NL8005411A

NL8005411A - 4-PHENYLFTALAZINE DERIVATIVES.

Info

Publication number: NL8005411A
Application number: NL8005411A
Authority: NL
Original assignee: Mitsubishi Yuka Pharma
Priority date: 1979-10-09
Filing date: 1980-09-30
Publication date: 1981-04-13
Also published as: IT1148727B; FR2468593A1; IT8025206A0; DE3038166A1; GB2063249A

Description

η i * - 1 - 4-fenylftalazinederivaten.η i * - 1 - 4-phenylphthalazine derivatives.

De uitvinding heeft betrekking op een 4-fenyl- ftalazinederivaat met de formule 1 van het formuleblad, of een farmaceutisch aanvaardbaar zout daarvan, waarbij X, NH of 0 voorstelt; R1 een alkylgroep met 1-5 koolstof- 5 atomen, een alkoxygroep met 1-5 koolstofatomen, een halogeenatoom, een alkoxycarbonylgroep met 2-6 koolstof- atomen in totaal, een carboxylgroep, een cyaangroep, een alkylcarbonylgroep met 2-4 koolstofatomen in totaal, 2 3 een hydroxyIgroep of een trifluormethylgroep; R en R , die aan elkaar gelijk kunnen zijn of van elkaar kunnen verschillen, (zij kunnen ook hetzelfde zijn als of verschillen van R1), stellen elk voor een alkylgroep met 1-5 koolstofatomen, een alkoxygroep met 1-5 koolstof-atomen, een halogeenatoom, een alkoxycarbonylgroep met 3_5 2-6 koolstof atomen in totaal, een carboxylgroep, een alkylcarbonylgroep met 2-4 koolstofatomen in totaal, een hydroxyIgroep of een trifluormethylgroep; en 1, m en n is een geheel getal van 0-3 (mits 1 gelijk is aan 1-3 en m gelijk is n gelijk is aan 0 wanneer X voor-20 stelt 0, en het geval, dat 1 gelijk is aan m gelijk is aan n gelijk is aan nul is uitgesloten wanneer X gelijk 1 2 is aan NH), terwijl elk meervoudig getal van R , R en 3 R aan elkaar gelijk zijn of van elkaar verschillen wanneer de gehele getallen 1, m en n gelijk zijn aan 25 twee of meer, en ook heeft de uitvinding betrekking op een werkwijze voor het bereiden daarvan.The invention relates to a 4-phenyl-phthalazine derivative of the formula 1 of the formula sheet, or a pharmaceutically acceptable salt thereof, wherein X represents NH, or O; R1 an alkyl group with 1-5 carbon atoms, an alkoxy group with 1-5 carbon atoms, a halogen atom, an alkoxycarbonyl group with 2-6 carbon atoms in total, a carboxyl group, a cyano group, an alkyl carbonyl group with 2-4 carbon atoms in total 2 3 a hydroxy group or a trifluoromethyl group; R and R, which may be the same or different from each other (they may also be the same or different from R1), each represent an alkyl group of 1-5 carbon atoms, an alkoxy group of 1-5 carbon atoms, a halogen atom, an alkoxycarbonyl group with 3-5 2-6 carbon atoms in total, a carboxyl group, an alkyl carbonyl group with 2-4 carbon atoms in total, a hydroxy group or a trifluoromethyl group; and 1, m and n is an integer from 0-3 (provided 1 equals 1-3 and m equals n equals 0 when X represents -20, and the case 1 equals m equal to n equals zero is excluded when X equals 1 2 to NH), while each multiple of R, R and 3 R are equal or different when the integers 1, m and n are equal to two or more, and the invention also relates to a method of preparing the same.

Als 4-fenylftalazinederivaten die analoog zijn aan die volgens de onderhavige uitvinding, zijn tot nu toe bekend l-aniline-4-fenylftalazine (Ber., 38^, 3923 30 (1905)), l-fenoxy-4-fenylftalazine (Journal of Pharma cology, j)8, 83 (1968)), 1-(2-(2-methylallyl)-fenoxy)-4-fenylftalazine, 1-(2-allylfenoxy)-4-fenylftalazine (Chem.Pharm.Bull., 2£, 1581-1595 (1976)). Deze verbindingen worden slechts als tussenprodukten beschreven 35 en er is geen sprake van toepassingen daarvan. De verbindingen l-(2-(2-methylallyl)fenoxy)-4-fenylftalazine an n* l 1 1 - 2 - en 1-(2-allyIfenoxy)-4-fenylthalazine zijn geschikt om een ringsluitingsreactie of andere onwenselijke reacties ten gevolge van dubbele bindingen in de sub-stituenten te ondergaan, zodat veranderingen in struc-5 tuur worden veroorzaakt.As 4-phenylphthalazine derivatives analogous to those of the present invention, hitherto known are 1-aniline-4-phenylphthalazine (Ber., 38 ^, 3923 (1905)), 1-phenoxy-4-phenylphthalazine (Journal of Pharma cology, j) 8, 83 (1968)), 1- (2- (2-methylallyl) -phenoxy) -4-phenylphthalazine, 1- (2-allylphenoxy) -4-phenylphthalazine (Chem. Pharm. Bull., 2, 1581-1595 (1976)). These compounds are only described as intermediates and there are no applications thereof. The compounds 1- (2- (2-methylallyl) phenoxy) -4-phenylphthalazine an n * l 1 1 - 2 - and 1- (2-allylphenoxy) -4-phenylthalazine are suitable for cyclization or other undesirable reactions. of double bonds in the substituents, causing changes in structure.

Anderzijds zijn studies verricht met betrekking tot l-alkyl-amino-4-fenylftalazinederivaat, 1-alkyloxy- 4-fenylftalazinederivaat (J.Med.Chem. 1_2, 555 (1969)) en 1-(piperazine-l-yl)-4-fenylftalazinederivaat (Japanse 10 octrooipublicatie 39944/1973) voor toepassingen daarvan als anti-ontstekingsmiddelen. lTanilinederivaten en l-fenoxyderivaten zijn echter niet beschreven.On the other hand, studies have been conducted regarding 1-alkyl-amino-4-phenylphthalazine derivative, 1-alkyloxy-4-phenylphthalazine derivative (J.Med.Chem. 1_2, 555 (1969)) and 1- (piperazin-1-yl) -4 -phenylphthalazine derivative (Japanese 10 patent publication 39944/1973) for uses thereof as anti-inflammatory agents. However, 1-taniline derivatives and 1-phenoxy derivatives have not been described.

Bij de onderhavige uitvinding zijn met succes de nieuwe verbindingen gesynthetiseerd, die worden weer-15 gegeven met de formule 1 van het formuleblad, welke verbindingen niet in de literatuur zijn beschreven.In the present invention, the new compounds have been successfully synthesized, which are represented by the formula 1 of the formula sheet, which compounds have not been described in the literature.

Voorts werd gevonden, dat deze verbindingen een krachtige belemmerende werking hebben tegen samenklontering van de bloedplaatjes. Daarom worden de verbindingen volgens 20 de uitvinding geacht toepasbaar te zijn ter voorkoming of genezing van kwalen, die worden geïnduceerd door het vermogen zoals hersentrombose, cerebraal infarct, myocardiaal infarct en arteriosclerotische kwalen. Een primair doel van de onderhavige uitvinding is daarom het 25 verschaffen van een nieuwe verbinding met de formule 1 van het formuleblad, die een krachtige belemmerende werkzaamheid heeft tegen samenklontering van bloedplaat jes .Furthermore, it has been found that these compounds have a potent inhibitory action against platelet aggregation. Therefore, the compounds of the invention are believed to be useful for the prevention or cure of ailments induced by the capabilities such as brain thrombosis, cerebral infarction, myocardial infarction and arteriosclerotic ailments. Therefore, a primary object of the present invention is to provide a novel compound of the formula (I), which has a potent inhibitory activity against platelet aggregation.

De verbinding volgens de uitvinding wordt 30 weergegeven met de formule 1 van het formuleblad, waarin alle symbolen als boven zijn gedefinieerd.The compound of the invention is represented by the formula 1 of the formula sheet, in which all symbols are defined as above.

In de formule 1 van het formuleblad kan de 12 3 alkylgroep die is voorgesteld door R , R en R bijvoorbeeld zijn een methyl-, ethyl-, propyl-, isopropyl-, 35 n-butyl-, t-butyl- en een amylgroep. Typerende voorbeelden van de alkoxygroep zijn methoxy, ethoxy, propoxy, butoxy en amyloxy. Als halogeenatomen kunnen worden vermeld fluor, chloor, broom, en jodium. De alkoxycarbonyl-groep kan bijvoorbeeld methoxycarbonyl, ethoxycarbonyl, 8005411 i * - 3 - propoxycarbonyl, butoxycarbonyl, amyloxycarbonyl, etc. omvatten. Als alkylcarbonylgroep kunnen worden toegepast acetyl, propionyl, butylyl of andere.For example, in formula 1 of the formula sheet, the 12 alkyl group represented by R, R and R may be a methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and an amyl group. Typical examples of the alkoxy group are methoxy, ethoxy, propoxy, butoxy and amyloxy. As halogen atoms can be mentioned fluorine, chlorine, bromine, and iodine. The alkoxycarbonyl group may include, for example, methoxycarbonyl, ethoxycarbonyl, 8005411 * 3 - propoxycarbonyl, butoxycarbonyl, amyloxycarbonyl, etc. The alkyl carbonyl group used may be acetyl, propionyl, butylyl or others.

In de verbindingen volgens de uitvinding kan 5 R1 bij voorkeur een alkylgroep, een alkoxygroep, een halogeenatoom of een trifluormethylgroep zijn. Ander-2 zijds kan R bij voorkeur een alkylgroep, een alkoxy- 3 groep of een halogeenatoom zijn, terwijl R een alkylgroep is.In the compounds of the invention, R 1 may preferably be an alkyl group, an alkoxy group, a halogen atom or a trifluoromethyl group. On the other hand, R may preferably be an alkyl group, an alkoxy-3 group or a halogen atom, while R is an alkyl group.

10 In de formule 1 van het formuleblad kunnen de gehele getallen, die zijn voorgesteld met 1, m en n variëren van nul tot drie. Maar er zijn enkele beperkingen afhankelijk van de soort van X. Wanneer X 0 voorstelt (een zuurstofatoom), moeten m en n gelijk zijn aan 15 nul, terwijl 1 kan variëren van 1-3. Wanneer X de groep NH voorstelt, is het geval dat alle gehele getallen nul zijn, echter uitgesloten; m.a.w. er is ten minste één substituent aan de aromatische kern. Wanneer X de groep NH voorstelt, zijn er daarom zoveel mogelijk 20 combinaties in het getal van de substituenten aan de aromatische kern. Gevonden werd, dat daarvan de volgende vier combinaties bijzondere voorkeur hadden: (1) 1 = 1-3, m = n = nul, (2) 1 = 1-2, m - 1-2, n = nul, 25 (3) 1 = 1-2, m = nul, n = 1-2, en (4) 1 = m = nul, n = 1-2.In formula 1 of the formula sheet, the integers represented by 1, m and n can range from zero to three. But there are some limitations depending on the type of X. When X represents 0 (an oxygen atom), m and n must be equal to 15, while 1 can range from 1-3. However, when X represents the group NH, all integers are zero, but are excluded; in other words, there is at least one substituent on the aromatic core. Therefore, when X represents the group NH, there are as many as possible combinations in the number of the substituents on the aromatic nucleus. It was found that the following four combinations were particularly preferred: (1) 1 = 1-3, m = n = zero, (2) 1 = 1-2, m - 1-2, n = zero, 25 (3 ) 1 = 1-2, m = zero, n = 1-2, and (4) 1 = m = zero, n = 1-2.

Wanneer X voorstelt O, is 1 bij voorkeur gelijk aan 1 of 2, terwijl m gelijk is n is gelijk aan nul.When X represents O, 1 is preferably equal to 1 or 2, while m equals n equals zero.

