GB1579678A - Pyrrolo (3,2-f)-quinazoline-1,3-diamine and compounds - Google Patents

Description

(54) PYRROLO 3,2-f QUINAZOLINE-1,3-DIAMINE AND RELATED COMPOUNDS (71) We, AMERICAN HOME PRODUCTS CORPORATION, a corporation organised and existing under the laws of the State of Delaware, United States of America, of 685, Third Avenue, New York 10017, New York, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to pyrrolo[3,2-f] quinazoline-1,3-diamine and to the 7 (substituted) and 7,8-(disubstituted) derivatives thereof, which compounds have biological activity. Also contemplated by this invention are pharmaceutical compositions containing the compounds and processes for making the compounds.

Various derivatives of 2,4-diaminoquinazoline and 2,4,6-triaminoquinazoline are described in the literature and are known to possess antifolic activity in bacterial systems. Such compounds are also known to exhibit antibacterial or antiprotozoal activity. For example, 2,4-diaminoquinazolines having an alkyl group at the 5-position and/or 6-position or having a trimethylene bridge between the 5- and 6-position possess antibacterial activity [see Hitchings et al., U.S. Patent 2,945,859 or De Graw et al., J. Med. Chem., 17, 762 (1974)]. 2,4-Diamino-6-I (arvlmethyl)aminol qnin- azolines; 2,4-diamino-6- ([(substituted aryl ) methyl] amino) -quinazolines; and 2,4 diamino-6-f ( (heterocyclic) methyl] amino)-quinazolines along with derivatives having a S-alkyl substituent or N6-alkyl substitutent exhibit antimalarial activity. [See Davoll et al., J. Med. Chem., IS, 812 (1972); Elslager et al., J. Med. Chem., 15, 1138 (1972); see also the review article by E. Elslager entitled, "New Perspectives on the Chemotherapy of Malaria, Filariasis, and Leprosy", Progress in Drug Research, 18, 99-172 (1974), in particular pages 111-116 and 152-154].

The pyrrolo[3,2-f]quinazoline-1,3-diamines of the invention differ from the known 2,4,6-triaminoquinazolines in that the 5-position and the N6 position of the latter are bridged by an ethylene moiety thus forming a novel tricyclic heterocycle.

The invention provides compounds of the general formula:

or a non-toxic acid addition salt thereof, wherein: either (a) X is hydrogen and Y is -CH2R or -R1 wherein R is hydrogen; methyl; ethyl; n-propyl; i-propyl; n-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, 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 the 3-position by amino or nitro; phenyl disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-positions by methyl, ethyl, n-propyl, methoxy, ethoxy, n-proDoxy, chlorine, bromine, iodine, or fluorine; phenyl trisubstituted in the 2,4,6 or 3,4,5-positions by methyl, ethyl, methoxy, or ethoxy; 2,3,5,6-tetra methylphenyl; 3,4-(methylene dioxy)phenyl; 1-naphthalenvl; 2-naph thalenyl; 2-methvl- 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; and R' is hydrogen; phenyl monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl, or carb ethoxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl; 2-cyano-4-aminophenyl; 3-methyl-4-nitrophenyl; 3-methyl-4-amino phenyl; 2-trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl-4-amino phenyl; 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; or (b) X is methyl, phenyl, or chlorine; and Y is hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl,'or 2,5-dimeth ylbenzyl; provided that when X is phenyl, Y may only be hydrogen or methyl, and when X is chlorine, Y may only be benzyl.

The terms " disubstituted and "trisubstituted ", as applied to substitutents on the phenyl ring of the compounds of Formula I, refer to compounds wherein the substitutents are identical for example, dichlorophenyl, dimethylphenyl, dimethoxyphenyl, trimethylphenyl or trimethoxyphenyl.

In subgeneric aspects, the invention comprises the following embodiments: (a) A compound of the general formula:

or a non-toxic acid addition salt thereof, wherein: R is as defined above; (b) A compound of the general formula:

or a non-toxic acid addition salt thereof, wherein: R1 is as defined above; (c) A compound of general formula:

or a non-toxic acid addition salt thereof, wherein: X is methyl, phenyl, or chlorine; and Y is hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl, or 2,5-dimeth ylbenzyl; provided that when X is phenyl, Y may only be hydrogen or methyl, and when X is chlorine, Y may only be benzyl.

Of special interest are the compounds 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine and the derivatives thereof having an 8-methyl or 8-phenyl substituent, which compounds can be used as intermediates for preparing the compounds of Formula I having a substituent at the N'-position.

The compounds of Formula I, wherein Y, X, R, and Rl are as hereinbefore defined or the salts thereof, inhibit the growth of bacteria in vitro as demonstrated in a standard tube dilution test employing seed agar or Wellcotest Sensitivity Test Agar fortified with 5% hemolyzed horse blood as the growth medium. (WELLCOTEST is a Registered Trade Mark) The compounds have shown activity in vitro against one or more of the following strains of bacteria: S. aureus smith, S. aureus 53-180, N. catarrhalis 8193, E. coli 9637, S. paratyphi 11737, K. pneumoniae 10031, or P. vulgans 6896. When tested in the above-described tube-dilution test, the compounds gave MIC values ranging from < 0.0009 8/my. to 250 8/my. against the test organisms.

In addition the compounds of Formula I exhibit in vitro antifolic acid activity, as demonstrated by the inhibition of Streptoccus faecalis ATCC 8043 grown in a folic acid medium.

The invention also provides compounds which will potentiate the antibacterial effects of sulfa drugs. When tested by the oral route of administration in mice, the following compounds gave a synergistic effect with sulfamethoxazole against bacterial infections: 7- (phenylmethyl) -7H-pyrrolo [3,2-f] quinazoline- 1,3 -diamine; 7- [4(4-fluorophenyl)methyl] -7H-pyrrolo [3,2-f] quinazoline- 1,3-diamine; 7- [ (4-cyanophenyl)methyl] -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine; 7- [ (3-cyanophenyl) methyl] -7H-pyrrolo [3,2-fl quinazoline- 1,3-diamine; 8-methyl-7- (phenylmethyl ) -7H-pyrrolo [3,2-f] quinazoline-1,3-diamine; 7- (4-cyanophenyl) -7H-pyrrolo [3 2-fl quinazoline-1.3-diamine; and 7- ( 2-thiazolyl) -7H-pyrrolo [3,2-f] quinazoline- 1,3-diamine.

In addition, the invention provides compounds which have antimalarial activity in vivo as evidenced by a standard blood schizonticidal test in mice infected with Plasm odium berghei KBG 173. The following compounds of Formula I have exhibited antimalarial activity when evaluated in the above-described test: (a) X is hydrogen and Y is -CH2R wherein: R is i-butyl; n-hexyl; 2-methyl-i propenyl; cyclohexyl; 2-phenylethyl; phenyl; phenyl monosubstituted in the 2-, 3-, or 4-position by chlorine, fluorine, methyl, cyano, or methoxy; 4-isopropylphenyl; 2-trifluoro methylphenyl; 3-trifluoromethylphenyl ; methylsulfonyl )phenyl; 4 acetylphenyl, 4-methylthiophenyl, 4-carbethoxyphenyl, 4-trifluorometh- oxyphenyl; phenyl monosubstituted in the 3-position by amino or nitro; 2,4-dimethylphenyl; 2,5-dimethylphenyl; 3,4-dimethylphenyl; 3,4 dimethoxyphenyl, 2,6-dichlorophenyl; 3,4-dichlorophenyl; 2,4,6-tri methylphenyl; 3,4,5-trimethoxyphenyl; 3,4- (methylene dioxy)phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl- 1-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; or 3 -thienyl; (b) X is hydrogen and Y is R' wherein R' is phenyl monosubstituted in the 2- or 4-position by nitro, or acetyl; 4-cyanophenyl; 3-methyl-4-nitro-phenyl; 2-thiazolyl; or 5-nitro-2-pyridinyl; (c) X is methyl and Y is hydrogen or 2,5-dimethylbenzyl.

Activity has also been demonstrated in vivo against P. cynomolgi infections in Rhesus monkeys as evidenced by the testing of 7 - (phenylmethyl) - 7H - pyrrolo [3,2-f]quinazoline - 1,3 - diamine; 7 - [(4 - methoxyphenyl)methyl] - 7H - pyrrolo [3,2-f]quinazoline - 1,3 - diamine; and 7 - [(2,5 - dimethylphenyl)methyl] - 7Hpyrrolo[3,2-f]quinazoline - 1,3 - diamine. The CDso values (CD = curing dose) of said compounds by 0.1 mg/kg/day, 0.316 mg/kg/day, and 1.0 mg/kg/day, respectively, after administration of the compound orally for seven days.

Activity against strains of P. berghei resistant to chloroquine, sulfones, cycloguanil, and pyrimethamine, is shown by the testing of 7-(phenylmethvl)-7H-pyrrolo[3,2-f]- quinazoline- 1 ,3-diamine and 7- [ (2,5-dimethylphenyl ) methyl] -7H-pyrrolo- [3,2-f] quinazoline-1,3-diamine in mice against such resistant strains.

Certain compounds also possess in vivo activity in mice (I.P.) against lymphocytic leukemia P-388 when tested according to the procedure described in Cancer Chemotherapy Reports, Volume 3, No. 2, page 9 (Protocol 1.200), September, 1972.

The compounds of Formula I wherein X is hydrogen and Y is CH,R showing such activity are: Dose R (mg/kg) T/C, % phenyl 10 149 4-cyanophenyla 20 138 4-methylsulfonyl 10 136 4-carbethoxyphenyl 10 141 3-nitrophenyl 5 163 4-methylphenyl 10 138 2,5-dimethylphenyl 10 142 3,4-dimethylphenyl 10 139 4-t-butylphenyl 5 125 3,4-dimethoxyphenyl 10 174 3,4,5-trimethoxyphenyl 10 163 3-aminophenylb 10 165 3-thienyl 10 147 2-pyridinyl 20 146 4-pyridinyl 15 142 2-quinolinyl 10 145 (a) Tested as the 1/5 hydrate; and (b) Tested as the dihydrochloride-monohydrate.

The processes contemplated by this invention are as follows: (A) A process for preparing a compound of the formula I wherein Y is other than hydrogen, X is other than chlorine, and the radical Y does not carry an amino group characterized in that a compound of the formula:

wherein: X is hydrogen, methyl, or phenyl; is reacted with an alkali metal base to form an alkali metal salt and the alkali metal salt is reacted with a compound of the formula: Y--Z (V) wherein Y is as defined immediately above and Z is a leaving group.

(B) A process for preparing a compound of the formula:

wherein: either a) X is hydrogen and Y1 is hydrogen; or -CH2R wherein R is as defined above excepting hydrogen and a radical carrying an amino group; or b) X is methyl, phenyl or chlorine and Y1 is hydrogen, benzyl, 3-cyanobenzyl, 4-cyanobenzyl or 2,5-dimethylbenzyl provided that when X is phenyl, Y1 is hydrogen and when X is chlorine Y1 is benzyl, characterized in that an acid addition salt (e.g. the hydrochloride salt) of a compound of the formula:

wherein: X and Y1 have the meanings defined with respect to Formula IX; is reacted with an alkali metal dicyanamide at a temperature of 185 to 215"C. in an aliphatic alcohol.

(C) A process for preparing a compound of the formula:

wherein: Y2 is 3-aminobenzyl, 2-aminophenyl, 4-aminophenyl, 2,4-diaminophenyl, 2 cyano-4-aminophenyl, 3 - methyl - 4 - aminophenyl or 2-trifluoromethyl 4-aminophenyl, characterized in that a compound of the formula:

wherein: Y3 is 3-nitrobenzyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 2-cyano 4-nitrophenyl, 3-methyl-4-nitrophenyl or 2-trifluoromethyl-4-nitro phenyl; is reduced.

In Process (A) the alkali metal base must be of sufficient strength to remove the proton from the indolic 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 Y-Z in order to attach the desired substituent at the 7-position. Examples of suitable alkali metal bases are sodium and potassium hydride, potassium t-butoxide, and lithium or potassium amide.

In the reagents Y-Z in which Y is bonded to Z via a methylene group, the preferred leaving group Z is a chlorine, bromine, or iodine atom. Other examples, of appropriate leaving groups (Z) are tosyloxy or mesyloxy. In the other reagents defined by YZ, the preferred leaving group is a fluorine, bromine, chlorine, or iodine atom.

The reaction is conveniently carried out in an inert solvent, such as dimethylformamide (DMF) or dimethylacetamide (DMA). In 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 Y-Z is added to the reaction mixture. In the reaction employing the reagent Y-Z, wherein Y is not linked to Z via a methylene group, it is preferred to heat the reaction mixture at a temperature above 50"C.

In Process (B), the appropriate 5-aminoindole (X), in the form of the acid addition salt, is heated at a temperature of 185--21SOC. with an alkali metal dicyanamide, such as sodium or potassium dicyanamide, in an aliphatic alcohol solvent. Best results are achieved if a > 2:1 molar ratio of the dicyanamide to the 5-aminoindole acid addition salt is employed. A molar ratio of about 2.5:1 is preferred. The reaction is conveniently carried out by heating the reactants at the reflux temperature of the solvent. Aliphatic alcohols having a boiling point of 185"C. to 21SOC. are preferred solvents. In a preferred method, the 5-aminoindole acid addition salt (X) is heated at reflux temperature in 1-octyl alcohol with sodium dicyanamide until the reaction is complete.

In Process (C), the reducing agent is any reagent capable of reducing an aromatic nitro group to an aromatic amino group and which will not affect other functions in the molecule. The preferred reducing agent is hydrogen in the presence of a noble metal catalyst, such as palladium-carbon. A pressure of one atmosphere is preferred.

The starting materials which are the 5-aminoindoles (X) and the reagent YZ are either known compounds or can be prepared by known methods for analogous compounds or by obvious modifications of the known methods.

The compounds of Formula I may be isolated and purified either in the form of the free bases or the acid addition salts. Methods for converting one such form to another will be obvious to one skilled in the art of chemistry.

For pharmacological use, the compounds of Formula I may be administered in the form of an acid addition salt of a non-toxic organic or inorganic acid. The salts may be prepared by methods well known in the art. Appropriate salts are those formed from the following acids: hydrochloric, hydrobromic, maleic, benzoic, pamoic, methanesulfonic, or acetic.

For pharmacological use, the compounds of Formula I may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice. For example, the compounds of Formula I may be administered orally in solid dosage forms, e.g. capsules, tablets, or powders, or in liquid forms, e.g. solutions or suspensions.

The compounds may also be injected parenterally in the form of sterile solutions or suspensions. Solid oral forms may contain conventional excipients, for instance, lactose, succrose, magnesium stearate, resins, and like materials. Liquid oral forms may contain various flavoring, coloring, preserving, stabilizing, solubilizing or suspending agents.

Parenteral preparations are sterile aqueous or non-aqueous solutions or suspensions which may contain various preserving, stabilizing, buffering, solubilizing, or suspending agents. If desired, additives, such as saline or glucose may be added to make the solutions isotonic.

