AU644035C

AU644035C - Quinazolines derivatives for enhancing antitumor activity

Info

Publication number: AU644035C
Application number: AU90592/91A
Authority: AU
Inventors: Jotham Wadsworth Coe; Anton Franz Fliri; Takushi Kaneko; Eric Robert Larson
Original assignee: Pfizer Corp SRL
Current assignee: Pfizer Corp SRL
Priority date: 1990-11-06
Filing date: 1991-10-10
Publication date: 1994-08-18
Anticipated expiration: 2011-10-10

Description

QUINAZOLINES DERIVATIVES FOR

ENHANCING ANTITUMOR ACTIVITY

Background of the Invention

This invention relates to 2,4-diaminoquinazolines and their use as sensitizers of tumor cells to anticancer agents.

In cancer chemotherapy the effectiveness of anticancer drugs is often limited by the resistance of tumor cells. Some tumors such as of the colon, pancreas, kidney and liver are generally innately resistant, and other responding tumors often develop resistance during the course of chemotherapy. The phenomena of multidrug resistance (MOR) is

characterized by the tumor cell's cross-resistance to structurally unrelated drugs. The drugs which are the target of resistance include adriaraycin, daunomycin, vinblastine, vincristine, actinomycin D and etoposide. The resistance cells are often associated with over- expression of the mdrl gene. This gene product is a family of 140-220 kd trans-membrane phosphoglycoprotein (P-glycoprotein) which functions as an ATP-dependent efflux pump. Thus, it has been postulated that this efflux mechanism keeps the intracellular level of the anticancer drug low, allowing the tumor cells to survive.

In recent years various substances such as verapamil, nifedipine and diltiazem have been used in in vitro experimental systems to reverse the MDR phenomena. More recently some of these agents have been tested clinically as MDR reversing agents. Little efficacy has been observed with verapamil or trifluoro- perazine. Thus, there is a need for an effective MDR reversing agent.

The 2,4-diaminoquinazolines are prepared by known methods utilizing 2,4-dichloroguinazolines [Postovskii and Goncharova, Zh. Obshch. Khim., 32, 3323 (1962)]. Curd et al. (J. Chem. Soc, 1947, 775) reported the synthesis of 2,4-dichloroquinazolines from the

corresponding 2,4 (1H, 3H)quinazolinedione. The

Wellcome Foundation discloses 2,4-diaminoquinazolines of general structure D as antibacterials [GB patent 806772 (1958)3. Hess [US 3,511,836 (1970)] patented compounds of structures E, F, and G as antihypertensive agents. Wijbe [GB patent 1,390,014 (1975)] patented a process for compounds of structure H and these

compounds are claimed to be antibacterials. Lacefield [US patent 3,956,495 (1976)] describes compounds of the general formula I as antithrombotic agents. Crenshaw

[US patent 4,098,788 (1978)] patented a process for the production of compounds of formula J. Hess [European Patent 0,028,473 (1981)] describes chloro- and alkoxy- substituted 2,4-diaminoquinazolines of formula K. Ife et al. describe compounds of general structur L as inhibitors of gastric acid secretion [WO 89/0527

(1989)]. Compounds of structures M and N were

published as phosphodiesterase inhibitors [Miller, J. Med. Chem., 28, 12 (1985)]. Richter et al. published compounds of structur O as inhibitors of dihydrofolate reductase [J. Med. Chem., 17, 943 (1974)]. In search of compounds with herbicidal activity Miki et al.

reported the synthesis of 2,4-dialkglaminoquinazolines (P) (Chem. Pharm. Bull. 30, 2313 (1982)]. Arylazido- prazosin (Q) has been shown to bind to P-glycoprotein [Safa et al., Biochem. Biophys. Res. Comm. 166, 259 (1990)].

Summary of the Invention

The compound of the present invention are of the formula

or a pharmaceutically acceptable acid addition salt thereof where X and X¹ are each hydrogen, alkyl of one to four carbon atoms, iodo, bromo, nitro, chloro, fluoro, methylthio, amino, alkylamino of one to three carbon atoms, methyl- sulfinyl, aminomethyl, (CH₃)₂S^®, dialkylaxinomethyl of three to seven carbon atoms, hydroxymethyl, morpholino, thio- morpholino, benzoylamino, substituted benzoylamino wherein said substituent is azido, methoxy, methyl, fluoro, chloro or trifluoromethyl, alkanoylamino having two to four carbon atoms, 4-methylpiperazino, piperazino, piperidino, pyrrolidino, dialkylamino of two to six carbon atoms or alkoxy of one to four carbon atoms; X² is hydrogen, alkyl of one to four carbon atoms or alkoxy of one to four carbon atoms; X and X¹ together are ethylenedioxy or methylenedioxy; R₁ is alkyl having one to four carbon atoms, cycloalkyl of three to seven carbon atoms, alkoxyalkyl said alkoxy having one to three carbon atoms and said alkyl having two to three carbon atoms or benzodioxan-2-ylmethyl; R₂ is hydrogen, alkyl of one to eight carbon atoms or benzyl; R₁ and R₂ when taken together with the nitrogen atom to which they are attached form (a) a moiety of the formula

where Q is hydrogen, alkoxy of one to three carbon atoms, hydroxy, alkanoylamino having two to four carbon atoms, alkyl of one to three carbon atoms, bromo, iodo, chloro, fluoro, nitro, morpholino, amino, alkylamino of one to three carbon atoms or dialkylamino of two to six carbon atoms, Q¹ is hydrogen, fluoro, chloro, bromo, alkyl having one to three carbon atoms or alkoxy having one to three carbon atoms, Q² is hydrogen or alkoxy of one to three carbon atoms, Q¹ and Q² together are methylenedioxy or ethylenedioxy, R is hydrogen, alkyl having one to four carbon atoms or alkoxy of one to three carbon atoms, m is an integer of 0-2, p is an integer of 1-2, R ₅ is hydrogen or dialkoxybenzyl said alkoxy having one to three carbon atoms and R and R₅ together are alkylene having one to three carbon atoms,

