5,6-Dihydropyrimidin-4(3H)one derivatives, and antiedema compositions and methods employing them

Abstract

An antiedema compound of the formula: ##STR1## in which R.sup.1 is methyl, ethyl, cyclohexyl, phenyl, m-tolyl, p-tolyl, p-tert-butylphenyl, m-trifluoromethylphenyl, m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, p-bromophenyl, o-hydroxyphenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-chlorobenzyl, m,p-dimethoxybenzyl, and o-pyridyl;R.sup.2 is hydrogen, p-tolyl, p-ethoxyphenyl, m-pyridyl, methyl or phenyl; andn is 1, 2 or 3And a process for the preparation thereof are disclosed.

Description

The present invention relates to new cis- and trans-5,6-alkylene-5,6-dihydro-pyrimidin-4(3H)-on derivatives of the formula I ##STR2## wherein R.sup.1 stands for a lower alkyl, aryl, substituted aryl, aralkyl, or heteroaryl group,

R.sup.2 stands for a hydrogen atom, or an alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl or heteroaryl group, n = 1, 2 or 3.

According to an other aspect of the invention there is provided a method for the preparation of the compounds of the formula I, wherein R.sup.1 and R.sup.2 have the same meaning as defined above, which comprises reacting 2-aminocycloalkane-carboxylic acid derivatives of the formula II ##STR3## wherein R.sup.3 stands for a hydroxyl, alkoxy or --NH--R.sup.2 group, wherein R.sup.2 has the same meaning as defined above,

R.sup.4 stands for a hydrogen atom, or a ##STR4## group, WHEREIN R.sup.1 has the same meaning as defined above, n has the same meaning as defined above with compounds of the formula III a -- b (iii) wherein A stands for a hydrogen atom, an alkoxy or amino group, or a halogen atom, B represents an --NH--R.sup.2, ##STR5## group R.sup.5 stands for an alkyl or aryl group, and R.sup.6 represents a hydrogen atom, an alkyl or aryl group.

There are only a few 5,6-alkylene-5,6-dihydropyrimidin-4(3H)-on derivatives already published. The basic compounds were described by Armarego and Kobayashi in J. Chem. Soc. 1969, 1635 and J. Chem Soc. (C) 1971, 238. The authors prepared, however, the unsubstituted derivatives of tetramethylene-pyrimidin-4(3H)-ons nominated as 4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on only, and the pharmacological activity of those compounds has not been even mentioned. It should be noted that the aromatic 4(3H)-on-quinazoline derivatives closely related with the above compounds possess narcotic and anticonvulsive properties. (J. Indian Chem. Soc. 26, 344 (1951), J. Pharmacy and Pharmacology 12, 501 (1960). The 2- and 2- and 3-substituted, 5,6-alkylene-5,6-dihydro-pyrimidin-4(3H)-on derivatives provided by the invention show outstanding antiinflammatory, antifebrile, analgesic and narcosis potentiating activity.

According to a preferred embodiment of the process provided by the invention 2-amino-1-cycloalkane-carboxylic acids of the formula II are reacted with alkyl- or aryl-imidates of the formula III. The imidates may be substituted or unsubstituted as well. In case that they are substituted, i.e. R.sup.6 is other than hydrogen, 3-substituted 5,6-alkylene-5,6-dihydro-pyrimidin-4(3H)-on derivatives are obtained. The reaction is carried out preferably in a suitable solvent, with heating. As solvent reaction-inert solvents, for example aromatic hydrocarbons, substituted aromatic hydrocarbons, ethers may be applied. An especially preferred solvent is chlorobenzene. The reaction may be accomplished at a temperature between 20.degree. C. and 150.degree. C. The reaction time may vary depending upon the reaction temperature and is between 4 and 30 hours. The progress of the reaction may be controlled by t.l.c. When the reaction is complete the reaction mixture is evaporated and the residue optionally is purified by recrystallization.

According to another embodiment of our process 2-amino-1-cycloalkanecarboxamides of the formula II are reacted with orthoacid-esters of the formula III under the conditions described above. In this case, if the carboxamide is N-substituted, 3-substituted pyrimidine derivatives are prepared.

