DE2731039A1 - 7- (SUBSTITUTED) -7H-PYRROLO SQUARE BRACKET ON 3.2 SQUARE BRACKET FOR -CHINAZOLINE-1,3-DIAMINE - Google Patents

Description

PROF. DR. DR. J. REITSTÖTTER DR.-ING. WOLFRAM BUNTE DR. WERNER KINZEBACH

D-SOOO MUNICH 4O. BAUERSTRASSE 22 FERNRUF (O89) 37 BS 83 TELEX S2I52OS ISAR O POSTAL ADDRESS: D-8OO0 MUNICH 43. POST BOX 7βΟ

Munich, July 8, 1977 M / 18 190

AMERICAN HOME PRODUCTS CORPORATION 685, Third Avenue, New York, N.Y. UNITED STATES.

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

The present invention relates to pyrrolo [3,2-f] -quinazolin-1, 3-diair.in and its 7- (substituted) - and 7,8- (disubstituted) Derivatives that are biologically active. The invention also relates to pharmaceutical compositions containing these compounds contain processes for the preparation of these compounds and intermediates used in these processes.

ι Various 2,4-diaminochinazoline and 2,4,6-triamino

quinazoline derivatives are described in the literature, the ι antifolic acid effect in bacterial systems (antifolic ι activity). Such compounds also have antibacterial or anti-protozoal effects.

709883/0891

M / 18 190

For example, 2,4-diaminochinazolines with an alkyl group in the 5-position and / or 6-position, or with a trimethylene bridge between the 5- and 6-positions have an antibacteriological effect [cf. Hatchings et al., U.S. Patent 2,945,859 or De Graw et al., J. Med. Chem., YT_, 762 (1974)]. 2,4-diamino-6 - [(arylmethyl) amino] quinazolines; 2,4-diamino-6- {[(substituted aryl) -methyl] -amino} -quinazolines and 2,4-diamino-6- {[(heterocyclic) -methyl] -amino} -quinazolines and derivatives with a 5- Alkyl substituents or N -alkyl substituents are effective against malaria. Davoll et al., J. Med. Chem., J_5, 812 (1972); Eislager et al., J. Med. Chem., 15 , 1138 (1972); and the report by E. Eislager, "New Perspectives on the Chemotherapy of Malaria, Filariasis and Leprosy", Progress in Drug Research, J_8, 99-172 (1974), particularly pages 111-116 and 152-154].

The pyrrolo [3,2-f] quinazoline-1,3-diamines according to the invention differ from the well-known 2,4,6-triaminoquinazolines in that the 5-position and the N -position of the latter are connected by an ethylene radical and so one form new tricyclic heterocycle.

The present invention relates to compounds of the general formula I:

NH ₂

N-Y

or their non-toxic acid addition salts, in which:

709 * 83/0895

! ! (a) X is hydrogen and j

j Y is -CH ₂ R or R ¹ , j

;

! where:.

ι;

! R is hydrogen; Methyl; Ethyl; n-propyl; i-propyl; ι j η-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-1- j

I propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl;

2-phenylethyl; 2-phenylvinyl; Phenyl; Phenyl in; 2-, 3- or 4-position monosubstituted by
Chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, j ethyl, n-propyl, i-propyl, η-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano,
Methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy or
Potassium carboxy; Phenyl, in the 3-position through amino or
Nitro monosubstituted; Phenyl in 2,3- 2,4-, 2,5-,
2,6-, 3,4- or 3,5-position disubstituted by
Methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy,
Chlorine, bromine, iodine or fluorine; Phenyl, in 2,4,6- or
3,4,5-position trisubstituted by methyl, ethyl,
Methoxy, or ethoxy; 2,3,5,6-tetramethylphenyl;
3,4- (methylen-dioxy) -phenyl; 1-naphthalenyl; 2-naphtha-; linyl; 2-methyl-1-naphthalenyl; 1-bromo-2-naphthalenyl; ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl;

and

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

R is hydrogen; 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-nitro-phenyl; 2-cyano-4-aminophenyl;

9883 / OaiS-

το

3-methyl-4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl 1-4-aminophenyl; 2-thiazolyl; 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-methy1-4-quinoliny1; 3-methyl-2-quinoxalinyl; Is 2-phenyl-4-quinolinyl or 2-benzothiazolyl; and

(b) X is methyl, phenyl or chlorine and

Y represents hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl, or 2,5-dimethylbenzyl; whereby A prerequisite is that when X is phenyl, Y can only be hydrogen or methyl, and if X stands for chlorine, Y can only mean benzyl.

The terms "disubstituted" or "disubstituted" used for the substituents on the phenyl ring of the compounds of the formula I "Trisubstituted" refer to compounds whose substituents are identical, for example dichlorophenyl, Dimethylphenyl, dimethoxyphenyl, trimethylphenyl, trimethoxyphenyl, or similar.

Another preferred embodiment relates to: (a) compounds of the general formula II:

H ₂ N

II

709883/08 9

or their non-toxic acid addition salts,

wherein

R is hydrogen; Methyl; Ethyl; n-propyl; i-propyl; η-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-1-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl; 2-phenylethyl; 2-phenylvinyl; Phenyl; Phenyl in 2-, 3- or 4-position monosubstituted by chlorine, bromine, iodine, fluorine, trifluoromethyl, ethyl, n-propyl, i-propyl, η-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, Methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, Carbethoxy, carboxyl, sodium carboxy or potassium carboxy; Phenyl, monosubstituted in the 3-position by amino or nitro; Phenyl, disubstituted 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; Phenyl, in 2,4,6- or 3,4,5-positions trisubstituted by methyl, ethyl, Methoxy or ethoxy; 2,3,5,6-tetramethylphenyl; 3,4- (methylenedioxy) phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-1-naphthalenyl; 1-bromo-2-naphthalenyl; 2-pyridinyl; 3-pyridir.yl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl; 3,5-dimethyl 1-4 isoxazolyl; Tetrahydro-2-furanyl or is benzo- [b] -thien-3-yl;

(b) Compounds of the general formula III:

III

709883/08 95

M / 18 190

-κ-

or the non-toxic acid addition salts, in which:

R is hydrogen, phenyl, monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or Carboxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitro-phenyl; 2-cyano-4-aminophenyl; 3-methyl 4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoro- ' methyl-4-nitrophenyl; 2-trifluoromethyl-4-aminophenyl; ' 2-thiazolyl; 2-pyridinyl; 5-nitro-2-pyridinyl; j

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-quinoxylinyl; Is 2-phenyl-4-quinolinyl or 2-benzothiazolyl;

(c) Compounds of the general formula IV:

\H

IV

X-Y

or their non-toxic acid addition salts, wherein

7 0 9 8 8 Ztüttt

M / 18 190

X stands for methyl, phenyl or chlorine and

Y hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyano

is benzyl or 2,5-dimethylbenzyl; where requirement j

is that when X is phenyl, Y is only hydrogen I.

or methyl, and when X is chlorine;

Y can only mean benzyl. \

Of particular interest are the compounds 7H-pyrrolo- i [3,2-f] -quinazoline-1,3-diamine and the derivatives thereof with j an 8-methyl or 8-phenyl substituent, which can be used as j Intermediate products for the preparation of the compounds of the formula I can be used with a substituent in the N position can.

The compounds of the formula I in which Y, X, R and R have the meanings given above, and their salts, inhibit the growth of bacteria in vitro, as in a standard test tube dilution test using seed agar or i "Wellcotest Sensitivity Test Agar ',' reinforced with 5% hemolyzed horse blood was shown as a growth medium. The compounds showed in vitro activity against one or more of the following bacterial strains: S. aureus smith, S. aureus 53-180, N. catarrhalis 8193, E. coli 9637, S. paratyphl 11737, K. pneumoniae 10031 or P. vulgaris 6896. In Ver; search with the serial dilution test described above gave the compounds MIC values of <0.0009 6 / ml to 250 6 / ml against the test organisms. j

In addition, the compounds of formula I show in vitro anti-folic acid activity, such as by inhibiting Streptoccus faecalis ATCC 8043, prepared in foic acid medium, has been proven.

TO 98B 3 ΠΤ & -9 S

ORIGINAL INSPECTED

The invention also provides compounds that have the anti-:

potentiate bacterial effects of sulfa drugs. After j

Oral administration to mice showed the following compounds fertilize a synergistic effect with sulfamethazole

bacterial infections: j

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

7- [(4-fluoropheny1) methyl] -7H-pyrrolo [3,2-f] -quinazoline- j 1,3-diamine;

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

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

8-methyl-7- (phenylmethyl) -7H-pyrrolo [3,2-f] -quinazolin- ι 1,3-diamine;

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

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

In addition, the invention encompasses compounds which in vivo i Have antimalarial effects as by standard

Blood schizont test in mice infected with Plasmodium berghei '

KBG 173 were infected. The following .

Compounds of formula I were according to the above!

Trial effective against malaria: J.

(a) X is hydrogen and
Y stands for -CH ₂ R,

in which '

R i-butyl; n-hexyl; 2-methyl-1-propenyl; Cyclohexyl;

2-phenethyl; Phery, äL _Q iköcyl · »o4pr 2-, 3-> or 4-position

monosubstituted with chlorine, fluorine, methyl, cyano or ι methoxy; 4-isopropylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; 4- (methylsulfonyl) phenyl; 4-acetylphenyl, 4-methylthiophenyl, 4-carbethoxy-; '■ phenyl, 4-trifluoromethoxyphenyl; Phenyl, monosubstituted in 3-position by amino or nitro; 2,4-dimethyl-. ι ■ '

j phenyl; 2,5-dimethylphenyl; 3,4-dimethylphenyl; 3,4-dimethoxyphenyl, 2,6-dichlorophenyl; 3,4-dichlorophenyl;

2,4,6-trimethylphenyl; 3,4,5-trimethoxyphenyl;

3,4- (methylen-dioxy) -phenyl; 1-naphthalenyl; 2-naphtha- ^!

linyl; 2-methyl-1-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; or 3-thienyl

means;

(b) X is hydrogen and

Y R denotes, where R is phenyl, in the 2- or 4-position monosubstituted by nitro or acetyl; 4-cyanophenyl, 3-methyl-4-nitrophenyl; 2-thiazolyl; or 5-nitro-2-pyridinyl means;

(c) X is methyl and

Y represents hydrogen or 2,5-dimethylbenzyl.

In vivo activity against P. cynomolgi infections in Rhesus monkeys was also found when the following compounds were tested: 7- (phenylmethyl) -7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine; 7 - [(4-methoxy) methyl] -7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine and 7 - [(2,5-dimethylphenyl) methyl] -7H-pyrrolo- [ 3,2-f] quinazoline-1,3-diamine. The CD_ _Q doses of these compounds are 0.1 mg / kg / day, 0.316 mg / kg / day or 1.0 mg / kg / day after oral administration of the compound for several days. ι

709883/0895

The effect against P. berghei strains against chloroquinine, j Sulphones, cycloguanil and pyrimethamine are resistant, j is tested by testing the compounds 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 shown against such resistant strains in mice.

Certain compounds are in vivo in mice (I.P.) effective against lymphocytic leukemia when viewed according to the procedure described in "Cancer Chemotherapy Reports, Volume 3, No. 2, page (Protocol 1 200), September 1972 ". The compounds of formula I wherein X is hydrogen and Y has the meaning -CH-R, which have such an activity are:

Phenyl

4-cyanophenyl ^a 4-methylsulfonyl 4-carbathoxyphenyl 3-nitrophenyl 4-methylphenyl 2,5-dimethylphenyl 3,4-dimethylphenyl 4-t-butylphenyl 3,4-dimethoxyphenyl 3,4,5-trimethoxyphenyl 3-aminophenyl 3-thienyl

2-pyridinyl 4-pyridinyl 2-quinolinyl

dose T / C,% (mg / kg) 10 149 20th 138 10 136 10 141 5 163 10 138 10 142 10 139 5 125 10 174 10 163 10 165 10 147 20th 146 15th 142 10 145

70 9 8837 D 8-a 5

; (a) Tested in the form of 1/5 hydrate, and!

! (b) tested as dihydrochloride monohydrate. '

The invention relates to the following methods:;

\

(A) Process for the preparation of the compounds of Formula V:;

NH,

^l 2 / -

N-Y

H ₂ N

wherein:

(a) X is hydrogen and Y is -CH ₂ R or -R ¹ ,

wherein:

R is hydrogen; Methyl; Ethyl; n-propyl; i-propyl;
η-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-1-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl;
2-phenylethyl; 2-phenylvinyl; Phenyl, phenyl in
2-, 3- or 4-position monosubstituted with chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl,
n-propyl, i-propyl, η-butyl; i-butyl, t-butyl,
Methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano,
Methylsulfonyl, acetyl, propionyl, methylthio,
Ethylthio, carbethoxy, carboxyl, sodium carboxy or

709883/0 * 95

Potassium carboxy; Phenyl, monosubstituted in the 3-position guided by nitro; Phenyl, in 2,3-, 2,4-, 2,5-,

2,6-, 3,4- or 3,5-positions disubstituted with ^:

Methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, j

Chlorine, bromine, iodine or fluorine; Phenyl, in2,4,6- or j

3,4,5-positions trisubstituted with methyl, ethyl, j

Methoxy or ethoxy; 2,3,5,6-tetramethylphenyl; '

3,4- (methylen-dioxy) -phenyl; 1-naphthalenyl; j

2-naphthalenyl; 2-methyl-1-naphthalenyl; 1-bromo j

2-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyri- j

dinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl, j

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

means and ^!

R phenyl, monosubstituted in the 2- or 4-position by nitro, cyano, acetyl, propionyl, methyl-

sulfonyl, trifluoromethyl, or carbethoxy; \

2, 4-dinitrophenyl; 2-cyano-4-nitrophenyl; 3-methyl- ^: 4-nitrophenyl; 2-trifluoromethyl-4-nitrophenyl;
2-thiazolyl; 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-quinoxylinyl; I 2-phenyl-4-quinolinyl or 2-benzothiazolyl

means; and ^!

(b) X is methyl or phenyl and!

Y methyl _t benzyl, 3-cyanobenzyl, 4-cyanobenzyl or ι

2,5-dimethylbenzyl, with the prerequisite

is that when X is phenyl, Y can only be methyl ι;

which is characterized in that a compound of the formula VI

N-H

VI

wherein:

X denotes hydrogen, methyl or phenyl, reacts with an alkali metal base, forming an alkali metal salt forms, which in turn is combined with a combination of the formulas

RCH ₂ -Z or R ¹ -Z

VII VIII

in which R and R have the meanings given for the formula V and Z is an emerging from the molecule Group represents.

709883/0896

M / 18 190

(B) Process for the preparation of compounds of the formula IX:

NH

wherein

Denotes hydrogen, methyl, phenyl or chlorine; and

.1

Y 'denotes hydrogen or -CH-R, in which R is methyl; Ethyl; n-propyl; i-propyl; η-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-1-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl; 2-phenylethyl; 2-phenylvinyl; Phenyl, phenyl monosubstituted in the 2-, 3- or 4-position with chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy , Ethoxy, n-propoxy, trifluoromethoxy, cyano, methyl [ sulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy or potassium carboxy; Phenyl monosubstituted in the 3-position by nitro; Phenyl, disubstituted in 2,3-, 2,4-, 2,5- 2,6-, 3,4- or 3,5-position with methyl, ethyl, n-propyl, methoxy, ethoxy-n-propoxy , Chlorine, bromine, iodine or fluorine; Phenyl in the 2,4,6 or 3,4,5 positions trisubstituted with methyl, ethyl, methoxy or ethoxy; 2,3,5,6-tetramethylphenyl; 3,4- (methylen-dioxy) -phenyl; 1-naphthalenyl; 2-naphtha- . linyl; 2-methyl-1-naphthalenyl; 1-bromo-2-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl; j

709883/0895

M / 18 190

ZA

3,5-dimethyl-4-isoxazolyl; Tetrahydro-2-furanyl or Means benzo [b] thien-3-yl;

which is characterized in that an acid addition salt of a compound of the formula X:

wherein X and Y have the meanings given for formula IX, n.it einam Alkalimetalldicyanamid at a temperature of about 185 ⁰ C to about 210 ⁰ C in an aliphatic alcohol, with the prerequisite that when X is chlorine, Y only - CH_R can mean.

(C) Process for the preparation of the compounds of the formula XI:

NH _n r = ^

XI

wherein: “2

3-aminobenzyl, 2-aminophenyl, 4-aminophenyl, 2-cyano-4-aminophenyl; 3-methyl-4-aminophenyl or 2-trifluoromethyl-4-aminophenyl means,

70988 ^ / 0895

which is characterized in that a compound of the formula XII:

NU. ,

NY ³

XII in which:

Y is 3-nitrobenzyl, 2-nitropheny, 4-nitrophenyl, 2-cyano-4-nitrophenyl _/ 3-methyl-4-nitrophenyl or 2-trifluoromethyl-4-nitrophenyl,

reduced.

