ITMI940916A1 - PRODUCTS PROVIDED WITH A NITROESTER TERMINAL GROUP EQUIPPED WITH ANTI-INFLAMMATORY AND / OR ANALGESIC ACTIVITY - Google Patents
PRODUCTS PROVIDED WITH A NITROESTER TERMINAL GROUP EQUIPPED WITH ANTI-INFLAMMATORY AND / OR ANALGESIC ACTIVITY Download PDFInfo
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- ITMI940916A1 ITMI940916A1 IT000916A ITMI940916A ITMI940916A1 IT MI940916 A1 ITMI940916 A1 IT MI940916A1 IT 000916 A IT000916 A IT 000916A IT MI940916 A ITMI940916 A IT MI940916A IT MI940916 A1 ITMI940916 A1 IT MI940916A1
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- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 18
- 230000001760 anti-analgesic effect Effects 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- 229940035676 analgesics Drugs 0.000 claims description 6
- 239000000730 antalgic agent Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 2
- 201000006474 Brain Ischemia Diseases 0.000 claims description 2
- 206010039966 Senile dementia Diseases 0.000 claims description 2
- 210000000748 cardiovascular system Anatomy 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 230000002107 myocardial effect Effects 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 4
- 229960004752 ketorolac Drugs 0.000 description 4
- 229940124599 anti-inflammatory drug Drugs 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 229960000905 indomethacin Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- -1 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxyamide Chemical compound 0.000 description 2
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- BRGYOIOOHWNSMI-UHFFFAOYSA-N 2,3-dihydro-1h-pyrrol-5-yl(phenyl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CCCN1 BRGYOIOOHWNSMI-UHFFFAOYSA-N 0.000 description 1
- LOWWSYWGAKCKLG-UHFFFAOYSA-N 2-(6-methoxynaphthalen-1-yl)acetic acid Chemical compound OC(=O)CC1=CC=CC2=CC(OC)=CC=C21 LOWWSYWGAKCKLG-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- FDDQRDMHICUGQC-UHFFFAOYSA-N pyrrole-1-carboxylic acid Chemical compound OC(=O)N1C=CC=C1 FDDQRDMHICUGQC-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
OGGETTO DELL'INVENZIONE OBJECT OF THE INVENTION
La presente invenzione ha per oggetto prodotti provvisti di un gruppo nitroestere terminale dotati di attivita' anti-infiammatoria e/o analgesica ed un procedimento per la loro preparazione. The present invention relates to products provided with a terminal nitroester group endowed with anti-inflammatory and / or analgesic activity and a process for their preparation.
Pure oggetto della presente invenzione e' l'impiego di tali prodotti come analgesici e/o anti-inflaminatori nonché' le composizioni farmaceutiche ad attività' analgesica e/o anti-inf iammatoria contenenti come principio attivo almeno uno dei suddetti prodotti provvisti di un gruppo nitroestere terminale. The object of the present invention is also the use of such products as analgesics and / or anti-inflammatory agents as well as pharmaceutical compositions with analgesic and / or anti-inflammatory activity containing as active principle at least one of the above products provided with a group terminal nitroester.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
Come e' noto, i farmaci ad attività' anti-infiammatoria ed analgesica comunemente impiegati, sono purtroppo caratterizzati da effetti collaterali negativi dovuti al fenomeno della tossicità'. Tale fenomeno ha assunto proporzioni preoccupanti, sia dal punto di vista sociale che economico; ad esempio solo negli Stati Uniti d'America si registrano annualmente migliaia di morti e centinaia di migliaia di ospedalizzazioni provocate dalla tossicità' di tali farmaci, con incidenza sulla spesa sanitaria di circa 6 miliardi di dollari. Dati analoghi si ricavano da Europa e Giappone. As is known, the commonly used anti-inflammatory and analgesic drugs are unfortunately characterized by negative side effects due to the phenomenon of toxicity. This phenomenon has assumed worrying proportions, both from a social and an economic point of view; for example, in the United States of America alone, thousands of deaths and hundreds of thousands of hospitalizations caused by the toxicity of these drugs are recorded annually, with an impact on health care costs of approximately 6 billion dollars. Similar data are obtained from Europe and Japan.