(b) 1, 2, 3, 4-tetrahydro-beta-carbol-2-yl or

(c) piperidino of the formula

where R₆ is pyridylmethoxy, alkoxyalkyleneoxy said alkoxy having one to three carbon atoms and said alkylene having two to three carbon atoms or benzoxazol-2-ylmethyl

(d) octahydroisoindol-2-yl or

(e) decahydroisoquinol-2-yl;

R₃ is

(a) cycloalkyl of three to seven carbon atoms,

(b) benzodioxan-2-ylmethyl

(c) aralkyl of the formula

wherein n is an integer of 1 or 0, W is O, S or a chemical bond, A is alkylene of one to four carbon atoms, Y is hydrogen, alkyl of one to three carbon atoms, fluoro, chloro, bromo, hydroxy, alkoxy of one to three carbon atoms, benzyloxy, nitro, dimethylamino or amino, Y¹ is hydrogen, alkoxy of one to three carbon atoms, chloro, fluoro, hydroxy or benzyloxy, Y² is hydrogen or alkoxy of one to three carbon atoms and Y and Y¹ together are methylenedioxy or ethylenedioxy,

(d) aralkyl of the formula

where R₇ is hydroxy, alkoxy of one to three carbon atoms or C₆H₅(CH₂)_t0, n is 1, t is an integer of 1 or 0, A is alkylene of one to four carbon atoms, Q³ and Q⁴ are each hydrogen or alkoxy of one to three carbon atoms and Q³ and Q⁴ together are methylenedioxy or ethylenedioxy,

(e) pyridylalkyl said alkyl having one to four carbon atoms,

(f) alkoxyalkyl said alkoxy having one to three carbon atoms and said alkyl having two to three carbon atoms,

(g) indolylalkyl of the formula

where A is alkylene of one to four carbon atoms, Q³ and Q⁴ are each hydrogen or alkoxy of one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(h) tetrahydronaphthalene of the formula

where A is alkylene of one to four carbon atoms, Q³ and Q⁴ are each hydrogen or alkoxy of one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy; (i) aralkanol of the formula

where W is O, S or a chemical bond and Q³ is hydrogen or alkoxy of one to three carbon atoms,

(j) 2,3-dihydro-2-hydroxyinden-1-yl,

(k) aracycloalkyl of the formula

wherein A is alkylene having one to four carbon atoms, Q³ and Q⁴ are each hydrogen or alkoxy having one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(1) indene of the formula

wherein Q³ and Q⁴ are each hydrogen or alkoxy of one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(m) naphthyl or

(n) 1-methylpyrrol-2-yl;

R₄ is hydrogen or alkyl of one to eight carbon atoms and R₃ and R₄ taken together with the nitrogen atom to which they are attached form

(a) a tetrahydroisoquinoline of the formula

where Q³ and Q⁴ are each hydrogen or alkoxy of one to three carbon atoms and Q³ and Q⁴ together are methylenedioxy or ethylenedioxy,

(b) piperidino of the formula

wherein R₈ is benzyl, alkoxyalkyleneoxy said alkoxy having from one to three carbon atoms and said alkylene having two to three carbon atoms or alkyl sulfonamide of the formula

where R₉ is alkyl of one to four carbon atoms

(c) 3-methyl-3-phenylpiperidino or

(d) piperazino of the formula

where R₁₀ is hydrogen, alkoxycarbonyl of two to six carbon atoms, acyl of one to six carbon atoms, hydroxyalkoxy- carbonyl of three to six carbon atoms, furoyl, benzoxazol-2- yl, pyrimid-2-yl or benzodioxan-2-ylcarbonyl.

A preferred group of compounds are those where X and X¹ are each alkoxy of one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

where Q¹ is alkoxy of one to three carbon atoms, R and R₅ are each hydrogen, p is 1, m is 0, R₃ is aralkyl of the formula

where Y¹ and Y² are each methoxy, n is 0 , W is a chemical bond, A is ethylene and R₄ is hydrogen. Especially preferred within this group are the compounds where X is 6 -methoxy, X¹ is 7-methoxy, Q is 5-hydroxy, Q¹ is 6-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 2-methoxy and Y² is 3 -methoxy, where X is 6-methoxy, X¹ is 7-methoxy, Q is 6-methoxy, Q¹ is 7 -methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4 -methoxy, where X is 6-methoxy, X¹ is 7-methoxy, Q is 7-methoxy, Q¹ is 8-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 2 -methoxy and Y² is 3-methoxy, where X is 6-methoxy, X¹ is 7-methoxy, Q and Q² are each hydrogen, Q¹ is 6-methoxy, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4-methoxy, where X is 6-methoxy, X¹ is 7-methoxy, Q is 5-methoxy, Q¹ is 6-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3 -methoxy and Y² is 4-methoxy, where X is 6-methoxy, X¹ is 7 -methoxy, Q is 6-methoxy, Q¹ is 7-methoxy, Q² is hydrogen, Y is 2-bromo, Y¹ is 4 -methoxy and Y² is 5-methoxy, where X is 6-methoxy, X¹ is 7-methoxy, Q is 6-methoxy, Q¹ is 8-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4-methoxy and where X is 6-methoxy, X¹ is 7 -methoxy, Q is 7-methoxy, Q¹ is 8-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4 -methoxy.

A second group of preferred compounds are those where X¹ and X² are each hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

where Q and Q¹ are each alkoxy of one to three carbon atoms, Q² is hydrogen, R and R₅ are each hydrogen, p is 1, m is 0, R₃ is aralkyl of the formula

wherein Y² is hydrogen, n is 0, W is a chemical bond and A is ethylene and R₄ is hydrogen. Especially preferred within this group are compound where X is 5-methoxy, Q is 6-methoxy, Q¹ is 7-methoxy, Y is 2-chloro and Y¹ is hydrogen, where X is 5-chloro, Q is 6-methoxy, Q¹ is 7-methoxy, Y is 2-chloro and Y¹ is hydrogen, where X is 5-methyl, Q is 6-methoxy, Q¹ is 7-methoxy, Y is 3-methoxy and Y¹ is 4-methoxy and where X is 6-dimethylamino, Q is 6-methoxy, Q¹ is 7-methoxy, Y is 3-methoxy and Y¹ is 4-methoxy.