In process (A), the alkali metal base must be strong enough to remove the proton from the indole nitrogen of the starting amine (VI) to give the alkali metal salt of the conjugate base. The salt is then reacted with the appropriate reagent RCH ₉ -Z or R -Z to introduce the desired substituent - or R -) in the 7-position. Examples ge

Suitable alkali metal bases are sodium and potassium hydride, potassium t-butoxide and lithium or potassium amide.

In the reagents of the formula RCH ₂ -Z, the preferred leaving group Z is chlorine, bromine or iodine. In the case of the reagents of the formula R -Z, the preferred leaving group is a fluorine, bromine, chlorine or iodine atom. Further examples of suitable leaving groups (Z) for RCH - Z are tosyloxy or mesyloxy. The reaction is suitably carried out in an inert solvent such as dimethylformamide (DMF) or dimethylacetamide (DMA). According to a preferred method, the 7-H-pyrrolo [3,2-f] quinazoline-1,3-diamine (VI) is treated with sodium \ hydride in dimethylformamide and the appropriate reagent (RCH-Z or R -Z) is added to the reaction mixture. In the reaction in which the reagent R -Z is used! is heated, the reaction mixture is preferably heated to a temperature above 50 ^° C. j

709883/0895

\ In the method (B), the appropriate 5-aminoindole (X) in the form of the acid addition salt to a temperature of about 185-215 ⁰ C with a Alkalimetalldicyanamid such as sodium or Kaliumdicyanamid heated in an aliphatic alcohol solvent. The best results are obtained when a molar ratio> 2: 1 of dicyanamide to 5-aminoindoleic acid addition salt is used. A molar ratio of 2.5: 1 is preferred. The reaction is conveniently carried out by heating the reactants to the reflux temperature of the solvent. Aliphatic alcohols

j are with a boiling point of about 185 ° C to about 215 ° C

preferred solvents. According to a preferred method

\ 5-aminoindole-acid addition salt (X) at reflux '■ in temperature is 1-octyl alcohol was heated with sodium dicyanamide, until the reaction is complete.

In the method (C), any reducing agent which converts the aromatic nitrate group into an aromatic can be used Can reduce the amino group and does not affect the other functions in the molecule. Preferred reducing agent is Hydrogen in the presence of a noble metal catalyst such as palladium on activated carbon. One atmosphere pressure : is preferred.

The 5-aminoindoles used as starting materials Formula (X) and the reagents RCH_-Z and R -Z are either known compounds or can be prepared by known processes for analogous compounds or by obvious modifications of known methods.

The compounds of the formula I can be isolated and purified either in the form of the free base or the acid addition salts will. Procedures for converting one form to the other are obvious to the chemist.

709883/0895

For pharmacological purposes, the compounds of Formula I used in the form of an acid addition salt of a non-toxic organic or inorganic acid will. The salts can be prepared by methods known in the art. Suitable salts are the following acids: hydrochloric acid, hydrogen bromide acid, maleic acid, benzoic acid, pamoic acid, methanesulfonic acid or acetic acid.

For pharmacological purposes, the compounds of the · formula may be administered I either alone or in combination with pharmaceutically acceptable carriers, the proportion and nature are determined by the solubility and chemical properties of the selected compounds, the chosen route of administration and standard pharmacological practice. For example, the compounds of the formula I can be administered orally in solid dosage forms, for example as capsules, tablets, or powder, or in liquid form, for example as solutions or suspensions. The compounds can also be injected parenterally in the form of sterile solutions or suspensions. Solid oral dosage forms can contain conventional additives such as lactose, sucrose, magnesium stearate, resins, and similar materials. Liquid oral administration forms can contain various flavoring, coloring, preserving, stabilizing, solvent or suspending agents. Parenteral preparations are sterile aqueous or non-aqueous solutions or suspensions which contain various preservatives, stabilizers, buffers, solubilizers or suspending agents. If desired, additives such as saline or glucose can be added to make the solutions isotonic.

The following examples illustrate the preparation processes and the use of the compounds according to the invention. All temperatures are measured ^{in 0 C.}

709883/0895

sr

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

A suspension of 168.6 g of 5-aminoindole hydrochloride, (prepared by treating a methanolic suspension of 5-aminoindole with an excess of isopropanolic Hydrogen chloride and diluting the salt solution with ether), 222 g of sodium dicyananide (which was previously recrystallized from methanol was) and 3 1 1-octanol is heated with thorough Stir (under a nitrogen atmosphere) for 13 hours and filter the hot mixture, washing the insoluble ones Components with 500 ml hot 1-octanol, dilute the diluted

j united filtrates with an equal volume of ether and

i acidifies to pH 1 with isopropanolic hydrogen chloride.

I Filtration (slowly) produces a fine, yellow precipitate

I hit collected and dissolved in 3 liters of warm water. Man

'' filters the aqueous solution through a coarse sintered glass frit.

After cooling to about 25 ^° C., the solution is washed with

i ethyl acetate and ether. Acidify the solution with aqueous

ι Sodium hydroxide results in a yellow precipitate, which

j collects, washed thoroughly with water and

j is dried constantly. The crude product (141.5 g) dissolves

j one in about 10 1 of methanol, treated with activated charcoal and

! filtered through Celite. The methanolic is concentrated Solution to a volume of about 400 ml, dilute with 200 ml acetone and cool.

; The solid that separates out is treated with cold acetone

ι washed and dried to obtain 77.6 g of the title Compound I is obtained, mp 263 -. 265 ⁰ C (dec.). Another 17.2 g of product; [Fp. 262-264 ⁰ C (decomp.)] Are isolated by removing the!

Concentrate crystallization mother liquors to a volume of about 40 ml, add 40 ml acetone and cool. Recrystallization of;

1.0 g of product [m.p. 263-265 ° C (dec.)] From methanol-acetone; gives 395 mg of the title compound, melting point 264 ° C. (dec.).

! 709883/0895

3 *

NMR (dDMSO): 57.14 (doublet, J-3Hz, 9H), 7.20 (doublet, J-9Hz,
5 or 6H), 7.54 (doublet, J-3Hz, 8H), 7.78 (doublet, J-9Hz,
5 or 6H), 11.65 (broad singlet, interchangeable, 7H) ppm;

95% EthOH 232.5 (£ 24,300), 258 (£ 22,120), 312 (£ - 8,090), j

Iu α X ι

340.5 (e 7420) nm; !

95% EthOH _{250 (£} . ₂₀ 940) ₂ 79 (£ 2 310), 330 (£ 7 140) nm. '

·. min

7-H-pyrrolo- [3,2-f] -quinazoline-1,3-diamine (5.62 g, prepared in a manner similar to that described above) in 300 ml | Methanol is treated with an excess of isopropylic hydrogen chloride and the solution is concentrated to one volume
! of about 100 ml, diluted with 200 ml of dimethoxyethane and:; cools thoroughly. You collect the salt and dry it. It weighs \

t

: 2.7 g. Concentration of the mother liquors gives a further 3.8 g of salt. j

j Recrystallization of the two solids from methanol-ethanol!

gives 5.26 g of the title compound in the form of the monohydro- j

Chloride salt, m.p.> 310 ^° C., '

I analysis C ₁ -H ₉ N ₅

Calculated: found:

Using conditions similar to those described above
led A. Rosowsky and N. Papathanasopoulos [J. Org. Chem.,
39 , 3293 (1974)] convert naphthylamines into 2,4-diaminobenzo [h] -quinazolines.

C. 96 H 28 N , 72 Cl / 05 % j 50, 81 4, 22nd 29 / 01 15th , 88 % i 50, 4, 30th 14th

709883/0895

J?

example

Procedure A

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 under a nitrogen atmosphere when 3.70 g of about 50/50 Sodium hydride mineral oil dispersion must be carefully added. After stirring for 1.5 hours, give one Solution of 9.30 g of benzyl chloride (8.5 ml) in 20 ml of dry dimethylformamide over about 10 minutes. The mixture is stirred for 5 hours. further and then add 120 ml of glacial acetic acid to the reaction mixture. After the solvent has been removed in vacuo, the Wash the residue thoroughly with an excess of aqueous potassium carbonate solution and filter. The solids are collected, washed with water and dried. The crude product is dissolved in 1.4 l of boiling methanol, treated with activated charcoal and filtered through Celite. The filtrate is concentrated to about 125 ml and cooled. The crystalline solid is collected, washed with acetone and recrystallized again from methanol, giving 11.76 g of the titre compound, melting point 228 °.

NMR (dDMSO): 65.53 (singlet, N-CH ₂ C ₆ H ₅ ), 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;

^ max ^{Eth0H 235 (e 26 900)} ' ^{260 (} £ ^{23 620)} ' ^{317 {€ 9 640)} '345 sh (£ 7 520) nm;

J (_ ^95% ϋΐϊ ° ^Η 243 < ^{£ 26} ° 20), 281 (C 2 430) nm.

709883/0895

Μ / 18 190 -J ^ T-

To a solution of 4.5 g of 7- (phenylmethyl) ^ H-pyrrolo- [3, 2-f] - j

quinazoline-1,3-diamine (which is loaded in a manner similar to that above |

written was prepared) in 300 ml of methanol is j

3 ml of glacial acetic acid and concentrated to a total volume of j

about 100 ml, cool, diluted with 100 ml acetone and filtered,:

2.5 g of salt are obtained. Concentration of the mother liquors to a volume of about 40 ml, dilution with 40 ml of acetone and filtering off results in 2.0 g of salt. Combine the two quantities obtained salt and crystallized from methanol-acetone to give 2.88 g of the title compound in the form of Monoacetatsalzes obtained, mp. 226 ⁰ C (dec.).

Procedure B

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

A suspension of 16.215 g of 5-nitroindole in 1.25 l of dry dimethylformamide is stirred under a nitrogen atmosphere and 5.280 g of about 50/50 sodium hydride mineral oil dispersion is added. After stirring for 1.5 hours, a solution of 13.3 g of benzyl chloride (12.1 ml) in 25 ml of dry dimethylformamide is added and the mixture is stirred for a further 5 hours. After adding 175 ml of acetic acid, the solvent is removed in vacuo, the residue is stirred with an excess of aqueous potassium carbonate solution and filtered off. The solids are collected, washed with water and dried. The crude product is dissolved in 2.5 l of boiling methanol, treated with activated charcoal and filtered through Celite. The filtrate is concentrated to about 400 ml and cooled. Collect the crystalline solid which yields 20.3 g, mp. 104-105 ⁰ C. A sample of 4.0 g is recrystallized from methanol to obtain 3.6 g of 1-benzyl-5-nitroindole is obtained, m.p. 103 ⁰ C.

709883/0895

C. , 41 H 80 N , 11 71 , 31 4, 84 11 , 02 71 4, 11

Analysis C ₁

calculated: found:

A suspension of 15.3 g of 1-benzyl-5-nitroindole, 1.0 g of 10% palladium on activated carbon in 400 ml of ethyl alcohol is hydrogenated at 1 atmosphere until the uptake of hydrogen ceases. The suspension is filtered and the solvent is removed. The resulting solid is dissolved in 50 ml of methyl alcohol, acidified with isopropanolic hydrogen chloride and the 5-amino-i-benzylindole hydrochloride is precipitated by adding 450 ml of ether; Mp. 244-245 ⁰ C dec.

Analysis C, _H, .N _O
15 14 2

calculated: found:

A suspension of 2.578 g of 5-amino-i-benzylindole hydrochloride, 2.228 g of sodium dicyanamide (which was previously recrystallized from methanol) and about 50 ml of dry octanol is refluxed for 4 hours with thorough stirring under a nitrogen atmosphere. The reaction mixture is filtered off and the filtrate is diluted with 150 ml of ether. The precipitate, which is obtained after acidification with isopropanolic hydrogen chloride, is filtered off and recrystallized from methanol, 0.3 g of a salt being obtained. A solution of 3 ml of 1 η sodium hydroxide and 1 ml of methyl alcohol is mixed thoroughly with this salt and crystallized, the resultant compound from methanol to give the title compound, mp. 223-224 ⁰ C, which is identical with the compound was prepared in Example 2 according to method A, demonstrated by mixed melting point and NMR spectrum comparisons. _:

709883/0898

C. , 89 H , 87 N , 87 Cl 37 69 , 54 5 , 73 10 , 91 13, 63 69 5 10 13,

Examples 3 - 60

Under conditions similar to those described in Example 2, 7H-pyrrolo- [3,2-f] quinazoline-1,3-diamine in dimethylformamide is converted into the Nind sodium salt with a dispersion of 50% sodium hydride in mineral oil and the salt
will use the specified halide during the likewise
given time, resulting in the 7- (substituted) -methyl-7-H-pyrrolo [3,2-f] -quinazoline-1,3-diamines listed in Table I.

709883/0895

Tabel

7- (substituted) -7-H-pyrrolo [3,2-f R. H ₉ N / rr \
1 JL N-CH ₂ R ] quinazoline-1,3-diamine Recryst.
Solution
medium ^a M.p., ° C VJ
C. 2-fluorophenyl te *
Alkylating agents M. 215-216 example 3-fluorophynyl 2-fluorobenzyl chloride React.
Time
(Hours) M. 245-247 ο
co 3 4-fluorophenyl 3-fluorobenzyl chloride 5 M-P-B, P 203 oo 4 2-chlorophenyl 4-fluorobonzyl chloride 5 M. 229 3-chloropenyl 2-chlorobenzyl chloride 6th M. 253-254 - ^ \ ° 6
OO 4-chlorophenyl 3-chlorobenzyl chloride 2 M. 217-218 co 7 2,6-dichlorophenyl 4-chlorobenzyl chloride 5 D. 307-308
(softens at ^m 8 3,4-dichlorophenyl a, 2,6-trichlorotoluene 3 N-W, M-P 253-255 (dec 9 2-trifluoromethyl
phenyl a, 3,4-trichlorotoluene 5 M. > 310 ^b
(softens at 298) 10 3-trifluoromethyl
phenyl (2-trifluoromethyl) benzyl
bromide 4th M, B 204-205 .) 11 4-trifluoromethylphenyl (3-trifluoromethyl) benzyl
chloride 5 M. C. 230) 12th 2-cyanophenyl (4-trifluoromethyl) benzyl
bromide 5 AT THE 176-180 NJ 13th 2-cyanobenzyl bromide 1 CO 14th 5 O
co

Ex. R. Table I (continued) React.
Time
(Hours.) 3.3 Recryst.
Solution
middle M.p., ° C 160) M / 18 15th 3-cyanophenyl Alkylating agents 5 4th M ^d 239-240 vo
O 16 4-cyanophenyl 3-cyanobenzyl bromide 1 3 M. 247-249
(softens at 17th 4-carbethoxyphenyl 4-cyanobenzyl bromide 5 5 E. 212-215 18th 3-nitrophenyl 4-carbethoxybenzyl bromide ^e 5.5 4th D, M 249-251 19th 2-methylphonyl 3-nitrobenzyl bromide 5 21 M. 241-242 C. > 20th 3-methylphenyl 2-Me thy 1 ben 7.y I lor id 6th M. 223 ^ t
to 21 4-methylphenyl 3-methylbenzyl chloride 2 M. 213-214 Ni CD
CO 22nd 2,4-dimethylphenyl α-chloro-p-xylene 5 M. 243-245 I. CO
^ 23 2,5-dimethylphenyl 2,4-dimethylbonzyl chloride 4th M ^g 269-271 \
I. O 24 2,6-dimethylphenyl 2,5-dimethylbonzyl chloride 3.5 D, M 287-290 (O 25th 3,4-dimethylphenyl 2,6-dimethylbenzyl chloride ^Ί 3,4-dimethylben / .yl chloride ^c 5 A. 21G-218 σι 26th 3,5-dimethylphenyl 3, S-dimethylbenzyl chloride * M. 261.5-263.0 27 2,4,6-trimethylphenyl 2,4,6-trimethylbenzyl
chloride M. 256 CO 28 2,3,5,6-tetramethyl
phenyl 2,3,5,6-tetramethylbenzyl
chloride D. 281-282 29 4-1sopropylphenyl 4-isopropylbenzyl chloride ^ A. 230-232 CD
CO
CO 30th 4-t-butylphenyl 4-t-butylbenzyl chloride M, A 279-280 31 4- (methylthio) phenyl 4- (methylthio) -benzyl-
chloride ^K A. 217-221