The following examples are illustrative of the methods of making and using the compounds of the invention. All temperatures are in centigrade.

Example 1.

7-H-Pyrrolo[3,2-f] quinazoline- 1,3 -diamine A suspension of 168.6 g. 5-aminoindole hydrochloride (prepared by treating a methanolic suspension of 5-aminoindole with excess isopropanolic hydrogen chloride and diluting the salt solution with ether), 222 g. sodium dicyanamide (previously recrystallized from methanol), and 3 1. 1-octanol are refluxed with thorough stirring (under nitrogen) for 13 hours, and the hot mixture is filtered. The insolubles are washed with 500 ml. hot 1-octanol; the combined filtrates are diluted with an equal volume of ether and are acidified to pH 1 with isopropanolic hydrogen chloride. A fine, yellow precipitate is collected by filtration (slow) and is dissolved in 3 1. warm water. The aqueous solution is filtered through a coarse, sintered glass funnel. Upon cooling to ca. 25"C., the solution is washed with ethyl acetate and with ether. Basification of the solution with aqueous sodium hydroxide affords a yellow precipitate which is collected, thoroughly washed with water and dried to constant weight. The crude product (141.5 g.) is dissolved in ca. 10 1. methanol, treated with charcoal, and filtered thru Celite. (CELITE is a Registered Trade Mark). The methanolic solution is concentrated to a volume of ca. 400 ml., diluted with 200 ml. acetone and chilled.

The solid that separates is washed with cold acetone and is dried to provide 77.6 g. of the title compound, m.p. 263--2650 (dec.). An additional 17.2 g. of product [m.p.

262--264" (dec.)] are isolated by concentrating the crystallization mother liquor to a volume of ca. 40 ml., adding 40 ml. acetone, and chilling. Recrystallization of a 1.0 g. quantity of product [m.p. 263--2650 (dec.)] from methanol-acetone gives 395 mg. title compound, m.p. 264 (dec.); NMR (dDMSO): 7.14 (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, exchangeable, 7H) p.p.m.; A 9m5a/x EtOH232.5 max (g 24,300), 258 (E 22,120), 312 (e 8,090), 340.5 (e 7,420) nm; A 95% EtOH250 min (e 20,940), 279 (e 2,310), 330 (e 7,140) nm.

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 excess isopropanolic hydrogen chloride, and the solution is concentrated to a volume of ca. 100 ml., diluted with 200 ml. dimethoxyethane, and thoroughly cooled. The salt is collected and dried.

Weight 2.7 g. Concentration of the mother liquor provides an additional 3.8 g. salt.

Recrystallization of the two solids from methanol-ethanol yields 5.26 g. title compound as the monohydrochloride salt m.p. > 310 .

Analysis for: C10HqN . HCl Calculated: C, 50.96; H, 4.28; N, 29.72; Cl, 15.05 Found: C, 50.81; H, 4.22; N, 30.01; Cl, 14.88 Employing conditions similar to those above, A. Rosowsky and N. Papathanaso poulos [J. Org. Chem., 39, 3293 (1974)] converted naphthylamines into 2,4-diamino benzo [h] quinazolines.

Example 2.

Method A 7-( Phenylmethyl) -7H-pyrrolo [3,2-f] quinazoline-1 ,3-diamine A suspension of 13.95 g. 7H-pyrrolo[3,2-f]quin zoline-1,3-diamine in 600 ml. dry dimethylformamide is stirred under nitrogen as 3.70 g. ca. 50% sodium hydridemineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 9.30 g. benzyl chloride (8.5 ml.) in 20 ml. dry dimethylformamide is added during ca.

10 min. Stirring is continued for 5 hours and then 120 ml. gl. acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred thoroughly with excess aqueous potassium carbonate solution and filtered. The solids are collected, washed with water, and dried. The crude product is dissolved in 1.4 1. boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 125 ml. and chilled. The crystalline solid is collected, washed with acetone, and again recrystallized from methanol to afford 11.76 g. title compound, m.p. 2280, NMR (dDMSO): # 5.53 (singlet, N-CH2C0H5), 7.12 (doublet, J-3Hz, 9H), 7.23 (doublet, 8Hz, or 6H), 7.63 (doublet, J = 3Hz, 8H), 7.77 (doublet, J = 9Hz, 5 or 6H) p.p.m.; A 95% EtOH235 (e 26,900), 260 (e 28,620), 317 (E 9,640), 345 max sh (e 7,520) nm; A m5in/ Et H243 (e 26,020), 281 (e 2,430) nm. min A solution of 4.5 g. 7-(phenylmethyl)-7H-pyrrolo-[3,2-f]quinazoline-1,3-diamine (prepared in a manner similar to that described above) in 300 ml. methanol-3- ml. gl. acetic acid is concentrated to ca. 100 ml. total volume, cooled, diluted with 100 ml. acetone and filtered to give 2.5 g. salt. Concentration of the mother liquor to a volume of ca. 40 ml., dilution with 40 ml. acetone and filtration provide 2.0 g. salt. The two lots of salt are combined and recrystallized from methanol-acetone to give 2.88 g. title compound as the monoacetate salt, m.p. 226 (dec).

Method B 7- ( Phenylmethyl) -7H-pyrrolo [3,2-f] quinazoline- 1,3-diamine A suspension of 16.215 g. of 5-nitroindole in 1.251. dry dimethylformamide is stirred under nitrogen as 5.280 g. of ca. 50% sodium hydride-mineral oil dispersion is added. After stirring for 1.5 hours, a solution of 13.3 g. benzyl-chloride (12.1 ml.) in 25 ml. dry dimethylformamide is added and stirring is continued for 5 hours. After the addition of 175 ml. of acetic acid, the solvent is removed (in vacuo) and the residue is stirred with an excess of aqueous potassium carbonate solution and filtered.

The solids are collected, washed with water and dried. The crude product is dissolved in 2.5 1. boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 400 ml. and chilled. The crystalline solid is collected to afford 20.3 g. of solid, m.p. 104-105 . A 4.0 g. sample is recrystallized from methanol to give 3.6 g. of 1-benzyl-5-nitroindole, m.p. 1030.

Analysis for: C1rH2N2O2 Calculated: C, 71.41; H, 4.80; N, 11.11 Found: C, 71.31; H, 4.84; N, 11.02 A suspension of 15.3 g. of 1-benzyl-5-nitroindole, 1.0 g. palladium on carbon (10%), in 400 ml. ethyl alcohol is hydrogenated at 1 atmosphere until the hydrogen uptake ceased. The suspension is filtered and the solvenr removed. The resulting solid is dissolved in 50 ml. methyl alcohol made acidic with isopropanolic hydrogen chloride and the 5-amino-1-benzylindole, hydrochloride is precipitatzd by the addition of 450 ml. of ether; m.p. 244-245 dec.

Analysis for: C1sHl4H2. H Cl Calculated: C, 69.89; H, 5.87; N, 10.87; Cl, 13.37 Found: C, 69.54; H, 5.73; N, 10.91; Cl, 13.63 A suspension of 2.578 g. of 5-amino-1-benzylindole, hydrochloride, 2.228 g. sodium dicyanamide (previously recrystallized from methanol), and ca. 50 ml. dry octanol is refluxed with thorough stirring (under nitrogen) for 4 hours. The reaction mixture is filtered and the filtrate is diluted with 150 ml. ether. The precipitate which is obtained upon acidification with isopropanolic hydrogen chloride is filtered and is recrystallized from methanol to afford 0.3 g. of a salt. A solution of 3 ml. 1 N sodium hydroxide and 1 ml. methyl alcohol is thoroughly mixed with the above salt and the resulting compound is recrystallized from methanol to afford the title compound, m.p.

223224o, which is identical with the compound produced in Example 2, method A, based on mixture melting point and NMR spectral comparisons.

Examples 3-60.

Employing conditions similar to those recorded in Example 2, 7H-pyrrolo [3,2-f] - quinazoline-1,3-diamine, in dimethylformamide, is converted to the sodium salt with ca. 50% sodium hydride-mineral oil dispersion and the salt is reacted with the indicated halide for the specified period to provide the 7-(substituted)methyl-7-H-pyrrolo [3,2-f] quinazoline-1,3-diamines described in Table I.

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

Example Reax. Time Recryst.

No. R Alkylating Agent (hours) Solv.2 m.p., C 3 2-flourophenyl 2-fluorobenzyl chloride 5 M 215-216 4 3-fluorophenyl 3-fluorobenzyl chlotide 5 M 245-247 5 4-fluorophenyl 4-fluorobenzyl chloride 6 M-P-B, P 203 6 2-chlorophenyl 2-chlorobenzyl chloride 2 M 229 7 3-chlorophenyl 3-chlorobenzyl chloride 5 M 253-254 8 4-chlorophenyl 4-chlorobenzyl chloride 3 M 217-218 9 1,6-dichlorophenyl &alpha;,2,6-trichlorotoluene 5 D 307-308 (softens 298) 10 3,4-dichlorophenyl &alpha;,3,4-trichlorotoluene 4 N-W, M-P 253-255 (dec) 11 2-trifluoromethylphenyl (2-trifluoromethyl)benzyl bromide 5 M > 310 b (softens 230) 12 3-trifluoromethylphenyl (3-trifluoromethylphenzyl chloride 5 M, B 204-205 13 4-trifluoromethylphenyl (4-trifluoromethylphenzyl bromide 1 M c 14 2-cyanophenyl 2-cyanobenzyl bromide 5 A, M 176-180 15 3-cyanophenyl 3-cyanobenzyl bromide 5 Md 239-240 16 4-cyanophenyl 4-cyanobenzyl bromide 1 M 247-249 (softens 160) 17 4-carbethoxyphenyl 4-carbethoxybenzyl bromide e 5 E 212-215 18 3-nitrophenyl 3-nitrobenzyl bromide 5.5 D, M 249-251 19 2-methylphenyl 2-methylbenzyl chloride 5 M 241-242 TABLE I (Continued) Example Reax. Time Recryst.

No. R Alkylating Agent (hours) Solv.a m.p., C 20 3-methylphenyl 3-methylbenzyl chloride 6 M 223 21 4-methylphenyl &alpha;-chloro-p-xylene 2 M 213-214 22 2,4-dimethylphenyl 2,4-dimethylbenzyl chloridef 5 M 243-245 23 2,5-dimethylphenyl 2,5-dimethylbenzyl chloride 4 M g 269-271 24 2,6-dimethylphenyl 2,6-dimethylbenzyl chloride h 3.5 D,M 287-290 25 3,4-dimethylphenyl 3,4-dimethylbenzyl chloride aa 5 A 216-218 26 3,5-dimethylphenyl 3,5-dimethylbenzyl chloride i 3.3 M 261.5-263.0 27 2,4,6-trimethylphenyl 2,4,6-trimethylbenzyl chloride 4 M 256 28 2,3,5,6-tetramethylphenyl 2,3,5,6-tetramethylbenzyl chloride 3 D 281-282 29 4-isopropylphenyl 4-isopropylbenzyl chloride j 5 A 230-232 30 4-t-butylphenyl 4-t-butylbenzyl chloride 4 M,A 279-280 31 4-(methylthio)phenyl 4-(methylthio) benzyl chloride k 21 A 217-221 32 2-methoxyphenyl 2-methoxybenzyl chloride l 4 M 213-216 33 3-methoxyphenyl 3-methoxybenzyl chloride m 4 M 205-207 34 4-methoxyphenyl 4-methoxybenzyl chloride 4 P,M-A,M 205-206 35 2,3-dimethoxyphenyl 2,3-dimethoxybenzyl chloride n 3 M 205.0-207.5 36 2,5-dimethoxyphenyl 2,5-dimethoxybenzyl chloride o 3 M 228-230 37 3,4-dimethoxyphenyl 3,4-dimethoxybenzyl chloride bb 4 M 222-226 (softens 218) 38 3,4-(methylenedioxy)- 3,4-(methlenedioxy)benzyl chloride p 3,8 M q 235.5-237.5 phenyl TABLE 1 (Continued) Example Reax. Time Recryst.

No. R Alkylating Agent (hours) Solv.a m.p., C 39 3,4,5-trimethoxyphenyl 3,4,5-trimethoxybenzyl chloride 4 M 240-241 40 4-ethoxyphenyl 4-ethoxybenzyl chloride r 2 B-A 200.5-203.0 41 3-thienyl 3-thenyl bromide s 2 M, A 212-213 (softens 210) 42 4-thiazolyl 4-chloromethylthiazole hydrochloride t 24 M 254-255 43 2-pyridinyl 2-picolyl chloride hydrochloride t 2.5 M, A-M, P, 223-224 M 44 3-pyridinyl 3-picolyl chloride, hydrochloride t 4 Mu 227 45 4-pyridinyl 4-picolyl chloride, hydrochloride t 6 P 232-234 (dec) 46 benzo[b]thien-3-yl 3-chloromethylbenzo[b]-thiopene v 3 D 277.5-278.0 47 1-naphthalenyl 1-chloromethylnaphthalene 6 M 259-261 (dec) 48 2-naphthalenyl 2-chloromethylnaphthalenyl 4 M, M-E 300-330w (dec) (softens 250) 49 2-methyl-1-naphthalenyl 1-chloromethyl-2-methylnaphthalene 5 M 279-281 (dec) 50 2-quinolinyl 2-chloromethylquinoline, 6 M 208 hydrochloride t 51 8-quinolinyl 8-quinolinylmethyl bromide 5 Mx 220-221 52 3,5-dimethyl-4-isoxazolyl 3,5-dimethyl-4-chloromethylisoxazole 3.3 Md 270.5-271.5 53 n-hexyl n-heptyl bromide 50 P 154 54 cyclohexyl bromomethylcyclohexane 71 E-B, E-P 192 y TABLE I (Continued) Example Reax. Time Recryst.

No. R Alkylating Agent (hours) Solv.a m.p., C 55 2-methyl-1-propenyl 1-chloro-3-methyl-2-butene 5 A z 56 2-phenylethyl 1-iodo-3-phenylpropane 65 M 182-183 57 2-phenylvinyl cinnamyl bromide 3 A 224-226 58 3,5-dimethoxyphenyl 3,5-dimethoxybenzyl chloride cc 19 M, A 213-215.5 59 2-thienyl 2-chloromethylthiophen dd 2 A 203-205 60 1-bromo-2-naphthalenyl 1-bromo-2(bromomethyl)-naphthalene 4 Mee 263.5-265.0 (a) A = acetone, B = acetonitrile, D = dimethylformamide, E = absolute ethanol, M = methanol, N = nitromethane, P = 1-propanol, W = water; (b) This compound is isolated as the hydrate bearing three-fourths molecule of water per molecule of diamine; (c. This compound is isolated as the hydrate bearing one-third molecule of water per molecule of diamine and melts at 220-223 , but the melt is not completely clear until 270 at which temperature substantial decomposition occurred.

