CH634069A5 - Process for preparing novel 7-substituted 7H-pyrrolo[3,2-f]quinazoline-1,3-diamines - Google Patents

Description

The present invention relates to a process for the preparation of new pyrrolo [3,2-f] -quinazolin-1,3-di-mines and 7- (substituted) and 7,8- (disubstituted) derivatives thereof. The compounds mentioned are biologically active.

Various derivatives of 2,4-diaminoquinazoline and 2,4,6-triaminoquinazoline are described in the literature and are known to have antifolic activity in bacterial systems. These compounds 60 are also known to be antibacterial or antiprotozoal active. For example, 2,4-Diaminoquinazolines which have an alkyl group in the 5-position and / or 6-position or have a trimethylene bridge between the 5- and 6-position have an antibacterial activity [see Hitchings et al., 65 U.S. Patent 2945,859 or De Graw et al., J. Med. Chem., 17, 762 (1974)]. 2,4-diamino-6 - [(arylmethyl) amino] quinazoline; 2,4-diamino-6 - {[(substituted aryl) methyl] amino} -quinazoline; and 2,4-diamino-6 - {[(heterocyclic) methyl] amino} -

quinazolines and the corresponding derivatives which have a 5-alkyl substituent or an N6-alkyl substituent are active against malaria. [See Davoll et al., J. Med. Chem., 15, 812 (1972); Eislageretal., J. Med. Chem., 15, 1138 (1972); see also the new article by E. Eislager "New Perspectives on the Chemotherapy of Malaria, Filariasis, and Leprosy", Progress in Drug Research, 18.99-172 (1974), especially pages 111-116 and 152-154.]

The [3,2-f] quinazoline-1,3-diamines which can be prepared according to the invention differ from the known 2,4,6-triaminoquinazolines in that they are connected in the 5-position and in the N "position by an ethylene group, so that they form new tricyclic heterocyclic compounds.

The compounds which can be prepared according to the invention have the following formula

X

NH,

N-Y

N

2nd

The compounds of formula I can also be present as non-toxic acid addition salts. In this compound of the formula I, the substituents have the following meaning:

(a) X is hydrogen and Y is -CFhR or-R1 wherein

R is defined as follows:

Hydrogen; Methyl; Ethyl; n-propyl: i-propyl; n-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-l-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl: 2-phenyethyl; 2-phenylvinyl; Phenyl; in the 2-, 3- or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n- Propoxy, tri-fluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy or potassium carboxy, phenyl monosubstituted by amino or nitro, in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-positions by methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, chlorine, bromine, iodine or fluorine disubstituted phenyl in 2,4, 6- or 3,4,5-positions trisubstituted by methyl, ethyl, methoxy or ethoxy phenyl, 2,3,5,6-tetramethylphenyl; 3,4- (methylene-dioxy) phenyl; 1-naphthalenyl: 2-naphthalenyl; 2-methyl-l-naphthalenyl;

1-bromo-2-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl; 3,5-dimethyl-4-isoxazolyl; Tetrahydro-2-furanyl or benzo [b] thien-3-yl;

and

R1 has the following meaning:

phenyl monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or carbethoxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl; 2-cyano-4-aminophenyl; 3-methyl-4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl-4-aminophenyl;

2-thiazolyl; 2-pyridinyl; 5-nitro-2-pyridinyl; 2-pyrimidinyI;

634069

2-pyrazinyl; 2-quinolinyl; 4-quinolinyl; 4-methyl-2-quino-linyl; 7-chloro-4-quinolinyl; 7-trifluoromethyl-4-quinolinyl; 2-methyl-4-quinolinyl; 3-methyl-2-quinoxalinyI; 2-phenyl-4-quinolinyl or 2-benzothiazolyl and

(b) X is methyl or phenyl and Y is methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl or 2,5-dimethylbenzyl; with the proviso that, X is phenyl, Y can only be methyl.

The terms "disubstituted" and "trisubstituted" as used for the substituents of the phenyl ring of the compounds of formula I refer to compounds in which the substituents e.g. the following are:

Dichlorophenyl, dimethylphenyl, dimethoxyphenyl, tri-methylphenyl, trimethoxyphenyl and the like.

The present invention also relates in preferred embodiments to the preparation of the following compounds:

(a) A compound of the general formula:

h2n and the non-toxic acid addition salts of the compound mentioned, in which the substituents have the following meanings:

R is especially hydrogen; Methyl; Ethyl; n-propyl;

1-propyl; n-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-l-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl; 2-phenylethyl; 2-phenylvinyl; Phenyl; in the 2-, 3- or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n -Propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy or potassium carboxy monosubstituted phenyl; in the 3-position by amino or nitro; monosubstituted phenyl; in 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-positions by methyl, ethyl, n-propyl, methoxy. Ethoxy, n-propoxy, chlorine, bromine, iodine or fluorine disubstituted phenyl; phenyl trisubstituted in 2,4,6- or 3,4,5-positions by methyl, ethyl, methoxy or ethoxy; 2,3,5,6-tetramethylphenyl; 3-4- (methylene-dioxy) phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-l-naphthalenyl; 1-bromo

2-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl; 3,5-dimethyl-4-isoxazolyl; Tetrahydro-2-furanyl or benzo [b] thien-3-yl;

(b) A compound of the following formula:

3rd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

634 069

4th

or the non-toxic acid addition salts of the compound mentioned, in which R1 has the following meaning:

R1 is preferably phenyl monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or carbethoxy; 2,4-dinitro-phenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl;

2-cyano-4-aminophenyl; 3-methyl-4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl-4-aminophenyl; 2-triazolyl; 2-pyridinyl; 5-nitro-2-pyridinyl; 2-pyrimidinyl; 2-pyrazinyl; 2-quinolinyl; 4-quinolinyl; 4-methyl-2-quinolinyl; 7-chloro-4-quinolinyl; 7-trifluoromethyl-4-quinolinyl; 2-methyl-4-quinolinyl;

3-methyl-2-quinoxalinyl; 2-phenyl-4-quinolinyl or 2-benzothiazolyl;

(c) A compound of the formula

X

NH,

N-Y

or the non-toxic acid addition salts of this compound, wherein

X is methyl or phenyl, and

Y is methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl or 2,5-dimethylbenzyl; means that if X is phenyl, Y can only be methyl.

Of particular interest is the compound 7H-pyrrolo- [3,2-f] quinazoline-1,3-diamine and its corresponding derivatives which have an 8-methyl or 8-phenyl substituent. These compounds can be used as intermediates for the preparation of compounds of the formula I which have a substituent in the N7 position.

The compounds of formula I, wherein Y, X, R and R1 are defined above, or the salts of said compounds prevent the growth of bacteria in vitro, as in a standard tube dilution test using Saatagar or Wellcotest Sensitivity Test Agar enhanced with 5% hemolosed horse blood as a wax medium was shown. The compounds mentioned are active in vitro against one or more strains of the following bacteria: S. aureus smith, S. aureus 53-180, N-catarrhalis 8193, E. coli 9637, S. paratyphi 11737, K. pneumoniae 10031, or P vulgaris 6896. When the tube dilution test described above was carried out, the compounds gave MIC values in the range from <0.0009 8 / ml to 250 S / ml compared to the test organisms.

In addition, the compounds of the formula I show an antifolic acid activity in vitro, as was shown by the inhibition of the growth of Streptoccus faecalis ATCC 8043 in a folic acid medium.

The compounds of formula I mentioned increase the antibacterial effect of “sulfa drugs”. If you e.g. Orally administered the following compounds to mice, a synergistic effect was achieved together with sulfamethoxazole against bacterial infections:

7- (phenylmethyl) -7 H-pyrrolo [3,2-f] quinazoline-1,3-diamine;

7 - [(4-Fuorphenyl) methyl] -7H-pyrrolo [3,2-f] -quinazoline-1,3-

diamine;

7 - [(4-cyanophenyl) methyl] -7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine;

7 - [(3-cyanophenyl) methyl] -7H-pyrrolo [3,2-f -] - quinazoline-1,3-diamine;

8-methyl-7- (phenylmethyl) -7H-pyrrolo [3,2-f] -quinazoline-

1,3-diamine;

7- (4-Cyanophenyl) -7H-pyrrolo [3,2-f | quinazoline-1,3-diamine, or

7- (2-thiazolyl) -7H-pyrrolo [3,2-f | quinazoline-1,3-diamine.

In addition, the aforementioned compounds of the formula I which can be prepared according to the invention and also the starting compounds of the formula VI used in the process according to the invention are active against malaria in vivo, as was shown by a standard blood schizonticidal test in mice which was carried out with Plasmodium berghei KBG 173 were infected. The following compounds of formula I are active against malaria when evaluated according to the test described above:

(a) X is hydrogen and Y is -CH: R wherein

R has the following meaning:

i-butyl; n-hexyl; 2-methyl-l-propenyl: cyclohexyl; 2-phenylethyl; Phenyl; phenyl monosubstituted by chlorine, fluorine, methyl, cyano or methoxy in the 2-, 3- or 4-position; 4-isopropylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; 4- (methylsulfonyl) phenyl; 4-acetylphenyl, 4-methylthiophenyl, 4-carbäthoxyphenyl, 4-trifluoromethoxyphenyl, phenyl monosubstituted in the 3-position by amino or nitro; 2,4-dimethylphenyl: 2,5-dimethylphenyl;

3,4-dimethylphenyl; 3,4-dimethoxyphenyl, 2,6-dichlorophenyl; 3,4-dichlorophenyl; 2,4,6-trimethylphenyl: 3,4,5-tri-methoxyphenyl; 3,4 (methylene-dioxy) phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-l-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl or 3-thienyl;

(b) X is hydrogen and

Y is equal to R1, in which R1 denotes phenyl monosubstituted by nitro or acetyl in the 2- or 4-position, or 4-cyano-phenyl; 3-methyl-4-nitrophenyl; Is 2-thiazolyl or 5-nitro-2-pyridinyl,

(c) X is methyl and Y is hydrogen or

2,5-dimethylbenzyl.

The activity was also demonstrated in vivo against P. cynomolgi infections in Rhesus monkeys, examining the following compounds: 7 (phenylmethyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine; 7 - [(4-methoxyphenyl) methyl] -7H-pyrrolo [3,3-f] quinazoline-1,3-diamine; and 7 - [(2,5-dimethylphenyl) methyl] -7H-pyrrolo- [3,2-f] chinazoline-1,3-diamine. The CDo doses of the compounds mentioned are 0.1 mg / kg / day, 0.316 mg / kg / day or 1.0 mg / kg / day when administered orally for 7 days.

Activity against P. berghei strains resistant to chloroquin, sulfones, cycloguanil and pyrimethamine in mice is demonstrated by using 7- (phenylmethyl) -7H-pyrrolo [3,2-f] quinazoline-1,3- diamine and 7 - [(2,5-dimethylphenyl) methyl] -7H-pyrrolo- [3,2-f] quinazoline-1,3-diamine in mice against the resistant strains were examined.

