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IE45427B1 - Pyrrold 3,2if quinazoline-1,3-diamine and related compounds - Google Patents

Pyrrold 3,2if quinazoline-1,3-diamine and related compounds

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Publication number
IE45427B1
IE45427B1 IE1345/77A IE134577A IE45427B1 IE 45427 B1 IE45427 B1 IE 45427B1 IE 1345/77 A IE1345/77 A IE 1345/77A IE 134577 A IE134577 A IE 134577A IE 45427 B1 IE45427 B1 IE 45427B1
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compound
methyl
phenyl
hydrogen
quinolinyl
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IE1345/77A
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IE45427L (en
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American Home Prod
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • General Health & Medical Sciences (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention provides a compound if the general formula: or a non-toxic acid addition salt thereof, wherein: (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-prophyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methlthio, ethylthio, carbethoxy, carbonyl, sodium carboxy, or potassium carboxy; phenyl monsubstituted 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; 2,3,5,6tetramethylphenyl; 3,4-(methylene dioxy)phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-1-naphthalenyl; 1-bromo-2-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl; 3,5-dimethyl-4-isoxazolyl; tetrahydro-2-furanyl; or benzo(B)thein-3-yl; and R1 is hydrogen; phenyl monosubstituted in the 2- or 4position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or carbethoxy: 2,4-dinitrophenyl; 2,4-diamino-phenyl; 2-cyano-4-nitrophenyl; 2-cyano-4-aminophenyl; 3-methyl-4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitro-phenyl; 2-trifluoromethyl-4-aminophenyl; 2-thiazolyl; 2-pyridinyl; 5-nitro-2-pyridinyl; 2-pyrimidinyl; 2-pyrazinyl; 2-quinolinyl; 4-quinolinyl, 4-methyl-2-quinolinyl; 7-chloro-4-quinolinyl; 7-trifluoromethyl-4-quinolinyl; 2-methyl-4-quinolinyl; 3methyl-2-quinoxalinyl; 2-phenyl-4-quinolinyl; or 2-benzothiazolyl; and (b) 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. The compounds inhibit the growth of bacteria in vitro as demonstrated in a standard tube dilution test employing seed agar or Wellcotest Sensitivity. In addition the compounds exhibit in vitro antifolic acid activity, as demonstrated by the inhibition of Streptoccus faecalis ATCC 8043 grown in a folic acid medium.

Description

This invention relates to pyrrolo[3,2-f]quinazoline-l,3-diamine and to the 7-(substituted) and 7,85 (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 10 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 antiba'cterial activity [see Hitchings et al., U. S. Patent 2,945,850 or De Graw et al., J. Med. Chem., 17, 762 (1974)]. 2,4-Diamino-6-[(arylmethyl)amino]quinazolines; 2,4diamino-6-{[(substituted aryl)methyi] amino}-quinazolines; and '20 2,4-diamino-6-{[(heterocyclic)methyl]aminoJ-quinazolines along with derivatives having a 5-alkyl substituent or Νθ-alkyl substitutent exhibit antimalarial activity. [See Davoll et al., J, Med. Gliem., 15, 812 (1972); Elslager et al,, 3. Med. Chem., 15, 1138 (1972); see also the review article by E. Elslager entitled, New Perspectives on the Chemotherapy of Malaria, - 2 4 5 4 2 7 Filariasis, and Leprosy, Progress in Drug Research, 18, 99172 (1974), in particular pages 111-116 and 152-154].
The pyrroloC3,2-f]quinazoline-l,3-diamines of the invention differ from the known 2,4,6-triaminoquinazolines β in that the 5-position and the N position of the latter are bridged by an ethylene moiety thus forming a novel tricyclic heterocycle.
The invention provides compounds of the general formula: N-Y or a non-toxic acid addition salt thereof, wherein: either (a) X is hydrogen and Y is -CHgR or -R1 wherein: R is hydrogen; methyl; ethyl; n-propyl; ipropyl; n-butyl; i-butyl; n-pentyl; nhexyl; 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-, 2,5-, 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-(methylenedioxy)phenyl; 1naphthalenyl; 2-naphthalenyl; 2-methyl-lnaphthalenyl; l-hromo-2-naphthalenyl; 2pyridinyl; 3-pyridinyl; 4-pyridinyl; 2quinolinyl; 8-quinolinyl; 2-thienyl; 3thienyl; 4-thiazolyl; 3,5-dimethyl-4isoxazolyl; tetrahydro-2-furanyl; or benzo[b]thien-3-yl; and is hydrogen; phenyl monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethj-1, or carbethoxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl; 2-cyano-4-aminoplienyl; 3-methyl-4nitrophenyl; 3-incthyl~4-nminophenyl; 2trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl-4-aminophenyl; 2-thiazolyl; 2- 4 *5-427 pyridinyl; 5-nitro-2-p.vridinyl; 2-pyrimidinyl; 2-pyrazinyl; 2-quinolinyl; 4quinolinyl; 4-methyl-2-quinolinyl; 7chloro-4-quinolinyl; 7-trifluoromethyl5 4-quinolinyl; 2-methyl-4-quinolinyl; 3methyl-2-quincKalinyl; 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-dimethylbenzyl; 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: II or a non-toxic acid addition salt thereof, wherein: R is as hereinbefore defined (b) Ά coinpound of the general formula: III or a non-toxic acid addition salt thereof, wherein: -t R 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-dimethylbenzyl; provided that when X is phenyl, Y may only be hydrogen or methyl, and when X is chlorine, Y may only be benzyl. 4S437 Of special interest are the compounds 7H-pyrrolo[3,2-f]quinazoline-l,3-diajnine 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 R1 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. vulgaris 6896. When tested in the above-described tube-dilution test, the compounds gave MIC values ranging from <0.0009 δ/ml. to 250 δ/ml. 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: <10427 7-(phenylme t’hyl )T7H-pyr rolo 13,2-f] quinazo line1,3-diamine; 7-[(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-f]quinazoline-1,3-diamine; 8- methyl-7-.(phenylniethyl )-7H-pyrrolo [ 3,2-f] quinazoline-1,3-diamine; 7-(4-eyanophenyl)-7I!-pyrrolo[3,2-f]qUinazoline1.3- diamine; anci 7-(2-thiazolyl)-7H-pyrrolo[3,2-f]quinazoline1.3- 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 Plasmodium 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-l-propenyl; cyclohexyl; 2-phenylethyl; phenyl; phenyl monosubstituted in the 2-, 3-, or 4position by chlorine, fluorine, methyl, cyano, or methoxy; 4-isopropylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; 4-(methylsulfonyl)phenyl; 48 acetylphenyl, 4-methylthiophenyl, 4carbethoxyphenyl, 4-trifluoromethoxyphenyl; phenyl monosubstituted in the 3position by amino or nitro; 2,4-dimethylphenyl; 2,5-dimethylphenyl; 3,4-dimethylphenyl; 3,4-dimethoxyphenyl, 2,6-dichlorophenyl; 3,4-dichlorophenyl; 2,4,6-trimethylphenyl; 3,4,5-trimethoxyphenyl; 3,4-(methylene dioxy)phenyl; 1-naphthalenyl; 2-naphthalenyl; 2-methyl-l-naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2quinolinyl; 8-quinolinyl; or 3-thienyl; (b) X is hydrogen and Y is R1 wherein R1 is phenyl monosubstituted in the 2- or 4-position by nitro, or acetyl; 4-cyanophenyl; 3-methyl-4-nitrophenyl; 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-l,3diamine; 7-[(4-methoxyphenyl)methyl]-7H-pyrrolo[3,2-fJquinazoline-1,3-diamine; and 7-[(2,5-dimethylphenyl)methyl]-7H-pyrrolo[3,2-fJquinazoline-l,3-diamine. The CDS0 values (CD = curing dose) of said com9 •427 pounds 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. berghci resistant to 5 chloroquine, sulfones, cycloguanil, and pyrimethamine, is shown by the testing of 7-(phenylmethyl)-7H-pyrroloL3,2-f)quinazoline1,3-diamine and 7-[(2,5-dimethylphenyl)methyl]-7H-pyrrolo[5,2-fJquinazoline-l,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, IS 1972. The compounds of Formula I wherein X is hydrogen and Y is -CHgR showing such activity are: R Cose (mg/kg) T/C, °/o phenyl 10 149 4-cyanophenyla 20 138 20 4-methylsulfonyl 10 136 4-carbethoxyphenyl· 10 141 3-nitrophenyl 5 163 4-methylphenyl 10 138 2,5-dimethylphenyl 10 142 25 3,4-dimethylphenyl 10 139 4-t-butylphenyl 5 125 3,4-dimethoxyphenyl 10 174 5,4,5-trimethoxyphenyl 10 163 3-aminophenyl 10 165 '•*24 3 ? R Dose (mg/kg) T/C, 3-thienyl 10 147 2-pyridinyl 20 146 5 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 10 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 >4.54 2.7 characterized in that a compound of the formula: wherein: (VI) X is hydrogen, methyl, or phenyl; is reacted with an alkaj i metal base to form an alkali metal salt and the alkali metal salt is reacted with a compound of the formula: (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: CtX) either a) X is hydrogen; and Y“ 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 Y is hydrogen, benzyl, 3-cyanobenzyl, 4-cyanobenzyl or 2,5-dimethylbenzyl provided that when X is phenyl, Y^ is hydrogen and when X is chlorine, Y^ is benzyl, characterized in that an acid addition salt (e.g. the hydrochloride salt) of a compound of the formula: X (X) 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 21O°C. in an aliphatic alcohol.
(C) A process for preparing a compound of the formula: wherein: Y2 is 3-aminobenzyl, 2-aminophenyl, or 4-aminophenyl; 2,4-diaminojiienyl, 2-cyano-4-aminophenyl, 3-methyl-4-aminc£henyl or trifluoramethyl-4-aminofhenyl characterized in that a compound of the formula: XII wherein: Y is 3-nitrobenzyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 2-Cyano-4-nitrophenyl, 3-methyl-4nitrophenyl or 2-trifluoromethyl-4-nitrophenyl; 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 Y - Z, 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 ^imethylacetamide (DMA). In a preferred method, the 7-H-pyrrolo /3,2-f/“quinazoline-l,3-diamine (VI) is I “ 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 - 215°C. 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 215°C. are preferred solvents. In a preferred method, the 5-aminoindole acid addition salt (X) is heated at reflux temperature in 1octyl 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 Y - z 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 ti» .127 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 1 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 he 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, solublizing 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. 43427 Example 1 7-H-I^yrrolo [ 3,2-Y] 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 31. 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. <ί&4 27 The Roll'd that separates is washed with cold acetone and is dried to provide 77.C g. of the title compound, m.p. 263-265° (dec.). An additional 17.2 g. of product [m.p. 262264° (dec.)) arc 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. 263-265° (dec.)) from methanol-acetone gives 395 mg. title compound, m.p. 264° (dec.); NMR (dDMSO): 6 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.; EtOH 232.5 (c 24,300),258 (e 22,120), 312 (e 8,090), 340.5 (e 7,420) nm; Et°H 250 20,940), 279 (e 2,310), 330 (e 7,140) nm. 7-H-Fyrrolo[3,2-£)quinazoline-l,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 methanolethanol yields 5.26 g. title compound as the monohydrochloride salt m.p. >310°.
Analysis for: Ο^θ^Ν,-.ΗΟΙ Calculated: C, 50.9S; H, 4.28; N, 29.72; Cl, 15.05 Found: C, 50.81; H, 4.22; N, 30.01; Cl, 14.88 <*5427 Employing conditions similar to those above, A. Rosowsky and N. Papathanasopoulos [J. Org. Chem., 39, 3293 (1974)] converted naphthylamines into 2,4-diaminobenzo[h]quinazolines.
Example 2 Method A 7-(Phenylmethyl)-7H-pyrrolo[3,2-£ ]quinazoline-1,3-diamine A suspension of 13.95 g. 7H-pyrrolo[3,2-fjquinazolineI, 3-diamine in 600 ml. dry dimethylformamide is stirred under nitrogen as 3.70 g. ca. 50% sodium hydride-mineral 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 II. 76 g. title compound, m.p. 228°, NMR (dDMSO): Λ 5.53 (singlet, «5 4 27 N-CH2c6n5), 7.12 (doublet, Et0H 235 (e 26,900), 260 (c 28,620), 317 (e 9,640), 345 sh (c 7,520) nm; λ^° Et0Ii 243 (e 26,020), 281 (e 2,430) nm.