(d) The crude product is thoroughly triturated with hot water prior to recrystallization; (e) Addition of 4-bromomethylbenzoyl bromide in benzene to absolute ethanol-benzene, stirring for 1.5 hours, removal of solvent and distillation of the residue provide this bromide, b.p. 104-117 /2mm., m.p. 35-38 (cloudy). A. F. Titley [J. Chem. Soc., 1928, 2581] reported b.p. 165 /18 mm., m.p. 35-36 ; (f) This chloride, b.p. 91 /10 mm., is obtained by adding the corresponding alcohol in benzene to thionyl chloride-benzene-pyridine according to the method of Neuman [J. Am. Chem. Soc., 62, 2295 (1940)], R. B. Akin et al., [J. Am. Chem. Soc., 69, 1268 (1937)] recorded b.p. 116-118 /16 mm. and 86-87 /7mm.

(g) The crude product is recrystallized twice from methanol, washed with 2:1 N sodium hydroxide-methanol, with water and dried prior to final recrystallization fr'om methanol; TABLE I (Continued) (h) The alcohol is converted by the method of Neuman (see footnote f) to the chloride, b.p. 75-77/2 mm. V. F. Raaen and J.F. Eastham [J. Am. Chem. Soc., 82, 1349(1960) listed b.p. 75-80 /1 mm.; (i) This halide, b.p. 103-104 /15 mm. is synthesized by the method of Neuman (see footnote f). B. van Zanten et al., Rec. trav. chim., 79, 1211 (1960) [C. A., 55, 7403e (1961)] reported b.p. 100-110 /15mm.; (j) This compound contains < 13% of the o-isopropyl isomer based on NMR examination. Chloromethylation of cumene according to the procedure of G. Blanc, [Bull. soc. chim. [4], 33, 317 (1933), also Org. Reactions, 1,67] gives 4-isopropyl benzyl chloride containing < 11% 2-isopropyl isomer (NMR evidence); (k) The crude halide prepared by the procedure of R. F. Czaja et al., U. S. Patent 3,953,520 is distilled twice to yield an oil, b.p.

93-96 /1 mm. which is 94% 4-methylthiobenzyl chloride by gas chromatographic assay. M.W. Goldberg and M. Janpulsky. U. S.

Patent 2,624,738 recorded b.p. 83 /0.3 mm.; (l) This chloride, b.p. 77-79 /2 mm., is prepared by the method of Z. Horii et al., Yakugaku Zasshi, 77, 252 (1957) [C. A., 51. 8671c (1957)] who reported b.p. 88-89 /4 mm.; (m) This chloride, b.p. 70-74 /2 mm. is obtained by the procedure of Z. Horii et a., (see footnote 1). J. W. Cornforth and R. Robinson (J. Chem. Soc., 1942, 686) reported b.p. 112-115 /10 mm.; (n) This chloride, b.p. 103-104 /2 mm., is synthesized by the method of J. Harley-Mason and A. H. Jackson (J, Chem, Soc., 1954, 1165) A. Kaufmann and H. Muller, [Chem. Ber., 51, 123(1918)] recorded b.p. 128.5-129.0/11 mm. (with decomposition); (o) This chloride, m.p. 65-58 after recrystallization from hexane, is prepared by the procedure of J. Harley-Mason and A. H. Jackson (see footnote n)who reported m.p. 70-72 ; (p) This chloride, b.p. 93-95 /2 mm. is synthesized by the method of Z. Horii et al., (see footnote 1). Spath and Schmitt, Monatsch.

53/54, 469 [Beilstein, 19, II, 21] recorded b.p. 89-91 /1 mm.; (q) The crude product is recrystallized twice from methanol, stirred one hour with a solution of 3.00 g. sodium methoxide-350 ml. methanol, washed with water, dried and recrystallized from methanol; (r) This chloride is synthesized by the method of Neuman (see footnote f), b.p. 96-103/2-3 mm. A. L. Mndzhoyan et. al. [C.A., 55, 14466b (1961)] listed b.p. 102-105 /1 mm.; (s) The directions of E. Campaign and B. F. Tullar (Org. Syn., Coll. Vol. IV, 921) are used and the twice-distilled, lachrymatory product (b.p. 59-67 /2-3 mm., ca. 6:4 mixture of 3-thenyl bromide and 2-bromo-3-methylthiophene by gas chromatographic assay) is used directly in the alkylation reaction; TABLE I (Continued) (t) 2.2 Molecules of sodium hydride per mole of substrate are used in this preparation in order to liberate the alkylating agent from its salt; (u) The crude product is crystallized from methanol and converted to a salt with excess isopropanolic hydrogen chloride. Recrystallization of the salt from methanol is followed by regeneration of the base (with aqueous sodium hydroxide) and final recrystallization of the diamine from methanol; (v) This halide, m.p. 38-40 after distillation (b.p. 139-141 /7 mm.) and recrystallization from pentane is prepared by the method of G. Wolf and F. Zymolkowski [Arch. Pharm., 309, 279 (1976)]. W. J. King and F. F. Nord [J. Org. Chem., 13, 635 (1948)] recorded b.p. 152-153 /11 mm. amd m.p. 39-40 ; (w) This compound is isolated as a monohydrate; (x) The crude diamine is recrystallized twice from methanol, thoroughly washed with N sodium hydroxide, with water, dried and finally recrystallized from methanol to yield the product as the hydrate bearing one/eighth molecule of water per molecule of diamine; (y) This compound is isolated as the hydrate bearing one-eighth molecule of water per molecule of diamine; (z) This product melts at 166-170 , resolidifies and remelts at 183-186 ; (aa) This chloride, b.p. 86-87/8 mm. is prepared by the method of Neuman (see footnote f), R. B. Herr et al., [J. Am. Chem. Soc., 79, 4229 (1957)] reported b.p. 95-96 /10 mm.; (bb) This chloride, m.p. 51 (after trituration with ether-hexane) is prepared by the procedure of F. Binns et al., [J. Chem. Soc. [C], 1970, 1134] who reported m.p. 46-48 ; (cc) This chloride, m.p. 46-47.5 after recrystallization from hexane, was prepared as described by R. Adams, S. MacKenzie Jr and S. Loewe, J. Am. Chem. Soc., 70, 664 (1948) who recorded m.p. 46 ; (dd) The chloride b.p. 77.0-77.5 /18-20 mm. was prepared according to the method recorded by Toyo Koatsu Industrial Inc., Jap. Pat.

9585 (1962), [C.A., 59, 3896b (1963)] who recorded b.p. 84-86 /20 mm.; (ee) The crude product was dissolved in methanol and treated with sodium methylate before crystallization.

Example 61.

7- ( (4-Acetylphenyl ) methyl] -7H-pyrrolo [3,2-f] quinazoline- 1,3-diamine a) Employing the procedure of H. B. Hass and M. L. Bender [J. Am. Chem.

Soc., 71, 1767 (1949)] 54.43 g. of a-bromo-p-tolunitrile in 600 ml. benzene is reacted with 16.49 g. of sodium methoxide to provide 33.24 g. (4-cyanobenzyl)methyl ether, b.p. 114-117 /5-6mm. (Hass and Bender reported b.p. 101-102 /4 mm.).

To 5.93 g. methyl lithium in 300 ml. anhydrous ether is added a solution of 33.11 g. (4-cyanobenzyl)methyl ether in 150 ml. 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, shaken and the organic layer separated. The aqueous phase is extracted with ether and the combined organic fractions are washed with brine, dried (sodium sulfate) and freed of solvent. The residue is stirred with 300 ml. N hydrochloric acid for one day and allowed to stand at ca 250 for two days. Water (350 ml.) is added and the product is extracted into ether. After washing with brine, the ethereal extracts are dried (sodium sulfate) and freed of solvent. Distillation of the residue yields 23.5 g. (4-acetylbenzyl)methyl ether, b.p.

97-1040/1-2mm. [Hass and Bender, J. Am. Chem. Soc., 71, 1767 (1949) reported b.p. 107--1090/3.5 mm.].

The above (4-acetylbenzyl)methyl ether (23.44 g.) is refluxed 2 hours with 50 ml.

48% hydrobromic acid. Dilution of the reaction mixture with 150 ml. water is followed by extraction of the product into ether and the extracts are washed with brine and dried (sodium sulfate). Solvent is removed and the residue is distilled. The product, b.p. 106-122"/1 mm., upon standing for 5 days partially solidifies. The minor liquid phase is removed by decantation and the solid fraction is redistilled thereby affording 16.24 g. 4-acetylbenzyl bromide, b.p. 1081160/2 mm. [Hass and Bender, J. Am.

Chem. Soc., ibid. recorded b.p. 134--136"/5 mm.]. b) In a manner similar to that of Example 2, Method A, 7.97 g. 7-H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 350 ml. dry dimethylformamide is converted to the sodium salt with 2.31 g. ca. 50% sodium hydride-mineral oil dispersion and the salt is treated with 4-acetylbenzyl bromide (10.23 g.) in 10 ml. dry dimethylformamide.

After stirring for 3 hours, the reaction mixture is treated with 5 ml. gl. acetic acid and freed of solvent. The residue is stirred with excess aqueous potassium carbonate solution, washed with water, with ether, and dried. Two recrystallizations of the crude product from methanol and thorough drying provide 9.82 g. of title compound, m.p. 224--2250.

Example 62.

7-1(3 Aminophenyl ) methyl] -7H-pyrrolo[ 3,2-f] quinazoline- 1,3-diamine A mixture of 7.3 g. 7-[( 3-nitrophenyl)methyl ]-7H-pyrrolo[3,2-f] quinazoline-1,3- diamine in 500 ml. gl. acetic acid and 0.7 g. 10% palladium-carbon catalyst is hydrogenated at atmospheric pressure and ca 250. After ca. 2.5 hours, hydrogen absorption ceases and the reaction mixture is filtered. The filtrate is freed of solvent and the residue is stirred in excess aqueous potassium carbonate solution, collected, washed with water and dried. This material is recrystallized (twice) from methanol and dried to yield 3.55 g. triamine.

A solution of triamine (3.4 g.) in 50 ml. N hydrochloric acid is diluted with 100 ml. acetone and chilled. The salt that separates is washed with acetone and dried to yield the title compound as the dihydrochloride, monohydrate, salt, dec. 328".

Analysis for: C17H,gN6 . 2HCI . H20 Calculated: C, 51.65; H, 5.10; Cl, 17.94; N, 21.26 Found: C, 51.40; H, 4.77; Cl, 18.22; N, 21.17 Example 63.

7- [ (4-Methylsulfonylphenyl )methyl] -7H-pyrrolo [3,2-f] quinazoline- 1,3 -diamine a) A solution of 56.0 g. 4-methylsulfonyl toluene in 2 1. benzene (made) anhydrous by distillation of ca. 300 ml. solvent) is cooled to ca. 25 C. and is treated with 57.5 g. N-bromosuccinimide and then with 5 g. benzoyl peroxide. The solution is refluxed 1.5 hours and then is allowed to stand at ca. 250 for 16 hours. After removal of the crystalline solid by filtration, the filtrate is freed of solvent, and the residual oil is dissolved in methanol. Thorough chilling of the methanolic solution gives a crystalline product which is recrystallized from methanol to yield 21.0 g. (4-methylsulfonyl)benzyl bromide, m.p. 9495 [D. A. A. Kidd and D. E. Wright (J. Chem. Soc., 1962, 1420) prepared this compound by a similar method and reported m.p. 93--940]. b) In a manner similar to that of Example 2, Method A, 3.98 g. 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in ca. 250 ml. dry dimethyltormamide are reacted with 1.06 g. ca. 50% sodium hydride-mineral oil dispersion and then with 5.48 g. (4-methylsulfonyl)benzyl bromide for 6 hours. The crude product is recrystallized (twice) from methanol to afford 4.82 g. title compound, m.p. 248 .

Example 64.

7- [ (4-Trifluoromethoxyphenyl)methyl] -7H-pyrrolo [ 3,2-f] - quinazoline-1,3-diamine a) A solution of 20.16 g. 4-trifluoromethoxybenzoic acid in 160 ml. dry tetrahydrofuran is added dropwise to a stirred suspension of 4.61 g. lithium aluminum hydride in 160 ml. dry tetrahydrofuran. The mixture then is refluxed for 3.5 hours, cooled and 25 ml. N sodium hydroxide is added cautiously. After stirring for 0.5 hours, the reaction mixture is filtered and the insolubles are thoroughly washed with hot tetrahydrofuran. The tetrahydrofuran fractions are freed of solvent and the residue is distilled to yield 15.82 g. (4-trifluoromethoxy) benzyl alcohol, b.p. 98-99 /9-10 mm.

[W. A. Sheppard, J. Org. Chem., 29, 1 (1964) reported b.p. 108 /25 mm.].

A solution of 15.72 g. (4-trifluoromethoxy)benzyl alcohol in 170 ml. thionyl chloride is refluxed for 14 hours and excess thionyl chloride is removed in vacuo.

Distillation of the residue yields 7.96 g. (4-trifluoromethoxy)benzyl chloride, b.p.

70-74 /11-15 mm.

Analysis for: C8H6FSC10 Calculated: C, 45.62; H, 2.87 Found: C, 45.66; H, 2.87 b) A solution of 4.98 g. 7H-pyrrolo [3,2-f] quinazoline-1,3-diamine in 250 ml dry dimethylformamide is stirred with 1.32 g. ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours and then a solution of 5.79 g. (4-trifluoromethoxy)benzyl chloride in 10 ml. dry dimethylformamide is added. After stirring 3.5 hours at room ca.

250, 40 ml. gl. acetic acid are added and stirring is continued for 15 min. Solvent is removed in vacuo and the residue is stirred with excess aqueous potassium carbonate, washed with water, with ether, and dried. Two recrystallizations of the crude product from methanol yield 7.56 g. title compound, m.p. 205.0-207.5 .

Example 65.

7-Methyl-7H-pyrrolo[3,2-f] quinazoline-1,3-diamine A solution of 5,98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 200 ml. dry dimethylformamide is stirred under nitrogen and 1.58 g. ca. 50% sodium hydridemineral oil dispersion is added carefully. After stirring for one hour, a solution of 4.47 g. (2.0 ml.) methyl iodide in 10 ml. dry dimethylformamide is added and stirring is continued. Two hours later, 15 ml. gl. acetic acid are added and the reaction mixture is freed of solvent (in vacuo). The residue is stirred with excess aqueous potassium carbonate solution for several hours and the solids are collected, washed with water and dried. A solution of this crude product in 200 ml. water-l0 ml. gl. acetic acid is washed with ether. Basification of the acidic solution gives a precipitate that is washed with water and then is crystallized from methanol-acetone to yield 3.44 g. title compound as a hydrate bearing one-third molecule of water per molecule of diamine, m.p.

2500; NMR (dDMSO): 8 3.88 (singlet, 7-CH3), 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 6 H), p.p.m.; A 93% Et H234 (E 25,280), 258 (E 24,340), 317 ( 9,090), 345 max EtOH234 sh (e 7,810) nm; A 95% Et H243 (e 23,570), 280 (e 2,040) min 243 (e 23,370), 280 (e 2,040) nm.