A third group of preferred compounds are those where X and X¹ are each alkoxy of one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

where Q² is hydrogen, R₅ is hydrogen, p is 1-2, R₃ is aralkyl of the formula

where Y and Y¹ are each alkoxy of one to three carbon atoms, Y² is hydrogen, n is 0, W is a chemical bond, A is ethylene and R₄ is hydrogen. Especially preferred within this group are compounds where X is 6-methoxy, X¹ is 7-methoxy, Q and Q¹ are each hydrogen, p is 1, R is methoxy, m is 0, Y is 2-methoxy and Y¹ is 3-methoxy, where X is 6-methoxy, X¹ is 7-methoxy, Q and Q¹ are each hydrogen, p is 2, R is hydrogen, m is 1, Y is 3-methoxy and Y¹ is 4-methoxy and where X is 6-methoxy, X¹ is 7-methoxy, Q is 7-amino, Q¹ is hydrogen, R is hydrogen, m is 0, p is 1, Y is 3-methoxy and Y¹ is 4-methoxy.

A fourth group of preferred compounds those where X and X¹ are each alkoxy of one to four carbon atoms, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

where Q³ and Q⁴ are each alkoxy of one to three carbon atoms, R₇ is methoxy, n is 1, A is methylene and R₄ is hydrogen.

Especially preferred within this group is the compound where

X is 6-methoxy, X¹ is 7-methoxy, Q is 6-fluoro, R is methoxy,

Q³ is 2-methoxy and Q⁴ is 3-methoxy.

A fifth group of preferred compounds are those where X¹ is alkoxy of one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

where Q and Q¹ are each alkoxy of one to three carbon atoms, Q² is hydrogen, p is 1, m is 0, R₃ is aralkyl of the formula

where Y² is hydrogen, n is 0, W is a chemical bond, A is ethylene and R, is hydrogen. Especially preferred within this group is the compound where X is 6-chloro, X¹ is 7-methoxy, Q is 6-methoxy, Q¹ is 7-methoxy, R and R₅ are each hydrogen, Y is 3-methoxy and Y¹ is 4-methoxy.

The present invention also includes a method of inhibiting a P-glycoprotein in a mammal in need of such treatment which comprises administering to said mammal a P-glycoprotein inhibiting amount of a compound of formula I. Preferred is the method where the mammal is a human suffering from cancer and said compound is administered before, with or after the administration to said human of an anticancer effective amount of a chemotherapeutic agent. Also included is a pharmaceutical composition for administration to a mammal which comprises a P-glycoprotein inhibiting amount of a compound of formula I, a pharmaceutically acceptable carrier and, optionally, an anticancer effective amount of a chemotherapeutic agent.

As previously indicated, the compounds of formula I form pharmaceutically acceptable acid addition salts. Said pharmaceutically acceptable acid addition salts include, but are not limited to, those with HCl, HBr, HNO₃, H₂SO₄, H₃PO₄, CH₃SO₃H, p-CH₃C₆H₄SO₃H, CH₃CO₂H, gluconic acid, tartaric acid, maleic acid and succinic acid. In the case of those compounds of the formula (I) which contain a further basic nitrogen, it will, of course, be possible to form diacid addition salts (e.g., the dihydrochloride) as well as the usual monoacid addition salt.

As one skilled in the art recognized, compounds of formula I have the potential for containing asymmetric carbon atoms. All these potential isomers are considered within the scope of the present invention.

The terms "alkyl" and "alkylene" are meant to embrace both straight chained and branched members.

Detailed Description of the Invention

Compounds of the present invention are prepared with the reaction of a 2,4-dichloroquinazoline with an equivalent of an appropriate amine, R₁R₂NH, followed by the reaction of the product, a 2-chloro-4-amino- quinazoline derivative, with a second equivalent of an appropriate amine, R₃R₄NH.

In a more detailed description of the procedure, one molar equivalent of an optionally substituted

2,4-dichloroquinazoline and one molar equivalent of a tertiary amine-acid scavenger, such as triethylamine, N-methylmorpholine or diethylisopropylamine and one molar equivalent of an amine, R₁ R₂NH, are combined in an anhydrous solvent such as dimethylacetamide, dioxane or N-methyl-2-pyrrolidone and maintained at from 0°C to about 25°C for a period of 1 to 48 hours.

The reaction mixture can be filtered and the filtrate concentrated to dryness in vacuo, or the reaction mixture can be quenched in water and the intermediate product either filtered or extracted with a water immiscible solvent such as methylene chloride or ethyl acetate. Removal of the extracting solvent provides the desired product. Frequently, the residual can be induced to crystallize by trituration with an organic solvent, and further purified by recrystallization or column chromatography.

The second step of the sequence leading to the products of the present invention consists of combining one molar equivalent of the appropriate 2-chloro-4- aminoquinazoline with either two molar equivalents of an amine, R₃R₄NH, or one equivalent of said amine and one equivalent of a tertiary amine-acid scavenger as described above in a reaction-inert solvent such as ethoxyethoxyethanol, butanol, amyl alcohol or

cyclohexanol for a period of 5 minutes to several hours at reaction temperatures of 100-200°C.

The reaction mixture can be cooled to room temperature and treated with a 1-N solution of an appropriate acid, such as hydrochloric acid to give a precipitate of the desired product as the hydrochloride salt.

Other acids would give the corresponding acid addition salt. In instances where the acid addition salt does not precipitate the free base product can be isolated by chromatographing the crude material on silica gel using an eluant such as chloroform, ethyl acetate, diethyl ether, methanol methylene chloride, ethanol or mixtures thereof and subsequently converted to the acid addition salt product. The products are isolated by removing the eluting solvents in vacuo. Purification of the product can be done by recrystallization.

Generation of the free base from an acid addition salt can readily be carried out by treating an aqueous solution or suspension of the salt with at least one equivalent of an organic or inorganic base followed by extraction of the free base product with a water immiscible solvent such as ethyl acetate or methylene chloride. Removal of the solvent gives the desired base.