J. I. Ex. R. Table I (continued) React.
Time
(Hours.) 4th Recryst.
Solution
medium ^a M.p., ° C M / 1 218) 210 I. 73 ' i 32 2-methoxyphenyl Alkylating agents 4th 2 M. 213-216 8 190 CO 33 3-methoxyphenyl 2-methoxybenzyl chloride 4th 2 M. 205-207 IS * 34 4-methoxyphenyl 3-methoxybenzyl chloride ^m 4th 24 P, M-A, M 205-206 35 2,3-dimethoxyphenyl 4-methoxybenzyl chloride ⁿ 3 2.5 M. 205.0-207.5 I. 36 2,5-dimethoxyphenyl 2,3-dimethoxybenzyl chloride ° 3 4th M. 228-230 D. 37 3,4-dimethoxyphenyl 2,5-dimethoxybenzyl chloride bb
4th 6th M. 222-226
(softens at ) RIGII CD
30th
JJ 38 3, 4- (methyldioxy) -
phenyl 3,4-dimethoxybenzyl chloride 3,4- (methylenedioxy) benzyl
chloride ρ 3.8 3 M ^q 235.5-237.5 SAUII 35 39 3,4,5-trimethoxyphenyl 3,4,5-trimoxybenzyl
chloride M. 240-241 CO
Vl 40 4-ethoxyphenyl 4-ethoxybenzyl chloride ^r B-A 200.5-203.0 ο
πι 41 3-thienyl 3-thenyl bromide ^S M, A 212-213
(softens at ^σ 42 4-thiazolyl 4-chloromethylthiazole
hydrochloride t M. 254-255 43 2-pyridinyl 2-picolyl chloride hydro
chloride, t M, A-M, P, M 223-224 44 3-pyridinyl 3-picolyl chloride hydro
chloride, * t M ^U 227 45 4-pyridinyl 4-picolyl chloride hydro-
chloride, t P. 232-234 (dec 46 Benzo [b] thien-3-yl 3-chloromethylbenzo tb] -
thiophene, ν D. 277.5-278.0

R. Table I (continued) React.
Time
(Hours.) 50 Recryst.
Solution
middle M.p., ⁰ ° C 00 ) I. Ex. 1-naphthalenyl Alkylating agents 6th 71 M. 259-261 (decomp.) VO
O K
9S 47 2-naphthalenyl 1-chloromethylnaphthalene 4th 5 M, M-E 300-330 ^w (decomp.)
(softened at 250 I. 48 2-methyl-1-naphthalenyl 2-chloromethylnaphthalenyl 5 65 M. 279-281 (decomp.) 49 2-quinolinyl 1-chloromethyl-2-methyl-
naphthalene 6th 3 M. 208 50 8-quinolinyl 2-chloromethylquinoline
hydrochloride, t 5 i ^CC 19 M ^X 220-221 51 3,5-dimethyl-4-
isoxazolyl 8-quinolinyl diethyl bromide 3,5-D.imethyl-4-chloromethyl-3,3
isoxazole 2 M ^d 270.5-271.5 52 n-hexyl n-heptyl bromide 4th P. 154 ^ 53 Cyclohexyl Bromine thy Icy c lohexane E-B, E-P 192 ^y 54 2-methyl-1-propeny1 1-chloro-3-methyl-2-butene A. Z 55 2-phenylethyl 1-iodo-3-phenylpropane M. 182-183 56 2-phenylvinyl Cinnamyl bromide A · 224-226 57 3,5-dimethoxypheny1 3,5-dimethoxybenzylchloric M, A 213-215.5 58 2-thienyl 2-chloromethylthiophene ^dd A. 203-205 59 1 -Broni-2-naphthalenyl 1 -Bromo-2- (broinmethyl) - M ^ee 263.5-265.0-4 60

naphthalene

(a) A = acetone, B = acetonitrile, ^ dimethylformamide, E = absolute ' ethanol, M = methanol, N = nitromethane, P = 1-propanol, j W = water;

(b) This compound is isolated as a hydrate, the

Has 3/4 molecules of water per molecule of diamine;

(c) This compound is isolated as a hydrate containing 1/3 molecule of water per molecule of diairan and at

Melts from 220 to 223 ^° C., but the melt is not completely clear up to 270 ^° C., where severe decomposition occurs. ^;

(d) The crude product is thoroughly triturated with hot water before crystallization.

(e) Adding 4-bromomethylbenzoyl bromide in benzene to absolute ethanol-benzene, stirring for 1.5 hours, removing the solvent and distilling the residue gives this bromide, b.p. 104-117 ° / 2mm, mp 35-38 °, (cloudy ). AF Titley [J. Chem. Soc. 1928 , 2581] report a bp 165 ° / 18 mm, mp 35-36 °;

(f) This chloride, boiling point 91%, is now obtained by adding the corresponding alcohol in benzene to thionyl chloride-benzene-pyridine according to the method of Neunann [J. Am. Chem. Soc., 6J2, 2295 (194o )]. RB Akin et al., [J. Am. Chem. Soc. 5_9, 1268 (1937)] describe a cap. 116-118 ° / 16 mm and 86-87 ° / 7 mm.

(g) The crude product is recrystallized twice from methanol, washed with 2: 1 η sodium hydroxide-methanol with water and dried from methanol before final recrystallization;

709883/0895

(h) The alcohol is converted ^{into the chloride using the Neumann method (see!} Note f) / bp 75-77 / 2mm. i VF Raaen and JF Eastham [J. At the. Chem. Soc., 82 , 1349 (1960) now describe a bp 75-80 ° / 1.

(i) This halide, bp. 103-104 ° / 15 mm, is after! drive synthesized by Neumann (see note f). j B. van Zanten et al., Rec. trav. chim. , 7_9, 1211 (1960) [CA., _55, 7403e (1961)] describe a bp 100-110 ° / 15 mm.

(j) This compound contains, as evidenced by NMR experiments

showed <13% of the o-isopropylene sorting. Chloromethylation of cumene by the method of G. Blanc, [Bull.soc. chim. [4], 21 » ³¹⁷ (1933), also Or. Reactions, λ_, 67] gives 4-isopropylbenzyl chloride which contains <11% 2-isopropyl isomer (NMR analyzes).

(k) The crude halide prepared by the method of R.F. Czaja et al., U.S. Patent 3,953,520 is issued twice distilled, resulting in an oil, boiling point 93-96 ° / 1mm, which is found to be 94% 4-methylthiobenzyl chloride by gas chromatography proves. M.V /. Goldberg and M. Janpulsky, U.S. U.S. Patent 2,624,738 describes a bp 83 ° / 0.3 mm.

(1) This chloride, b.p. 77-79 ° / 2 mm, is produced according to the method of Z. Horii et al., Yakugaku Zasshi, 11_,

(1957) [CA.

describe.

(1957) [CA., 51, 8671c (1957)] which have a bp 88-89 ° / 4mm

(m) This chloride, b.p. 70-74 ° / 2, is now obtained according to the method of Z. Horii et al., (see Note 1). JW Cornforth and R. Robinson (J. Chem. Soc, 1942 , 686) describe a bp 112-115 ° / 10 mm.

(n) This chloride, b.p. 103-104 ° / 2 mm, is made according to the procedure

709883/0895

m / 18 190 -> f -

j synthesized by J. Harley-Mason and AHJackson (J. Chem. Soc., 1954 , j 1165). A. Kaufmann and H. Muller, [Chem. : Ber. 51_ _f 123 (1918)] describe a b.p. 128.5-129.0 ° / j 11mm (with decomposition).

j (o) This chloride, melting point 65 ° -68 °, is after recrystallization ; from hexane by the method of J. Harley-Mason and A.H. Jackson manufactured (see note η) which describe an mp 70-72 °.

(p) This chloride, b.p. 93-95 ° / 2mm, is prepared according to the method of Z. Horii et al., (see note 1). Späth and Schmitt, monthly sch. 53/54 , 469 [Beilstein, 1_9, II, 21] describe a Kp. 89-91 ° / 1 mm.

(q) The crude product is recrystallized twice from methanol, one hour with a solution of 3.00 g of sodium methylate-350 ml of methanol stirred, washed with kasser, dried and recrystallized from methanol.

(r) This chloride is produced by the Neumann method (see note f), bp 96-103 ° / 2-3 mm. A.L. Mndzhizan, et al. [CA., 5_5, 14466b (1961)] a bp 102-105 ° / 1 mm.

(s) Follow E. Campaign and B.F. Tullar (Org.Syn., Coll. Vol. IV, 921) and the twice distilled, tear-irritating product (b.p. 59-67 / 2-3 mm, approx. 6: 4 mixture of 3-thenyl bromide and 2-bromo-3-methylthiophene, gas chromatography) is used directly in the alkylation reaction.

(t) 2.2 molecules of sodium hydride per mole of substrate are used in this process to select the alkylating agent to release its salt.

709B83 / 0 BS 5

it \

(u) The crude product is recrystallized from methanol and!

with an excess of isopropanolic hydrogen chloride j

converted into a salt. After the recrystallization of: The regeneration of the base follows the salt from methanol

(with aqueous sodium hydroxide) and the final>

Recrystallization of the diamine from methanol. ;

(v) This halide, m.p. 38-40 °, becomes after distillation '. (Bp. 139-141 ° / 7 mm) and recrystallization from pentane
according to the method of G. Wolf and F. Zymolkowski
produced [Arch. Pharm., 309, 279 (1976)]. WJ King
and FF Nord [J. Org. Chem., J_3 ' ⁶³⁵ (1948)
a bp 152-153 ° / 11mm and a mp 39-40 °.

(w) This compound is isolated in the form of the monohydrate. \

(x) The crude diamine is recrystallized twice from methanol, washed thoroughly with sodium hydroxide and with water,
dried and finally recrystallized from methanol,
the product being in the form of a hydrate,
that contains 1/8 molecule of water per molecule of diamine.

(y) This compound is isolated in the form of a hydrate containing 1/8 molecule of water per molecule of diamine.

(z) The product melts at 166-170 °, resolidifies
and melts again at 183-186.

(aa) This chloride, b.p. 86-87 ° / 8 mm, is made according to the procedure
manufactured by Neumann (see note f), RB Herr
et al., [J. At the. Chem. Soc, Jl ' ⁴²²⁹ (1957)]
a bp 95-96 ° / 10 mm.

(bb) This chloride, melting point 51 °, is prepared (after trituration with ether-hexane) by the method of F. Binns et al., [J. Chem. Soc. [C], 1970 , 1134] which describe a: m.p. 46-48 .

709883 / 089-5

(cc) This chloride, melting point 46-47.5 °, becomes after recrystallization prepared from hexane as described by R. Adams, S. MacKenzie Jr. and S. Loewe, J.An.Cher .. Soc, 7-0, 664 (1948), which report a fp. 46.

(dd) The chloride, b.p. 77.0-77.5 ° / 18-20 mm, is prepared by the method of Toyo Koatsu Industrial Inc., Jap. Pat. 9585 (1962), [CA., 5-9, 3896b (1963)], which describe a cap. 84-86 ° / 20 mm.

(ee) The crude product is dissolved in methanol and treated with sodium methylate before crystallization.

709883/08 ^ 5

sv

example

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

According to the procedure of H.B. Hass and M.L. Bender [J. Am. Chem. Soc, 21/1767 (1949)] there are 54.43 g of a-bromo-p-tolunitrile reacted in 600 ml of benzene with 16.49 g of sodium methylate, 33.24 g of (4-cyanobenzyl) methyl ether, boiling point 114-117 ° / 5-6 mm. (Hass and Bender report a cap. 101-102 ° / 4 mm).

A solution of 33.11 g of (4-cyanobenzyl) 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 refluxed for 5 hours. After cooling, the reaction mixture is poured into 500 ml of 20% w / v. Ammonium chloride solution, shake and separate the organic layer. The aqueous phase is extracted with ether and the combined organic fractions are washed with brine, dried (over sodium sulfate) and the solvent is removed. The residue is stirred with 300 ml of hydrochloric acid for one day and then left to stand at about 25 for 2 days. 3 50 ml of water are added and the product is extracted into ether. After washing with saline, the essential extracts are dried (sodium sulfate) and the solvent is removed. Distillation of the residue gives 23.5 g of (4-acetylbenzyl) methyl ether, boiling point 97-104 ° / 1-2 mm. [Hass and Bender, J.Am.Chem. Soc, Τλ_, 1767 (1949) report a bp 107-109 ° / 3.5 mm].

709883/0895

The abovementioned (4-acetylbenzyl) methyl ether (23.44 g) is refluxed with 50 ml of 48% strength hydrobromic acid for 2 hours. After diluting the reaction mixture with 150 ml of water, the product is extracted into ether, the extracts are washed with sodium chloride solution and dried (sodium sulfate). The solvent is removed and the residue is distilled. The product, b.p. 106-122 ° / 1 mm, partially solidifies after standing for 5 days. The slight liquid phase is removed by decanting and the solid fraction is _{distilled again (} 16.24 g of 4-acetylbenzyl bromide being obtained, b.p. 108-116 ° / 2 mm. [Hass and Bender, J. Am. Chem .Soc., Above,; report a bp 134-136 ° / 5 mm].

Transferred in a manner similar to that described in Example 2 ' 7.97 g of 7-H-pyrrolo [3.2-f] quinazoline-1,3-diamine in 350 ml dry dimethylformamide into the Nind sodium salt with 2.31 g of a dispersion of 50% sodium hydride in mineral oil and treated the salt with 10.23 g of 4-acetylbenzyl chloride in 10 ml of dry dimethylformamide. After stirring for 3 hours, the reaction mixture is treated with 5 ml Glacial acetic acid and removes the solvent. The residue is stirred with an excess of aqueous potassium carbonate solution, washes with water and with a'ther and dries. Two recrystallization of the crude product from methanol and thorough Drying gives 9.82 g of the title compound, mp 224-225 °.

Example 62

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

A mixture of 7.3 g of 7 - [(3-nitrophenyl) methyl] -7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine in 500 ml glacial acetic acid

709883/0895

M / 18 190 -> tf - £ / O I UJ3

and 0.7 g of 10% palladium-on-charcoal catalyst j is hydrogenated at atmospheric pressure and about 25 ⁰ C. After about 2.5 hours i listen to the hydrogen absorption and ι filtering the reaction mixture. The solvent is removed from the filtrate and the residue is stirred in excess aqueous potassium carbonate solution, collected and washed
him with water and dry. The material is made twice
Recrystallized methanol and dried, 3.55 g
Triamin receives.

A solution of 3.4 g of triamine in 50 ml of η hydrochloric acid j it is diluted with 100 ml of acetone and cooled. The separated salt is washed with acetone and dried, whereby: gives the title compound in the form of the dihydrochloride monohydrate salt, dec. 328 ° C.

Analysis C ₁ -H _1C N, · 2HCl-H ₀ O

1/1 DO ί

calculated: 51.65

found: 51.40

Example 63

H 10 Cl , 94 N , 26 5, 77 17th , 22 21 , 17th 4, 18th 21

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

A solution of 56.0 g of 4-methylsulfonyltoluene in 2 l of benzene
(made anhydrous by distilling about 300 ml of solvent), it is cooled to about 25 ^° C. and treated with 57.5 g
N-bromosuccinimide and then with 5 g of benzoyl peroxide. One heats up
reflux the solution for 1.5 hours and then leave it at about
Stand 25 ° for 16 hours. After the crystalline solid has been removed by filtration, the solvent is removed
from the filtrate, and dissolve the residual oil in methanol.

709883/0895

Thorough cooling of the methanolic solution gives a j

crystalline product which, recrystallized from methanol, gives 21.0 g of (4-methylsulfonyl) benzyl bromide, melting point 94-95 °, [DAA Kidd and DE Wright (J. Chern. Soc, 1962 , 1420) similarly made this compound and reported mp 93-94 °].

Similar to Example 2, 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 a dispersion of about 50% sodium hydride in mineral oil and then Reacted for 6 hours with 5.48 g of (4-methylsulfonyU-benzyl bromide. The crude product is recrystallized twice from methanol, giving 4.82 g of the title compound, melting point 248 ° _;

Example 64

7-t (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. Then you heat them up Mixture refluxed for 3.5 hours, cooled and carefully added 25 ml η sodium hydroxide. After getting 0.5 hours has stirred, the reaction mixture is filtered and the insolubles are washed thoroughly with hot tetrahydrofuran washed. The solvent is removed from the tetrahydrofuran fractions and the residue is distilled, 15.82 g of (4-trifluoromethoxy) benzyl alcohol are obtained 98-99 ° / 9-10 mm. [W.A. Sheppard, J. Org. Chem., 2-9, 1 (1964) report a bp 108 ° / 25 mm].

709883/0895

SY

A solution of 15.72 g (4-trifluoromethoxy) benzyl alcohol in 170 ml of thionyl chloride is heated on the back | for 14 hours flow and remove excess thionyl chloride in vacuo. j Distilling the residue gives 7.96 g (4-trifluoromethoxy) -, benzyl chloride, b.p. 70-74 ° / 11-15 mm.