A solution of 3.32 g. of 7-methyl-7H-pyrrolo[3,2-f] quinazoline-1,3-diamine in 50 ml. ethanol is treated with 3 ml. of gl. acetic acid. Addition of 250 ml. ether gives a precipitate that is recrystallized from methanol-ethanol to yield 3.07 g. title compound as the monoacetate salt, m.p. 247--2490 (dec.).

Example 66.

7-( 3-Methylbutyl ) -7H-pyrrolo [3,2-f] quinazoline- 1,3-diamine In a manner similar to that of Example 2, Method A, 3.98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in ca. 210 ml. dry dimethylformamide are reacted with 1.06 g. ca. 50% sodium hydride-mineral oil dispersion and then with 4.06 g. 1-iodo-3-methylbutane. The reaction time is four hours. The crude product is recrystallized from acetone and from acetone-methylene chloride to yield 2.58 g. diamine, m.p. 185195 (softens 1800).

A solution of 2.5 g. preceding diamine is dissolved in 100 ml. N hydrochloric acid-400 ml. methanol and the solution is concentrated to a volume of ca. 100 ml. and chilled. The salt that separates is recrystallized from methanol-ethanol to provide 1.70 g. title compound as a monohydrochloride, hemihydrate salt, m.p. 300 (dec.).

Example 67.

7- [ (Tetrahydro-2-furanyl)methyl] -7H-pyrrolo- [3,2-f] quinazoline- 1 ,3-diamine In a manner similar to that of Example 2, Method A, 3.98 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in ca. 260 ml. dry dimethylformamide are reacted with 1.06 g. ca. 50% sodium hydride-mineral oil dispersion and then with 3.63 g. tetrahydrofurfuryl bromide. After stirring the mixture at ca. 250 for 24 hours, 0.21 g. ca. 50% sodium hydride-mineral oil dispersion are added. Stirring is continued for one-hour, 0.73 g. tetrahydrofurfuryl bromide is added, and, after stirring for 6 hours, the reaction mixture is kept at ca. 250 for ca. 70 hours. Processing of the reaction mixture in the manner described in Example 2 (Method A) yields a brown gum which is dissolved in 40 ml. N hydrochloric acid. Dilution of the aqueous acidic solution with 40 ml. acetone gives crystals that are collected and twice recrystallized from methanol-acetone to yield 1.20 g. title compound as a monohydrochloride salt bearing one-third molecule of water per molecule of diamine salt, m.p. 310--3110 (dec.).

Analysis for: Ci,Hi7NO . HCl . 1/3 H20 Calculated: C, 55.30; H, 5.77; Cl, 10.88; N, 21.50 Found: C, 55.32; H, 5.65; Cl, 10.85; N, 21.85 Example 68.

7-(4-Carboxybenzyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, sodium salt A suspcnsion of 3.98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (20 mmoles) in 350 ml. dry dimethylformamide is stirred (under nitrogen) with 2.11 g. ca. 50% sodium hydride-mineral oil dispersion (44 mmoles) for 1.5 hours. 4-Bromomethyl benzoic acid (4.73 g., 22 mmoles) is added, and stirring is continued for 5 hours and the mixture is allowed to stand at ca. 25 overnight. The solvent is removed (in vacuo) and the residue is dissolved in 200 ml. water. After washing with chloroform and filtration, the aqueous solution is adjusted to pH ca. 4 with acetic acid and permitted 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. Dissolution of the resulting solid in dilute aqueous sodium hydroxide and acidification of the aqueous solution to pH ca. 5 with acetic acid yields a product which is washed with water and dried. This material (2.5 g.) is dissolved in 70 ml. N sodium hydroxide and the solution is filtered. Upon standing, a salt separates which is collected, washed with acetone, recrystallized from methanol and dried to yield 1.31 g. title compound as the hydrate, bearing one-fourth molecule of water per molecule of sodium salt, m.p. > 360".

Analysis for: ClRHI.,N"02Na . 0.25 H20 Calculated: C, 60.08; H, 4.06; N, 19.46 Found: C, 59.94; H, 3.88; N, 19.44 Example 69.

7-(4-Carboxybenzyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine A solution of 15.94 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 800 ml. dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50 /0 sodium hydridemineral oil dispersion for 1.5 hours. Addition of 10.66 g. 4-fluorobenzonitrile is followed by heating of the reaction mixture at 95" for 6 hours. Glacial acetic acid (40 ml.) is added and the solvent is removed in vacuo. The residue is stirred thoroughly with excess aqueous potassium carbonate solution, collected, washed with water and dried.

Two recrystallizations of the crude product from dimethylformamide, followed by washing with a small amount of dimethylformamide, with methanol and thorough drying, yield the title compound, m.p. 3440 (dec.), NMR (dDMSO): A 7.17 (doublet J = 9Hz, 5 or 6H), 7.42 (doublet, J = 3Hz, 9H), 7.76-7.95 (four protons multiplet, 5 or 6H, 8H and two protons meta to the cyano group), 8.09 (two proton doublet, J = 8Hz, two protons ortho to the cyano group) p.p.m.

Examples 70-95.

Employing conditions similar to those recorded in Example 69, 7-H-pyrrolo [3,2-f]quinazoline-1,3-diamine, in dimethylformamide, is converted to the sodium salt with ca. 50% sodium hydride-mineral oil dispersion. The salt is treated with the indicated halide for the period and at the temperature noted to provide the 7-substituted-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine described in Table II.

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

Reax.

Temp. Reax. Time Recrvst.

No. R Alkylating Agent ( C) (hours) Solv.a m.p., C 70 2-acetylphenyl 2-fluoroacetophenone 70 5 M 250-252 71 4-acetylphenyl 4-fluoroacetophenone 65-70 13 D 290 72 4-propionylphenyl 4-fluoropropiophenone 80 6 M, D 262-264 (dec) 73 2-cyanophenyl 2-fluorobenzonitrile 80 5 D-A,M 317-319 (dec) 74 4-(methylsulfonyl)phenyl 4-methylsulfonyl-fluorobenzene 75 5 D 309-310 (dec) 75 4-carbethoxyphenyl ethyl 4-fluorobenzoate 65 5 M, D 232 76 2-nitrophenyl 2-fluoronitrobenzene 90 5 M 296-299 (dec) 77 4-nitrophenyl 2-fluoronitrobenzene 70 5 Db > 340 78 2,4-dinitrophenyl 2,4-dinitrofluorobenzene 80 5 Dc 335(dec) 79 2-cyano-4-nitrophenyl 2-chloro-5-nitrobenzonitrile 95 6 D 343 (dec) 80 3-methyl-4-nitrophenyl 5-fluoro-2-nitrotoluene 85-90 4 M 267 (dec)d 81 2-thiazolyl 2-bromothiazole 110 4 D, Me 250 82 5-nitro-2-pyridinyl 2-chloro-5-nitropyridine 65 14 D 340 (dec) TABLE II (Continued) Reax.

Example Temp. Reax. Time Recryst.

No. R Alkylating Agent ( C) (hours) Solv.a m.p.; C 83 2-pyridinyl 2-fluoropyridine 110 6 Mf 264-265 (dec) 84 2-pyrimidinyl 2-chloropyrimidine 100 3.5 D 314-315 (dec) 85 2-pyrazinyl 2-chloropyrazine 94 6 D 283-284 86 2-quinolinyl 2-chloroquinoline 75 12 M 270-272 87 4-quinolinyl 4-chloroquinoline 95 6 D 286-287 88 4-methyl-2-quinolinyl 4-chlorolepidine 100 10 D 257-258 89 7-chloro-4-quinolinyl 4,7-dichloroquinoline 96 6 D 319-320 (dec) 90 7-trifluoromethyl-4-quinolinyl 4-chloro-7-(trifluoromethyl)quinoline 95 6 Mg 283 91 2-methyl-4-quinolinyl 4-chloroquinaldine 105 6 Bh 265 92 3-methyl-2-quinoxalinyl 2-chloro-3-methylquinoxaline 104 6 D, M 298-299 (dec) 93 2-trifluoromethylphenyl 2-fluorobenzotrifluoride 110 6 Af 236-237 94 2-trifluoromethyl-4-nitrophenyl 2-fluoro-5-nitrobenzotrifluoride 110 6 Mg 319-320 95 2-phenyl-4-quinolinyl 4-chloro-2-phenylquinoline 110 5 Mg 190-195i (a) A = acetone, B = acetonitrile, D = dimethylformamide, M = methanol; (b) The product is triturated with methanol after recrystallization; (c) The crude product is triturated with boiling acetone and with boiling methanol prior to recrystallization; (d) This compound is isolated as the hydrate bearing two-thirds of a molecule of water per molecule of diamine; TABLE II (Continued) (e) The curde product is thoroughly triturated with boiling water. The insoluble solids and the solids isolated from aqueous triturate upon cooling to room temperature are combined and recrystallized; (f) The crude product is thoroughly triturated with boiling water prior to recrystallization; (g) This compound is isolated as the hydrate bearing one-fourth molecule of water per molecule of diamine; (h) The crude product is triturated with boiling acetone prior to recrystallization; and (i) Compound starts gasing at 170 Example 96 7-(4-Aminophenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine A mixture of 3.20 g. 7-(4-nitrophenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, 200 ml. gl. acetic acid and 0.5 g. 10% palladium-carbon catalyst is hydrogenated at atmospheric pressure and ca. 25 . After about 1.25 hours, hydrogen absorption ceases, the mixture is filtered and the filtrate is freed of solvent. The residue is recrystallized (twice) from water and then is stirred with aqueous potassium carbonate solution.

Washing of the precipitate thus formed with water and drying is followed by recrystallization from acetone thereby providing 1.48 g. title compound, dec. 180-185 (softens 140 ) as the hydrate bearing one-fourth molecule of water per molecule of triamine.

Analysis for: C16H14N6.0.25 H2O Calculated: C, 65.18; H, 4.96; N, 28.51 Found: C, 65.34; H, 4.92; N, 28.37 Example 97.

7-(2-Benzothiazolyl)-7H-pyrrolo-[3,2-f]quinazoline-1,3-diamine To 3.98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine dissolved in 250 ml. dry dimethylformamide are added, with stirring under nitrogen, 1.15 g. ca. 50% sodium hydride-mineral oil dispersion. After stirring for 1.5 hours, 3.90 g. 2-chlorobenzothiazole are added and the mixture is heated at 95 for 3 hours. An additional 1.29 g.

2-chlorobenzothiazole are added and heating at 95 is continued for 11 hours. A third portion of 2-chlorobenzothiazole (1.29 g.) is added and heating at 95 is continued for 8 hours. The reaction mixture is processed as in Example 69 and the crude product is recrystallized (twice) from dimethylformamide and is thoroughly dried to yield 2.30 g. 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. 2-methylindole in 320 ml. conc. sulfuric acid is added 34.00 g. sodium nitrate during a period of 65 minutes keeping the reaction temperature at O5 . After stirring 10 minutes longer, the reaction mass is poured into 3 Kg. ice and, ca. 20 minutes later, the yellow solids are collected, thoroughly washed with water and dried. The crude product, in ca. 3 1. chloroform is flushed thru a 1 Kg. column of neutral activity III alumina. Removal of solvent from the chloroform eluates and drying of the solids provide 57.2 g. 2-methyl5-nitroindole, m.p. 169--1720 (softens 162 ). [W. E. Noland et al. J. Org. Chem, 28, 2262 (1963) prepared this compound by a similar procedure and reported m.p.

176.0-176.5 ].

(b) To Grace No. 28 Raney nickel catalyst (8.8 g. wet weight, after thorough washing with water and with absolute ethanol) in 30 ml. absolute ethanol is added a solution of 8.81 g. 2-methyl-5-nitroindole in 140 ml. warm absolute ethanol. The mixture is hydrogenated in a Parr apparatus at ca. 3 atmospheres pressure and ca.

290. Hydrogen absorption ceases in about 1 hour and the catalyst is removed by filtration through a Celite bed. The cake is washed thoroughly with boiling ethanol and the combined ethanolic fractions are freed of solvent. Recrystallization of the crude product from ethanol-water yields 5.55 g. 5-amino-2-methylindole as a mauve solid, m.p.

151.5-154.5 . [W. E. Noland et al., J. Org. Chem., 28, 2262 (1963) prepared this compound similarly and recorded m.p. 157--159"].

A solution of 5.44 g. of the above amine in 50 ml. methanol is cooled in an icewater bath and is treated with excess isopropanolic hydrogen chloride and then with 150 ml. anhydrous et

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

Example Reax. Time Recryst.

No. R Alkylating Agent (hours) Solv.a m.p., C 99 methyl methyl iodide 2 M 305-309 (dec) 100 benzyl benzyl chloride 19 M 267-270 101 3-cyanobenzyl 3-cyanobenzyl bromide 2 Mb 277-280 (dec) 102 4-cyanobenzyl 4-cyanobenzyl bromide 2 c 329-332 (dec) (softens 327) 103 2,5-dimethylbenzyl 2,5-dimethylbenzyl chloride 18 M, D 308-311 (dec) (a) M = methanol, D = dimethylformamide; (b) This reaction is conducted at 0 and the crude product is triturated (twice) with acetone prior to recrystallization; (c) This reaction is sonducted at 0 . The crude product is recrystallized from dimethylformamide and the two crops of brown solid isolated are combined and extracted successively with boiling acetonitrile and with boiling methanol. Concentration and chilling of the combined acetonitrile and methanol extracts yields a buff solid which is finally recrystallized from methanol.

Example 104.

8-Chloro-7-(phenylmethyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (a) Nitration of 6.66 g. oxindole in 25 ml. conc. sulfuric acid with 2.1 ml. fuming nitric acid is conducted according to the procedure of W. C. Sumpter et al., J. Amer. Chem. Soc., 67, 499 (1945). Crystallization of the crude product from 50% acetic acid and from methanol yields 3.85 g. 5-nitrooxindole, m.p. 240-242 .

(Sumpter et al. recorded m.p. 240-241 ).

(b) Pyrrolidine (600 g.) and 110.0 g. 5-nitrooxindole are refluxed 1.5 hours and the dark solution is allowed to stand at ca. 250 overnight. The yellow crystals that separate are collected, washed with ether and dried to give 143 g. solid. A 20 g. portion is recrystallized from methanol thereby providing 1-[(2-amino-5-nitrophenyl)acetyl]pyrrolidine, m.p. 210-211 .

(c) Benzaldehyde (51.16 g.) and 10.0 g. 1-[(2-amino-5-nitrophenyl)acetyl]pyrrolidine are combined and heated under a short distillation column for ca. 10 min.

During this period the distillation temperature rises from 100" to 1760 and approximately 15 ml. of distillate are collected. The reaction mixture then is cooled, poured into 700 ml. anhydrous ether and chilled. Recrystallization (methanol) of the solids that separate gives 9.70 g. 1-[[5-nitro-2-[(phenylmethylene)amino]phenyl]acetyl]pyrrolidine, m.p. 170-171 .