Compounds of formula I are inhibitors of the functions of P-glycoprotein, particularly human mdr 1 protein or P-glycoprotein related and membrane

associate proteins which are participating in the transport of xenobiotics or proteins across membranes e.g., cell membranes of eukariotic and proeukariotic origin e.g., pmfdr, however not exclusive or restricted to these examples.

Compounds enclosed in general formula I are useful in combination chemotherapy of cancer, malaria, viral infections such as AIDS, in therapy of septic shock syndrome or inflammation and may be useful in enhancing the tissue penetration of drugs where the penetration of these xenobiotics is limited due to the presence of P-glycoprotein or P-glycoprotein related functional proteins. Compounds of formula I increase the

activity/efficacy of adriamycin, daunomycin, etoposide, epipodophyllotoxin congoners, actinomycin D, emetin, vincristin, vinblastin, chloroquine, antracyclin antibiotics and of drugs which are structurally and functionally related to the above mentioned examples, in particular when the activity of these drugs has been shown to be limited due to the presence and function of P-glycoprotein, e.g. human mdr 1 protein or

P-glycoprotein related proteins.

The compounds of the present invention are evaluated as potentiators of chemotherapeutic agents using a Cellular Drug Retention Assay. This assay was designed to study the effect of compounds on cellular retention of radiolabeled drug. In this case

14C-adriamycin retention by multidrug resistant human carcinoma cells, KBV1, is measured.

KBV1 cells are routinely grown in tissue culture as monolayers in DMEM high glucose medium containing 1 ug/ml vinblastine 10% heat inactivated fetal calf serum and supplemented with Glutamine, Pen-Strep and Garamycin.

The assay protocol (described below) should be applicable, with minor modifications, to a wide variety of cell lines grown in tissue culture.

Assay Protocol:

(1) Seed replicate 6-well tissue culture plates with 1.2 x 10E6 cells per 2 ml per well in absence of Vinblastine;

(2) Incubate 24 hrs at 37 degrees in humidified incubator (5% CO2);

(3) Aspirate off the spent media and overlay monolayers with 2 ml/well of fresh medium that is 2 uM in Adriamycin (2 uM unlabeled Adriamycin + 20000 cpm of 14C-Adr) and the test agent at concentrations varying from 0 to 100 uM;

(4) Following incubation for 3 hours at 37 degrees in humidified incubator, remove media and wash monolayers twice with 2 ml of ice-cold buffered saline;

(5) Detach monolayers using 0.5 ml of

trypsin/EDTA, collect detached cells and transfer to scintillation vial. Rinse wells once with 0.5 ml of buffered saline and add to same vial containing cells;

(6) Add 5 ml of Beckman Ready-Safe scintillation fluid to vial, vortex and determine radioactivity per sample using a scintillation counter (10 minutes per sample);

(7) For background control: pre-incubate

monolayers at 4 degrees for 15 minutes then remove media and add fresh ice-cold media containing Adr (see step 3). Following incubation for 3 hours at 4 degrees remove media and wash monolayers twice with 2 ml ice-cold buffered saline, then proceed as in step 5;

(8) Results are expressed as T/C and ED3x values as defined below:

T/C = pmoles Adr per 10E6 cells treated with test agent/

pmoles Adr per 10E6 untreated cells

ED3x = concentration of test agent that

produces a 3 fold increase in cellular accumulation of radiolabeled Adr, i.e. T/C = 3.

Calculations:

Specific cpm = [sample cpm - background cpm] Specific activity = [cpm/total cone, of Adr] pmoles Adr = [specific cpm/specific activity] pmoles Adr per 10E6 cells = [(pmoles Adr per well/number of cells per well) x 10E6 cells]

As previously mentioned compounds of the present invention and salts thereof are useful in potentiating the anticancer effects of chemotherapeutic agents.

Such agents can include adriamycin, daunomycin, aclacinomycin A, actinomycin C, actinomycin D,

mithramycin, toyomycin, vinblastine, maytansine, bruceantin, homoharintonin, anguindin, neocarcino- statin, mitomycin C and anthramycin.

The compounds of the present invention can be administered with, 24 hours before or up to 72 hours after the administration of the chemotherapeutic agents. When administered with said agents, they can be taken either separately or coadministered in the same formulation.

The compounds of the present invention whether taken separately or in combination with an anti-cancer agent, are generally administered in the form of pharmaceutical compositions comprising at least one of the compounds of formula I and optionally a chemotherapeutic agent, together with a pharmaceutically acceptable vehicle or diluent. Such compositions are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like, and, for parenteral administration, in the form of injectable solutions or suspensions, and the like.

For use in the potentiation of anti-cancer agents in a mammal, including man, a compound of formula I is given in an amount of about 0.5-100 mg/kg/day, in single or divided doses. A more preferred dosage range is 2-50 mg/kg/day, although in particular cases, at the discretion of the attending physician, doses outside the broader range may be required. The preferred route of administration is generally oral, but parenteral administration (e.g. intramuscular, intravenous, intradermal) will be preferred in special cases, e.g., where oral absorption is impaired as by disease, or where the patient is unable to swallow. The present invention is illustrated by the following examples, but is not limited to the details or scope thereof.

EXAMPLE 1

2-(N-Methyl-3,4-dimethoxyphenethylamino)-4-(1,2,3,4- tetrahydro-6,7-dimethoxyisoquinol-2-yl)-6,7-dimethoxy- quinazoline hydrochloride (I: X = 6-CH₃O; X¹ = 7-CH₃O;

X² = H; R₁R₂N = 6,7-(CH₃O)₂-1,2,3,4-tetrahydroiso- quinol-2-yl; R₃ = 3,4(CH₃O) ₂phenethyl; and R₄ = CH₃)

-----------------------------------------------------------------------------------------------------

A. 2-chloro-4-(1,2,3,4-tetrahydro-6,7-dimethoxy- isoquinol-2-yl)-6,7-dimethoxyquinazoline

To 26.59 g of 2,4-dichloro-6,7-dimethoxyquina- zoline and 20.39 g of triethylamine in 250 ml of warm

dimethylacetamide was added 23.1 g of 1,2,3,4-tetra- hydro-6,7-dimethoxyisoquinoline in 300 ml of dry

dimethylacetamide and the reaction mixture stirred at

room temperatures under exclusion of moisture for 16

hours. The precipitate was filtered and the filtrate

concentrated to dryness under reduced pressure. The

residual product was recrystallized from methanol,

40.6 g, m.p. 183-186ºC.