Certain compounds also have in vivo activity in mice (I.P.) against lymphocyclic leukemia P-388 when examined by the method described in Cancer Chemotherapy Reports, Volume 3,

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

5

634069

No. 2, page 9 (minutes 1,200) September, 1972. The compounds of the formula I in which X is hydrogen and Y is -CH2R show such activity. They are summarized in the following table:

R

Dose (mg / kg)

T / C,%

Phenyl

10th

149

4-cyanophenyl'1

20th

138

4-methylsulfonyl

10th

136

4-carbethoxyphenyl

10th

141

3-nitrophenyl

5

163

4-methylphenyl

10th

138

2,5-dimethylphenyl

10th

142

3,4-dimethylphenyl

10th

139

4-t-butylphenyl

5

125

3,4-dimethoxyphenyl

10th

174

3,4,5-trimethoxyphenyl

10th

163

3-aminophenylb

10th

165

3-thienyl

10th

147

2-pyridinyl

20th

146

4-pyridinyl

15

142

2-quinolinyl

10th

145

• Tested as 15 hydrate and tested as dihydrochloride monohydrate.

The process according to the invention for the preparation of compounds of the formula I is characterized in that a compound of the formula

NH,

N-H

wherein

X is hydrogen, methyl or phenyl, with an alkali metal base to form an alkali metal salt and the alkali metal salt with a corresponding compound of the formula

(VII) RCH2Z or (VIII) R'-Z

wherein R and R1 are defined above, and Z represents a leaving group, and the compounds obtained are optionally converted into the corresponding salts.

In the process according to the invention, the alkali metal base must be strong enough to remove the proton from the indole nitrogen of the starting amine of the formula (VI) and to form the alkali metal salt of the conjugate base. The salt is then reacted with the appropriate reagent RCH2-Z or R'-Z to introduce the desired substituent (RCH2- or R'-) in the 7-position. Examples of suitable alkali metal bases are with sodium and potassium hydride, potassium tert-butoxide and lithium or potassium amide.

In the reagent of formula RCH2-Z, the preferred leaving group is a chlorine, bromine or iodine atom. In the reagents of formula R'-Z, the preferred exit

Group a fluorine, bromine, chlorine or iodine atom. Other examples of suitable leaving groups (Z) for RCH2-2 are tosyloxy or mesyloxy. The reaction is usually carried out in an inert solvent, e.g. Dimethylformamide (DMF) or in dimethylacetamide (DMA). In a preferred embodiment of the process, 7-H-pyrrolo [3,2-f] -quinazoline-1,3-diamine (VI) is reacted with sodium hydride in dimethylformamide and then the corresponding reagent, namely (RCH2-Z or R '-Z) to the reaction mixture. In the reaction in which the reagent R'-Z is used, it is preferred to heat the reaction mixture to a temperature of more than 50 ° C.

The reagents of the formulas RCH2-Z and R'-Z are either known compounds or they can be prepared by known methods for analog compounds or by obvious modifications of known methods.

The compound of formula I can be isolated and purified, either in the form of the free base or in the form of the acid addition salt. Methods of converting one form to another are known to those skilled in the art.

For pharmacological uses, the compounds of formula I can be administered in the form of acid addition salts of a non-toxic organic or inorganic acid. These salts can be prepared by known methods. Preferred salts are those which are prepared with the acids mentioned below: hydrochloric acid, hydrobromic acid, maleic acid, benzoic acid, pamoic acid, methalsulfonic acid or acetic acid.

For pharmacological use, the compounds of formula I can be administered either alone or together with pharmaceutically acceptable carrier materials, the proportions and also the type of carrier being determined by the solubility and the chemical properties of the selected compound, also by the chosen route of administration and pharmaceutical practice. So e.g. compounds of formula I can be administered orally in the form of solid dosage forms, e.g. Capsules, tablets or powders, or in liquid forms such as e.g. in solutions or as suspensions. The compounds mentioned can also be administered in the form of injections by the parenteral route or in the form of sterile solutions or suspensions.

Solid oral forms of administration can include conventional additives such as e.g. contain the following: lactose, succrose, magnesi stearate, resins and like materials. Liquid oral forms usually contain various flavors, colors, preservatives, stabilizers that simplify solubility or suspending agents. Parenteral preparations are usually sterile aqueous or non-aqueous solutions or suspensions that contain various preservatives, stabilizers, buffer substances, solubilizers or suspending agents. If desired, additives can be added, e.g. Saline or glucose so that the solutions to be administered are isotonic.

Preferred examples of the method according to the invention are shown in the examples below. All temperatures are given in ° C.

example 1

7- (phenylmethyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine

A suspension of 13.95 g of 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 600 ml of dry dimethylformamide is stirred in a nitrogen atmosphere and then 3.70 g of about 50% is carefully added to it Dispersion of sodium hydride in mineral oil. After going for 1.5 hours

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

634 069

6

stirred, a solution of 9.30 g of benzyl chloride (8.5 ml) in 20 ml of dimethylformamide is added over about 10 minutes. The mixture is then stirred for a further 5 hours and finally 120 ml of glacial acetic acid (added in vacuo), the residue is stirred with an excess 5 of an aqueous potassium carbonate solution and then filtered. The solids are combined, washed with water and dried. The crude product is dissolved in 1.41 boiling methanol, treated with charcoal and filtered through Celite. Then the filtrate is concentrated to a volume of about 125 ml and cooled. The crystalline solid is collected, washed with acetone and recrystallized again from methanol to give 11.76 g of the title compound, which has a melting point of 228 ° C. The compound mentioned has the following analysis results: NMR (dDMSO): S5.53 (singlet, N-CmCaHs), 7.12 (doublet, J-3Hz, 9H), 7.23 (doublet, 8Hz, 5 or 6H), 7.63 (doublet, J = 3Hz, 8H), 7.77 (doublet, J = 9Hz, 5 or 6H) ppm; / vmäxElOH235 (c 26.900), 260 (c 28.620), 317 (c 9.640), 345 sh (c 7.520) nm; ElOH243 (c 26.020), 281 (c 2.430) nm. 20

A solution of 4.5 g of 7- (phenylmethyl) -7H-pyrrolo- [3,2-f] chianzoline-1,3-diamine (prepared in the same manner as described above) in 300 ml of methanol-3- ml of glacial acetic acid is concentrated to a total volume of about 100 ml, cooled, diluted with 100 ml of acetone and filtered to give 2.5 g of a salt. The concentration of the mother liquor to a volume of about 40 ml, dilution with 40 ml of acetone and filtration gives 2.0 g of the salt. The two amounts of the salt are combined and recrystallized from methanol-acetone, giving 2.88 g of the title compound which is in the form of a monoacetate salt and has a melting point of 226 ° C. with decomposition.

Examples 2-59 Using conditions similar to those given in Example 1, 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in dimethylformamide is converted into the "N-ind sodium salt", using about a 50% dispersion of sodium hydride in mineral oil, and finally the salt is reacted with the corresponding halide for a fixed period of time to give the 7- (substituted) methyl-7-H-pyrrolo [3.2 -f] to obtain quinazoline-1,3-diamines, which are described in Table I below.

Table I

7- (Substituted) -7-H-pyrrolo [3,2-fjquinazolin-1,3-amines

-CH2R

Example No.

R

Alkylating agent

Response time in hours

Solvents for recrystallization- "

Melting point in C °

2nd

2-fluorophenyl

2-fluorobenzyl chloride

5

M

215-216

3rd

3-fluorophenyl

3-fluorobenzyl chloride

5

M

245-247

4th

4-fluorophenyl

4-fluorobenzyl chloride

6

M-P-B, P

203

5

2-chlorophenyl

2-chlorobenzyl chloride

2nd

M

229

6

3-chlorophenyl

3-chlorobenzyl chloride

5

M

253-254

7

4-chlorophenyl

3-chlorobenzyl chloride

3rd

M

217-218

8th

2,6-dichlorophenyl a-2,6-trichlortuluol

5

D

307-308

(softens 298)

9

2,4-dichlorophenyl a-3,4-trichlorotoluene

4th

N-W, M-P

253-255

decomposition

10th

2-trifluoromethylphenyl

(2-trifluoromethyl) benzyl bromide

5

M

310h

(softens 230)

11

3-trifluoromethylphenyl

(3-trifluoromethyl) benzyl chloride

5

M, B

204-205

12

4-trifluoromethylphenyl

(4-trifluoromethyl) benzyl bromide

1

M

c

13

2-cyanophenyl

2-cyanobenzyl bromide

5

AT THE

176-180

14

3-cyanophenyl

3-cyanobenzyl bromide

5

Md

239-240

15

4-cyanophenyl

4-cyanobenzyl bromide

1

M

247-249

(softens 160)

16

4-carbethoxyphenyl

4-carbethoxybenzyl bromide

5

E

212-215

17th

3-nitrophenyl

3-nitrobenzyl bromide

5.5

D, M

249-251

18th

2-methylphenyl

2-methylbenzyl chloride

5

M

241-242

19th

3-methylphenyl

3-methylbenzyl chloride

6

M

223

20th

4-methylphenyl

-Chlor-p-xylene

2nd

M

213-214

21st

2,4-dimethylphenyl

2,4-dimethylbenzyl chloride f

5

M

243-245

22

2,5-dimethylphenyl

2,5-dimethylbenzyl chloride

4th

Me

269-271

23

2,6-dimethylphenyl

2,5-dimethylbenzyl chloride h

3.5

D, M

287-290

24th

3,4-dimethylphenyl

3,4-dimethylbenzylchloridaa

5

A

216-218

25th

3,5-dimethylphenyl

3,5-dimethylbenzyl chloride '

3.3

M

261.5-263.0

26

2,4,6-T rimethy lpheny 1

2,4,6-trimethylbenzyl chloride

4th

M

256

27th

2,3,5,6-tetramethyl

2,3,5,6-tetramethylbenzyl chloride

3rd

D

281-282

phenyl

7 634 069

Table l (continued) 7- (Substituted) -7-H-pyrrolo [3,2-f] quinazoline-1,3-aynines

Example No.