30 De verbinding met de formule 1 kan ook een farmaceutisch aanvaardbaar zout vormen via de reactie van de basische stikstof daarvan met een zuur. Bijvoorbeeld kunnen worden vermeld zouten van anorganische zuren zoals zoutzuur, zwavelzuur, broomwaterstofzuur, 35 fosforzuur, etc. of methaay-siulfonzuur, tolueensulfonguur, benzeensulfonzuur, azijnzuur, glycolzuur, gluturonzuur, maleïnezuur, oxaalzuur, ascorbinezuur, citroenzuur, s ali cy1zuur, etc.The compound of formula 1 can also form a pharmaceutically acceptable salt via the reaction of its basic nitrogen with an acid. For example, mention can be made of salts of inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, etc., or methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, glycolic acid, gluturonic acid, maleic acid, oxalic acid, ascorbic acid, citric acid, salicylic acid, etc.

In het hiernavolgende zijn concrete voor- 8005411 - 4 - beelden van de verbindingen opgesomd, die worden weergegeven met de formule 1 van het formuleblad.Specific examples of the compounds are listed below, which are represented by the formula 1 of the formula sheet.

Verbinding No. Naam van de verbinding 1 1-(4-methylanilino)-4-fenylftalazine 5 2 l-(3-methylanilino)-4-fenylftalazine 3 1-(2-methylanilino)-4-fenylftalazine 4 1-(4-ethylanilino)-4-fenylftalazine 5 1-(2-ethylanilino)-4-fenylftalazine 6 1-(4-n-butylanilino)-4-fenylftalazine 10 7 1-(3-n-butylanilino)-4-fenylftalazine 8 1-(4-t-butylanilino)-4-fenylftalazine 9 1-(4-methoxyanilino)-4-fenylftalazine 10 1-(3-methoxyanilino)-4-fenylftalazine 11 1-(3-propoxyanilino)-4-fenylftalazine 15 12 1-(4-n-butoxyanilino)-4-fenylftalazine 13 1-(4—fluoranilino)-4-fenylftalazine 14 1-(3-fluoranilino)-4-fenylftalazine 15 1-(2-fluoranilino)-4-fenylftalazine 16 l-(4-chlooranilino)-4-fenylftalazine 20 17 1-(3-chlooranilino)-4-fenylftalazine 18 1-(2-chlooranilino)-4-fenylftalazine 19 1-(4-broomanilino)-4-fenylftalazine 20 1-(3-broomanilino)-4-fenylftalazine 21 ' l-(4-joodanilino)-4-fenylftalazine 25 22 1-(3-joodanilino)-4-fenylftalazine 23 1-(4-ethoxycarbonylanilino)-4-fenyl- ftalazine 24 1-(4-carboxyanilino)-4-fenylftalazine 25 l-(4-cyaananilino)-4-fenylftalazine 30 26 1-(4-acetylanilino)-4-fenylftalazine 27 1-(4-trifluormethylanilino)-4-fenylftalazine 28 1-(3-trifluormethylanilino)-4-fenylftalazine 35 29 1-(2-trifluormethylanilino)-4-fenyl ftalazine 30 1-(3-hydroxylanilino)-4-fenylftalazine 31 1-(2,3-dimethylanilino)-4-fenylftalazine 8005411Connection No. Name of Compound 1 1- (4-methylanilino) -4-phenylphthalazine 5 2 1- (3-methylanilino) -4-phenylphthalazine 3 1- (2-methylanilino) -4-phenylphthalazine 4 1- (4-ethylanilino) - 4-phenylphthalazine 5 1- (2-ethylanilino) -4-phenylphthalazine 6 1- (4-n-butylanilino) -4-phenylphthalazine 10 7 1- (3-n-butylanilino) -4-phenylphthalazine 8 1- (4- t-butylanilino) -4-phenylphthalazine 9 1- (4-methoxyanilino) -4-phenylphthalazine 10 1- (3-methoxyanilino) -4-phenylphthalazine 11 1- (3-propoxyanilino) -4-phenylphthalazine 15 12 1- (4 -n-butoxyanilino) -4-phenylphthalazine 13 1- (4-fluoroanilino) -4-phenylphthalazine 14 1- (3-fluoroanilino) -4-phenylphthalazine 15 1- (2-fluoroanilino) -4-phenylphthalazine 16 l- (4 -chloranilino) -4-phenylphthalazine 20 17 1- (3-chloroanilino) -4-phenylphthalazine 18 1- (2-chloroanilino) -4-phenylphthalazine 19 1- (4-bromoanilino) -4-phenylphthalazine 20 1- (3- bromoanilino) -4-phenylphthalazine 21 '1- (4-iodoanilino) -4-phenylphthalazine 25 22 1- (3-iodoanilino) -4-phenylphthalazine 23 1- (4-ethoxycarbonylanilino) -4-phenylphthalazine 24 1- ( 4-carboxyanilino) -4-phenylphthalazine 25 1- (4-cyanoanilino) -4-phenylphthalazine 30 26 1- (4-acetylanilino) -4-phenylphthalazine 27 1- (4-trifluoromethylanilino) -4-phenylphthalazine 28 1- (3-trifluoromethylanilino) -4-phenylphthalazine 35 29 1- (2-trifluoromethylanilino) -4-phenyl-phthalazine 30 1- (3-hydroxylanilino) -4-phenylphthalazine 31 1- (2,3-dimethylanilino) -4-phenylphthalazine 8005411

