NO751350L - - Google Patents

Info

Publication number
NO751350L
NO751350L NO751350A NO751350A NO751350L NO 751350 L NO751350 L NO 751350L NO 751350 A NO751350 A NO 751350A NO 751350 A NO751350 A NO 751350A NO 751350 L NO751350 L NO 751350L
Authority
NO
Norway
Prior art keywords
urea
oxo
cyclohexen
compounds
approx
Prior art date
Application number
NO751350A
Other languages
Norwegian (no)
Inventor
P E Aldrich
G H Berezin
B I Dittmar
Original Assignee
Du Pont
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US05/555,308 external-priority patent/US4002767A/en
Application filed by Du Pont filed Critical Du Pont
Publication of NO751350L publication Critical patent/NO751350L/no

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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Foreliggende oppfinnelse angår fremstillingen av l-t-alkyl-3-(substituert cyclohexenyl)-ureaer som oppviser antihypertensiv aktivitet i varmblodige dyr. En representativ forbindelse er 1-t-butyl-3~(3-oxo-1-cyclohexcn-1-yl)-urea„ The present invention relates to the preparation of 1-t-alkyl-3-(substituted cyclohexenyl)-ureas which exhibit antihypertensive activity in warm-blooded animals. A representative compound is 1-t-butyl-3~(3-oxo-1-cyclohexcn-1-yl)-urea„

Visse guanidinderivater av t-carbinaminer har antihypertensiv (hypotensiv) aktivitet. Spesifikke eksempler er t-alkyl-cyano-guanidiner som 1-t-amyl-3-cyanoguanidin som beskrevet av S. M. Gadekar, S. Nibi og E. Cohen, J. Med. Chem •• , 11, 811 (1968); og forskjellige derivater av t-butylguanidiner som beskrevet av J. H. Short, C. W. Ours, W. J. Ranus, Jr., J. Med. Chem., 11, 1129 Certain guanidine derivatives of t-carbinamines have antihypertensive (hypotensive) activity. Specific examples are t-alkyl-cyano-guanidines such as 1-t-amyl-3-cyanoguanidine as described by S. M. Gadekar, S. Nibi and E. Cohen, J. Med. Chem•• , 11, 811 (1968); and various derivatives of t-butylguanidines as described by J. H. Short, C. W. Ours, W. J. Ranus, Jr., J. Med. Chem., 11, 1129

(1968). (1968).

Ureaderivater er imidlertid ikke representert i omfattende diskusjoner av antihypertensive midler. Disse diskusjoner innbe-fatter w. T. Corner og A. W. Gomoll, Medicinal Chemistry, 3-utgave, A. Burger, Wiley-Interscience, New York, 1970, side 1019-1064i og Medicinal Chemistry, bind 7, "Antihypertensive Agents," However, urea derivatives are not represented in comprehensive discussions of antihypertensive agents. These discussions include w. T. Corner and A. W. Gomoll, Medicinal Chemistry, 3rd edition, A. Burger, Wiley-Interscience, New York, 1970, pages 1019-1064i and Medicinal Chemistry, Volume 7, "Antihypertensive Agents,"

E. Schlittler, Academic Press, New York, 1967. De urea-avledede forbindelser ifølge foreliggende oppfinnelse gir effektiv behandling av hypertensjon, men er allikevel'forskjellige strukturelt og kjemisk fra de vanlige kjente antihypertensive midler. E. Schlittler, Academic Press, New York, 1967. The urea-derived compounds according to the present invention provide effective treatment of hypertension, but are nevertheless structurally and chemically different from the commonly known antihypertensive agents.