(d) A solution of 16.0 g. 1-[ [5-nitro-2-[(phenylmethylene)amino]phenyl]- acetyl]pyrrolidine in 400 ml. hot methanol is stirred under nitrogen and 16.0 g. sodium borohydride are added in portions during ca. 20 min. such that refluxing is maintained.

The reaction mixture is refluxed an additional 20 minutes and then is diluted with an equal volume of water. A yellow precipitate forms and the solid is collected, dried, recrystallized from methanol and dried to provide 13.2 g. 1-[[5-nitro-2-[(phenylmethyl)amino]phenyl]acetyl]pyrrolidine, m.p. 128-129 as the hydrate bearing oneeighth molecule of water per molecule aminoamide.

Analysis for: C1,H21N,O3 .0.125 H20 Calculated: C, 66.79; H, 6.27; N, 12.30 Found: C, 66.72; H, 6.36; N, 12.29 (e) Acetic acid (2.5 1.), 500 ml. N hydrochloric acid and 90.0 g. 1-[[5-nitro-2 [(phenylmethyl)amino]phenyl]acetyl]pyrrolidine are refluxed three hours and the reaction mass is concentrated (in vacuo) to a volume of ca. 0.5 1. and cooled. The yellow solid is collected and dried to afford 67.3 g. solid, m.p. 137--138". A 5.0 g. portion is recrystallized from methanol and dried to provide 3.50 g. 1-benzyl-5-nitrooxindole, m.p. 143--144"; NMR (dDMSO): 8 3.83 (two proton singlet, 3H, 3H), 4.97 (two proton singlet, -NCH2-), 7.10 (doublet, J = 9Hz, 7H-), 7.33 (five proton singlet, phenyl protons), 8.17 (two proton singlet, 4 and 6 protons) p.p.m.

(f) Phosphorus oxychloride (100 ml.), 5 ml. pyridine and 10.0 g. 1-benzyl-5 nitrooxindole are refluxed 3 hours and the reaction mass concentrated in vacuo (in hood) to a gum which is dissolved in 500 ml. chloroform and stirred with 0.5 1. saturated aqueous sodium bicarbonate solutions for 4 hours. Adjustment of the pH to Ca 9 with potassium carbonate is followed by stirring for one hour. The organic phase is separated, washed with brine, dried (magnesium sulfate) and flushed thru a 500 g. column of neutral, activity III alumina. Removal of solvent from the chloroform eluates gives a solid which is dried to produce 9.1 g. 1-benzyl-2-chloro-5-nitroindole, m.p.

106-107 , NMR (CDCl3): # 5.40 (two proton singlet, -N-CH2-) 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 refluxing and stirred solution of 25.7 g. 1-benzyl-2-chloro-5-nitrooxindole in 600 ml. methanol and 180 ml. toluene is treated with a solution of 45 g. commercial NaSH ( x H2O) in 320 ml. methanol during a period of 10 minutes and refluxing is continued. At subsequent intervals of 1/2 and one hour, the addition of NaSH ( x H2O) in methanol is repeated exactly and the reaction mixture is refluxed 2.5 hours longer.

Following filtration, the organic solution is freed of solvent and the residue is thoroughly washed with water and dried. The resulting solid (19.7 g.) is dissolved in 200 ml. acetone and the solution is acidified with excess isopropanolic hydrogen chloride and diluted with 1 1. anhydrous ether. A gum forms which is separated by decantation, thoroughly triturated with acetone and dried to afford 16.1 g. 5-amino-1-benzyl-2chloro-indole, hydrochloride, m.p. 228 (dec.).

Analysis for: C1,H1,ClN2 . HCl Calculated: C, 61.44; H, 4.81; Cl, 24.19; N, 9.56 Found: C, 61.16; H, 4.71; Cl, 23.78; N, 9.42 (h) A mixture of 14.65 g. 5-amino-1-benzyl-2-chloro-indole hydrochloride.

11.14 g. sodium dicyanamide (previously recrystallized from methanol) and 300 ml. l-octanol is refluxed 3 hours and then is allowed to stand at room temperature overnight. A solid (A) is separated by filtration, mixed with 200 ml. hot methanol and 400 ml. water and added to the mixture. Filtration of the mass yields a solid which, after washing with ether, melts at 280-2830.

The octanolic filtrate, from which solid A is removed, is diluted with 700 ml. anhydrous ether and acidified with excess isopropanolic hydrogen chloride. The salt that forms is recrystallized from methanol and then is stirred with 50 ml. methanol100 ml. N sodium hydroxide. Crude diamine is collected and, after washing with water and drying, melts at 280-2830. The solids melting at 280-2830 are combined, recrystallized from dimethylformamide, washed with methanol and thoroughly dried to give 4.26 g. title compound, m.p. 285--286".

Analysis for: C17H14ClN, Calculated: C, 63.06; H, 4.36; Cl, 10.95; N, 21.62 Found: C, 62.89; H, 4.34; Cl, 10.84; N, 21.58 Example 105.

8-Phenyl-7H-pyrrolo [3,2-f] quinazoline-1,3-diamine (a) Nitration of 9.66 g. 2-phenylindole [previously purified by recrystallization from toluene and by dissolution in anhydrous ether, treating with charcoal, filtration, and removal of solvent, m.p. 184186 (softens 1800)] in 200 ml. concentrated sulfuric acid with a solution of 4.67 g. sodium nitrate in 100 ml. concentrated sulfuric acid is conducted in the manner reported by W. E. Noland et al., J. Org. Chem. 31, 65 (1966). The crude product is recrystallized from methanol thereby yielding 8.28 g.

5-nitro-2-phenylindole, m.p. 192--1940. (Noland, et al., recorded m.p. 2012030).

(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 at ca. 3 atmospheres pressure and ca. 27 in a Parr apparatus. Hydrogen absorption ceases in ca. 3 hours and the reaction mixture, after dilution with ca. 300 ml. methylene chloride is filtered thru a Celite bed. The insolubles are washed with methylene chloride and with boiling ethanol. Removal of solvent from the combined organic solutions yields 6.51 g. 5-amino-2-phenylindole, m.p. 227--2290 (softens 217 ), Noland et al., J. Org. Chem., 31, 65 (1966), prepared this amine similarly and reported m.p. 234--2350.

Addition of excess isopropanolic hydrogen chloride to a solution of 6.42 g. 5amino-2-phenylindole in 125 ml. methanol is followed by dilution with 700 ml. anhydrous ether and chilling. The salt that forms is collected, recrystallized from methanol (acidified with several drops isopropanolic hydrogen chloride)-ether and dried to give 4.98 g. amine hydrochloride. Recrystallization of a 1.1 g. portion in the same manner provide 0.82 g. 5-amino-2-phenylindole, hydrochloride, m.p. 314--318" (dec., softens 280e).

Analysis for: C14H12N . HCl Calculated: C, 68.71; H, 5.35; Cl, 14.49; N, 11.45 Found: C, 68.48; H, 5.32; Cl, 14.50; N, 11.49 c) Sodium dicyanamide (22.26 g., previously recrystallized from methanol)..

24.47 g. 5-amino-2-phenylindole hydrochloride and 700 ml. l-octanol are heated to reflux with stirring, 100 ml. solvent are distilled to assure anhydrous conditions, and refluxing is continued for 3 hours. The hot reaction mixture is filtered and the insoluble are washed with boiling l-octanol. The combined octanolic fractions, after cooling, are treated with 25 ml. concentrated hydrochloric acid and diluted with 3 1. acetone. After standing ca 20 minutes the hydrochloride salt that separates is collected, washed with acetone and dried. A solution of the salt in ca. 800 ml. boiling water is filtered, cooled, and basified with aqueous sodium hydroxide solution. The brown base that forms is thoroughly washed with water, dried and crystallized from methanol to yield 14.98 g. diamine, m.p. 318--3190 (dec., softens 2700). Recrystallization of a 4.5 g. portion of this material from methanol and from acetone, followed by thorough drying yields 3.09 g. title compound, m.p. 322--323" (dec., softens 320 ).

Analysis for: C,H1,N Calculated: C, 69.80; H, 4.76; N, 25.44 Found: C, 69.85; H, 4.61; N, 25.51 Example 106.

7-Methyl- 8-phenyl-7H-pyrrolo [3,2-f] quinazoline- 1,3 -diamine In a manner similar to that recorded in Example 2 (Method A), 6.88 g. 8-phenyl 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 300 ml. dry dimethylformamide is treated with 1.44 g. Ca. 50% sodium hydride-mineral oil dispersion and the salt is reacted with 4.26 g. methyl iodide for 3 hours. The crude product is recrystallized from methanol (twice) and from acetonitrile to give 3.54 g. title compound, m.p. 295.0-296.5 (dec., softens 288 ).

Example 107.

The ability of the compounds of Formula I to inhibit the growth of bacteria in vitro is demonstrated in the following test procedure: A stock solution or suspension of the test compound at a concentration of 2500 tug/ml. is prepared utilizing a suitable solvent or medium such as aqueous sodium hydroxide, aqueous lactic acid, methyl cellosolve, dimethylsulfoxide, dimethylacetamide, ethylene glycol, dimethylformamide, formamide, propylene glycol, acetone or methanol.

Two-fold dilutions are made by adding appropriate amounts of sterile water to the solution or suspension of the test substance. One ml. quantities of each dilution are incorporated into seed agar or Wellcotest Sensitivity Test Agar fortified with 5% hemolyzed horse blood (9 ml. vol.) in sterile Petri dishes to give plates containing varying concentrations of the test compound. The hardened surfaces of each plate are incubated with the test organism, and the plates are incubated for 18 hours at 3 s0C.

The in vitro antibacterial activity of the compounds tested is expressed as the "minimal inhibitory concentration" (MIC) which is defined as the least amount of material (,ug/ml.) that completely inhibits the test organism.

The in vitro antibacterial activities of compounds of the invention are set forth in Tables IV-VI below which sets forth the MIC values of various compounds when tested according to the above described procedure: TABLE IV In vitro Antibacterial Activity of 7-Substituted Methyl-7H-Pyrrolo[3,2-f]Quinazoline-1,3-Diamines

MIC (y/ml.) Compound S. S. N. E. S. K. P. of aureus aureus catarrhalis coliparatyphi pneumoniae vulgaris Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 2 phenylb 1.95 1.95 0.061 1.95 1.95 1.95 7.81 B 3 2-fluorophenyl 0.488 0.244 0.0152 0.488 0.976 0.122 0.976 B 4 3-fluorophenyl 0.244 0.031 < 0.009 0.244 0.488 0.061 0.488 B 5 4-fluorophenylc 0.244 0.122 0.0038 0.122 0.488 0.031 0.488 B 6 2-chlorophenyl 0.976 0.976 0.061 0.976 1.95 0.976 7.81 B 7 3-chlorophenyl 1.95 0.976 0.244 7.81 31.3 0.976 31.3 B 8 4-chlorophenyl 0.976 0.244 0.0038 0.976 0.976 0.122 0.976 B 9 2,6-dichlorophenyl 250 250 0.488 > 250 > 250 15.6 > 250 B 10 3,4-dichlorophenyl 0.976 0.488 0.061 3.90 31.3 0.488 31.3 B 11 2-trifluoromethylphenyl 0.488 0.244 < 0.0009 1.95 3.90 0.122 62.5 B 12 3-trifluoromethylphenyl 0.488 0.244 0.122 0.976 7.81 0.488 62.5 B TABLE IV (continued) MIC (&gamma;/ml.) Compound S. S. N. E. S. K. P. of aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 13 4-trifluoromethylphenyl 1.95 0.976 0.031 3.90 15.6 0.976 31.3 B 14 2-cyanophenyl 0.244 0.244 0.061 0.244 0.488 0.122 1.95 B 15 3-cyanophenyld 0.061 0.031 0.0038 0.122 0.488 0.031 0.976 B 16 4-cyanophenyl 0.244 0.122 0.0076 0.244 0.488 0.061 1.95 B 17 4-carbethoxyphenyl 1.95 1.95 0.488 7.81 > 250 1.95 > 250 B 18 3-nitrophenyle 0.122 0.061 0.0152 0.488 0.976 0.122 3.90 B 19 2-methylphenyl 0.488 0.488 0.0152 0.976 3.90 0.122 7.81 B 20 3-methylphenyl 0.976 0.488 0.031 0.488 1.95 1.95 1.95 B 21 4-methylphenyl 0.976 0.488 0.0152 0.976 1.95 0.122 1.95 B 22 2,4-dimethylphenyl 0.244 0.244 0.0152 0.976 3.40 0.244 7.81 B 23 2,5-dimethylphenyl 3.90 0.976 0.244 31.3 125 1.95 250 B 24 2,6-dimethylphenyl 250 250 0.122 250 > 250 15.6 > 250 B 25 3,4-dimethylphenyl 1.95 0.976 0.122 1.95 31.3 0.488 62.5 B 26 3,5-dimethylphenyl 0.976 0.488 0.031 7.81 15.6 0.244 15.6 B 27 2,4,6-trimethylphenyl 250 250 0.244 > 250 > 250 31.3 > 250 B 28 2,3,5,6-tetramethylphenyl 15.6 15.6 0.244 > 250 > 250 3.90 > 250 B TABLE IV (continued) MIC (&gamma;/ml.) Compound S. S. N. E.S. K. P. of aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 29 4-isopropylphenyl 1.95 0.976 0.244 7.81 62.5 0.488 62.5 B 30 4-t-butylphenyl 7.81 3.90 0.976 250 > 250 3.90 > 250 B 31 4-(methylthio)phenyl 0.976 0.488 0.0152 0.488 3.90 0.122 31.3 B 32 2-methoxyphenyl 0.976 0.976 0.061 1.95 7.81 0.244 3.90 B 33 3-methoxyphenyl 3.90 0.976 0.976 0.488 7.81 0.488 7.81 B 34 4-methoxyphenyl 0.976 0.244 0.0152 0.488 0.976 0.061 0.976 B 35 2,3-dimethoxyphenyl 0.488 0.244 1.122 0.488 15.6 0.488 7.81 B 36 2,5-dimethoxyphenyl 0.244 0.122 0.031 0.976 3.90 0.031 3.90 B 37 3,4-dimethoxyphenyl 0.244 0.122 0.0152 0.488 1.95 0.061 1.95 B 38 3,4-(methylenedioxy)- 7.81 1.95 0.244 7.81 15.6 1.95 31.3 B phenyl 39 3,4,5-trimethoxyphenyl 0.122 0.061 0.0152 0.976 3.90 0.122 7.81 B 40 4-ethoxyphenyl 1.95 0.488 0.122 1.95 7.81 3.90 7.81 B 41 3-trienyl 0.976 0.976 0.0152 0.244 0.976 0.061 1.95 B 42 4-thiazolyl 0.488 0.244 0.0038 0.244 0.976 0.122 0.976 B 43 2-pyridinyl 0.976 0.488 < 0.0009 0.488 0.244 0.061 0.244 A TABLE IV (continued) MIC (&gamma;/ml.) Compound S. S. N. E. S. K. P. of aureus aureus catarrhalis coli paratyphi pnenmoniae vulgaris Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 44 3-pyridinyl 7.81 0.976 < 0.009 0.488 0.488 0.122 7.81 A 45 4-pyridinyl 0.122 0.122 0.0038 0.244 0.488 0.122 0.488 A 46 benzo[b]thien-3-yl 31.3 31.3 1.95 125 > 250 15.6 > 250 B 47 1-naphthalenyl 3.90 0.976 0.0019 15.6 62.5 0.976 31.3 A 48 2-naphthalenyl 125 125 0.244 250 > 250 7.81 > 250 A 49 2-methyl-1-naphthalenyl 125 125 0.122 > 250 > 250 15.6 > 250 B 50 2-quinolinyl 0.976 0.488 0.0038 7.81 7.81 0.122 7.81 A 51 8-quinolinyl 0.244 0.122 0.0152 0.244 1.95 0.122 7.81 B 52 3,5-dimethyl-4-isoxazolyl 1.95 0.976 0.0152 0.976 1.95 0.244 3.90 B 53 n-hexyl 31.3 15.6 0.488 31.3 62.5 3.90 250 B 54 cyclohexyl 7.81 3.90 0.0152 1.95 7.81 0.488 3.90 A 55 2-methyl-1-propenyl 1.95 0.976 0.0038 3.90 7.81 0.488 7.81 A 56 2-phenylethyl 250 250 250 250 250 250 250 A 57 2-phenylvinyl 1.95 0.976 0.122 3.90 15.6 0.488 7.81 B 58 3,5-dimethoxyphenyl 0.488 0.244 0.061 0.976 1.95 0.122 15.6 B 59 2-thienyl 0.244 0.061 0.0019 0.061 0.244 0.061 0.244 B TABLE IV (continued) MIC (&gamma;/ml.) Compound S. S. N. E. S. K. P. of auteus auteus catarrhalis coli paratyphi pneumoniae vulgatis Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 60 1-bromo-2-naphthalenyl 31.3 15.6 0.488 > 250 > 250 15.6 > 250 B 61 4-acetylphenyl 0.244 0.122 0.0076 0.488 0.976 0.061 1.95 B 62 3-aminophenylf 0.488 0.244 0.061 0.244 0.976 0.122 1.95 B 63 4-(methylsulfonyl)phenyl 0.122 0.122 0.0152 0.976 0.976 0.122 7.81 B 64 4-(trifluoromethoxy)- 0.976 0.244 0.031 3.90 62.5 0.122 62.5 B phenyl 65 hydrogeng 62.5 7.81 0.031 0.976 3.90 1.95 1.95 A 66 2-methylpropylh 1.95 0.976 0.0038 0.976 3.90 0.244 3.90 A 67 tetrahydro-2-furanyli 3.90 0.976 0.0038 1.95 7.81 0.488 3.90 A 68 4-carboxyphenyl, 250 250 62.5 > 250 > 250 > 250 250 B sodium salt a Growth medium: A = Seed agar with 5% hemolyzed horse blood.