B. 2-(N-methyl-3,4-dimethoxyphenethylamino)-4- (1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol-2-yl)-

6,7-dimethoxyquinazoline hydrochloride

A mixture of 840 mg of the product of Example 1A

and 1.28 g of N-methyl-3,4-dimethoxyphenethylamine in 1

ml of ethoxyethoxyethanol was stirred under an inert

atmosphere for 1 hour at 150°C. The reaction mixture

was cooled to room temperature and passed through a

column packed with 30 g of silica gel under 2.5

atmosphere of nitrogen pressure with 500 ml of

chloroform. The product was eluted with 2% (V:V)

methanol in chloroform. The fraction containing the product (Rf 0.47 10% methanol in chloroform on silica) was concentrated in vacuo and the crude residue crystallized from IN hydrochloric acid in methanol- water (1:1, V:V), 271 mg, m.p. 190-192°C, M⁺ = 575.40.

EXAMPLES 2-71

Employing the procedure of Example 1 and starting with the appropriate starting reagents, the following compounds were prepared as their hydrochloride salt unless otherwise indicated:

Example 2: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y = 4-CH₃O and Y² = H; m.p. 194-195°C, M⁺ 560.20.

Example 3: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q, Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 185-186°C, M⁺ 500.30. Example 4: X = 6-C₂H₅O; X¹ = 7-C₂H₅O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 121-122°C, M⁺ 588.30.

Example 5: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y, Y¹ and Y² = H; m.p. 219-226°C,

M⁺ 500.20.

Example 6: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ - H; Q, Q¹, Q² = H; A = -(CH₂)₂-; W = (-) ; n = 0; Y,

Y¹ and Y² = H; m.p. 199-201°C, M⁺ 440.20.

Example 7: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q, Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 2-CH₃O; Y¹ and Y² = H; m.p. 140-142°C, M⁺ 471.00.

Example 8: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-) ; n = 0; Y = 2-CH₃O; Y and Y² = H;

m.p. 232.5-234°C, M⁺ 531.00.

Example 9: X = 6-CH₃O; X¹ = 7-CH₃O; X = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

A = -CH₂CH(CH₃)-; W = 0; n = 1 ; Y, Y¹ and Y² = H;

m.p. 105-107°C, M⁺ 545.00.

Example 10: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = 0; n = 0; Y = 2-1; Y¹ = 4-1; and Y² = 6-1;

m.p. 175-180°C, M⁺ 894.90.

Example 11: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; w = (-); n = 0; Y = 4-CH₃O; Y¹ and Y² = H;

m.p. 113-115.5°C, M⁺ 531.00. Example 12: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q, Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0;

Y ⁵= 4-CH₃O; Y¹ and Y² = H; m.p. 204-205°C, M+ 471.00.

Example 13: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 2-Cl; Y¹ and Y² = H;

m.p. 130-132.5°C, M⁺ 535.00.

Example 14: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-) ; n = 0; Y = 3-CH₃O; Y = 4-CH₃O; and

Y² = 5-CH₃O; m.p. 217-218°C, M⁺ 591.10.

Example 15: X, X¹, X² = H; R, R₄, R₅ = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0;

Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 108-109.5°C

(free base), M⁺ 501.3.

Example 16: X, X¹, X² = H; R, R₄, R₅ = H; Q, Q¹,

Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O;

Y¹ = 4-CH₃O; and Y = H; m.p. 123.5-124.5°C (free base), M⁺ 441.20.

Example 17: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = S; n = 1; Y, Y¹ and Y² = H; m.p. 112-114°C, M⁺

533.2.

Example 18: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-) ; n = 0; Y = 4-NO₂; Y¹ and Y² = H;

m.p. 210-213°C, M⁺ 546.3. Example 19: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(C H₂)₂ -;

W = (-); n = 0; Y = 2-CH₃O; Y = 3-CH₃O; and Y² = H; m.p. 108-111°C, M⁺ 561.00.

Example 20: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(C H₂)₂ -;

W = (-); n = 0; Y = 3-CH₃O; Y¹ = 5-CH₃O; and Y² = H; m.p. 234-235°C, M⁺ 561.40.

Example 21: X = 6-CH₃O; X¹ = 7-CH₃O; X = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 4-Cl; and Y¹ and Y² = H;

m.p. 111-113°C, M⁺ 535.30.

Example 22: X = 6-CH₃O; X¹ = 7-CH₃O; X = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 2-CH₃O; Y¹ = 5-CH₃O; and Y² = H; m.p. 201-203°C, M⁺ 561.40.

Example 23: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

A = -(CH₂)₂-; W = (-); n = 0; Y = 4-CH₃; and Y¹ and

Y² = H; m.p. 230-323°C, M⁺ 515.4.

Example 24: X = 6-CH₃O; X¹ = 7-CH₃O; X² = 8-CH₃O; R,

R₄, R₅ = H; Q; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q = H;

A = -(CH₂)₂-; W = (-); n = 0; X = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 180-182°C, M⁺ 591.10.

Example 25: X = 6-CH₃O; X¹ = 7-CH₃O; X = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q = H; A = -(C H₂)₂ -;

W = (-); n = 0; Y = 4-C₂H₅O; Y¹ and Y² = H;

m.p. 105-210°C, M⁺ 545.00. Example 26: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y and Y² = H;

m.p. 109-111°C, M⁺ 531.00.

Example 27: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 2-Br; Y¹ = 4-CH₃O; and Y² = 5-CH₃O; m.p. 176-179°C, M⁺ 641.10.

Example 28: X, X¹, X² = H; Q = 6-CH₃O; Q¹ = 7-CH₃O;

Q² = H; R, R₄, R₅ = H; A = -(C H₂)₂ -; W = (-); n = 0;

Y = 2-CH₃O; Y¹ = 3-CH₃O; and Y² = H; m.p. 208-209°C, M⁺ 501.10.

