FI57100C - PROCEDURE FOR THE FRAMEWORK OF THIOALKYLAMINE N- (3-THIOPHENYLPROPYL) -N- (3,3-DIPHENYLPROPYL) AMIN JAEMTE DESS SALTER MED PHARMACOLOGICAL EQUIPMENT - Google Patents
PROCEDURE FOR THE FRAMEWORK OF THIOALKYLAMINE N- (3-THIOPHENYLPROPYL) -N- (3,3-DIPHENYLPROPYL) AMIN JAEMTE DESS SALTER MED PHARMACOLOGICAL EQUIPMENT Download PDFInfo
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- FI57100C FI57100C FI1946/72A FI194672A FI57100C FI 57100 C FI57100 C FI 57100C FI 1946/72 A FI1946/72 A FI 1946/72A FI 194672 A FI194672 A FI 194672A FI 57100 C FI57100 C FI 57100C
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- FI
- Finland
- Prior art keywords
- formula
- amine
- compound
- thiophenylpropyl
- diphenylpropyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 7
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940005657 pyrophosphoric acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 238000005353 urine analysis Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
R3F*1 Μ 01) koulu™*,OLKAIN ,„1nnR3F * 1 Μ 01) school ™ *, SHOULDER, „1nn
WÄ l J l ; utlAgcnincsskkipt 9 /1UUWÄ l J l; utlAgcnincsskkipt 9 / 1UU
Patent läedclelat ^ ^ (51) Kv.lk?/ine.a.^ C 07 C 149/42 SUOMI—FINLAND (21) »»»«***— - Pwwfwaimnn 19^6/72 (22) Hakamlipttvt—AnaBknlnpdag 07.07 ·72 (23) AlkupiM—GIMgh«tad«g 07.07.72 (41) Tullut |ulktMlul — Bllvlt offontllg l6.01.73Patent reversal ^ ^ (51) Kv.lk?/ine.a.^ C 07 C 149/42 FINLAND — FINLAND (21) »» »« *** - - Pwwfwaimnn 19 ^ 6/72 (22) Hakamlipttvt — AnaBknlnpdag 07.07 · 72 (23) AlkupiM — GIMgh «tad« g 07.07.72 (41) Tullut | ulktMlul - Bllvlt offontllg l6.01.73
Patentti· Ja r.ki,t.HhallltU· NlhtMktlpwon |. kuuhullu** p*m._Patent · Ja r.ki, t.HhallltU · NlhtMktlpwon |. Crescent ** p * m._
Patant- och ragietaratyralsan ' ' Ameiun utkgd oeh uti^krifun pubifcmd 29.02.80 (32)(33)(31) ^««T etuellwu*—Btglrd priori»·* 15.07.71Patant- och ragietaratyralsan '' Ameiun utkgd oeh uti ^ krifun pubifcmd 29.02.80 (32) (33) (31) ^ «« T etuellwu * —Btglrd priori »· * 15.07.71
Italia-Italien(lT) 3^76 A/71 (71) ALFA farmaceutici spa, Via Ragazzi del '99 n. 5» U0133 Bologna, Italia- ' Italien(lT) (72) Pietro Bianchini, Modena, Eupremio Vitale, Bologna, Guido Guerra,Italia-Italien (lT) 3 ^ 76 A / 71 (71) ALFA pharmaceutical spa, Via Ragazzi del '99 n. 5 »U0133 Bologna, Italy- 'Italien (lT) (72) Pietro Bianchini, Modena, Eupremio Vitale, Bologna , Guido Guerra,
Bologna, Giustino Censoni, Bologna, Italia-Italien(lT) (7^) Forssen & Salomaa Oy (5k) Menetelmä uuden tioalkyyliamiinin, N-(3-tiofenyyli-propyyli)-N-(3,3-di-fenyylipropyyli)amiinin ja sen suolojen valmistamiseksi, jolla on farmakologisia ominaisuuksia - Förfarande för framställning av en ny tio-alkylamin, N-(3-tiofenylpropyl)-N-(3,3-difenylpropyl)amin jämte dess salter, med farmakologiska egenskaperBologna, Giustino Censoni, Bologna, Italy-Italy (1T) (7 ^) Forssen & Salomaa Oy (5k) Method for the preparation of a new thioalkylamine, N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine and its salts having pharmacological properties - Förfarande för framställning av en ny thio-alkylamine, N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) Amine residue in the form of pharmacological agents
Esillä oleva keksintö koskee menetelmää uuden kaavan 0 „ CH - CH2 - CH2 - NH - CH2 - CH2 - CH2 - S - Γ 7 (I) ' o mukaisen tioalkyyliamiinin ja sen suolojen valmistamiseksi. Keksinnön mukaisella uudella tioalkyyliamiinilla on arvokkaita farmakologisia ominaisuuksia.The present invention relates to a process for the preparation of a new thioalkylamine of the formula O-CH-CH2-CH2-NH-CH2-CH2-CH2-S-Γ 7 (I) 'o and its salts. The novel thioalkylamine of the invention has valuable pharmacological properties.