According to a still further embodiment of our process 2-amino-1-cycloalkanecarboxamides of the formula II are reacted with amidines of the formula III. The reaction is preferably carried out in such a manner that to the mixture of 2-amino-1-cycloalkane-carboxylic acid and a salt of the amidine a calculated amount of alkali- and alkali earth-alcoholate is added in order to deliberate amidin base, and thereafter -- if necessary -- the reaction is promoted by heating. The reaction mixture is filtered hot and the product is obtained by crystallization of the mixture.

One can proceed also by reacting an ester of 2-amino-1-cycloalkane-carboxylic acid with N,N-dimethyl-formamide-chloride and thus preparing N,N-dimethyl-N-[2-(ethoxy-carbonyl)-cyclohexyl]-formamidine hydrochloride. The reaction is carried out preferably in a solvent.

Examples of suitable solvents are aliphatic and aromatic hydrocarbons, halogenated hydrocarbons and ethers. The reaction temperature is between 0.degree. C. and 60.degree. C., and the product is obtained by evaporating the mixture and may be purified by recrystallization. Reacting the thus obtained N,N-dimethyl-N-[2-(ethoxy-carbonyl)-cycloalkyl]-formamidine with ammonia or amines the 5,6-alkylene-5,6-dihydropyrimidin-4(3H)-on derivatives are obtained. During the reaction the reacting amine replaces the dimethylamine split off, whereupon the resulted new formamidine derivative reacts with the vicinal ethoxy-carbonyl group. The ring closure reaction results in the formation of a 5,6-alkylene-5,6-dihydropyrimidin-4(3H)-on derivative and alcohol. The reaction can be effected in dioxane but also other reaction-inert solvents, for example other ethers, hydrocarbons, chlorinated hydrocarbons etc. may be used. The ammonium salts and substituted ammonium salts precipitating during the reaction are filtered off, and the product is obtained by evaporating the reaction mixture and may be purified, if necessary, by various physical methods. A very effective purification method is for example thin layer chromatography.

The above reactions may be effected with the same results using cis- or trans-2-amino-1-cycloalkane-carboxylic acids or their derivatives, but the mixture of the cis- and trans-compounds may be also applied. Further details of our invention are illustrated with the following Examples without limiting the scope of the invention to the Examples.

EXAMPLE 1

Cis- or trans-2-amino-1-cyclohexane-carboxylic acid (0.01 mole) is suspended in chlorobenzene (20 ml) and an ethylimidate derivative (0.012 mole) is added. The reaction mixture is refluxed and the progress of the reaction is followed by thin layer chromatography (silica-gel -- benzene -- ethanol 4:1). When the reaction is completed (about 15 to 20 hours) the mixture is evaporated under reduced pressure and the residue is crystallized. The characteristics of the thus obtained 2-substituted cis- and trans-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-ons are listed in Table 1.