B = Wellcotest Sensitivity Test Agar with 5% hemolyzed horse blood. b This compound is tested as the free diamine. c This compound, prepared in the manner recorded in Example 5, is isolated and tested as the hydrate bearing one-fourth molecule of water per molecule of diamine, m.p. 198-199 . d This compound, prepared in the manner recorded in Example 15, is isolated and tested as the hydrate bearing one-fourth molecule of water per molecule of diamine, m.p. 240 .

TABLE IV (continued) e This compound, prepared in the manner recorded in Example 18, is isolated and tested as the hydrate bearing one-eighth molecule of water per molecule of diamine, m.p. 246 . f This compound is tested as the dihydrochloride, monohydrate, salt. g This compound is tested as the monoacetate salt. h This compound is tested as the monohydrochloride, hemihydrate salt. i This compound is tested as the monohydrochloride salt bearing one-third molecule of water per molecule of diamine salt.

TABLE V In vitro Antibacterial Activity of 7-Substituted-7H-Pyrrolo[3,2-f]Quinazoline-1,3-Diamines

H2N HN Q E C zcM I Compound S. S. N. E. S. K. P. of aureus aureus catarrhalis coli paratyphi pneumontae vulgaris Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 1 hydrogenb 31.3 31.3 0.244 3.90 31.3 7.81 15.6 A 69 4-cyanophenyl 0.976 0.488 0.031 0.976 31.3 0.122 125 B 70 2-acetylphenyl 0.061 0.031 0.0076 0.244 0.488 0.0152 0.976 B 71 4-acetylphenyl 1.95 0.488 0.031 0.976 7.81 0.122 15.6 B 72 4-propionylphenyl 31.3 7.81 0.031 15.6 > 250 31.3 > 250 B 73 2-cyanophenyl 0.031 0.0152 0.0038 0.122 0.122 0.0152 0.488 B 74 40-(methylsulfonyl)- 0.976 0.976 0.0152 0.976 7.81 0.244 15.6 B phenyl 75 4-carbethoxyphenyl 125 7.81 0.122 > 250 > 250 250 > 250 B 76 2-nitrophenyl 0.244 0.244 0.031 0.976 1.95 0.244 3.90 B 77 4-nitrophenyl 3.90 3.90 0.031 7.81 62.5 0.976 250 B 78 2,4-dinitrophenyl 0.0076 0.0076 0.0019 3.90 > 250 0.031 > 250 B TABLE V (continued) MIC (&gamma;/ml.) Compound S. S. N. E. S. K. P. of aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 79 2-cyano-4-nitrophenyl 0.488 0.488 0.244 15.6 > 250 1.95 > 250 B 80 3-methyl-4-nitrophenyl 62.5 7.81 0.0152 > 250 > 250 0.976 > 250 B 81 2-thiazolyl 0.488 0.244 0.0152 0.976 1.95 0.244 3.90 B 82 5-nitro-2-pyridinyl 0.976 3.90 0.031 > 250 > 250 31.3 > 250 B 83 2-pyridinyl .976 0.488 0.0076 0.488 0.976 0.244 0.976 B 84 2-pyrimidinyl 15.6 3.90 0.061 7.81 > 250 0.976 > 250 B 85 2-pyrazinyl 3.90 1.95 0.122 0.976 3.90 0.976 3.90 B 86 2-quinolinyl > 250 > 250 0.122 > 250 > 250 > 250 > 250 B 87 4-quinolinyl 0.031 0.0152 0.031 0.488 0.976 0.031 1.95 B 88 4-methyl-2-quinolinyl 62.5 31.3 0.061 62.5 > 250 31.3 > 250 B 89 7-chloro-4-quinolinyl 0.488 0.122 0.244 15.6 > 250 0.488 250 B 90 7-trifluoromethyl- 0.122 0.031 0.031 0.244 31.3 0.244 250 B 4-quinolinyl 91 2-methyl-4-quinolinyl 0.061 0.061 0.031 1.95 1.95 0.061 3.90 B 92 3-methyl-2-quinoxalinyl 1.95 0.488 0.122 7.81 > 250 0.976 > 250 B 93 2-trifluoromethylphenyl 0.061 0.031 0.0076 0.244 0.976 0.061 1.95 B TABLE V (continued) MIC (&gamma;/ml.) Compound S. S. N. E. S. K. P. of aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris Example R Smith 53-180 8193 9637 11737 10031 6896 Mediuma 94 2-trifluoromethyl 0.122 0.122 0.061 31.3 62.5 0.488 125 B 4-nitrophenyl 95 2-phenyl-4-quinolinyl 31.3 7.81 15.6 250 > 250 250 > 250 B 96 4-aminophenyl 0.488 0.244 0.0152 0.244 0.488 0.031 0.976 B 97 2-benzothiazolyl 250 125 0.488 > 250 > 250 62.5 > 250 B a Growth medium: A = Seed agar with 5% hemolyzed horse blood.

B = Wellcotest Sensitivity Test Agar with 5% hemolyzed horse blood. b This compound is tested as the hydrochloride salt.

TABLE VI In vitro Antibacterial Activities of 7,8-Substituted-7H-Pyrrolo[3,2-f]Quinazoline-1,3-Diamines

MIC (&gamma;/ml.) Compound S. S. N. E. S. K. P. of aureus aureus catarrhalis coli paratyphi pneumoniae vulgaris Example R R1 Smith 53-180 8193 9637 11737 10031 6896 Mediuma 98 hydrogen methyl 31.3 31.3 1.95 3.90 15.6 3.90 15.6 B 99 methyl methyl 31.3 31.3 0.061 0.244 1.95 0.244 0.976 B 100 benzyl methyl 1.95 0.976 0.122 0.488 3.90 0.244 15.6 B 101 3-cyano- methyl 0.122 0.061 0.0038 0.488 3.90 0.061 3.90 B benzyl 102 4-cyano- methyl 0.976 0.976 0.061 1.95 7.81 0.244 31.3 B benzyl 103 2,5-di- methyl 31.3 7.81 1.95 250 > 250 15.6 > 250 B methylbenzyl 104 benzyl chloro 3.90 0.976 0.061 3.90 7.81 0.244 31.3 B 105 hydrogen phenyl 7.81 15.6 62.5 62.5 125 31.3 > 250 B 106 methyl phenyl 62.5 125 31.3 > 250 > 250 3.90 > 250 B a Growth medium: B = Wellcotest Sensitivity Agar with 5% hemolyzed horse blood.

Example 108.

The ability of compounds of this invention to demonstrate synergistic action against antibacterial infections in mice when administered with sulfomethoxazole is demonstrated in the following test procedure: The test agents are weighed, suspended in 0.5% aqueous carboxymethyl cellulose, homogenized (glass tissue grinder) and diluted according to the design of the experiment. Mice (male, 18+1 g., CD-i strain) are pre-weighed, pooled, infected at random intraperitoneally with a 0.5 ml. standardized suspension (LD9s+5%) of the bacterial organism in 5% gastric mucin and treated at random with single doses of the test agents either at the time of infection or six hours after infecting. The treated groups consist of ten mice per dosage level. Deaths are recorded daily for 14 days and the PD,.,0 (mice are treated at time of infection) and CD,, (mice are treated six hours after infecting) values are calculated by the method of Reed and Muench [Amer. J.

Hyg., 27, 493 (1938)].

TABLE VII In vivo Antibacterial Synergism Data (Mouse) for 7,8-Substituted-7H-Pyrrolo[3,2-f]Quinazoline-1,3-Diamines

PD50a or CD50b Values, mg. per kg., p.o.

Compound of Example R R1 Organism Hoursc Cpd. SMd SM/Cpd.

2 benzyle H Proteus mirabilis 190 0 22.5 8.2 1.56-7.78 5 4-fluorobenzyl H Proteus mirabilis 190 0 9.8 7.4 1.56-1.56 16 4-cyanobenzylf H Proteus mirabilis 3 0 22.7 9.9 6.25/2.11 3.13/2.28 1.56/6.56 0.78/7.11 16 4-cyanobenzylf H Proteus vulgaris 347 0 > 200 43.2 6.25/6.25 3.13/9.67 1.56/ > 12.5 0.78/ > 12.5 16 4-cyanobenzylf H Proteus vulgaris 347 6 > 400 60 25/5.07 12.5/4.66 6.25/8.83 3.11/7.28 16 4-cyanobenzylf H Escherichia coli W-102 0 > 800 95 25.0/15.9 12.5/15.6 6.25/53.1 3.13/67.8 TABLE VII (continued) Compound of Example R R1 Organism Hoursc Cpd. SMd SM/Cpd.

16 4-cyanobenzylf H Escherichia coli W-102 6 > 400 356 100/37 50/37 25/89 12.5/50 16 4-cyanobenzylf H Proteus mitrobilis 190 0 18.6 7.61 3.11/2.44 1.56/3.39 0.78/8.78 0.39/ > 12.50 16 4-cyanobenzylf H Proteus mirabilis 190 6 159 14 3.11/2.33 1.46/4.0 0.78/ > 6.25 0.39/ > 6.25 100 benzyl Me Proteus mirabilis 190 0 36.6 5.1 1.56/3.11 15 3-cyanobenzylg H Proteus mirabilis 190 0 8.8 7.6 1.56/2.67 69 4-cyanophenyl H Proteus mirabilis 190 0 > 400 6.25 3.11/2.55 1.56/9.39 0.78/ > 12.5 0.39/ > 12.5 81 2-thiazolylh H Proteus mirabilis 190 0 22.3 12.5 3.11/6.25 1.56/ > 12.5 a This value is the dose required to protect half of the mice from death when the mice are treated immediately after infecting. b This value is the dose required to protect half of the mice from death when the mice are treated 6 hours after infecting. c This value is the number of hours elapsing between infecting and dosing of the mice. d SM = sulfomethoxazole.

TABLE VII (continued) e This compound is tested as the free diamine. f This compound, prepared in the manner recorded in Example 16, is isolated and tested as the hydrate bearing one-fifth molecule of water per molecule of diamine, m.p. 247-253 (softens 150 ). g This compound, prepared in the manner recorded in Example 15, is isolated and tested as the hydrate bearing one-fourth molecule of water per molecule of diamine, m.p. 240 . h In this experiment groups of five mice are used at each level.

Example 109.

The antimalarial effects of the compounds of Formula I are demonstrated, and elicited by means of the test procedure described below: Utilizing yound ICR/HA Swiss mice and a standard inoculum of Plasmodium berghei KBG 173, it is possible to produce a uniform disease faral to 100% of untreated animals within 6 to 8 days with a mean survival time of 6.2 days. Test animals weigh from 18 to 22 grams but weight variations in any given experimental or control group are confined to 2-3 grams. All animal in any given test are approximately of the same are. Animals on test are housed in metal-topped plastic cages, given a standard laboratory diet and water ad libitum.

Test animals receive an intraperitoneal injection of 0.5 ml. of 1:100 dilution of heparinized heart's blood with aminimum of 90% parasitized cells (4 x 107 cells), drawn from donor mice infected one week earlier with Plasmodium berghei. The donor strain is maintained by weekly passages in separate groups of mice inoculated with a 0.5 ml. of 1:500 dilution of heparinized heart's blood.

Test compounds are administered after dissolution or suspension in peanut oil. A single dose is given subcutaneously 72 hours after the mice are infected with Plasmodium berghei. At this time a 10-15 percent parasitemia has developed; the disease is well established but has not produced sufficient debility to alter the response of the host to toxic effects of the drug on test. Since treatment is withheld for three days to permit the infection to become well established and death occurs in unteated controls within 6-8 days, it is felt that this system presents a candidate compound with the maimum challenge. In order to check factors such as changes in the infectivity of Plasmodium berghei or in the susceptibility of the host or to detect technical errors, a group of infected animals treated with pyrimethamine at dose levels producing definite increases in survival time is prior to the sixth day, when untreated controls begin to die, are regarded as nonparasitic and become the basis for toxicity evaluations. Treated animals are kept under observation for 60 days. Survivors at the end of this period of time are considered as cured. In calculating mean survival time, toxic deaths and 60-day survivors are nor included.