Foreliggende oppfinnelse angår fremstillingen av forbindelser med den generelle formel: The present invention relates to the preparation of compounds with the general formula:

hvor R^, R2ogR^er alkyl med 1-3 carbonatomer eller alkeny1 med 2 eller 3 carbonatomer, med de forbehold at det totale antall carbon- where R^, R2 and R^ are alkyl with 1-3 carbon atoms or alkeny1 with 2 or 3 carbon atoms, with the proviso that the total number of carbon

atomer av R1pluss R2pluss R^ikke overstiger 5, og at to av R.^ ,atoms of R1plus R2plus R^do not exceed 5, and that two of R.^ ,

R 2 og R3„ kan være forenet under dannelse av en cycloalkyl- eller cycloalkenylgruppe, eller passende farmasøytiske salter av disse forbindelser, som natrium-, kalium- og calciumsaltene. R 2 and R 3„ may be united to form a cycloalkyl or cycloalkenyl group, or suitable pharmaceutical salts of these compounds, such as the sodium, potassium and calcium salts.

De antihypertensive forbindelser som er mest foretrukket på grunn av deres høye grad av antihypertensiv aktivitet, er: 1 -t -buty 1 - 3- ( 3-oxo-l -cyclohexen.-1 -y 1) -urea , The antihypertensive compounds which are most preferred because of their high degree of antihypertensive activity are: 1-t-buty 1-3-(3-oxo-l-cyclohexen.-1-y 1)-urea,

l-t-amyl-3-(3-oxo-1-cyclohexen-1-y1)-urea, og 1-t-amyl-3-(3-oxo-1-cyclohexen-1-yl)-urea, and

1-(1-methylcyclopentyl)-3-(3-oxo-1-cyclohexen-1-yl)-urea. 1-(1-Methylcyclopentyl)-3-(3-oxo-1-cyclohexen-1-yl)-urea.

Forbindelsene med formel I fremstilles lett ifølge følgende ligning: The compounds of formula I are easily prepared according to the following equation:

Reaktantene oppvarmes under tilbakeløp i benzen under kata-lyse av p-toluensulfonsyre. Vannet fjernes under tilbakeløpskok-ningen, hvilket gir produktforbindelsen. The reactants are heated under reflux in benzene under the catalysis of p-toluenesulfonic acid. The water is removed during reflux, which gives the product compound.

Saltene av forbindelsene med formel I kan fremstilles ved å behandle forbindelsen med en alkoholisk eller vandig oppløsning av en ekvimolar mengde av det respektive alkalihydroxyd og inndampe til tørrhet. Da saltene av disse forbindelser hydrolyserer lett, er slike salter i alminnelighet mindre ønskelige for anvendelse ved fremstilling av farmasøytiske preparater, enn forbindelsene selv. The salts of the compounds of formula I can be prepared by treating the compound with an alcoholic or aqueous solution of an equimolar amount of the respective alkali hydroxide and evaporating to dryness. As the salts of these compounds hydrolyse easily, such salts are generally less desirable for use in the manufacture of pharmaceutical preparations than the compounds themselves.

Eksempel 1Example 1

l- t- buty1- 3-( 3- oxo- 1- cyclohexen- 1- yl)- urea1-t-buty1-3-(3-oxo-1-cyclohexen-1-yl)-urea

Til en oppløsning av 11,2 g 1,3-cyclohexandion i 250 ml benzen tilsettes 11,6 g t-butylurea og 100 mg p-toluensulfonsyre. Oppløs-ningen oppvarmes under, tilbakeløp under nitrogen under vannfjernelse i.3 timer. Ved utløpet av denne tid avkjøles oppløsningen, og det utfelte produkt fjernes ved filtrering. Produktet omkrystalliseres fra acetonitril, hvorved man får 14 g 1-t-butyl-3-(3-oxo-l-cyclo- To a solution of 11.2 g of 1,3-cyclohexanedione in 250 ml of benzene, 11.6 g of t-butyl urea and 100 mg of p-toluenesulfonic acid are added. The solution is heated under reflux under nitrogen while removing water for 3 hours. At the end of this time, the solution is cooled, and the precipitated product is removed by filtration. The product is recrystallized from acetonitrile, whereby 14 g of 1-t-butyl-3-(3-oxo-1-cyclo-

hexen-1-yl)-urea raed smeltepunkt 223 - 225°C.hexen-1-yl)-urea, melting point 223 - 225°C.