Table 1__________________________________________________________________________ ##STR6##Melting point and analysis data for 2-substituted 4a,5,6,7,8,8a-hexahydroquinazolin-4(3H)-on (I) M.p. .degree. C. Analysis Formula for the solvent calculated Configura- molar used for found (%) YieldR.sup.1 tion weight crystallisation C H N % Remark__________________________________________________________________________methyl cis C.sub.9 H.sub.14 N.sub.2 O 146-148 64.99 8.47 16.85 51.31 From cis-amide 166.22 sublimated 64.70 8.78 16.70 with ortho- esthercyclohexyl cis C.sub.14 H.sub.22 N.sub.2 O 158 71.75 9.46 11.96 21.80 when prepared vom 234.33 ether 71.96 9.67 11.63 cis-acid, mixture may be separated from ether by crystallizationphenyl cis C.sub.14 H.sub.16 N.sub.2 O 186-187 73.65 7.02 12.28 84.21 JATE 57 228.29 chlorobenzene 73.20 7.06 12.01phenyl trans C.sub.14 H.sub.16 N.sub.2 O 207-209 73.65 7.02 12.28 67.21 JATE 58 228.29 chlorobenzene 73.89 6.95 12.47m-tolyl cis C.sub.15 H.sub.18 N.sub.2 O 146-148 74.35 7.49 11.56 69.29 JATE 118 242.31 chlorobenzene 74.41 7.79 11.67p-tolyl cis C.sub.15 H.sub.18 N.sub.2 O 171-173 74.35 7.49 73.21 JATE 122 242.31 chlorobenzene 74.50 7.89 from cis-amino acidp-tolyl trans C.sub.15 H.sub.18 N.sub.2 O 222 74.35 7.49 11.56 75.67 JATE 111 242.31 chlorobenzene 74.69 7.89 11.58p-tert. trans C.sub.18 H.sub.24 N.sub.2 O 230-231 76.02 8.45 9.85 87.36 JATE 110butylphenyl 284.40 chlorobenzene 76.40 8.32 10.51m-trifluoromethyl- C.sub.15 H.sub.15 F.sub.3 N.sub.2 O 164-165 60.81 5.10 9.46 71.32 JATE 161phenyl 296.29 ethanol 60.56 5.20 9.35 from cis-amino acidm-fluorophenyl cis C.sub.14 H.sub.15 FN.sub.2 O 120-123 68.27 6.14 11.37 78.71 JATE 117 246.29 chlorobenzene 68.41 6.43 10.88m-fluorophenyl trans C.sub.14 H.sub.15 FN.sub.2 O 213 68.27 6.14 11.37 79.73 JATE 104 246.29 ethanol 68.20 6.29 11.76p-fluorophenyl cis C.sub.14 H.sub.15 FN.sub.2 O 191-193 68.27 6.14 11.37 78.47 JATE 103 246.29 chlorobenzene 68.75 6.50 10.95p-fluorophenyl trans C.sub.14 H.sub.15 FN.sub.2 O 233 68.27 6.14 11.37 50.00 246.29 ethanol 68.16 6.24 12.15m-chlorophenyl cis C.sub.14 H.sub.15 ClN.sub.2 O 162-164 64.01 5.76 10.66 71.30 JATE 105 262.74 chlorobenzene 63.66 5.89 10.95p-chlorophenyl trans C.sub.14 H.sub.15 ClN.sub.2 O 211 64.01 5.76 10.66 74.15 JATE 106 262.74 ethanol 64.22 6.10 11.26p-chlorophenyl C.sub.14 H.sub.15 ClN.sub.2 O 178-181 64.01 5.76 10.66 68.98 JATE 83 262.74 ethanol 64.25 5.77 10.46 from cis amino acidp-chlorophenyl C.sub.14 H.sub.15 ClN.sub.2 O 247-249 64.00 5.75 10.65 64.05 JATE 84 262.74 chlorobenzene 64.70 5.85 10.90 from trans amino acidm-bromophenyl C.sub.14 H.sub.15 BrN.sub.2 O 167-170 54.74 4.92 9.12 79.27 JATE 107 307.20 ethanol 54.56 4.93 9.46 from cis amino acidm-bromophenyl trans C.sub.14 H.sub.15 BrN.sub.2 O 206-207 54.74 4.92 9.12 64.21 JATE 108 307.20 ethanol 54.72 5.11 9.11p-bromophenyl cis C.sub.14 H.sub.15 BrN.sub.2 O 188-193 54.74 4.92 9.12 82.37 307.20 chlorobenzene 55.17 4.89 9.12p-bromophenyl C.sub.14 H.sub.15 BrN.sub.2 O 252-253 54.74 4.92 9.12 69.73 307.20 chlorobenzene 54.82 5.14 9.03 from trans amino acido-hydroxyphenyl C.sub.14 H.sub.16 N.sub.2 O.sub.2 217-220 68.83 6.60 11.47 67.23 244.28 ethanol 68.54 6.82 12.06p-methoxyphenyl C.sub.15 H.sub.18 N.sub.2 O.sub.2 189-191 69.75 7.03 10.85 81.26 258.32 ethanol 70.01 7.09 10.67p-methoxyphenyl trans C.sub.15 H.sub.18 N.sub.2 O.sub.2 188-190 69.75 7.03 10.85 71.27 258.32 chlorobenzene 68.82 7.38 10.86p-nitrophenyl C.sub.14 H.sub.15 N.sub.3 O.sub.3 202-204 61.53 5.53 15.38 52.15 273.29 ethanol 61.41 5.70 15.06 from cis amino acidp-nitrophenyl C.sub.14 H.sub.15 N.sub.3 O.sub.3 247-250 61.53 5.53 15.38 34.17 273.29 benzene 61.47 5.83 15.32 from trans amino acidbenzyl trans C.sub.15 H.sub.18 N.sub.2 O 149-151 74.40 7.43 11.57 42.47 242.32 benzene 74.38 7.71 11.60 from cis amino acid in ether fractionated cryst.p-chlorobenzyl cis C.sub.15 H.sub.17 ClN.sub.2 O 133-135 65.09 6.19 10.12 51.30 276.77 ethanol-ether 65.00 6.46 10.05 from cis amino acidm,p-dimethoxy- trans C.sub.17 H.sub.22 N.sub.2 O.sub.3 135-137 67.54 7.28 9.27 27.9 from cisbenzyl 302.38 benzene 67.60 7.17 9.19 amino acid in ether fractionated cryst. -o-pyridyl C.sub.14 H.sub.15 N.sub.3 O 101-103 69 .69 6.27 17.42 37.40 from trans 241.29 ether 69.13 6.81 17.43 amino acid__________________________________________________________________________