Analysis C ₀ HF-ClO

O D J

C. 62 H , 87 45, 66 2 , 87 45, 2

calculated: found:

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

Example 65

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, the mixture is stirred under a nitrogen atmosphere and 1.58 g of a dispersion of is carefully added about 50% sodium hydride in mineral oil too. After stirring for one hour, a solution of 4.47 g (2.0 ml) of methyl

709883/0895

M / 18 190

iodide in 10 ml of dry dimethylformamide and stirring is continued. Two hours later, 15 ml of glacial acetic acid are added and removed! the solvent in vacuo from the reaction mixture. The residue is stirred with excess aqueous potassium carbonate solution for a few hours, the solids are collected, washed with water and dried. A solution to this raw ^; The product in 200 ml of water-10 ml of glacial acetic acid is washed with ether. Making the acidic solution basic gives a precipitate which is washed with water and then recrystallized from methanol-acetone to give 3.44 g of the title compound j in the form of a hydrate containing 1/3 molecule of water per ^: molecule of diamine, m.p. 250 °.

NMR (dDMSO): 63.88 (singlet, 7-CH ₃ ), 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) p.p.m.

95% EthOH _{234 (£ 25} 280), 258 (£ 24 540), 317 (£ 9 090),

ITl clX

345 sh (£ .7 810) nm;

95% EthoH min

A solution of 3.32 g of 7-methyl-7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 50 ml of ethanol is treated with 3 ml of glacial acetic acid. After adding 250 ml of ether, a precipitate is obtained, which recrystallized from methanol-ethanol 3.97 g of the title compound in the form of the monoacetate salt, m.p. 247-249 (dec.).

709883/0896

27 Ί1

Μ / 18 190 - ^ CT- 4th IO \

Example 66 7- (3-Methylbutyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine

Similar to Example 2, 3.98 g of 7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine are obtained in about 210 ml of dry dimethylformamide with 1.06 g of a dispersion of about 50% sodium hydride in mineral oil and then with 4.06 g of 1-iodo-3-methylbutane implemented. The reaction time is 4 hours. The crude product is made from acetone and from acetone-methylene chloride recrystallized, giving 2.58 g of diamine, melting point 185-195 ° (softens at 180 °).

A solution of 2.5 g of the aforementioned diamine is dissolved in 100 ml η hydrochloric acid-400 ml methanol, concentrate the solution to a volume of about 100 ml and cool. That The salt which has been separated off is recrystallized from methanol-ethanol, 1.70 g of the title compound being obtained in the form of the monohydrochloride hemihydrate salt obtained, m.p. 300 ° (decomp.).

Example 67

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

Similar to Example 2, 3.98 g of 7H-pyrrolo [3,2-f] -quinazoline-1,3-diamine are obtained in about 260 ml of dry dimethylformamide with 1.06 g of a dispersion of about 50% sodium hydride in mineral oil and then reacted with 3.63 g of tetrahydrofurfuryl bromide. After keeping the mixture at for 24 hours has stirred for about 25 °, 0.21 g of dispersion of about 50% sodium hydride in mineral oil is added. One stirs another Hour, then 0.73 g of tetrahydrofurfuryl bromide are added and after stirring for 6 hours, the reaction mixture is allowed to stand for about 70 minutes at about 25 °. Forwarding

709883/0895

C. 30th H 77 Cl , 88 N 50 55, 32 5, 65 10 , 85 21 85 55, 5, 10 21

5?

Working the mixture as described in Example 2 (method A) gives a brown gum, which is dissolved in 40 minutes of hydrochloric acid. Diluting the aqueous, acidic solution having \ 40 ml acetone gives crystals which are collected and recrystallized twice from methanol-acetone to give 1.20 g obtained j of the title compound as a monohydrochloride salt containing 1/3 molecule of water per molecule of diamine , M.p. 310-311 ° (dec.).

Analysis C ₁₅ H ₁₇ N ₅ O

calculated:
found:

Example 68

7- (4-Carboxybenzyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine, sodium salt

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 stirred with 2.11 g of a dispersion under a nitrogen atmosphere of about 50% sodium hydride mineral oil (44 mmol) for 1.5 hours. 4.73 g (22 μl - '. Ol) 4-3rommethylbenzoic acid are added to, stir for a further 5 hours and let the mixture stand at about 25 ° overnight. The solvent is removed in Vacuum and dissolve the residue in 200 ml of water. After washing with chloroform and filtering off, the aqueous solution is made Solution with acetic acid to about pH 4 and left to stand overnight. The solids are collected, washed with water and dried. Recrystallization of the crude product from acetic acid and washing with methanol is carried out twice. Picking up the resulting solid in dilute aqueous sodium hydroxide and acidifying the aqueous

solution

709883/0895

with acetic acid to about pH 5 gives a product which is washed with water and dried. You solve this material (2.5 g) in 70 ml η sodium hydroxide and filtered the solution. After standing, a salt settles, which is collected with Washed acetone, recrystallized from methanol and dried 1.31 g of the title compound is obtained as a hydrate containing 1/4 molecule of water per molecule of sodium salt,

I. M.p.> 360. H ₁₅ N ₅ O ₃ Na-O, 25 H ₃ O 08 H 06 N 46 % Analysis C ₁ Q C. 94 4, 88 19 44 % 60, 3, 19 calculated: 59, found:

Example 69 7- (4-Cyanophenyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine

A solution of 15.94 g of 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 800 ml of dry dimethylformamide, the mixture is stirred under a nitrogen atmosphere for 1.5 hours with 4.61 g of a dispersion of about 50% sodium hydride in mineral oil. 10.66 g of 4-fluorobenzonitrile are added and the reaction mixture is heated 6 hours at 95 °. 40 ml of glacial acetic acid are added and the solvent is removed in vacuo. The residue becomes thorough stirred with an excess of aqueous potassium carbonate solution, collected, washed with water and dried. Twice Recrystallization of the crude product from dimethylformamide and subsequent washing with a small amount of dimethylformamide and with methanol and thorough drying gives the title compound, m.p. 344 ° (dec.).

709883/0895

NMR (dDMSO): 67.17 (doublet, J = 9Hz, 5 or 6H), 7.42 (doublet, J = 3Hz, 9H), 7.76-7.95 (four proton multiplet, 5 or 6H, 8H and two protons meta to the cyano group), 8.09 (two protons Doublet, J = 8Hz, two protons ortho to the cyano group) p.p.m.

Examples 70-95

Using conditions similar to those described in Example 69, 7-H-pyrrolo [3,2-f] quinazoline-1,3-diamine in Dimethylformamide converted into the sodium salt with a dispersion of about 50% sodium hydride in mineral oil. The salt is with the listed halide for the specified time and at the temperatures also listed implemented, whereby the 7-substituted-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines described in Table II result.

709883/0895

*** Ex.
ο 70 R. <o
OO 71 2-acetylphenyl OO
co 72 4-acetylphenyl 's »
O 73 4-propionylphenyl if
ep 74 2-cyanophenyl on 4- (methylsuflonyl) - J 75 phenyl 76 4-carbethoxyphenyl I. 77 2-nitrophenyl 78 4-nitrophenyl 79 2,4-dinitrophenyl 80 2-cyano-4-nitrophenyl 81 3-methyl-4-nitrophenyl 82 2-thiazolyl 83 5-nitro-2-pyridinyl I.
I. 2-pyridinyl I.

Table II

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

H ₀ N

NO

React. React. Recryst.
Temp. Time. Solvent ( ⁰ C) (hour) medium

Alkylating agents

2-fluoroacetophenone 70 5 M.

4-fluoroacctophenone 65-70 13D

4-fluoropropiophenone 80 6 M, D.

2-fluorobenzonitrile 80 5 D-A, M

(4-methylsulfonyl) fluoro- 75 5 D benzene

Ethyl 4-fluorobenzoate 65 5 M, D

2-fluoronitrobenzene 90 5 M

4-fluoronitrobenzene 70 5D

2,4-Dinitrofluorobenzene 80 5 D ^c

2-chloro-5-nitrobenzonitrile 95 6 D "

5-fluoro-2-nitrotoluene 85-90 4 M.

2-bromothiazole 110 4 D, M ^e

2-chloro-5-nitropyridine 65 14 D

2-fluoropyridine 110 6 M ^f

Mp. ⁰ C

250-252

290

262-264 (decomp.)

317-319 (decomp.)

309-310 (decomp.)

232

296-299 (decomp.)

> 340

335 (decomp.) Fsj

343 (dec.) £ j

267 (decomp.) ^D - »

250 p

340 (decomp.) <*

264-265 (decomp.)

Tabel

Ex.

84 85 86 87 88 89 90

2-pyrimidinyl 2-pyrazinyl 2-quinolinyl 4-quinolinyl 4-methyl-2-quinolinyl 7-chloro-4-quinolinyl

7-tri fluoromethy1-4-chinr> i i nyl II (continued)

Alkylating agents

2-chloropyrimidine

2-chloropyrazine

2-chloroquinoline

4-chloroquinoline

4-chlorolepidine

4,7-dichloroquinoline

4-chloro-7- (trifluoromethyl) quinoline

2-Mrf ι-4-quinolinyl 4-chloroquinaldine 3-Mciivv 1-2-quinoxaliny] 2-chloro-3-methyl-

quinoxdline

2-Tr-fluoromethylphenyl 2-fluorobenzotrfluoride

2-trifluoromethyl 1-4-nitrophenyl

2-fluoro-5-nitrobenzotrifluoride

2-phenyl-4-quinolinyl 4-chloro-2-phenylquinoline React.

Temp. (° C)

100 94 75 95

100 96 95

105 104

110 110

110

React. Recryst. Time solvent (hours) medium

Mp. ⁰ C

3.5 D 314-315 (decomp.)

6 D 283-284

12 M 270-272

6 D 286-287

10 D 257-258

6 D 319-320 (anger.)

6 Μ ⁹

6 B

6 D, M 208-299

6 A ^f 236-237

6 M ° 319-320

M ^y 190-195 "

O CjO UD

M / 18 190 -A * -

(a) A = acetone, B = acetonitrile, D = dimethylformamide, M = methanol.

(b) After recrystallization, the product is triturated with methanol.

(c) The crude product is triturated with boiling acetone and with boiling methanol before recrystallization.

(d) This compound is isolated as a hydrate containing 2/3 molecules, water per molecule of diamine. I.

(e) The crude product is thoroughly triturated with boiling water. The insoluble solids and the solids which are isolated from the aqueous trituration suspension are combined after cooling to room temperature and recrystallize them.

(f) The crude product is thoroughly triturated with boiling water before recrystallization.

(g) This compound is isolated as a hydrate containing 1/4 molecule of water per molecule of diamine.

(h) The crude product is triturated with boiling acetone before recrystallization; and !

(i) The connection changes into a gas from 170 °.

709883/0895

'3

EXAMPLE 96

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

A mixture of 3.20 g of 7- (4-nitrophenyl) -7H-pyrrolo- [3.2-f] -quinazoline-1,3-diamine, 200 ml of glacial acetic acid and 0.5 g of 10% palladium on activated carbon catalyst one hydrogenates at about 25 ° and atmospheric pressure. After about 1.25 hours, the hydrogen uptake ceases, the mixture is filtered and the solvent is removed from the filtrate. The residue is recrystallized twice from water and then stirred with aqueous potassium carbonate solution. Washing of the precipitate thus formed with water and drying is followed by recrystallization from acetone, whereby 1.48 g of the title compound, decomp. 180-185 ° (softens at 140 °), as a hydrate containing 1/4 molecule of water per molecule of triamine.

Analysis C ₁₆ H ₁₄ N ₆ OO, 25th

I calculated:

C. 18th H 96 N 51 65, 34 4, 92 28, 37 65, 4, 28,

found:

Example 97
7- (2-Benzothiazolyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine

1.15 g of a dispersion of about 50% sodium hydride in mineral oil are added to 3.98 g of 7H-pyrrolo [3.2-f] quinazoline-1,3-diamine, dissolved in 250 ml of dry dimethylformamide, while stirring under a nitrogen atmosphere . After stirring for 1.5 hours, 3.90 g of 2-chlorobenzothiazole are added and the mixture is heated to 95 ° for 3 hours. A further 1.29 g of 2-chlorobenzothiazole are added and the mixture is heated to 95 ° for a further 11 hours. Are then added to a third portion (1.29 g) of 2-chlorobenzothiazole and heated for 8 hours to 95 °.

709883/0895

27?

M / 18 190 -> «r- A / O

The reaction mixture is processed further as described in the example, and the crude product crystallizes out twice Dimethylformamide and dry it thoroughly to give 2.30 g of the title compound, m.p. 326 ° (dec.).

Example 98

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

(a) To a thoroughly cooled and stirred solution of 52.47 g of 2-methylindole in 320 ml of conc. sulfuric acid 34.00 g of sodium nitrate are added over a period of 65 minutes, the reaction temperature being kept between zero and 5 °. After stirring for a further 10 minutes, the reaction mass is poured into 3 kg of ice for about 20 minutes later the yellow solids are collected, washed thoroughly with water and dried. The raw product roughly 3 liters of chloroform is sent through a column filled with 1 kg of neutral aluminum oxide of the activity level III is filled. Removing the solvent from the chloroform eluates and drying the solids results 57.2 g of 2-methyl-5-nitroindole, m.p. 169-172 ° (softens at 162 °). [W.E. Noland et al., J. Org. Chem., 2-8, 2262 (1963) made this product by a similar process and reported a mp 176.0-176.5 °].

(b) A solution of 8.81 g of 2-methyl-5-nitroindole in 140 ml is added to Grace No. 28 Raney nickel catalyst (8.8 g wet weight after thorough washing with water and with absolute ethanol) in 30 ml of absolute ethanol warm absolute ethanol. The mixture is hydrogenated in a Parr hydrogenator at about 3 atmospheres pressure and about 29 °. After about 1 hour , the hydrogen absorption stops and the catalyst is through

7Ö9883 / 08O

M / 18 190 ρ » 4 / O I

Celite filtered. The filter cake is washed thoroughly with boiling ethanol and the solvent is removed from the combined ethanol fractions. Recrystallization of the crude product from ethanol-water gives 5.55 g \ 5-amino-2-methylindole as a mauve solid, mp I. 151,5-154.5 °. [WE Noland et al., J. Org. Chem., 2_8, '■ 2262 (1963) found this compound to similar

Way and report a fp. 157-159].

A solution of 5.44 g of the above amine in 50 ml _: methanol is cooled in an ice-water bath and treated with an excess of isopropanolic hydrogen chloride and then with 150 ml of anhydrous ether. After the resulting mixture has cooled to 0 for about 10 minutes, the salt is collected, washed with ether and dried, recrystallization of the salt from methanol (acidified with a few drops of isopropanolic hydrogen chloride) -ether and thorough drying gives 3.82 g of 5 -Amino-2-methylindole hydrochloride, decomp. 280-289 °, (darkens at 268 °).

(c) A mixture of 23.75 g of 5-amino-2-methylindole hydrochloride, 28.94 g of sodium dicyanamide (previously from methanol recrystallized) and 800 ml of 1-octanol is heated to Reflux, distilled about 100 ml of solvent (b.p. about 196) to produce anhydrous conditions, and the mixture is refluxed with stirring for 21 hours. The hot reaction mixture is filtered off and washes the insolubles with boiling 1-0ctanol. The octanolic fractions are combined, cools to about 25 °, acidifies with excess isopropanolic hydrogen chloride and dilutes with about 2 liters anhydrous ether. After leaving to stand for about 1.5 hours, the solids are collected, washed with water

709883 / O & 9-5

M / 18 190

washed free ether, twice with about 100 ml of cold

Triturated methanol, washed with ether and dried. j

The raw hydrochloric! is in 400 ml of water / 50 ml η chlorine;

Hydrogen acid dissolved, filtered off, and the acid,

Solution is washed with ether, cooled and with over-!

I basified with excess aqueous sodium hydroxide. j A yellow-brown solution separates from the basic solution

Solid from the collected, washed with water, ge j

dries and is recrystallized from methanol, wherein ι

11.68 g of buff-colored solid are obtained. A part !

4.08 g of this diamine is crystallized from methanol

to give 3.67 g of the title compound, dec. ;

324-327 ° C, j

NMR (dDMSO): δ 2.48 (singlet, 8-CH ₃ ), 6.88 (singlet, 9H), 7.15 (doublet, J = 9Hz, 5 or 6 H), 7.68
(Doublet, J = 9Hz, 5 or 6 H), 11.38 (broad
Singlet, interchangeable / ppm ^:

95% EthOH

Πι α. Χ

95% EthOH min

352 (£ 9110) nm;

255 (£ 18 570), 285.5 (C 1 720), 335 (€. 8 680)

nm.

Analysis C ₁

calculated: found:

C. , 95 5 H N , 85 61 , 72 5 , 20 32 , 86 61 , 11 32

9883/08 ^ 3

M / 18 190

Examples 99-103 '

; 8-Methyl-7H-pyrrolo [3,2-quinazoline-1,3-diamine is converted in a manner similar to that described in Example 2, Method A in dimethylformamide into the Nind sodium salt I with a dispersion of about 50% sodium hydride in mineral ; oil and treats the salt for the specified time j with the listed halide, whereby the 7- (substitj ierte) -e-methyl-TH-pyrrolo- [3,2-f] -quinazoline-1,3-diamine I according to Table III.