R

Alkylating agent

Response time in hours

Solvent to crystallize

Melting point in C °

28

4-isopropylphenyl

4-isopropylbenzyl chloride j

5

A

230-232

29

4-t-butylphenyl

4-t-butylbenzyl chloride

4th

M. A

279-280

30th

4- (methylthio) phenyl

4- (methylthio) benzyl chloride k

21st

A

217-221

31

2-methoxyphenyl

2-methoxybenzyl chloride

4th

M

213-216

32

3-methoxyphenyl

3-methoxybenzyl chloride m

4th

M

205-207

33

4-methoxyphenyl

4-methoxybenzyl chloride

4th

P, M-A, M

205-206

34

2,3-dimethoxyphenyl

2,3-dimethoxybenzyl chloride "

3rd

M

205.0-207.5

35

2,5-dimethoxyphenyl

2,5-dimethoxybenzyl chloride

3rd

M

228-230

36

3,4-dimethoxyphenyl

3,4-dimethoxybenzyl chloride hb

4th

M

222-226

(softens 218)

37

3,4- (methylene

3,4- (methylenedioxy) benzyl

3.8

M-i

235.5-237.5

dioxy) phenyl chloride p

38

3,4,5-trimethoxyphenyl

3,4,5-trimethoxybenzyl chloride

4th

M

240-241

39

4-ethoxyphenyl

4-ethoxybenzylchloride

2nd

B-A

200.5-203.5

40

3-thienyl

3-thienyl bromide

2nd

M, A

212-213

(softens 210)

41

4-thiazoIyl

4-chloromethylthiazole hydro

24th

M

254-255

chloride 1

42

2-pyridinyl

2-picolyl chloride hydrochloride 1

2 5

M, A-M, P, M

223-224

43

3-pyridinyl

3-picolyl chloride hydrochloride '

4th

M "

227

44

4-pyridinyl

4-picolyl chloride hydrochloride '

6

P

232-234

(Decomposition)

45

Benzo [b] thien-3-yl

3-chloromethylbenzo [b] thiopenv

3rd

D

277.5-278.0

46

l-naphthalenyl

1-chloromethylnaphthalene

6

M

259-261

(Decomposition)

47

2-naphthalenyl

2-chloromethylnaphthalenyl

4th

M, M-E

300-330 »

(Decomposition)

(softens 250)

48

2-methyl-l-

l-chloromethyl-2-methyl

5

M

279-281

naphthalenyl naphthalene

(Decomposition)

49

2-quinolinyl

2-chloromethylquinoline hydro

6

M

208

chloride 1

50

8-quinolinyl

8-quinolinylmethyl bromide

5

M'-

220-221

51

3,5-dimethyl-4-

3,5-dimethyl-4-chloro

3.3

MJ

270.5-271.5

isoxazolyl methylisoxazole

52

n-hexyl n-hexyl bromide

50

P

154

53

Cyclohexyl

Bromomethylcyclohexyl

71

E-B, E-P

192>

54

2-methyl-1-propenyl

1-Chloro-3-methyl-2-butene

5

A

e.g.

55

2-phenylethyl

1-iodo-3-phenylpropane

65

M

182-183

56

2-phenylvinyl

Cinnamyl bromide

3rd

A

224-226

57

3,5-dimethoxyphenyl

3,5-dimethoxybenzyl chloridecc

19th

• M, A

213-215.5

58

2-thienyl

2-chloromethylthiophendd

2nd

A

203-205

59

1 -Brom-2-naphthalenyI

1 -Brom-2 (bromomethyl) -

4th

Mee

263.5-265.0

naphthalene

■ A = acetone. B = acetonitrile, D = dimethylformamide, H = absolute ethanol, M = methanol, N = nitromethane. P = t-propanol, W = water.

"This compound is isolated as a hydrate, which contains 3/4 molecules of water per molecule of the diamine.

L This compound is isolated as a hydrate, which contains 1/3 molecules of water per molecule of the diamine and has a melting point of 220-223 ° C. The

Melt is not completely clear up to a temperature of 270 ° C, and then substantial decomposition occurs.

J The crude product is completely triturated with hot water before recrystallization;

1 addition of 4-bromomethylbenzoyl bromide into the benzene to give absolute ethylbenzene, stirring during 1 '/; Hours, removal of solvent and distillation of the residue to obtain the bromide, which had a boiling point of 104-117 ° C at 2 mm and a melting point of 35-38 ° C (cloudy). A.F. Titley [J. Chem. Soc., 1928, 2581] published a boiling point of 165 ° C at 18 mm and a melting point of 35-36 ° C;

'This chloride with a boiling point of 91 ° C at 10 mm is obtained by the corresponding alcohol in benzene to thionyl chloride-benzene-pyridine after by Neuman [J. At the. Chem. Soc., 62, 2295 (1940)]. R.B. Akin et al., [J. At the. Chem. Soc., 59, 1268 (1937)], and a boiling point of 116-118 ° C at 16 mm and 86-87 ° C at 7 mm is found;

? The crude product is recrystallized twice from methanol, washed with 2: 1 N sodium hydroxide methanol, then dried with water and before recrystallization from methanol;

'■ The alcohol is converted to chloride using the Neuman method (see f), which has a boiling point of 75-77 ° C at 2 mm. V.F.

Raaen and J.F. Eastham [J. At the. Chem. Soc., 82, 1349 (1960)] found a boiling point of 75-80 ° C at 1 mm.

This halide with a boiling point of 103-104 ° C at 15 mm is produced by the Neuman method (see f). B. van Zanten et al., Ree. trav. chim., 79, 1211 (1960) [C.A., 55.7403e (1961)] found a boiling point of 100-110 ° C at 15 mm.

This compound contains less than 13% of the o-isopropyl isomer, as determined by NMR analysis. By chloromethylation of cumen by the method of G. Blanc, [Bull. soc. chim. (4), 33.317 (1933) and (Org. Reactions, 1.67)] give 4-isopropyitol> enzyl chloride, which contains less than 1 l% of the 2-isopropyl isomer (investigation by NMR).

1 The crude halide is prepared using the R.F. Czaja et al., U.S. 3,953,520 and is distilled twice to give an oil

634069

8th

which has a boiling point of 93-96 ° C at I mm. It contains 94% 4-methylthiobenzyl chloride, determined by gas chromatography. M.W. Goldberg and M. Janpulsky, U.S. Patent No. 2,624,738, found a boiling point of 83 ° C at a pressure of 0.3 mm.

'This chloride with a boiling point of 77-79 ° C at 2 mm is obtained according to the method of Z. Horii et al., Yakugaku Zasshi, 77,252 (1957) [C.A., 51, 8671c

(1957)], whereby a boiling point of 88-89 ° C at 4 mm was found.

■ "This chloride with a boiling point of 70-74 ° C at 2 mm is obtained by the method of Z. Horii et al., (See FIG. 1). J.W. Cornforth and R. Robinson (J.

Chem. Soc., 1942,686) found a boiling point of 112-115 ° C at 10mm.

"This chloride with a boiling point of! 03-104 ° C at 2 mm is synthesized according to the method of J. Harley-Mason and AH Jackson (J. Chem. Soc., 1954, 1165). A. Kaufmann and H. Muller [ Chem. Ber., 51, 123 (1918)] found a boiling point of 128.5-129.0 at 11 mm with decomposition.

This chloride with a melting point of 65-68 ° C after recrystallization from hexane is made by the method of J. Harley-Mason and A.H. Jackson prepared as under n, where a melting point of 70-72 ° C was specified.

p This chloride with a boiling point of 93-95 ° C at a pressure of 2 mm is synthesized according to the method of Z. Horii et al., (see under 1). Spath and Schmitt, Monthly. 53/54, [Beilstein I1 '. II, 21] found a boiling point of 89-91 ° C at 1 mm.

"The crude product is recrystallized twice from methanol, stirred for one hour with a solution of 3.00 g of sodium methoxide in 350 ml of methanol, with

Washed water, dried and recrystallized from methanol.

~ This chloride is produced using the Neuman process (see f), boiling point 96-103 ° C at 2-3 mm. A.L. Mndzhizan et al., [C.A., 55, 14466b (1961 i) found a boiling point of 102-105 ° C at 1 mm.

• The methods of E. Campaign and B.F. Tullar (Org. Syn., Coll. Vol. IV, 921), and the twice-distilled lachrymatyric product (boiling point 59-67 ° C at 2-3 mm, about 6: 4 mixture of 3-thenyl bromide and 2-bromo-3 -methylthiophene, determined by gas chromatography) is used directly in the subsequent alkylation.

1 2.2 Molecules of sodium hydride per mole of substrate are used here to free the alkylating agent from its salt.

■ * The crude product is crystallized from methanol and converted into a salt by reaction with an excess of hydrogen chloride in isopropanol. By recrystallization of the salt from methanol, followed by regeneration of the base (with aqueous sodium hydroxide) and subsequent recrystallization of the diamine from methanol.

■ This halide with a melting point of 38-40 ° C, after distillation (boiling point 139-141 ° C at 7 mm) and recrystallization from pentane is by the method of G. Wolf and F. Zymolkowski [Arch. Pharm. 309, 279 (1976)], W.J. King and F.F. North [J. Org. Chem., 13, 635 (1948)]. In this publication, a boiling point of 152-153 ° C at 11 mm and a melting point of 39-40 ° C is given.

"This compound is isolated in the form of the monolydrate.

• The crude diamine is recrystallized twice from methanol, it is washed completely with normal sodium hydroxide, then dried with water and finally recrystallized from methanol, whereby the product is contained in the form of the hydrate, which has 1 »molecule per molecule of the diamine.

This compound is isolated in the form of its hydrate, which contains one molecule of water per molecule of the diamine.

'This product melts at 166-170 ° C, it solidifies again and melts again at 183-186 ° C.

This chloride with a boiling point of> 6-87 ° C at 8 mm is produced by the Neuman method (see under f); R.B. Herr et al., [J. At the. Chem. Soc., 79.4229 (1957)] found a boiling point of 95-96 ° C. at 10 mm.

i B This chloride with a melting point of 51 ° C (after trituration with ether-hexane) is obtained by the method of F. Binnset al., [J. Chem. Soc. [C], 1970 1134], where a melting point of 46-48 ° C is also given.

This chloride with a melting point of 46-47.5 ° C after recrystallization from hexane was prepared by the method of R. Adams, S. MacKenzie Jr. and S. Loewe, J. Am. Chem. Soc., 70,664 (1948), which describes a melting point of 46 ° C.

J1 The chloride with a boiling point of 77.0-77.5 ° C at 18-20 mm was made according to the method of Toyo Koatsu Industriai inc .. Jap. Pat. 958511962): [C.A. 59,

3896b (1963)] where a boiling point of 84-86 ° C at 20 mm was given.

--- The crude product was dissolved in methanol and treated with sodium methylate before crystallization.

Example 60

7 - [(4-Acetylphenyl) methyl] -7H-pyrrolo [3,2-fj-quinazoline-1,3-diamine

Using the method of H. B. Hass and M. L. Bender [J. At the. Chem. Soc., 71, 1767 (1949)], 54.43 g of a-bromo-p-toli <nitrii were reacted in 600 ml of benzene with 16.49 g of sodium methoxide, 33.34 g of (4-cyanobezyl) - methyl ether with a boiling point of 114-117 ° C at 5-6 mm. (Hass and Bender found a boiling point of 101-102 ° C at 4 mm.)