EXAMPLE 2

Following the procedure of Example 1, reacting cis- or trans-2-amino-1-cycloheptane-carboxylic acid (0.01 mole) in chlorobenzene (20 ml.) with an ethylimidate derivative (0.012 mole) cis- and trans-5,6-pentamethylene-5,6-dihydropyrimidine-4(3H)-on derivatives listed in table 2 are obtained.

Table 2__________________________________________________________________________ ##STR7##Melting point and analysis data for 2-substituted trans-5,6-pentamethylene5,6-dihydropyrimidine-4(3H)-on M.p. .degree. C. Analysis for the solvent Calculated Formula used for found YieldR.sup.1 Configuration molar weight crystallization C: H: N: % Remarks__________________________________________________________________________phenyl cis C.sub.15 H.sub.18 N.sub.2 O 145-146 74.40 7.44 11.56 65.17 242.32 ethanol 73.68 7.36phenyl trans C.sub.15 H.sub.18 N.sub.2 O 180-183 74.40 7.44 11.56 42.51 242.32 ethanol 74.40 7.55p-tert-butyl- C.sub.19 H.sub.26 N.sub.2 O 193-197 76.51 8.72 9.32 37.15 from transphenyl 298.36 benzene 76.60 9.09 9.66 amino acidm-chlorophenyl C.sub.15 H.sub.17 ClN.sub.2 O 187-195 65.08 6.19 10.12 33.50 from trans 276.77 ethanol 65.02 6.24 9.92 amino acidp-chlorophenyl C.sub.15 H.sub.17 ClN.sub.2 O 208-209 65.08 6.19 10.12 41.15 from trans 276.77 ethanol 65.29 5.85 10.57 amino acidp-bromophenyl C.sub.15 H.sub.17 BrN.sub.2 O 236 55.94 5.63 8.70 68.10 JATE 88 321.23 chlorobenzene 55.61 5.37 8.74 from trans amino acidp-nitrophenyl C.sub.15 H.sub.17 N.sub.3 O.sub.3 240-243 62.71 5.96 14.62 38.20 JATE 90 287.32 chlorobenzene 62.66 6.15 14.51 from trans amino acid__________________________________________________________________________

TABLE 3

Following the procedure of Example 1, with the reaction of cis- or trans-2-amino-1-cyclohexane-carboxylic acid (0.01 mole) in 20 ml. of chlorobenzene with N-substituted-ethylimidate the cis- and trans-2,3-disubstituted-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on derivatives listed in table 3 are obtained.