Tra i farmaci noti ad attività' anti-infiammatoria e/o analgesica, vi sono alcuni prodotti particolarmente tossici, quali ad esempio l'acido 5-benzoil-l,2-diidro-3H-pirrolo[l,2-a]pirrolo-l-carbossilico o Ketorolac [W.H.ROOKS et al. Agents Actions 12,684 (1982)] e l'acido l-( 4-clorobenzoil)-5-metossi-2-metil-lH-indol-3-acetico o Indometacina - [C.D.KLAASSEN, Toxicol. Appl.Pharmacol. 38,127 (1976)]. Notevoli problemi di tossicità' gastrointestinale e generale sono stati riscontrati anche per la 5-cloro-3-(2-tenoil)-2-ossindolo-l-carbossiammide o Tenidap [P.KATZ et al. Arthrititis Rheum. 31, Suppl.,S52 (1988)]. In particolare il Ketorolac e' stato ritirato dal commercio in alcuni paesi proprio a causa della sua tossicità' gastrointestinale, mentre l 'Indometacina è uno dei farmaci anti-infiammatori che ha provocato il maggior numero di morti dall'anno della ,sua introduzione in commercio. Rispetto ad altri farmaci anti-infiammatori e/o analgesici noti, Ketorolac ed Indometacina provocano, a causa degli effetti collaterali già' descritti, lesioni assai estese ed in particolare per quanto riguarda la tossicità' gastrointestinale, sono stati riscontrati decessi avvenuti anche in pazienti in età' infantile. Among the known drugs with anti-inflammatory and / or analgesic activity, there are some particularly toxic products, such as the acid 5-benzoyl-1,2-dihydro-3H-pyrrole [1,2-a] pyrrole- 1-carboxylic or Ketorolac [W.H.ROOKS et al. Agents Actions 12,684 (1982)] and 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid or Indomethacin - [C.D.KLAASSEN, Toxicol. Appl.Pharmacol. 38.127 (1976)]. Considerable gastrointestinal and general toxicity problems were also found for 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxyamide or Tenidap [P.KATZ et al. Arthrititis Rheum. 31, Suppl., S52 (1988)]. In particular, Ketorolac has been withdrawn from the market in some countries precisely because of its gastrointestinal toxicity, while Indomethacin is one of the anti-inflammatory drugs that caused the greatest number of deaths since the year of its introduction on the market. . Compared to other known anti-inflammatory and / or analgesic drugs, Ketorolac and Indomethacin cause, due to the side effects already described, very extensive lesions and in particular as regards gastrointestinal toxicity, deaths have also been reported in patients in childhood.
Analoghi problemi sono stati riscontrati quando vengono impiegati 4-idrossi-2-metil-N-2-piridinil- 2H-tieno Similar problems have been encountered when 4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno are used
[2,3-e] -1,2-tiazina-3-carbossiammide 1,1-diossido o Tenoxicam o 4-idrossi-2-metil-N-2- piridinil- 2H-1,2 benzotiazina-3-carbossiammide l,l-diossido o Piroxicam, nonché' quando si impiega acido-6-metossi-2-naftilacetico o un suo precursore. ' [2,3-e] -1,2-thiazine-3-carboxyamide 1,1-dioxide or Tenoxicam or 4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2 benzothiazine-3-carboxyamide l , 1-dioxide or Piroxicam, as well as when 6-methoxy-2-naphthylacetic acid or a precursor thereof is used. '
Appare quindi evidente la necessita' di poter disporre di farmaci che, pur mantenendo buona attività' antiinfiammatoria e/o analgesica, risultino in generale non tossici. It therefore appears evident the need to be able to dispose of drugs which, while maintaining good anti-inflammatory and / or analgesic activity, are generally non-toxic.
SCOPI DELL'INVENZIONE AIMS OF THE INVENTION
Scopo della presente invenzione e' quello di mettere a disposizione prodotti dotati di attività' antiinfiammatoria e/o analgesica che risultino ben tollerati rispetto ai noti farmaci ad attività' anti-infiammatoria e/p analgesica. The purpose of the present invention is to provide products with anti-inflammatory and / or analgesic activity which are well tolerated with respect to known drugs with anti-inflammatory and / or analgesic activity.
Altro scopo della presente invenzione e' quello di realizzare un procedimento per la preparazione di prodotti ad attività' anti-infiammatoria e/o analgesica che risultino ben tollerati. Another purpose of the present invention is to provide a process for the preparation of products with anti-inflammatory and / or analgesic activity which are well tolerated.