A solution of 33.11 g (4-cynanobenzyl) methyl ether in 150 ml of anhydrous ether is added to 5.93 g of methyl lithium in 300 ml of anhydrous ether, and the reaction mixture is then heated under reflux for 5 hours. After cooling, the reaction mixture obtained is poured into 500 ml of a 20% w / v ammonium chloride solution, shaken and the organic layer is separated off. The aqueous phase is extracted with ether and the combined organic fractions are washed with brine, dried over sodium sulfate and freed from the solvent. The residue is stirred with 300 ml of normal hydrochloric acid for one day and then left to stand at a temperature of about 25 ° C. for two days. Then 350 ml of water are added and the product is extracted into ether. After washing with brine, the ethereal extracts are dried over sodium sulfate and freed from the solvent. Distillation of the residue gives 23.5 g of (4-acetylbenzyl) methyl ether with a boiling point of 97-104 ° C at 1-2 mm. [Hass and Bender, J. Am. Chem. Soc., 71, 1976 (1949) found a boiling point of 107-109 ° C at 3.5 mm.]

23.44 g of the (4-acetylbenzyl) methyl ether described above are mixed together with 50 ml of 48% hydrobromic acid for 2 hours

3s reflux heated. The reaction mixture obtained is diluted with 150 ml of water, followed by extraction of the product in ether. The extracts are washed with brine and then dried over sodium sulfate. The solvent is removed and the residue is distilled-40 liert. The product obtained has a boiling point of 106-122 ° C at 1 mm, and after being left to stand for 5 days, it becomes partially solid. The smaller liquid phase is removed by decanting and the solid fraction is distilled again, giving 16.24 g of 4-acetylbenzyl bromide 45 with a boiling point of 108-116 ° C. at 2 mm. [Hass and Bender, J. Am. Chem. Soc., Ibid] found a boiling point of 134-136 ° C at 5 mm.

In a similar manner to that described in Example 1, 7.97 g of 7-H-pyrrolo [3,2-f] quinazoline-1,3-50 diamine in 350 ml of dry dimethylformamide are converted into the sodium sodium salt Add 2.31 g of an approximately 50% dispersion of sodium hydride in mineral oil and finally treat the salt obtained with 10.23 g of 4-acetylbrornide in 10 ml of dry dimethylformamide. 55 After stirring for 3 hours, the reaction mixture is treated with 5 ml of glacial acetic acid and freed from the solvent. The residue is stirred with an excess of an aqueous potassium carbonate solution, washed with water, then with ether and finally dried. 60 two recrystallizations of the crude product from methanol and complete drying give 9.82 g of the compound mentioned in the title, which has a melting point of 224-225 ° C.

65 Example 61

7 - [(4-Methylsulfonylphenyl) methyl] -7H-pyrrolo [3,2-f-quinazoline-1,3-diamine To a solution of 56.0 g of 4-methylsulfonyltoluene in 21

9

634069

Benzene (the benzene is anhydrous by distilling about 300 ml of the solvent) is cooled to about 25 ° C. and then reacted with 57.5 g of N-bromosuccinimide and finally with 5 g of benzoyl peroxide. The solution is refluxed for 1 Vi hours and then left to stand at about 25 ° C for 16 hours. After removal of the crystalline solid by filtration, the filtrate is freed from the solvent and the remaining oil is dissolved in methanol. By cooling the methanolic solution, a crystalline product is obtained which, by recrystallization from methanol, gives 21.0 g (4-methylsulfonyl) benzyl bromide with a melting point of 94-95 ° C. [D.A.A. Kidd and D.E. Wright (J. Chem. Soc., 1962, 1420)] prepared the named compound by a similar process and stated a melting point of 93-94 ° C.

In a similar manner as described in Example 1, 3.98 g of 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in about 250 ml of dry dimethylformamide with 1.06 g of about 50% strength Sodium hydride mineral oil dispersion reacted and then for a further 6 hours with 5.48 g (4-methylsulfonyl) benzyl bromide. The crude product is recrystallized twice from methanol and 4.82 g of the title compound with a melting point of 248 ° C. are obtained.

Example 62

7 - [(4-Trifluoromethoxyphenyl) methyl] -7H-pyrrolo- [3,2-f] quinazoline-1,3-diamine

A solution of 20.16 g of 4-trifluoromethoxybenzoic acid in 160 ml of dry tetrahydrofuran is added dropwise to a stirred suspension of 4.61 g of lithium aluminum hydride in 160 ml of dry tetrahydrofuran. The mixture is then heated under reflux for 3.5 hours, cooled and then 25 ml of N sodium hydroxide are very carefully added. It was then stirred for half an hour and finally the reaction mixture was filtered and the insoluble part was washed carefully with hot tetrahydrofuran. The tetrahydrofuran fractions are freed from the solvent and then the residue is distilled, giving 15.82 g of (4-trifluoromethoxy) benzyl alcohol with a boiling point of 98-99 ° C. at 9-10 mm. [W.A. Sheppard, H. Org. Chem., 29.1 (1964)] found a boiling point of 108 ° C at 25 mm.

A solution of 15.72 g (4-trifluoromethoxy) benzyl alcohol in 170 ml thionyl chloride is refluxed for 14 hours and then the excess thionyl chloride is removed in vacuo. Distillation of the residue gives 7.96 g of (4-trifluoromethoxy) benzyl chloride, which has a boiling point of 70-74 ° C. at 11-15 mm.

Analysis for: CsHeFaCIO

Calculated: C 45.62 H 2.87 Found: C 45.66 H 2.87

A solution of 4.98 g of 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 250 ml of dry dimethylformamide is mixed with 1.32 g of an approximately 50% sodium hydride mineral oil dispersion for 1.5 hours stirred for a long time and then a solution of 5.79 g (4-trifluoromethoxy) benzyl chloride in 10 ml of dry dimethylformamide is added. After stirring at a temperature of 25 ° C for 3.5 hours, 40 ml of glacial acetic acid are added to the reaction mixture and stirring is continued for a further 15 minutes. The solvent is removed in vacuo and the residue is stirred with an excess of aqueous potassium carbonate, washed with water, then with ether and finally dried. Two recrystallizations of the crude product from methanol give 7.56 g of the title compound with a melting point of 205.0-207.5 ° C.

Example 63

7-methyl-7H-pyrrolo [3,2-f] quinazoline-1,3-diamine

A solution of 5.98 g of 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 200 ml of dry dimethylformamide is stirred in a nitrogen atmosphere and then very carefully 1.58 g of about 50% added sodium hydride mineral oil dispersion. The mixture was stirred for 1 hour, a solution of 4.47 g (2.0 ml) of methyl iodide in 10 ml of dry dimethylformamide was added and stirring was continued. 2 hours later, 15 ml of glacial acetic acid are added and the reaction mixture obtained is freed from the solvent in vacuo. The residue is stirred with an excess of an aqueous potassium carbonate solution for a few hours, the solids are collected, washed with water and dried. A solution of this crude product in 200 ml of water in 200 ml of glacial acetic acid is washed with ether. By adding an aqueous solution, the reaction mixture becomes basic and a precipitate is obtained, which is washed with water and which is finally recrystallized from methanol-acetone, giving 3.44 g of the title compound in the form of a hydrate, which Vi molecule of water per molecule receives the diamine; Melting point 250 ° C; NMR (dDMSO): 8 3.88 (singlet, 7-CHs), 7.02 (doublet, J = 3Hz, 9H), 7.15 (doublet, J = 9Hz, 5 or 6H), 7.41 (doublet , J = 3Hz, 8H), 7.72 (doublet, J = 9Hz, 5 or 6H) ppm; CaoH 234 (c 25.280), 258 (c 24.540), 317 (c 9.090), 345 sh (c 7.810) nm; A, ^ El0H 243 (c 23.570), 280 (c 2.040) nm.

A solution of 3.32 g of 7-methyl-7H-pyrrolo [3,2-f] -china-zoline-1,3-diamine in 50 ml of ethanol is treated with 3 ml of glacial acetic acid. The addition of 250 ml gives a precipitate which is recrystallized from methanol-ethanol, giving 3.07 g of the title compound as a monoacetate salt with a melting point of 247-249 ° C. with decomposition.

Example 64

7- (3-Methylbutyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine

In a similar manner as described in Example 1, 3.98 g of 7H-pyrrolo [3,2-f | quinazoline-1,3-diamine in about 210 ml of dry dimethylformamide with 1.06 g of about 50% - ige sodium hydride mineral oil dispersion and then reacted with 4.06 g of l-iodo-3-methylbutane. The response time is 4 hours. The crude product is recrystallized from acetone and then from acetone-methylene chloride, giving 2.58 g of the diamine with a melting point of 185-195 ° C. (softened at 180 ° C.).

A solution of 2.5 g of the diamine mentioned above is dissolved in 100 ml of N-hydrochloric acid-400 ml of methanol and then the solution is concentrated to a volume of approximately 100 ml and cooled. The salt separates and is recrystallized from methanol-ethanol, giving 1.70 g of the title compound in the form of the monohydrochloride, hemihydrate salt with a melting point of 300 ° C. (with decomposition).

Example 65

7 - [(Tetrahydro-2-furanyl) methyl] -7H-pyrrolo- [3,2-f] chinazolin-1,3-diamine

In a similar manner as described in Example 1, 3.98 g of 7H-pyrrolo [3,2-f) quinazoline-1,3-diamine in about 260 ml of dry dimethylformamide with 1.06 g of an about 50% sodium hydride mineral oil dispersion and then reacted with 3.63 g of tetrahydrofurfuryl bromide. The mixture is then stirred at about 25 ° C.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

634069

10th

Finally, 0.21 g of an approximately 50% sodium hydride mineral oil dispersion is added for 24 hours. The mixture is stirred for a further 1 hour, 0.73 g of tetrahydrofurfuryl bromide is added, and after stirring for 6 hours, the reaction mixture obtained is left to stand at about 25 ° C. for about 70 hours. After working up the reaction mixture as described in Example 2, Method A, a brown, rubbery mass is obtained which is dissolved in 40 ml of N hydrochloric acid. By diluting the aqueous acidic solution with 40 ml of acetone, crystals are obtained which are collected and recrystallized twice from methanol-acetone, giving 1.20 g of the title compound as the monohydrochloride salt, which has one molecule of water per molecule of the diamine salt. The compound has a melting point of 310-311 ° C with decomposition.

dried hydroxide and filter the solution. The solution is allowed to stand, a salt is separated off, which is collected, washed with acetone and recrystallized from methanol and dried, giving 1.31 g of the title compound in the form of the hydrate which has one molecule of water per molecule of the sodium salt and has a melting point which is more than 360 ° C.