Table 3__________________________________________________________________________ ##STR8##Melting point and analysis data for 2,3-disubstituted 4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-one (III) M.p. .degree. C. Analysis for the solvent calculated Formula used for found YieldR.sup.1 R.sup.2 Configuration molar weight crystallization C: H: N: % Remark__________________________________________________________________________methyl p-tolyl cis C.sub.16 H.sub.20 N.sub.2 O 71-74 74.96 7.86 10.93 37.15 JATE 169 265.34 n-hexane 75.13 8.09 10.63 from acid amide with o-acid-estermethyl p-ethoxy- C.sub.17 H.sub.22 N.sub.2 O.sub.2 179-180 71.30 7.74 9.78 32.21 JATE 170 phenyl 286.36 ethanol 71.03 7.46 9.94 from acid amide with o-acid-estermethyl p-ethoxy- C.sub.17 H.sub.22 N.sub.2 O.sub.2 94-97 71.30 7.74 14.27 from cis- phenyl 286.36 ether-petroleum 70.54 7.56 aminoacid ether with imino- ethermethyl p-ethoxy C.sub.17 H.sub.22 N.sub.2 O.sub.2 177-178 71.30 7.74 10.35 from cis- phenyl 286.36 ether aminoacid with imino- etherethyl m-pyridyl C.sub.14 H.sub.17 N.sub.3 O 115-118 69.11 7.04 17.27 31.17 from acid- 243.30 diisopropylether 68.64 7.03 16.66 amide with o-acid- estherethyl p-tolyl C.sub.17 H.sub.22 N.sub.2 O 63-66 75.52 8.20 10.36 33.27 from acid 270.36 n-hexane 75-57 8.42 10.64 amide with o-acid- esterphenyl methyl cis C.sub.15 H.sub.18 N.sub.2 O 80-82 74.36 7.49 11.56 21.51 from cis- 242.32 ether 74.80 7.39 11.27 with imino- etherphenyl p-tolyl C.sub.21 H.sub.22 N.sub.2 O 200-203 79.21 6.96 8.80 34.35 from acid 318.40 ethylacetate 79.56 7.34 8.63 amide with o-acid- esterphenyl phenyl C.sub.20 H.sub.20 N.sub.2 O 180-182 78.92 6.62 9.20 20.13 from cis- 304.39 ether 78.54 6.27 9.20 aminoacid with imino- ether__________________________________________________________________________

EXAMPLE 4

N-substituted 2-amino-1-cyclohexane-carboxamide (0.01 mole) is suspended in chlorobenzene (25 ml.) and boiled with orthoacid ester (0.011 mole) for 8 to 10 hours. The chlorobenzene is distilled off under reduced pressure and the residue is crystallized. The thus obtained 2,3-disubstituted 4a,5,6,7,8,8a-hexahydro-quinazoline-4(3H)-on derivatives were set forth in table 3.

EXAMPLE 5

cis-2-Amino-1-cyclopentane-carboxylic acid (12.92 g., 0.1 mole) is boiled with ethylbenzimidate (16.41 g., 0.11 mole) for 20 hours according to the procedure of Example 1. Thus 14.1 g. of 2-phenyl-cis-5,6-trimethylene-5,6-dihydropyrimidine-4-(3H)-on are obtained. Melting point after recrystallization from ethanol: 130.degree. C. to 140.degree. C.

Analysis for C.sub.15 H.sub.12 N.sub.2 O; Calculated: C 72.86% H 6.59% N 13.07%; Found: C 73.43% H 6.74% N 13.13%.

EXAMPLE 6

cis-2-Amino-1-cyclohexane-carboxylic acid (1 g., 0.005 mole) and p-methoxy-benzamidine-hydrochloride (1.3 g., 0.005 mole) are suspended in chlorobenzene (50 ml.). To the suspension sodium ethylate (0.4 g., 0.005 mole) is added and then mixture is boiled for 20 hours. Thereafter the resulted sodium chloride and the unreacted amino-acid component are filtered off hot. At 0.degree. C. 2-(p-methoxy-phenyl)-cis-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on precipitates, which is filtered off and crystallized from benzene until its melting point is constant.

Yield: 0.8 g., melting point: 188.degree.-191.degree. C.

Analysis for C.sub.15 H.sub.18 N.sub.2 O.sub.2 ; Calculated: C 69.75% H 7.03% N 10.85%; Found: C 69.91% H 7.11% N 10.68%.

EXAMPLE 7

To the mixture of N,N-dimethyl-formamidechloride (12.99 g., 0.01015 mole) and abs. chloroform (20 ml.) ethyl-(cis-2-amino-1-cyclohexanecarboxylate) (14.32 g., 0.1 mole) in 40 ml. of abs. chloroform is added dropwise, assuring that the reaction temperature does not exceed 40.degree. C. Thereafter chloroform is distilled off and the residue is crystallized from dioxane. 22.38 g. of white, hygroscopic N,N-dimethyl-N-cis-2 -(ethoxy-carbonyl)-cyclohexyl-formamidine-hydrochloride are obtained.

Melting point: 137.degree. C. to 142.degree. C.