Tämän keksinnön mukainen yhdiste, jolla on yllä oleva kaava (I), on osoittautunut huomattavan aktiiviseksi käsiteltäessä kolmea tavallista kokeellisesti aikaansaatua mahahaavatyyppiä, sillä on heikko spasmolyyttinen teho ja se on hyödyllinen ihmislääketieteessä.The compound of the present invention represented by the above formula (I) has been shown to be remarkably active in the treatment of three common experimentally induced types of gastric ulcers, has weak spasmolytic activity and is useful in human medicine.
Yllä olevan kaavan (1) mukaisen yhdisteen farmaseuttisesti hyväksyttäviin suoloihin kuuluvat suolat, jotka on muodostettu happojen kanssa, jotka eivät 2 57100 lisää esillä olevan yhdisteen sisällistä myrkyllisyyttä. Nämä hapot voivat olla sekä epäorgaanisia että orgaanisia. Epäorgaanisista hapoista voidaan käyttää esimerkiksi seuraavia: kloorivetyhappo, bromivetyhappo, jodivetyhappo, fosforihappo, metafosforihappo, pyrofosforihappo, rikkihappo ja typpihappo.Pharmaceutically acceptable salts of the compound of formula (1) above include salts formed with acids that do not increase the intrinsic toxicity of the present compound. These acids can be both inorganic and organic. Among the inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, pyrophosphoric acid, sulfuric acid and nitric acid can be used.
Orgaanisista hapoista, jotka ovat farmaseuttisesti hyväksyttäviä, voidaan käyttää esimerkiksi seuraavia: etikkahappo, muurahaishappo, propionihappo, viinihappo, omenahappo ja sitruunahappo.Among the organic acids which are pharmaceutically acceptable, for example, acetic acid, formic acid, propionic acid, tartaric acid, malic acid and citric acid can be used.
Yllä olevan kaavan (I) mukainen yhdiste valmistetaan esillä olevan keksinnön mukaan kondensoimalla kaavanThe compound of formula (I) above is prepared according to the present invention by condensing the formula
OO
CH - CH2 - CH2 - NH2 (II)CH - CH2 - CH2 - NH2 (II)
OO
mukainen amiini kaavan x - ch2 - ch2 - ch2 - S - ^ ^ (III) mukaisen halogenoidun yhdisteen kanssa tai kondensoimalla kaavan h2n - ch2 - ch2 - ch2 - S ^ (IV) mukainen amiini kaavan 3 57100amine of formula x - ch2 - ch2 - ch2 - S - ^ ^ (III) or by condensing an amine of formula h2n - ch2 - ch2 - ch2 - S ^ (IV) with a halogenated compound of formula 3 57100
OO
CH - CH- - CH - X (V)CH - CH- - CH - X (V)
OO
mukaisen halogenoidun yhdisteen kanssa, jolloin kaavoissa X merkitsee jotakin seu-raavista halogeeneista: kloori, bromi ja jodi. Vielä erään esillä olevan keksinnön toisen menetelmän mukaan voidaan kaavan (I) mukaista yhdistettä valmistaa konden-soimalla kaavan (II) mukainen amiini kaavan 0 = c - CH2 - CH2 - S - ^ Λ (VI) mukaisen karbonyyliyhdisteen kanssa ja pelkistämällä kondensaatiotuote yhdisteeksi (I). Tai sitten yhdistettä voidaan valmistaa siten, että kondensoidaan kaavan (IV) mukainen amiini kaavan Q .wherein X in the formulas represents one of the following halogens: chlorine, bromine and iodine. According to another method of the present invention, a compound of formula (I) may be prepared by condensing an amine of formula (II) with a carbonyl compound of formula 0 = c - CH 2 - CH 2 - S - (VI) and reducing the condensation product to compound (I). ). Alternatively, the compound may be prepared by condensing an amine of formula (IV) of formula Q.
CH - CH- - CH- - C = 0 (VII) • 0 mukaisen karbonyyliyhdisteen kanssa.CH - CH- - CH- - C = O (VII) • with a carbonyl compound.
Yhdisteiden (II) ja (III) ja yhdisteiden (IV) ja (V) kondensaatio suoritetaan a) lisäämällä kaavan (II) mukainen amiini kaavan (III) mukaiseen halogeeni-yhdisteeseen lämpötilassa 30-100°C 3-6 tunnin aikana edullisesti liuoksessa ja inertissä atmosfäärissä, tai b) lisäämällä kaavan (IV) mukainen amiini kaavan (V) mukaiseen halogeeniyhdis-teeseen lämpötilassa 30-100°C 3-6 tunnin aikana, edullisesti liuoksessa ja inertissä atmosfäärissä.The condensation of compounds (II) and (III) and compounds (IV) and (V) is carried out a) by adding an amine of formula (II) to a halogen compound of formula (III) at a temperature of 30-100 ° C for 3-6 hours, preferably in solution and in an inert atmosphere, or b) adding an amine of formula (IV) to a halogen compound of formula (V) at a temperature of 30 to 100 ° C for 3 to 6 hours, preferably in solution and under an inert atmosphere.