Analysis for: Ci8Hi5N502Na * 0.25H20

Calc .: Found .:

60.08 59.94

H 4.06 H 3.88

N N

19.46 19.44

Analysis for: CisHirNs-HCl • V3H2O

Calc .: Found .:

C C

55.30 55.32

H H

5.77. 5.65

Cl Cl

10.88 10.85

N N

21.50 21.85

Example 66

Sodium salt of 7- (4-carboxybenzyl) -7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine

A suspension of 3.98 g of 7H-pyrrolo [3,2-f] quinazoline 1,3-diamine (20 mmol) in 350 ml of dry dimethylformamide is mixed with 2.11 g of an approximately 50% sodium hydride mineral oil in a nitrogen atmosphere Dispersion (44 mmol)

Stirred for 1.5 hours. 4.73 g (22 mmol) of 4-bromomethyl-benzoic acid are added and then the mixture is stirred for a further 5 hours and the mixture is finally left to stand at a temperature of 25 ° C. overnight. The solvent is removed in vacuo and the rest is dissolved in 200 ml of water. After washing with chloroform and after filtering, the pH of the aqueous solution is adjusted to about 4 by adding acetic acid and left to stand overnight. The solids are collected, washed with water and dried. The crude product is recrystallized from acetic acid and washed with methanol, these operations being carried out twice. A product is obtained by dissolving the solid obtained in aqueous sodium hydroxide and acidifying the aqueous solution to a pH of 5 with acetic acid.

which is washed with water and then dried. This material (2.5 g) is dissolved in 70 ml N sodium hy

Table II

7- (Substituted) -7H-pyrrolo [3,2-f) quinazoline-1,3-diamines

Example 67

is 7- (4-cyanophenyl) -7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine

A solution of 15.94 g7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 800 ml of dry dimethylformamide is mixed in a nitrogen atmosphere with 4.61 g of an approximately 50% sodium 20 umhydride mineral oil dispersion 1. Stirred for 5 hours. Then 10.66 g of 4-fluorobenzonitrile are added and the reaction mixture is heated at a temperature of 95 ° C. for 6 hours. 40 ml of glacial acetic acid are added and then the solvent is removed in vacuo. The residue is carefully stirred with an excess of an aqueous potassium carbonate solution, collected, washed with water and dried. Two recrystallizations of the crude product from dimethylformamide, followed by washing with a small amount of dimethylformamide 30 and with methanol and after thorough drying gives the title compound which has a melting point of 344 ° C. with decomposition. NMR (dDMSO): 8 7.17 (doublet, J = 9Hz, 5 or 6H), 7.42 (doublet, J = 3Hz, 9H), 7.76-7.95 (4 protons multiplet, 5 or 6H, 8 H and two protons in 35 meta to the cyano group), 8.09 (two proton doublet, J = 8Hz, two protons in ortho to the cyano group) ppm

Examples 68-93 Using the reaction conditions given in Example 67, 7-H-pyrrolo [3,2-f] chinazoline-1,3-diamine in dimethylformamide is converted into the sodium salt with the addition of a 50% solution Sodium hydride mineral oil dispersion. The salt is reacted with the corresponding halide for a certain period of time and at the temperatures indicated, the 7-substituted-7H-pyrrole [3,2-f] china-zoline-1,3-diamines obtained in Table II being obtained will.

NO

Example R No.

Alkylating agent

Reaction temperature in ° C

Response time in hours

Solvent for recrystallization'1

Melting point in ° C

68 2-Acethylphenyl

69 4-acethylphenyl

70 4-propionylphenyl

2-fluoroacetophenone 4-fluoroacetophenone 4-fluoropropiophenone

71

2-cyanophenyl

2-fluorobenzonitrile

70

65-70 80

80

5

13

6

M D

M, D D-A, M

250-252 290

262-264 (decomposition) 317-319 (decomposition)

11

634 069

Table II

7- (Substituted) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamines

Example R Alkalizing Agent Reaction Reaction Time Solvent to melting point

No. temperature in hours recrystallize * in ° C

in ° C

72

4- (methylsulfonyl) -

4- (methylsulfonyl)

75

5

D

309-310

phenyl fluorobenzene

(Decomposition)

73

4-C arbäthoxypheny 1

Ethyl 4-fluorobenzoate

65

5

M, D

232

74

2-nitrophenyl

2-fluoronitrobenzene

90

5

M

296-299

(Decomposition)

75

4-nitrophenyl

4-fluoronitrobenzene

70

5

Ie

> 340

76

2,4-dinitrophenyl

2,4-dinitrofluorobenzene

80

5

Dc

335

(Decomposition)

77

2-cyano-4-nitro

2-chloro-5-nitrobenzonitrile

95

6

D

343

phenyl

(Decomposition)

78

3-methyl-4-nitro

5-fluoro-2-nitrotoluene

85-90

4th

M

267

phenyl

(Decomposition)

79

2-thiazolyl

2-bromothiazole

110

4th

D, Mu

250

80

5-nitro-2-pyridinyl

2-chloro-5-nitropyridine

65

14

D

340

(Decomposition)

81

2-pyridinyl

2-fluoropyridine

110

6

Mf

264-265

(Decomposition)

82

2-pyrimidinyl

2-chloropyrimidine

100

3.5

D

314-315

(Decomposition)

83

2-pyrazinil

2-chloropyrazine

94

6

D

283-284

84

2-quinolinyl

2-chloroquinoline

75

12

M

270-272

85

4-quinolinyl

4-chloroquinoline

95

6

D

286-287

86

4-methyl-2-

4-chloro-epidine

100

10th

D

257-258

quinolinyl

319-320

87

7-chloro-4-quinolinyl

4,7-dichloroquinoline

96

6

D

(Decomposition)

88

7-trifluoromethyl-4-

4-chloro-7- (trifluoromet-

95

6

Ms

283

quinolinyl hyl) chino! in

89

2-methyl-4-

4-chloroquinine din

105

6

B "

265

quinolinyl

298-299

90

3-methyl-3-quinox-

2-chloro-3-methyl-quinoxa-

104

6

D, M

alinyl lin

(Decomposition)

91

2-trifluoromethyl

2-fluorobenzotrifluoride

110

6

A '

236-237

phenyl

319-320

92

2-trifluoromethyl-4-

2-fluoro-4-nitrobenzotri-

110

6

Ms

nitrophenyl fluoride

93

2-phenyl-4-quinolinyl

4-chloro-2-phenylquinoline

110

5

Ms

190-195 '

■ A = acetone, B = acetonitrile, D = dimethylformamide, M = methanol:

"The product is triturated with methanol after recrystallization:

The crude product is triturated with boiling acetone and with boiling methanol before recrystallization;

This compound is isolated in the form of the hydrate and contains -.1 one water molecule per molecule of the diamine;

- The raw product is completely rubbed with boiling water. The insoluble solids and the solids obtained after trituration from the aqueous layer after cooling to room temperature are purified and recrystallized:

'The complete product is completely triturated with boiling water before recrystallization;

^ This compound is isolated in the form of the hydrate and contains 4 molecules of water per molecule of the diamine;

"The crude product is triturated with boiling acetone before recrystallization: and at 170 ° C the compound begins to give off gas.

Example 94

7- (2-Benzothiazolyl) -7H-pyrrolo- [3,2-f] quinazoline-1,3-diamine

To 3.98 g of 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine, dissolved in 250 ml of dry dimethylformamide, 1.115 g of an approximately 50% sodium hydride mineral oil dispersion are added with stirring in a nitrogen atmosphere. The mixture was stirred for a further 1 hour, 3.90 g of 2-chlorobenzothiazole were added and the mixture was then heated at 95 ° C. for 3 hours. An additional 1.29 g of 2-chlorobenzot-hiazole is added and heating is continued at 95 ° C for 11 hours. A third portion of 2-chloro-benzothiazole (1.29 g) is added and heating is continued at 95 ° C for 8 hours. The reaction mixture is worked up in the same way as in

Example 69 is given, and the crude product is recrystallized twice from dimethylformamide and dried completely, yielding 2.30 g of the title compound with a melting point of 326 ° C. (decomposition).

Examples 95-99

60 In a similar manner to that described in Example 1, 8-methyl-7H- [3,2-f-] quinazoline-1,3-diamine in dimethylformamide is converted into the N-ind sodium salt with an approx. 50% sodium hydride mineral oil dispersion is transferred and the salt is treated with the corresponding halo-65 genid for a certain period of time, the 7 (substituted) 8-methyl-7H-pyrrolo [3,2-f-] quinazoline 1,3-diamines are formed, which are summarized in Table III below.

634069

12

Table III

7- (Substituted) -8-methyl-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines

Hey

example

R

Alkylating agent

reaction time

Solvent for

Melting point

No.

in hours

Recrystallize11

inC °

95

methyl

Methyl iodide

2nd

M

305-309 (decomposition)

96

Benzyl

Benzyl chloride

19th

M

267-270

97

3-cyanobenzyl

3-cyanobenzyIbromide

2nd

Mh

277-280 (decomposition)

98

4-cyanobenzyl

4-cyanobenzyl bromide

2nd

c

329-332 (Dec.) (Softens 327)

99

2,5-dimethylbenzyl

2,5-dimethylbenzyl chloride

18th

M, D

308-311 (decomposition)

■ M = methanol, D = dimethylformamide:

* The reaction is carried out at 0 ° C. and the crude product is triturated twice with acetone before recrystallization:

- The reaction is carried out at 0 ° C. The crude product is recrystallized from dimethylformamide and two crops of a brown solid are isolated and combined and extracted in succession with boiling acetonitrile and with boiling methanol. By concentration and by cooling the combined acetonitrile and methanol extracts, a leather-colored solid is obtained which is finally recrystallized from methanol.

Example WHERE

7-methyl-8-phenyl-7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine

In a similar manner as described in Example 1, 6.88 g of 8-phenyl-7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine in 300 ml of dry dimethylformamide with 1.44 g of a treated about 50% sodium hydride mineral oil dispersion and the salt is reacted with 4.26 g of methyl iodide for 3 hours. The crude product is recrystallized twice from methanol and once from acetonitrile, and 3.54 g of the title compound are obtained with a melting point of 295.0-296.5 ° C (decomposition, softened at 288 ° C).

Antibacterial Activities The ability of the compounds of Formula I to prevent bacterial growth in vitro is demonstrated in the following test procedure:

Prepare a stock solution or suspension of the test compound at a concentration of 2500 p.m / ml by using a suitable solvent or medium such as e.g. aqueous sodium hydroxide, aqueous lactic acid,

Methyl cellic acid, dimethyl sulfoxide, dimethylacetamide, ethylene glycol, dimethylformamide, formamide, propylene glycol, acetone or methanol. Two-fold dilutions are made by adding appropriate amounts of sterile water to the solution or suspension of the test substance. One milliliter of each dilution is placed in seed agar or Wellcotest Sensitivity Test Agar, which is amplified with 5% hemolyzed horse blood (9 ml vol.) And is in sterile Petri vessels, giving plates containing different concentrations of the Test connection included. The hardened surfaces of each plate are incubated with the test organism and the plates are incubated at 35 ° C for 18 hours. The in vitro antibacterial activity of the compounds examined is expressed as the “minimum inhibitory concentration” (MIC), which is defined as the smallest amount of material (um / ml) that completely inhibits the test organisms.