Compounds are considered active which produce a cure in at least one test animal or which produce significant increases in mean survival times of the treated animals as compared with the mean survival times of untreated controls, provided that no drug related deaths (toxicity) are noted at the active dose.

The results of antimalarial testing of compounds of this invention are set forth in Tables VIII, IX and X.

TABLE VIII 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. per kg., s.c. administration)

Compound Highest Lowest Dose Min. Curing of Non-Lethal Cuting All Dose Example R Dosea Mice (Cure/Treat) #MSTb Dose 2 phenylc 160 80 20 (2/5)d 10.9 20d 3 2-fluorophenyl 80 80 10 (3/5) 9.8 5 4 3-fluorophenyl 40 40 10 (1/5) 8.3 10 5 4-fluorophenyle 80 20 5 (2/5) 7.1 2.5 6 2-chlorophenyl 160 20 20 (5/5) 8.3 5 7 3-chlorophenyl 160 10 2.5 (2/5) 7.7 1.25 8 4-chlorophenyl 40 20 10 (2/5) 8.1 5 10 3,4-dichlorophenyl 40 10 2.5 (2/5) 10.2 2.5 12 3-trifluoromethylphenyl - - 5 (1/5) 7.5 2.5 14 2-cyanophenyl 160 40 10 (1/5) 8.9 10 15 3-cyanophenyl f 40 10 1.25 (2/5) 9.6 1.25 16 4-cyanophenyl g - - 5 (1/5) 8.4 10 TABLE VIII (continued) Compound Highest Lowest Dose Min. Curing of Non-Lethal Curing All Dose Example R Dosea Mice (Cure/Treat) #MSTb Dose 18 2-nitrophenylh 40 10 2.5 (3/5) 7.4 2.5 19 2-methylphenyl - - 40 (3/5) 8.5 40 20 3-methylphenyl 320 20 5 (4/5) 6.9 5 21 4-methylphenyl 160 20 10 (2/5) 7.5 5 23 2,5-dimethylphenyl 640i 40 10 (3/5) 7.9 5 27 2,4,6-trimethylphenyl 80 40 5 (3/5) 7.3 2.5 29 4-isopropylphenyl 20 20 10 (1/5) 10.2 10 32 2-methoxyphenyl 160 40 10 (3/5) 10.5 10 34 4-methoxyphenyl 160 20 5 (2/5) 11.5 5 37 3,4-dimethoxyphenyl 80 20 10 (1/5) 6.9 2.5 39 3,4,5-trimethoxyphenyl 160 160 40 (2/5) 7.1 20 43 2-pyridinyl 80 80 20 (2/5) 11.6 20 44 3-pyridinyl 160 160 80 (3/5) 8.3 40 45 4-pyridinyl - - 80 (3/5) 9.7 40 47 1-naphthalenyl 80 20 5 (2/5) 9.2 5 48 2-naphthalenyl 160 40 20 (4/5) 7.3 5 TABLE VIII (continued) Compound Highest Lowest Dose Min. Curing of Non-Lethal Curing All Dose Example R Dosea Mice (Cure/Treat) #MSTb Dose 49 2-methyl-1-naphthalenyl 80 20 20 (5/5)d - 50 2-quinolinyl 160 5 1.25 (2/5) 6.9 1.25 51 8-quinolinyl 40 20 5 (1/5) 6.4 5 53 n-hexyl 640i 640 320 (2/5) 9.5 160 54 cyclohexyl - - - 8.5 40 55 2-methyl-1-propenyl - - 640 (3/5) 9.3 320 56 2-phenylethyl 640i 320 160 (3/5) 10.7 80 61 4-acetylphenyl 40 20 2.5 (4/5) 12.0 5 63 4-(methylsulfonyl)phenyl - - 10 (1/5) 6.5 5 66 2-methylpropylj - - - 8.1 320 9 2,6-dichlorophenyl 160k 40k 5k (1/5) - 11 2-trifluoromethylphenyl 40 10 1.25 (1/5) 7.3 0.63 25 3,4-dimethylphenyl 80k 10k 5k (2/5) 6.5k 2.5k 31 4-(methylthio)phenyl 40k 20k 2.5k (4/5) 6.2k 1.25k 33 3-methoxyphenyl 40 40 10 (1/5) 7.6 5 38 3,4-(methylenedioxy)phenyl - - 10 (2/5) 12.2 2.5 41 3-thienyl 320k 160k 20k (3/5) - - TABLE VIII (continued) Compound Highest Lowest Dose Min. Curing of Non-Lethal Curing All Dose Example R Dosea Mice (Cure/Treat) #MSTb Dose 62 3-aminophenyl 80 20 5 (3/5) 7.8 1.25 64 4-trifluoromethoxyphenyl 10 10 2.5 (2/5) 9.6 1.25 17 4-carbethoxyphenyl 80 20 10 (1/5) 6.0 2.5 22 2,4-dimethylphenyl 80k 5k 5k (5/5) 7.6k 2.5k a This is the highest dose with no deaths for any reason. b This abbreviation indicates the increase in mean survival time of treated animals as compared to untreated controls at the dose indicated in the adjacent column. c This compound is tested as the monoacetate salt described in Example 2. d This is the lowest dose tested. e See Table IV, footnote c. f See Table IV, footnote d. g See Table VII, footnote f. h See Table IV, footnote e. i This is the highest dose tested. j See Table IV, footnote h. k Mice alive on day 14 considered as "cured", no 60-day data available.

TABLE IX Activity of 7,8-Substituted-7H-Pyrrolo[3,2-f]Quinazoline-1,3-Diamines Against Plasmodium berghei KBG 173 Malaria in Mice (All Doses Are mg. kg., s.c. Administration

Compound Highest Lowest Dose Min. Curing of Non-Lethal Curing All Dose Exampla R R1 Dosea Mice (Cure/Treat) #MSTb Dose 98 hydrogen methyl - - 160 (3/5) 13.9 160 103 2,5-dimethyl- methyl 80c 5c 1.25c(1/5) 6.8c 1.25c benzyl a This is the highest dose with no deaths for any reason. b This abbreviation indicates the increase in mean survival time of treated animals as compared to untreated controls at the dose indicated in the adjacent column. c Mice alive on day 14 considered as "cured", no 60-day data available.

TABLE X Activity of 7-Substituted-7H-Pyrrolo[3,2-f]Quinazoline-1,3-Diamines Plasmodium berghei KBG 173 Malaria in Mice (All Doses Are in mg. per kg. s.c. Administration

Compound Highest Lowest Dose Min. Curing of Non-Lethal Curing All Dose Example R Dosea Mice (Cure/Treat) #MSTb Dose 69 4-cyanophenyl 20 20 5 (3/5) 11 2.5 70 2-acetylphenyl - - 40 (1/5) 9.2 40 71 4-acetylphenyl - - 40 (1/5) 8.8 20 76 2-nitrophenyl - - 40 (45) - 77 4-nitrophenyl 640 640 160 (5/5) 28.3 40 80 3-methyl-4-nitrophenyl 640 640 640 (5/5) 13.9 160 81 2-thiazolyl - - 640 (4/5) 8.3 160 82 5-nitro-2-pyridinyl - - 160c (1/5) - a This is the highest dose with no deaths for any reason. b This abbreviation indicates the increase in mean survival time of treated animals as compared to untreated controls at the dose indicated in the adjacent column. c Mice alive on day 14 considered as "cured", no 60-day data available.

Example 110.

Single doses of 7-(phenylmethyl)-7H-pyrrolo [3,2-f] quinazoline-1,3-diamine (active moiety) were intraperitoneally administered in 0.5% carboxymethylcellulose at a constant dose volume of 10 ml./kg., to groups of 10 mice/dose level. (Charles River COBS CD Strain Albino mice, male, weight 21.0-25.29). Daily observations were made on all mice for the duration of experiment (14 days). The resulting LD was 54.5 mg./kg. (95% confidence limits of 48.6-93.4) all deaths occurred 4-5 days post-drug-administration.

The compound produced decreased spontaneous motor activity, bradypnea, ptosis, and stretching with indrawn sides in all mice within 1 hour after i.p. injection. In addition, rough coats and decreased fecal elimination were observed on day 2 postdrug-administration. These effects lasted up to 6 days in the low dose animals and 14 days in those animals having received the highest dose. All mice alive on day 14 were sacrified and necropsied. Macroscopically, the tissues appeared normal.

Claims (164)

WHAT WE CLAIM IS:

1. A compound of the general formula:

or a non-toxic acid addition salt thereof, wherein: either (a) X is hydrogen and Y is -CH2R or -R1 wherein: R is hydrogen; methyl; ethyl; n-propyl; i-propyl; n-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-l-propenyl; cyclobutyl; cyclopentyl; cyclohexyl; 2 phenylethyl; 2-phenylvinyl; phenyl; phenyl monosubstituted in the 2-, 3-, or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy, or potassium carboxy; phenyl monosubstituted in the 3-position by amino or nitro; phenyl disubstituted in the 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 the 2,4,6- or 3,4,5-positions by methyl, ethyl, methoxy, or ethoxy; 2,3 ,5,6-tetramethylphenyl; 3,4- (methyl- ene dioxy)phenyl; l-naphthalenyl; 2-naphthalenyl; 2-methyl- 1 -naph- thalenyl; l-bromo-2-naphthalenyl; 2-pyridinyl; 3 -pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl; 3,5-dimethyl 4-isoxazolyl; tetrahydro-2-furanyl; or benzo[b]thien-3-yl; and R1 is hydrogen; phenyl monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl, or carbeth oxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl; 2 cyano-4-aminophenyl; 3 -methyl-4-nitrophenyl; 3 -methyl-4-aminophenyl; 2 - trifluoromethyl - 4 - nitrophenyl; 2-trifluoromethyl-4-aminophenyl; 2 thiazolyl; 2-pyridinyl; 5 -nitro-2-pyridinyl; 2-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 - quin oxalinyl; 2-phenyl-4-quinolinyl; or 2-benzothiazolyl; or (b) X is methyl, phenyl, or chlorine; and Y is hydrogen, methyl, benzyl, 3-cyano benzyl, 4-cyanobenzyl, or 2,5-dimethylbenzyl; provided that when X is phenyl, Y may only be hydrogen or methyl, and when X is chlorine, Y may only be benzyl.

2. A compound as defined in Claim 1 wherein X is hydrogen and Y is -CH2R where R is as defined in Claim 1.

3. A compound as claimed in claim 2 wherein R is n-hexyl; i-propyl; i-butyl; 2 methyl-l-propenyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; phenyl mono-substituted in the 2,3 or 4 position by fluorine chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, or n-propoxy; 2,5-dimethylphenyl; 3,4-dimethoxyphenyl 2,4,6-trimethyiphenyl; 3,4-dichlorophenyl; 3,4,5-trimethoxyphenyl; l-naphthalenyl; 2-naphthalenyl; 2-methyl- 1 -naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4pyridinyl; 2-quinolinyl; or 2-phenylethyl.

4. A compound as claimed in Claim 2 wherein R is hydrogen, tetrahydro-2furanyl, 4-thiazolyl; or phenyl mono-substituted in the 2,3 or 4 position by cyano, trifluoromethyl, or methylsulfonyl.

5. The compound as defined in Claim 2 wherein R is phenyl.

6. The compound as defined in Claim 2 wherein R is 2-fluorophenyl.

7. The compound as defined in Claim 2 wherein R is 3-fluorophenyl.

8. The compound as defined in Claim 2 wherein R is 4-fluorophenyl.

9. The compound as defined in Claim 2 wherein R is 2-chlorophenyl.

10. The compound as defined in Claim 2 wherein R is 3-chlorophenyl.

11. The compound as defined in Claim 2 wherein R is 4-chlorophenyl.

12. The compound as defined in Claim 2 wherein R is 2,6-dichlorophenyl.

13. The compound as defined in Claim 2 wherein R is 3,4-dichlorophenyl.

14. The compound as defined in Claim 2 wherein R is 2-trifluoromethylphenyl.

15. The compound as defined in Claim 2 wherein R is 3-trifiuoromethylphenyl.

16. The compound as defined in Claim 2 wherein R is 4-trifluoromethylphenyl.

17. The compound as defined in Claim 2 wherein R is 2-cyanophenyl.

18. The compound as defined in Claim 2 wherein R is 3-cyanophenyl.

19. 'l'he compound as defined in Claim 2 wherein R is 4-cyanophenyl.