Pure un altro scopo ancora della presente invenzione e' quello di mettere a disposizione composizioni farmaceutiche ad attività' anti-infiammatoria e/o analgesica che risultino molto ben tollerate. Yet another object of the present invention is to provide pharmaceutical compositions with anti-inflammatory and / or analgesic activity which are very well tolerated.
DESCRIZIONE DELL'INVENZIONE DESCRIPTION OF THE INVENTION
Questi ed altri scopi ancora e relativi vantaggi che meglio saranno chiariti dalla descrizione che segue, vengono raggiunti da prodotti aventi la seguente formula generale: These and other objects and related advantages which will be better clarified by the following description, are achieved by products having the following general formula:
dove : where is it :
R e ' scelto tra R is chosen from
y e' scelto tra y is chosen from
- catene alchiliche C1-C10 lineari o.ramificate, sostituite o non sostituite; - linear or branched, substituted or unsubstituted C1-C10 alkyl chains;
Piu' particolarmente, sempre secondo la presente invenzione, quando detto R e' : More particularly, always according to the present invention, when said R is:
e detto Y e' uguale ad.una catena alchilica lineare a 4 atomi di carbonio non sostituita, il prodotto risultante ha la seguente fòrmula: and said Y is equal to an unsubstituted 4-carbon linear alkyl chain, the resulting product has the following formula:
Si e' visto infatti che la presenza di un gruppo portatore di ossido nitrico esogeno quale ad esempio il gruppo nitroestere terminale sui composti di formula (I), e· in grado di prevenire o quantomeno di ridurre l'eventuale tossicità' generale ed in particolare gastrointestinale caratteristica dei noti composti ad attività anti-infiammatoria e/o analgesica. It has in fact been seen that the presence of an exogenous nitric oxide carrier group such as the terminal nitroester group on the compounds of formula (I), is able to prevent or at least reduce any general toxicity and in particular gastrointestinal characteristic of the known compounds with anti-inflammatory and / or analgesic activity.
I composti di formula generale (I) hanno mostrato eccellente efficacia per quanto riguarda l'attività' anti-infiammatoria e/o analgesica e soprattutto hanno mostrato un'ottima tollerabilità generale. Detti composti di formula (I) sono risultati di estrema utilità' nel trattamento terapeutico degli stati infiammatori, nel trattamento delle patologie che richiedono l'impiego di analgesici, nonché' nel trattamento delle patologie che prevedono l'impiego abbinato di analgesici ed anti-infiammatori, ed hanno dimostrato migliore maneggevolezza e/o efficacia proprio grazie alla loro buona tollerabilità'. The compounds of general formula (I) showed excellent efficacy as regards the anti-inflammatory and / or analgesic activity and above all they showed excellent general tolerability. Said compounds of formula (I) have proved extremely useful in the therapeutic treatment of inflammatory states, in the treatment of pathologies that require the use of analgesics, as well as in the treatment of pathologies that require the combined use of analgesics and anti-inflammatories. , and have shown better handling and / or effectiveness thanks to their good tolerability '.
I composti di formula (I) sono anche utilizzabili nel trattamento delle affezioni a carico dell'apparato cardiovascolare e del sistema nervoso centrale, nel trattamento delle ischemie miocardiche e cerebrali, in episodi di trombosi arteriosa ed in condizioni di demenza senile. The compounds of formula (I) can also be used in the treatment of diseases affecting the cardiovascular system and the central nervous system, in the treatment of myocardial and cerebral ischemias, in episodes of arterial thrombosis and in conditions of senile dementia.
Inoltre, quando R e' uguale a (V), i prodotti di formula (I) mostrano .elevata tollerabilità generale ed anche una migliore efficacia nei trattamenti patologici degli stati infiammatori e/o analgesici- per i quali vengono impiegati. Moreover, when R is equal to (V), the products of formula (I) show a high general tolerability and also a better efficacy in the pathological treatments of the inflammatory and / or analgesic states for which they are used.
Sempre secondo la presente invenzione, i prodotti di formula generale .(I) quando R e' (II), (III) e (IV)., vengono preparati secondo un procedimento che prevede le seguenti fasi: Still according to the present invention, the products of general formula (I) when R is (II), (III) and (IV)., Are prepared according to a process which includes the following steps:
- reazione tra il composto di formula generale - reaction between the compound of general formula
opportunamente attivato ed il composto di formula generale suitably activated and the compound of general formula
dove y e' scelto tra where y is chosen from
- catene alchiliche C1-C10 lineari o ramificate, sostituite o non sostituite; - linear or branched C1-C10 alkyl chains, substituted or unsubstituted;
ed X può' essere uguale o diverso da X', ma entrambi scelti tra: Cl, Br, I, con ottenimento dei prodotti aventi la seguente formula: and X can 'be the same or different from X', but both are chosen from: Cl, Br, I, obtaining the products having the following formula:
- reazione del prodotto di formula (XIV) con un composto in grado di formare un nitròestere terminale quale ad esempio argento nitrato, - reaction of the product of formula (XIV) with a compound capable of forming a terminal nitròester such as for example silver nitrate,
con ottenimento dei prodotti di formula generale (I). with obtaining the products of general formula (I).