Molemmat reaktiot a) ja b) voidaan suorittaa happoa sitovan aineen läsnäollessa, joka sitoo muodostuneen halogeenivetyhapon.Both reactions a) and b) can be carried out in the presence of an acid scavenger which scavenges the hydrohalic acid formed.
4 571004 57100
Reaktion suorituksen jälkeen reaktioseosta pidetään 30-100°C:n lämpötilassa 3-6 tuntia, sitten sen annetaan seistä huoneen lämpötilassa noin 12 tuntia.After carrying out the reaction, the reaction mixture is kept at 30 to 100 ° C for 3 to 6 hours, then allowed to stand at room temperature for about 12 hours.
Keksinnön mukainen yhdiste saadaan sakan erottamisen jälkeen suodoksesta vapaana emäksenä tavanomaisin menetelmin, kuten väkevöimällä pieneen tilavuuteen, liuottamalla jäännös kloroformiin, käsittelemällä hapolla, pesemällä vedellä ja tekemällä alkaliseksi amooniumhydroksidilla.After separation of the precipitate, the compound of the invention is obtained as a free base from the filtrate by conventional methods such as concentrating to a small volume, dissolving the residue in chloroform, treating with acid, washing with water and basifying with ammonium hydroxide.
Raakatuote saadaan yleensä paksuna öljynä, joka tulee kiinteäksi lisättäessä orgaanisia liuottimia; raakatuote voidaan puhdistaa kiteyttämällä.The crude product is usually obtained as a thick oil which solidifies on addition of organic solvents; the crude product can be purified by crystallization.
Kuten jo mainittiin, yllä oleva kondensaatioreaktio suoritetaan edullisesti liuot-timissa, kuten alifaattisissa alkoholeissa, alifaattisissa tai aromaattisissa eettereissä, alifaattisissa tai aromaattisissa hiilivedyissä, esim. metanolissa, etanolissa, propanolissa, etyleeniglykolissa, etyleeniglykolimonoalkyylieettereissä, etyleeniglykolidialkyylieettereissä, anisolissa, ligroiinissa, bentseenissä tai tolueenissa.As already mentioned, the above condensation reaction is preferably carried out in solvents such as aliphatic alcohols, aliphatic or aromatic ethers, aliphatic or aromatic hydrocarbons, e.g.
Kun kondensaatioreaktiossa muodostuu halogeenivetyhappoa sen poistamiseen sopivia emäksisiä aineita ovat esimerkiksi kollidiini, pyridiini, N, N-dimetyylianiliini, N, N-dietyylianiliini, trietyyliamiini ja kinoliini.When hydrohalic acid is formed in the condensation reaction, suitable basic substances for its removal include, for example, collidine, pyridine, N, N-dimethylaniline, N, N-diethylaniline, triethylamine and quinoline.
Kaavan (I) mukaisen yhdisteen farmaseuttisesti hyväksyttäviä suoloja voidaan saada muuttamalla emäs suolaksi liuottimessa, johon vapaa emäs on liukoinen, reaktiossa ekvivalenttisen määrän kanssa happoa tai liuottamalla asteittain vapaa emäs hapon liuokseen.Pharmaceutically acceptable salts of a compound of formula (I) may be obtained by converting a base into a salt in a solvent in which the free base is soluble by reaction with an equivalent amount of acid or by gradually dissolving the free base in an acid solution.
Keksintöä valaistaan seuraavillä esimerkeillä:The invention is illustrated by the following examples:
Esimerkki 1 120 g kuumaa 3-tiofenyyli-l-bromipropaania lisättiin hitaasti typpiatmosfäärissä liuokseen, jossa oli 110 g 3,3-difenyylipropyyliamiinia isopropanolissa, ja 150 ml trietyyliamiinia. Seosta keitettiin sitten palauttaen 5 tuntia, ja sen annettiin seistä huoneen lämpötilassa 12 tuntia.Example 1 120 g of hot 3-thiophenyl-1-bromopropane were slowly added under a nitrogen atmosphere to a solution of 110 g of 3,3-diphenylpropylamine in isopropanol and 150 ml of triethylamine. The mixture was then refluxed for 5 hours and allowed to stand at room temperature for 12 hours.
Saostunut trietyyliamiinihydrobromidi suodatettiin, ja suodos väkevöitiin. Öljymäi-nen jäännös liuotettiin kloroformiin, ja sitten liuos kyllästettiin kloorivety-kaasulla ja pestiin jälkeenpäin useampia kertoja lämpimällä vedellä. Liuos kuivattiin vedettömällä natriumsulfaatilla, sitten liuotin haihdutettiin.The precipitated triethylamine hydrobromide was filtered off, and the filtrate was concentrated. The oily residue was dissolved in chloroform, and then the solution was saturated with hydrogen chloride gas and then washed several times with warm water. The solution was dried over anhydrous sodium sulfate, then the solvent was evaporated.
