such as treatment of anxiety, sleep disorders, depression, psychosis, schizophrenia, migraine, ischemic neuronal damage, asthma, hypertension, urticaria, analgesia and emesis.
  • the invention relates to a method of preparing the above mentioned compounds wherein a compound of formula (II)
  • R 2 has the meaning set forth above, and Q is a leaving group, e.g. halogen such as chloro, is reacted with a compound of formula (III)
  • A, Y and R 1 have the meanings set forth above and W is O or S, to form a compound of formula (I) wherein X is O or S.
  • the compounds of the present invention have been tested for binding to various CNS receptor subtypes jn vitro in mice.
  • TEST 1 Jn yjtro inhibition of DOPAMINE D2 receptor binding
  • Radioactive-labelled ligand 3 H-Spiroperidol is incubated with isolated cell- membrane fragments at 37°C for a given period of time. Following complet ⁇ ed incubation, the incubate is filtered through GF/B filters which are rinsed following filtration to remove unspecifically adhered radioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters is indicative of the amount of ligand bound specifically as well as nonspecifically to the mem ⁇ branes.
  • Polytron kinematica is rinsed with milli-Q-H 2 0 before and after use.
  • Male Wistar rats, 150-200 g are decapitat ⁇ ed, striatum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial containing 10 ml ice-cold D2 buffer.
  • Homo- genization is performed applying polytron kinematica (homogenizer) setting 6 for 20 sec.
  • the homogenizer is rinsed with 10 ml D2 buffer in another centrifuging vial.
  • the 10 ml rinsing buffer is added to the tissue vial. Centri- fugation at 18,000 rpm for 10 min.
  • the test result is shown in Table I as IC 50 indicating the concentration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand 3 H-SCH 23390 is incubated with isolated cell- membrane fragments in incubation buffer at 30°C for a given period of time. Following completed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered ra ⁇ dioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.
  • D1 binding will stand concentrations of up to approx. 20% of these solvents without affecting the binding. Most stock solutions are stable at 4°C. Attention should, however, be paid to any precipitation, change in colour etc. Test-substance dilutions are always made fresh every day. When weighing out test substances, it is attempted to weigh out approx. 1 mg of substance. Less than 0.8 mg must never be weighed out and only in ⁇ frequently more than 2 mg (for economy reasons), dependent, however, on conc./assay.
  • the test result is shown in Table I as IC 50 indicating the concentration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand 3 H-Ketanserine is incubated with isolated cell membrane fragments at 37°C for a given period of time. Following complet ⁇ ed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered radioactivity. As op ⁇ posed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.
  • the preparation is made in ice bath. Polytron kinematica is rinsed with milli- Q-H 2 0 before and after use. Male Wistar rats, 150-200 g are decapitated. Frontal cortex is removed quickly and weighed (approx. 200 mg). Frontal cortex is added to centrifuging vial containing 10 ml ice-cold D2 buffer. Homogenization applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifug- ing vial. The 10 ml rinsing buffer is added to the tissue vial. Centrifuged at 18,000 rpm for 10 min. at 4°C. Final pellet is transferred to 125 x vol. of same buffer. (Ex 200 mg in 25 ml D2 buffer). Can be stored for approx. 30 min. at 0°C. Assay:
  • the compounds of the invention may be placed into the form of pharmaceutical composi ⁇ tions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, sus- pensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additio- nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and digly- cerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvi- nylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or like can be used when a sweetened vehicle can be employed.
  • the compound of the invention is dis ⁇ claimedd in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet which may be prepared by conventional tabletting tech ⁇ niques contains: Active compound 1.0 mg

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des dérivés de 1,2,5-thiadiazole selon la formule (I) dans laquelle A représente un hydrocarbure acyclique saturé de 2 à 6 atomes de carbone, droit ou ramifié; Y représente CH ou N; X représente O, S, NH, NCH3 ou CH2; R1 représente 1,2-benzisothiazol-3-yle, 1,2-benzisoxazol-3-yle, 1H-indazol-3-yle ou 1-méthyle-1H-indazol-3-yle, pouvant tous être substitués; ou R1 représente 4-fluorobenzoyle ou phényle optionnellement substitué; R2 représente aryle ou hétéroaryle optionnellement substitué. L'invention décrit également les sels pharmaceutiquement acceptables de ces dérivés. Ces dérivés et leurs sels sont utiles dans le traitement des indications concernant le système nerveux central, le système cardio-vasculaire ou les maladies gastro-intestinales.
PCT/DK1994/000198 1993-05-26 1994-05-25 Derives de 1,2,5-thiadiazole, leur preparation et leur utilisation WO1994027996A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69238/94A AU6923894A (en) 1993-05-26 1994-05-25 1,2,5-thiadiazole derivatives, their preparation and use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0604/93 1993-05-26
DK60493A DK60493D0 (da) 1993-05-26 1993-05-26 Kemiske forbindelser, deres fremstilling og anvendelse