Analysis for C.sub.12 H.sub.23 ClN.sub.2 O; Calculated: C 54.84% H 8.82% N 10.66% Cl 13.4%; Found: C 54.38% H 8.94% N 11.08% Cl 13.55%.

The melting point of the picrate is: 114.degree. C. to 116.degree. C.

Analysis for C.sub.18 H.sub.25 N.sub.5 O.sub.9 ; Calculated: C 47.48% H 5.53% N 15.38%; Found: C 47.51% H 5.78% N 15.31%.

EXAMPLE 8

N,N-Dimethyl-N-cis-2-(ethoxy-carbonyl)-cyclohexenyl-formamidine-hydrochloride (1 g. 0.0038 mole) is suspended in abs. dioxane (20 ml.) and dry ammonia-gas is introduced into the mixture within 1.5 hours. The precipitated ammoniumchloride is filtered off, and the solution is evaporated to dryness. The dry residue is dissolved in chloroform and separated from the starting material on silicagel thin layer, with 8 : 2 petrolether -- chloroform solvent mixture by chromatography. The hexahydroquinazoline spot is scratched from the layer and the substance is dissolved with chloroform. Thus 0.2 g. of cis-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on, melting at 133.degree. to 134.degree. C. are obtained.

Analysis for C.sub.8 H.sub.12 N.sub.2 O; Calculated: C 63.13% H 7.95% N 18.41%; Found: C 63.11% H 7.84% N 18.31%.

3-(p-tolyl)-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on

N-p-tolyl-cis-2-amino-1-cyclohexane-carboxanilide (0.01 mole, 2.32 g.) is dissolved in chlorobenzene (40 ml.) and the solution, after the addition of ethyl-o-formiate (1.63 g.) is refluxed for 6 hours. The solvent is distilled off under reduced pressure. The residue is crystallized from petroleum ether. Thus a white, crystalline product, melting at 79.degree. C. to 82.degree. C. is obtained.

Yield: 1.25 g. (51.51%).

Analysis for C.sub.15 H.sub.18 N.sub.2 O (242.32); Calculated: C 74.35% H 7.49% N 11.56%; Found: C 73.93% H 7.43% N 11.76%.

2-Phenyl-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on

N-butyl- or N-phenyl-cis-2-amino-1-cyclohexane-carboxamide (0.01 mole) is dissolved in 40 ml. chlorobenzene and after the addition of ethyl-phenyl-imidate (0.011 mole) the solution is refluxed for 50 hours. The solvent is distilled off under reduced pressure (2.5 Hgmm.) and the residue is crystallized from the below-identified solvents.

(a) Starting substance: N-butyl-cis-2-amino-1-cyclohexane-carboxamide

Product: White crystalline solid, melting 165.degree. C. to 167.degree. C. (from ethanol)

Yield: 73.81%

Analysis for C.sub.14 H.sub.16 N.sub.2 O (228.30) Calculated: C 73.65% H 7.02% N 12.28%; Found: C 73.25% H 7.05% N 12.15%.

(b) Starting substance: N-phenyl-cis-2-amino-1 -cyclohexane-carboxanilide.

Product: white, crystalline compound, melting at 165.degree. C. to 168.degree. C. (ethanol)

Yield: 69.65%

Analysis for C.sub.14 H.sub.16 N.sub.2 O (228.30); Calculated: C 73.65% H 7.02% N 12.28%; Found: C 73.65% H 7.28% N 11.79%.

(c) Starting substance: cis-2-amino-1-cyclohexanecarboxamide

Product: white, crystalline compound, melting at 168.degree. C. to 170.degree. C. (ethanol).

Yield: 65.27%.

Analysis for C.sub.14 H.sub.16 N.sub.2 O (228.30); Calculated: C 73.65% H 7.02% N 12.28%; Found: C 73.22% H 7.20% N 11.99%.

2-Phenyl-3-methyl-4a,5,6,7,8,8a-hexahydroquinazoline-4(3H)-on

N-Methyl-benzamide-imidachloride (0.01 mole) is dissolved in abs. acetone (20 ml.) and ethyl-hexahydroantranilate (0.02 mole) in acetone (40 ml.) is added dropwise, at 0.degree. C. The mixture is allowed to stand at room temperature overnight, whereupon the acetone is distilled off. The base is set free on a Varion AD anion-exchanger, and the unreacted ester is distilled off under reduced pressure (2.5 Hgmm.). The residue is crystallized from petroleum ether. Melting point: 79.degree.-82.degree. C., yield: 38.25%.