A solution of 4.5 g. ?-(phenylmethyl)-7H-pyrrolo[3,2-f]quinazoline-j,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, rii.p. 226° (dec).
Method B 7-(Phenylmethyl)-7R-pyrrolo[3,2-f]quinazoline-1,3-diamine A suspension of 16.215 g. of 5-nitroindole in 1.25 1 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. benzylchloride (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 43 7 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 ge of solid, m.p. 104-105°. A 4.0 g. sample is recrystallized from methanol to give 3.6 g. of 1-benzyl5-nitroindole, m.p. 103°.
Analysis for; ci5Hi2N2°2 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 l-benzyl-5-nitroindole, 1.0 g. palladium on carbon (1096), in 400 ml. ethyl alcohol is hydrogenated at 1 atmosphere until the hydrogen uptake ceased. The suspension is filtered and the solvent removed. The resulting solid is dissolved in 50 ml. methyl alcohol made acidic with isopropanolic hydrogen chloride and the -amino-l-benzylindcle,hydrochloride is precipitated by the addition of 450 ml. of ether; m.p. 244-245° dec.
Calculated: Found: “15η14η2* C, 69.89; H, 5.87; N, 10.87; Cl, 13.37 C, 69.54; H, 5.73; N, 10.91; Cl, 13.63 A suspension of 2.578 g. of 5-amino-l-benzylindole, 25 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. 223-224°,which is identical with the compound produced in Example 2, method A, based on mixture melting point and NMR specti’al comparisons.
Examples 3-60 Employing conditions similar to those recorded in Example 2, 7H-pyrrolo[3,2-f]quinazoline-l,3-diamine, in di15 methylformamide, is converted to the sodium salt with ca. 50)6 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-U-pyrrolo[3,2-.fIquinazoline-1,3-diamines described in Table I. 7-(Substituted)-7-H-pyrroloC3,2-f^]quinazoline-l,3-diamines +>« W .
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Hass and M. L.
I Bender [J. Am. Chem. Soc., 71, 1767 (1949)] 54.43 g. of a-bromo-ji-tolunitrile in 600 ml. benzene is reacted with 16.49 g. of sodium methoxide to provide 33.24 g. (4-cyanobenzyl)metbyl 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 205» 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. 25° for two days. Water (350 ml.) is added arid 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. 97-104°/l-2mm. [Hass and Bender, J. Am. Chem. Soc., 71, 1767 (1949) reported b.p. 107-109°/3.5 mm.]. 84 27 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. 106122°/1 mm., upon standing for 5 days partially solidifies.
The minor liquid rhase is removed by decantation and the solid fraction is redistilled thereby affording 16.24 g. 4-acetylbenzyl bromide, b.p. 108-116°/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)quinazolinc-l,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. 224-225°.
Example 62 7-[ (3-Aminophenyl)methyl]-7H-pyrrolo[3,2-f) quinazoline-1,3-diamine A mixture of 7.3 g. 7-[(3-nitrophenyl)methyl)-7Hpyrrolo[3,2-_f)33 quinazoline-1,3-diamine in 500 ml. gl. acetic acid and 0.7 g. 10?ό palladium-carbon catalyst is hydrogenated at atmospheric pressure and ca., 25°. 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: 15 Calculated: Found: C17H16N6,2HC1-H2° C, 51.65; H, 5.10; Cl, 17.94; N, 21.26 C, 51.40; H, 4.77; Cl, 18.22; N, 21.17 Example 63 7-[(4-Me thylsulfonylphenyl)me thyl]-7Hpyrrolo[3,2-f ] quinazoline-1,3-diamine a) A solution of 56.0 g. 4-methylsulfonyltoluene 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. 25° for 16 hours. After removal of the crystalline solid by 4542 filtration, the filtrate is freed of solvent, and the residual oil is dissolved in methanol. Thorough chilling of the methano lie solution gives a crystalline product which is recrystallized from methanol to yield 21.0 g. (4-methylsulfonyl)benzyl bromide, m.p. 94-95° [D.A.A. Kidd and D. E. Wright (J. Chem. Soc., 1962, 1420) prepared this compound by a similar method and reported m.p. 93-94°]. b) In a manner similar to that of Example 2,MathodA, 3.98 7H-pyrrolo[3,2~f]quinazoline-l,3-diamine in ca. 250 ml. dry dimethylformamide are reacted with 1.06 g. ca. 50% sodium hydride-mineral oil dispersion and then with 5.48 g. (4methylsulfonyl)benzyl bromide for 6 hours. The crude product is recrystallized (twice) frcm methanol to afford 4.82 g. title compound, m.p. 248° Example 64 7-[(4-Trifluoromethoxyphenyl)methyl]-7H-pyrrolo[3,2-£]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 tetrahydrofuren. 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 tetrahydrofuren. The tetrahydrofuran fractions are freed Gia? of solvent and the residue is distilled to yield 15.82 g. (4-trifluoromethoxy)benzyl alcohol, b.p. 98-99°/9-10 mm.
CW. 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. ?0-74°/ll-15 mm.
Analysis for: CnH^F-ClO 1 ooo 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]quinazoline1, 3-diamine in 250 ml dry dimethylformamide is stirred with 1.32 g. ca. 50% sodium hydride-mineral oil disperson 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. 25°, 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 63 7-Methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine A solution of 5.98-g. 7H-pyrrolo[3,2-f]quinazoline1,3-diaraine in 200 ml. dry dimethylformamide is stirred under nitrogen and /,.58 g. ca. 50% sodium hydride-mineral 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-10 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. 250°; NMR (dDMSO): δ 3.88 (singlet, 7-¾), 7.02 (doublet, J=3Hz, 9H), 7.15 (doublet, J-9Hz, 5 or 6H), 7.41 (doublet, J=3Hz, 8H), 7.72 (doublet, J-9Hz, 5 or 6H),p.p.m.; Et0H 234 (e 25,280), 258· (e 24,540), 317 (e 9,090), 345 sh (e 7,810) nm; Et0H 243 (« 23,570), 280 («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 pre37 cipitate that is recrystallized from methanol-ethanol to yield 3.07 g. title compound as the monoacetate salt, m.p. 247-249° (dec.).
Example 66 7-(3-Methylbu syl)-7H-pyrrolo[3,2-fJ quinazoline-1,3-diamine In a manner similar to that of Example 2 Method A, 3.98 g. 7H-pyrroloC3,2-f]quinazoline-l,3-diamine in ca. 210ml. dry dimethylformamide are reacted with 1.06 g. ca. 5OJ0 sodium hydride-mineral oil dispersion and then with 4.06 g. l-iodo-510 methylhutane. The reaction time is four hours. The crude product is recrystalli2ed from acetone and from acetonemethylene chloride to yield 2.58 g. diamine, m.p. 185-195° (softens 180°).
(. 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 methanolethanol to provide 1.70 g. title compound as a monohydrochloride, hemihydrate salt, m.p. 300° (dec.).
Example 67 7-C(Tetrahydro-2-furanyl)methyl]-7H-pyrroloC 3,2-f]quinazoline-1,3-diamine In a manner similar to that of Exanple 2 Mathod A, 3.98 g. of ?Η-ργΓΓθ1θ(3,2-£]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. 25° , for 24 hours, 0.21 g. ca. 50% sodium hydride-mineral oil dispersion are added. Stirring is continued for one-hour, 0.73 g. tetrahydro^urfuryl bromide is added, and, after stirring for 6 hours, the reaction mixture is kept at ca. 25° for ca. 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. 310-31V (dec.).
Analysis for: 015Η17Ν50·Η01·1/3 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-pyrro1o[3,2-f]quinazoline-1,3-diamine, sodium salt A suspension of 3.98 g. ΤΠ-ργΓΓοΙοΕΒ^-,Τ Iquinazoline1,3-diamine (20 nmoles) in 350 ml. dry dimethylformamide is stirred (under nitrogen) with 2.11 g. ca. 50% sodium hydridemineral 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. Re10 crystallization 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: C|gH^gNgO2NaO.25 H^O Calculated: C, 60.08; H, 4.06; N, 19.46 Found: C, 59.94; H, 3.88; N, 19.44 *54 27 Example 69 7-(4-Cyanophenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine A solution of 15.94 g. 7H-pyrrolo[3,2-f]quinazoline5 1,3-diamine in 800 ml. dry dimethylformamide is stirred, under nitrogen, with 4.61 g. ca. 50% sodium hydride-mineral 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 dinethylformamide, followed by washing with a small amount of dimethylformamide, with methanol and thorough drying, yield the title compound, m.p. 344°(dec.), NMR (dDMSO): Λ 7.17 (doublet, J»SHz, 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 j 7-H-pyrrolo[3,2-f]quinazoline-l,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-diamines described in Table II. 4S4 27 z-\ zb z-s z-s O O Φ 0 Φ Φ Φ Φ Ό Ό Ό Ό \z sp zb zb υ 0 03 X< © O’ © φ Φ io CO P P © Ό Ό 03 03 to tO 03 z-s sp I o o 01 1 M © 01 CO w X* to to to © co P o to © to tO x< 03 03 03 to tO 03 03 A to to 7-(Subs ti tuted)-7H-pyrrolo E3,2-f]quinazoline—1,3-di amines P fifi 5b · fe > ϋ ρ Φ 0 cec • Μ X A S. ess A Η O B3HX X ftHs a bo A A a «Ηή Φ P E3* O AZ w ε d> a fl o ε β β β. io » to w in io in io io to O O I o o > io oo ® to Pin co O O 10 p· co a Φ P fi N Φ fi Φ fi fi Φ £3 O N fi Φ £3 kw Φ · kM Φ JS P P Φ c c fe 0 J3 JS ft P £3 Φ φ 0 fe ft ft o fi fi 0 & £3 3 P 0 o P 0 o fe 0 0 P P P P ft N M 0 fe fe fi Φ Φ o fi P 3 P P O 1 Φ Φ fe Φ 3 Φ P P P fe to Φ fi fi ft £3 fi fi M fi fi P i P 0 0 o 0 Ρ Φ t o 0 P OP fe fe fe fe N X< fe fe fi fe fe 0 0 0 c JS fi o 0 p 0 p 3 3 3 3 Ρ φ P 3 3 XJ P P P P P P φ ja 5b P P 1 JS fi M M M M S J3 M M X* Q I I 1 1 1 P 1 1 * 1 01 4 X* 03 X* Φ 03 x< 03 03 P >» | fl ·· zb p Φ p P 5b P £3 5b 5b fi 5b ft fi fi Φ fi 0 P P Φ 0 JS £ fe >1 5b JS P M ft P P £3 P fi C ft 5b P 5b ib 5b ft P Φ Φ P fi 3 X C fi 0 c £S £5 5b Φ fi 0 Φ Φ fe 1 ft ft fi JS P £3 £3 £3 P X* P P 0 ft >»P P ft ft P 1 5b ib P 0 £5 5b Φ O 0 fi . 0 P P ft c P fi β fe fe P fi Φ Φ 0 fi Φ Φ fe P P XJ fl υ υ fe 5b B JS fi P P 1 >> fi fi ft I 0 1 P* ft a υ ι fi I fi 1 X 0 I l 03 1 X* i X· 1 I X* 1 X* ci 1 X* oT ci oi M co Μ M M 00 © Μ Μ M 3-methyl-4-nitrophenyl 5-fluoro-2-nitrotoluene 85-90 4 M 267 (dec) O CO ;427 z-\ fi fi Ό fi fi Ό fi fi Ό P «1« Sb · k > fi P © O «cn • 01 X fi k fi S 3 fi P o «ft 42 X «Ο fl SO Ο fi o «ft^ P fl fi e4 < fc£ fl P P fi © N fi P Λ P o ε O k Λ CM fi ft ft · S O fi<£ X Cd ο in οι fi fi in in P 01 l·- CO Ό <0 P co r* 00 in 03 I to t CM 1 01 CM 1 01 O 1 P 1 p * to o 1 to l> P ft co r* CO in to Ol to 01 01 03 CM O ol w cn ft « S tn to tO CM 10 LO CO P in rin to co in CO fi fi Ό o I co OJ bO a S to co co in a in p o o P P fi fl P •O P k Sb a o k p P fl I in ί o k o P gX fi I Sb fl P fi fl P *3 P k Fb ft o k o fl P ft I fi fl P •o •r4 ε P k lb ft o k P kfl fi I.