The antibacterial activities in vitro of the compounds obtained according to the invention are given in the following 55 Tables IV-VII, which contain the MIC values of the various compounds investigated, which were investigated by the method described above.

45

am '

major of

In spie

1

2nd

3rd

4th

5

6

7

8th

9

10th

11

12

13

14

15

16

17th

18th

19th

20th

21st

22

23

24th

25th

26

27th

28

29

30th

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

13

634069

Table IV

In vitro antibacterial activities of 7-substituted methyl-7H-pyrroIo [3,2-f-] quinazoline-1,3-diamines

N-CH2R

MIC (Y / ml.)

R

S.

S.

N.

E.

s.

K.

p.

Me-

aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris diui

Smith

53-180

8193

9637

11737

10031

6896

Pheny! B

1.95

1.95

0.061

1.95

1.95

1.95

7.81

B

2-fluorophenyl

0.488

0.244

0.0152

0.488

0.976

0.122

0.976

B

3-fluorophenyl

0.244

0.031

<0.0009

0.244

0.488

0.061

0.488

B

4-fluorophenylc

0.244

0.122

0.0038

0.122

0.488

0.031

0.488

B

2-chlorophenyl

0.976

0.976

0.061

0.976

1.95

0.976

7.81

B

3-chlorophenyl

1.95

0.976

0.244

7.81

31.3

0.976

31.3

B

4-chlorophenyl

0.976

0.244

0.0038

0.976

0.976

0.122

0.976

B

2,6-dichlorophenyl

250

250

0.488

> 250

> 250

15.6

> 250

B

3,4-dichlorophenyl

0.976

0.488

0.061

3.90

31.3

0.488

31.3

B

2-trifluoromethylphenyl

0.488

0.244

<0.0009

1.95

3.90

0.122

62.5

B

3-trifluoromethylphenyl

0.488

0.244

0.122

0.976

7.81

0.488

62.5

B

4-TrifIuormethyIpheny [

1.95

0.976

0.031

3.90

15.6

0.976

31.3

B

2-cyanophenyl

0.244

0.244

0.061

0.244

0.488.

0.122

1.95

B

3-cyanophenyld

0.061

0.031

0.0038

0.122

0.488

0.031

0.976

B

4-cyanophenyl

0.244

0.122

0.0076

0.244

0.488

0.061

1.95

B

4-carbethoxyphenyl

1.95

1.95

0.488

7.81

> 250

1.95

> 250

B

3-nitrophenylc

0.122

0.061

0.0152

0.488

0.976

0..122

3.90

B

2-methylphenyl

0.488

0.488

0.0152

0.976

3.90

0.122

7.81

B

3-methylphenyl

0.976

0.488

0.031

0.488

1.95

1.95

1.95

B

4-methylphenyl

0.976

0.488

0.0152

0.976

1.95

0.122

1.95

B

2,4-dimethylphenyl

0.244

0.244

0.0152

0.976

3.40

0.244

7.81

B

2,5-dimethylphenyl

3.90

0.976

0.244

31.3

125

1.95

250

B

2,6-dimethylphenyl

250

250

0.122

250

> 250

15.6

> 250

B

3,4-dimethylphenyl

1.95

0.976

0.122

1.95

31.3

0.488

62.5

B

3,5-dimethylphenyl

0.976

0.488

0.031

7.81

15.6

0.244

15.6

B

2,4,6-trimethylphenyl

250

250

0.244

> 250

> 250

31.3

> 250

B

2,3,5,6-tetramethylphenyl

15.6

15.6

0.244

> 250

> 250

3.90

> 250

B

4-isopropylphenyl

1.95

0.976

0.244

7.81

62.5

0.488

62.5

B

4-t-butylphenyl

7.81

3.90

0.976

250

> 250

3.90

> 250

B

4- (methylthio) phenyl

0.976

0.488

0.0152

0.488

3.90

0.122

31.3

B

2-methoxyphenyl

0.976

0.976

0.061

1.95

7.81

0.244

3.90

B

3-methoxyphenyl

3.90

0.976

0.976

0.488

7.81

0.488

7.81

B

4-methoxyphenyl

0.976

0.244

0.0152

0.488

0.976

0.061

0.976

B

2,3-dimethoxyphenyl

0.488

0.244

0.122

0.488

15.6

0.488

7.81

B

2,5-dimethoxyphenyl

0.244

0.122

0.031

0.976

3.90

0.031

3.90

B

3,4-dimethoxyphenyl

0.244

0.122

0.0152

0.488

1.95

0.061

1.95

B

3,4- (methylenedioxy) phenyl

7.81

1.95

0.244

7.81

15.6

1.95

31.3

B

3,4,5-trimethoxypheny 1

0.122

0.061

0.0152

0.976

3.90

0.122

7.81

B

4-ethoxyphenyI

1.95

0.488

0.122

1.95

7.81

3.90

7.81

B

3-thienyl

0.976

0.976

0.0152

0.244

0.976

0.061

1.95

B

4-thiazolyl

0.488

0.244

0.0038

0.244

0.976

0.122

0.976

B

2-pyridinyl

0.976

0.488

<0.0009

0.488

0.244

0.061

0.244

A

3-pyridinyl

7.81

0.976

<0.0009

0.488

0.488

0.122

7.81

A

4-pyridinyl

0.122

0.122

0.0038

0.244

0.488

0.122

0.488

A

Benzo [b] thien-3-yl

31.3

31.3

1.95

125

> 250

15.6

> 250

B

1-naphthalenyl

3.90

0.976

0.0019

15.6

62.5

0.976

31.3

A

2-naphthalenyl

125

125

0.244

250

> 250

7.81

> 250

A

2-methyl-1-naphthalenyl

125

125

0.122

> 250

> 250

15.6

> 250

B

2-quinolinyl

0.976

0.488

0.0038

7.81

7.81

0.122

7.81

A

8-quinolinyl

0.244

0.122

0.0152

0.244

1.95

0.122

7.81

B

634069 14

Table / K (continued)

In vitro antibacterial activities of 7-substituted methyl-7H-pyrrolo [3,2-f-] quinazoline-1,3-diamines

Ver R S. S. N. E. S. K. P. Me-

bin- aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris dium- '

Smith 53-180 8193 9637 11737. 10031 6896

of examples

51

3,5-dimethyl-4-isoxazolyl

1.95

0.976

0.0152

0.976

1.95

0.244

3.90

B

52

n-hexyl

31.3

15.6

0.488

31.3

62.5

3.90

250

B

53

Cyclohexyl

7.81

3.90

0.0152

1.95

7.81

0.488

3.90

A

54

2-methyl-1-propenyl

1.95

0.976

0.0038

3.90

7.81

0.488

7.81

A

55

2-phenylethyl

250

250

250

250

250

250

250

A

56

2-phenylvinyl

1.95

0.976

0.122

3.90

15.6

0.488

7.81

B

57

3,5-dimethoxyphenyl

0.488

0.244

0.061

0.976

1.95

0.122

15.6

B

58

2-thienyl

0.244

0.061

0.0019

0.061

0.244

0.061

0.244

B

59

l-bromo-2-naphthalenyl

31.3

15.6

0.488

> 250

> 250

15.6

> 250

B

60

4-acethylphenyl

0.244

0.122

0.0076

0.488

0.976

0.061

1.95

B

61

4- (methylsulfonyl) phenol

0.122

0.122

0.0152

0.976

0.976

0.122

7.81

B

62

4- (trifluoromethoxy) phenyl

0.976

0.244

0.031

3.90

62.5

0.122

62.5

B

63

Hydrogen 6

62.5

7.81

0.031

0.976

3.90

1.95

1.95

A

64

2-methylpropylh

1.95

0.976

0.0038

0.976

3.90

0.244

3.90

A

65

Tetrahydro-2-furanyl '

3.90

0.976

0.0038

1.95

7.81

0.488

3.90

A

66

4-carboxyphenyl,

Sodium salt

250

250

62.5

> 250

> 250

> 250

250

B

J Growth medium: A = seed agar with 5H hemolyzed horse blood

B = Wellcotest Sensitivity Test Agar with 5% hemolyzed horse blood.

h This compound was examined as the free diamine.

c This compound, prepared by the method of Example 5, is isolated and examined in the form of the hydrate with '/ <molecule of water per molecule of diamine, the compound having a melting point of 198-199 ° C.

d This compound was prepared and isolated according to the procedure of Example 15 and examined in the form of the hydrate with a molecule of water per molecule of the diamine, the melting point being 240 ° C.

This compound was prepared by the method of Example 18, isolated and tested as a hydrate with a molecule of water per molecule of diamine, the hydrate having a melting point of 246 ° C.

»This compound was tested as a monoacetate salt.

h This compound was tested as a monohydrochloride, hemihydrate salt.

'This compound was tested as the monohydrochloride salt, which had Vs molecule of water per molecule of the diamine salt.

Table V

In vitro antibacterial activities of 7-substituted-7H-pyrrolo [3,2-f-] chianzolin-1,3-diamines

NO

MIC (Y / ml.)

Ver

R

S.

S.

N.

E.

S.

K.

P.

Me bond

aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris diu from Bei

Smith

53-180

8193

9637

11737

10031

6896

game

(Output connection)

y

15.6

1

hydrogen

31.3

31.3

0.244

3.90

31.3

7.81

A

67

4-cyanophenyl

0.976

0.488

0.031

0.976

31.3

0.122

125

B

68

2-AcethylphenyI

0.061

0.031

0.0076

0.244

0.488

0.0152

0.976

B

69

4-acethylphenyl

1.95

0.488

0.031

0.976

7.81

0.122

15.6

B

70

4-propionylphenyl

31.3

7.81

0.031

15.6

> 250

31.3

> 250

B

71

2-cyanophenyl

0.031

0.0152

0.0038

0.122

0.122

0.0152

0.488

B

72

4- (methylsulfonyl)

15.6

B

phenyl

0.976

0.976

0.0152

0.976

7.81

0.244

73

4-carbethoxyphenyl

125

7.81

0.122

> 250

> 250

250

> 250

B

74

2-nitrophenyl

0.244

0.244

0.031

0.976

1.95

0.244

3.90

B

75

4-nitrophenyl

3.90

3.90

0.031

7.81

62.5

0.976

250

B

76

2,4-dinitrophenyl

0.0076

0.0076

0.0019

3.90

> 250

0.031

> 250

B

77

2-cyano-4-nitrophenyl

0.488

0.488

0.244

15.6

> 250

1.95

> 250

B

78

3-methyl-4-nitrophenyl

62.5

7.81

0.0152

> 250

> 250

0.976

> 250

B

15 634 069

Table K (continued)

In vitro antibacterial activities of 7-substituted-7H-pyrrolo [3,2-f-] chianzolin-1,3-diamines