f Af A

- 5 - 32 1-(2,4-dimethylanilino)-4-fenylftalazine 33 1-(2,5-dimethylanilino)-4-fenylftalazine 34 1-(3,4-dimethylanilino)-4-fenylftalazine 35 1-(2,5-diethylanilino)-4-fenylftalazine 5 36 1-(2,5-dipropylanilino)-4-fenylftalazine 37 1-(2,5-dimethoxyanilino)-4-fenylftalazine 38 1-(3,4-dimethoxyanilino)-4-fenylftalazine 39 1-(2,5-dichlooranilino)-4-fenylftalazine 40 1-(3,4-dichlooranilino)-4-fenylftalazine 10 41 1-(2,5-difluoranilino)-4-fenylftalazine 42 1-(3-chloor-4-methylanilino)-4-fenyl- ftalazine 43 1-(2-methyl-3-chlooranilino)-4-fenylftalazine 15 44 1- (2-methyl-4-chlooranilino)-4-fenyl ftalazine 45 1-(3-methyl-4-chlooranilino)-4-fenyl- ftalazine 46 1-(3-fluor-4-methylanilino-4-fenyl- 20 ftalazine 47 1-(2-methoxy-5-methylanilino)-4-fenyl- ftalazine 48 1-(5-chloor-2-methoxyanilino)-4-fenylftalazine 25 49 1-(2-methyl-5-tri fluorine thy 1 ani lino) -4- fenylftalazine 50 1-(2-methoxy-5-trifluormethylanilino)- 4-fenylftalazine 51 1-(2,4,6-trimethylanilino-4-fenyl- 30 ftalazine 52 1-(3,4,5-trimethoxyanilino)-4-fenylftalazine 53 l-anilino-4-(4-methylfenyl)ftalazine 54 1-(4-methylanilino)-4-(4-methylfenyl)- 35 ftalazine 55 1-(4-butylanilino)-4-(4-methylfenyl)- ftalazine 56 1-(2,5-dimethylanilino)-4-(4-methylfenyl) ftalazine 8005411 - 6 - 57 1-(3-methoxyanilino)-4-(4-methylfenyl)- ftalazine 58 1-(4-butoxyanilino)»4-(4-methylfenyl)- ftalazine 5 59 1-(2,5-dimethoxyanilino)-4-(4-methyl fenyl) ftalazine 60 1-(3-chlooranilino)-4-(4-methylfenyl)- ftalazine 61 1-(3-broomanilino)-4-(4-methylfenyl)- 10 ftalazine 62 1-(3-fluoranilino)-4-(4-methylfenyl)- ftalazine 63 4-(4-methylfenyl)-1-(3-trifluormethyl- anilino)ftalazine 15 64 1-(5-chloor-2-methoxyanilino)-4-(4-methyl fenyl) ftalazine 65 1-(3-chloor-4-methylanilino)-4-(4-methyl- fenyl)ftalazine 66 1-(4-ethoxycarbonylanilino)-4-(4-methyl- 20 fenyl)ftalazine 67 1-anilino-4-(4-butylfenyl)ftalazine 68 4-(4-butylfenyl)-1-(2,5-dimethylanilino)- ftalazine 69 4- (4-butylfenyl) -1- (2,5-dimethoxyanilino),- 25 ftalazine 70 4-(4-butylfenyl)-1-(3-chlooranilino)- ftalazine 71 4-(4-butylfenyl)-1-(3-trifluormethyl- anilino)ftalazine 30 72 4-(4-butylfenyl)-1-(5-chloor-2-methoxy- anilino)ftalazine 73 l-anilino-4-(2,4-dimethylfenyl)ftalazine 74 l-anilino-4-(4-methoxyfenyl)ftalazine 75 1-(4-butylanilino)-4-(4-methoxyfenyl)- 35 ftalazine 76 1-(2,5-dimethylanilino)-4-(4-methoxy- fenyl)ftalazine 77 1-(2,5-dimethoxyanilino)-4-(4-methoxy- fenyl)ftalazine 8005411 r 4 - 7 - 78 1-(3-chlooranilino)-4-(4-methoxyfenyl)- ftalazine 79 4-(4-methoxyfenyl)-1-(3-trifluormethyl- anilino)ftalazine 5 80 1-(5-chloor-2-methoxyanilino)-4-(4-me thoxyfenyl) ftalazine 81 1-(4-ethoxycarbonylanilino )-4-(4-methoxyfenyl) ftalazine 82 l-anilino-4-(4-butoxyfenyl)ftalazine 10 83 4-(4-butoxyfenyl)I7(2,5-dimethylanilino)- ftalazine 84 4-(4-butoxyfenyl) -1- (2,5-dimethoxyanilino) = ftalazine 85 4-(4-butoxyfenyl)-1-(3-chlooranilino)- 15 ftalazine 86 4-(4-butoxyfenyl)-1-(3-trifluormethyl- anilino)ftalazine 87 4-(4-butoxyfenyl)-1-(5-chloor-2-methoxy- anilino)ftalazine 20 88 l-anilino-4-(2,4-dimethoxyfenyl)ftalazine 89 1-(2,5-dimethylanilino)-4-(2,4-dimethoxyfenyl) ftalazine 90 1-(2,5-dimethoxyanilino)-4-(2,4-dimethoxy- fenyl)ftalazine 25 91 1- (3-chlóoranilino) --=4- (2,4-dimethoxy fenyl) ftalazine 92 4-(2,4-dimethoxyfenyl)-1-(3-trifluor- methylanilino)ftalazine 93 1-(5-chloor-2-methoxyanilino)-4-(2,4— 30 dimethoxyfenyl)ftalazine 94 l-anilino-4-(4-chloorfenyl)ftalazine 95 4-(4-chloorfenyl)-1-(2,5,dimethyl- anilino)ftalazine 96 4-(4-chloorfenyl)-1-(2,5-dimethoxy- 35 anilino)ftalazine 97 1-(3-chlooranilino)-4-(4-chloorfenyl)- ftalazine 98 4-(4-chloorfenyl)-1-(3-trifluormethyl- anilino)ftalazine 80 05 4 1 1 - 8 - 99 1-(5-chloor-2-methoxyanilino)-4- (4-chloorfenyl)ftalazine 100 l-anilino-4-(4-broomfenyl)ftalazine 101 l-anilino-4-(4-fluorfenyl)ftalazine 5 102 1-(2,5-dimethylanilino)-4-(4-fluor fenyl) ftalazine 103 1-(2,5-dimethoxyanilino)-4-(4-fluorfenyl) ftalazine 104 1-(3-chlooranilino)-4-(4-fluorfenyl)- 10 ftalazine 105 4-(4-fluorfenyl)-1-(3-trifluormethyl- anilino)ftalazine 106 1-(5-chloor-2-methoxyanilino)-4-(4- fluorfenyl)ftalazine 15 107 l-anilino-4-(4-ethoxycarbonylfenyl)- ftalazine 108 1-(2,5-dimethylanilino)-4-(4-ethoxycarbonylfenyl) ftalazine 109 1-(2,5-dimethoxyanilino)-4-(4-ethoxy- 20 carbonylfenyl)ftalazine 110 1-(3-chlooranilino)-4-(4-ethoxycarbonyl- - fenyl)ftalazine 111 4-(4-ethoxycarbonylfenyl)-1-(3-trifluor- methylanilino)ftalazine 25 112 1-(5-chloor-2-methoxyanilino)-4-(4- ethoxycarbonylfenyl)ftalazine 113 l-anilino-6-methyl-4-fenylftalazine 114 l-anilino-7-methyl-4-fenylftalazine 115 1-(2,5-dimethylanilino)-6-methyl-4- 30 fenylftalazine 116 1-(2,5-dimethylanilino)-7-methyl-4- fenyIftalazine 117 1-(2,5-dimethoxyanilino)-6-methyl-4- fenylftalazine 35 118 1-(2,5-dimethoxyanilino)-7-methyl-4- fenyIftalazine 119 1-(3-chlooranilino)-6-methyl-4-fenyl- ftalazine 120 1-(3-chlooranilino)-7-methy-4-fenyl- 80 0 5 4 1 1 ftalazine - 9 - 121 6-methyl-4-fenyl-l-(3-trifluormethyl- anilino)ftalazine 122 7-methyl-4-fenyl-l-(3-trifluormethyl- anilino)ftalazine 5 123 l-(5-chloor-2-methoxyanilino)-6-methyl- 4-fenylftalazine 124 1-(5-chloor-2-methoxyanilino)-7-methyl- 4-fenyIftalazine 125 l-anilino-6,7-dimethyl-4~fenyIftalazine 10 126 1-(4-butylanilino)-6,7-dimethyl-4-fenyl- ftalazine 127 1-(2,5-dimethylanilino)-6,7-dimethyl-4- fenyIftalazine 128 1-(2,5-dimethoxyanilino)-6,7-dimethyl' 15 4-fenylftalazine 129 1-(4-butoxyanilino)-6,7-dimethyl-4- fenyIftalazine 130 1-(3-chlooranilino)-6,7-dimethyl-4- fenylftalazine 20 131 6,7-dimethyl-4-fenyl-l-(3-trifluor- methylanilino)ftalazine 132 1-(5-chloor-2-methoxyanilino)-6,7- dimethyl- 4- feny If talazine 133 1-(3-chloor-4-methylanilino)-6,7-dimethyl- 25 4-fenylftalazine 134 6,7-dimethyl-l-(4-ethoxycarbonylanilino)- 4-fenylftalazine 135 l-anilino-5,8-dimethyl-4-fenyIftalazine 136 1-(3-chlooranilino)-5,8-dimethyl-4- 30 fenylftalazine 137 l-anilino-6,7-dibutyl-4-fenyIftalazine 138 l-anilino-6,7-dimethoxy-4-fenylftalazine 139 6,7-dimethoxy-l-(2,5-dimethylanilino)- 4-fenylftalazine 35 140 6,7-dimethoxy-l-(2,5-dimethoxyanilino)- 4-fenylftalazine 141 1-(3-chlooranilino)-6,7-dimethoxy-4- fenylftalazine 142 6,7-dimethoxy-4-fenyl-l-(3-trifluor- 8005411 - 10 - methylanilino)ftalazine 143 1- (5-chloor-2“met±ioxyanil:Lno) -6,7- dimettoxy-4-fenylftalazine 144 1-(4-butylanilino)-6,7-dimethoxy-4- 5 fenylftalazine 145 1-(4-butoxyanilino)-6,7-dimettoxy-4- fenylftalazine 146 l-anilino-5,8-dimettoxy-4-fenyl- ftalazine 10 147 l-anilino-6,7-dibutoxy-4-fenylftalazine 148 l-anilino-6,7-dichloor-4-fenylftalazine 149 6,7-dichloor-l-(2,5-dimettylanilino)-4- fenylftalazine 150 6,7-dichloor-l-(2,5-dimethoxyanilino)-4- 15 fenylftalazine 151 1-(3-chlooranilino)-6,7-dichloor-4- fenylftalazine 152 6,7-dichloor-4-fenyl-l-(3-trifluor- methylanilino)ftalazine 20 153 l-(4-chloor-2-mettoxyanilino)-6,7- dichloor-4-fenyIftalazine 154 l-anilino-5,8-dichloor-4-fenylftalazine 155 l-anilino-6-ethoxycarbonyl-4-fenyl- ftalazine 25 156 l-anilino-6,7-dimethyl-4-(4-methyl- fenyl)ftalazine 157 1-(4-butylanilino)-6,7-dimethyl-4-(4- methylfenyl)ftalazine 158 6,7-dimethyl-1-(2,5-dimethylanilino)-4- 30 (4-methylfenyl)ftalazine 159 6,7-dimethyl-l-(3-methoxyanilino)-4- (4-methylfenyl)ftalazine 160 1-(2,5-dimethoxyanilino)-6,7-dimettyl-4- (4-methylfenyl)ftalazine 35 161 1-(3-chlooranalino)-6,7-dimethyl-4- (4-methylfenyl)ftalazine 162 6,7-dimethyl-4-(methylfenyl)-l-(3- trifluormethylanilino)ftalazine 163 1-(4-chloor-2-methoxyanilino)-6,7- 8005411 - 11 - dimethyl-4-(4-methylfenyl)ftalazine 164 6,7-dimethy1-1-(4-ethoxycarbonylanilino)- 4-(4-methylfenyl)ftalazine 165 l-anilino-4-(4-butylfenyl)-6,7-di- 5 methylftalazine 166 l-anilino-6,7-dimethyl-4-(4-methoxy- fenyl)ftalazine 167 6,7-dimethyl-l-(2,5-dimethylanilino)- 4-(4-methoxyfenyl)ftalazine 10 168 1-(2,5-dimethoxyanilino)-6,7-dimethyl- 4-(4-methoxyfenyl)ftalazine 169 1-(3-chlooranilino)-6,7-dimethyl-4- (4-methoxyfenyl)ftalazine 170 6,7-dimethy1-4-(4-methoxyfenyl)-1- 15 (3-trifluormethylanilino)ftalazine 171 1-(5-chloor-2-methoxyanilino)-6,7- dimethyl-4-(4-methoxyfenyl)ftalazine 172 l-anilino-4-(4-butoxyfenyl)-6,7- dimethylftalazine 20 173 l-anilino-4-(2,4-dimethoxyfenyl)-6,7- dimethylftalazine 174 l-anilino-4-(4-chloorfenyl)-6,7- dime thylf talazine 175 1-(3-chlooranilino)-4-(4-chloorfenyl)- 25 6,7-dimethyIftalazine 176 1-(3-chloor-4-methylanilino)-4-(4- chloorfenyl)-6,7-dimethylftalazine 177 l-anilino-6,7-dimethy1-4-(4-fluorfenyl)- ftalazine 30 178 l-anilino-6,7-dimethyl-4-(4-ethoxy- carbonylfenyl)ftalazine 179 l-anilino-6,7-d-methoxy-4-(4-methylfenyl) ftalazine 180 6,7-dimethoxy-l-(2,5-dimethylanilino)- 35 4-(4-methy-fenyl)ftalazine 181 6,7-dimethoxy-l-(2,5-dimethoxyanilino)- 4-(4-methylfenyl)ftalazine 182 1-(3-chlooranilino)-6,7-dimethoxy-4- (4-methylfenyl)ftalazine 8005411 - 12 - 183 l-anilino-4-(4-butylfenyl)-6, 7- dimethoxyftalazine 184 l-anilino-6,7-dimethoxy-4-(4-methoxy- fenyl)ftalazine 5 185 l-anilino-6,7-dimethoxy-4-(2,4-dimethoxy- fenyl)ftalazine 186 l-anilino-4-(4-chloorfenyl)-6,7- dimethoxyftalazine 187 l-anilino-6,7-dimethoxy-4-(4-fluorfenyl)- 10 ftalazine 188 l-anilino-6,7-dimethoxy-4-(4-ethoxy- carbonyl fenyl)ftalazine 189 l-anilino-6,7-dichloor-4-(4-methyl- fenyl)ftalazine 15 190 l-anilino-4-(4-butylfenyl)-6,7-dichloor- ftalazine 191 l-anilino-6,7-dichloor-4-(4-methoxy- fenyl)ftalazine 192 l-anilino-4-(4-butoxyfenyl)-6,7- 20 dichloorftalazine 193 l-anilino-6,7-dichloor-4-(2,4-dimethoxy- fenyl)ftalazine 194 l-anilino-4-(4-chloorfenyl)-6,7- dichloorftalazine 25 195 l-anilino-6,7-dichloor-4-(4-fluorfenyl)- ftalazine 196 l-anilino-6,7-dichloor-4-(4-ethoxycarbonyl- fenyl)ftalazine 197 l-anilino-4-(4-carboxyfenyl)ftalazine 30 198 4-(4-carboxyfenyl)-1-(2,5-dimethyl- anilino)ftalazine 199 4.- (4-carboxyfenyl) -1- (2,5-dimethoxy- anilino)ftalazine 200 4-(4-carboxyfenyl)-1-(3-chlooranilino)- 35 ftalazine 201 4-(4-carboxyfenyl)-1-(3-trifluormethyl- anilino)ftalazine 202 4-(4-carboxyfenyl)-l-(5-chloor-2- methoxyanilino)ftalazine 80 05 4 1 1 - 13 - 203 l-anilino-4-(4-hydroxyfenyl)ftalazine 204 1-(2,5-dimethylanilino)-4-(4-hydroxy- fenylftalazine 205 1-(2,5-dimethoxyanilino)-4-(4-hydroxy- 5 fenyl)ftalazine 206 l-,(3-chlooranilino)-4-(4-hydroxyfenyl)- ftalazine 207 4-(4-hydroxyfenyl)-1-(3-trifluormethyl- anilino)ftalazine 10 208 1-(5-chloor-2-methoxyanilino)-4-(4- carboxyfenyl)ftalazine 209 1-(4-acetylanilino)-4-(4-methylfenyl)- ftalazine 210 1-(4-acetylanilino)-6,7-dimethyl-4- 15 fenylftalazine 211 1-(4-methylfenoxy)-4-fenylftalazine 212 1-(3-methylfenoxy)-4-fenylftalazine 213 1-(2-methylfenoxy)-4-fenylftalazine 214 1-(4-ethyIfenoxy)-4-fenylftalazine 20 215 1-(2-ethylfenoxy)-4-fenylftalazine 216 1-(4-n-butyIfenoxy)-4-fenylftalazine 217 1-(3-n-butylfenoxy)-4-fenylftalazine 218 1-(4-t-butyIfenoxy)-4-fenylftalazine 219 1-(4-methoxyfenoxy)-4-fenylftalazine 25 220 1-(3-methoxyfenoxy)-4-fenylftalazine 221 1-(3-propoxyfenoxy)-4-fenylftalazine 222 1-(3-butoxyfenoxy)-4-fenylftalazine 223 1-(4-fluorfenoxy)-4-fenylftalazine 224 1-(3-fluorfenoxy)-4-fenylftalazine 30 225 1-(4-chloorfenoxy)-4-fenylftalazine 226 1-(3-chloorfenoxy)-4-fenylftalazine 227 1-(2-chloorfenoxy)-4-fenylftalazine 228 1-(4-broomfenoxy)-4-fenylftalazine 229 1-(3-broomfenoxy)-4-fenylftalazine 35 230 1-(3-joodfenoxy)-4-fenylftalazine 231 1-(4-ethoxycarbonyIfenoxy)-4-fenyl- ftalazine 232 1-(4-carboxyfenoxy)-4-fenylftalazine 233 l-(4-4-cyaanfenoxy)-4-fenylftalazine 8005411 - 14 - 234 1- (4-acetylfenoxy) -4-fenylftalazine 235 1-(4-trifluormethylfenoxy)-4- fenylftalazine 236 l-(3-trifluormethylfenoxy)-4- 5 fenylftalazine 237 1-(3-hydroxyfenoxy)-4-fenylftalazine 238 1- (2,3-diiuethylfenoxy) -4-fenylftalazine 239 1-(2,5-dimethylfenoxy)-4-fenylftalazine 240 1-(2,5-diethylfenoxy)-4-fenylftalazine 10 241 1-(2,5-dipropylfenoxy)-4-fenylftalazine 242 1-(2,5-dimethoxyfenoxy)-4-fenylftalazine 243 1-(3,4-dimethoxyfenoxy)-4-fenylftalazine 244 1-(2,5-dichloorfenoxy)-4-fenylftalazine 245 l-[2,6-dichloorfenoxy)-4-fenylftalazine 15 246 1-(2,5-difluorfenoxy)-4-fenylftalazine 247 1-(3-chloor-4-methyIfenoxy)-4-fenyl- ftalazine 248 1-(3-methyl-4-chloorfenoxy)-4-fenylftalazine 20 249 1-(3-fluor-4-methylfenoxy)-4-fenyl ftalazine 250 11-(2-methoxy-4-chloorfenoxy)-4-fenylftalazine 251 1-(2-methoxy-5-methylfenoxy)-4-fenyl- 25 ftalazine 252 1-(2-methyl-4-trifluormethylfenoxy)- ftalazine 253 1-(2,4,6-trimethylfenoxy)-4-fenyl- ftalazine 30 80 05 4 1 1 - 15 -- 5 - 32 1- (2,4-dimethylanilino) -4-phenylphthalazine 33 1- (2,5-dimethylanilino) -4-phenylphthalazine 34 1- (3,4-dimethylanilino) -4-phenylphthalazine 35 1- (2 , 5-diethylanilino) -4-phenylphthalazine 5 36 1- (2,5-dipropylanilino) -4-phenylphthalazine 37 1- (2,5-dimethoxyanilino) -4-phenylphthalazine 38 1- (3,4-dimethoxyanilino) -4 -phenylphthalazine 39 1- (2,5-dichloroanilino) -4-phenylphthalazine 40 1- (3,4-dichloroanilino) -4-phenylphthalazine 10 41 1- (2,5-difluoroanilino) -4-phenylphthalazine 42 1- (3 -chloro-4-methylanilino) -4-phenyl-phthalazine 43 1- (2-methyl-3-chloroanilino) -4-phenylphthalazine 