709883/0895

Table III

co co co

Ex.

99 100 101 102

103

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

Me

Methyl benzyl 3-cyanobenzyl 4-cyanobenzyl

Alkylating agents

Methyl iodide benzyl chloride 3-cyanobenzyl bromide 4-cyanobenzyl bromide

React.
Time
(Hours.) Recryst.
Solution
medium ^a M.p., ° C ι ! 2 M. 305-309 (dec. 19th M. 267-270 ι
327) 2 M ^b 277-280 (dec. 2 C. 329-332 (dec.
(softens at

2,5-dimethylbenzyl 2,5-dimethylbenzyl chloride

M, D

308-311 (dec.) I

(a) M = methanol, D = dimethylformamide;

(b) This reaction is carried out at 0 ⁰ C and the crude product is triturated twice with acetone i before recrystallization. i

(c) This reaction takes place at 0 °. The crude product is recrystallized from dimethylformamide and the two quantities of brown solids obtained are combined and first with boiling aceto nitrile and then extracted with boiling methanol. Concentrate and cool the combined Acetonitrile and methanol extracts give a buff-colored solid that eventually comes out Methanol is recrystallized.

Example 104

j (a) 6.66 g of oxindole are nitrated in 25 ml of conc. Sulphurized) Combine 51.16 g of benzaldehyde and 10.0 g of 1 .- [(2-amino-

5-nitrophenyl) acetyl] pyrrolidine and heated about

acid with 2.1 ml of fuming nitric acid according to the ver j drive from W.C. Sumpter et al., J. Amer. Chem. Soc, j [7, | 499 (1945). Crystallization of the crude product from 50% acetic acid and from methanol gives 3.85 g of 5-nitro-oxindole, Mp 240-242 ° (Sumpter et al. Report a mp 240-241 °).

(b) 600 g of pyrrolidine and 110.0 g of 5-nitro-oxindole I are heated for 1.5 hours and the dark solution is left at about 25 ° above i Standing at night. The separating yellow crystals! are collected, washed with ether and dried, 143 g of solid being obtained. One serving of 20 g; is recrystallized from methanol, 1 [(2-amino-5-nitrophenyl) acetyl] pyrrolidine obtained, m.p. 210-211 °.

Under a short distillation column for 10 minutes. During this time the distillation temperature rises from 100 ° to 176 ° and you collect about 15 ml of distillate. The reaction mixture is then cooled, poured into 700 ml of anhydrous ether and cooled. Recrystallization of the Separating solids from methanol gives 9.70 g of 1 - [[5-nitro-2 - [(phenylmethylene) amino] phenyl] acetyl] pyrrolidine, 170-171 °.

(d) A solution of 16.0 g of 1 - [[5-nitro-2 - [(phenylmethylene ) -amino] -phenyl] -acetyl] -pyrrolidine in 400 ml of hot methanol under a nitrogen atmosphere and gives 16.0 g of sodium borohydride in portions over about 20 minutes so that the reflux temperature is maintained remain. The reaction mixture is then refluxed for a further 20 minutes and then diluted with an equal

709883/0895

H 27 N , 30 6, 36 12th , 29 6, 12th

Volume of water. A yellow precipitate forms the solid is collected, dried, recrystallized from methanol and dried to give 13.2 g 1 - [[5-Nitro-2 - [(phenylmethyl) -amino] -phenyl] -acetyl] -pyrrolidine, m.p. 128 to 129 ° obtained in the form of the hydrate, that contains 1/8 molecule of water per molecule of aminoamide.

Analysis C ₁₉ H ₃₁ N ₃ O ₃ -O, 125 H ₃

C.
! calculated: 66.79

found: 66.72

(e) 2.5 1 of acetic acid and 500 ml of η hydrochloric acid are heated and 90.0 g of 1-f [5-nitro-2 - [(phenylmethyl) amino] phenyl] acetyl] pyrrolidine Reflux for 3 hours and concentrate the reaction mass in vacuo to a volume of about 0.5 l and cool. The yellow solid is collected and dried to give 67.3 g of solid, mp 137-138 °. One serving of 5.0 g is recrystallized from methanol and dried, giving 3.50 g of 1-benzyl-5-nitro-oxindole, melting point 143-144 °;

NMR (dDMSO): δ 3.83 (two proton singlet, 3H, 3H), 4.97 (two proton singlet, -N-CH ₂ -), 7.10 (doublet, J = 9Hz, 7H-), 7 , 33 (five. Proton singlet, phenyl protons, 8.17 (two proton singlet, 4 and 6 protons) ppm

(f) 100 ml of phosphorus oxychloride, 5 ml of pyridine and 10.0 g of 1-benzyl-5-nitro-oxindole are heated for 3 hours on Reflux and concentrate the reaction mass (hot) in vacuo to a gum, which is dissolved in 500 ml of chloroform

709883/0895

dissolved and stirred for 4 hours with 0.5 l of saturated aqueous: sodium bicarbonate solution. The pH is adjusted to about 9 with potassium carbonate and the mixture is then stirred for a further hour. The organic phase is separated off: washed with saline solution, dried (magnesium sulfate) and passed through a 500 g column with neutral; Alumina of activity level III sent. After >

Removal of the solvent from the chloroform eluates

a solid is obtained which, when dried, 9.1 g; 1-Benzyl-2-chloro-5-nitroindole gives, m.p. 106-107 °; i

NMR (CDCl ₃ ): δ 5.40 (two proton singlet, -N-CH ₃ -),

6.68 (singlet, 3H), 6.98-7.36 (six! Proton multiplet, phenyl proton and 7H), 8.00 (doublet of doublet, J = 9Hz, J = 2Hz, 6H) ', 8.42 (doublet, J = 2Hz, 4H) p.p.m.

(g) A solution, stirred at reflux temperature, of 25.7 g of 1-benzyl-2-chloro-5-nitro-oxindole in 600 ml of methanol and 180 ml of toluene is treated with a solution of 45 g of commercially available NaSH (xH ₂ O) in 320 ml of methanol for 10 minutes and continued to reflux. In i

successive intervals of 1/2 and 1 hour i repeat exactly the addition of NaSH (xH_O) in methanol and heat the reaction mixture for a further 2.5 hours. After filtering off, the solvent is removed from the solution and the residue is washed thoroughly with ^! Water and dry. The resulting solid (19.7 g) is dissolved in 200 ml of acetone and the solution is acidified with excess hydrogen chloride and diluted with 1 liter of anhydrous ether. There is formed a gum which was separated by decantation, thoroughly triturated with acetone [and is dried to give 16.1 g of 5-amino-i-benzyl-2-chloro-indole hydrochloride is obtained; mp. 228 ° C (dec. ).

709883/0895

190 ClN ₂ -HCl C. η H 81 Cl 27 19th 3 1039 Analysis C ₁₅ H ₁ , 61 4, 71 24, 78 61 4, 23, N calculated: , 44 9 .56% found: , 16 9 , 42%

(h) A mixture of 14.65 g of 5-amino-1-benzyl-2-chloroindole hydrochloride, 11.14 g of sodium dicyanamide (previously from methanol j

recrystallized) and 300 ml of 1-octanol are heated for 3 hours

at reflux and then left at room temperature overnight

stand. A . Solid (A) is removed by filtration;

separates, with 200 ml of hot methanol and 400 ml of water: mixes and added to the mixture. Filter the mass

results in a solid which, after washing with ether, has:

280-283 ° melts. '

The octanolic filtrate from which the solid A is removed is diluted with 700 ml of anhydrous ether and acidified with excess isopropanolic hydrogen chloride. The salt which forms is recrystallized from methanol and then with 50 ml of methanol-100 ml η sodium hydroxide touched. The crude diamine is collected and, after washing with water and drying, melts at 280-283 °. The solids, which melt at 280-283 °, are combined, recrystallized from dimethylformamide and washed with Methanol and dry thoroughly to give 4.26 g of the title compound, m.p. 285-286 °.

Analysis C ₁ ^ H ₁

calculated: found:

C. 06 H 36 Cl 95 N , 62 63, 89 4, 34 10, 84 21 , 58 62, 4, 10, 21

709883/0895

2731Q39

M / 18 190 -J ^ r- Ä / OIUO3

Example 105

i 8-Phenyl-7H-pyrrolot3,2-f] quinazoline-1,3-diaraine

(a) The nitration of 9.66 g of 2-phenylindole [previously purified was made by recrystallization from toluene and dissolving in anhydrous ether, treatment with activated charcoal, Filter off and remove the solvent, melting point 184-186 ° (softens at 180 °)] in 2CO ml of conc. sulfuric acid with a solution of 4.67 g of sodium nitrate in 100 ml of conc. Sulfuric acid is carried out as described by W.E. Noland et al., J.Org.Chem. 3J [, 65 (1966). The crude product is uir.kristallisiert from methanol, whereby 8.28 g of 5-nitro-2-phenylindole are obtained, melting point 192-194 ° (Noland et al. report a melting point 201-203 °).

(b) A mixture of 7.86 g 5-nitro-2-phenylindole, 100 ml absolute ethanol and 10 g (wet weight) Grace No. ' 28 Raney nickel, (previously washed with water and with absolute ethanol) is hydrogenated in a Parr device at a pressure of about 3 atmospheres and about 27 °. The uptake of hydrogen ceases after about 3 hours and, after dilution with about 300 ml of methylene chloride, the reaction mixture is filtered through a layer of Celite. The insoluble components are washed with methylene chloride and with boiling ethanol. Removal of the solvent from the combined organic solutions gives 6.51 g of 5-amino-2-phenylindole, melting point 227-229 ° (softens at 217 °). Noland et al., J.Org.Chem. ^21/65 (1966) prepared this amine in a similar manner and reported a mp 234-235 °.

709883/0895

C. , 71 H 35 Cl , 49 N , 45 68 , 48 5, 32 14th , 50 11 , 49 68 5, 14th 11

You give an excess of isopropanolic chlorine

hydrogen to a solution of 6.42 g of 5-amino-2-phenylindql in 125 ml of methanol, then diluted with 700 ml of water

free ether and cools down. The salt that has formed is collected from methanol (acidified with some!

Drops of isopropanolic hydrogen chloride) -ether recrystallized and dried, giving 4.98 g of amine: hydrochloride, recrystallization of a portion of j 1.1 g in the same way gives 0.82 g of 5-amino-2-phenyl-iindole hydrochloride, melting point 314-318 ° (decomp. Softens at 280 °) J

Analysis C ₁₄ H ₁ -N ₀ ^ HCl

calculated: found:

Sodium dicyanamide (22.26 g, previously recrystallized from methanol), 24.47 g of 5-amino-2-phenylindole hydrochloride and 700 ml of 1-octanol are heated with stirring at reflux, 100 ml of solvent are distilled off to Ensure anhydrous conditions and reflux for a further 3 hours. The hot one is filtered Reaction mixture and wash the insoluble components with boiling 1-octanol. After cooling down, they are treated combined octanolic fractions with 25 ml of conc. Hydrochloric acid and diluted with 3 liters of acetone. After standing for about 20 minutes, the hydrochloride salt that separates out is collected, washed with acetone and dried. A solution of the salt in about 800 ml of boiling water is filtered, cooled and made basic with aqueous sodium hydroxide solution. The brown base that forms is thoroughly mixed with Washed with water, dried and recrystallized from methanol, 14.98 g of diamine being obtained, melting point 318 ° -319 °

709881/0898

C. , 80 H 76 N , 44 69 , 85 4, 61 25th , 51 69 4, 25th

(Decomposition, softened at 270 °). Umrystallization of a 4.5 g i

A portion of this material from methanol and acetone and subsequent drying gives 3.09 g of the title compound,

Mp. 322-323 ° (decomposes softened at 320 °). ■

Analysis C ₁ -H ₁ -N ,. !

calculated: found:

Example 106 7-Methyl-8-phenyl-7H-pyrrolo [3,2-f] quinazoline-1,3-diamine

Treated similarly as described in Example 2 (Method A) 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 dispersion of about 50% sodium hydride in mineral oil and sets the salt 3 hours with 4.26 g of methyl iodide. The crude product is recrystallized from methanol (twice) and from acetonitrile, 3.54 g of the title compound are obtained, m.p. 295.0-296.5 ° (dec., softens at 288 °).

Example 107

8,9,10,11-tetrahydro-7H-pyrimido- [4,5- c] -carbazole-1,3-diamine

(a) To a partial solution of 91.88 g (4-nitro-phenyl) hydrazine 58.88 g of cyclohexanone and 0.34 ml of glacial acetic acid are again added to 1 l of boiling absolute ethanol. Man heats the dark brown-red solution for 1 hour and then cools • down thoroughly. The solid that separates out becomes

709883/0895

collected, washed with cold methanol and dried,
102 g of the crystalline 4-nitrophenylhydrazone
of cyclohexanone, m.p. 143-146. Remove the
Solvent from the combined ethanolic-methanolic solutions gives a slightly gununi-like solid which is recrystallized from methylene chloride, washed with hexane and dried, a further 20.8 g
Hydrazone yield, m.p. 138-141 ° (softens at 133 °).
W. Borsche, A. Witte and W. Bothe [Ann., 359 , 49 (1908); j CA., 2, 1716 ³ (1908)
for this connection.

CA., 2, 1716 ³ (1908)] report a m.p. 146-147 ° I

(b) 122.6 g of the abovementioned hydrazone are carefully heated; in 1.5 1 conc. Hydrochloric acid. When the reflux temperature is reached, vigorous bubbling occurs, with a brown solid separating out in a few minutes. ; The mixture is refluxed for 1 hour, cooled,
collect the solid, wash with water and dry.
Recrystallization of the crude product from methanol and drying gives 92.1 g of 6-nitro-1,2,3,4-tetrahydrocarbazole, melting point 171.5-173.0 ° (softens at 169 °). DS Deorha and SS Joshi
[J.Org.Chem., 2! £, 3527 (1961)] report a m.p. of
177 °.

(c) hydrogenation of 43.25 g of 6-nitro-1,2,3,4-tetra-hydrocarbazole ί in 750 ml of absolute ethanol with 50 g (wet weight) Grace

No. 28 Raney nickel, as described in Example 98, part b, gives 36.1 g of light pink solid.
This amine and another 26.7 g in a similar one! Experiments are combined and recrystallized from '• toluene, giving 55.95 g of 6-amino-; 1,2,3,4-tetrahydrocarbazole obtained, m.p. 146-150 °. RJ ^: Brinton et al, J. Chem. Soc. 1956 , 4783) presented this
tricyclic amine by Raney nickel hydrazine reduction
of 6-nitro-1,2,3,4-tetrahydrocarbazole and report ■

^{an Fp} · ¹⁵¹ - ¹⁵² ° 709883/0895. j

I The above amine (55.80 g) in 300 ml of methanol

j is acidified with excess isoproanolic chlorine

'hydrogen, dilute the solution with 2.6 1 water

free Xther and cool down. The salt is collected with

Ether washed and dried, giving 61.82 g

\ 6-Amino-1,2,3,4-tetrahydrocarbazole hydrochloride is obtained,

^! M.p. 285-288 ° (dec.).

(d) sodium dicyanamide (71.23 g, previously recrystallized from methanol), 71.27 g of 6-amino-1,2,3,4-tetra-hydrocarbazole hydrochloride and 2 1 1-octanol are heated on Reflux, distill about 230 ml of solvent to ensure anhydrous conditions, and heat another 21 hours at reflux. The hot reaction mixture is filtered and the insolubles are washed with hot 1-octanol. The combined octanolic fractions are cooled, then acidified with an excess isopropanolic hydrogen chloride, diluted with about 2.6 l of anhydrous Xther and cooled. The mustard-colored one Precipitate is collected, dried, washed twice with 400 ml portions of cold methanol (acidified with a few drops of isopropanolic hydrogen chloride), washed with ether and dried. One Suspension of the buff-colored hydrochloride in 1.5 l of water is treated with an excess of aqueous Sodium hydroxide solution and stir the mixture vigorously for about 1 hour. The base is collected, washed with water, dried and recrystallized from methanol, giving 24.66 g of buff-colored diamine, melting point 300-303 °, (softens at 297 °). A portion of 7 g of the base is recrystallized from methanol and dried, 6.17 g of the title compound are obtained, m.p. 303-306 ° (softens at 285 °).