Con riferimento all'Esempio 1 qui di seguito riportato, dato a solo titolo indicativo e non limitativo del presente trovato, viene descritta la preparazione del composto di formula (XI). With reference to Example 1 reported below, given as an indication only and not limitative of the present invention, the preparation of the compound of formula (XI) is described.
ESEMPIO 1 EXAMPLE 1
Preparazione del composto di formula: Preparation of the compound of formula:
a) In una sospensione di sodio idruro all'80% (0.16 g) in DMF (15 mi) vennero gocciolati sotto agitazione 1.15 a) In a suspension of 80% sodium hydride (0.16 g) in DMF (15 ml) 1.15 were dropped under stirring
g di Ketorolac sciolti in 20 mi di DMF. g of Ketorolac dissolved in 20 ml of DMF.
La miscela di reazione venne lasciata sotto agitazione a 40°C per 15 minuti, venne aggiunto 1 il di 1,4-dibromobutano e la miscela di reazione venne lasciata sotto agitazione a temperatura ambiente per una notte. The reaction mixture was stirred at 40 ° C for 15 minutes, 1 l of 1,4-dibromobutane was added and the reaction mixture was stirred at room temperature overnight.
Il solvente venne quindi evaporato a préssione ridotta ed il residuo trattato con acqua e cloruro di metilene. La fase organica venne separata, anidrificata su sodio solfato ed il solvente venne allontanato a pressione ridotta a dare un residuo che venne purificato per cromatografia su gel di silice utilizzando una miscela eluente etere/etere di petrolio 4/6 (v/v). Furono raccolte le frazioni di testa, venne evaporato il solvente a pressione ridotta e furono ottenuti 0,75 g di prodotto di formula: The solvent was then evaporated at reduced pressure and the residue treated with water and methylene chloride. The organic phase was separated, dried over sodium sulphate and the solvent was removed under reduced pressure to give a residue which was purified by chromatography on silica gel using a 4/6 (v / v) ether / petroleum ether eluent mixture. The overhead fractions were collected, the solvent was evaporated under reduced pressure and 0.75 g of the formula product were obtained:
b) Ad una soluzione di (XI) (0.75 g) in 20 ml di acetonitrile, venne aggiunta una soluzione di AgN03 (0.5 g) in 5 ml di acetonitrile. La miscela di reazione venne lasciata sotto agitazione a temperatura ambiente per 48 ore. Il solvente venne quindi allontanato sotto pressione ed il residuo trattato con acqua e cloruro di metilene. La fase organica venne separata, anidrificata su sodio solfato e privata del solvente a pressione ridotta. Il residuo venne purificato per filtrazione su gel di silice utilizzando una miscela eluente etere/etere di petrolio 4/6. Furono riunite le frazioni di testa, venne evaporato il solvente a pressione ridotta e furono ottenuti 0.35 g di (XI). b) A solution of AgN03 (0.5 g) in 5 ml of acetonitrile was added to a solution of (XI) (0.75 g) in 20 ml of acetonitrile. The reaction mixture was left under stirring at room temperature for 48 hours. The solvent was then removed under pressure and the residue treated with water and methylene chloride. The organic phase was separated, dried over sodium sulphate and deprived of the solvent under reduced pressure. The residue was purified by filtration on silica gel using a 4/6 ether / petroleum ether eluent mixture. The overhead fractions were combined, the solvent was evaporated under reduced pressure and 0.35 g of (XI) was obtained.
Sono stati effettuati degli studi biologici sui composti di formula (I) ed in particolare sui composti seguenti: Biological studies have been carried out on the compounds of formula (I) and in particular on the following compounds:
Sono state determinate l'attività· anti-infiammatoria, la tollerabilità' gastrointestinale e l'attività' antiaggregante piastrinica dei suddetti composti. The anti-inflammatory activity, the gastrointestinal tolerability and the antiplatelet activity of the above compounds were determined.