Connection of example

R

S.

aureus smith

S.

aureus 53-180

N.

catarrhalis 8193

E.

coli

9637

s.

paratv phi 11737

K.

pneumoniae 10031

P.

vulgaris 6896

Medium-'

79

2-thiazolyl

0.488

0.244

0.0152

0.976

1.95

0.244

3.90

B

80

5-nitro-2-pyridinyI

0.976

3.90

0.031

> 250

> 250

31.3

> 250

B

81

2-pyridinyl

0.976

0.488

0.0076

0.488

0.976

0.244

0.976

B

82

2-pyrimidinyl

15.6

3.90

0.061

7.81

> 250

0.976

> 250

B

83

2-pyrazinyl

3.90

1.95

0.122

0.976

3.90

0.976

3.90

B

84

2-quinolinyl> 250

> 250

0.122

> 250

> 250

> 250

> 250

B

85

4-quinolinyl

0.031

0.0152

0.031

0.488

0.976

0.031

1.95

B

86

4-methyl-2-quinolinyl

62.5

31.3

0.061

62.5

> 250

31.3

> 250

B

87

7-chloro-4-quinolinyl

0.488

0.122

0.244

15.6

> 250

0.488

250

B

88

7-trifluoromethyl-4-

250

B

quinolinyl

0.122

0.031

0.031

0.244

31.3

0.244

90

2-methyl-4-quinolinyl

0.061

0.061

0.031

1.95

1.95

0.061

3.90

B

91

3-methyl-2-quinoxalinyl

1.95

0.488

0.122

7.81

> 250

0.976

> 250

B

92

2-trifluoromethylphenyl

0.061

0.031

0.0076

0.244

0.976

0.061

1.95

B

93

2-trifluoromethyl-4-nitro

B

phenyl

0.122

0.122

0.061

31.3

62.5

0.488

125

94

2-phenyl-4-quinolinyl

31.3

7.81

15.6

250

> 250

250

> 250

B

95

2-benzothiazolyl

250

125

0.488

> 250

> 250

62.5

> 250

B

• 'Growth medium: A = seed agar with 5% hemolyzed horse blood

B = Wellcotest Sensitivity Test Agar with 5% hemolyzed horse blood. h This compound was examined in the form of its hydrochloride salt.

Table VI

In vitro antibacterial activities of 7,8-substituted-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines

H2N

H2N

NO

MIC (Y / ml.)

Connection of example

Ri

S. S. N.E.

aureus aureus catarrhalis coli

Smith 53-180 8193 9637

S. K. P. Me-

paratvphi pneumoniae vulgaris dium- '11737' 10031 6896

96

methyl

methyl

31.3

31.3

0.061

0.244

1.95

0.244

0.976

B

97

Benzyl

methyl

1.95

0.976

0.122

0.488

3.90

0.244

15.6

B

98

3-cyanobenzyl

methyl

0.122

0.061

0.0038

0.488

3.90

0.061

3.90

B

99

4-cyanobenzyl

methyl

0.976

0.976

0.061

1.95

7.81

0.244

31.3

B

100

2,5-dimethyl

> 250

B

benzyl

methyl

31.3

7.81

1.95

250

> 250

15.6

101

methyl

Phenyl

62.5

125

31.3

> 250

> 250

3.90

> 250

B

"Growth medium: B = Wellcotest Sensitivity with 5% hemolyzed horse blood.

634069

16

Table VII

In vitro antibacterial activities of 7-substituted-8,9,10, l I-tetrahydro-7-H-pyrimido [4,5-c] carbazole-1,3-diamines

H2N

NO

MIC (Y / ml.)

Ver R

binding example

S. S. N. F ..

aureus aureus catarrhalis coli

Smith 53-180 8193 9637

S.K.

paratyphi pneumoniae 11737 10031

P. Me-

vulgaris diunv1 6896

102 benzyl> 250 250 0.122> 250> 250> 250> 250 B

103 methyl 62.5 62.5 3.90> 250 250 62.5> 250 B

• 'Growth medium: B = Wellcotest Sen-. tivity agar with 5% hemolyzed horse blood.

Antibacterial properties

The ability of the compounds obtainable according to the invention of a synergistic action against antibacterial infections in mice is demonstrated when these sulfamethoxazole are administered according to the following test method:

The test agents are weighed, suspended in 0.5% aqueous carboxymethyl cellulose, homogenized (glass fabric crusher) and diluted accordingly, depending on the experiment to be carried out. Mice (male 18 ± 1 g, CD-1 strain) were weighed, distributed, randomly intraperitoneally with 0.5 ml of a standardized

Suspension (LÜ95 ± 5%) of the bacterial organisms infected in 5% gastric mucin and randomly treated with single doses of the test agents either during the 30 infection period or 6 hours after the infection. The treated groups consist of 10 mice per dose level. The dead mice were registered daily for 14 days and the PDso (the mice are treated at the time of infection) and the CDo (the mice 3s are treated 6 hours after infection)

are made using the method of Reed and Muench [Amer. J. Hyg., 27,493 (1938)].

Table VIII

In vivo antibacterial synergistic information (mice) for 7,8-substituted-7H-pyrrolo [3,2-f] quinazoIin-l, 3-diamine PDjir1 or CDs «1 'values, mg. per kg, p.o.

R1

of example

1

Benzyl

H

Proteus mirabilis

190

0

22.5

8.2

1.56 / 7.78

4th

4-fluorobenzyl

H

Proteus mirabilis

190

0

9.8

7.4

1.56 / 1.56

15

4-cyanobenzyl1

H

Proteus mirabilis

3rd

0

22.7

9.9

6.25 / 2.11 3.13 / 2.28 1.56 / 6.56 0.78 / 7.11

15

4-cyanobenzyl1

H

Proteus vulgaris

347

0

200

43.2

6.25 / 6.25 3.13 / 9.67 l, 56 /> 12.5 0.78 /> 12.5

17th

Table VIII (continued)

634 069

Compound R from example

R,

Organisms

Hourly connection SMd

SM. connection

15

15

96 14 67

79

4-Cyanobenzyl1 4-Cyanobenzyl1 4-Cyanobenzylr 4-Cyanobenzyl1 4-Cyanobenzyl1 Benzyl

3-cyanobenzyl '

4-cyanobenzyl1 '

Thiazolyl'1

H

H

H

H

H

Me

H

H

H

Proteus vulgaris

Proteus mirabilis Proteus mirabilis Proteus mirabilis

Proteus mirabilis

347 6> 400

Escherichia coli W-102 0> 800

Escherichia coli W-102 6> 400

Proteus mirabilis 190 0

190 0

190 0

190 0

190 0

18.6

Proteus mirabilis 190 6 159

36.6

400

22.3

60 25 / 5.07

12.5 / 4.66 6.25 / 8.83 3.11 / 7.28

95 25.0 / 15.9 12.5 / 15.6 6.25 / 53.1 3.13 / 67.8

356 100/37 50/37 25/89 12.5 / 50

7.61 3.11 / 2.44 1.56 / 3.39 0.78 / 8.78 0.39 /> 12.50

14

5.1 7.6

3.11 / 2.33 1.56 / 4.0 0.78 /> 6.25 0.39 /> 6.25

1.56 / 3.11

1.56 / 2.67

6.25 3.11 / 2.55 1.56 / 9.39 0.79 / 12.5 0.39 / 12.5

12.5 3.11 / 6.25 1.56 / 12.5

This value represents the dose needed to protect half of the mice from death if the mice are treated immediately after infection. 'This value represents the dose needed to protect half of the mice from death if the mice are treated 6 hours after infection. This represents the number of hours between infection of the mice and administration of the agent.

'SM = sulfomethoxazole

- This compound is tested in the form of free diamine.

'This compound, prepared by the procedure of Example 16, is isolated and tested in the form of the hydrate containing' -s molecule of water per molecule of diamine and has a melting point of 247-253 ° C (softens at 150 ° C).

This compound, prepared by the method of Example 15, is isolated and tested as a hydrate containing 'm molecule of water per molecule of diamine and has a melting point of 240 ° C.

h In this experiment, groups of 5 mice are used for each dose level.

Antimalarial effects

The antimalarial effects of the compounds of the formula I obtained according to the invention are demonstrated and shown by the following test method:

Young ICR / HA Swiss mice and a standard Plasmodium berghei KBG 173 inoculum are used. It is possible to produce a disease which is fatal to 100 ° or untreated animals within 6-8 days, the mean survival time being 6 , Two days. The test animals weigh 18-22 g, but there may also be weight differences in any experimental or control group of 2-3 g. All animals were subjected to all tests and were approximately the same age. The animals that were tested were in plastic cages with a metallic top layer and were given a standard laboratory diet and water ad libitum. 55 The animals were given intraperitoneal injections from 0.5 ml of a 1: 100 dilution of heparinized cardiac blood with a minimum of 90% cells containing parasites (4 x 107 cells). These infected cells were obtained from donor mice that had been infected with 60 Plasmodium berghei a week before. The effectiveness of the donor strain is maintained by weekly runs in various groups of mice inochulated with 0.5 ml of a 1: 500 dilution of heparinized heart blood.

65 The test compounds are administered as a solution or as a suspension in peanut oil. A single dose is administered subcutaneously after 72 hours where the mice have been infected with Plasmodium berghei. At this time

634 069

18th

point 10-15% of the parasites had developed; the disease was easily recognized, but there was no way to develop sufficient weakness to change the guest's response to the toxic effects of the drug being tested. Since the treatment was carried out for 3 days so that the infection could “nest” well and dead animals appeared in controls within 6-8 days in the untreated animals, it is believed that this system is a preferred compound with a maximum requirement. To determine such factors as e.g. Changes in Plasmodium berghei infection or in the sensitivity of the guest or to find technical errors, a group of infected animals were treated with pyrimethamine at dose level, which produced certain increases in survival time, with each test including a positive control .

In each experiment, the test compounds were administered in graduated dosage forms. With highly active compounds, an increased dose level subsequently increases the survival time of the treated mice. However, if the active drug is toxic to the guest, this toxicity can limit it

Mean factor; Continuous increases in dose levels also increase the toxic effects and can shorten the survival time. Deaths before the 6th day when uncontrolled animals 5 start to die are considered non-parasitic and are the basis for the toxicity evaluations. Treated animals are observed for 60 days. Surviving animals after this period are considered to be healed. When the survival time is calculated, toxic deaths and 60-day survivors are not included.

The compound obtainable according to the invention is considered active if at least one of the test animals is cured or if a significant increase in the survival time of treated animals is found compared to the survival time of untreated animals, but with the proviso that the medicaments administered do not Death occurs when administered in amounts of the active dose (toxicity).

The results of the antim al aria tests of the compounds of the formula I obtained according to the invention are summarized in Tables IX, X and XI below.