709883/0895

m / 18 190

9 /

NMR (dDMSO): δ 1.67-1.97 (four proton multiplet, j -CH ₂ CH ₂ CH ₂ CH ₂ -), 2.63-3.17 (four proton I multiplet, -CH ₂ CH ₂ CH ₂ CH ₂ -), 6.92 (doublet, j J = 9Hz, 5 or 6H), 7.50 (doublet, J = 9Hz, 5 j or 6H), 11.07 (broad singlet, exchangeable , 7-H) ppm j

analysis

C. , 38 H 97 N 65 calculated: 66 , 33 5, 94 27 46 found: 66 5, 27

example

108

8,9,10,11-Tetrahydro-7- (phenylmethyl) -7H-pyrimido- [4,5- c] -carbazole-1,3-dimaine

200 ml of dry dimethylformamide, 6.33 g of 8,9,10,11-tetrahydro-7H-pyrimido [4,5-c] carbazole-1,3-diamine and 1.32 g of a dispersion of about 50% sodium hydride in mineral oil one stirs
about 1 hour. Then give one for about 5 minutes
A solution of 3.48 g of benzyl chloride in 5 ml of dry dimethylformamide is added and the mixture is stirred for a further 19 hours. One treats the ^;

Reaction mixture with 15 ml glacial acetic acid, removes the solution

the residue
medium and stir / with an excess of aqueous potassium carbonate

solution, washes with water and dries. Recrystallization of the solid twice from methanol gives 5.40 g of solid in two fractions. To isolate the diamine in the form of the
To ensure free base, stir 4.8 g of this material
in 60 ml of methanol with 1.37 g of sodium methylate for 2 hours. Diluting the suspension with 300 ml of water, washing the precipitate with water and drying results in a cream-colored
Diamine, m.p. 220-223 ° (softens at 218 °).

709883/0895 )

? 3

Recrystallization of the base from methanol gives 2.69 g of the title compound, melting point 223.5-226.0 ° as a hydrate, the Contains 1/5 molecule of water per molecule of diamine.

C. , 68 H 22nd N 18th 72 , 77 6, 24 20, 18th 72 6, 20,

Analysis C ₂₁ H ₂₁ N ₅ -0.20

calculated:
found:

Example 109

8,9,10,11 -Tetrahydro ^ -methyl ^ H-pyrimido [4,5-c] carbazole-

1,3-diamine

150 ml dry dimethylformamide, 4.62 g 8,9,10,11-tetrahydro-7H-pyrimido [4,5-c] carbazole-1,3-diamine and 0.96 g of a dispersion of about 50% sodium hydride in mineral oil the mixture is stirred for 1 hour under a nitrogen atmosphere. A solution of 2.84 g of methyl iodide is then added over a period of 10 minutes in 10 ml of dry dimethylformamide and stirring is continued for about 2 hours. Add 20 ml of glacial acetic acid and remove it Solvent. The residue is stirred for 2 hours with 12 g of sodium methylate-150 ml of methanol and the mixture is diluted with 750 ml of water. The solids are collected, washed with water, dried, recrystallized twice from methanol and dried thoroughly to give 1.96 g of the title compound, m.p. 288-292 ° (softens at 285 °).

709883/0895

Example 110

The ability of the compounds of formula I to inhibit bacterial growth in vitro is demonstrated by the following
Test procedure proven:

Prepare a stock solution or suspension of the test compound at a concentration of 2500 µg / ml by adding
a suitable solvent such as aqueous sodium hydroxide, aqueous lactic acid, methyl cellosolve, dimethyl sulfoxide, dimethylacetamide, ethylene glycol, dimethylformamide, i formamide, propylene glycol, acetone or methanol is used. Twice the dilutions are prepared by adding suitable amounts of sterile water to the solution or suspension of the test substance. 1 ml volumes of each dilution are placed in · Seed agar or Wellcotest Sensitivity Test Agar, reinforced with \ 5% hemolyzed horse blood (9 ml vol.) I cups in sterile Petri, so that plates obtained having different concentrations of the test compound. The hardened surfaces of each plate with the ^{Testorganis-:} men incubated and held for 18 hours at 35 ⁰ C. The in vitro
antibacterial effect of the tested compounds is obtained with; "minimal inhibitory concentration"(MIC); denotes what corresponds to the lowest amount of material (ug / ml) j which completely inhibits the test organisms.

The in vitro antibacterial activities of the compounds according to the invention are listed in Tables IV-VII,
which indicate the MIC values of various compounds,
which have been tested according to the procedure described above:

709883/0896

Table IV

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

'O Verb. according to R. phenyl I. H ₂ N ^ JL N-CH ₀ R MIC E. (Y / ml.) K.
pneumo- P. medium CD
OO
00 example 2-fluorophynyl N ^
x ^ N coil S.
para niae vulgaris (U 3-fluorophynyl. S. ί) (> 37 typhi 10031 68 9ü * · *. 4- fluorophenyl ^c am'eiis ■ 11737 B. O
3D O
00 2-chlorophenyl Sin.it h S. N.
cat.'ir- B. IGINA! to 2 3-chlorophenyl aurcus rlm.lis 1.95 1.95 7.81 B. (71 3 53-IHO 81.!) 3 0.488 1.95 0.122 0.976 Z 4th 1.95 0.244 0.976 0.061 0.488 (P
Ό
m 5 0.488 0.122 0.488 0.031 0.488 ff> Q 6th 0.244 1.95 0.061 0.976 0.488 0.976 7.81 CO σ 7th 0.244 0.244 0.0152 7.81 1.95 0.976 31.3 0.976 0.031 <0.0009 31.3 1.95 0.122 0.0038 0.976 • 0.061 0.976 0.244

Table IV (cont.)

Verb. According to example R

<O
OO
OO
GO

* N »

op

CO

8 9

10 11 12 13

14 15 16 17 18

4-chlorophynyl

2,6-dichlorophynyl

3,4-oichloropliciiyl

2-TJri f liioroinc thylphcnyl

3-tri fluoromethylphenyl

4-trifluoromethylphenyl

2-cyanophynyl

3-cyanophyllium

4-cyanophynyl

4-carbethoxyphenyl

3-nitrophenyl

MTC (Y / ml.)

N. S.

SS catar- Έ. paraaureus aureus rhalis coli typhi
Smith 53-180 8193 9G37 11737

0.976 0.244 0.0038 0.976 0.976
250 0.188>250> 250

0.976 0.488 0.061 3.90 31.3

K.

pneumo-

niao

10031

0.488 0.244 <0.0009 1.95

3.90

1.95 0.976 0.031 3.90 15.6

0.244 0.244 0.061 0.244 0.488

0.061 0.031 0.0038 0.122 0.488

0.244 0.122 0.0076 0.244 0.488

1.95 1.95. 0.488 7.81> 250

0.122 0.061 0.0152 0.488 0.976

-66 -

0.976

P.

vulgaris 6896 Ncditim ^a

0.122 0.976

15.6> 250

0.488 31.3

0.122 62.5

0.488 0.244 0.122 0.976 7.81 0.488 62.5

31.3

0.122 1.95

0.031 0.976

0.061 1.95

1.95> 250

0.122 3.90

Table IV (cont.)

2-M2thy.lphonyl S.
aureus
Smith S.
aureus
53-180 N.
catar-
rhalis
81 <> 3 MIC (Y / ml.) K.
pneumo-
niac
10031 P.
vulgaris
6896 .81 Medium ⁰ 3-methylphenyl 0.488 0.488 0.0152 *
E.
coil
9637 S.
para
typhi
11737 0.122 7, .95 B. Verb according to
Example " •
4-methylphonyl
2,4-dimethyl
phcnyl 0.976 0.488 0.031 0.976 3.90 1.95 1, .95
, 81 B. 19th 2,5-dimethyl
phcnyl 0.976
0.244 0.488
0.244 0.0152
0.0152 0.488 1.95 0.122
0.244 1,
7th B.
B. 20th 2,6-dimethyl
phcnyl 3.90 0.976 0.244 0.976
0.976 1.95
3.40 1.95 250 B. 21
ο 22
CO
00 3,4-dinicthyl
phcnyl 250 250 0.122: 31.3 125 15.6 > 250 5 B. ο 23
O 3,5-i) imothyl-
phonyl 1.95 0.976 0.122 250 > 250 0.488 62. 6th B. oo 24
CO
cn 2,4,6-trimothyl
phcnyl 0.976 0.488 0.031 1.95 31.3 0.244 15th B. 25th 2,3,5,6-Tctra-
methylphynyl 250 250 7.81 15.6 31.3 > 250 Bk> 26th 15.6 15.6 0.244> 250 > 250 3.90 > 250 31039
CQ 27 0.244> 250 > 250 28

R. S. tab Hurry IV (cont.) E. (Y / ml.) K. P. medium -J 4-isopropylphynyl aureus MIC coli S. pneuino- vulgaris B. B ^ 4-jt-butylphynyl Smith N. 9037 para niae 6896 B. CD Verb, acc 4- (methylthio) phenyl 1.95 S. catar- 7.81 typhi 10031 62.5 B. OJ 2-MctnOxyphenyl 7.81 aureus rhalis 250 11737 0.488 > 250 B. U) example 3-mothoxyphenyl 0.976 53-180 81.93 0.488 62.5 3.90 31.3 B. 29 0.976 0.976 0.244 1.95 > 250 0.122 3.90 30th 4-methoxyphynyl 3.90 3.90 0.976 0.488 3.90 0.244 7.81 B. 31 0.488 0.0.152 7.81 0.488 «A 32 2,3-nLmethoxy- 0.976 0.976 0.061 0.488 7.81 0.976 B. P. 33 phcnyl 0.976 0.976 0.061 OO 2,5-dimethyl 0.488 0.188 • 0.976 7.81 B. oo 34 phcnyl 0.244 0.0152 0.488 co 3,4-dimethyl
phenyl 0.244 0.976 15.6 3.90 B. * "** 35. 3,4- (methylene- 0.244 0.122 0.031 B. ο
co , dioxy) phenyl 0.244 0.488 3.90 1.95 co
ut 36 3,4,5-trimethoxy 7.81 0.122 0.031 7.81 0.061 31.3 phenyl 1.95 1.95 37 0.122 0.122 0.0152 0.976 15.6 7.81 38 1.95 0.244 0.122 3.90 39 0.061 0.0152

Tabel

Verb according to the example

40 41 42 43 44 45 46

47 48 49

50 51

4-thoxyphenyl 3-thiionyl 4-T hi a zo IyI 2-Pyri (linyl 3-f yi'i (liny I 4-P> yricUny.l

B cn / .o L * b_] tld.cn-3-yl

1-N.a] jhthal itiyl 2-naphthalenyl

2-methyl-1-liaphthaliiiyl

2-quinolinyl 8-quinolinyl

S.

aurcus Smith

1.95 0.976 0.488 0.97G 7.81 0.122 31.3

aurcus 53-180

0.488 0.976 0.244 0.488 0.97G 0.122 31.3

3.90 0.976

125

125

0.976 0.488

0.244 0.122

N.

catarrha.lis
8193

IV (cont.)

MIC (V / m l.)

E. coli

9037

0.122 1.95

0.0152 0.244

0.0038 0.244

<0.00 () 9 O.4H8

<0.0009 0.488

0.0038 0.214

1.95 125

0.0019 15.6 0.244 250 0.122> 250

0.0038 7.81 0.0152 0.244

7.81
0.976
0.976
0.244
0.488
0.488
> 250

62.5
> 250
> 250

7.81
1.95

K.

pneunio

niac

10031

3.90

0.061

0.122

0.061

0.122

0.1
15.6

22nd

0.122
0.122

P.

vulgar! s 6896

7.81 1.95 0.976 0.244 7.81 0.488> 250

0.976 31.3
7.81> 250
15.6> 250

7.81 7.81

medium

B B B A A A B

AWAY

IS »A ^ I

B->

Table IV (cont.)

Verb according to the example

3,5-dimethyl-4-isoxazolyl

n-Hcxyl Cyclohexyl

2-methyl-propynyl

2-phenylethyl 2-phenylvinyl

3,5-diniothoxyphynyl

2-thionyl

l-bromo-2-naphthalenyl

4-acetylphenyl 3-aninophenyl

S.

aureus Sriii th

1.95

31.3 7.81 1.95

_MIC (v / ml.)

S. catar- E. para-

aureus rlialis coli tvnhi

53-180 8193 9G37 IJ737

0.976 0.0152 0.976

15.6 0.488 31.3

3.90 0.0152 1.95

0.976 0.0038 3.90

1.95

250 250 250

1.95 0.976 0.122 3.90 15.6

0.488 0.244 0.061 0.976 I.95

0.244 0.061 0.0019 0.061 0.244

31.3 15.6 0.488> 250> 250

0.244 0.122 0.0076 0.488 0.976

0.488 0.244 0.061 0.244 0.976

K.

pneumoniae
10031

0.244

P.

vulgaris 689G

3.90

62 .5 3. 90 250 90 7th .81 0. 488 3. 81 7th .81 0. 488 7th

250

0.488 7.81

0.122 15.6

0.061 0.244

15.6> 250

0.061
0.122

1.95
1.95

Mediuni ^a B

B A

A B B

B B

IN »« J

CO

co

Verb according to the example

4 - (: methylsulfonyl) phenyl

4- (trifluoromethyl) phyl

Hydrogen ^ 2-methylpropyl

Totrahydro-2-furanyli

4-carboxyphenyl, sodium salt

tab Hurry IV (Cont.) 976 Cv / ml.) K.
pnoumo-
niac
10031 • Medium ⁰ MIC 90 S.
para
typhi
11737 0, P.
vulgaris
6896 B. S.
aureus
Smith S.
aurcus
53-180 N.
catar-
rhalis
8193 E.
coli
9637 976 0.976 0. 7.81 B. 0.122 0.122 0.0152 0. 976 62.5 1. 62.5 A. 0.976 0.244 0.031 3. 95 3.90 0. 1.95 A I 62.5 7.81 0.031 0. 3.90 0. 3.90 A 53
• 1.95 0.976 0.0038 0. 7.81 .122 3.90 3.90 0.976 0.0038 1. .122 , 95 , 244 , 488

250

250

62.5> 250

> 250> 250

250

Growth medium: A = Secd AGar with 5% humolyzed horse blood

B-Wollcotest Sensitivity Test Agar with 5% hemolyzed horse blood.

This compound is tested in the form of free diamine.

This compound, prepared as described in Example 5, is isolated and tested in the form of the hydrate, which contains 1/4 molecule of water per molecule of diamine, m.p. 198-199

Table IV (cont.)

This compound, prepared as described in Example 15, is isolated and tested in the form of the hydrate, which contains 1/4 molecule of water per molecule of diamine, m.p. 240 °.

^e This compound, prepared as described in Example 18, is isolated and tested as a hydrate containing 1/8 molecule of water per molecule of diamine, m.p. 246.

This compound is tested in the form of the dihydrochloride monohydrate salt. * This compound is tested as a monoacetate salt.

This compound is tested as the monohydrochloride hemihydrate salt.

This compound is tested as the monohydrochloride salt, 1/3 molecule of water per molecule Contains diamine salt.

'■> 72 ^ -J

Table V

In vitro antibacterial activity of 7-substituted 7H-pyrrolo [3.2- £] quinazoline -1,3-diamines

CO OO CD CaJ

NO

hydrogen S.
nurous
Sini th S.
nurouß
Π3-1Η0 N.
cntar-
rli.-i.lis
St. 93 MlC (Y / inl.) K.
pneumo
nia ο
1003.1. P.
vulßuris
GKi) G Medium* 4-cyanophenyl 31.3 31.3 0.214 E.
coli S.
pnra-
typlrl
1J 77.7 7.81 15.6 A. Verb according to
example 2-acetylphonyl 0.976 0.488 0.031 3.90 31.3 0.122 125 B. •1 4-acetylphenyl 0.061 0.031 0.0076 0.976 31.3 0.0152 0.976 B. 69 4-propionyl
phonyl 1.95 0.488 0.031 0.244 0.488 0.122 15.6 B. 70 2-cyanophenyl 31.3 7.81 0.031 0.976 7.81 31.3 > 250 B. 71 4- (methylsulfonyl) -
phcnyl 0.031 0.0152 0.0038 15.6 > 250 0.0152 0.488 BCJ 72 0.976 0.976 0.0152 0.122 0.122 0.244 15.6 BO
CO 73 0.976 7.81 74

Table V (cont.)

verb . according to 4-carbethoxy-
phcnyl Example yy 2-nitrophenyl 75 4-nitrophenyl 7G 2,4-dinitro
phenyl ^ .77 2-cyano-4-
niti'ophcnyl
3-methyl-4-
nitrophcnyl to 78
OO
OO 2-thiazolyl ^ 79
O
OO
co 80
cn 5-nitro-2-
pyridinyl 81 2-pyridinyl 82 2-pyrimidinyl 83 2-pyrazinyl 84 85

S. S.

aurcus aurcus
Sini th 53-lflO

125

G2.5

MTC (V / ml.)