Infrarødt og NMR-spektrum stemmer overens med den tUskrevne st ruktur. Infrared and NMR spectra agree with the written structure.

Eksempel 2- 9Example 2-9

Ved anvendelse av fremgangsmåten i eksempel 1 gir reak-When using the method in example 1, react

tantene i kolonne 2 de respektive produkter i kolonne 3- the items in column 2 the respective products in column 3-

Fremgangsmåteforbindelsene kan administreres ved behandling av hypertensjon på en hvilken som helst måte som bringer den aktive forbindelse i kontakt med området for virkningen i legemet hos et varmblodig dyr. Eksempelvis kap administrasjon være parenteral, dvs. subkutan, intravenøs, intramuskulær eller intraperitoneal, alternativt eller samtidig kan administrasjon skje ad oral vei. The method compounds can be administered in the treatment of hypertension by any means that brings the active compound into contact with the site of action in the body of a warm-blooded animal. For example, administration can be parenteral, i.e. subcutaneous, intravenous, intramuscular or intraperitoneal, alternatively or at the same time administration can take place orally.

Uttrykket varmblodige dyr er her anvendt for å betegne med-lemmer av dyreriket som har en homøostatisk mekanisme og innbe-fatter pattedyr og fugler. The term warm-blooded animals is used here to denote members of the animal kingdom that have a homeostatic mechanism and include mammals and birds.

Den administrerte dose er avhengig av'alder, helse og vekten av pasienten, graden av sykdom, typen av samtidig behandling, be-handlingshyppighet og den ønskede virkning. Vanligvis kan en daglig dose av aktiv forbindelse være fra ca. 0,1 til 50 mg/kg legemsvekt. Vanligvis er fra 0,5 til ZfO , og fortrinnsvis 1,0 til 20, mg/kg pr. dag ■ administrert i én eller flere doser daglig, effektivt til å få de ønskede resultater. For de sterkere forbindelser som fremstilles ifølge oppfinnelsen, f.eks. 1-(1-methylcyclopehty1)-3-(3- oxo-1-cyclohexen-1-yl)-urea, 1-t-butyl-3-(3-oxo-1-cyclohexen-1-yl)-urea og 1-t-arayl-3-(3-oxo-1-cyclohexen-1-y1)-urea, vil dagsdoser variere fra ca. 0,1 til 20 mg/kg, fortrinnsvis 0,5 til 15 mg/kg, The administered dose depends on the age, health and weight of the patient, the degree of illness, the type of concomitant treatment, the frequency of treatment and the desired effect. Generally, a daily dose of active compound can be from approx. 0.1 to 50 mg/kg body weight. Usually from 0.5 to ZfO , and preferably 1.0 to 20, mg/kg per day ■ administered in one or more doses daily, effective in obtaining the desired results. For the stronger compounds produced according to the invention, e.g. 1-(1-methylcyclopehty1)-3-(3-oxo-1-cyclohexen-1-yl)-urea, 1-t-butyl-3-(3-oxo-1-cyclohexen-1-yl)-urea and 1-t-arayl-3-(3-oxo-1-cyclohexen-1-y1)-urea, daily doses will vary from approx. 0.1 to 20 mg/kg, preferably 0.5 to 15 mg/kg,

og helst 1,0 til 10 mg/kg.and preferably 1.0 to 10 mg/kg.

Den antihypertensive aktivitet av fremgangsmåteforbindelsene fremgår av forsøk utført i hypertensive rotter og av videre forsøk som viser en blodtrykkssenken.de virkning i normotensive hunder. The antihypertensive activity of the process compounds is evident from experiments carried out in hypertensive rats and from further experiments showing a blood pressure-lowering effect in normotensive dogs.