Analysis for C.sub.15 H.sub.18 N.sub.2 Oj (242.32); Calculated: C 74.36% H 7.49% N 11.56%; Found: C 74.68% H 7.38% N 11.32%.

2-(m-chlorophenyl)-cis-5,6-trimethylene-5,6-dihydro-pyrimidine-4(3H)-on

Following the procedure of Example 1, cis-2-amino-1-cyclopentane-carboxylic acid (12.92 g.) is boiled with ethyl-m-chloro-benzimidate (20.2 g.) for 20 hours. 17 g. of 2-(m-chlorophenyl)-cis-5,6-trimethylene-5,6-dihydro-pyrimidine-4(3H)-on are obtained. Melting point: 138.degree. C. to 140.degree. C. (ethylacetate).

Analysis for C.sub.13 H.sub.13 ClN.sub.2 O Calculated: C 62.78% H 5.27% N 11.26%; Found: C 62.85% H 5.42% N 11.06%.

EXAMPLE 9

A tablet of the following composition is prepared: 2-(m-chlorophenyl)-cis-5,6-trimethylene-5,6-dihydro-

______________________________________pyrimidine-4-(3H)-on 50 mg.Amilopectine 10 mg.Crystalline cellulose 60 mg.Stearic acid 12 mg.Talcum 13 mg.Total weight: 145 mg.______________________________________

The active ingredient and crystalline cellulose are admixed and homogenized in the above-given proportion. The corresponding quantities of stearinic acid and talcum are homogenized and passed through a 100-mesh sieve whereupon it is added to the above mixture and tableted under moderated pressure.

2-(m-chloro-phenyl)-5,6-5dimethylene-5,6-dihydro-pyrimidine-4(3H)-on prepared according to the method described in the last paragraph of Example 8, causes an inhibition of 39% during carragenin-induced oedema-test in mice, when applied in 6 mg./kg. p.o. dose.

The obtained inhibition is in the same order of magnitude as that caused by indomethacine. On the other hand the toxicity of the above compound of the formula I is LD.sub.50 = 1600 mg./kg. p.o., while that of the indomethacine 33 mg/kg., p.o., i.e. the therapeutic index of our compounds is more favorable than that of indomethacine.

The compounds of the present invention thus have the same utility as indomethacine in human and animal therapy in dosages equal to or up to 50 times greater than those hitherto used for indomethacine.

Claims

1. A compound of the formula: ##STR9## wherein (a) R.sup.1 is methyl, cyclohexyl, phenyl, m-tolyl, p-tolyl, p-tert-butylphenyl, m-trifluoromethylphenyl, m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, p-bromophenyl, o-hydroxyphenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-chlorobenzyl, m,p-dimethoxyphenyl, or o-pyridyl, R.sup.2 is hydrogen and n is 2; or

(b) R.sup.1 is phenyl, p-tert-butylphenyl, m-chlorophenyl, p-chlorophenyl, p-bromophenyl or p-nitrophenyl; R.sup.2 is hydrogen and n is 3; or

(c) R.sup.1 is phenyl or m-chlorophenyl, R.sup.2 is hydrogen and n is 1; or

(d) R.sup.1 is methyl, R.sup.2 is p-tolyl or p-ethoxyphenyl, and n is 2; or

(e) R.sup.1 is ethyl, R.sup.2 is m-pyridyl or p-tolyl; and n is 2; or

(f) R.sup.1 is phenyl, R.sup.2 is methyl, phenyl or p-tolyl and n is 2.