Publications (1)

Publication Number Publication Date
WO1994027996A1 true WO1994027996A1 (fr) 1994-12-08

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DK (1) DK60493D0 (fr)
WO (1) WO1994027996A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0709381A1 (fr) * 1994-10-24 1996-05-01 Eli Lilly And Company Composés hétérocycliques, leur préparation et leur application
EP0774256A1 (fr) * 1995-11-13 1997-05-21 Eli Lilly And Company Utilisation d'une thiadiazole azacyclique ou azabicyclique dans le traitement de l'anxiété
WO2000051999A1 (fr) * 1999-03-03 2000-09-08 American Home Products Corporation Nouveaux derives de diazol utilises comme agents serotoninergiques
WO2023144764A1 (fr) 2022-01-29 2023-08-03 Suven Life Sciences Limited Composes de benzoisothiazole et de benzoisoxazole pour le traitement de troubles mentaux

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659721A (en) * 1984-02-10 1987-04-21 Ludwig Heumann & Co. Gmbh Alkanol derivatives, and pharmaceutical preparation containing these compounds
US4707482A (en) * 1984-12-10 1987-11-17 Sandoz Ltd. 4-(2,1,3-benzoxadiazol and benzothiadiazol-4-4L)-1,4-dihydropyridine-3,5-dicarboxylic acid esters useful as antihypertensives
EP0341722A2 (fr) * 1988-05-12 1989-11-15 Bristol-Myers Squibb Company Utilisation de dérivés d'oxydes de thiadiazole pour préparer une composition pharmaceutique pour traiter les troubles de la mobilité gastro-intestinale
WO1992008718A1 (fr) * 1990-11-14 1992-05-29 Pfizer Inc. Neuroleptiques a base de 4-(1,2-benzisoxazolyle)piperidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659721A (en) * 1984-02-10 1987-04-21 Ludwig Heumann & Co. Gmbh Alkanol derivatives, and pharmaceutical preparation containing these compounds
US4707482A (en) * 1984-12-10 1987-11-17 Sandoz Ltd. 4-(2,1,3-benzoxadiazol and benzothiadiazol-4-4L)-1,4-dihydropyridine-3,5-dicarboxylic acid esters useful as antihypertensives
EP0341722A2 (fr) * 1988-05-12 1989-11-15 Bristol-Myers Squibb Company Utilisation de dérivés d'oxydes de thiadiazole pour préparer une composition pharmaceutique pour traiter les troubles de la mobilité gastro-intestinale
WO1992008718A1 (fr) * 1990-11-14 1992-05-29 Pfizer Inc. Neuroleptiques a base de 4-(1,2-benzisoxazolyle)piperidine

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0709381A1 (fr) * 1994-10-24 1996-05-01 Eli Lilly And Company Composés hétérocycliques, leur préparation et leur application
US5646289A (en) * 1994-10-24 1997-07-08 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5665745A (en) * 1994-10-24 1997-09-09 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5672709A (en) * 1994-10-24 1997-09-30 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5821371A (en) * 1994-10-24 1998-10-13 Eli Lilly And Comany Heterocyclic compounds and their preparation and use
US5821370A (en) * 1994-10-24 1998-10-13 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5929247A (en) * 1994-10-24 1999-07-27 Eli Lilly And Company Heterocyclic compounds and their preparation and use
EP0774256A1 (fr) * 1995-11-13 1997-05-21 Eli Lilly And Company Utilisation d'une thiadiazole azacyclique ou azabicyclique dans le traitement de l'anxiété
US5852037A (en) * 1995-11-13 1998-12-22 Eli Lilly And Company Method for treating anxiety
WO2000051999A1 (fr) * 1999-03-03 2000-09-08 American Home Products Corporation Nouveaux derives de diazol utilises comme agents serotoninergiques
WO2023144764A1 (fr) 2022-01-29 2023-08-03 Suven Life Sciences Limited Composes de benzoisothiazole et de benzoisoxazole pour le traitement de troubles mentaux

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Publication number Publication date
DK60493D0 (da) 1993-05-26
AU6923894A (en) 1994-12-20

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