öljymäinen jäännös muuttui kiinteäksi lisättäessä isopropanolin ja eetterin 1 : 1 (v/v) seosta, minkä jälkeen tuote kiteytettiin isopropanolista.the oily residue became solid upon addition of a 1: 1 (v / v) mixture of isopropanol and ether, after which the product was crystallized from isopropanol.
5 571005 57100
Saatiin 50 N-(3-tiofenyylipropyyli)-N-(3,3-difenyylipropyyli)amiinia, jolla oli sulamispiste 115-116°C.50 N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine with a melting point of 115-116 ° C were obtained.
Analyysi: C % H % N %Analysis: C% H% N%
Laskettu kaavasta ^24^28^ Cl S 72,42 7,09 3,51 Löydetty 72,73 7,25 3,63Calculated from the formula ^ 24 ^ 28 ^ Cl S 72.42 7.09 3.51 Found 72.73 7.25 3.63
Esimerkki 2Example 2
Liuosta, joka sisältää 3,5 g 3-tiofenyylipropyyliamiinia (valmistettu C.A. 52 16131 d mukaisesti) sekä 6 ml trietyyliamiinia 20 ml:ssa bentseeniä, kuumennetaan noin 50°C:een, lisätään 5,3 g 3,3-(bis-fenyyli)-l-bromipropaania (valmistettu C.A. 69 86494 y mukaisesti), keitetään palauttaen 12 tunnin ^ ajan ja annetaan senjälkeen seistä 8 tuntia.A solution of 3.5 g of 3-thiophenylpropylamine (prepared according to CA 52 16131 d) and 6 ml of triethylamine in 20 ml of benzene is heated to about 50 ° C, 5.3 g of 3,3- (bis-phenyl) are added. ) -1-bromopropane (prepared according to CA 69 86494 y) is refluxed for 12 hours and then allowed to stand for 8 hours.
Trietyyliamiinihydrobromidi poistetaan suodattamalla, kirkas suodos haihdutetaan tyhjiössä ja jäännöksenä oleva öljy liuotetaan 12 ml:aan kloroformia ja kyllästetään kloorivetykaasulla.The triethylamine hydrobromide is removed by filtration, the clear filtrate is evaporated in vacuo and the residual oil is dissolved in 12 ml of chloroform and saturated with hydrogen chloride gas.
Orgaaninen liuos pestään vedellä, kuivataan ja haihdutetaan kuiviin tyhjiössä. Jäännöksenä saatu öljy kiteytetään 40 ml:sta etyyliasetaattia. Kiinteä tuote erotetaan suodattamalla, pestään etyylieetterillä ja kuivataan tyhjiössä.The organic solution is washed with water, dried and evaporated to dryness in vacuo. The residual oil is crystallized from 40 ml of ethyl acetate. The solid product is filtered off, washed with ethyl ether and dried in vacuo.
Saadaan 3,9 g N-(3-tiofenyylipropyyli)-N-(3,3-difenyylipropyyli)amiinia (saantoarvo 46,5 %).3.9 g of N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine are obtained (yield 46.5%).
Esimerkki 3 10,6 g 3,3-difenyylipropyyliamiinia ja 9,9 g 3-tiofenyylipropionialdehydiä (valmistettu C.A. 59 8635 e mukaisesti) keitetään palauttaen 25 ml:ssa bentseeniä ^ 30 minuutin ajan.Example 3 10.6 g of 3,3-diphenylpropylamine and 9.9 g of 3-thiophenylpropionaldehyde (prepared according to C.A. 59 8635 e) are boiled under reflux in 25 ml of benzene for 30 minutes.
Liuotin poistetaan tislaamalla tyhjiössä ja jäännösöljyä käsitellään 25 ml:11a metanolia ja 3 ml:11a vettä.The solvent is removed by distillation in vacuo and the residual oil is treated with 25 ml of methanol and 3 ml of water.
Saatuun emulsioon lisätään vähitellen 0,75 g natriumboorihydridiä, minkä jälkeen sitä keitetään palauttaen 30 minuutin ajan.0.75 g of sodium borohydride are gradually added to the resulting emulsion, followed by boiling under reflux for 30 minutes.
Liuotin poistetaan tislaamalla tyhjiössä ja jäännöksenä oleva öljy liuotetaan 6 57100 28 ml:aan kloroformia ja saatu liuos kyllästetään kloorivetykaasulla.The solvent is removed by distillation in vacuo and the residual oil is dissolved in 28,500 ml of 28 ml of chloroform and the resulting solution is saturated with hydrogen chloride gas.