15 44 1- (2-methyl-4-chloroanilino) -4-phenyl phthalazine 45 1- (3-methyl-4-chloroanilino) -4-phenyl-phthalazine 46 1- (3-fluoro-4-methylanilino-4-phenyl-20-phthalazine 47 1- (2-methoxy-5-methylanilino) -4-phenyl- phthalazine 48 1- (5-chloro-2-methoxyanilino) -4-phenylphthalazine 25 49 1- (2-methyl-5-trifluorine thy 1 anilino) -4-phenylphthalazine 50 1- (2-methoxy-5-trifluoromethylanilino ) - 4-phenylphthalazine 51 1- (2,4,6-trimethylanilino-4-phenyl-30 phthalazine 52 1- (3,4,5- trimethoxyanilino) -4-phenylphthalazine 53 l-anilino-4- (4-methylphenyl) phthalazine 54 1- (4-methylanilino) -4- (4-methylphenyl) - 35 phthalazine 55 1- (4-butylanilino) -4- ( 4-methylphenyl) - phthalazine 56 1- (2,5-dimethylanilino) -4- (4-methylphenyl) phthalazine 8005411 - 6 - 57 1- (3-methoxyanilino) -4- (4-methylphenyl) - phthalazine 58 1- (4-butoxyanilino) »4- (4-methylphenyl) -phthalazine 5 59 1- (2,5-dimethoxyanilino) -4- (4-methylphenyl) phthalazine 60 1- (3-chloroanilino) -4- (4- methylphenyl) - phthalazine 61 1- (3-bromoanilino) -4- (4-methylphenyl) - 10 phthalazine 62 1- (3-fluoroanilino) -4- (4-methylphenyl) - phthalazine 63 4- (4-methylphenyl) - 1- (3-Trifluoromethyl-anilino) phthalazine 15 64 1- (5-chloro-2-methoxyanilino) -4- (4-methylphenyl) phthalazine 65 1- (3-chloro-4-methylanilino) -4- (4 -methyl-phenyl) phthalazine 66 1- (4-ethoxycarbonylanilino) -4- (4-methyl-phenyl) phthalazine 67 1-anilino-4- (4-butylphenyl) phthalazine 68 4- (4-butylphenyl) -1- (2,5-dimethylanilino) - phthalazine 69 4- (4-butylphenyl) -1- (2,5-dimethoxyanilino), - 25 phthalazine 70 4- (4-butylphenyl) -1- (3-chloroanilino) - phthalazine 71 4- (4-butylphenyl) -1- (3-trifluoromethylanilino) phthalazine 30 72 4- (4-butylphenyl) -1- (5-chloro-2-methoxyanilino) phthalazine 73 l-anilino-4- (2,4-dimethylphenyl) phthalazine 74 l-anilino-4- (4-methoxyphenyl) phthalazine 75 1- (4-butylanilino) -4- (4-methoxyphenyl) - 35 phthalazine 76 1- (2,5-dimethylanilino) -4- (4-methoxyphenyl) phthalazine 77 1- (2,5-dimethoxyanilino) -4- (4-methoxyphenyl) phthalazine 8005411 r 4 - 7 - 78 1- (3 -chloranilino) -4- (4-methoxyphenyl) -phthalazine 79 4- (4-methoxyphenyl) -1- (3-trifluoromethylanilino) phthalazine 5 80 1- (5-chloro-2-methoxyanilino) -4- (4 -m thoxyphenyl) phthalazine 81 1- (4-ethoxycarbonylanilino) -4- (4-methoxyphenyl) phthalazine 82 l-anilino-4- (4-butoxyphenyl) phthalazine 10 83 4- (4-butoxyphenyl) I7 (2.5- dimethylanilino) - phthalazine 84 4- (4-butoxyphenyl) -1- (2,5-dimethoxyanilino) = phthalazine 85 4- (4-butoxyphenyl) -1- (3-chloroanilino) - 15 phthalazine 86 4- (4-butoxyphenyl ) -1- (3-trifluoromethyl-anilino) phthalazine 87 4- (4-butoxyphenyl) -1- (5-chloro-2-methoxy-anilino) phthalazine 20 88 l-anilino-4- (2,4-dimethoxyphenyl) phthalazine 89 1- (2,5-dimethylanilino) -4- (2,4-dimethoxyphenyl) phthalazine 90 1- (2,5-dimethoxyanilino) -4- (2,4-dimethoxyphenyl) phthalazine 25 91 1- (3-chloroananilino) - = 4- (2,4-dimethoxyphenyl) phthalazine 92 4- (2,4-dimethoxyphenyl) -1- (3-trifluoro - methylanilino) phthalazine 93 1- (5-chloro-2-methoxyanilino) -4- (2,4-30 dimethoxyphenyl) phthalazine 94 l-anilino-4- (4-chlorophenyl) phthalazine 95 4- (4-chlorophenyl) - 1- (2,5, dimethylanilino) phthalazine 96 4- (4-chlorophenyl) -1- (2,5-dimethoxy-anilino) phthalazine 97 1- (3-chloroanilino) -4- (4-chlorophenyl) - phthalazine 98 4- (4-chlorophenyl) -1- (3-trifluoromethylanilino) phthalazine 80 05 4 1 1 - 8 - 99 1- (5-chloro-2-methoxyanilino) -4- (4-chlorophenyl) phthalazine 100 l-anilino-4- (4-bromophenyl) phthalazine 101 l-anilino-4- (4-fluorophenyl) phthalazine 5 102 1- (2,5-dimethylanilino) -4- (4-fluoro phenyl) phthalazine 103 1- (2,5-dimethoxyanilino) -4- (4-fluorophenyl) phthalazine 104 1- (3-chloroanilino) -4- (4-fluorophenyl) - 10 phthalazine 105 4- (4-fluorophenyl) -1- (3-trifluorom ethyl anilino) phthalazine 106 1- (5-chloro-2-methoxyanilino) -4- (4-fluorophenyl) phthalazine 15 107 l-anilino-4- (4-ethoxycarbonylphenyl) phthalazine 108 1- (2,5-dimethylanilino ) -4- (4-ethoxycarbonylphenyl) phthalazine 109 1- (2,5-dimethoxyanilino) -4- (4-ethoxy-carbonylphenyl) phthalazine 110 1- (3-chloroanilino) -4- (4-ethoxycarbonyl- - phenyl) ) phthalazine 111 4- (4-ethoxycarbonylphenyl) -1- (3-trifluoromethylanilino) phthalazine 25 112 1- (5-chloro-2-methoxyanilino) -4- (4-ethoxycarbonylphenyl) phthalazine 113 l-anilino-6- methyl 4-phenylphthalazine 114 1-anilino-7-methyl-4-phenylphthalazine 115 1- (2,5-dimethylanilino) -6-methyl-4-phenylphthalazine 116 1- (2,5-dimethylanilino) -7-methyl -4-phenyphthalazine 117 1- (2,5-dimethoxyanilino) -6-methyl-4-phenylphthalazine 35 118 1- (2,5-dimethoxyanilino) -7-methyl-4-phenyphthalazine 119 1- (3-chloroanilino) - 6-methyl-4-phenyl-phthalazine 120 1- (3-chloroanilino) -7-methyl-4-phenyl- 80 0 5 4 1 1 phthalazine - 9 - 121 6-methyl-4-phenyl-1- (3- trifluoromethyl- anilino) phthalazine 122 7-methyl-4-phenyl-1- (3-triflu ormethyl- anilino) phthalazine 5 123 l- (5-chloro-2-methoxyanilino) -6-methyl-4-phenylphthalazine 124 1- (5-chloro-2-methoxyanilino) -7-methyl- 4-phenylphthalazine 125 l-anilino -6,7-dimethyl-4-phenylphthalazine 10 126 1- (4-butylanilino) -6,7-dimethyl-4-phenyl-phthalazine 127 1- (2,5-dimethylanilino) -6,7-dimethyl-4- phenyphthalazine 128 1- (2,5-dimethoxyanilino) -6,7-dimethyl '15 4-phenylphthalazine 129 1- (4-butoxyanilino) -6,7-dimethyl-4-phenyphthalazine 130 1- (3-chloroanilino) -6 7-dimethyl-4-phenylphthalazine 20 131 6,7-dimethyl-4-phenyl-1- (3-trifluoromethylanilino) phthalazine 132 1- (5-chloro-2-methoxyanilino) -6,7-dimethyl- 4 - pheny If talazine 133 1- (3-chloro-4-methylanilino) -6,7-dimethyl- 4-phenylphthalazine 134 6,7-dimethyl-1- (4-ethoxycarbonylanilino) - 4-phenylphthalazine 135 l-anilino- 5,8-dimethyl-4-phenylphthalazine 136 1- (3-chloroanilino) -5,8-dimethyl-4-phenylphthalazine 137 l-anilino-6,7-dibutyl-4-phenylphthalazine 138 l-anilino-6,7 -dimethoxy-4-phenylphthalazine 139 6,7-dimethoxy-1- (2,5-dimethylanilino) - 4-phenylphthalazin e 35 140 6,7-dimethoxy-1- (2,5-dimethoxyanilino) -4-phenylphthalazine 141 1- (3-chloroanilino) -6,7-dimethoxy-4-phenylphthalazine 142 6,7-dimethoxy-4-phenyl -1- (3-trifluoro- 8005411-10 - methylanilino) phthalazine 143 1- (5-chloro-2 "with ± ioxyanil: Lno) -6,7-dimettoxy-4-phenylphthalazine 144 1- (4-butylanilino) - 6,7-dimethoxy-4-5-phenylphthalazine 145 1- (4-butoxyanilino) -6,7-dimettoxy-4-phenylphthalazine 146 l-anilino-5,8-dimettoxy-4-phenyl-phthalazine 10 147 l-anilino- 6,7-dibutoxy-4-phenylphthalazine 148 l-anilino-6,7-dichloro-4-phenylphthalazine 149 6,7-dichloro-1- (2,5-dimettylanilino) -4-phenylphthalazine 150 6,7-dichloro- 1- (2,5-dimethoxyanilino) -4-15 phenylphthalazine 151 1- (3-chloroanilino) -6,7-dichloro-4-phenylphthalazine 152 6,7-dichloro-4-phenyl-1- (3-trifluoro- methylanilino) phthalazine 20 153 l- (4-chloro-2-metoxyanilino) -6,7-dichloro-4-phenylphthalazine 154 l-anilino-5,8-dichloro-4-phenylphthalazine 155 l-anilino-6-ethoxycarbonyl-4 -phenyl-phthalazine 25 156 l-anilino-6,7-dimethyl-4- (4-methyl-phenyl) phthalazine 157 1- (4-butyla nilino) -6,7-dimethyl-4- (4-methylphenyl) phthalazine 158 6,7-dimethyl-1- (2,5-dimethylanilino) -4-30 (4-methylphenyl) phthalazine 159 6,7-dimethyl- 1- (3-Methoxyanilino) -4- (4-methylphenyl) phthalazine 160 1- (2,5-dimethoxyanilino) -6,7-dimettyl-4- (4-methylphenyl) phthalazine 35 161 1- (3-chloroanalino) -6,7-dimethyl-4- (4-methylphenyl) phthalazine 162 6,7-dimethyl-4- (methylphenyl) -1- (3-trifluoromethylanilino) phthalazine 163 1- (4-chloro-2-methoxyanilino) -6 , 7- 8005411 - 11 - dimethyl-4- (4-methylphenyl) phthalazine 164 6,7-dimethyl-1- (4-ethoxycarbonylanilino) - 4- (4-methylphenyl) phthalazine 165 l-anilino-4- (4- butylphenyl) -6,7-dimethyl-phthalazine 166 l-anilino-6,7-dimethyl-4- (4-methoxyphenyl) phthalazine 167 6,7-dimethyl-1- (2,5-dimethylanilino) - 4 - (4-methoxyphenyl) phthalazine 10 168 1- (2,5-dimethoxyanilino) -6,7-dimethyl- 4- (4-methoxyphenyl) phthalazine 169 1- (3-chloroanilino) -6,7-dimethyl-4- (4-methoxyphenyl) phthalazine 170 6,7-dimethyl-1- (4-methoxyphenyl) -1-15 (3-trifluoromethylanilino) phthalazine 171 1- (5-chloro-2-methoxyanilino) -6,7-d imethyl-4- (4-methoxyphenyl) phthalazine 172 l-anilino-4- (4-butoxyphenyl) -6,7-dimethylphthalazine 20 173 l-anilino-4- (2,4-dimethoxyphenyl) -6,7-dimethylphthalazine 174 1-anilino-4- (4-chlorophenyl) -6,7-dimethylphalazine 175 1- (3-chloroanilino) -4- (4-chlorophenyl) - 6,7-dimethylphthalazine 176 1- (3-chloro- 4-methylanilino) -4- (4-chlorophenyl) -6,7-dimethylphthalazine 177 l-anilino-6,7-dimethy1-4- (4-fluorophenyl) -phthalazine 30 178 l-anilino-6,7-dimethyl- 4- (4-ethoxy-carbonylphenyl) phthalazine 179 l-anilino-6,7-d-methoxy-4- (4-methylphenyl) phthalazine 180 6,7-dimethoxy-1- (2,5-dimethylanilino) - 35 4 - (4-methylphenyl) phthalazine 181 6,7-dimethoxy-1- (2,5-dimethoxyanilino) - 4- (4-methylphenyl) phthalazine 182 1- (3-chloroanilino) -6,7-dimethoxy-4 - (4-methylphenyl) phthalazine 8005411 - 12 - 183 l-anilino-4- (4-butylphenyl) -6,7-dimethoxyphthalazine 184 l-anilino-6,7-dimethoxy-4- (4-methoxyphenyl) phthalazine 5 185 l-anilino-6,7-dimethoxy-4- (2,4-dimethoxyphenyl) phthalazine 186 l-anilino-4- (4-chlorophenyl) -6,7-dimethoxyphthalazine 187 l-anil ino-6,7-dimethoxy-4- (4-fluorophenyl) - 10 phthalazine 188 l-anilino-6,7-dimethoxy-4- (4-ethoxy-carbonyl phenyl) phthalazine 189 l-anilino-6,7-dichloro -4- (4-methylphenyl) phthalazine 15 190 L-anilino-4- (4-butylphenyl) -6,7-dichlorophthalazine 191 L-anilino-6,7-dichloro-4- (4-methoxy- phenyl) phthalazine 192 l-anilino-4- (4-butoxyphenyl) -6,7-20 dichlorophthalazine 193 l-anilino-6,7-dichloro-4- (2,4-dimethoxyphenyl) phthalazine 194 l-anilino- 4- (4-chlorophenyl) -6,7-dichlorophthalazine 25 195 l-anilino-6,7-dichloro-4- (4-fluorophenyl) -phthalazine 196 l-anilino-6,7-dichloro-4- (4- ethoxycarbonylphenyl) phthalazine 197 l-anilino-4- (4-carboxyphenyl) phthalazine 30 198 4- (4-carboxyphenyl) -1- (2,5-dimethyl-anilino) phthalazine 199 4.- (4-carboxyphenyl) - 1- (2,5-dimethoxyanilino) phthalazine 200 4- (4-carboxyphenyl) -1- (3-chloroanilino) - 35 phthalazine 201 4- (4-carboxyphenyl) -1- (3-trifluoromethylanilino) phthalazine 202 4- (4-carboxyphenyl) -1- (5-chloro-2-methoxyanilino) phthalazine 80 05 4 1 1 - 13 - 203 l-anilino-4- (4-hydroxyphenyl) phthalazine 204 1- (2, 5-dimethylanilino) -4- (4-hydroxy-phenylphthalazine 205 1- (2,5-dimethoxyanilino) -4- (4-hydroxy-phenyl) phthalazine 206 L -, (3-chloroanilino) -4- (4- hydroxyphenyl) - phthalazine 207 4- (4-hydroxyphenyl) -1- (3-trifluoromethylanilino) phthalazine 10 208 1- (5-chloro-2-methoxyanilino) -4- (4-carboxyphenyl) phthalazine 209 1- (4 -acetylanilino) -4- (4-methylphenyl) -phthalazine 210 1- (4-acetylanilino) -6,7-dimethyl-4-phenylphthalazine 211 1- (4-methylphenoxy) -4-phenylphthalazine 212 1- (3- methylphenoxy) -4-phenylphthalazine 213 1- (2-methylphenoxy) -4-phenylphthalazine 214 1- (4-ethylphenoxy) -4-phenylphthalazine 20 215 1- (2-ethylphenoxy) -4-phenylphthalazine 216 1- (4-n -butylphenoxy) -4-phenylphthalazine 217 1- (3-n-butylphenoxy) -4-phenylphthalazine 218 1- (4-t-butylphenoxy) -4-phenylphthalazine 219 1- (4-methoxyphenoxy) -4-phenylphthalazine 25 220 1 - (3-methoxyphenoxy) -4-phenylphthalazine 221 1- (3-propoxyphenoxy) -4-phenylphthalazine 222 1- (3-butoxyphenoxy) -4-phenylphthalazine 223 1- (4-fluorophenoxy) -4-phenylphthalazine 224 1- ( 3-fluorophenoxy) -4-phenylphthalazine 30 225 1- (4-chlorophenoxy) -4-f enylphthalazine 226 1- (3-chlorophenoxy) -4-phenylphthalazine 227 1- (2-chlorophenoxy) -4-phenylphthalazine 228 1- (4-bromophenoxy) -4-phenylphthalazine 229 1- (3-bromophenoxy) -4-phenylphthalazine 35 230 1- (3-iodophenoxy) -4-phenylphthalazine 231 1- (4-ethoxycarbonyphenoxy) -4-phenylphthalazine 232 1- (4-carboxyphenoxy) -4-phenylphthalazine 233 1- (4-4-cyanophenoxy) -4 -phenylphthalazine 8005411 - 14 - 234 1- (4-acetylphenoxy) -4-phenylphthalazine 235 1- (4-trifluoromethylphenoxy) -4-phenylphthalazine 236 1- (3-trifluoromethylphenoxy) -4-5 phenylphthalazine 237 1- (3-hydroxyphenoxy ) -4-phenylphthalazine 238 1- (2,3-diethyl-phenoxy) -4-phenylphthalazine 239 1- (2,5-dimethylphenoxy) -4-phenylphthalazine 240 1- (2,5-diethylphenoxy) -4-phenylphthalazine 10 241 1 - (2,5-dipropylphenoxy) -4-phenylphthalazine 242 1- (2,5-dimethoxyphenoxy) -4-phenylphthalazine 243 1- (3,4-dimethoxyphenoxy) -4-phenylphthalazine 244 1- (2,5-dichlorophenoxy) -4-phenylphthalazine 245 1- [2,6-dichlorophenoxy) -4-phenylphthalazine 15 246 1- (2,5-difluorophenoxy) -4-phenylphthalazine 247 1- (3-chloro-4-methylphenoxy) -4-phenyl- phthalazine 2 48 1- (3-methyl-4-chlorophenoxy) -4-phenylphthalazine 20 249 1- (3-fluoro-4-methylphenoxy) -4-phenyl phthalazine 250 11- (2-methoxy-4-chlorophenoxy) -4-phenylphthalazine 251 1- (2-methoxy-5-methylphenoxy) -4-phenyl-phthalazine 252 1- (2-methyl-4-trifluoromethylphenoxy) -phthalazine 253 1- (2,4,6-trimethylphenoxy) -4-phenyl- phthalazine 30 80 05 4 1 1 - 15 -