CM fi o fl k P o P 3 fi fi 1 fi fi 0 P C c P fi fl c fi fl ft P P fl ft •rt fl· P ft P 3 43 P P ft . P 3 k 0 P Ρ φ N o o »3 σ P fl fi fi fl fi s s ft 0 '-'ft s SP k >» ft o k © P fl O' o k fi fi 1 I CM 01 P s cr o k © P λ a ι ρ a ο P o k o P Λ o I p k O P P I £> ib S3 P ft o fl « P P P k P 3 3 ►x Sb P P cr σ· P ft c P Sb Sb l l I >» P ib c fl CM P ft 01 s 3 fl P P 1 1 0 I • P •ri P P P P © N © Ό s N © © >» k fi k •rl P fi fl s »fl o P P k k k P P P P 43 P Sb Sb Sb 3 3 fi 43 P fl ft | ft ft t cr cr ε , □ CM in 1 CM ( 01 < CM I 01 P 1 P r· P oitopintoo-cocJi co. eo co co co oo ® fi 1 5, 0» O* I /-s O P k Sb 0 42 ft P 43 fi fi a l P to fi t X © 0 k fl 0 P P 3 43 σ fi I CM I ii PP fi >> ε a o P kP o © 3 fl P ft ft 3 ρ cr k ι P p 1 >5 fl P P o fl P cr ι p I ib P fi ε CM I fi X o fl P & cf, I P P Sbsb X fl P p fi P ε l to -trifluoromethyl- 2-fluorobenzotrifluori Ol P 01 01 <31 to P coco >9 · fa > © μ © O «W • tfi X © fa «S3 © μ o ME* 43 O 0] w I <7> μ w io Ci μ I o o bO X bO X TABLE II (Continued) X GO gO © © o MB*'*' β ©, a μ P © j? fa P o N a © Li P μ a I to © I Ό ο μ fa Li 0 0 a a μ μ fafa I ca © s μ μ ο a μ g. μ >9 a © ari a ι CJ I Li o μ £ u I 3* μ o a P © a o •μ P a N μ © μ 3 © © Ό © 42 a μ Ρ β ο g •3 -β a o a © © P fa 3 a •μ © μ Ρ fa a 1β£ 3 o Ό S Ν •μ fa μ ο μ fa © μ © μ a Ρ 0 μ 3 « © 3 μ £ fa Ρ © © 3 W a μ μ >9 3 ΰ £ © fa 43 9 fa © P © μ 3 © © μ 0Ρ fa g 3 © 3 © a fa Ο W © μ © Ρ fl μ a μ 0 © δ fa μ S £ © 0 μ Ρ ρ μ ο 3 fa £ δ 0« μ • 0 43 Ο fa 0 fa Ρ © fa © μ (Α Ρ Ρ 2 Ό 3 Ο 3 fa >Ρ £ Ό μ a 43 bOtS bO ρ ο a a μ μ •η a It fa 0 Ρ 0 Ο X © Ρ 43 © © © bO «* fa © 8 42 a © 3 •μ Ρ 0 *3 fa fa •μ a μ © ω 3 s g Ρ a - © μ μ 43 Ό © 6 3 μ © Ρ £ μ © Ρ 3 0 μ 0 Ρ Β h μ 0 43 3 fa 9 μ a fa 3-Ρ >9 3 43 Ό Ρ μ 43 43 Ρ >9 μ fa Ρ Ρ «μ 43 faP © © ϊ Ρ 6 S © 3 •μ Ό 43 >99 Ό «5 © μ &o 3* Ed μ I Tt* a 1 μ μ μ >9 0 43 c P μ © μ 3 a >> a4 o a 1 fa © 3* 0 42 1 a a μ μ 0 >» a μ P © fa μ 43 p a a I ca 1 01 fa Ρ μ C Ο ’3 *β © Ρ fa Ρ μ fa a Ρ •μ fa ρ ίβ μ W Ό © Ρ μ Ο Μ μ rl Ο Λ 4) »3 » β* Ο « U Ο (U J3.fi •Η -Η Μ S .Hg Ρ (μ a •μ μ μ ο £ $ μ Ό © Ρ fa μ fa ρ >> μ i a ο fa ο W μ isolated as the hydrate bearing one-fourth molecule of water per molecule of «ί* ο w Ci © Ρ © © 3 © © 3 © s μ μ 9 *9 ·· 9 μ 3 3 Ό Ρ *0 © *9 Τ3 ll μ 0 3 Ό Ο Ρ © Ο »3 CQ fa Ν a fa 3 Ν · fa a. Ρ a-μ 3 &μ μ a 9 © μ 0 © 0 Η 0 © 3 © μ a a © ϋ) μ © δ- a *3 »3 3 ε μ *9 μ 3 Ό ε 0 0 3Ρ Q S 3 Ρ 9 0 © Ρ fa fa W © 3 fa « W fa © a © a © >9 »μ ©Τ3 >9 © μ . © fa W Ό μ fa 3 6 3 © © © •μ © μ © © μ 3 II 43 43 © 42 μ 43 0 © £ 42 1 μ 6* 6* fa Ε- 0 £-· 'Λ fa ρ μ ό μ μ μ μ μ μ μ 3 £ © •Q © μ 60 sp sp SP sp sp SP SP Example 96 7-(4-Aminophenyl)-7H-pyrrolo[3,2-fJquinazaline-1,3-diamine A mixture of 3.20 g. 7-(4-nitrophenyl)-7H-pyrrolo5 [2,3-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. 180185° (softens 140°) as the hydrate bearing one-fourth molecule of water per molecule of triamine.
Analysis for; ^θΗ^Νθ «0.25 HgO 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-fjquinazoline-1,3-diamine To 3.98 g. 7H-pyrrolo[3,2-f]quinazoline-l,3-diamine dissolved in 250 ml. dry dimethylformamide are added, with stirring under nitrogen, 1.15 g. ca. 50% sodium hydridemineral 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 stiri'ed solution of 52.47 g. 2-methylindole in 320 ml. cone, sulfuric acid is added 34.00 g. sodium nitrate during a period of 65 minutes keeping the reaction temperature at 0-5°. 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-methyl-5nitroindole, m.p. 169-172° (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°]. *5427 (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. 29°. 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 5.53 g. 5amino-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 ice-water bath and is treated with excess isopropanolic hydrogen chloride and then with 150 ml. anhydrous ether. After chilling the resulting mixture for ca. 10 min. at 0°, the salt is collected, washed with ether and dried. Recrystallization of the salt from methanol (acidified with several drops isopropanolic hydrogen chloride)ether and thorough drying afford 3.82 g. 5-amino-2-methylindole hydrochloride, dec. 280-289° (darkens 268°). (c) A mixture of 23.75 g. 5-amino-2-methylindole, hydrochloride, 28.94 g. sodium dicyanamide (previously recrystallized from methanol) arid 800 ml. 1-octanol is’heated to reflux, ca. 100 ml. solvent is distilled (b.p. ca. 196°) to 4ΰ·137 insure anhydrous conditions, and the mixture is refluxed lor 21 hours with stirring. The hot reaction mixture is filtered and the insolubles are washed with boiling 1-octanol. The octanolic fractions are combined, cooled to ca. 25°, acidified with excess isopropanolic hydrogen chloride and diluted with ca. 2 1. anhydrous ether. After standing ca. 1.5 hours, the solids are collected, washed with anhydrous ether,triturated (twice) with ca. 100 ml. cold methanol, washed with ether and dried. The crude hydrochloride is dissolved in 400 ml. water10 50 ml. N hydrochloric acid, filtered and the acidic solution is washed with ether, chilled and basified with excess aqueous sodium hydroxide solution. A yellow-brown solid separates from the basic solution and is collected, washed with water, dried and recrystallized from methanol to provide 11.68 g. buff solid. A 4.08 g. portion of this diamine is recrystallized from methanol to yield 3.67 g. title compound, dec. 324-327°, NMR (dDMSO): δ 2.48 (singlet, 8-CHg), 6.88 (singlet, 9H), 7.15 (doublet, J=9Hz, 5 or 6 H), 7.68 (doublet, J=9IIz, 5 or 6 H), 95% EtOH 11.38 (broad singlet, exchangeable) p.p.m.; k„' 233 max (e 26,880), 264 (e 19,640), 328 e 8,740), 352 (e 9,110) nm; Et°H 255 <e 18,570), 285.5 (el,720), 335 (s 8,680) nm.
Analysis for: Calculated: Found: 0, 61.95; H, 5.20; N, 32.85 C, 61.72; II, 5.11; N, 32.86 *5427 Examples 99 - 103 In a manner similar to that recorded in Example 2, (Method A) 8-methyl-7H-pyrrolo[3,2-f]quinazoline-l,3-diamine, in dimethylformamide, is converted to the Nind-sodium salt with ca. 50% sodium hydride-mineral oil dispersion and the salt is treated with the indicated halide for the specified period to afford the 7-(substituted)8-methyl-7H-pyrrolo. [3,2-f]quinazoline-l,3-diamines described in Table III. Ο Q • Ο. £ /—s /-¼ /-¼ /-¼ F· /-¼ ϋ ϋ 0 CI 0 Φ φ φ to Φ Ό Ό Ό V—/ VI 's-Ζ φ o o £ Cl Φ rH o F* co top X 19 CJ CJ to X to I I 1 I O f in F- F- 05 M CO o © F* Civ-/ o to CJ CJ to to S X X X 0 a X 01 05 CJ CJ CO X X Φ T3 •rt fi O pH φ Φ X Ό Ό 0 •rt •rt ε ε pH o 0 5b fi fi N Φ X X £ Ό Φ Φ •rt X X X •β fi 5b 5b X •rt O N N 5b X £ S X 0 X Φ Φ P •rt 0 X X 2 o o S pH X fl c •rt 5b 5b £ £ Ό X ti 5b 5b | P a 0 0 W 0 φ 1 1 P s X w CJ X 5b M £ Φ X X X 5% 5b X N N 5b £ £ X Φ Φ P X X 2 o o ε X X £ £ •rt 5b 5b £ £ Ό X N 5b 5b 1 P C 0 0 in Φ Φ 1 1 P ε X to CJ ο Ό •rt ε « ε fi ο X X £ Ρ Φ ε •rt Ό η X conducted at 0° and the crude product is triturated (twice) with acetone prior Φ Η £2* * ε ο δ18 ο £ <0 X ρ φ ε Μ S «Ρ ϋϊ £ •rt Ν •rt £ X Ο X -rt £ Ρ Ρ Ο Μ £ >» Φ fi fi Ο Φ W fi •rt X ο F ρ 0) o X CJ to 05 o o o o X X X X 43427 fcOO «CH Ό Ή ·Η HP L BHP tO O *H ana · ε o-i ΟΛΗ Ο «η ρ lS fflii Λ .μ Ρ >>·β 4> «Η Φ S ε β a _ Η > Η S ΟΗΰΟ « β a ε »οη Ο β ο _ h ο ό ο « » SXS Μ ΜΡΡ TABLE III (Continued) β Ο _ Ρ ΝΌΗΗ Η« Ο « ΡΡ Ρ ρ ο ω» each Ρ hH h « Ρ Ρ Ο &ΧΡ ® ί. «Η C °_·β ® Ό Ο >» *§«Ρ 3«§§ ©CM Ρ fi ©fa Ofafa . flfirt OQ Ό S firt 0 0 fa fa ©rtfi A C© © © rt © fa ©fi Ό fi G > fl O fcOUO © © rt rt ·κ © ©rt 0 fi rt © OQ P © fl OQ fi rt rt firt ' fl 0 *O ©fi O rt 8 rt fi rt © U fi fi S fi rt *0 *0 ¢5 rt rt © 5 rt © rt 0 © rt © fa fi >> fifi _ Ό fi OQ g fa, rt rt O ©rt © © & fi OQ fa fi ΑΌ rt rt © fl X fafi© c © © © rt rt O rt © rt £ rt fl © rt fa fi fi rtfi © © rt rt fafi fi © rt O S fi rt rt Ό © Ά fi fi © fi P fi fi fi © SwZ Λ5 4 37 Example 104 8-Chloro-7-(phenylmethyl)-7H-pyrroloC 3,2-f) quinazoline-1, 3-diamine (a) Nitration of 6.66 g. oxindole in 25 ml. cone. 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)6 acetic acid and from methanol yields 3.85 g. -nitrooxindole, m.p, 240-242°. (Sumpter et al. recorded Ιθ 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. 25° 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 lC(2-amino-5-nitrophenyl)acetyl]pyrrolidine, m.p. 210-211° (c) Benzaldehyde (51.16 g.) and 10.0 g. 1-C(2-amino5-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 176° and approximately 15 ml. of distillate are collected. The reaction mixture then is cooled, poured into 700 mi. anhydrous ether and chilled. Recrystallization (methanol) of the solids that separate gives 9.70 g. l-C[5-nitro-2-[(phenylniethylene)amino]25 phenyl)acetyl]pyrrolidine, m.p. 170-171°. κ, (d) A solution of 16.0 g. l-[[5-nitro-2-[(phenylmethylene)amino]phenyl]acetyj.]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. l-[[5-nitro-2-[(phenylmethyl)amino]phenyl]acetyl]pyrrolidine, m.p. 128-129° as the hydrate bearing one-eighth molecule of water per molecule aminoamide.