Table IX

Activity of 7- (substituted) methyl-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines against Plasmodium berghei KBG 173

Connection R Highest Lowest Min. AMST! Can of examples non-lethal can, all (healing /

Can "mice cure treatment)

1

Phenylc

160

80

20th

(2/5)> <

10.9

20'1

2nd

2-fluorophenyl

80

80

10th

(3/5)

9.8

5

3rd

3-fluorophenyl

40

40

10th

(1/5)

8.3

10th

4th

4-fluorophenyls

80

20th

5

(2/5)

7.1

2.5

5

2-chlorophenyl

160

20th

20th

(5/5)

8.3

5

6

3-chlorophenyl

160

10th

2.5

(2/5)

7.7

1.25

7

4-chlorophenyl

40

20th

10th

(2/5)

8.1

5

9

3,4-dichlorophenyl

40

10th

2.5

(2/5)

10.2

2.5

11

3-trifluoromethylphenyl

-

-

5

(1/5)

7.5

2.5

13

2-cyanophenyl

160

40

10th

(1/5)

8.9

10th

14

3-cyanophenylr

40

10th

1.25

(2/5)

9.6

1.25

15

3-cyanophenyl8

-

-

5

(1/5)

8.4

10th

17th

3-nitrophenyl1 '

40

10th

2.5

(3/5)

7.4

2.5

18th

2-methylphenyl

-

40

(3/5)

8.4

40

19th

3-methylphenyl

320

20th

5

(4/5)

6.9

5

20th

4-methylphenyl

160

20th

10th

(2/5)

7.5

5

22

2,5-dimethylphenyl

640 '

40

10th

(3/5)

7.9

5

26

2,4,6-trimethylphenyl

80

40

5

(3/5)

7.3

2.5

28

4-isopropylphenyl

20th

20th

10th

(1/5)

10.2

10th

31

2-methoxyphenyl

160

40

10th

(3/5)

10.2

10th

33

4-methoxyphenyl

160

20th

5

(2/5)

11.2

5

36

3,4-dimethoxyphenyl

80

20th

10th

(1/5)

6.9

2.5

38

3,4,5-trimethoxyphenyl

160

160

40

(2/5)

7.1

20th

42

2-pyridinyl

80

80

20th

(2/5)

11.6

20th

43

3-pyridinyl

160

160

80

(3/5)

8.3

40

44

4-pyridinyl

-

-

80

(3/5)

9.7

40

46

1-naphthalenyl

80

20th

5

(2/5)

9.2

5

19 634069

Table IX (continued)

connection

R

Highest lowest

Min. Healing can

AMST

Can of examples

non-lethal

Can all

(Cure/

Can '

Mice heals

Treatment)

47

2-naphthalenyl

160

40

20th

(4/5)

7.3

5

48

2-Methy 1-1 -naphthaleny I

80

20th

20th

(5 / 5r

-

-

49

2-quinolinyl

160

5

1.25

(2/5)

6.9

1.25

50

8-quinolinyl

40

20th

5

(1/5)

6.4

5

52

n-hexyl

640 '

640

320

(2/5;

9.5

160

53

Cyclohexyl

-

-

-

-

8.5

40

54

2-methyl-1-propenyl

-

-

640

(3/5)

9.3

320

55

2-phenylethyl

640 '

320

160

(3/5)

10.7

80

60

4-acethylphenyl

40

20th

2.5

(4/5)

12.0

5

61

4- (methylsulfonyl) phenyl

-

-

10th

(1/5)

6.5

5

64

2-methylpropyl '

-

-

8.1

320

8th

2,6-dichlorophenyl

160k

40k

5k

(1/5)

-

-

10th

2-trifluoromethylphenyl

40

10th

1.25

(1/5)

7.3

0.63

24th

3,4-dimethylphenyl

80k

10k

5k

(2/5)

6.5k

2.5k

30th

4- (methylthio) phenyl

40k

20k

2.5k

(4/5)

6.2k

1.25 '

32

3-methoxyphenyl

40

40

10th

(1/5)

7.6

5

37

3,4- (methylenedioxy) phenyl

-

-

10th

(2/5)

12.2

2.5

40

3-thienyl

320k

160k

20th

(3/5)

-

-

62

4-trifluoromethoxyphenyl

10th

10th

2.5

(2/5)

9.6

1.25

16

4-carbethoxy

80

20th

10th

(1/5)

6.0

2.5

21st

2,4-dimethylphenyl

80k

5k

5k

(5/5)

7.6k

2.5k

! This value represents the highest dose, with no death occurring for any reason.

"The cut indicates that the increase in mean survival of treated animals compared to untreated animals in the can indicated in the adjacent column.

This compound is tested in the form of the monoacetate salt as described in Example 2.

1 This is the lowest can tested.

See Table IV, footnote c.

See Table IV, footnote d.

See Table VIII, footnote f.

"See Table IV, footnote.

This is the highest tested can.

See Table IV, footnote h.

'The mice that were still alive after 14 days are considered "cured", data for 60 days are not accessible.

Table X

Activities of 7,8-substituted-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines against Plasmodium berghei KBG 173 malaria in mice (all doses are in mg. Per kg., SC administration)

Connection of example

R

Ri

Highest non-lethal

Can "

Lowest can that heals all mice

Min. Healing can

(Cure/

Treatment)

AMSTh

Can

99

2,5-dimethylbenzyl

Methyl o oo

5 '

1.25c (1/5)

00 vo

1.25-

1 This is the highest dose that causes no deaths for no reason.

K These reductions show the increase in the mean survival time of treated animals compared to untreated animals at a can indicated in the adjacent column.

■ Mice that are still alive on the 14th day are considered “cured”, no data with 60 days are accessible.

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20th

Table XI

Activities of 7-substituted-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines Plasmodium berghei KBG 173 malaria in mice

(All doses are in mg. Per kg. S.c. administration)

Connection of example

R

Highest non-lethal

Can- '

lowest can that heals all mice

Min. Healing can

(Cure/

Treatment)

AMST "

Can

67

4-cyanophenyl

20th

20th

5

(3/5)

11

2.5

68

2-AcethyIpheny!

-

-

40

(1/5)

9.2

40

69

4-acetylphenyl

-

-

40

(1/5)

8.8

20th

74

2-nitrophenyl

-

-

40

(4/5)

-

-

75

4-nitrophenyl

640

640

160

(5/5)

28.3

40

78

3-methyl-4-nitro

640

640

640

(5/5)

13.9

160

79

2-thiazolyl

-

-

640

(4/5)

8.3

160

80

5-N itro-2-pyridi tiyl

-

-

160e

(1/5)

-

~

■ 'This is the highest dose where there are no deaths for any reason.

"This reduction shows the increase in the mean survival time of treated animals compared to untreated animals at the dose indicated in the neighboring column.

- Mice still alive on day 14 are considered "cured": data for 60 days are not accessible.

Attempted activity

Individual doses of 7- (phenylmethyl) -7H-pyrrolo- [3,2-f | -quinazoline-1,3-dianiine (active part) are intraperitoneally administered in 0.5% carboxymethyl cellulose at a constant rate Dose volume of 10 ml / kg administered to groups of 10 mice per dom. Level. (Charles River COBS CD strain albino mice, male, weight 21.0-25.29). All mice were observed daily for the duration of the experiment, 14 days. The LD5 "obtained was 54.5 mg / kg (95% confidence limits of 48.6-93.4; and all deaths occurred within 4-5 days after drug administration.

The compound obtainable according to the invention spontaneously reduce motor activity, bradypnea, ptosis and expansion with the sides drawn in in all mice within one hour after the injection. An additional 35 rough coats and decreased fecal excretion were observed on the 2nd day after drug administration. These effects lasted up to day 6 in animals receiving the low doses and 14 days in those receiving the highest doses. All mice that were still alive on day 14 were sacrificed and examined. Macroscopic examinations have shown that the tissues are in normal condition.

B

Claims (7)

634 069 PATENT CLAIMS 1. Process for the preparation of a compound of the formula N-Y (I) wherein: (a) X is hydrogen and Y is -CH2R or -R1, where R has the following meaning: Hydrogen: methyl; Ethyl; n-propyl; i-propyl; n-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-l-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl; 2-phenylethyl; 2-phenylvinyl; Phenyl; in the 2-, 3- or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl; i-butyl; t-butyl; Methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbäthoxy, carboxyl, sodium carboxy or potassium carboxy, in 3-position by amino in Nitro monosubstituted phenyl; in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-positions by methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, chlorine, Bromine, iodine, or fluorine disubstituted phenyl; in 2,4,6 or 3,4,5 positions 5 methyl, ethyl, methoxy or ethoxy trisubstituted phenyl; 2,3,5,6-tetramethylphenyl; 3,4- (methylene-dioxy) phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-l-naphthalenyl; l-bromo-2-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 10 3-thienyl; 4-thiazolyl; 3,5-dimethyl-4-isoxazolyl; Tetra-hydro-2-furanyl; or benzo [b] thien-3-yl; and R1 has the following meaning: monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or carbethoxy 15 phenyl; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl; 2-cyano-4-aminophenyl; 3-methyl-4-nitro-phenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitro-phenyl; 2-trifluoromethyl-4-aminophenyl; 2-thiazolyl; 2-pyridinyl; 5-nitro-2-pyridinyl; 2-pyrimidinyl; 2-pyrazinyl; 20 2-quinolinyl; 4-quinolinyl; 4-methyl-2-quinolinyl; 7-chlorine 4-quinolinyl; 7-trifluoromethyl-4-quinolinyl; 2-methyl-4-quinolinyl; 3-methyl-2-quinoxalinyl; 2-phenyl-4-quinolinyl or 3-benzothiazolyl; or 25 (b) X is methyl or phenyl and Y is methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl or 2,5-dimethylbenzyl, with the proviso that if X is phenyl, Y can only be methyl, and non-toxic acid addition salts of these compounds, characterized in that 30 compounds of the formula (VI) wherein 4s that the alkali metal base is sodium hydride and that Z in X is hydrogen, methyl or phenyl, with an alkali RCH2Z means chlorine, bromine or iodine. tallbase to the corresponding alkali metal salt and the alkali metal salt with a corresponding compound of the formula (VII) RCH2-Z or R'-Z (VIII) wherein R and R1 are defined above, and Z represents a leaving group, and the compounds obtained are optionally converted into the corresponding salts. 2. The method according to claim 1, characterized in that X is hydrogen and Y is -CH2R. 3. The method according to claim 1, characterized in that X is hydrogen and Y = R '. 4. The method according to claim 1, characterized in that X is methyl or phenyl. 5. The method according to claim 2, characterized in that the alkali metal base is sodium hydride and that Z in RCH2Z is chlorine, bromine or iodine. 6. The method according to claim 3, characterized in that the alkali metal base is sodium hydride and that Z in R'-Z means chlorine, bromine, iodine or fluorine. 7. The method according to claim 4, characterized in 50