2. The compound defined in claim 1 wherein R.sup.1 is methyl, R.sup.2 is hydrogen and n is 2.

3. The compound defined in claim 1 wherein R.sup.1 is cyclohexyl, R.sup.2 is hydrogen and n is 2.

4. The compound defined in claim 1 wherein R.sup.1 is phenyl, R.sup.2 is hydrogen and n is 2.

5. The compound defined in claim 1 wherein R.sup.1 is m-tolyl, R.sup.2 is hydrogen and n is 2.

6. The compound defined in claim 1 wherein R.sup.1 is p-tolyl, R.sup.2 is hydrogen and n is 2.

7. The compound defined in claim 1 wherein R.sup.1 is p-tert-butylphenyl, R.sup.2 is hydrogen and n is 2.

8. The compound defined in claim 1 wherein R.sup.1 is m-trifluoromethylphenyl, R.sup.2 is hydrogen and n is 2.

9. The compound defined in claim 1 wherein R.sup.1 is m-fluorophenyl, R.sup.2 is hydrogen and n is 2.

10. The compound defined in claim 1 wherein R.sup.1 is p-fluorophenyl, R.sup.2 is hydrogen and n is 2.

11. The compound defined in claim 1 wherein R.sup.1 is m-chlorophenyl, R.sup.2 is hydrogen and n is 2.

12. The compound defined in claim 1 wherein R.sup.1 is p-chlorophenyl, R.sup.2 is hydrogen and n is 2.

13. The compound defined in claim 1 wherein R.sup.1 is m-bromophenyl, R.sup.2 is hydrogen and n is 2.

14. The compound defined in claim 1 wherein R.sup.1 is p-bromophenyl, R.sup.2 is hydrogen and n is 2.

15. The compound defined in claim 1 wherein R.sup.1 is o-hydroxyphenyl, R.sup.2 is hydrogen and n is 2.

16. The compound defined in claim 1 wherein R.sup.1 is p-methoxyphenyl, R.sup.2 is hydrogen and n is 2.

17. The compound defined in claim 1 wherein R.sup.1 is p-nitrophenyl, R.sup.2 is hydrogen and n is 2.

18. The compound defined in claim 1 wherein R.sup.1 is benzyl, R.sup.2 is hydrogen and n is 2.

19. The compound defined in claim 1 wherein R.sup.1 is p-chlorobenzyl, R.sup.2 is hydrogen and n is 2.

20. The compound defined in claim 1 wherein R.sup.1 is m,p-dimethoxyphenyl, R.sup.2 is hydrogen and n is 2.

21. The compound defined in claim 1 wherein R.sup.1 is o-pyridyl, R.sup.2 is hydrogen and n is 2.

22. The compound defined in claim 1 wherein R.sup.1 is phenyl, R.sup.2 is hydrogen and n is 3.

23. The compound defined in claim 1 wherein R.sup.1 is p-tert-butylphenyl, R.sup.2 is hydrogen and n is 3.

24. The compound defined in claim 1 wherein R.sup.1 is m-chlorophenyl, R.sup.2 is hydrogen and n is 3.

25. The compound defined in claim 1 wherein R.sup.1 is p-chlorophenyl, R.sup.2 is hydrogen and n is 3.

26. The compound defined in claim 1 wherein R.sup.1 is p-bromophenyl, R.sup.2 is hydrogen and n is 3.

27. The compound defined in claim 1 wherein R.sup.1 is p-nitrophenyl, R.sup.2 is hydrogen and n is 3.

28. The compound defined in claim 1 wherein R.sup.1 is phenyl, R.sup.2 is hydrogen, and n is 1.

29. The compound defined in claim 1 wherein R.sup.1 is m-chlorophenyl, R.sup.2 is hydrogen and n is 1.

30. The compound defined in claim 1 wherein R.sup.1 is methyl, R.sup.2 is p-tolyl and n is 2.

31. The compound defined in claim 1 wherein R.sup.1 is methyl, R.sup.2 is p-ethoxyphenyl and n is 2.

32. The compound defined in claim 1 wherein R.sup.1 is ethyl, R.sup.2 is m-pyridyl and n is 2.

33. The compound defined in claim 1 wherein R.sup.1 is ethyl, R.sup.2 is p-tolyl and n is 2.

34. The compound defined in claim 1 wherein R.sup.1 is phenyl, R.sup.2 is methyl and n is 2.

35. The compound defined in claim 1 wherein R.sup.1 is phenyl, R.sup.2 is phenyl and n is 2.

36. The compound defined in claim 1 wherein R.sup.1 is phenyl, R.sup.2 is p-tolyl and n is 2.

37. An antiedema composition which comprises an effective amount of the compound defined in claim 1 with at least one pharmaceutically acceptable inert carrier or diluent.

38. A method of treating edema in animals which comprises the step of orally administering an effective amount of the compound defined in claim 1.