Liuos pestään vedellä, kuivataan ja väkevöidään tyhjiössä. Jäännösöljy kiteytetään 80 ml:ssa etyyliasetaattia ja kiinteä tuote erotetaan suodattamalla, pestään etyylieetterillä ja kuivataan tyhjiössä.The solution is washed with water, dried and concentrated in vacuo. The residual oil is crystallized from 80 ml of ethyl acetate and the solid product is filtered off, washed with ethyl ether and dried in vacuo.
Saadaan 4,5 g N-(3-tiofenyylipropyyli)-N-(3,3-difenyylipropyyli)-amiinia (saantoarvo 22,5 %).4.5 g of N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine are obtained (yield 22.5%).
Esimerkki 4 3,5 g 3-tiofenyylipropyyliamiinia (valmistettu C.A. 52 16131 d mukaisesti) sekä 5,2 g 3,3-bis-(fenyyli)-propionihappoaldehydiä (valmistettu C.A. 72 43154 g mukaisesti) keitetään palauttaen 10 ml:ssa bentseeniä 30 minuutin ajan. Liuotin tislataan pois tyhjiössä ja jäännöksenä olevaa öljyä käsitellään 10 ml:11a metanolia ja 1 ml:11a vettä. Saatuun emulsioon lisätään vähitellen 0,40 g natriumboorihydridiä, minkä jälkeen keitetään palauttaen 30 minuutin ajan. Liuotin tislataan pois ja jäännöksenä oleva öljy liuotetaan 12 ml:aan kloroformia ja liuos kyllästetään kloorivetykaasulla.Example 4 3.5 g of 3-thiophenylpropylamine (prepared according to CA 52 16131 d) and 5.2 g of 3,3-bis- (phenyl) propionic acid aldehyde (prepared according to CA 72 43154 g) are boiled under reflux in 10 ml of benzene for 30 minutes. I drive. The solvent is distilled off in vacuo and the residual oil is treated with 10 ml of methanol and 1 ml of water. 0.40 g of sodium borohydride are gradually added to the resulting emulsion, followed by refluxing for 30 minutes. The solvent is distilled off, and the residual oil is dissolved in 12 ml of chloroform, and the solution is saturated with hydrogen chloride gas.
Liuos pestään vedellä, kuivataan ja haihdutetaan kuiviin tyhjiössä.The solution is washed with water, dried and evaporated to dryness in vacuo.
Jäännöksenä oleva öljy kiteytetään 20 ml:sta etyyliasetaattia. Kiinteä tuote erotetaan suodattamalla, pestään etyylieetterillä ja kuivataan tyhjiössä.The residual oil is crystallized from 20 ml of ethyl acetate. The solid product is filtered off, washed with ethyl ether and dried in vacuo.
Saadaan 4,8 g N-(3-tiofenyylipropyyli)-N-(3,3-difenyylipropyyli)-amiinia (saantoarvo 57,5 %).4.8 g of N- (3-thiophenylpropyl) -N- (3,3-diphenylpropyl) amine are obtained (yield 57.5%).
Edellä valmistetusta yhdisteestä on suoritettu seuraavat myrkyllisyystutkimukset : 1 - akuutti myrkyllisyys hiirellä ja rotalla 2 - subakuutti myrkyllisyys rotalla (28 vrk) 3 - krooninen myrkyllisyys rotalla (13 viikkoa) 4 - krooninen myrkyllisyys rotalla ja marsulla (26 viikkoa) 5 - teratologia rotilla ja kaniineilla 57100 7 1 - Akuutti myrkyllisyys hiirellä ja rotallaThe following toxicity studies have been performed on the compound prepared above: 1 - Acute toxicity in mice and rats 2 - Subacute toxicity in rats (28 days) 3 - Chronic toxicity in rats (13 weeks) 4 - Chronic toxicity in rats and guinea pigs (26 weeks) 5 - 57100 7 1 - Acute toxicity in mice and rats
Alla olevassa taulukossa nähdään aineen DL^-arvot yhden ainoan antokerran jälkeen intravenöösisti, intraperitoneaalisti, subkutaanisti ja oraalisti.The table below shows the DL 2 values of the substance after a single administration intravenously, intraperitoneally, subcutaneously and orally.
ANTOTAPA (°) DL50 (mg/Kg) „ SUKUPUOLI HIIRI (sveitsil.) SUKUPUOLI ROTTA (Wistar) i.v. M 17,15 F 19,70 (16,59 - 17,76) (19,16 - 20,25) i.p. M 39,40 F 59,72 (24,38 - 63,54) (38,52 - 92,57) s.c. M >1000 F >1000 p.o. M >1000 F >1000 (°) Weil & Thomson menetelmä (luotettavuusväli P* 0,05) 2 - Subakuutti myrkyllisyyskoe rotalla Kestoaika : 28 vrkMETHOD OF ADMINISTRATION (°) DL50 (mg / Kg) “SEX MOUSE (Swiss) SEX RAT (Wistar) i.v. M 17.15 F 19.70 (16.59-17.76) (19.16-20.25) i.p. M 39.40 F 59.72 (24.38-63.54) (38.52-92.57) s.c. M> 1000 F> 1000 p.o. M> 1000 F> 1000 (°) Weil & Thomson method (confidence interval P * 0.05) 2 - Subacute toxicity test in rat Duration: 28 days
Eläin : Wistar-rotat (Morini), molempia sukupuolia Annos : 50 mg/kg s.c.Animal: Wistar rats (Morini), both sexes Dose: 50 mg / kg s.c.