Example 29: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 3-Cl; Y¹ = 4-Cl; and Y² = H;

m.p. 135-138°C, M⁺ 569.30.

Example 30: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R,

R₄ = H; R₅ = 3,4-(CH₃O)C₆H,CH₂-; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; A = -(C H₂)₂ -; W = (-); n = 0;

Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 156-159°C,

M⁺ 711.40.

Example 31: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹= 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = O; n = 0; Y = 2-Cl; Y¹ and Y² = H; m.p.

126.5-128°C, M⁺ 535.00.

Example 32: X = 6-CH₃O; X = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q = H; A = -(CH₂)₂-; W = 0; n = 0; Y = 4-Cl; Y¹ and Y² = H; m.p. 218-219°C, M⁺ 535.00.

SUBSTITUTE Example 33 : X = 6-CH₃O; X = 7-CH₃O; X² = H; R, R₄ , R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = - (CH₂)₂-;

W = 0; n = 0; Y = 4-Cl; Y and Y² = H; m.p. 120-122°C,

M⁺ 551.30.

Example 34: X = 6-CH ₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(C H₂)₂ -;

W = (-); n = 0, Y + Y¹ = 3,4-CH₂OCH₂-; and Y² = H; m.p.

231.5-233°C, M⁺ 545.30.

Example 35: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(C H₂)₂ -;

W = 0; n = 0; Y = 4-CH₃O; Y¹ and Y² = H;

m.p. 115-119°C, M⁺ 547.30.

Example 36: X = 6-CH₃O; X¹ - 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -CH₂-;

W = (-); n = 0; Y = 2-CH₃O; Y¹ = 3-CH₃O; and

Y² = 4-CH₃O; m.p. 176.5-178.5°C, M⁺ 577.40.

Example 37: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 4-OH; Y¹ = 3-C₂H₅O; and Y² = H;

138-142°C, M⁺ 561.30.

Example 38: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 4-OH; Y¹ = 3-CH₃O; and Y² = H;

m.p. 232-235°C, M⁺ 547.30.

Example 39: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q, Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0;

Y = 3-CH₃O; Y¹ and Y² = H; m.p. 125.5-141.4°C,

M⁺ 471.20. Example 40: X = 6-CH₃O; X = 7-CH₃O; X = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q ¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

Y = 3-C₆H₅CH₂O; Y¹ = 4-C₆H₅CH₂O; and Y² = H;

m.p. 204-206°C, M⁺ 713.60.

Example 41: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q, Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0;

Y = 2-CH₃O; Y¹ = 3-CH₃O; and Y² = H;

m.p. 189.5-191.5°C, M 501.30.

Example 42: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 7-CH₃O; Q = 8-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 3-CH₃O; Y = 4-CH₃O; and Y² = H; m.p. 195-196°C, M⁺ 561.30.

Example 43: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 189-191°C, M⁺ 515.30.

Example 44: X = 6-CH₃O; X¹, X² = H; R, R₄, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 2-CH₃O; Y¹ = 3-CH₃O; and Y² = H; m.p.

212-215°C, M⁺ 531.00.

Example 45: X = 6-CH₃O; X¹, X² = H; R, R₄, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(-CH₂)₂-;

W = (-); n = 0; Y = 2-Cl; Y¹ and Y² = H;

m.p. 221-223°C, M⁺ 505.20.

Example 46: X = 6-CH₃O; X¹, X² = H; R, R₄, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y²-H;

m.p. 206-208°C, M⁺ 531.20. Example 47: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

A = -CH(CH₃)CH₂CH₂-; W = (-); n = 0; Y, Y¹, Y² = H; m.p. 198-200°C, M⁺ 529.00.

Example 48: X = 6-CH₃O; X¹ = 7-C :Hι₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -CH₂-;

W = (-); n = 0; Y = 4-CH₃O; Y and Y = H;

m.p. 155-156°C, M⁺

Example 49: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q = 7-CH₃O; Q² = H; A = -CH₂-;

W = (-); n = 0, Y, Y¹, R¹ = H; m.p. 169-171°C;

M⁺ 487.00.

Example 50: X = 6-F; X¹ = 7-F; X² = H; R, R₄, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H;

m.p. 112-114°C, M⁺ 537.3.

Example 51: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 4-F; Y¹ and Y² = H; m.p. 225-227°C,

M⁺ 519.30.

Example 52: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R,

R₅ = H; R₄ = C₂H₅; Q = 6-CH₃; Q¹ = 7-CH₃O; Q² = H;

A = -CH₂-; W = (-); n = 0; Y = 4-C₂H₅O; Y¹ and Y² = H; m.p. 201-203°C, M⁺ 545.40.

Example 53: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R,

R₅ = H; R₄ = C₂H₅; Q, Q¹, Q² = H; A = -CH₂-; W = (-); n = 0; Y = 4-C₂H₅O-; Y¹ and Y² = H; m.p. 167-168°C,

M⁺ 485.30. Example 54: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 4-OH; Y¹ and Y² = H;

m.p. 151-153°C, M⁺ 517.30.

Example 55: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-NO₂; Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H;

m.p. 212-214°C, M⁺ 546.30.

Example 56: X, X¹ = H; X² = 8-CH₃O; R, R₄, R. = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 2-CH₃O; Y¹ = 3-CH₃O; and Y² = H;

m.p. 90-92°C (free base), M⁺ 531.30.

Example 57: X = 6-CH₃; X¹, X² = H; R, R₄, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 2-Cl; Y¹ and Y² = H; m.p. 212-214°C,

M⁺ 489.00

Example 58: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H;

m.p. 160-162°C, M⁺ 531.00.

Example 59: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 5-CH₃O; C¹ , Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H;

m.p. 197-198.5°C, M⁺ 531.00.

Example 60: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ - H; Q = 6-CH₃O; Q¹ = 8-CH₃O, Q = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y = 4-CH₃O; and Y² = H; m.p. 146-149ºC, M⁺ 561.30. Example 61: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 7-C1; Q¹, Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H;

m.p. 190-193°C, M⁺ 535.00.