N. S.
catar- E. pararhalis coli typhi 8,193 9637 11737

7.81

0.122> 250

0.244 0.244 0.031 0.97C 1.95

3.90 3.90 0.031 7.81 G2.5

0.007G 0.007G 0.0019 3.90> 250

0.488 0.488 0.244 15.G> 250

7.81 0.0152> 250> 2f) 0

K.

pneumoniae 10031

P.

vulgaris 689G

250

> 250

0.488 0.244 0.0152 0.976 1.95

0.976 3.90 0.031> 250> 250

0.976 0.488 0.0076 0.488 0.976 0.244

15.6 3.90 0.061 7.81> 250

3.90 1.95 0.122 0.976 3.90

Medium ⁰

0 .244 3 .90 B. 273 ' f 0 .976 250 B. 1039 0 .031 > 250 B. t 1 .95 > 250 B. 0. , 976 > 250 B. 0. , 244 3. 90 B. 51. 3 > 250 B. 0.
0. 244
976 0.
> 250 976 OQ OQ 0. 976 3. 90 B.

2-JChj.nolinyl S.
aurcus
Smith T a b e lie V (cont.) (Y / ml.) K.
pncuino
niae
10031 P.
vulgaris
6896 Modium ^a 4-quinolinyl > 250 MIC S.
para
typhi
11737 > 250 > 250 B. 4-M ^ thy1-2-
quinolinyl 0.031 S.
aurcus
53-180 N.
catar-
rhalis
8193 E.
coli
9637 > 250 0.031 1.95 B. 7-chloi * o-4-
quinolinyl
7-Tri Γ 7 uoroinethy 1-
4-quinolinyl 62.5 > 250 0.122 > 250 0.97G 31.3 > 250 B. 0
Verb according to
Example _R 2-methyl-4-quino-
linyl 0.488
0.122 0.0152 0.031 0.488 > 250 0.488
0.244 250
250 B.
B. 86 S-methyl ^ -chino-
xalinyl 0.061 31.3 0.061 62.5 > 250
31.3 0.061 3.90 B. 87 2-tri fluoro-
methylphenyl 1.95 0.122
0.031 0.244
0.031 15.6
0.244 1.95 0.976 > 250 B. 88
■ «• a 2- Tr ifluoromothy1-
4-nitrophenyl 0.061 0.061 0.031 1.95 > 250 0.061 1.95 B. S H9
OO
00
<* »90
ο 2- Fhcnyl-4- quino-
linyl 0.122 0.488 0.122 7.81 0.976 0.488 125 B ^ o
CO Ξ 91
cn 31.3 0.031 0.0076 0.244 62.5 250 > 250 BO
U)
CO 92 0.122 0.061 31.3 > 250 93 7.81 15.6 250 94 95

Table V (cont.)

Verb according to the example

96 4-aminophenyT

97 2-benzothiazolyl

S.
aureus
53-J.H0 N.
catar-
rhalis
8193 MIC (Y / ml.) K.
pncuino
niac
10031 VU P.
6896 medium S.
aureus
Smith 0.244
125 *
E.
coli
9G37 S.
para
typlii
11737 0.031
62.5 0
> 250 .976 B.
B. 0.488
250 0.0152 0.244
0.488> 250 0.488
> 250

Growth medium: A = seed agar with 5% hemolysed rfcrdc blood.

B- = Wellcotest Sensitivity Test Agar with 5? » hemolyzed horse blood.

This compound was tested in the form of the hydrochloride salt.

IS »CJ

Tabel

VI

In vitro antibacterial activities of 7,8-substituted 7Η-Ρυγτο1ο [3.2- £ iquinazoline -1,3-diamines

Verb according to
Example " hydrogen Hithyl H ₂ N 5 0 .3 R ¹ E.
co I MTC (Y / ml .) .6 K.
pneumo
nia ο
10031 P.
vulgaris
GHi) G .6 medium 98 methyl methyl S.
nurous ι
Smith! S.
UIf (MlS
13-1 HO 0 .3 _k
NK
ψ 3. i
7th S.
para
tvphi
11737 .95 3.90 15th .97G B. 709883 99 B cncyl methyl 31.3 31 O .97G N.
catar-
fhalis
H1 i) 3 0. 90 15th .90 0.244 0 .6 B. 380/1 100 3-cyano-
benzyl methyl 31.3 31 7th .0Gl 1.05 0. 244 1 , 90 0.244 15th , 90 B. cn 101 4-cyano-
benzyl methyl 1.95 .97G 0.0Eq 0. 488 3 < 81 0.061 3. 3 B. 102 2.5-ÜL-
methyl-
benzyl methyl 0.122 .81 0.122 1. 488 3, 0.244 31. • 103 0.976 0.0038 250 95 7th 15.6 > 250 31.3 0.061 > 250 1.95

-77 -

Table VI (cont.)

MIC (γ / ml.)

Verb. According to example η

S.

aurcus Smith

S.

aiireus 53-180

N.

catar-

rhalis

8193

E.

coli 9637

K.

pneuino
niae
10031

P.

vulgaris
689G

Benzyl Chloro 3.90 0.976 O.OGl 3.90 7.81

Hydrogen phenyl 7.81 15.6 62.5 G2.5

Methyl phenyl G2.5 125 31.3> 250> 250

0.244 31.3
31.3> 250
3.90> 250

to growth medium: B = Wellcotest Sensitivity Agar with 5% hemo.lysed horse blood.

Medi um

B 0 B

N)

-J CO

CD

CO

co

Table VII

cd connection according to ¹⁰ example

5

<o

109

In vitro antibacterial activities of 7-substituted-8,9,10,11 · tetrahydro-7II-pyrite nido [4,5-c] carbazole -1 , 3-diamines η

hydrogen

Benzyl methyl

NO

S.

aurcus Smith

62.5> 250 G2.5

S.

nurcus
53-180

125
250
62.5

N.

remove

rhalis

8193

MIC (Y / ml.)

E.

coil 9037

S.

paratyphi
11737

L25 125

0.122> 250 3.90> 250

K.

pncunio-

nine

10031

125
> 250
62.5

P.

6 H 90

> 250
> 250
> 250

\ Medium** _%

B B B

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

_ 79 _

CO O

CjO

Example 111 i

The synergistic effect that occurs when the inventive \

appropriate compounds against bacterial infections!

Mice co-administered with sulfomethazole will i shown on the basis of the following experiment:

The test materials are weighed in 0.5% aqueous carboxymethyl cellulose suspended, homogenized (tissue grinder made of glass) and diluted depending on the test plan. ;

i The mice (male, 18+; 1 g, CD-1 strain) are pre-weighed,; grouped, and intraperitoneally with 0.5 ml
standardized (LDqc + ^ 5%) bacterial suspension in 5% gastric: mucus infected and with single doses of the test substances ^; either at the time of infection or 6 hours after
Infection treated. The treated groups consist of
10 mice per dose range. Deaths are daily for 14 days
recorded long and the PD ₅₀ (mice are recorded at the time point
treated infection) and CD ₅₀ (Mar. ^u se be 6 hours
treated after infection) values, will be according to the procedure
by Reed and Muench [Amer. J. Hyg., 2T_, 493 (1938)]. '

709883/0895

Table VIII

^ Verb. according to

⁰⁰ example oo

16

16

In vivo antibacterial synergism values (mice) for

7,8-substituted-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines

Benzyl

4-cynnobenzyl

4-fluoro II

benzyl

4-cyano _f H

benzyl

H ₀ N

NO

away

or CD ₅₀ values, mg. per kg., po

organism

Hrs. C

Protons
inlrnTuTis 190 0 Protcufl
mirabilis 190 0 Proteus 0 mirabilis 3 Proteus 0 vulgaris 347

Cpcl. SM * ¹

22.5

9.8 22.7

> 200

8.2 7.4 9.9

43.2

SM / Cpd. ,

1.56 / 7.78 1.56 / 1.56

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

6.25 / 6.25 ⁰ ^

3.13 / 9.67 room

1.56 / XL2.5

0.78 /> 12.5 Ζλ

Table VIII (cont.)

Verb according to
example

IG

IG

00 CaJ

S ¹⁶

16

100

4- cyano- II

benzyl *

4-cyano. H

benzyl ¹

4-cyano II

benzyl *

4-cyano II

benzyl ¹

4-cyano- II

benzyl *

organism

.Hours. ^c .

Proteus
vüTp; nris 347 6th Eschorichia 0 coIi WJ.02
Escheri clii.a G

Benzyl

coli W-1U2

Pro to t is 0

mirabTfis l!) 0

Proteus
mirabiiis 190

Proteus 0

mirabiiis 190

Cpd.

SM ^d

> 400

18.6

36.6

60

95

356

7.61

14th

5.1

SM / Cpd.

25 / 5.07 12.5 / 4.66 6.25 / 8.83 3.11 / 7.28

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

100/37

50/37

25/89

12.5 / 50

3.11 / 2.44 1.56 / 3.39 0.78 / 8.78 0.39 / XL2.50

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

1.56 / 3.11

Table VIII (cont.)

Verb according to the example

15 69

81

3-cyano-H

benzyl * »

4-cyano-H

phenyl »

2-ihiazolyl "II

organism Hours.· Proteus 0 mirabilis 190 Proteus 0 mirabilis 190 Proteus 0 mirnbilis 190

Cpd. . SM *

8.8

7.6

6.25

12.5

SM / Cpd.

1.56 / 2.67

3.11 / 2.55 -Y

1.56 / 9.39 <*)

0.7H />]. 2.5 - ♦

0.39 /> 12.5 2

3.11 / 6.25 CO 1.56 / M2.5

This value corresponds to the dose that is required to cut half of the mice before death
protect if the mice are treated immediately after infection.

This value corresponds to the dose that is required to cut half of the mice before death
protect if the mice are treated 6 hours after infection.

This value corresponds to the number of hours between the infection and the treatment of the Mice perish.

SM = sulfomethazole

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

This compound, prepared as described in Example 16, is tested and isolated in the form of the hydrate, which contains 1/5 molecule of water per molecule of diamine, m.p. 247-253 ° (softens be / 150 °).

This compound, prepared as described in Example 15, is isolated and tested in the form of the hydrate, which contains 1/4 molecule of water per molecule of diamine, m.p. 240.

Groups of 5 mice in each dose range are used in this experiment.

Example 112

The antimalarial effects of the compounds of Formula I are illustrated using the test procedure described below and proven:

When using young ICR / HA Swiss mice and a standard inoculum from Plasmodium berghei KBG 173, one can

j uniform disease that is 100% untreated

j Animals are fatal within 6 to 8 days, whereby the! mean survival time is 6.2 days. The experimental animals ; weigh 18 to 22 g, but weight variations are limited to 2-3 g in any test or control group. All animals used in the experiments are about the same age. The test animals are in plastic cages housed with metal lids, received a standard laboratory diet and water ad libitum.

The test animals are intraperitoneally 0.5 ml of a 1: 100 dilution of heparinized heart blood with a A minimum of 90% parasite cells (4 10 cells), obtained from donor mice, injected one week beforehand had been infected with Plasmodium berghei. The donor base is maintained by separating weekly Inoculate groups of mice with 0.5 ml of a 1: 500 dilution of heparinized heart blood.

The test compounds are dissolved or administered in suspension in peanut oil. A single dose is given subcutaneously 72 hours after infection with Plasmodium berghei ver ^ hands off. At this point a 10-15% parasitemia has developed; the disease is manifest, but has not yet developed enough debility to assess the host animal's response to the toxic effects of the investigated Alter drug. As the treatment for 3 days

709883/0895

M / 18 190

delayed so that the infection spreads well '

and death in untreated control animals within!

Occurs 6 to 8 days, this system is likely for the too;

ι maximum connection to be tested. ·

To discover factors such as changes in Plasmodium berghei infectivity or susceptibility; of the host animal, or to rule out technical errors ^:

becomes a group of infected animals treated with pyrimethamine ^:

Cans were treated, the survival time significantly ^': increase, used in each experiment as a positive control.

In each experiment, the test compounds are administered in graduated doses. For highly active connections one follows Increasing the dose usually increases the survival time of the treated mice. However, if an active connection is toxic to the living being, this toxicity can be a limiting factor; constant increases in dose enlarge also the toxic effects and can lead to a reduction in survival time. Deaths before Day 6, when the untreated animals begin to die, are considered non-parasitic and serve as a base for toxicity assessments. Treated animals are observed for 60 days. Animals that survive this period, are considered cured. When calculating the mean survival time, deaths due to toxicity are used and animals that survive 60 days are not included.

Compounds are said to be active when they have a cure or significant healing in at least one animal Extension of the survival time of the treated animals compared to the mean survival time of the untreated Control animals cause no drug-related (toxicity) deaths at the active dose.

709883/0895

ήΟΙ

The results regarding the antimalarial effect of the Compounds according to the invention are listed in Tables IX, X and XI.

.7u.a8.8 3 / oa «----

Tabel

IX

Activity of 7- (substituted) -methyl-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines against Plasmodium berghei KBG 173 malaria in mice (all doses are mg / kg, subcutaneous)

Verb according to
example - · - ■ R. . H ₀ N I N-CH ₀ R lowest
healing dose
(cured / treated) (2/5) ^d
' (3/5)
(1/5) AMST ^b Kl
to 2
3
4th Phenyl ⁰
2-fluorophynyl
3-Fluorophcny1 H ₀ N 20th
10
10 (2/5) 10.9
9.8
8.3 1039 - »4
O
(O 5 4-Fluorophynyl ^e highest,
non-lethal
Dose a lowest dose,
which all mice
heals 5 (5/5) 7.1 dose 883/0895 6th 2-chlorophenyl 160
.80
40 80
80
40 20th (2/5) 8.3 20th ^d
5
10 7th 3-chlorophenyl 80 20th 2.5 (2/5) 7.7 2.5 8th 4-chlorophenyl 160 20th 10 (2/5) 8.1 5 10 3,4-dichlorophenyl 160 10 2.5 10.2 1.25 40 20th 5 40 10 2 ^

-χ.

Table IX (cont.)

link

according to

example

12th

14th 15th 16 ro 98 19th CD co 20th O 21 CD

27

29 32 34

3-trifluoromethylphenyl

2-cyanophynyl

3-cyanophynyl

4-C yano phenyl * »

3-Nitrophynyl ^h

2-methylphenyl

3-methylphenyl

4-methylphenyl

2,5-dimethylphenyl

2,4,6-trimethylphynyl

4-isopropylphynyl 2-methoxyphenyl 4-methoxypheny1

highest, non-lethal

IGO 40

320 IGO G40 ¹ 80

20 160 160

lowest dose,
which all mice
- heals

lowest
healing dose
(cured / treated)

(1/5)

AMST

7.5

DOS

40 • 10 10 (1/5) 8.9 10 10 ~ 1. 25 (2/5) 9.6 1.25 20th 5 (1/5) 8.4 10 20th 2. 5 (3/5) 7.4 2.5 40 40 (3/5) 8.4 40 40 5 (-1/5) G. 9 5 20th 10 (2/5) 7.5 5 40 10 (3/5) 7.9 5 20th 5 (3/5) 7.3 2.5 10 (1/5) 10.2 10 10 (3/5) 10.5 10 ISj 5 (2/5) 11.2 5 <*>
O
O
co

Table IX (cont.)

Connection according to the example

37 39

43 44

50 51 53 54 55

3,4-dimethylphenyl

3,4,5-trimethylphenyl

2-pyridinyl 3-pyridinyl

O
co 45 4-pyriUinyl OO
OO 47 1-naphthalenyl co 48 2-Napiithaliny.l O OO 49 2-methyl.-l-naph- \ D
ewm tha.lt nyl

2-quinolinyl 8-quinolinyl η.-hexyl cyclohexyl

2-methyl-propenyl

highest non-lethal dose a

80 160

80 160

160

160 40 64O ¹

lowest dose, lowest

the dose healing all mice

heals (healed / treated) _AXfC _b _, _ Δη bt

20 160

80 160

20 40 20

20 640

(1/5)

40

(2/5)

20th (2/5) 80 (3/5) 80 (3/5) 5 (2/5) 20th (V5) 20th (5/5) 1.25 (2/5) 5 (1/5) 320 (2/5) 640 (3/5)

6.9 7.1

11.6 8.3 9.7 9.2 7.3

6.9 1.25 6.4 5 9.5 160 8.5 4 <£ 9.3 Ca)
320- *
CD
CO
CO

-K-

Table IX (cont.)

link
according to the example R. highest,
non-lethal
Dose a lowest dose,
which all mice
heals. 56 2-phenylethyl 04O ¹ 320 61 4-acetylphenyl 40 20th 63 4- (methylsulfonyl) -
phenyl - 66 2-methylpropyl ^ - CD
co Il
00
u> 2,6-dichlorophynyl
2-Tri f .1 uoroinethyl-
phcnyl lGO ^k
40 40 ^k
10 3,4-pimethylphenyl 80 ^k 10 ^k OO
cd 31
cn 4- (Mothylthio) -
phonyl 4O ^k 20 ^k 33 3-methoxyphynyl 40 40 38 3,4- (methylenedi-
oxy) phenyl - 41 3-ihienyl 320 ^k 160 ^k 62 3-aminophenyl 80 20th 64 4-trifluoromethoxy
phenyl 10 10

lowest
healing dose (cured / treated)

IGO (3/5)

2.5 (4/5)

(1/5)

5 ^k (1/5) 1.25 (1/5)

5 ^k (2/5) 2.5 ^k (4/5)

(1/5)

(2/5)

20 ^k (3/5)

(3/5)

2.5 (2/5)

AMST "

10.7

12.0

6.5

8.1

7.3

6.5 ^k G.2 ^k

7.6 12.2

7.8 9.6

Tab 1 1 e IX (cont.)