I disse forsøk ble rotter gjort hypertensive ved gjentatte injeksjoner av desoxycorticosteron-acetat (DOCA) og ved å gi rottene saltoppløsning å drikke i det vesentlige i henhold til metoden beskrevet av Stanton og White [Arch. Intern. Pharmacodyn., 154, 351 (1965)]. Graderte dosemengder av hver forbindelse administreres oralt til grupper på 8 hypertensive rotter. Forbindelsen fremstilles i et vandig polyvinylalkohol/acacia-medium og administreres i et volum-t il-legemsvektforhold på 5,0 ml/kg. 16 hypertensive rotter som fikk det vandige medium ad samme vei, tjente som kontrolldyr i hvert forsøk. På forskjellige tidspunkter efter behandling vanligvis 90 minutter, ble det systoliske arterielle blodtrykk av hver rotte bestemt ved en modifikasjon av mikrofon-manometermetoden |Friedman, M. og Freed, S. C., Proe. Soc. Exp. Biol. and Med,, 7_Q_, 670 (1959)]. Den dose av forbindelse som frem-bringer en reduksjon på 30 mm Hg i blodtrykket sammenlignet med det gjennomsnittlige systoliske arterielle blodtrykk hos kontroll-dyrene, bestemmes så (effektiv dose 30). Eksempelvis fikk man en ED30 på 15 mg/kg oralt med l-t-butyl-3-(3-oxo-1-cyclohexen-1-yl)-urea, og en ED30-verdi på 8,5 mg/kg ble erholdt oralt med 1-(1-methylcyclopentyl)-3-(3-oxo-l-cyclohexen-l-yl)-urea. In these experiments, rats were made hypertensive by repeated injections of desoxycorticosterone acetate (DOCA) and by giving the rats saline to drink essentially according to the method described by Stanton and White [Arch. Intern. Pharmacodyn., 154, 351 (1965)]. Graded doses of each compound are administered orally to groups of 8 hypertensive rats. The compound is prepared in an aqueous polyvinyl alcohol/acacia medium and administered at a volume-to-il body weight ratio of 5.0 ml/kg. 16 hypertensive rats receiving the aqueous medium by the same route served as control animals in each experiment. At various times after treatment, usually 90 minutes, the systolic arterial blood pressure of each rat was determined by a modification of the microphone-manometer method |Friedman, M. and Freed, S. C., Proe. Soc. Exp. Biol. and Med,, 7_Q_, 670 (1959)]. The dose of compound which produces a 30 mm Hg reduction in blood pressure compared to the mean systolic arterial blood pressure in the control animals is then determined (effective dose 30). For example, an ED30 of 15 mg/kg was obtained orally with l-t-butyl-3-(3-oxo-1-cyclohexen-1-yl)-urea, and an ED30 value of 8.5 mg/kg was obtained orally with 1-(1-Methylcyclopentyl)-3-(3-oxo-1-cyclohexen-1-yl)-urea.

I et forsøk med hunder ble disse forbindelser administrert intravenøst (i.v.) til 8 anestiserte normotensive hunder i henhold til en kumulativ doseplan. Arterielt blodtrykk ble opptegnet direkte gjennom en arteriell kanyle og en polygraf ved hvilken det bestemmes at forbindelsen viser statistisk signifikant blodtrykks - senkning i sammenligning med kont rollverdien før dosering, og til virkningen av mediet i kontrolldyr. In a dog experiment, these compounds were administered intravenously (i.v.) to 8 anesthetized normotensive dogs according to a cumulative dose schedule. Arterial blood pressure was recorded directly through an arterial cannula and a polygraph by which it is determined that the compound shows statistically significant blood pressure lowering in comparison with the control value before dosing, and to the effect of the medium in control animals.

Fremgangsmåteforbindelsene kan anvendes i nyttige farmasøy-tiske preparater i slike doseformer som tabletter, kapsler, pulver-pakker, flytende oppløsninger, suspensjoner eller eliksirer for oral administrasjon; flytende for parenteral anvendelse, og i visse tilfelle suspensjoner for parenteral anvendelse. I slike preparater vil den aktive bestanddel vanligvis være tilstede i en mengde på minst 0,5 vekt% beregnet på totalvekten av preparatet og ikke over 95 vekt%. The process compounds can be used in useful pharmaceutical preparations in such dosage forms as tablets, capsules, powder packets, liquid solutions, suspensions or elixirs for oral administration; liquid for parenteral use, and in certain cases suspensions for parenteral use. In such preparations, the active ingredient will usually be present in an amount of at least 0.5% by weight calculated on the total weight of the preparation and not more than 95% by weight.