Example 62: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 5-CH₃O; Q , Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 2-CH₃O; Y¹ = 3-CH₃O; and Y² = H;

m.p. 199-200°C, M⁺ 531.00.

Example 63: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q = 5-CH₃O; Q , Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 2-Cl; Y¹and Y² = H; m.p. 210-211°C,

M⁺ 505.30.

Example 64: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R = C₂H₅O; R₄, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O;

Q² = 8-CH₃O; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O;

Y¹ = 4-CH₃O; and Y² = H; m.p. 138-140°C, M⁺ 635.00.

Example 65: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R = CH₃O;

R₄, R₅ = H; Q = 7-CH₃O; Q¹ = 8-CH₃O; Q² = H;

A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 178-180°C, M⁺ 591.50.

Example 66: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R = C₂H₅O-; R₄, R₅ = H; Q = 6-CH₃O; Q¹, Q² = H;

A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 86-88°C, M⁺ 575.40.

Example 67: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R = C₂H₅O-; R₄, R₅ = H; Q = 7-CH₃O; Q¹ = 8-CH₃O;

Q² = H; A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O;

Y¹ = 4-CH₃O; and Y² = H; m.p. 168-169°C, M⁺ 605.40. Example 68 : X = H; X¹ = 7-CH₃O; X² = 8-CH₃O; R, R₄ ,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = - (C H₂)₂ -;

W = (-) ; n = 0 ; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H ; m.p. 138-140°C , M⁺ 561 . 40.

Example 69 : X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄ ,

R₅ = H; Q = 6-CH₃O; Q = 7-CH₃O; Q² = 8-CH₃O;

A = -(CH₂)₂-; W = (-); n = 0; Y = 3-CH₃O; Y¹ = 4-CH₃O; and Y² = H; m.p. 157-158°C, M⁺ 591.30.

Example 70: X = H; X¹ = 7-CH₃O; X² = 8-CH₃O; R, R₄,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; A = -(CH₂)₂-;

W = (-); n = 0; Y = 3-CH₃O; Y = 4-CH₃O; and Y² = H; m.p. 147.5-151°C, M⁺ 561.40.

Example 71: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₄,

R₅ = H; Q, Q¹, Q² = H; A = -(C H₂)₂ -; W = (-) ; n = 0;

Y = 3-CH₃O; Y¹ = 4-OH; and Y² = H; m.p. 169-171.5°C,

M 487.20

EXAMPLES 72-106

Using the procedure of Example 1, and starting with the requisite reagents, the following compounds were prepared as their hydrochloride salts unless

indicated otherwise:

Example 72: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q, Q¹,

Q² = H;

R₃NR₄ = m.p. 181-182°C

M⁺ 452.20

Example 73: X = 6-CH₃O; X = 7-CH₃O; X² = H; Q, Q¹,

Q² = H;

R₃NR₄ = CHCH₂CH₂NH- m.p. 224-225°C M⁺ 531.20 Example 74: X 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ 7-CH₃O; Q² = H;

R₃NR₄ = CHCH₂CH₂NH- m.p. 226-229°C M⁺ 531.20

Example 75: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 181-183ºC

M⁺ 572.30

Example 76: X = 6-CH₃O; X 7-CH₃O; X² = H; Q, Q¹, Q ₂ = H;

R₃NR₄ = m.p. 154-156°C

M⁺ 512.10

Example 77: X 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 145.5-148°C M⁺ 527.00 Example 78: X = 6-CH₃O; X¹ = 7-CH₃CH₂CH₂O; X = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 170-171°C M⁺ 573.20

Example 79: X 6-C₂H₅O; X¹ = 7-C₂H₅O; X = H;

Q = 6-CH₃O; Q¹ 7-CH₃O; Q = H;

R₃NR₄ = m.p. 196-200°C

M⁺ 573.20

Example 80: X 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 233-235ºC

M⁺ 540.00

Example 81: X 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p 133-135.5°C M⁺ 555.00

Example 82: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p 225-227°C

M⁺ 570.20 Example 83: X = 6-CH₃O; X¹ = 7-CH..O; X = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 200-221°C (dec)

M⁺ 571.00

Example 84: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 186.5-188°C

(free base)

M⁺ 502.20 Example 85: X = 6-CH₃O; X¹ = 7-CH₃O; X = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 202.5-204.5°C

M⁺ 513.20

Example 86: X, X¹, X² = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 158-159°C (free base)

M⁺ 484.53 Example 87: X = 6-CH₃O; X 7-CH₃O; X² = 8-CH₃O;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 214-217ºC M⁺ 574.3

Example 88: X, X¹, X² = H; Q = 6-H₃O; Q¹ = 7-CH₃O;

Q² = H;

R₃NR₄ = m.p. 148-150°C

(free base)

M⁺ 512.2 Example 89: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p 163-167°C

M⁺ 587.30 Example 90: X = 6-CH₃O; X¹ = 7-CH₃O X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 134-136.5°C

M⁺ 577.40

Example 91: X = 6-CH₃O; X¹ - 7-CH₃O; X = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 211-213°

M⁺ 591.20

Example 92: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 214-216°C

M 591.30

Example 93: X = 6-CH₃; X¹, X² = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 192-194°C

M⁺ 499.20

Example 94: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q, Q¹,

Q² = H;

R₃NR₄ = m.p. 155-156°C M⁺ 478.00

Example 95: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q, Q¹, Q² = H;

R₃NR₄ = m.p. 225-235°C M⁺ 500.00

Example 96: X 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ 7-CH₃O; Q² = H;

R₃NR₄ = C₂H₅O(CH₂)₂NH m.p. 185-186°C

M⁺

Example 97: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 240-242°C M⁺ 560.00

Example 98: X 6-CH₃O; X¹ 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 238.5-240°C

M⁺ 545.00

Example 99: X 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 232-233°C

M⁺ 561.00

Example 100: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 229-230°C

M⁺ 572.00

Example 101: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = m.p. 165-168 dec°C

M⁺ 628.00

Example 102: X = 6-CH₃O; X¹ = 7-CH₃O; X = H; Q, Q¹,

Q = H;