Analysis for; C|gH2iNjj0jj«0,125 HgO 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. l-[[5-nitro-2-[(phenylmethyl)amino]phenyl]acetyljpyrrolidine 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. l-benzyl-5-nitrooxindole, m.p. 143-144°; NMR (dDMSO):. δ 3.83 . (two proton singlet, 3H, 3H), 4.97 (two proton singlet, -NCHg-), 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.
C 4 2 7 (f) Phosphorus oxychloride (100 mJ.), 5 ml. pyridine and 10.0 g. l-bpnzyl-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. Re10 moval of solvent from the chloroform eluates gives a solid which is dried to produce 9.1 g. l-benzyl-2-chloro-5-nitroindole, m.p. 106-107°, NMR (CDClg): 6 5.40 (two proton singlet, -NCHO~) 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. l-benzyl-2-chloro-5-nitrooxindole in 600 ml. methanol and 180 ml. toluene is treated with a solution of 45 g. commercial NaSK (xHgO) 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 (xHgO) 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 throughly 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 54 27 chloride and diluted with 11. anhydrous ether. A gum forms which is separated by decantation, thoroughly triturated with acetone and dried to afford 16.1 g. 5-amino-l-benzyl-2-chloroindole, hydrochloride, m.p. 228’ (dec).
Analysis for; ClgH13ClN2.HCl Calculated; C, 61.44; H, 4.81; Cl, 24.19; N, 9.56 Found: C, 61.16; H, 4.71; Cl, 23.73; N, 9.42 (h) A mixture of 14.65 g. 5-amino-l-benzyl-2-chloroindole hydrochloride, 11.14 g. sodium dicyanamide (previously recrystallized from methanol) and 300 ml. 1-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 280-283°.
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. methanol-100 ml. N sodium hydroxide. Crude diamine is collected and, after washing with water and drying, melts at 280-283°.
The solids melting at 280-283° are combined, recrystallized from dimethylformamide, washed with methanol and thoroughly dried to give 4.26 g. title compound, m.p. 285-286°.
Analysis for: C^II^ClNg 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 • 57 ΰ ·1 27 Example 105 8-Phenyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (a) Nitration of 9.66 g. 2-phenylindole [previously 5 purified by recrystallization from toluene and by dissolution in anhydrous ether, treating with charcoal, filtration, and removal of solvent, m.p. 184-186° (softens 180°)] 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 V. E. Noland et al., J. Org. Chem., 51, 65 (1966). The crude product is recrystallized from methanol thereby yielding 8.28 g. 5-nitro-2-phenylindole, m.p. 192-194°. (Noland, et al., recorded m.p. 201-203°). (b) A mixture of 7.86 g. 5-nitro-2-phenylindole, 100 ml. absolute ethanol and 10 g. (wet weight) Grace No. 28 Raney nickel (previously washed with water and with absolute ethanol) is hydrogenated at ca. 3 atmospheres pressure and ca. 27° in a Parr apparatus. Hydrogen absorption ceases in ca. 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. 227-229° (softens 217°), Noland et al.. J. Org. Chem., 31, 65 (1966), prepared this amine similarly and reported m.p. 234-235°.
Addition of excess isopropanolic hydrogen chloride to a solution of 6.42 g. 5-amino-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 280°).
Analysis for: C14H12N2*HC1 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. 1-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 insolubles are washed with boiling 1-octanol. The combined octanolic fractions, after cooling, are treated with 25 ml. concentrated hydrochloric acid and diluted witii 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. 318-319° (dec., softens 270°). Recrystallization of a 4.5 g. portion of this material from methanol and from acetone, followed by thorough drying yields 3.09 g. titlp compound, m.p. 322-323° (dec., softens 320°).
Analysis for: C16H13N5 Calculated: C, 69.80; H, 4.76; N, 25.44 Found: C, 69.85; H, 4.61; N, 25.51 Example 106 7-Me thy1-8-phenyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine In a manner similar to that recorded in Example (Method A), 6.88 g. 8-phenyl-7H-pyrrolo[3,2-f]quinazoline1,3-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. 295.0-29S.5 (dec., softens 288°). · 4 3 7 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 pg/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 35° C. The in vitro antibacterial activity of the compounds tested is ex20 pressed as the minimal inhibitory concentration (MIC) which is defined as the least amount of material (pg/ml.) that completely inhibits the test organism. iS4 2'7 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: ca 03 05 ffl co β rt as Α rt © SCO ><0 co co ¢0 rt r* co co rt to CO © M* CO • • • a r- o o O rt to I © Brt ©W xs«g firt < ftSi iSfc a w«! SS S ΜΗ CJ rt rt co co 10 CJ co to IS £* 0) rt o o Ci © • • • • • a rt o O o o © CO 00 CO 10 Γ* co GO to © © xf< © • a • • • rt o o o rt W ¢0 01 io ao 03 rt N © «Ρ 01 rt • rt tO a • ff aH88 rt o o o co l·* © 1.“ • &ΗΚ> Z-S5S O LOOi SO 00 • ®iH CO ’ ’ S W «J 10 • ® +» CO «I -I H CO o IO tf V Ol rt CJ Φ SP IO to CJ © 0J © rt © © a a a a a a rt O © o O © CO xF M* © IO co •tf M· r* to © XT CJ 01 © © a a a « a a rt © © O © rt o s § © · £ o h I V to O © £ A O fa © T Ί* r •ft o I % o •ft s rt •s I « to oi to m< ift «ο •rt .& 0« fcO© X 05 fi© > © I o ε χ • 3 ow W 0 I X F· tO οι κ! SS A-PH 03 ¢0 05 © 03 03 © © F* © Γ- w © to 10 © to 05 Ο 0 • * « • 4 « • • © 0 X 04 CS X X © X 10 to © © to ?ϋ 03 00 03 © © C4 X X ¢4 00 03 © Γ- C3 w © X © X Ο X © © • • • • • • « β 0 w X O O 0 o O 0 o © CO 00 © F* © X oo © © O w O 00 © * rf rf • • • • • « • O 0 X to F* © 0 0 © © © X TABUS IV (continued) •Η EH n-itO HOOT ϋ oi I ta • S 3 M S:-p ti cn ta Α ή ο t< oo a οο co M O O © rf ¢4 0 w F· Q rf 03 © © © © 03 X • • • • • • σ to X © » © 0 w 01 A © 00 oo X 0 01 X X M co © a 03 w © O «a· © © X 0 © O * • • • • 0 0 a © © © O Tj· M wo s 00 « -t ta to ri* co 3 © ri* X 01 rf co t? «a1 F- rf w 03 03 M* CJ 01 © 03 0 X • • • • • * 0 0 O o 0 © O 0 0 W N W -, 43 » ta w © © © © M· H F- F* © © 10 53· OT «f © © rf © ¢1 O « * « • • • a a a 0 p O O © X O O O w M «I I o fi o I rf ί O fi X X X ti b X fi *β « I X © 04 04 I Q fi O X X X O rb X fi © Φ X rf 04 *« to J P ti ε o . fi o x 2? X fi **? t ί +> ti ε ο fi . ο fix ϊ!λ -tj> A M I s -P ti ε Q fi O X fi γ 04 <ς!« X X >-4 >? s C fl S ω S) tu 43 43 43 A A A 1 0 fl O fl 3 !b >s 0 O ti t 1 0J I w 1 4-carbethoxyphenyl 1.95 1.95 0.488 7.81 >250 1.95 >250 3-nitrophenyl® · 0.122 0.061 0.0152 0.488 0.976 0.122 3.90 © § ί 0X0« 04θ ε I g CO © X to M* W X X CO X 4 2 7 anon ca ca ta •ri c, • K W>« HO) SCO f CO to © I o E H «Son » o So ass; CJ CJ P IO ft CJ P tP TP CJ to • « © o CJ 10 o o 10 to to P 10 to CJ CJ CJ CJ A Λ Λ co Tp 10 00 TP o ft to Tp CJ to ft * • • « • e P 10 © © P to P to W I Sin S<4»H ASS 8 LO 10 © ft ft tP to © « • « • • P to IO © P IO o o CJ IO to P IO in P CJ d d Λ Λ Λ TABLE IV (continued) •ri t• Η» HO« CO I M • <33» O id CO © © © © r- © > r- © P © Tp ft © © ft © • • • • • • • © © © o P <2 P c· S © to © ¢5 w CJ d 03 Λ A CJ CJ d © P w w Tp CJ Cl P «< TP P © P H Tp Cl CJ © TP © © © o CJ P P © d CJ • • • . • • • • • • O © © o © © o o o © WO seo •'Sri W ti I s!w «10 3£ > »40 to © © © Tp © © © © © © TP I> © Tp Tp tP CJ ft ft TP © • • « • • « ♦ * o O © © © s © © 8 © P d d © •50 to Tp © © I> TP O © £ TP ft ft ca ft ft ft © • « • • • • • o o © © © g P o 8 © P d « Kl & » •g I © Ψ d ? © § £ Ψ w P & © £ P t «? tP I s is ?! ...... •f ft IO ft «ft i OH .§£ I s P OH s b •ri S « 0 > H I s P ©P ε cj - © 4& »’ £ OH .§& Ό a 1 -a in_ft ·£ +» » E Sh « ω •*rG *.ft d r> g& H » 8£ +> ft I H <0 **»£» 10+) e 0 » S ¢3 OP p. ri O Cd. l·· d oo d u H h • a a ωω HO 3® >tO I o Θ r-i • 3 ®n W A AO 3HO ftSH a a a ra a a a o to a Λ ca o P M P O tO © CO © CO © © • • • • • • w M O M tt P CO 03 X1 GO P co P P CO o 01 X4 CO CO co w CO x< © P 01 x< o x4 © o • • • • • • • * • © w © o © © © © o © © P P M © to IO © CG © © © © © β • · • • • « • 03 o tt M M O to tt P © to P ? ι—i W IO o TABLE IV (continued) I HCΑΛ» • h p.