20. The compound as defined in Claim 2 wherein R is 4-carbethoxyphenyl.

21. The compound as defined in Claim 2 wherein R is 3-nitrophenyl.

22. The compound as defined in Claim 2 wherein R is 2-methylphenyl.

23. The compound as defined in Claim 2 wherein R is 3-methylphenyl.

24. The compound as defined in Claim 2 wherein R is 4-methylphenyl.

25. The compound as defined in Claim 2 wherein R is 2,4-dimethylphenyl.

26. The compound as defined in Claim 2 wherein R is 2,5-dimethylphenyl.

27. The compound as defined in Claim 2 wherein R is 2,6-dimethylphenyl.

28. The compound as claimed in Claim 2 wherein R is 3,4-dimethylphenyl.

29. The compound as defined in Claim 2 wherein R is 3,5-dimethylphenyl.

30. The compound as defined in Claim 2 wherein R is 2,4,6-trimethylphenyl.

31. The compound as defined in Claim 2 wherein R is 2,3,5,6-tetramethylphenyl.

32. The compound as defined in Claim 2 wherein R is 4-isopropylphenyl.

33. The compound as defined in Claim 2 wherein R is 4-t-butylphenyl.

34. The compound as defined in Claim 2 wherein R is 4-(methylthio)phenyl.

35. The compound as defined in Claim 2 wherein R is 2-methoxyphenyl.

36. The compound as defined in Claim 2 wherein R is 3-methoxyphenyl.

37. The compound as defined in Claim 2 wherein R is 4-methoxyphenyl.

38. The compound as defined in Claim 2 wherein R is 2,3-dimethoxyphenyl.

39. The compound as defined in Claim 2 wherein R is 2,5-dimethoxyphenyl.

40. The compound as defined in Claim 2 wherein R is 3,4-dimethoxyphenyl.

41. The compound as defined in Claim 2 wherein R is 3,4-(methylenedioxy)phenyl.

42. The compound as defined in Claim 2 wherein R is 3,4,5-trimethoxyphenyl.

43. The compound as defined in Claim 2 wherein R is 4-ethoxyphenyl.

44. The compound as defined in Claim 2 wherein R is 3-thienyl.

45. The compound as defined in Claim 2 wherein R is 4-thiazolyl.

46. The compound as defined in Claim 2 wherein R is 2-pyridinyl.

47. The compound as defined in Claim 2 wherein R is 3-pyridinyl.

48. The compound as defined in Claim 2 wherein R is 4-pyridinyl.

49. The compound as defined in Claim 2 wherein R is benzo[b]thien-3-yl.

50. The compound as defined in Claim 2 wherein R is l-naphthalenyl.

51. The compound as defined in Claim 2 wherein R is 2-naphthalenyl.

52. The compound as defined in Claim 2 wherein R is 2-methyl-1-naphthalenyl.

53. The compound as defined in Claim 2 wherein R is 2-quinolinyl.

54. The compound as defined in Claim 2 wherein R is 8-quinolinyl.

55. The compound as defined in Claim 2 wherein R is 3,5-dimethyl-4-isoxazolyl.

56. The compound as defined in Claim 2 wherein R is n-hexyl.

57. The compound as defined in Claim 2 wherein R is cyclohexyl.

58. The compound as defined in Claim 2 wherein R is 2-methyl-1-propenyl.

59. The compound as defined in Claim 2 wherein R is 2-phenylethyl.

60. The compound as defined in Claim 2 wherein R is 2-phenylvinyl.

61. The compound as defined in Claim 2 wherein R is 3,5-dimethoxyphenyl.

62. The compound as defined in Claim 2 wherein R is 2-thienyl.

63. The compound as defined in Claim 2 wherein R is l-bromo-2-naphthalenyl.

64. The compound as defined in Claim 2 wherein R is 4-acetylphenyl.

65. The compound as defined in Claim 2 wherein R is 3-aminophenyl.

66. The compound as defined in Claim 2 wherein R is 4-methylsulfonylphenyl.

67. The compound as defined in Claim 2 wherein R is 4-trifluoromethoxyphenyl.

68. The compound as defined in Claim 2 wherein R is hydrogen.

69. The compound as defined in Claim 2 wherein R is isobutyl.

70. The compound as defined in Claim 2 wherein R is tetrahydro-2-furanyl.

71. The compound as defined in Claim 2 wherein R is 4-(sodium carboxy)phenyl.

72. A compound as defined in Claim 1 wherein X is hydrogen and Y is R' wherein Rl is as defined in Claim 1.

73. The compound as defined in Claim 72 wherein Rl is 4-cyanophenyl.

74. The compound as defined in Claim 72 wherein Rl is 2-acetylphenyl.

75. The compound as defined in Claim 72 wherein Rl is 4-acetylphenyl.

76. The compound as defined in Claim 72 wherein R' is 4-propionylphenyl.

77. The compound as defined in Claim 72 wherein Rl is 2-cyanophenyl.

78. The compound as defined in Claim 72 wherein Rl is 4-(methylsulfonyl)phenyl.

79. The compound as defined in Claim 72 wherein Rl is 4-carbethoxyphenyl.

80. The compound as defined in Claim 72 wherein R1 is 2-nitrophenyl.

81. The compound as defined in Claim 72 wherein Rl is 4-nitrophenyl.

82. The compound as defined in Claim 72 wherein Rl is 2,4-dinitrophenyl.

83. The compound as defined in Claim 72 wherein Rl is 2-cyano-4-nitrophenyl.

84. The compound as defined in Claim 72 wherein Rl is 3-methyl-4-nitrophenyl.

85. The compound as defined in Claim 72 wherein Rl is 2-thiazolyl.

86. The compound as defined in Claim 72 wherein Rl is 5-nitro-2-pyridinyl.

87. The compound as defined in Claim 72 wherein Rl is 2-pyridinyl.

88. The compound as defined in Claim 72 wherein Rl is 2-pyrimidinyl.

89. The compound as defined in Claim 72 wherein R' is 2-pyrazinyl.

90. The compound as defined in Claim 72 wherein R1 is 2-quinolinyl.

91. The compound as defined in Claim 72 wherein R1 is 4-quinolinyl.

92. The compound as defined in Claim 72 wherein Rl is 4-methyl-2-quinolinyl.

93. The compound as defined in Claim 72 wherein Rl is 7-chloro-4-quinolinyl.

94. The compound as defined in Claim 72 wherein Rl is 7-trifluoromethyl-4quinolinyl.

95. The compound as defined in Claim 72 wherein Rl is 2-methyl-4-quinolinyl.

96. The compound as defined in Claim 72 wherein Rl is 3-methyl-2-quinoloxalinyl.

97. The compound as defined in Claim 72 wherein R' is 2-trifluoromethylphenyl.

98. The compound as defined in Claim 72 wherein Rl is 2-trifluoromethyl-4nitrophenyl.

99. The compound as defined in Claim 72 wherein Rl is 2-phenyl-4-quinolinyl.

100. The compound as defined in Claim 72 wherein Rl is 4-aminophenyl.

101. The compound as defined in Claim 72 wherein R is 2-benzothiazolyl.

102. The compound as defined in Claim 72 wherein Rl is hydrogen.

103. A compound as defined in Claim 1 wherein X is methyl, phenyl, or chlorine; and Y is hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl, or 2,5-dimethylbenzyl; provided that when X is phenyl, Y may only be hydrogen or methyl, and when X is chlorine, Y may only be benzyl.

104. The compound as defined in Claim 103 wherein Y is methyl and X is methyl.

105. The compound as defined in Claim 103 wherein Y is hydrogen and X is methyl.

106. The compound as defined in Claim 103 wherein Y is benzyl and X is methyl.

107. The compound as defined in Claim 103 wherein Y is 3-cyanobenzyl and X is methyl.

108. The compound as defined in Claim 103 wherein Y is 4-cyanobenzyl and X is methyl.

109. The compound as defined in Claim 103 wherein Y is 2,5-dimethylbenzyl and X is methyl.

110. The compound as defined in Claim 103 wherein X is chlorine and Y is benzyl.

111. The compounds as defined in Claim 103 wherein X is phenyl and Y is hydrogen.

112. The compound as defined in Claim 103 wherein X is phenyl and Y is methyl.

113. A compound as claimed in any one of Claims 1, 2, 12, 20, 21, 23, 25, 27 29, 31, 33, 34, 38, 39, 44, 49, 54, 55, 60-65, 67, 72-101 and 103 to 112, when in the form of a non toxic acid addition salt.

114. A compound as claimed in Claim 113 wherein the salt is the hydrochloride hydrobromide, maleate benzoate, pamoate, methanesulfonate or acetate.

115. A compound as claimed in any one of Claims 3, 511,13, 22, 24, 26, 30, 32, 35, 36, 37, 40, 42, 43, 46-48, 50-53, 56-59, 69 and 91 when in the form of a non toxic acid addition salt.

116. A compound as claimed in Claim 115 wherein the salt is the hydrochloride, hydrobromide, maleate, benzoate, pamoate, methanesulfonate or acetate.

117. A compound as claimed in any one of Claims 14-19, 45, 66, 68 and 70 when in the form of a non toxic acid addition salt.

118. A compound as claimed in Claim 117 wherein the salt is the hydrochloridP hydrobromide, maleate, benzoate, pamoate, methanesulfonate or acetate.

119. A process for preparing a compound according to Claim 1 wherein Y is other than hydrogen, X is other than chlorine and the radical Y does not carry an amino group, which comprises reacting a corresponding compound of formula:

with an alkali metal base to form an alkali metal salt and reacting the alkali metal salt with a compound of the formula: Y-z (v) in which formulae Y and X are as defined hereinabove and Z is a leaving group; and if desired isolating the product as the free base or as a non toxic acid addition salt.

120. A process as claimed in Claim 119 wherein the alkali metal base is sodium hydride, potassium hydride, potassium t-butoxide or lithium or potassium amide.

121. A process as claimed in Claim 119 wherein the alkali metal base is sodium hydride.

122. A process as claimed in Claim 119 or 120 wherein Y is RCH2- and Z is chlorine, bromine, iodine, tosyloxy or mesyloxy.

123. A process as claimed in Claim 119 or 120 wherein Y is R1- and Z is fluorine, chlorine, bromine or iodine.

124. A process as claimed in any one of Claims 119 to 121 wherein X is hydrogen and Y is -CH.2R.

125. A process as claimed in any one of Claims 119 to 121 wherein X is hydrogen and Y is R'.

126. A process as claimed in any one of Claims 119 to 121 wherein X is methyl or phenyl.

127. A process as claimed in Claim 120 wherein X is hydrogen, R is as defined in Claim 3 or Claim and Z is chlorine, bromine or iodine.

128. A process as claimed in Claim 121 wherein X is hydrogen, R is as defined in Claim 3 and Z is chlorine, bromine or iodine.

129. A process as claimed in Claim 121 wherein X is hydrogen, R is as defined in Claim 4 and Z is chlorine, bromine or iodine.

130. A process for preparing a compound of the formula: wherein: either

a) X is hydrogen and Y1 is hydrogen or CH2R wherein R is as defined in Claim 1 except hydrogen and a radical carrying an amino substituent, or b) X is methyl, phenyl or chlorine and Y' is hydrogen, benzyl, 2,5-dimethyl benzyl, 3-cyanobenzyl or 4-cyanobenzyl provided that when X is phenyl Y' is hydrogen and when X is chlorine Y' is benzyl, which comprises reacting an acid addition salt of a compound of the formula:

wherein: X and Y1 have the meanings defined hereinabove; with an alkali metal dicyanamide at a temperature of 1850 to 2150C. in an aliphatic alcohol and if desired isolating the product as the free base or non toxic acid addition salt.

131. A process as claimed in Claim 130 wherein the aliphatic alcohol is l-octyl alcohol.

132. A process as claimed in Claim 130 or Claim 131 wherein the alkali metal dicyanamide is sodium dicyanamide.

133. A process as claimed in any one of Claims 130 to 132 which is effected using a molar ratio of alkali metal dicyanamide to 5-aminoindole of > 2:1.

134. A process as claimed in Claim 133 wherein the molar ratio is about 2.5:1.

135. A process as claimed in any one of Claims 130 to 134 wherein X is hydrogen.

136. A process as claimed in any one of Claims 130 to 135 wherein yl is hydrogen.

137. A process as claimed in any one of Claims 130 to 135 wherein Y' is -CH2R.

138. A process as claimed in any one of Claims 130 to 134 wherein X is methyl or phenyl.

139. A process as claimed in any one of Claims 130 to 134 and 138 wherein Y' is hydrogen.

140. A process as claimed in any one of Claims 130 to 134 wherein X is chlorine and Y1 is benzyl.

141. A process as claimed in Claim 130 wherein X is hydrogen and Y1 is hydrogen or CH2R wherein R is i-propyl, n-butyl, i-butyl, n-hexyl, 2-methyl-1-propenyl, cyclobutyl, 2-phenylethyl, phenyl, phenyl monosubstituted in the 2,3 or 4 position by chlorine, bromine, iodine, fluorine, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy or n-propoxy; 2,5-dimethylphenyl, 3,4-dimethoxyphenyl, 3,4-dichlorophenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethoxyphenyl, l-naphthalenyl, 2-naphthalenyl, 2-methyl-1 - naphthalenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl or 2-quinolinyl.

142. A process as claimed in Claim 130 wherein X is hydrogen and Y is CH2R wherein R is phenyl substituted in the 2, 3 or 4 position by trifluoromethyl, cyano or methylsulfonyl; 4-thiazolyl or tetrahydro-2-furanyl.

143. A process as claimed in Claim 141 wherein the alkali metal dicyanamide is sodium dicyanamide.

144. A process as claimed in Claim 142 wherein the alkali metal dicyanamide is sodium dicyanamide.

145. A process as claimed in any one of Claims 130-144 wherein the acid addition salt of the compound of formula (X) is the hydrochloride.

146. A process for preparing a compound of the formula:

wherein: Y2 is 3-aminobenzyl, 2-aminophenyl, 4-aminophenyl, 2,4-diaminophenyl, 2-cyano 4-aminophenyl, 3-methyl-4-aminophenyl or 2-trifluoromethyl-4-aminophenyl, which comprises reducing a compound of the formula:

wherein: Y, is 3-nitrobenzyl, 2-nitrophenyl, or 4-nitrophenyl, 2,4-dinitrophenyl, 2-cyano 4-nitrophenyl, 3 -methyl-4-nitrophenyl or 2-trifluoromethyl-4-nitrophenyl; and if desired isolating the product as a free base or a non-toxic acid addition salt.

147. A process as claimed in Claim 146 wherein the reducing agent is hydrogen in the presence of a noble metal catalyst.

148. A process as claimed in Claim 147 wherein the noble metal catalyst is palladium-carbon.

149. A process for preparing a compound of formula I substantially as hereinbefore described with reference to any one of Examples 2A, 5, 8, 10, 19, 20, 23, 27, 34, 37, 43 to 45, 47 to 50, 53 to 56 and 66.

150. A process for preparing a compound of formula I substantially as hereinbefore described with reference to any one of Examples 11 to 16, 42, 63b, 65 and 67.

151. A process for preparing a compound of formula I substantially as hereinbefore described with reference to any one of Examples 2B, 98c, 104h and 105c.

152. A process for preparing a compound of formula I substantially as hereinbefore described with reference to any one of Examples 3, 4, 6, 7, 9, 17, 22, 24 to 26, 28 to 33, 35, 36, 38 to 41, 46, 51, 52, 57 to 60, 61b, 64b, 68 to 95, 97, 99 to 103 and 106.

153. A process for preparing a compound of formula I substantially as hereinbefore described with reference to Example 62 or 96.

154. A process for preparing a compound of formula I substantially as hereinbefore described with reference to Example 1.

155. A compound of formula I whenever prepared by a process as claimed in any one of Claims 119 to 126, 130 to 140, 145 to 148 and 151 to 153.

156. A compound of formula I whenever prepared by a process as claimed in any one of Claims 127 and 141 to 144.

157. A compound of formula I whenever prepared by a process as claimed in any one of Claims 128, 149 and 154.

158. A compound of formula I whenever prepared by a process as claimed in Claim 129 or 150.

159. A compound according to Claim 1 as hereinbefore described with reference to any one of Examples 1, 2A, 5, 8, 10, 19, 20, 23, 27, 34, 37, 43 to 45, 47 to 50, 53 to 56 and 66.

160. A compound according to Claim 1 as hereinbefore described with reference to any one of Examples 11 to 16, 42, 63b, 65 and 67.

161. A compound according to Claim 1 as hereinbefore described with reference to any one of Examples 3, 4, 6, 7, 9, 17, 22, 24 to 26, 28 to 33, 35, 36, 38 to 41, 46, 51, 52, 57 to 60, 61b, 62, 64b and 68 to 97.

162. A pharmaceutical composition comprising a compound of formula I as claimed in any one of Claims 1, 2, 12, 20, 21, 23, 25, 27 to 29, 31, 33, 34, 38, 39, 41, 44, 49, 54, 55, 60 to 65, 67, 71 to 101 and 103 to 114 in association with a pharmaceutically acceptable carrier.

163. A pharmaceutical composition comprising a compound of formula I as claimed in any one of Claims 3, 5 to 11, 13, 22, 24, 26, 30, 32, 35 to 37, 40, 42, 43, 46 to 48, 50 to 53, 56 to 59, 69, 102, 115 and 116 in association with a pharmaceutically acceptable carrier.

164. A pharmaceutical composition comprising a compound of formula I as claimed in any one of Claims 4, 14 to 19, 45, 66, 68, 70, 117 and 118 in association with a pharmaceutically acceptable carrier.