Werkwijze voor het bereiden van de verbinding 1.Method for preparing the compound 1.

De verbinding met de formule 1 van het formuleblad kan worden bereid volgens elke geschikte werkwijze die niet in het bijzonder is beperkt. De verbinding met 5 de formule 1 kan langs de reactieroute, die is weergege ven in het reactieschema A van het formuleblad worden gesynthetiseerd.The compound of the formula 1 of the formula sheet can be prepared by any suitable method which is not particularly limited. The compound of formula 1 can be synthesized along the reaction route shown in reaction scheme A of the formula sheet.

In de formules 2 en 3 stelt X' voor de groep -NH2 of -OH; Y stelt voor een halogeenatoom (bijvoorbeeld 10 chloor, broom of jodium), een groep met de formule 4 4 -S(0) -R (p=0-2, R is een C. - alkyl-, fenyl- of gesub-P 2 stitueerde fenylgroep) of een groep met de formule -OR 5 (R is een alkyl-, fenyl- of een gesubstitueerde fenylgroep); en alle andere symbolen zijn als boven 15 gedefinieerd.In formulas 2 and 3, X 'represents the group -NH2 or -OH; Y represents a halogen atom (e.g., 10 chlorine, bromine or iodine), a group of the formula 4 4 -S (0) -R (p = 0-2, R is a C.- alkyl, phenyl or sub- P2-substituted phenyl group) or a group of the formula -OR 5 (R is an alkyl, phenyl or a substituted phenyl group); and all other symbols are as above 15.