> M A kiH ft+> H © © © CG P © (0 © © co P M| © © X4 X4 X4 • Htt • • a a • • BI O© M O © P o o © o© to 0! I ffl • (3hm *312 Ah® WO 3® . AH W h I 3» AlO ta 3Λ • O p W' til M Ol © GO X< P CO 01 01 03 © to P © IO 03 P 10 X4 M P © M P 03 tt P x< ©J © © o © © P o © 03 k • a • • • • • a o Ό © o o © o © O O © © © © W** x< Ol 03 M o © M M X4 X4 Ol 03 10 © © X4 © © 03 01 P P © • • • • • a • © tt © © O © o © © P © © © © X* X4 to P M M © M © X4 X* P © © © © © © X* 03 03 © a • * • • « a « P M o © tt O o © * © M 3,4,5-trimethoxy- 0.122 0.061 0.0152 0.976 3.90 0.122 7.81 © © P Ol tt X· 10 Cl tt tt tt tt tt tt © tt co tt «© tt 03 03 • S CL, fcoto P 01 300 ft Φ a< co to a* P co 01 01 Cl 00 P • • • • • ft © o c* o P g /< P o to to © to CM Λ I >!#n * S52 β·κο ftfiH H to O M -A OJ 01 Cl · OJ r-ί r-i © r» p oi co CM CM P LO p IO P δΐί,Β © to P 00 co P r· P· P 3 co P co 01 tn CM P P to co « « • • • • • • © © © © © © 03 © © ts to © io io ? ? TABLE IV (continued) • S n «§$ ι n .&Sw Oh® §g . « H ten n os M* a* so a· « a* ¢0 Ό 00 a< 01 «3 i-1 to P CO Cl Cl CO § n to tn IO OS to s 0) P CM Λ cM CM P s to CM P to S3 Λ © GO © CM © to N CO c* P ea o IS © © P © co P w © © « • « • • • « g • P © © © IS © P to » Β B S3 S3 o P H ρ s S S (3 fl p rt P 3 « 3 P •rt P a ft ϋ & H C fi fi P P I a ft ft £ £ 9 § § I I HMM iH & I « HH άΙ ¾ S 3 s c i? •ri P I I Ol 8-qulnolinyl 0.244 0.122 0.0152 0.244 1.95 0.122 7.81 o h oi to <# b to o- co tn 5J, γ}, *ψ «I a ‘7 W •rt A yjo H© SCO >© I o S H * 3 ©to U3 © GJ O C-HO ftflH I »rtf* 43 W • fa A1S ι/) f* 5ζμ Ap »rt •rtO• H rt CQ O© O© I w j· §3» © fa GO MO SCO • ©H W fa 2 3 to 3 to 43 • «·μ iw ft! »3 © 3 H ο.μ a &°S I 8 © ω η 03 o o H •rt GJ GJ CO GO « • 4 • w o to £S O Γ- io io OJ 01 CO IO ’i* OJ to OJ £ OJ OJ to H a CQ CQ $ ca o © IO OJ Λ CQ CQ to OJ to OJ co co 00 co -cr co OJ H H GO OJ CO CO H o co o • a 4 o o © o to o to H ca to OJ cd H rrt to xi- CO CO co GJ 01 a e a 4 a is Γ* © to to H H o to O o CO Γ- rt GJ GJ CJ © 4 • 4 4 rrt to H to © to ca w © OJ GO 03 to to 01 H GO 4 H © c o o • OJ H 4 CO © 4 o o o o to M o o co o <0 IS OJ o to Λ co co g /? co co Γ- co <0 co rt* H 01 r* © IS IS © ca © © © © © 01 O © H • a • * • a • • a o to rt o o o © o to o ΙΟ OJ CQ »4* to •rt to to 00 © to co © © M* ca to 01 a a a • a 6 • a a H H Γ- O rrt o o H o W IO to 03 ι m· I P o © N T3 O I M to μ w OJ io 0.488 0.244 0.061 0.244 0.976 0.122 ! 43 rrt μ H rrt fe ft· fe Η fe fe X (3 a fe 1 s a o (3 , © a rrt HH p •rt 43 1 ir) 42 © fe 1 fe © > P 71 W >> A x: 5? •rt fl H rrt © rrt >> 1 c rrt A H © fe© fe fe ε fe C O 0 fe 0 b 42 >3 A 3 a •h a 0 ε h P a X 0 P © © © <© © •h Ο B © •rt a rrt © fa 43 ( 43 43 C43 © ε 43 © ε a a a to A ? 43+> 3 3 cl & 1 01 1 01 I 01 »* rt 1 03 r-t I <ϊ* to w μ to to w to co to co to GJ to o CO r-f OJ co co *5437 rt rt M3 Is co io IO ci ca co 3 • I to to o IO ca I . I « w “Si§ ¢3 01 4< CO CM 03 W 4« co rt rt Ci ca xp « • • « • O Q rt o o rc o o g fl- co Ss IO ca Λ © w § A ra © N H TABLE IV (continued) • ©rt W b I 3 to raw 3λ M *** Ml HSSi I w .S3» *332 « LCO ca co to co co H O H l·· w Ci 05 05 σι 05 • » • • 1 O to o o rt 01 co 00 w • rt rt co to rt to to Q Q O o o o O • • • • • o o o o O g fl ca w ca o ,ϊ P'S.
L Bi O'-, .. 3 s? ΛΗ L| O Ϊ5 go +,0 '-'M B ι ii 3S Μ Λ K Bi ΪΖ' I 4< w (0 H CO IS Cl co n co 52 r« r« Λ 01 io ca β, ©a rt P o'* o m l L a 2$ rcp © w HH Ο H SP I)fcp Wrt to £ § P &8 ω+> «ο nSH oh O O cose 11 », <« ω Bi lh ·· g fcfl H £ £§ 0 I A >jJ § •J 0 b +> O 23 Si'S S3 O o rc 9 P rt © P o ia I S & ca 1 Tf A •s δ W to H CO CO co co co co I o •ri 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°.
TABUS IV (continued 0 rt 0 rt 1 0 fi fi rt fa fa . O *3 5 ε >> >> x: fi fa 0 ο 0 A »c fi +> rt fa 0 ra ra rt fi fi I d *a 0 0 rt rt rt O ra ra 0 0 0 -P •p rt K 0 fi fi © fi fi rt O Ό Ό ε 0 · 0 « rto rt o «© fi© fi© fa rt rt rt M4 •d O 03 © 03 fi ra ra • rt ri · rt · « rt T A A rt rt © ra « ra ' rt fi fi •ri ε *«-t ε fi ra ra o ·> ·» ·> «- 0 fcfl to 0 00 0 *· rt fi rt fi rt fi © fi •h rt rt rt h fa 0 g 0 S fi rt 3 rt fi >» © Art Art *3 fi εΰ g »O rt 3 fi g rt Xrt Rrt 0 rt ca o a o fi Λ fi 0 ra fi 0 fi 0 ε «* ·© rt rt rt rt « 0 fi fi — rt © 0 ifi © © rt •rt rt 0 V φ φ Ό fi fa fa Ό rt Ό rt rt ra O O fa o fa o fa © rt rt ο ε ο ε 0 fi rt o 0 rt rt 0 0 0 0 fa fi fi © o fa 0 fa 0 0 rt fa ii A A 0 © 'O fa fa 0 >> >» 0 fa 0 fa rQ fi fi fi fi 0 fi o o o o firt firt fi fi fi fi fi fi fi fi rt © 0 0 g > S S ε ε ε Φ ©rt ’© © © 0 fi o fi 0 fi fi fi fi. rt rt rt rt •p rt 0 ©· firt .p g ra fi ra fi ra fi ra « *B 0 1© 0 *d fit 0 rt 0 rt © © © © fa O fa 0 rt rt rt rt · fi s fi ε ra ra ra ra rt A A · © © 0 . ©rt 0fi ©fi •p rt rt rt fi fart fa ra ra Afa Afi ra ra03 « 3 bfl rt rt rt •rl © *0 *rt Ό - -fi rfi«H »0 0 TJ Ort 3 0 § § g B1 © fi © fi © © o Ort AO AO & A A AfiJ ε ε ε ε ε. SB1 8 ε? .o 0 o 0 0 ο rt 0 0 rt •rl ra © η ε ra ra . ra •rl Λ •ri rt rt &8 fi 0 Λ 4) fi fi fi Hfi Η.Ο E-* £< Ό ο rt ho fi •rl < 03 © © © 45437 fi Ρ feW • fi © ft bOflO j© ι a • 3 h a Zhao SS5 no 3« • AH h I 3 W A a oh e &® ί I S O M( © © M © © • « • 10 10 o to o P 03 P a P «3 A I g P • S 03 03 IO 03 P 03 P ¢3 © P O P • « • • M o o o I ρ M fi Λ tO A Sh ftHH © © H tt tt X* 00 « P P © tt tt ΗΓ• H W wss? © Th © © M Th M © © Cl © • • • w o o o a X* P IS P X4 w 2 tt 03 o © © • « • • O © o o oo OO Th H » O V to /? H n Λ • AH W hH leg © P M © IO w © © © w « • P o © P P w w «I P P P b >> >> fl c 1, fi & Φ H Λ Φ £ i £ e? fi ft P P Ο H S 0 H ib H S bo fl P P a a 0 fi 0 0 0 A ib o 0 ti t o I fi | fi 1 c. ft & 1 X4 1 CJ I X4 1 X4 O) a H b· c2 2-eyanophenyl Ο.Ο31 0.0152 0.0038 0.122 0.122 0.0152 0.488 4-(methylsulfonyl)- 0.976 0.976 0.0152 0.976 7.81 0.244 15.6 phenyl » C- p. £ ω ft k© • « © CU fcoco ft© © 0· © ί o S P «3 on W fi fi o fift O kCH © © a © o fO o o o o £0 © © © © © 03 01 03 03 03 A Λ A A P © P © P P to © N P ¢3 © © © © 03 « • • O o © © P o O IO Cl o © Λ O to Λ P P ¢3 © I** © © 0© I ft IS «£to • k ftlS © β Kp aft ft to © © IS © g P 03 © © © P o o o © © © © © 10 03 01 Ol Ol el Λ A Λ A Λ TABLE V (continued) PIS • p to « o© o© • I w k ft to • fift© S-p fift g-g00 g z< or ft © r* © © o © © © P © r- © P c* © © © © P © © « • • o • • • « to © © o o o . r* o P 03 W A M Λ © CM M © P P P © in H Γ* P 03 to o P P H to o © 03 © o 03 o O o o o P • • « • • • • o o o o © o © o o to© fl© • fift cn k ( Sto fi© CQ © IS o o P P to to fl£ • fift IS O' © © © © o o © © 0- c* OJ © o P to P © © « • « • « « w 03 P o to o © 03 © o o o © © P «1 I I Is A fi o a P P p P ft tb 1 fcb . >> S ci fl o β I β P H ft fl ρ fi fi fi 1 fi P fi s 1 b ib ft £ £ +> P £ 1 £ P W fi fl *3 a a a H ι a ρ a o 1 ·Η ft ρ ft o o a b 2 © b° N 0 Ό *fl ε N k k •rt fi β k £ k fi fi H ft •η fi ft ft « 41 «ft ft ft ft 4» fi k k k •rl •ri 1 fi >»ft fift £ »H b Ρ» S ? At* Cl 0 β Εβ ft 1 a a F 9* CM P M OM to 1 CM 1 to CM 01 CM fi φ 3 H OM C Pi ο ε § 8 O Cd © t* © IS CQ tS > N © C· P 03 © © to P © © .© © co co co co CQ CO TABUS V (continu, ft woo rri CO I I rri r 3 «Η “H§ I -ri > «2» PN • P © « o© o © ι a .&38 e+; sd g-g® « ΦΡ st w a 3£ > » +> W | H gig «I O tri & ftO P S P P § Ϊ I CJ © ft cn © © Λ © © o » © © © © 03 Ol 03 Λ © Tp P © © Tp © Γ* tP 01 o ft • • • * o o © o co o to d oo ri* © w © ft © ft ft © • • • • © o © P P © © 03 © © © © © 03 01 ¢3 Λ A A © Tp Tp © Tp © P Tp τρ © © Ol ft © CJ w « • • • • • 4 • © 03 © o P c* o P © P © © ri w CJ $ P iri » o co r03 co v P © 03 P » © 03 © © w Tp P © • • « « « o 03 o o o © » a 4¾ I P P P £§ ®i ri> Ϊ& © P Li 0 - o fi S3 Q ©* I £ © * fi op LtP © O fi fi S3 •η σ h I γ ri· g ί I Tp I P £1 3-5 r d ι o β I I “ίκ to & co co cn o CO ft ft «0 o S3 p· af ? 0 Lt J2 O CL ®P ss •ri w ti 0 +> = I “ 01 £h si ε © ?*S Li ft O O fi Li PP P P P fi Li I γ rf CJ I o Ϊ rri C >> as d © ft © ft fi S 4 3 7 ί © Bi—ί υ to w®ao «ΉΟ Pl H Hi S&S5 Pi+> HI «Xlto MS ι n .sas R?|S •1 too BOO • OH M L I Sw «ro Ih ω·0·Η «ι β § -A 0 S fi g <3 ω rt ca <0 Γ* o • © rt to g /? t rc © Ό rt © • to « a o co co • 03 <0 © w 1 rc © N o TH Μ» 03 • g fl 2“ β Λ naw o _ © 03 g 5? SS 0 to GO (0 L • rt CO L 3 P O ** ο ω rt • • Λ*$ fi o 5 o Ί3+> P to NO ft u © rc 5 03 • o to 15 H s 01 rt rt *P tOrt • ® 0 £ H co ’ a fi a co P © •gw . © a o O 10 P b ω P 01 3 © ewp fi 0 _ © rc rt w fi rc © rt ©rt P H © © to rt «> © £ o N P fi fi w © a a «· rt ft P g rc 0 o 3- fi fi N •H fi i Ή o © rt ·? fi g 4 to 1 N S 1 1 u M £ Q 05 fi a • ·*’ 74 * ffl » Λ ¢0 to •rf bS • SO ft. 60® na © © M © a 8 w • « • · • © © to w P P P tt In vitro Antibacterial Activities of 7,8-Substituted-7H__ I o H . 3 AW Hi Α «Ο CHO ftfiH Ρ M • p W ti O© 0©l I fi ! feptt • SP© X4 X4 P X4 © X4 X4 © X4 © ¢3 03 © 03 • « w © © © o to CO M as • AH W h I 3» en z κΝ to Si • AH W hH At <21 «I X4 co © o X4 co co to © 03 X4 X4 © • • • • » w o o o P P 03 8 P to © 03 o © © o P o o • • « * e P © o o o © P © M © M to to © © © • • • * a P P O © © w w 03 © to 03 M w w © P © • » # « • P P P © © w tt s *8 a & p 4) ε £? ί S ® t* © Ο H 03 w © O O O ’ o Η H P P ta •rt Cfi fcfl® X© I © ε x • ρ Φ to W Φ fi O flrtO ftCX ra & 85 A+>H, ra ra ra to $? o © ca Λ rf rf ca o 0) to © © © X X © tv © ca x TABLE VI (continued) *ZJSS «88 OT • · © ca © ι w βμ» ιβΗ® 2+J «SH carats o h OT » 1§ rag? Sto fi© 03 3Λ 4 φ «Ρ W fix fit ca .