200 " p.c.200 "p.c.
Huomioitu; - ulkonäkö - kuolleisuus - ravinnon kulutus - kehonpainon muutos - virtsan analyysi - hematologia - veren kemia - maksan kemia 57100 8 - patologinen makrotutkimus ja elinten painot - histologiacatered; - appearance - mortality - food consumption - change in body weight - urine analysis - hematology - blood chemistry - liver chemistry 57100 8 - pathological macro study and organ weights - histology
Tulokset:Score:
Kuumallakaan kokeillulla annoksella ei ilmennyt merkitseviä muutoksia verrattuna kontrollina käytettyihin eläimiin.No significant changes were observed at either the hot dose tested compared to control animals.
3 - Pidennetty myrkyllisyyskoe rotalla Kestoaika : 13 viikkoa3 - Extended toxicity test on rats Shelf life: 13 weeks
Eläimet : Wistar-rotat (Morini), molempia sukupuolia Annos : 150 mg/kg p.o.Animals: Wistar rats (Morini), both sexes Dose: 150 mg / kg p.o.
Samat kokeet kuin subakuutilla myrkyllisyydellä.Same experiments as for subacute toxicity.
Missään tapauksessa ei ollut merkitseviä muutoksia verrattuna kontrollina käytettyihin eläimiin.In any case, there were no significant changes compared to the control animals.
4 - Pidennetty myrkyllisyyskoe rotalla ja marsulla Kestoaika : 26 viikkoa4 - Extended toxicity test on rat and guinea pig Duration: 26 weeks
Eläimet : Wistar-rotat (Morini), molempia sukupuolia Annokset : 25 - 75 - 150 mg/kg p.o. rotalla 500 mg p.o. marsullaAnimals: Wistar rats (Morini), both sexes Doses: 25 - 75 - 150 mg / kg p.o. rat 500 mg p.o. the guinea pig
Samat kokeet kuin subakuutilla myrkyllisyydellä.Same experiments as for subacute toxicity.
Missään tapauksessa ei ollut olennaisia muutoksia verrattuna kontrollina käytettyihin eläimiin.In any case, there were no significant changes compared to the control animals.
5 - Teratologia rotalla ja kaniinilla Sikiömyrkyllisyys rotalla:5 - Teratology in rats and rabbits Fetal toxicity in rats:
Kyseistä yhdistettä on annettu suun kautta annoksena 100 mg/kg 28 vrk. Molemmissa kokeissa on otettu huomioon seuraavat parametrit: 9 57100 - kiinnittyneiden alkioiden luku ja niiden jakautuminen kohdussa - reabsorptioiden lukumäärä - poistuneiden sikiöiden luku - kuolleiden sikiöiden luku - poikkeama, epämuodostumien tyyppi ja lukumäärä - sikiöiden paino - histologinen pitkittäisleikkaus sikiöstä kokonaisuudessaan - sikiöiden luurangot (saatu puhdistamalla alkaleilla ja värjäämällä Alizarin S:llä) " - reisiluun pituudet ja jakautumat eri luokkiinThe compound was administered orally at a dose of 100 mg / kg for 28 days. The following parameters were taken into account in both experiments: 9 57100 - number of attached embryos and their distribution in the uterus - number of reabsorbings - number of fetuses removed - number of dead fetuses - deviation, type and number of malformations - weight of fetuses - alkali and staining with Alizarin S) "- femur lengths and distributions into different categories
Yhdisteen antaminen lääkkeeksi ei tarkastelussa muuttanut parametrejä mil-' lään tavalla kaikki seikat huomioiden.The administration of the compound as a drug did not change the parameters in any way, considering all the factors.