Volgens deze werkwijze laat men de uitgangs-verbinding met de formule 2 van het formuleblad, n.l. l-chloor-4-fenylftalazine of het derivaat daarvan, reageren met een benzeenderivaat met de formule 3 van het 20 formuleblad, al of niet in aanwezigheid van een oplos middel, bij voorkeur in aanwezigheid van een katalysator, zodat een 4-fenylftalazinederivaat met de formule 1 van het formuleblad wordt bereid.According to this method, the starting compound of the formula II of the formula sheet, i.e. 1-Chloro-4-phenylphthalazine or its derivative, react with a benzene derivative of the formula (III), whether or not in the presence of a solvent, preferably in the presence of a catalyst, so that a 4-phenylphthalazine derivative with the formula 1 of the formula sheet is prepared.

De uitgangsmaterialen, d.w.z. l-chloor-4-fenyl-25 ftalazine met de formule 2 of derivaten daarvan werden gesynthetiseerd volgens de methode, die is beschreven in het Journal of Pharmacology 8£, 576 (1966) of soortgelijke methoden.The starting materials, i.e. 1-chloro-4-phenyl-25-phthalazine of the formula 2 or derivatives thereof, were synthesized according to the method described in Journal of Pharmacology 8, 576 (1966) or similar methods.

Als benzeenderivaten met de formule 3, die 30 moeten reageren met de verbinding met de formule 2 als bovenvermeld, kunnen geschikte gesubstitueerde anilinen of gesubstitueerde fenolen worden gebruikt.Suitable benzene derivatives of the formula III which are to react with the compound of the formula II as mentioned above may use suitable substituted anilines or substituted phenols.

De reactietemperatuur kan liggen in het traject van -20 tot 250°C, bij voorkeur tussen -10 en 180°C.The reaction temperature can range from -20 to 250 ° C, preferably between -10 and 180 ° C.

35 De reactietijd kan 5 min. tot 24 uur bedragen, bij voor keur van 10 min. tot 10 uur.The reaction time can be from 5 min to 24 hours, preferably from 10 min to 10 hours.

Wanneer een katalysator dient te worden gebruikt, kan een organische base zoals ammoniak, triethylamine, piperidine of pyridine worden gebruikt, of een anorganische base zoals natriumcarbonaat, kaliumcarbonaat, natrium- ft n o 5 411 - 16- hydroxide , kaliumhydroxide, natriumhydride of natrium-amide kan worden toegevoegd in een molverhouding ten opzichte van de verbinding met formule 2 van het formuleblad in het traject van 0,5-5, bij voorkeur 1-3.When a catalyst is to be used, an organic base such as ammonia, triethylamine, piperidine or pyridine can be used, or an inorganic base such as sodium carbonate, potassium carbonate, sodium ft no 5 411-16-hydroxide, potassium hydroxide, sodium hydride or sodium amide can be added in a molar ratio to the compound of formula 2 of the formula sheet in the range of 0.5-5, preferably 1-3.

5 Een andere mogelijkheid is, dat men een metaal zoals koper, magnesium, cadmium, natrium of kalium in een molverhouding ten opzichte van de verbinding 2 van het formuleblad in het traject van 0,001-2, bij voorkeur van 0,01-1,5 gebruikt.Another possibility is to use a metal such as copper, magnesium, cadmium, sodium or potassium in a molar ratio to the compound 2 of the formula sheet in the range of 0.001-2, preferably 0.01-1.5 used.

10 Wanneer een oplosmiddel dient te worden ge bruikt, kan een oplosmiddel worden toegepast dat een ether is, zoals ethylether, tetrahydrofuraan en dioxaan; gehalogeneerde alkanen zoals chloroform, methyleenchlo-ride, etc.; alcoholen zoals methanol, ethanol, etc.; 15 aromatische koolwaterstoffen zoals benzeen, tolueen, xyleen, etc.; amiden zoals dimethylformamide, dimethyl-aceetamide, etc.; en dimethylsulfoxide; enz.When a solvent is to be used, a solvent may be used which is an ether, such as ethyl ether, tetrahydrofuran and dioxane; halogenated alkanes such as chloroform, methylene chloride, etc .; alcohols such as methanol, ethanol, etc .; Aromatic hydrocarbons such as benzene, toluene, xylene, etc .; amides such as dimethylformamide, dimethyl acetamide, etc .; and dimethyl sulfoxide; etc.

De verbinding met de formule 3 van het formuleblad kan worden gebruikt in een hoeveelheid van 20 0,5-30 molen, bij voorkeur 1-20 molen, per mol ver binding met de formule 2.The compound of the formula (III) can be used in an amount of 0.5-30 moles, preferably 1-20 moles, per mole of compound of the formula 2.

Na voltooiing van de reactie kan het reactie-mengsel worden uitgegoten in een grote overmaat water of als zodanig worden opgelost in een oplosmiddel zoals 25 chloroform teneinde daarin te worden geneutraliseerd.After the completion of the reaction, the reaction mixture can be poured into a large excess of water or dissolved as such in a solvent such as chloroform to be neutralized therein.

Desgewenst kunnen de neergeslagen kristallen na concentratie worden verzameld door filtratie, of een andere mogelijkheid is, dat het produkt met een geschikt oplosmiddel zoals chloroform wordt geëxtraheerd, wanneer geen 30 neerslag optreedt, waarna men herkristalliseert of chromatografie toepast volgens de conventionele werkwijze.If desired, the precipitated crystals may be collected after concentration by filtration, or alternatively, the product may be extracted with a suitable solvent such as chloroform, if no precipitate occurs, then recrystallize or apply chromatography by the conventional method.

De onderhavige uitvinding wordt verder toege-icht aan de hand van de volgende voorbeelden, waardoor de onderhavige uitvinding niet wordt beperkt.The present invention is further illustrated by the following examples, which does not limit the present invention.

35 Voorbeeld X.35 Example X.

Synthese van 1-(4-methylanilino)-4-fenylftalazine (Verbinding no. Ij .Synthesis of 1- (4-methylanilino) -4-phenylphthalazine (Compound no. Ij.

Aan 2,41 g l-chloor-4-fenylftalazine werd 5,35 g p-toluidine en 70 mg koperpoeder toegevoegd.5.35 g of p-toluidine and 70 mg of copper powder were added to 2.41 g of 1-chloro-4-phenylphthalazine.

8005411 • ^ - 17 -8005411 • ^ - 17 -

Het mengsel werd daarna onder verhitting 1 uur lang geroerd, terwijl de reactietemperatuur op 100°C werd gehouden. Nadat men het reactiemengsel had laten afkoelen, voegde men een grote overmaat chloroform daar-5 aan toe. De ontstane onoplosbare stoffen werden afge- filtreerd en het filtraat werd met een 5%'s waterige natriumhydroxide-oplossing en daarna met water gewassen.The mixture was then stirred under heating for 1 hour while maintaining the reaction temperature at 100 ° C. After the reaction mixture was allowed to cool, a large excess of chloroform was added thereto. The resulting insolubles were filtered off and the filtrate was washed with 5% aqueous sodium hydroxide solution and then with water.

De organische laag werd gedroogd en geconcentreerd, en het residu werd uit ethanol herkristalliseerd zodat 10 910 mg (opbrengst: 29%) bleekgele kristallen werden verkregen.The organic layer was dried and concentrated, and the residue was recrystallized from ethanol to give 10 910 mg (yield: 29%) of pale yellow crystals.

Smeltpunt: 185-186°C.Melting point: 185-186 ° C.

I.R. : 1630 cm"1, 1510 cm"1, 1410 cm"1.I.R. : 1630 cm "1, 1510 cm" 1, 1410 cm "1.

M.S. : 310 (M+ - 1).M.S. : 310 (M + -1).

15 Voorbeeld II-XXX.Example II-XXX.

De verbindingen, zoals zijn weergegeven in de tabel A werden volgens methoden soortgelijk aan die van voorbeeld X gesynthetiseerd.The compounds, as shown in Table A, were synthesized by methods similar to those of Example X.

Tabel A.Table A.

8005411 * - 18 - TABEL A.8005411 * - 18 - TABLE A.

1 I ί —————————1 I ί —————————

V^“ I sm.p.’ T Έ> /rm ~ 1 Λ/ OV ^ “I sm.p.’ T Έ> / rm ~ 1 Λ / O

bin- . , 1 *·/m M.S.bin-. , 1 * / m M.S.

beeld ^ X C___ ! ( 2 ) 20 2— 3270,1575,1520 3l0(fl£-l) II 203 1410,790 ( 3 ) 188 3200,1500,1400 3ll(M+)image ^ X C___! (2) 20 2— 3270,1575,1520 3l0 (fl £ -l) II 203 1410,790 (3) 188 3200,1500,1400 3ll (M +)

IIIIII

1200,755 296 -----1 ( 4 ) 206- 2990,1625,1520 32 4 (M-l)1200,755 296 ----- 1 (4) 206- 2990,1625,1520 32 4 (M-l)

IVIV

207 1420,780 (6) 189- 2860,1620,1520 353(M+) 190 1420,780 310 (9) 206- 2950,1640,1510 327 (M+) ^ 20 7.5 1420,1240,785 312 J —“ ' ”r π- nil .....207 1420.780 (6) 189-2860,1620,1520 353 (M +) 190 1420,780 310 (9) 206-2950,1640,1510 327 (M +) ^ 20 7.5 1420,1240,785 312 J - “' ”R π- nil .....

( 10 ) 1 96 3000,1610,1500 326 (λί-1) VII 1400,1155,780 (12) 1 68-5 2950,1620,1505 369 (λΓ)(10) 1 96 3000,1610,1500 326 (λί-1) VII 1400,1155,780 (12) 1 68-5 2950,1620,1505 369 (λΓ)

VIIIVIII

-169 1410,1240,790 312 ( 1 3 ) 2 06- 3050,1620.1520 314(\f-l)-169 1410,1240,790 312 (1 3) 2 06- 3050,1620.1520 314 (\ f-l)

IXIX

207 1410,1220,780 8005411 t · * Λ - 19 -207 1410,1220,780 8005411 t * Λ - 19 -

vervolg Tabel Acontinued Table A

Voor- Ver- ‘sm.?. , D y “1 λ, c •beeld; bin- 1 R/t» M.S.Front- "Sm.?" , D y “1 λ, c • picture; bin- 1 R / t »M.S.

ding ./ *Cthing ./ * C

(1 4) 239- 3280,1620,1520 314 (M^l)(1 4) 239- 3280,1620,1520 314 (M ^ l)

XX

240 1400,1140,790 (16) 193- 1620,1580,1500 330 + XI KM > 194 1400,820,770 332 (17) 191- 1600,1510,1420 330 + XII }(M ) 194 ! 1390,770 332 i i _I _ i (18) 170- 3440,1600,1520 330 + I }(M) XIII ! 1713 1400,1040,760 332 __i___L___ |(19) 219- 3000,1625,1510 376 +240 1400,1140,790 (16) 193-1620,1580,1500 330 + XI KM> 194 1400,820,770 332 (17) 191-1600,1510,1420 330 + XII} (M) 194! 1390,770 332 i i _I _ i (18) 170-3440,1600,1520 330 + I} (M) XIII! 1713 1400,1040,760 332 __i___L___ | (19) 219- 3000,1625,1510 376 +

XIV }(M-DXIV} (M-D

222 1400,820,760 374 (23) 236- 3000,1720,1615 369 , XV KM) 2373 1520,1410,1280 368 i___;_|__ (2 5) 24 0- 3360,2210,1610 321 (Μ-1) 242.5 1510,1400,790 (26) 247— 3400,1680,1600 338(M^l)222 1400,820,760 374 (23) 236-3000,1720,1615 369, XV KM) 2373 1520,1410,1280 368 i ___; _ | __ (2 5) 24 0- 3360,2210,1610 321 (Μ-1) 242.5 1510,1400,790 (26) 247—3400,1680,1600 338 (M ^ l)

XVIIXVII

248.5 1520,1400,1280 (28) 174- 3040,1630,1520 364(M^l)248.5 1520,1400,1280 (28) 174-3040,1630,1520 364 (M ^ l)

XVIIIXVIII

1 75.5 1 410,1340,1100 80 05 4 t f1 75.5 1 410,1340,1100 80 05 4 t f

SS

.-20-vervolg Tabel A..-20-continued Table A.