Foruten den aktive forbindelse ifølge oppfinnelsen kan det hypertensive preparat inneholde en fast eller flytende ikke-toksisk farmasøytisk bærer for den aktive bestanddel. Besides the active compound according to the invention, the hypertensive preparation may contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.

Kapslene, tablettene og pulverne vil i alminnelighet inneholde fra ca. 1% til ca. 95%, og fortrinnsvis fra ca. 5% til 90 vekt% aktiv bestanddel. Disse doseformer inneholder fortrinnsvis fra ca. 5 mg til ca. 5C0 mg aktiv bestanddel, idet ca. 7 - The capsules, tablets and powders will generally contain from approx. 1% to approx. 95%, and preferably from approx. 5% to 90% by weight active ingredient. These dosage forms preferably contain from approx. 5 mg to approx. 5C0 mg of active ingredient, with approx. 7 -

250 mg er mest foretrukket.250 mg is most preferred.

Den farmasøytiske bærer kan være en steril væske som vann, eller en passende olje innbefattende dem av petroleum, dyr eller vegetabilsk olje av syntetisk opprinnelse, f.eks. jordnøttolje, soyabønneolje, mineralolje og sesamolje. I alminnelighet er vann, saltlake, vandig dextrose (glucose) og beslektede sukkeroppløs-ninger og glycoler som propylenglycol eller polyethylenglycoler foretrukne flytende bærere, særlig for injeksjonsoppløsninger. Sterile injiserbare oppløsninger vil vanligvis inneholde fra ca. 0,5% til ca. 25%, og fortrinnsvis ca. 1% til ca. ' 10 vekt% aktiv bestanddel. The pharmaceutical carrier may be a sterile liquid such as water, or a suitable oil including those of petroleum, animal or vegetable oil of synthetic origin, e.g. peanut oil, soybean oil, mineral oil and sesame oil. In general, water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injection solutions. Sterile injectable solutions will usually contain from approx. 0.5% to approx. 25%, and preferably approx. 1% to approx. ' 10% by weight active ingredient.

Oral administrasjon kan skje i form av en passende suspensjon eller sirup, hvori den aktive, bestanddel vanligvis vil utgjøre fra ca. 0,7 til ca. 10%, og fortrinnsvis ca, 1% til ca. 5 vekt%. Den farmasøytiske bærer i preparatet kan være et vandig medium som et aromatisk vann, en sirup eller et farmasøytisk planteslim. Oral administration can take place in the form of a suitable suspension or syrup, in which the active ingredient will usually amount to approx. 0.7 to approx. 10%, and preferably approx. 1% to approx. 5% by weight. The pharmaceutical carrier in the preparation can be an aqueous medium such as an aromatic water, a syrup or a pharmaceutical mucilage.

Passende farmasøytiske bærere er beskrevet i "Remington's Pharmaceutical Sciences" av E. W. Marin, en velkjent referansebok Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Marin, a well known reference book

i faget . In the subject .

Claims (2)