Yllä valmistetun yhdisteen farmakodynaamisten ominaisuuksien tutkimiseksi on suoritettu seuraavat kokeet: 1 - Kokeet in vitro a) antispastinen aktiviteetti b) reseptorisalpausvaikutus 2 - Mahahaavan vastainen aktiviteetti _ - stressihaava - Shay-haava - Reserpiini-haava - Prednisoloni-haava - Histamiini-haava - Serotoniini-haava - Indometasiini-haava - glukoosi-haava 3 - Analgeettinen ja anesteettinen aktiviteetti 4 - Muut farmakologieet aktiviteetit 10 571 00 1 - Kokeet in vitro a) Antispastinen aktiviteetti:To investigate the pharmacodynamic properties of the compound prepared above, the following experiments have been performed: 1 - In vitro experiments a) antispastic activity b) receptor blocking effect 2 - antiulcer activity _ - stress wound - Shay wound - Reserpine wound - Prednisolone wound - Histamine wound - Serotonin wound - Indomethacin wound - glucose wound 3 - Analgesic and anesthetic activity 4 - Other pharmacological activities 10 571 00 1 - In vitro tests (a) Antispastic activity:
Sitä on kokeiltu rottien ja marsujen eristettyjen elimien osilla eri pitoisuuksilla histamiinin (H), asetyylikoliinin (Ach.), serotoniinin (5 HT), bradykiniinin (BK), BaC^n ja oksitosiinin (OXIT) kanssa.It has been tested on parts of isolated organs of rats and guinea pigs with different concentrations of histamine (H), acetylcholine (Ach.), Serotonin (5 HT), bradykinin (BK), BaCl 2 and oxytocin (OXIT).
Seuraavassa taulukossa on esitetty inhibiitiot %:eina ja asiaan kuuluva ED,^: KOKEET ΙΟ-4 10"5 10"6 ED^gThe following table shows the inhibitions in% and the relevant ED, ^: EXPERIMENTS ΙΟ-4 10 "5 10" 6 ED ^ g
Ach. 68.0 84.0 22.0 2 x 10"5 H 71.5 36.9 28.3 4 x 10"5Ach. 68.0 84.0 22.0 2 x 10 "5 H 71.5 36.9 28.3 4 x 10" 5
BaCl2 76.7 22.5 13.0 3 x ΙΟ-5 BK 69.0 17.0 — 3 x 10-5 5 HT inhibiitio riippuu kosketusajasta OXIT supistukset lisääntyvät b) Reseptorisalpausvaikutus:BaCl2 76.7 22.5 13.0 3 x ΙΟ-5 BK 69.0 17.0 - 3 x 10-5 5 HT inhibition depends on contact time OXIT contractions increase b) Receptor blocking effect:
Yhdisteen aiheuttama reseptoriosien salpauksen kestoaika on määrätty mittaamalla antiserotoniinivaikutusaika in vitro.The duration of compound-induced receptor blockade is determined by measuring the duration of antiserotonin action in vitro.
2 - Mahahaavan vastainen aktiviteetti Tämä aktiviteetti arvioituna kokeilla käyttäen erilaista vaikutusmekanismia on esitetty seuraavassa taulukossa: 11 571 002 - Anti-gastric ulcer activity This activity, evaluated by experiment using a different mechanism of action, is shown in the following table: 11 571 00
KOE Annos ANTO- INHIBIITIOEXPERIENCE Dose ADMINISTRATION INHIBITION
mg/kg TAPA %mg / kg TAPA%
Stressihaava 5 os 51 10 " 58 20 " 63Stress ulcer 5 os 51 10 "58 20" 63
Shay-haava 10 s.c. 45 20 " " 50 _ Reserpiini-haava 20 S.c. 48Shay wound 10 s.c. 45 20 "" 50 _ Reserpine Wound 20 S.c. 48
Prednisoloni-haava 10 i.m. 75Prednisolone Wound 10 i.m. 75
Histamiini-haava 50 os 63 ^ 100 " 92 10 s.c. 82 20 " " 92Histamine wound 50 os 63 ^ 100 "92 10 s.c. 82 20" "92
Serotoniini-haava 10 s.c. 75 50 os 72,5Serotonin wound 10 s.c. 75 50 os 72.5
Indometasiini-haava 25 os 60 50 " 73 125 " 76 250 " 88Indomethacin wound 25 os 60 50 "73 125" 76 250 "88
Glukoosi-haava 50 os 64 3 - Analgeettinen ja anesteettinen aktiviteettiGlucose wound 50 os 64 3 - Analgesic and anesthetic activity
Analgeettinen aktiviteetti on arvioitu seuraavilla kokeilla: - kemiallisten aineiden aiheuttamat supistukset - leikkaus rotan häntäänAnalgesic activity has been evaluated in the following experiments: - chemical contractions - rat tail surgery
Molemissa kokeissa tuote osoittautui tehottomaksi.In both experiments, the product proved ineffective.