© © F* 05 © « • © tt © X ca X a X 05 © © • • 4 to tv ca © «1 & Φ •s H & S ra e o ω o s £ £ •P Φ s rf © © s s s Growth medium: B=Wellcotest· Sensitivity Agar with 5% hemolyzed horse K «I 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 carbo'iymethyl 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, in10 fected at random intraperitoneally with a 0.5 ml. standardized suspension (LDgg±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. · 15 Deaths are recorded daily for 14 days and the PD5Q (mice are treated at time of infection) and CDgQ (mice are treated six hours after infecting) values are calculated by the method of Reed and Muench [Amer. J. Hyg., 27, 493 (1938)]. .77 Λΰ427 co tv • F© © X 00 © X X 03 © Η « · » · 03 © F· © © ©tv · · 03 © OJ 01 • · x x © © Λ A ©to©© ©to©co Cl X © F> 03 X © F* • a · « *·«* ©wxo ©wxo © n <0· w CO 03 Vi X X 0 X X w a w to X fi X fi X fi X fi fi © X § © X 8 © X 8 © X 9 tt 0 0 3 0 3 0 X fi •rt fi •rt fi •rt fi fi fi E fi E fi E fi £l a tfl V c « Λ OH g & fl Η o ^43 1 H >i§ E?,a X I X h 043 Z8 Μ © tO GO Ο © GO CM © © p GO WX-COM W LO tO M PP 10© MM©O to tOGO 10 g X< © 00 · X4 tO M CM > · ρ CM tO CO Λ © © tO CM CM to o · · • a © © CM X* A Λ ©©©P CM «CMP CM · · P©tO © 10 © to • a CM P LOCM · · CMP© tO © © 10 io O 10 CM CM P P © GO © p © M tO P © ¢0 © P © M tO tOPOO WHO© © © to X* P 36.6 5.1 1.56/3.11 M X» to a ρ as P fi P « P fl P p h fife ΚΪ1 1¾ »8 Oj3 K W S W H ,H1 f1 1 H 1 H §& Is Is Is SA 0Λ oa oa oa Th Th X» <* •2 P P fi P a a 1? Λ «I to to to t- to © · · to · © toweioi CJCl Π3 »3 • ·μμ • μ © © CJ OJ© Α Λ © A Ρ Ρ 3 3 © μ © © © μ © © © to μ to C* to μ W fa fa • • 9 » · • · Ρ Ρ μ »HOO to μ © © fa fa 3 3 © © © © μ μ a ε SB cal IO CM H ©· P a © to TABLE Vir (continued) Ol © *3 ε © «a © © rt S b •3 e ο a O μ a SI O © μ μ rt rt Δ fa •rt e «Τ1 © P μ © μ μ P o © P o & o Ή τί © fa to £.S *-g © a P μ .0 μ μ Ρ © © Ρ ο & ο Ρ *3 © fa Ί CD R . ϋ ο •Η ε ο <Ρ Ο §> μ Μ ο »3 •3 I ϊ μ a μ § © © a S’ β §· «I to trt 1= Γ •ΈΜ h h j?A I μ © © © Β fe «μ «μ μ ο a Ο Ρ Ο *3 μ ό S Ν © 3 © fa ©μ μ a © a α a PP ρμ Ρ μ 1 3 3 « fa 03 μ , μ © fe Ρ ©μ ©μ 'β & rt g © S 3 © 3 oi © •rt 5 Β ι-Ι Β Μ j3 Μ Ο •rtrt StO rt ρ ce •rt CD P o ε o ft rt ta II © © Ρ P 3 3 fa fa »3 *3 Η a © © a · a μ<—\ P 0 WO co 3 to 3 μ *3 Ό © 3 © ρ a P ω © 3 © Ρ © ρμ P ο & 3 3 βνμ § 3 3 0 »3» »3 © to © · Ρ W po 3 ί μ is 33 © τΗ © ¢4 • 3 03 3 μ μ μ · © » A W A M · © *Ηε μ s μ is 4- © to ~ to © 3 μ © μ a Ο a *3 ©μ ©s μ 8 μ a a A3 Αμ Ο |S 1’ X 3 © a W O *§ c 0 fl o •rt ID •rtrt *3 rt 3 © •a a BJ « 3 B o Β B a • BJ o t3rt © Rrt R O © a ο o O S fa ο B o 3 α ® . 3 R R R © μ ft © 'ϋ R ft R μ © O 2 R ε 2 tc 2 CD © a Sp © fa a +> 3 3 μ ε g S 3 μ μ © CD B=rt a rt rt O μ Ρ P o P Srt ο 3 tJ CD 3 3 •rtrt rt 3 A 3 B a >3 BJ O •3 B ο © Β B Brt fa Ρ Rrt R O bO 3 Β O B S © &S ft - R Ρ ® - ®rt Ρ ω Rrt RP a AP ftR © μ Rl 3 6 '•rt «•o μ »3 ’S'? 'S'f £ A § 3 B § o Ο o a o a χ Α ao ft o © ε B B „ 0 o ta o ta 3 © o s Ο B μ •rt •rt a 3 ta r cn R Ρ μ •rt a •rt a β rt B Hrt a © «rt to rt itS427 Example log The antimalarial effects of the compounds of Formula I are demonstrated, and elicited by means of the test procedure described below: Utilizing young ICR/HA Swiss mice and a standard inoculum of Plasmodium berghei KBG 173, it is possible to produce uniform disease fatal 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 ex perimental or control group are confined to 2-3 grams. All ani· mals in any given test are approximately of the same age. 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 0.3 ml. of 1:100 dilution of heparinized heart’s blood with a minimum of 90% parasitized cells (4 x 10 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 25 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 untreated controls within 6-8 days, it is felt that this system presents a candidate compound with the maximum -i5437 Ί',,-Ρ *' 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 in5 creases in survival time is included in a positive control'in every experiment.
In each experiment test compounds are administered in graded dosages. With highly active compounds, increases in dose levels are usually followed by increases in the survival time of the treated mice. However, if an active drug is toxic for the host, its toxicity may become a limiting factor; continued increases in dose levels also increase the toxic effects and may result in the diminution of survival times. Deaths 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 not 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 25’ dose* The results of antimalarial testing of compounds of this invention are set forth in Tables vm, ix and X. *5427 φ »| o ft © © © o c3 P © © ¢3 © H © Activity of 7-(Substituted)Methyl-7H-Pyrrolo[3,2-f]Quinazoline-l,3-Diamines Against Plasmodium berghei KBG 173 Malaria, in Mice (All Doses are mg, per kg., s.e. administration) ft CO to P to r- P 4 « 4 « • 4 o ft CO co r- © P *fi z\ /*> z-\ W © © © © w W X X X X X X 03 w P 01 © 03 03 s—/ z '-z S—z z z o © o © o © 03 o 03 P P 03 P © < 5 © < 5 O © © 0 5 τρ 0 o © © P P p P H P P P P >> >0 b >> fi β fi. fi fi fi 0 « o Φ Φ rt Λ rt rt rt rt ft ft ft ft ft ft 0 o 0 0 0 0 0 in h b Li Li P o O 0 o o O fi 3 fi P P p fi P —I P rt rt rt 0 rt V , 0 1 Q I ϋ I *5 ft 03 to I TP C3 to TP 3,4-dichlorophenyl 40 10 2.5 (2/5) 10.2 2.5 03WTpW©HCOO P Φ to to CM 01 • • o CM © ft Q ft w o* cm o w to ft P to to CM © © to ft ft to t* m co Ό a* Ί* « β · . · · © © CQ 0- © © to to Λ © to ts* fco ft x“\ xs Z—V ft X—v /*> x-\ to W to to to to to to to to K X X X X \ \ ft H 03 ft to to P CM to to ·»·* S-X s-z s-/ to CM to • « to o ft to CM © to O O to H P ft ft TABIE VHI(continued) Φ Mft Oft ooo o -p.fi m-pce ο β) « 60 I O a|S o o o 01 to K> ft «a o H b b fi 1 fi Φ H •P ft ω. £ ft ri H £ b 41 ft ft b b b a fi s b >» Jb fi fi fi ft •p o fi fi β fi o 0) 4) 41 fi 91 Φ φ o £ fi fi £ S o . fi £ £ £ a A A ft •ri sm A a a a ft T* H « Sr H H b O o o 0 b b g P b fit S3 fi ci 3 k £ fi fi ft 1 fi •rl 41 fi ¢5 3 ft ft +> +> Ό CO 41 fifi b ?b ib ft Φ 4) 4) 1 -fi O I 0 I o t ? ? ? ? to * A » CM 1 to 1 P to CM W 1 a· oi 4—iaopropylphenyl 20 20 10 (1/5) 10.2 2-methoxyphenyl 160 40 10 (3/5) 10.5 4-methoxyphenyl 160 20 5 (2/5) 11.2 a· Β co co oi Η Η Η Η H ft to > CM CM CM © CM P to «5427 «I « © o o CM O X* © tt CM tt © CM © © © © © X* CM P W © X* w w • · · · © © © 00 zp P p zP zP /P zp zp zP zP to © © © © © © © © © X X X X X X X X X X P CM CM w W CM X4 © CM P S«Z w s«z s-z \-z 'w' © CM • © O © © O © © © P © P X* CM © © CM CM © CM W TABUS V33J (continued) Shi (§«! +> too tt GH il © © © O © © <3 S © © © © 1 © © © a v X* P P I P H © κι I H AH & flg ft I A ·*£} X» ft *· W P XJ P P I *o I1 Sh & ΓΙΟ a to ι ο I t* ? ?* ? M rt H 4, § HH J.& £3 P fi Jfl BP » Μ* a t- a a •j* Th ν* Th Th Th fl o fl Ί I I CM © P I 1, 4) P ΰ & 2-methyl-l- --- — 640 (3/5) 9.3 Ο h to Th a a a a a a •i<342‘7 I! O to to 00 © fi 1 © © I * • o I o OI 03 1 © fi to CJ to to 01 to to Ol rt CO > o © rt i © -H © r*« 03 © 03 1 00 © • • • « I · • * a • 1 · • g 03 © 00 1 b· © © 0- 03 I 0· Gi rt rt I rt 1 to s rt /—k © © W » rt S-/ © • s-z O 03 s z-\ z-\ z-\ X“\ /> x-\ /»1 © © © © © © © © © X X \ \ \ \ \ \ rt rt 03 Xf rt 03 w W 03 s-/ o o x·/ v»/ © · fi 03 © © fi ♦ fi X • © rt © 03 O O o w 03 rt rt 03 TABLE VIH (continued) Wrt| Ort +> too 2 s:' ir O ii I O O I M< —I Ο Μ1 ϋ Ο «3 Ο ίβ ΗΛ Μ+ί!β ο ® a W afQ Κ 'ο Ο © •ο rt Ο Χί4 fi fi Ο Ο C0 Χί4 Ο Χί* » s s CO Μ Pit S rt ϊ I Χ“\ rt 1 rt b W 1 b fi b fi rt cf ‘rt 0 fi 0 I rt rt $ rt •fi rt fi 0 S? rt b A 0 A o fi fi rt s rt A © s rt •H 0 Ort b 0 fi 0 fa © b fi fi rt is fi fi 03 fa O fa 3 rt >>fi , 0 A rt fi* rt O rt rt c? fi 0 rt fi Ti t! fi firt 0 brt Λ rtfi b A b fi b b 0 rt ·** E 3 b 0 0 A fi 0 t> rt fi 0 0 fi rt rt *0 rt q rt fa rt na rt fi 0 0 fi rt Ό b·, 0 rt fi rt 0 B fi 0 T fa fi I β jfi 0 i 5? fi « | Y A ψ © rt a xF 9¾ ? Xf 0 rt i rt 4 ci 03* ci © I ^4 1 w ©* 1 to 1 © .