1. Fremgangsmåte ved fremstilling av forbindelser med den generelle formel: 1. Procedure for the preparation of compounds with the general formula: hvor Rn , R- og R0 er alkyl med 1-3 carbonatomer eller alkenyl med 12 3where Rn, R- and R0 are alkyl with 1-3 carbon atoms or alkenyl with 12 3 2 eller 3 carbonatomer, med de forbehold at det totale antall av carbonatomer av R pluss R„ pluss R„ ikke overstiger 5, og at to av 1 2 j Rn , R og R kan være forenet under dannelse av en cycloalkyl-12 3 eller cycloalkenylgruppe; eller passende farmasøytiske salter av disse forbindelser, karakterisert ved at en forbindelse med formelen: 2 or 3 carbon atoms, with the proviso that the total number of carbon atoms of R plus R„ plus R„ does not exceed 5, and that two of 1 2 j Rn , R and R can be united to form a cycloalkyl-12 3 or cycloalkenyl group; or suitable pharmaceutical salts of these compounds, characterized in that a compound of the formula: hvor R 1, R 2 og R i er som ovenfor angitt, omsettes med en forbindelse med formelen: where R 1, R 2 and R i are as indicated above, is reacted with a compound of the formula: 2. Fremgangsmåte ifølge krav 1 ved fremstilling av l-t-butyl-3-(3-oxo-1-cyclohexen-1-yl)-urea, karakterisert ved at 1-t-butylurea omsettes med 1j 3-cyclohexandion. ifølge krav 1 2. Process according to claim 1 for the production of 1-t-butyl-3-(3-oxo-1-cyclohexen-1-yl)-urea, characterized in that 1-t-butylurea is reacted with 1j 3-cyclohexanedione. according to claim 1 3- Fremgan gsmate/ved fremstilling av l-t-amyl-3~ (3-oxo-1-cyclohexen-1-yl)-urea, karakterisert ved at l-t-amylurea omsettes med 1,3-cyclohexandion.3- Process for preparing l-t-amyl-3~ (3-oxo-1-cyclohexen-1-yl)-urea, characterized in that l-t-amylurea is reacted with 1,3-cyclohexanedione. 4- Fremgangsmåte ifølge krav 1 ved fremstilling av l-(l-methyl-cyclopentyl)-3-(3-oxo-1-cyclohexen-1-yl)-urea, karakterisert ved at 1-(1-methylcyclopentyl)-urea omsettes med 1,3-cyclohexandion.4- Method according to claim 1 for the production of 1-(1-methyl-cyclopentyl)-3-(3-oxo-1-cyclohexen-1-yl)-urea, characterized in that 1-(1-methylcyclopentyl)-urea is reacted with 1,3-cyclohexanedione.
NO751350A 1974-04-17 1975-04-16 NO751350L (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US46169774A 1974-04-17 1974-04-17
US52544574A 1974-11-20 1974-11-20
US05/555,308 US4002767A (en) 1974-11-20 1975-03-11 1-Tertiary-alkyl-3-(substituted cyclohexenyl)ureas as antihypertensive agents

Publications (1)

Publication Number Publication Date
NO751350L true NO751350L (en) 1975-10-20

Family

ID=27412847

Family Applications (1)

Application Number Title Priority Date Filing Date
NO751350A NO751350L (en) 1974-04-17 1975-04-16

Country Status (18)

Country Link
JP (1) JPS50148337A (en)
AR (1) AR206020A1 (en)
CA (1) CA1051029A (en)
CH (1) CH611273A5 (en)
DD (1) DD119223A5 (en)
DE (1) DE2516556A1 (en)
DK (1) DK134318B (en)
ES (1) ES436647A1 (en)
FI (1) FI751127A (en)
FR (1) FR2267766B1 (en)
GB (1) GB1457245A (en)
IE (1) IE40999B1 (en)
IL (1) IL47097A (en)
LU (1) LU72305A1 (en)
NL (1) NL7504568A (en)
NO (1) NO751350L (en)
PH (1) PH11869A (en)
SE (1) SE398116B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0004959A1 (en) * 1978-04-24 1979-10-31 Ciba-Geigy Ag Process for preparing 3-oxo-cyclopentenyl ureas, compounds thus obtained, pharmaceutical compositions containing them and 3-oxo-cyclopentenylisothio ureas
JPS54151218A (en) * 1978-04-24 1979-11-28 British Hovercraft Corp Ltd Split preventive device
ATE63901T1 (en) * 1987-02-09 1991-06-15 Ciba Geigy Ag NEW CYCLOHEXANDIONES.