L'attività' anti-infiammatoria e' stata determinata mediante il metodo dell'edema da carragenina nel ratto, come descritto da C.A.WINTER et al. (1962) Proc.Soc.Exp.Biol .Med. 111,544. The anti-inflammatory activity was determined by the carrageenan edema method in the rat, as described by C.A. WINTER et al. (1962) Proc.Soc.Exp.Biol .Med. 111.544.
La tollerabilità' gastrointestinale e’ stata valutata per somministrazione orale nel ratto. Gastrointestinal tolerability was evaluated by oral administration in the rat.
L'attività' anti-aggregante piastrinica e' stata determinata su piastrine umane stimolate da acido arachidonico, secondo il metodo descritto da V.BERTELE et al. (1983) Science 220, 517. The anti-aggregating activity of platelets was determined on human platelets stimulated by arachidonic acid, according to the method described by V.BERTELE et al. (1983) Science 220, 517.
I risultati sono riportati in Tabella 1, come valori relativi all'attività' anti-infiammatoria, antiaggregante e della tollerabilità' gastrointestinale dei composti in esame, espressi come rapporto di potenza relativo al prodotto di base preso come standard unita- 1 rio. The results are reported in Table 1, as values relating to the anti-inflammatory, antiplatelet activity and gastrointestinal tolerability of the compounds under examination, expressed as a power ratio relative to the basic product taken as a unit standard.
E' stata valutata approssivamente la tossicità' acuta dei composti in esame per somministrazione orale di una dose singola di sostanza a gruppi di 10 topini. L'incidenza di letalità' e la comparsa di sintomatologia tossica sono state riportate entro un periodo di osservazione di 14 giorni. Anche dopo somministrazione di una dose di 100 mg/Kg di ciascun composto, gli animali non manifestano alcun segno di tossicità' apparente. The acute toxicity of the test compounds by oral administration of a single dose of substance to groups of 10 mice was approximately evaluated. The incidence of lethality and the occurrence of toxic symptoms were reported within an observation period of 14 days. Even after administration of a dose of 100 mg / kg of each compound, the animals did not show any signs of apparent toxicity.
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Priority Applications (34)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940916A IT1269735B (en) | 1994-05-10 | 1994-05-10 | Products having a terminal nitroester group with anti- inflammatory and/or analgesic activity |
| AU78092/94A AU678063B2 (en) | 1993-10-06 | 1994-09-23 | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| US08/624,508 US5700947A (en) | 1993-10-06 | 1994-09-23 | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| ES94928801T ES2120070T3 (en) | 1993-10-06 | 1994-09-23 | NITRIC ESTERS GIVEN WITH AN ANTI-INFLAMMATORY AND / OR ANALGESICAL ACTIVITY AND ITS PREPARATION PROCEDURE. |
| BR9407749A BR9407749A (en) | 1993-10-06 | 1994-09-23 | Process acid derivatives for their preparation and pharmaceutical compositions |
| EP94928801A EP0722434B1 (en) | 1993-10-06 | 1994-09-23 | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| DE69412109T DE69412109T2 (en) | 1993-10-06 | 1994-09-23 | SALT ACID ESTER WITH AN ANTI-INFLAMMATORY AND / OR PAIN-RELATING EFFECT AND METHOD FOR THE PRODUCTION THEREOF |
| AT94928801T ATE168986T1 (en) | 1993-10-06 | 1994-09-23 | SALT ACID ESTERS WITH ANTI-INFLAMMATORY AND/OR PAIN-RELIEVING EFFECT AND METHOD FOR THE PRODUCTION THEREOF |
| JP51058595A JP3775796B2 (en) | 1993-10-06 | 1994-09-23 | Nitrate esters having anti-inflammatory activity and / or analgesic activity and methods for producing them |
| KR1019960701746A KR100343243B1 (en) | 1993-10-06 | 1994-09-23 | Nitric esters with anti-inflammatory and / or analgesic activity and methods for their preparation |
| PCT/EP1994/003182 WO1995009831A1 (en) | 1993-10-06 | 1994-09-23 | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| HU9600874A HU218923B (en) | 1993-10-06 | 1994-09-23 | Nitric esters having anti-inflammatory and/or analgesic activity, pharmaceutical compns. contg. them and process for their preparation |