Voor- Ver- . -1 beeld binding Sm. p. * R/O» M.S.Front- Dist. -1 image binding Sm. p. * R / O »M.S.

No. /‘CNo. / "C

(31 ) 240- 3200,1520,1415 325 (MT)(31) 240-3200,1520,1415 325 (MT)

XIXXIX

242 790,770 310242 790,770 310

_____ I_____ I

(32) 2065 3400,1500,1400 | 325(M+) XX i -2075 810,780 ! 310 i (3 3) 20 2- 3200,1500,1400 I 325(λΓ)(32) 2065 3400,1500,1400 | 325 (M +) XX i -2075 810.780! 310 i (3 3) 20 2- 3200,1500,1400 I 325 (λΓ)

XXIXXI

20 3.5 810,780 310 (34) 204- 3200,1510,1420 324(M-l) XXII j 204-5 790,770 XXIII (3 7) 2 1 5- 3440,1610,1520 3 57(M+) 216 1430,790 326 (43) 217 1590,1510,1410 347 , XXIV }(M ) 780,700 345 , (44) 232- 3400,1490,1400 347 + XXV )(M ) 232.5 820,780,700 345 (42) 171- 3000,1610,1500 346 + XXVI } (M-i: 172 1400,775,700 344 (4 7 ) 1 2 9- 3 4 50,1530,1430 34l(i\l+)20 3.5 810,780 310 (34) 204-3200,1510,1420 324 (Ml) XXII j 204-5 790,770 XXIII (3 7) 2 1 5- 3440,1610,1520 3 57 (M +) 216 1430,790 326 (43 ) 217 1590,1510,1410 347, XXIV} (M) 780,700 345, (44) 232-3400,1490,1400 347 + XXV) (M) 232.5 820,780,700 345 (42) 171-3000,1610,1500 346 + XXVI } (Mi: 172 1400,775,700 344 (4 7) 1 2 9- 3 4 50,1530,1430 34l (i \ l +)

XXVIIXXVII

132 1230,790,710 310 fin « ...... -J-J---------- - 8005411 - 21 - vervolg Tabel A.132 1230,790,710 310 fin «...... -J-J ---------- - 8005 411 - 21 - continued Table A.

ï°r:. 7^. sm.P. ïR/»-1 m.s.ï ° r :. 7 ^. sm.P. ïR / »- 1 m.s.

beeld binding p „ 'image binding p „'

'No ' U"No" you

‘ -(4 8) 7 4.5— 1600,1500,1420 364 + XXVTII ^ 75 1220,790,780 362 (51) 200— 3200,1500,1400 339(M+) t mX 202.5 780,700 (24) 25Q< 3360,1680,1600 340(M-l) 30« 1520,1410,780 8005411 - 22 -- (4 8) 7 4.5— 1600,1500,1420 364 + XXVTII ^ 75 1220,790,780 362 (51) 200— 3200,1500,1400 339 (M +) t mX 202.5 780,700 (24) 25Q <3360.1680, 1600 340 (Ml) 30 «1520,1410,780 8005411 - 22 -

Voorbeeld XXXI.Example XXXI.

Synthese van 1-(2-methylfenoxy) -4-fenylftalazine (Verbinding no. 213).Synthesis of 1- (2-methylphenoxy) -4-phenylphthalazine (Compound No. 213).

Aan 1,20 g l-chloor-4-fenylftalazine werd 5 5,40 g o-cresol en 360 mg kaliumhydroxide toegevoegd.5.20 g of o-cresol and 360 mg of potassium hydroxide were added to 1.20 g of 1-chloro-4-phenylphthalazine.

Het ontstane mengsel werd onder verhitting 2 uren lang geroerd, zodat de reactietemperatuur op 100°C werd gehouden. Nadat het reactiemengsel in 12 ml van een waterige oplossing met daarin 3,6 g kaliumhydroxide 10 was opgelost, was uitgegoten, werden de kristallen gewonnen door neerslag onder filtratie. De ruwe kristallen werden in chloroform opgelost, met water gewassen, gedroogd en geconcentreerd. Het residu werd herkristalliseerd uit ethanol-n-hexaan, zodat 725 mg 15 (opbrengst 46%) witte kristallen werden verkregen.The resulting mixture was stirred under heating for 2 hours to maintain the reaction temperature at 100 ° C. After the reaction mixture was dissolved in 12 ml of an aqueous solution containing 3.6 g of potassium hydroxide, the crystals were collected by precipitation under filtration. The crude crystals were dissolved in chloroform, washed with water, dried and concentrated. The residue was recrystallized from ethanol-n-hexane to give 725 mg (yield 46%) of white crystals.

Smeltpunt: 136,5-137,5°C.Melting point: 136.5-137.5 ° C.

I.R. : 1490 cnf1, 1385 cm-1, 1230 cm"1, 1190 cm 1, 790 cm 1, 750 cm M.S. : 312 (M+).I.R. : 1490 cm -1, 1385 cm -1, 1230 cm -1, 1190 cm -1, 790 cm -1, 750 cm M.S.: 312 (M +).

20 Voorbeeld XXXII-XLIV.Example XXXII-XLIV.

Volgens werkwijzen, die soortgelijk zijn aan die, welke in voorbeeld XXXI zijn beschreven, werden de verbindingen gesynthetiseerd die zijn weergegeven in de tabel B.According to procedures similar to those described in Example XXXI, the compounds shown in Table B were synthesized.

2525

Tabel B.Table B.

8005411 - 23 - TABEL B.8005411 - 23 - TABLE B.

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'beeld ding - ,'picture thing -,

No. / UNo. / U

--I---1 - (212) 148- 1490,1390,1250 | 312(M ) xxxn . j 150 1165,800,770 j 295 (214) 1 7 1.5 1510,1385,1210 326 (λί) xxxxxx -172 850,770,700 311 (218) 211- 2970,1500,1390 354(M+) xxxrv 2125 1230,790 339 (219) 163- 1 510,1390,1205 328(M+) XXXV 1 64 1030,850,700 1 21 (227) 171- 1550,1480,1380 331 + XXXVI } 1) 172 1230,790,780 297 1228) 1 79- 1490,1380,1220 376 + XXXVTT } ) 1 80 1010,790 378 (234) 139- 1700,1600,1380 340 + XXXVIII }(M ) 1 4 1.5 1220,850,800 325 . _______ ! _____ -- _ (236) 1 19— ! 1450,1385,1330 366(M+)--I --- 1 - (212) 148-1490,1390,1250 | 312 (M) xxxn. j 150 1165,800,770 j 295 (214) 1 7 1.5 1510,1385,1210 326 (λί) xxxxxx -172 850,770,700 311 (218) 211-2970,1500,1390 354 (M +) xxxrv 2125 1230,790 339 (219) 163-1 510,1390,1205 328 (M +) XXXV 1 64 1030,850,700 1 21 (227) 171-1550,1480,1380 331 + XXXVI} 1) 172 1230,790,780 297 1228) 1 79-1490,1380, 1220 376 + XXXVTT}) 1 80 1010,790 378 (234) 139-1700,1600,1380 340 + XXXVIII} (M) 1 4 1.5 1220,850,800 325. _______! _____ - _ (236) 1 19—! 1450,1385,1330 366 (M +)

XXXIX IXXXIX I

121 1170,1120,900 365 (226) 149- 1595,1380,1220 332 + XL } (M ) 1 4 9.5 890,795,700 3 34 (239) 153- 1570,1385,1250 326 φΓ)121 1170,1120,900 365 (226) 149-1595,1380,1220 332 + XL} (M) 1 4 9.5 890,795,700 3 34 (239) 153-1570,1385,1250 326 φΓ)

XLIXLI

_ 155 1120,770 309 8005411 . ’ - 24 - vervolg Tabel B.155 1120,770 309 8005411. - 24 - continued Table B.

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XLII }(M ) -156 1170,1050,790 348 (244) 1 75.5 1 580,1470,1365 365(M-l)XLII} (M) -156 1170,1050,790 348 (244) 1 75.5 1 580,1470,1365 365 (M-l)

XLIIIXLIII

___-1765 1 220,1090,770 331_ (245) 210- 1450,1380,1360 366(M+) ' 2 1 0.5 1240,770 331 8005411 - 25 -___- 1765 1 220,1090,770 331_ (245) 210-1,450,1380,1360 366 (M +) '2 1 0.5 1240.770 331 8005411 - 25 -

Voorbeeld XLV.Example XLV.

Synthese van 1-(3-chlooranilino-4-(4-methylfenyl)-ftalazine.Synthesis of 1- (3-chloroanilino-4- (4-methylphenyl) phthalazine.

(Verbinding no. 60) .(Compound No. 60).

5 Aan 172 mg l-chloor-4-(4-methylfenyl)ftalazine werd 319 mg m-chlooraniline toegevoegd, en het ontstane mengsel werd 1 uur lang onder roeren op 100°C verhit. Nadat men het reactiemengsel tot kamertemperatuur had laten afkoelen, werd een grote overmaat chloroform er 10 aan toegevoegd, waarna werd gewassen met 5%'s waterige natriumhydroxide en daarna met water, De organische laag werd gedroogd en geconcentreerd. Het residu werd uit ethanol herkristalliseerd, dat 145 mg (opbrengst 62%) bleekgele kristallen werden verkregen.319 mg of m-chloroaniline was added to 172 mg of 1-chloro-4- (4-methylphenyl) phthalazine, and the resulting mixture was heated to 100 ° C for 1 hour with stirring. After the reaction mixture was allowed to cool to room temperature, a large excess of chloroform was added and washed with 5% aqueous sodium hydroxide and then with water. The organic layer was dried and concentrated. The residue was recrystallized from ethanol to give 145 mg (yield 62%) of pale yellow crystals.

15 Smeltpunt: 211,5-212°C.Melting point: 211.5-212 ° C.

I.R. : 595 cm"1, 1510 cm"1, 1475 cm"1, 1405 cm ^, 770 cm 1, M.S. : 345 (M+), 343 (M+), 344.I.R. : 595 cm ", 1510 cm", 1475 cm "1, 1405 cm ^ 770 cm 1, M.S.: 345 (M +), 343 (M +), 344.

Voorbeeld XLVI-CIX.Example XLVI-CIX.

20 De verbindingen, zoals zijn weergegeven in de tabel C hebben de formule 4 van het formuleblad en werden bereid volgens de werkwijzen, die soortgelijk zijn aan die, welke zijn beschreven in voorbeeld XLV.The compounds, as shown in Table C, have the formula 4 of the formula sheet and were prepared according to the procedures similar to those described in Example XLV.

Tabel C.Table C.

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Farmacologische tests:Pharmacological tests:

Slagaderlijk bloed van een konijn werd gecentrifugeerd ter verkrijging van plasma, dat rijk was aan bloedplaatjes. Aan een hoeveelheid van 250 μΐ van 5 het plasma werd 5 μΐ van elke farmaceutische oplos sing toegevoegd. Na 2 min. incubatie werd samenklontering van bloedplaatjes geïnduceerd door aan het mengsel 3 pg collageen toe te voegen. De verandering in samenklontering van bloedplaatjes werd 10 min. lang waarge-10 nomen en geregistreerd door middel van een aggregometer.Rabbit arterial blood was centrifuged to obtain platelet-rich plasma. To 250 μ van of the plasma was added 5 μΐ of each pharmaceutical solution. After 2 min incubation, platelet aggregation was induced by adding 3 µg of collagen to the mixture. The change in platelet aggregation was observed for 10 min and recorded by an aggregometer.