Compound highest lowest dose, lowest
according to St-letale, the dose healing all mice

Example R ^ tI heals ( cured / treated ) AMST ° Dosi s

17 4-carbethoxyphenyl 80 20 10 (1/5) 6.0

22 2,4-Dimethylphynyl 80 ^k 5 ^k 5 ^k (5/5) 7.6 ^k 2.5 ^k

^a Highest dose with no deaths from any reason.

«4 This abbreviation denotes the increase in the average survival time of those treated

ο animals compared to untreated control animals in the one in the adjacent column

^CD indicated dose.

oo,

oo This compound is tested in the form of the monocetate salt described in Example 2. '.

«^ This is the lowest tested; Dose S? ^e See Table IV, note c.

<° ^f See Table IV, Note d. on _σ

^ See Table VIII, note f.

See Table IV, note e. This is the highest dose tested. ^ See Table IV, note h.

Mice still alive on the 14th day are considered "cured", 60-day values are ^ not available. ^ j

Tabel

co co αο co

as co cn

link

according to the example

Activity of 7,8-substituted-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines against Plasmodium berghei KBG 173 malaria in mice (all doses in mg / kg, subcutaneous)

98 103

hydrogen

2,5-dimethylbenzyl

M othyl M ethyl

highest, non-lethal dose a

80 *

lowest dose that cures all mice

lowest
healing; dose
(gelioilt / bundled) AMST ^b dose

IGO (3/5) 13.9 160

1.2iS ^c (l / 5) G.8 ^C 1.25 *

Highest dose with no fatalities for any reason.

This abbreviation denotes the increase in the mean survival time of the treated animals compared with untreated control animals at the doses given in the adjacent column.

Mice still alive on the 14th day are considered "cured"; 60-day values are not IV available.

- 92 -

CO

CO CO

Tabel

XI

Activity of 7-substituted-7H-pyrrolo [3,2-f] quinazoline-1,3-diamines
Plasmodium berghei KBG 173 malaria in mice (all doses in mg / kg, subcutaneous)

H ₀ N

NO

^ Connection
_o according to example R. highest,
non-lethal lowest dose,
which all mice lowest healing
dose (3/5) AMST ⁰ dose CO 69 4-Cynrophynyl Dose a heals (gel lcilt / treated) (V5) 11 2.5 1883 / 70 2-acetylphenyl 20th 20th 5 (1/5) 9.2 40 O
00 71 4-ACOtylphenyl - 40 (4/5) 8.8 20th CD
en 76 2-nitrophenyl - 40 (5/5) 77 4-nitrophenyl - 40 (5/5) 28.3 40 80 3-methyl-4-nitro 640 640 160 (4/5) 13.9 160 81 2- itiiazoIyI 640 640 640 (1/5) 8.3 160 82 5-nitro-2-pyri-
dinyl - 640 —— - 160 ^C

m / 18 190

Table XI (cont.)

Highest dose with no fatalities for any reason.

This abbreviation denotes the increase in mean survival time of the treated animals compared to untreated control animals in the case of the ί indicated in the adjacent column given dose.

Mice that are still alive on day 14 are said to be "cured", no 60-day values available.

70 9883/0895

M / 18 190

Example 113

Single doses of 7- (phenylmethyl) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine (active ingredient) were intraperitoneally in 0.5% carboxymethyl cellulose at a constant Dose volume of 10 ml / kg administered to groups of 10 mice per dose level.

(Charles River COBS CD strain albino mice, male, weight 21.0-25.29). During the duration of the experiment ! (14 days) all mice were observed daily. The one from it; resulting LD dose was 54.5 mg / kg (95% confidence

limit of 48.6-93.4), all deaths occurred 4 to 5 days ^! after drug administration.

ι The joint caused decreased spontaneous locomotor activity, bradypnea, ptosis and stretching with the recruited

'■ Pages in all mice within 1 hour of ip transfer

! submission. In addition, coarse fur and a reduced tendency to clear feces were observed on day 2. These effects lasted for those with low levels

■ Doses of treated animals up to 6 days and of the animals treated with the highest dose 14 days. On the 14th day, all of the mice that were still alive were sacrificed and dissected. Macroscopically, the tissues appeared normal.

709883/0895

Claims (1)

R is hydrogen; Methyl; Ethyl; n-propyl; i-propyl; η-butyl; i-butyl; n-pentyl; n-hexyl, 2-methyl-1-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl; 2-phenylethyl; 2-phenylvinyl; Phenyl; Phenyl, Monosubstituted in the 2, -, 3-, or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, Ethyl, n-propyl, i-propyl, η-butyl, i-butyl, t-butyl, Methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, Ethylthio, carbethoxy, carboxyl, sodium carboxy or potassium carboxy; Phenyl monosubstituted in 3-position by amino or nitro; Phenyl disubstituted in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 positions through methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, chlorine, bromine, iodine, 709883/0895 ORIGMAL INSPECTED or fluorine; Phenyl, trisubstituted in 2,4,6- 'or 3,4,5-position by methyl, ethyl, methoxy,! or ethoxy; 2,3,5,6-tetramethylphenyl; 3,4- (Me-: ethylene-dioxy) -phenyl; 1-naphthalenyl; 2-naphtha- linyl; 2-methyl-1-naphathalinyl; 1-bromo-2-, naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyri- j dinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; i 3-thienyl; 4-thiazolyl; 3,5-dimethyl-4-isoxazolyl; , Tetrahydro-2-furanyl or benzo [b] thien-3-yl means, and, R is hydrogen; 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-trifluorir.ethyl-4-nitrophenyl; 2-trifluoromethyl-4-aminophenyl; 2-thiazolyl; 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; Is 2-phenyl-4-quinolinyl or 2-benzothiazolyl, and ' (b) X is methyl, phenyl or chlorine and Υ for hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzl or 2,5-dimethylbenzyl, with the prerequisite that when X is phenyl, Υ is only hydrogen or methyl can, and when X is chlorine, Y can only be benzyl. 709883/0895 Copy Compounds according to claim 1, characterized in that : that ι ! X represents hydrogen; ! , ι Y stands for -CH - R, and! R is hydrogen; Methyl; Ethyl; n-propyl, i-propyl; η-butyl; j i-butyl; n-pentyl; n-hexyl; 2-methyl - "; - propenyl; cyclo-butyl; cyclopentyl; cyclohexyl; 2-phenylethyl; 2-phenylvinyl; phenyl; phenyl, monosubstituted in 2-, 3- or 4-position by chlorine, bromine, iodine, fluorine, Trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, η-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, Carboxyl, sodium carboxy or potassium carboxy; phenyl, monosubstituted in 3-position by amino or nitro; phenyl, disubstituted in 2,3- 2,4-, 2,5-, 2,6-, 3,4- or 3,5- Position by methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, chlorine, bromine, iodine or fluorine; phenyl, trisubstituted in 2,4,6 or 3,4,5 positions by methyl, ethyl, methoxy or ethoxy; 2,3,5,6-tetramethylphenyl; 3,4- (methylenedioxy) phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-1-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] thiene- ^; 3-yl means. 3. Compounds according to claim 2, characterized in that that R; Phenyl, 2-fluorophenyl, 3-fluoropheny1, 4-fluorophehy1, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 709883/0895 COPY 2,6-dichloropheny1, 3,4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4-carbethoxyphenyl, j 3-nitrophenyl _# 2-methylphenyl, ; 3-methylphenyl / ι 4-methylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl, '2,6-dimethylphenyl, 3,4-dimethylphenyl, 2,4,6-trimethylphenyl, 2,3,5,6-tetramethylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4- (methylthio) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4 -Methoxyphenyl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4- (methylenedioxy) -phenyl, 3,4,5-trimethoxyphenyl, 4-ethoxyphenyl, 3-thienyl,
4-thiazolyl, 709883/0895 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, Benzo [b] thien-3-yl, 1-naphthalenyl, 2-naphthalenyl, 2-methy1-1-naphthalenyl, 2-quinolinyl, 8-quinolinyl, 3,5-dimethyl-4-isoxazoly1, n-hexyl, Cyclohexyl, 2-methy1-1-propeny1, 2-phenylethyl, 2-phenylviny1, 3,5-dimethoxyphenyl, 2-thienyl, i-bromo-2-naphthalenyl, 4-acetylpheny1, 3-aminophenyl, 4-methylsulfonylphenyl 4-trifluoromethoxyphenyl, hydrogen, isobutyl, Tetrahydro-2-furanyl, or 4- (sodium carboxy) phenyl means. Compounds according to claim 1, characterized in that X means hydrogen Y stands for R ¹ and R is hydrogen; Phenyl, monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, 709883/0895 Methylsulfonyl, trifluoromethyl or carbethoxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitro-, phenyl; 2-cyano-4-aminophenyl; 3-methyl-4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl-4-ainophenyl; 2-thiazolyl; 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; Means 2-phenyl-4-quinolinyl or 2-benzothiazolyl. 5. Compounds according to claim 4, characterized in that R 4-cyanophenyl, 2-acetylphenyl, 4-acetylphenyl, 4-propionylphenyl, 2-cyanophenyl, 4- (methylsulfonyl) -phenyl, 4-carbathoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 2-cyano-4-nitrophenyl, 3-methyl-4-nitrophenyl, 2-thiazolyl, 5-nitro-2-pyridinyl, 2-pyridinyl, 2-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 4-quinolinyl, 4-methyl-2-quinolinyl, 709883/0895 7-chloro-4-quinolinyl, 7-trifluoromethyl-4-quinolinyl, 2-methyl-4-quinolinyl, 3-methyl-2-quinoxalinyl / 2-trifluoromethylphenyl, 2-trifluoromethyl-4-nitrophenyl, 2-Pheny1-4-quinoliny1, 4-aminopheny1, 2-benzothiazolyl or Means hydrogen. 6. Compounds according to claim 1, characterized in that X is methyl, phenyl or chlorine and Y represents hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl or 2,5-dimethylbenzyl, with the prerequisite that when X is phenyl, Y can only be hydrogen or methyl, and when X is chlorine, Y can only stand for benzyl. 7. Compounds according to claim 6, characterized in that Y is methyl and X is methyl. 8. Compounds according to claim 6, characterized in that Y is hydrogen and X is methyl. 709883/0895 9. Compounds according to claim 6, characterized in that Y is benzyl and X is methyl. 10. Compounds according to claim 6, characterized in that that Y is 3-cyanobenzyl and X is methyl. 11. Compounds according to claim 6, characterized in that Y is 4-cyanobenzyl and X is methyl. 12. Compounds according to claim 6, characterized in that Y is 2,5-dimethylbenzyl and X is methyl. 13. Compounds according to claim 6, characterized in that that X is chlorine and Y is benzyl. 14. Compounds according to claim 6, characterized in that Y is phenyl and Y is hydrogen. 15. Compounds according to claim 6, characterized in that that X is phenyl and Y is methyl. 16. Process for the preparation of the compounds of the general formula wherein (a) X is hydrogen and for -ι what Y is -CH ₂ R or -R ¹ . R is hydrogen; Methyl, ethyl; n-propy ".; ir-propyl; η-butyl; i-butyl, n-pentyl, n-hexyl; 2-methyl-1-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl; 2-phenylethyl; Γ-phenylvinyl; Phenyl; Phenyl, monosubstituted in 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; Phenyl, monosubstituted in 3-position by nitro; Phenyl, disubstituted 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; Phenyl trisubstituted in 709883/0895 ΊΟ Ι 2,4,6- or 3,4,5-positions by methyl, xthyl,
Methoxy or ethoxy; 2,3,5,6-tetramethylphenyl; ' 3,4- (methylenedioxy) phenyl; 1-naphthalenyl; | 2-naphthalenyl; 2-methyl-1-naphthalenyl; i 1-brora-2-naphthalenyl, 2-pridinyl; 3-pyridinyl; ; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; i 3-thienyl; 4-thiazolyl; 3,5-dimethyl-4-isoxazolyl; ; Tetrahydro-2-furanyl; or benzo [b] thien-3-yl; | means, and ^; R phenyl, monosubstituted in the 2- or 4-position
by nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or carbethoxy;
2,4-dinitrophenyl; 2-cyano-4-nitrophenyl; 3-methyl-4-nitrophenyl; 2-trifluorioethyl-4-nitrophenyl;
2-thiazolyl; 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
means, and (b) X is methyl or phenyl and Y is methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl
or 2,5-dimethylbenzyl, with the prerequisite
is that when X is phenyl, Y is only methyl
can mean. 709883/0895 ! characterized in that compounds of the general formula: N-H wherein: X denotes hydrogen, methyl or phenyl, reacts with an alkali metal base, an alkali metal salt being formed forms, and this alkali metal salt in turn with a compound of the formulas RCH ₂ -Z or R ¹ Z implements, wherein R and R have the meanings given above and Z is a group leaving the molecule means. 17. The method according to claim 16, characterized in that that X is hydrogen and Y is -CH-R. 18. The method according to claim 16, characterized in that X is hydrogen b
Has meanings that X denotes hydrogen and Y denotes those given for R. 709883/0895 19. The method according to claim 16, characterized in that that X is methyl or phenyl. 20. The method according to claim 17, characterized in that the alkali metal base is sodium hydride and Z in the group -CH ₃ Z represents chlorine, bromine or iodine. 21. The method according to claim 18, characterized in that the alkali metal base is sodium hydride and Z in the group R -Z represents chlorine, bromine, iodine or fluorine. 22. The method according to claim 19, characterized in that the alkali metal base is sodium hydride and Z in the -CH-Z group represents chlorine, bromine or iodine. 23. Process for the preparation of compounds of the general formula wherein: 8.83 / _Q.8UR X is hydrogen, methyl, phenyl or chlorine] .and ι Y ^{1 is} hydrogen or -CH ₂ R, · wherein; R methyl; Ethyl; n-propyl; i-propyl; η-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-1-propenyl; Cyclobutyl; Cyclopentyl; Cyclohexyl; 2-phenylethyl; 2-phenylvinyl; Phenyl; Phenyl, monosubstituted in 2-, 3- or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, Methyl, ethyl, n-propyl, i-propyl, η-butyl, i-butyl, t-butyl, methoxy, xthoxy, n-propoxy, Trifluoromethoxy, cyano, methylsulfonyl, acetyl, Propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy or potassium carboxy; Phenyl monosubstituted in the 3-position by nitro; Phenyl, disubstituted 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; Phenyl, trisubstituted in 2,4,6- or 3,4,5 positions by methyl, ethyl, methoxy or Ethoxy, 2,3,5,6-tetraniethylphenyl; 3,4- (methylenedioxy) phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-1-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 is characterized in that an acid addition salt of a compound of the formula Y ¹ 709883/0805 wherein X and Y have the meanings given above, with an alkali metal dicyanamide at a temperature of about 185 ° bi,
Converts alcohol, of about 185 ° to about 210 aliphatic in a ⁰ C with the prerequisite that when X stands for chlorine, Y can only mean -CH-R. 24. The method according to claim 23, characterized in that X is hydrogen. 25. The method according to claim 24, characterized in that Y ^{1 represents} hydrogen. 26. The method according to claim 24, characterized in that Y ^{1 represents} -CH ₂ R. 27. The method according to claim 23, characterized in that X is methyl or phenyl. 28. The method according to claim 27, characterized in, that Y is hydrogen. 29. The method according to claim 23, characterized in that X stands for chlorine and Y has the meanings -CH-R
owns. 30. The method according to any one of claims 23 to 29, characterized in that the aliphatic alcohol is 1-octyl alcohol is. 709883/0895 M / 18 190 / is- 31. Process for the preparation of compounds of the general formula NH NY ² wherein: Y for 3-aminobenzyl, 2-aminophenyl, 4-aminophenyl, 2-cyano-4-aminophenyl, 3-methyl-4-aminophenyl or 2-trifluoromethyl-4-aminophenyl, characterized in that a compound of the general formula: NH NY ^v wherein: Y ^{3 is} 3-nitrobenzyl, 2-nitrophenyl, 4-nitrophenyl, 2-cyano-4-nitrophenyl, 3-methyl-4-nitrophenyl or 2-trifluoromethyl-4-nitrophenyl, reduced. 709883/0895 32. The method according to claim 31, characterized in that that the reducing agent is hydrogen in the presence of a noble metal catalyst. 33. A pharmaceutical agent consisting of a compound according to claim 1 together with a pharmaceutical compatible carrier. 709883/0895