| SI9430181T SI0722434T1 (en) | 1993-10-06 | 1994-09-23 | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| RU96108907A RU2136653C1 (en) | 1993-10-06 | 1994-09-23 | Nitroesters exhibiting anti-inflammatory and/or analgetic activity, methods of their synthesis, pharmaceutical compositions |
| DK94928801T DK0722434T3 (en) | 1993-10-06 | 1994-09-23 | Nitric acid esters having anti-inflammatory and / or analgesic activity and methods for their preparation |
| CA002173582A CA2173582C (en) | 1993-10-06 | 1994-09-23 | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| US08/737,426 US5861426A (en) | 1994-05-10 | 1995-04-04 | Nitro compounds of the formula A-Xi -NO2 and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities |
| CA002190087A CA2190087C (en) | 1994-05-10 | 1995-04-04 | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities |
| AU22156/95A AU702662B2 (en) | 1994-05-10 | 1995-04-04 | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic acitivities |
| KR1019960706360A KR100387359B1 (en) | 1994-05-10 | 1995-04-04 | Anti-inflammatory, non-allergic and anti-thrombotic nitro compounds and their compositions |
| AT95915185T ATE184589T1 (en) | 1994-05-10 | 1995-04-04 | NITRO COMPOUNDS AND PREPARATIONS THEREOF HAVING ANTI-INFLAMMATORY, PAIN-RELIEVING AND ANTITHROMBOTIC EFFECTS |
| EP95915185A EP0759899B1 (en) | 1994-05-10 | 1995-04-04 | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic acitivities |
| DE69512232T DE69512232T2 (en) | 1994-05-10 | 1995-04-04 | NITRO CONNECTIONS AND THEIR PREPARATIONS WITH ANTI-FLAMMING, PAINT RELEASING AND ANTITHROMBOTIC EFFECTS |
| DK95915185T DK0759899T3 (en) | 1994-05-10 | 1995-04-04 | Nitro compounds and their compositions with anti-inflammatory, analgesic and antithrombotic activities |
| BR9507634A BR9507634A (en) | 1994-05-10 | 1995-04-04 | Compounds or their compositions and their use |
| ES95915185T ES2139199T3 (en) | 1994-05-10 | 1995-04-04 | NITRO COMPOUNDS AND COMPOSITIONS THAT CONTAIN THEM THAT PRESENT AN ANTI-INFLAMMATORY, ANALGESICAL AND ANTI-THROMBOTIC ACTIVITY. |
| RU96123280A RU2145595C1 (en) | 1994-05-10 | 1995-04-04 | Nitroxycompounds and pharmaceutical composition based on thereof showing anti-inflammatory, analgetic and antithrombocytic activity |
| JP52861595A JP4043046B2 (en) | 1994-05-10 | 1995-04-04 | Nitro compounds having anti-inflammatory, analgesic and antithrombotic activity and compositions thereof |
| PCT/EP1995/001233 WO1995030641A1 (en) | 1994-05-10 | 1995-04-04 | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic acitivities |
| SI9530312T SI0759899T1 (en) | 1994-05-10 | 1995-04-04 | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic acitivities |
| HU9603107A HU227280B1 (en) | 1994-05-10 | 1995-04-04 | Nitro compounds and their compositions having anti-inflammatory, analgesic and antithrombotic acitivities |
| IL11325595A IL113255A0 (en) | 1994-05-10 | 1995-04-05 | New compounds and their compositions having anti-inflammatory analgesic and anti-thrombotic activities |
| US08/902,570 US5780495A (en) | 1993-10-06 | 1997-07-29 | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| GR990403169T GR3032078T3 (en) | 1994-05-10 | 1999-12-08 | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic acitivities |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI940916A IT1269735B (en) | 1994-05-10 | 1994-05-10 | Products having a terminal nitroester group with anti- inflammatory and/or analgesic activity |
Publications (3)
| Publication Number | Publication Date |
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| ITMI940916A0 ITMI940916A0 (en) | 1994-05-10 |
| ITMI940916A1 true ITMI940916A1 (en) | 1995-11-10 |
| IT1269735B IT1269735B (en) | 1997-04-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| ITMI940916A IT1269735B (en) | 1993-10-06 | 1994-05-10 | Products having a terminal nitroester group with anti- inflammatory and/or analgesic activity |
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|---|---|
| IT (1) | IT1269735B (en) |
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| Publication number | Publication date |
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| ITMI940916A0 (en) | 1994-05-10 |
| IT1269735B (en) | 1997-04-15 |
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