Anestettinen aktiviteetti on arvioitu seuraavilla kokeilla: - sarveiskalvon kosketusrefleksin häviäminen kaniinilla - infiltraatioanesteesia marsullaAnesthetic activity has been evaluated in the following experiments: - loss of corneal contact reflex in rabbits - infiltration anesthesia in guinea pigs
Claims (3)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT347671 | 1971-07-15 | ||
IT347671 | 1971-07-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
FI57100B FI57100B (en) | 1980-02-29 |
FI57100C true FI57100C (en) | 1980-06-10 |
Family
ID=11108082
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FI1946/72A FI57100C (en) | 1971-07-15 | 1972-07-07 | PROCEDURE FOR THE FRAMEWORK OF THIOALKYLAMINE N- (3-THIOPHENYLPROPYL) -N- (3,3-DIPHENYLPROPYL) AMIN JAEMTE DESS SALTER MED PHARMACOLOGICAL EQUIPMENT |
Country Status (17)
Country | Link |
---|---|
JP (1) | JPS5224012B1 (en) |
AR (4) | AR197088A1 (en) |
AT (2) | AT321272B (en) |
BE (1) | BE786147A (en) |
BR (1) | BR7204677D0 (en) |
CA (1) | CA1003859A (en) |
CH (2) | CH589618A5 (en) |
DK (1) | DK133298C (en) |
ES (4) | ES404743A1 (en) |
FI (1) | FI57100C (en) |
FR (1) | FR2145639B1 (en) |
GB (1) | GB1345319A (en) |
MX (1) | MX3738E (en) |
NL (1) | NL153862B (en) |
NO (1) | NO134800C (en) |
SE (1) | SE388607B (en) |
ZA (1) | ZA724511B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1080455B (en) * | 1977-06-17 | 1985-05-16 | Alfa Farmaceutici Spa | N 3 FENILTIOPROPIL 3.3 DIPHENYL REPLACED PROPILAMINS EQUIPPED WITH PHARMACOLOGY ACTIVITIES |
-
1972
- 1972-06-29 NO NO2334/72A patent/NO134800C/no unknown
- 1972-06-30 ZA ZA724511A patent/ZA724511B/en unknown
- 1972-07-07 FI FI1946/72A patent/FI57100C/en active
- 1972-07-10 CH CH1314575A patent/CH589618A5/xx not_active IP Right Cessation
- 1972-07-10 CH CH1031172A patent/CH582138A5/xx not_active IP Right Cessation
- 1972-07-11 ES ES404743A patent/ES404743A1/en not_active Expired
- 1972-07-12 FR FR7225278A patent/FR2145639B1/fr not_active Expired
- 1972-07-12 MX MX72570U patent/MX3738E/en unknown
- 1972-07-12 BE BE786147A patent/BE786147A/en unknown
- 1972-07-14 DK DK352272A patent/DK133298C/en active
- 1972-07-14 AT AT979273A patent/AT321272B/en not_active Expired
- 1972-07-14 JP JP47070048A patent/JPS5224012B1/ja active Pending
- 1972-07-14 NL NL727209820A patent/NL153862B/en not_active IP Right Cessation
- 1972-07-14 SE SE7209286A patent/SE388607B/en unknown
- 1972-07-14 AT AT607272A patent/AT318560B/en not_active IP Right Cessation
- 1972-07-14 BR BR4677/72A patent/BR7204677D0/en unknown
- 1972-07-14 CA CA147,175A patent/CA1003859A/en not_active Expired
- 1972-07-17 AR AR243108A patent/AR197088A1/en active
- 1972-07-17 GB GB3338072A patent/GB1345319A/en not_active Expired
-
1973
- 1973-08-03 AR AR249439A patent/AR197154A1/en active
- 1973-08-03 AR AR249440A patent/AR197155A1/en active
- 1973-08-03 AR AR249438A patent/AR197153A1/en active
-
1975
- 1975-01-28 ES ES434221A patent/ES434221A1/en not_active Expired
- 1975-01-28 ES ES434220A patent/ES434220A1/en not_active Expired
- 1975-01-28 ES ES434219A patent/ES434219A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
DK133298B (en) | 1976-04-26 |
CH582138A5 (en) | 1976-11-30 |
SE388607B (en) | 1976-10-11 |
CH589618A5 (en) | 1977-07-15 |
DK133298C (en) | 1976-09-20 |
MX3738E (en) | 1981-06-05 |
FR2145639A1 (en) | 1973-02-23 |
JPS5224012B1 (en) | 1977-06-28 |
BE786147A (en) | 1972-11-03 |
DE2232939A1 (en) | 1973-01-18 |
ES434220A1 (en) | 1976-12-16 |
CA1003859A (en) | 1977-01-18 |
FR2145639B1 (en) | 1976-03-05 |
FI57100B (en) | 1980-02-29 |
AR197088A1 (en) | 1974-03-15 |
DE2232939B2 (en) | 1975-10-02 |
AT318560B (en) | 1974-10-25 |
NO134800B (en) | 1976-09-06 |
ZA724511B (en) | 1973-03-28 |
NL7209820A (en) | 1973-01-17 |
ES434219A1 (en) | 1976-12-01 |
BR7204677D0 (en) | 1973-11-01 |
AR197153A1 (en) | 1974-03-15 |
ES434221A1 (en) | 1976-12-01 |
AR197155A1 (en) | 1974-03-15 |
AR197154A1 (en) | 1974-03-15 |
AT321272B (en) | 1975-03-25 |
ES404743A1 (en) | 1976-01-01 |
NO134800C (en) | 1976-12-15 |
NL153862B (en) | 1977-07-15 |
GB1345319A (en) | 1974-01-30 |
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