Also Published As

Publication number Publication date
DK163975A (en) 1975-10-18
PH11869A (en) 1978-08-04
SE398116B (en) 1977-12-05
FI751127A (en) 1975-10-18
IL47097A (en) 1978-03-10
IL47097A0 (en) 1975-06-25
FR2267766B1 (en) 1978-10-06
IE40999B1 (en) 1979-09-26
LU72305A1 (en) 1976-03-17
GB1457245A (en) 1976-12-01
JPS50148337A (en) 1975-11-27
IE40999L (en) 1975-10-17
FR2267766A1 (en) 1975-11-14
AU8013475A (en) 1976-10-21
DK134318B (en) 1976-10-18
SE7503522L (en) 1975-10-20
AR206020A1 (en) 1976-06-23
DK134318C (en) 1977-04-18
DD119223A5 (en) 1976-04-12
CH611273A5 (en) 1979-05-31
CA1051029A (en) 1979-03-20
ES436647A1 (en) 1977-08-01
NL7504568A (en) 1975-10-21
DE2516556A1 (en) 1975-10-30

Similar Documents

Publication Publication Date Title
US4009847A (en) 1-Tertiary-alkyl-3-(substituted thienyl)ureas and 1-tertiary-alkyl-3-(substituted thietyl)ureas as antihypertensive agents
DE1445154C3 (en) 1,4-Dihydro-1,8-naphthyridinderi derivatives and a process for their preparation
FI60560B (en) FRAMEWORK FOR THE SUBSTANCE OF THERAPEUTIC SUBSTITUTES SUBSTITUTES OF PYRIDYLGUANIDINE SAMT DERAS TAUTOMERA FORMER
JP6311038B2 (en) Nitroxyl donors with improved therapeutic index
EP1807412A1 (en) Cyclic diarly ureas suitable as tyrosine kinase inhibitors
EP2943463B1 (en) Fluorinated cbd compounds, compositions and uses thereof
IL29569A (en) 1,4-dihydropyridine derivatives and their production
CS240974B2 (en) Production method of n formyl a n-hydroxymethyl-3-phenoxy-1-azetidincarboxamides
SU1470190A3 (en) Method of producing 6-/4ъ-acetyl-2-methylimidazol-1-yl/-8-methyl-2-(1n)-carbostyrene
PL140765B1 (en) Process for preparing 3-phenoxy-1-azetidinecarboxamides
NO751350L (en)
WO2014084658A1 (en) Composition for preventing or treating heart disease
WO2004050612A1 (en) S-substituted n-1-[(hetero)aryl]alkyl-n′-[(hetero)aryl] alkylysothiocarbamides, method for the production thereof, physiologically active s-substituted n-1-[(hetero)aryl]alkyl-n′-[(hetero)aryl]alkylysothiocarbamides, a pharmaceutical compound and curing method
DE2538424A1 (en) NEW OXAZOLIDINONE, METHOD OF PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
SU1468424A3 (en) Method of producing derivatives of hydantoin
JP2000500465A (en) Blood regulatory compounds
CN114716366A (en) 3-hydroxypyridine-4-ketone derivatives and application thereof in inhibition of renal cell iron death
CN1455770A (en) (2-azabicyclo [2,2,1] hept-7-yl] methanol derivatives as nicotinic acetylcholine receptor agonisis
CH636353A5 (en) ENOLAETHER AND METHOD FOR THE PRODUCTION THEREOF.
NO144070B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF FURYLURAES WITH ANTI-HYPERTENSIVE EFFECT
US4001425A (en) Methods of treating hypertension and pharmaceutical compositions comprising 1-tertiary-alkyl-3-(substituted furyl)ureas as antihypertensive agents
JPS5935387B2 (en) Di-substituted phenol ethers of 3-amino-2-hydroxypropane, their preparation and pharmaceutical uses
US4070479A (en) 1-Tertiary-alkyl-3-(substituted thienyl)ureas and 1-tertiary-alkyl-3-(substituted thietyl)ureas as antihypertensive agents
US4094988A (en) Method of treating gastric ulcers using 5,6-dihydro-1,4-dithiinoxides
EP0114950A1 (en) 1-Cyano-3-(fluoralkyl)guanidines