Het percentage, waarmee de samenklontering van bloedplaatjes werd belemmerd werd met de volgende formule berekend:The percentage by which platelet clotting was inhibited was calculated using the following formula:

Tc - Ts 15 Be lemmer ingsper cent age = - x 100Tc - Ts 15 Limitation Percent Age = - x 100

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slechts een oplosmiddel is toegevoegd en T de graad 5 van samenklontering is, wanneer een farmaceutische oplossing is toegevoegd.only one solvent is added and T is the grade 5 of agglomeration when a pharmaceutical solution is added.

20 Tabel D geeft belemmeringspercentages bij aangegeven molconcentraties voor elke verbinding.Table D gives inhibition percentages at indicated mole concentrations for each compound.

Zoals uit de resultaten naar voren komt werd gevonden, dat van deze verbindingen de anilinoftalazinederivaten in het algemeen krachtiger werkzaamheid hadden dan de 25 fenoxyftalazinederivaten.As apparent from the results, it was found that of these compounds, the anilinophthalazine derivatives generally had more potent activity than the phenoxyphthalazine derivatives.

Tabel D.Table D.

8005411 - 35 - TABEL D.8005411 - 35 - TABLE D.

molconcentratie 1mole concentration 1

Voorbeeld Verbinding ”3 x 10-6 1Q-6 ----(Tl UT 333 I ’ ' ττ ( 2 ) 8 0.6 6 6.1 III (3) 100 60.9 2γ ( 4 ) lOO 100 v ( 6 ) 100 100 VI ( 9 ) 7 6.6 3 9.1Example Connection ”3 x 10-6 1Q-6 ---- (Tl UT 333 I '' ττ (2) 8 0.6 6 6.1 III (3) 100 60.9 2γ (4) 100 100V (6) 100 100 VI ( 9) 7 6.6 3 9.1

Vil (10) 100 100Skin (10) 100 100

Vin 02) 100 100 2X (13) 100 100 χ (14) 100 100 XI (16) 100 385 XII (17) 100 100 XIII (18) 100 100 XIV ( 1 9 ) 100 100 XV (23 ) 6 5.5 5 0.9 XVI (2 5 ) 13.6 - XVII (26) 100 2 1.1 XVIII (28) 100 100 XIX (31) 82.5 24.6 8005411 ' , - - 36 - vervolg Tabel D.Vin 02) 100 100 2X (13) 100 100 χ (14) 100 100 XI (16) 100 385 XII (17) 100 100 XIII (18) 100 100 XIV (1 9) 100 100 XV (23) 6 5.5 5 0.9 XVI (2 5) 13.6 - XVII (26) 100 2 1.1 XVIII (28) 100 100 XIX (31) 82.5 24.6 8005411 ', - - 36 - continued Table D.

1 /Oorbeeld Verbinding molconcentratie N0* 3 x 10“6 10“6 XX (32). 100 45.3 XXI (33) 100 100 XXII (34) 100 100 XXIII (37) 100 10° XXIV (43) 100 100 XXV (44) 8 S5 5 6.5 XXVI (42 ) 1 00 100 XXVii (47) 100 100 XXVIII (48 ) 100 100 XXIX (51) 10° 100 XXX (24) 13-4 “ * XXXI (213) 10° 1001 / example compound molar concentration N0 * 3 x 10 “6 10” 6 XX (32). 100 45.3 XXI (33) 100 100 XXII (34) 100 100 XXIII (37) 100 10 ° XXIV (43) 100 100 XXV (44) 8 S5 5 6.5 XXVI (42) 1 00 100 XXVii (47) 100 100 XXVIII ( 48) 100 100 XXIX (51) 10 ° 100 XXX (24) 13-4 "* XXXI (213) 10 ° 100

XXXII (212) 1 00 5UXXXII (212) 1 00 5U

XXXIII (214) 100 30,4 XXXIV (218) 6 3.8 9.6 XXXV (219) 100 100 XXXVI (227) 7 3-4 2 3.8 XXXVII (228) 100 2 8.9 XXXVIII (234) 104 XXXIX (236) 1 00 1 00 XL (226) 100 '100 8005411 - 37 - vervolg Tabel D.XXXIII (214) 100 30.4 XXXIV (218) 6 3.8 9.6 XXXV (219) 100 100 XXXVI (227) 7 3-4 2 3.8 XXXVII (228) 100 2 8.9 XXXVIII (234) 104 XXXIX (236) 1 00 1 00 XL (226) 100 '100 8005411 - 37 - continued Table D.

molconcentratie _____ ; Voorbeeld Verbinding 'c cmole concentration _____; Example Connection 'c c

No. 3x10 b 10 ö XKE - (239) 100 100 XLII (248) 100 ’25.5 yp^-pj (244) 68.4 26.3 XLTV (245) .84.1 15.9 XLV (60) 100 100 XLVX (63) 100 1Q0 XLVTI (56) 100 7.6 XLVIII (59) 100 100 XLiX (64) 100 100 L (78) 100 ' 100 ! LI (79) 100 100 | ui (76) 33.6 11.8 UII (77) 100 100 UV (80) 100 100 lv (97) ïoo loo LVI (98) 100 100 !No. 3x10 b 10 ö XKE - (239) 100 100 XLII (248) 100 '25 .5 yp ^ -pj (244) 68.4 26.3 XLTV (245) .84.1 15.9 XLV (60) 100 100 XLVX (63) 100 1Q0 XLVTI (56) 100 7.6 XLVIII (59) 100 100 XLiX (64) 100 100 L (78) 100 '100! LI (79) 100 100 | onion (76) 33.6 11.8 UII (77) 100 100 UV (80) 100 100 lv (97) oo loo LVI (98) 100 100!

Lvn (95) 58.7 15.1 LVIII (96) 100 9.2 UX (99) 100 100 LX (70) 28.0 23.4 LXI (71) 100 26.2 LXII (68) 55.8 lxiii (69) ïoo ; ïoo 8005411 * . ' - 38 - vervolg Tabel D.Lvn (95) 58.7 15.1 LVIII (96) 100 9.2 UX (99) 100 100 LX (70) 28.0 23.4 LXI (71) 100 26.2 LXII (68) 55.8 lxiii (69) 1000; 800 80011 *. - 38 - continued Table D.

voosbèeia Verbinding molccnoentratle I No· 3 x IQ'6 | IQ'6 IXEV (72) 10° 54.9 LXV (85) ' 30.5 IS.3 LXVI (86) 48.2 25.9 lxvii (83) 27.9 LXVIII (84) 100 100 ixrx (87) 61.2 35.8 lxx (104) 100 66.7 ixxr (105) 100 74.1 lxxii (102) 100 69.8 IXXEU (103) 100 91.9 lxev (106) 84.4 50.0 LXV (91) 92.6 10.6 LXVI (92) 29.7 lxvii (89) 100 84.9 lxviii (90) 30.5 11.9 tmx (93) 17.7 LXXX (110) 12.0voosbèeia Compound molccnoentratle I No · 3 x IQ'6 | IQ'6 IXEV (72) 10 ° 54.9 LXV (85) '30.5 IS.3 LXVI (86) 48.2 25.9 lxvii (83) 27.9 LXVIII (84) 100 100 ixrx (87) 61.2 35.8 lxx (104) 100 66.7 ixxr ( 105) 100 74.1 lxxii (102) 100 69.8 IXXEU (103) 100 91.9 lxev (106) 84.4 50.0 LXV (91) 92.6 10.6 LXVI (92) 29.7 lxvii (89) 100 84.9 lxviii (90) 30.5 11.9 tmx (93) 17.7 LXXX (110) 12.0

Lffli (111) 48.2 36*5 lxxxii (108) 30.5 4.3 lxxxiii (109) 100 100 LXXXIV (112) 100 100 {(¾¾) 100 100 80 0 5 4 1 1 ) · - 39 - vervolg Tabel D.Lffli (111) 48.2 36 * 5 lxxxii (108) 30.5 4.3 lxxxiii (109) 100 100 LXXXIV (112) 100 100 {(¾¾) 100 100 80 0 5 4 1 1) - - 39 - continued Table D.

. . ,. iTiolconcentratie. . ,. iTiol concentration

Voorbeeld Verbinding.-ë—-— ----Example Connection.-ë —-— ----

No. 10 3 x 10~b__10~° LXXXVI /(121) 93.1 34.5 • .(122) LXXXVII f (115) 100 100 1(116) LXXXVIII r (117) 100 100 l(118) LXXXIX r (123) 100 100 1(124) XC (125) 100 xcr (130) 100 XCEI (131) 100 XCIII (127) 100 23.1 XCEV (128) 100 XCV (132) 100 XCVI (138) 9.1 XCVII (141) 10.7 XCVIII (142) 46.3 cm (145) 8.9 CEV (151) 13.3 CV (152) 100 15.2 CVII (150) 15.8 CVEII (153) 27.6 ___L___________ - 8005411 - 40 -No. 10 3 x 10 ~ b__10 ~ ° LXXXVI / (121) 93.1 34.5 •. (122) LXXXVII f (115) 100 100 1 (116) LXXXVIII r (117) 100 100 l (118) LXXXIX r (123) 100 100 1 (124) XC (125) 100 xcr (130) 100 XCEI (131) 100 XCIII (127) 100 23.1 XCEV (128) 100 XCV (132) 100 XCVI (138) 9.1 XCVII (141) 10.7 XCVIII (142) 46.3 cm (145) 8.9 CEV (151) 13.3 CV (152) 100 15.2 CVII (150) 15.8 CVEII (153) 27.6 ___L___________ - 8005411 - 40 -

Veiligheid.Safety.

Gevonden werd, dat elk van de verbindingen volgens de onderhavige uitvinding een zeer lage toxiciteit had, n.l. niet minder dan 5000 mg/kg in termen 5 van LD5q, zoals werd gemeten bij orale toediening bij de muis.It was found that each of the compounds of the present invention had very low toxicity, viz. not less than 5000 mg / kg in terms of LD5q, as measured by oral administration in the mouse.

Conclusies.Conclusions.

80054118005411

Claims

14. A process for preparing a 4-phenylphthalazine derivative of the formula 1 of the formula sheet, 8005411-43 - characterized by X representing NH or O; R1 an alkyl group with 1-5 carbon atoms, an alkoxy group with 1-5 carbon atoms, a halogen atom, an alkoxycarbonyl group with 2-6 carbon atoms in total, 5 a carboxyl group, a cyano group, an alkyl carbonyl group with 2-4 carbon atoms in total a hydroxy1-23 group or a trifluoromethyl group; R and R which may be the same or different from each other (they may also be the same or different from R1), each representing an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a halogen atom, an alkoxycarbonyl group with 2-6 carbon atoms in total, a carboxyl group, an alkylcarbonyl group with 2-4 carbon atoms in total, a hydroxyl group or a trifluoromethyl group; and each of the letters 1, m and n represents an integer from 0-3 (provided 1 equals 1-3 and m equals n equals zero when X represents O, and the case where 1 equals m is equal to n equals 20 to zero is excluded when X represents NH) where 12 3 each multiple of R, R and R are equal or different when the integers 1, m and n are 2 or more, and one has a compound of the formula II of the formula sheet, wherein Y is a halogen atom, a group of the formula -S (O) -R ^, wherein p

4 P is equal to Q-2, R represents an alkyl, phenyl or a substituted phenyl group or a group of the formula -OR, R represents a C, ς alkyl, phenyl or a sub- 1- 0 2 3 represents phenyl group positioned; and R, R, m and n are defined as above, react with a compound of formula 3 of the formula sheet wherein X 1 represents -NH 2 or -OH, and R 1 and 1 are defined as above.

15. Materials and methods as described or included in the description and / or the examples. 8005411