—trifluorometho: phenyl § 3 ewe &oe I s o w © rt © © ©Ort © rt © rt 03 © © CO © © rt 03 xf xj* © © -45427 A IO to • · ca ca X © tO to w to X X H to O **« TABLE Vmfcontlnui •X O to 03 rt «J Ό Ί § c s *8 ©rc S© rt £g Srt firc •rt fi •d a •I w fi 'S oil rc © rt rt •ti rt to Λ © rt rt 0 rt rt co © S* C rt wrc w • © rc © © ϊ © w © rt rt •rt •s § © rt © fi£3 fi rt © « rc © • © © • •ti 1 c? rt w ©rt rc © rt CQ © c? 0 rt © to © © o © o © © 3 s rc rtrt rt 0 rt rt fi rt rc rt >fi rt fi fi w rc 0 © rt g 0 rc rt © rt rt © fi fi 0 fi rt fi H © w W rt rt rt rt © rt w rt S rt © firt co 0 © rt © © o H έ rc •fi o © « © 0 o © •fi o fi 3 γ u rt b rt & rt rt » rt w rt rc O rc rt rt rt o rc 1 £ fi fi rc rt r H * •M fi Λ rc ca ca ca d « £ rt rt fi © Q «I A •ο ϋ ,iS437 ti w © cS M| • o O X »1 © X »£ φ to © to -ρ Η 3 •rl Ο s3 ® o w\ ο α> Γδ £ ο . ΚΗ Ο Η Q < Ρ too ^.5 g «I © χ to ο © ΰ ο <0 ο I fi ο X ο I ο © I X £ Φ Ο £ ε ο φ Μ £ X £ S X «β φ *£ φ £ X 0 £ §Β XX χ ο ΰ χ g-s 3 § 3 3 ·η «Ό β ” S.8 e+3 a a •rt'rt »•3 M X si o‘rt • Φ Λ X W X X X ‘3 0 «*£ Φ tb >> X © ifl £ © £,£ X X « ΟΧ Φ φ ο id ε ε »g +> fi £ ΗΗ I >?>> H4J Ν -a+> β I 4> ® to ΒΛ « Μ 05 ο Φ X ·§ X ’ £ X £ Ό ·£ O © O fl »« Φ or CQ ol Al o ri« O CJ o o o TP © (0 H rt Activity of 7-Substituted-7H-PyrroloE3,2-f]Quinazoline-1,3-Diamines. Plasmodium berghei _KBG 173 Malaria in Mice (All Doses Are in mg. per kg, s.c. Administration) CJ 00 ! w ft to • • I · « • 0) © I © © © 1 CJ P © © © © © © © © X X X X X X X X © P P w © Tp P o XC o ri* O ri1 o o o o © Tp © P © © P «I < © rt P +> rt s P • 7* •d b fi fi >» S b V V fi fi 1 rt A £3 Λ « 0> rt b 1 ft ft Λ Λ | P d rt rt ft ft H 0 1 S ►, o o s N prt rt rt S. b -fi © b rri 0 rt rt rt ri rt fi υ ? 0 ? Φ ? 1 rt rt d-a d ri1 d <* » d in ¾ « ft o 0) (0 O rt <0 t t* t* t- I» o ¢0 rt. d Off ® 4 27 xf φ § P P £5 o o s-z g ω CD Φ fe £ fi fe W Λ *8 © •a o fl P •g Φ fi o xs p fi Φ ft Λ A _k Φ P a a > p fi a+j P P A A A A h fi fi Φ P •Η +> ϋ g gg 2d ,45427 Example 110 Single doses of 7-(phenylmcthyl)-7H-pyrrolo[3,2-f]quinazoline-l,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 21.025.29.) Daily observations were made on all mice for the duration of experiment (14 days). The resulting LDg0 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 post-drug-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 sacrificed and necropsied. Macroscopically, the tissues appeared normal.

Claims (10)

    CLAIMS:
  1. l.A compound of the general formula: (I) or a non-toxic acid addition salt thereof, wherein: 5 either (a) X is hydrogen and Ύ is -CH 2 R or -R 1 wherein: R is hydrogen; methyl; ethyl; n-propyl; ipropyl; n-butyl; i-butyl; n-pentyl; n1q 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, tri· 15 fluoromethyl, methyl, ethyl, n-propyl, i-p?opyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, 'carb 2Q ethoxy, 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. 2. ,5-, 2,5-, 3,4-, or 3,5-positions by methyl, ethyl, n-propyl, methoxy, ethoxy, Λ3427 n-propoxy, chlorine, bromine, iodine, or fluorine; phenyl trisubstituted in the 2,4,6- or 3,4,5-po8itions by methyl, ethyl, methoxy, or ethoxy; 2,3, 5,6-tetramethyl phenyl; 3,4-(methylene dioxy)phenyl; l-naphthalenyl; 5 2-naphthalenyl; 2-methyl-1-naphthalenyl; l-bromo-2naphthalenyl; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thianyl; 4- thiazolyl; 3,5-dimethyl-4-isoxazolyl; tetrahydro-2furanyl; or benzo[b]thien-3-yl; 10 and R ia hydrogen; phanyl monoaubstituted in the 2-or 4-position by amino, nitro,cyano,acetyl,propionyl, methylsulfonyl, trifluoromethyl, or carbethoxy; 2,4dinitrophenyl; 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-amincphenyl; 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-trifluoromathyl-4-quinolinyl; 2-methyl-4-quinclinyl; 3-methyl-2-quinoxalinyl; 2-phenyl-4-quinolinyl; or 2-benzothiazolyl; or (b) X is methyl, phenyl, or chlorine; and Y ia hydrogen, methyl, benzyl, 3-cyancbenzyl, 4-cyanobenzyl, or . 2,5-dimethylbenzyl; provided that uhen X ia phenyl, Y may only bs hydrogen or methyl, end uhen X id chlorine, Y may only be benzyl. 2, A compound ae defined in Claim 1 wherein X is hydrogen and Y is -CE^R where R is as defined in Claim 1.
  3. 3. A compound as claimed in claim 2 wherein R is n-hexyl; i-propyl; i-butyl; 2-methyl-l-propenyl; cyclobutyl; cyclopentyl; cyclohBxyl; phenyl; phenyl monosubstituted in the 2,3 or 4 position by fluorine 5 chlorine, bromine, iodine, methyl, ethyl, n-propyl, 1- propyl, methoxy, ethoxy, or n-propoxy; 2,5-dimethylphenyl; 3,4-dimethoxyphenyl; 2,4,6-trimethylphenyl; 3,4-diohlorophenyl; 3,4,5trimethoxyphenyl; 1-naphthalenyl; 2-naphthalenyl; 2- methyl-l-naphthalenyls 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-quinolinyl; or 2-phenylethyl 4. A compound as claimed in Claim 2 wherein R is hydrogen, tetrahydro-2-furanyl, 4-thiazolyl; or phenyl mono-substituted in the 2,3 or 4 position by cyano, 15 trifluororaethyl, or methylsulfonyl. 5. The compound as defined in Claim 2 wherein R is phenyl. S. .The compound as 2-fluorophenyl. defined in Claim 2 wherein R is 7. The compound as 3-fluorophenyl. defined in Claim 2 wherein R is 8. The compound as 4-fluorophenyl. defined in Claim 2 wherein R is 9. The compound as 2-chlorophenyl. defined in Claim 2 wherein R is 10 .The compound as 3-chlorophenyl, defined in Claim 2 wherein R is 11 .The compound as defined in Claim 2 wherein R is 4-chlorophenyl. *5427 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- trifluoromsthylphenyl. 15. The compound as defined in Claim 2 wherein R is 3trifluoromethylphenyl. 15. The compound as defined in Claim 2 wherein R is 410 trifluoromethylphenyl. 17. The compound as defined in Claim 2 wherein R is 2cyanophenyl. 18. The compound as defined in Claim 2 wherein R is 3cyanophenyl. 15 19. The compound as defined in Claim 2 wherein R is 4cyanophenyl. 20·· The compound as defined in Claim 2 wherein R is 4carbethoxyphenyl. 21. The compound as defined in Claim 2 wherein R ia 3 20 nitrophenyl. 22. The compound as defined in Claim 2 wherein R is 2methylphenyl. 23. The compound as defined in Claim 2 wherein R is 3« methylphenyl. 25 24. The compound as defined in Claim 2 wherein R is 4methylphenyl. 25. The compound as defined in Claim 2 wherein R is 2,495 437 dimathylphenyl. 26. Tha compound as defined in Claim 2 uherein dimathylphenyl. 27. The compound as defined in Claim 2 uherein dimethylphenyl. 28. The compound as claimed in Claim 2 uherein dimethylphenyl. 29. The compound as defined in Claim 2 uherein dimethylphenyl. 30. The compound as defined in Claim 2 uherein trimethylphenyl. 31. The compound as defined in Claim 2 uherein 6-tetramethylphenyl. 32. The compound as defined in Claim 2 uherein iaopropylphenyl. 33. The compound as defined in Claim 2 uherein bu'tylphenyl. 34. The compound as defined in Claim 2 uherein (mBthylthio)phenyl. 35. The compound as defined in Claim 2 uherein methoxyphenyl. 36. The compound as defined in Claim 2 uherein methoxyphenyl. 37. The compound as defined in Claim 2 uherein methexyphenyl. 38. The compound as defined in Claim 2 uherein dimethoxyphanyl. R is 2,5R is 2,6R is 3,4R is 3;5is 2,4,6is 2,3,5, is 4is 4-tis 4is 2is‘ 3is 4is 2,396 4 5 4 2 7 39. The oompound as defined in Claim 2 wherein R is 2,5- dimethoxyphenyl. 40. Ths compound as defined in Claim 2 wherein R is 3,4- dimethoxyphenyl. 5 41. The compound as defined in Claim 2 wherein R is 3,4- (methylenedioxy)phenyl. 42. The compound as trimethoxyphenyl. 43. The compound as defined in Claim 2 wherein R is 3,4,5· 4- defined in Claim 2 wherein R is 10 ethoxyphenyl. 44. The compound as defined in Claim 2 wherein R is 3- thienyl. 45. The compound as defined in Cl arm 2 wherein R is 4- thiazolyl. 15 . 46. The compound as defined in Claim 2 wherein R is 2- pyridinyl. 47.. The compound as defined in Claim 2 wherein R 18 3- pyridinyl. 48, The compound as defined in Claim 2 wherein R is 4- 20 pyridinyl. 49. The compound as defined in Claim 2 wherein R is benzo[b]thien-3-yl. 50. The compound naphthalenyl. as defined in Claim 2 wherein R is 1- 25 51. The compound naphthalenyl. as defined in Claim 2 wherein R is 2- 52, The compound as defined in Claim 2 wherein R is 2- *5427 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 dBFined in Claim 2 wherein R is 2- phenylethyl. 60. The compound a3 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 aa defined in Claim 2 wherein R is 2- thienyl. 63. The compound as defined in Claim 2 wherein R is 1- bromo-2-naphthalenyl. 64. The compound as defined in Claim 2 wherein R is 4- acetylphenyl. 65. The compound aa defined in Claim 2 wherein R ie 3amirtophenyl.
  4. 4.S427 66. The compound as defined in Claim 2 wherein R is 4methylsulfonylphenyl. 67. The compound as defined in Claim 2 wherein R is 4trifluoromethoxyphenyl. 5 68. The hydrogen. compound as defined in Claim 2 wherein R is 69. The isobutyl. compound as defined in Claim 2 wherein R is 70. The compound as defined in Claim 2 wherein R is 10 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 1 wherein R 1 is as defined in Claim 1. 4B437 73. Tha compound as defined in Claim 72 wherein R is 4- cyanophsnyl. 1 R 74. Ths compound as defined in Claim 72 wherein is 2- acatylphanyl. 5 75. Tha compound as defined in Claim 72 wharein 1 R is 4- acatylphanyl. 1 R 76. Tha compound as defined in Claim 72 uherein is 4- propionylphanyl. 1 R 77. Tha compound as defined in Claim 72 uherain is 2- 10 cyanophsnyl. 1 R 78. Tha compound as da fined in Claim 72 uharain is 4- (methylsulfonyl)phanyl. 1 R' 79. Tha compound as defined in Claim 72 uherain is 4- carbethoxyphenyl. R 1 15 80'. Tha oompound as defined in Claim 72 uharain is 2- nitrophenyl. R 1 81. Tha compound as defined in Claim 72 uherein is 4- nitrophenyl. R 1 82. The compound as defined in Claim 72 wherein is2 :,4- 20 dinitrcphenyl. 83. Tha compound as defined in Claim 72 uharain R 1 is 2- cyanc-4-nitrophenyl. 84, Tha compound as defined in methy1-4-nitrophenyl. Claim 72 wherein R 1 is 3- 25 85. Tha oompound aa dafinad thiazolyl. in Claim 72 wherein R 1 is 2- 100 *342? ι 86. The compound as defined in Claim 72 wherein R is
  5. 5. -nitro-2-pyridinyl. 87. The compound as defined in Claim 72 wherein R is 2-pyridinyl. 88. The compound as defined in Claim 72 wherein R 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 R is 2-quinolinyl. 91. The compound as defined in Claim 72 wherein R is 4-quinolinyl. 92. The compound ao defined in Claim 72 wherein R is 4-methyl-2-quinolinyl. 93. The compound as defined in Claim 72 wherein R is 7-chloro-4-quinolinyl. 94. The compound as defined in Claim 72 wherein R is 7-trifluoromethyl-4-quinolinyl. 95. Tha compound as defined in Claim 72 wherein R is 2- methyl-4-quinolinyl. Ί 96. The compound as defined in Claim 72 wherein R 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 R is 2-trifluoromethyl-4-nitrophenyl. 99. The compound as defined in Claim 72 wherein R is 2-phBnyl-4-quinolinyl. 101 “1 100. Ths compound as defined in Claim 72 wherein R is 4-aminophenyl. •1 101. The compound as defined in Claim 72 wherein R is 2-benzothiazolyl. -I 5 102.Tha compound as defined in Claim 72 wherein R 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-dimethylbanzyl; 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 15 is methyl and X is methyl. 105,.The compound aa defined in Claim 103 wherein Y ia hydrogen and X is mathyl. 106.The compound as defined in Claim 103 wherein Y is benzyl and X is methyl. 20 107.The compound aa defined in Claim 103 wherein Y is 3- cyanobenzyl and X ia 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 25 2,5-dimethylbenzyl and X ia methyl. 110. The compound as defined in Claim 103 wherein X is chlorine and Y is benzyl. 102 4542? 111. The compounds as defined in Claim 103 uherein X i3 phenyl and Y is hydrogen. 112. The compound as defined in Claim 103 uherein X is phenyl and Y is methyl. 5 113. Λ 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 tha form of a non toxic acid addition salt. 114. A compound as claimed in Claim 113 uherein the 10 salt is tha hydrochloride hydrobromide, maleate benzoate, pamoate, methanesulfonate or acetate. 115. A compound as claimed in any one of Claims 3,5-11,13,22,24,26,30,32,35,36,37,40,42, 43, 46-48, 50-53, 56-59, 69 and 91 uhen in the form of a non Ί _ toxic acid addition salt. 116,. A compound as claimed in Claim 115 uherein the salt ia 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 uhen in the form of a non toxic acid addition salt. 118. A compound aa claimed in Claim 11 uherein the salt is the hydrochloride, hydrcbromide, maleate, benzoate, pamoate, methanesulfonate or acetate. 25 119, A process for preparing a compound according to Claim 1 wherein Y is other than hydrogen and X is other than chlorine and the radical Y does not carry an amino group, which emprises reacting a corresponding compound of formula: 103 -43427 with an alkali metal base to form'an alkali metal salt and reacting the alkali metal salt, with a compound of _ 5 the formula: Y - Z (V) in which formula Y and X are as defined hereinabove and Z is a leaving group; and if desired isolating the product as the free baae or as a non toxic
  6. 6. 10 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. 15 121. A process as claimed in Claim 119 wherein the alkali metal base is sodium hydride. 104 4S437 122. A process as claimed in Claim 119 or 120 wherein Y is RCH 2 - and Z is chlorine, bromine, iodine, tosyloxy or mesoloxy. 123. A process as claimed in Claim 119 or 120 wherein Y is R 1 5 and Z is fluorine, chlorine, hronine or iodine; 124. A process as claimsd in any one of Claims 119 to 12 wherein X is hydrogen and Y is -CHjR. 125. A process as claimed in any one of Claims 119 to 121 wherein X is hydrogen and Y is 10 r1 · 126. A process as claimed in any one of Claims 119 to 121 wherein X is methyl or phenyl. 127. A process as claimsd in Claim 120 wherein X is hydrogen,R is as defined in Claim 3 or Claim 4 15 and Z is chlorine, bromine or iodine. 126. 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 2o hydrogen, R ia as defined in Claim 4 and Z is chlorine,bromine or iodine. 105 4ΰΊ37 wherein: either a) X is hydrogen; and 5 Y 1 is hydrogen or -CHjR therein 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 10 Y^ is hydrogen, benzyl, 2,5-dimethylbenzyl, 3-cyanobenzyl or 4-cyanobenzyl provided that when X is phenyl Y^ is hydrogen and when X is chlorine, Υ 1- is benzyl. ο 106 484 27 uhich comprises reacting an acid addition salt of a compound of the formula: uherein: 5 X and Y have the meanings defined hereinabove; uith an alkali metal dicyanamide at a temperature of 185° to 215°C, in an aliphatic alcohol and if desired isolating the product as the free base or non toxic acid addition salt. Iq 131. A process as claimed in Claim 130 uharein the aliphatic alcohol is 1-octyl alcohol. 132. A process as claimed in Claim 130 or Claim 131 uharein the alkali metal dicyanamide is sodium dicyanamide, 15 133. A process as claimed in any. one of Claims 130 to 132 uhich is effected using a molar ratio ofalkali metal dicyanamide to 5-aminoindole of >2:1. 134. A process as claimed in Claim 133 uherein the molar radio ia about 2.5:1. 2o 135. A process as claimed in any one of Claims 130 to' 134 uherein X is hydrogen. 136. A process as claimed in any one of Claims 130 to 135 wherein Y is hydrogen. 107 137. 138. 5 139. 140. A process as claimed in any one of Claims 130 1 to 135 ynerein Y is -CHgR. A process as claimed in any ana of Claims 130 to 134 uherein X is methyl or phenyl. A process as claimed in any one of Claims 130 to 134 and 138 uherein Y is hydrogen. A process as claimed in any one of Claims 130 to 134 uherein X is chlorine and 7 is benzyl. 108 43427 141. A process as claimed in Claim 131 wherein X is <1 hydrogen and Y is hydrogen or CHjR wherein R is 1- propyl, n-butyl, i-butyl, n-hexyl, 2-methyl-1propenyl, oyolobutyl, 2-phenylethyl, phenyl, 5 phenyl manasubstituted 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, 3,4dichlorophenyl, 2,4,6-trimethylphenyl, 3,4,5 10 trimethoxyphenyl, 1-nsphthalenyl, 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 1 is CHjjR wherein R is phenyl substituted in the 2,3 or 15 4 position by trifluoromethyl, cyano or methylsulfonyl; 4-thiazolyl or tetrahydro-2-futanyl. 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 2 0 alkali metal dicyanamide is sodium dicyanamide. 145. A process as claimed in any one of Claims 130-144 wherein the acid addition salt of ths compound of formula (X) is the hydrochloride. 146. A process for preparing a compound of the formula; 109 *S427 (XI ) uhersinϊ 2 Y is 3-aminobenzyl, 2-aminophenyl, 4-aminophenyl, 2,4-diaminophenyl, 2-cyano-4-aminophenyl, 3-methyl5 4-aminophenyl or 2-trifluoromethyl-4-aminophenyl, uhich comprises reducing a compound of the formula: uherein: Y ia 3-nitrobenzyl, 2-nitrophenyl, 4-nitrophenyl, 10 2,4-dinitrophenyl, 2-cyano-4-nitrophenyl, 3-methyl4-nitrophenyl or 2-trifluoromethyl-4-nitrophenyl; and if desired isolating the product as a free base or a ηαπ-tcxic acid addition salt. 147. A process as claimed in Claim 146 uherein the 15 reducing agent is hydrogen in the presence of a noble metal catalyst. 148. A process as claimed in Claim 147 uherein the noble metal catalyst is palladium-carbon. HO 15 4 27 149. A process for preparing a compound of formula I substantially as hereinbefore described uith 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 5 and 66, 150. A process for preparing a compound of formula I substantially aa hereinbefore described uith reference to any one of Examples
  7. 7. 11 to 16, 42, 63b, 65 and 67. 20 151. A process for preparing a compound of formula I substantially as hereinbefore described uith reference to any one of Examples 28, 98c, 104h and 105c. , 152. A process for preparing a compound cf formula I substantially as hereinbefore described uith is 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. 2q 153. A process for preparing a compound of formula I substantially as hereinbefore described uith . reference to Example 62 or 96. 154. A process for preparing a compound of formula I substantially as hereinbefore described uith 25 reference to Example 1. HI 155. A compound of formula I whenever prepared by a process as claime'd 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 SO, 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, 6lb, 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,
  8. 8. 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 112 103 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 5 11,
  9. 9. 13, 22, 24, 26, 30, 32, 3S to 37, 40, 42, 43, 46 to 46, 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 10 of formula I as claimed in any one of Claims 4,
  10. 10. 14 to 19, 45, 66, 68, 70, 117 and 118 in association with a pharmaceutically acceptable carrier.
IE1345/77A 1976-07-09 1977-06-29 Pyrrold 3,2if quinazoline-1,3-diamine and related compounds IE45427B1 (en)

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US7262297B2 (en) * 2003-05-15 2007-08-28 Hoffmann-La Roche Inc. Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors
US11077109B2 (en) * 2017-08-01 2021-08-03 The Trustees Of Princeton University Compounds having antibacterial activity and methods of use
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DE2731039A1 (en) 1978-01-19

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