R₃NR₄ = m.p. 206-210°C

M⁺ 469.30

Example 103: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q = H; Q¹ = 7-CH₃O; Q² = 8-CH₃O;

R₃NR₄ = m.p. 200-202ºC

M⁺ 591.00

Example 104: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = M⁺ 548.30

Example 105 : X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O ; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = - m.p. 168-170°C

M⁺ 582. 30

Example 106 : X = 6-CH₃O; X¹ = 7-CH ₃O; X² = H;

Q = 6-CH₃O ; Q¹ = 7-CH₃O; Q² = H;

R₃NR₄ = (CH₃OCH₂CH₂ ) ₂ ) N- m.p . ºC

M 513 . 00

EXAMPLE 107

2-(3,4-Dimethoxyphenethylamino)-4-(2,3,4,5-tetrahydro- 2-benzoazep-2-yl)-6,7-dimethoxyquinazoline hydro- chloride (I: X = 6-CH₃O; X¹ = 7-CH₃O; R₁R₂N = 2,3,4,5- tetrahydro-2-benzazep-2-yl;

R₃ = 3,4-(CH₃O)₂C₆H₃(CH₂)₂-; and R₄ = H)

A. 2-chloro-4-(2,3,4,5-tetrahydrobenzazep-2-yl)-6,7- dimethoxyquinazoline

A mixture of 1.0 g of 2,3,4,5-tetrahydro-2- benzazepine, 1.76 g of 2,4-dichloro-6,7-dimethoxyquina- zoline and 1.0 g of triethylamine in 25 ml of methylene chloride was stirred at room temperature under nitrogen for three hours. An additional 290 mg of the

benzazepine was added and stirring continued over 48 hours. The reaction mixture was diluted with 100 ml of methylene chloride and the organic solution washed successively with 1N hydrochloric acid (3 x 75 ml), water (2 x 75 ml), a saturated sodium bicarbonate solution (2 x 75 ml), water (2 x 75 ml) and a brine solution (1 x 75 ml). The organic phase was separated, dried over sodium sulfate and concentrated to a foam, 2.15 g. The residue was treated with reluxing methanol and cooled in a refrigerator. The resulting solids were filtered and dried, 1.84 g. A small sample was recrystallized from methanol, m.p. 164-165°C.

B. 2-(3,4-dimethoxyphenethylamino)-4-(2,3,4,5-tetra- hydrobenzazep-2-yl)-6,7-dimethoxyquinazoline hydrochloride

A mixture of 1.109 g of the product of Example 107A, 543 mg of 3,4-dimethoxyphenethylamine and 387 mg of diisopropylethylamine in 1.1 g ethoxyethoxyethanol was stirred under nitrogen at 170°C for five hours.

The reaction mixture was cooled to room temperature and diluted with 5 ml of methylene chloride. This solution was chromatographed without pressure on 60 g of silica gel using methylene chloride as the eluant, taking 15 fractions. Fractions 3-6 were combined and the elution continued under pressure with 2% methanol-methylene chloride, taking 14 fractions. Fractions 8-12 were combined and concentrated to give an oil which was dissolved in 6 ml of 1N hydrogen chloride in methanol. The resulting solids were filtered and dried, 679 mg, m.p. 226-228°C. Fractions 3-6 when carried through the same procedure gave 170 mg of the hydrochloride salt. Anal. Calc'd for C₃₀H₃₄N₄O₄ · HCl: C, 65.4; H,

10.2; N, 6.4..

Found: C, 65.3; H, 10.1; N, 6.5.

EXAMPLES 108-138

Employing the procedure of Example 107 and starting with the appropriate reagents, the following compounds were prepared:

Example 108: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H, m = 0; p = 1;

NR₃R₄ =

m.p. 205-206°C M⁺ 531.2. Example 109: X = 6-CH₃O; X = 7-CH₃O X² = H; R, R₅ = H; Q, Q¹ = H; Q² = 8-CH₃O; m = 0; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃ (CH₂)₂NH

m.p. 187-188°C M⁺ 531.0.

Example 110: X = 6-CH₃; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 2-ClC₆H₄ (CH₂)₂NH

m.p. 156-157°C M⁺ 489.0.

Example 111: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q = 5-CH₃O; Q¹ = 6-CH₃O; Q² = H; m = 0; p = 1; R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 175-177°C

M⁺ 561.1.

Example 112: X = 6-Cl; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 2-ClC₆H₄ (CH₂)₂NH

m.p. 241-242°C

M⁺ 509.03.

Example 113: X = 5-Cl; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 2-ClC₆H₄ (CH₂)₂NH

m.p. 166-167°C

M⁺ 509.0.

Example 114: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 5-CH₃O; Q¹ = 6-CH₃O; Q² = H; R, R₅ = H; m = 0;

p = 1; R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 209°C

M⁺ 561.27. Example 115: X = 5-Cl; X¹, X² - H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 106-107°C

M⁺ 535.3.

Example 116: X = 5-Cl; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 200-202°C

M⁺ 535.20.

Example 117: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q = H; Q¹ = 7-CH₃O; Q² = 8-CH₃O; m - 0; p = 1; R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 194.5-195.5°C

M⁺ 561.0.

Example 118: X = 5-Cl; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 197-198°C

M⁺ 531.4.

Example 119: X = 6-Cl; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 214-215°C

M⁺ 535.40.

Example 120: X = 5-Cl; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 178-179°C

M⁺ 531.4. Example 121: X = 5-Cl; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 2-ClC₆H₄(CH₂)₂NH

m.p. 178-179°C

M⁺ 505.3.

Example 122: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1; R₃R₄N = 2-I-4,5-(CH₃O)₂C₆H₂(CH₂)₂NH

m.p. 216-217°C (free base)

M⁺ 687.0.

Example 123: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q = H; Q¹ = 7-CH₃O; Q² = 8-CH₃O; m = 0; p = 1; R₃R₄N = 2-ClC₆H₄(CH₂)₂NH

m.p. 197-198°C

M⁺ 547.1.

Example 124: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R = CH₃O; R₅ = H; Q = 6-F; Q¹, Q² = H; m = 0; p = 1; R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 215-217°C

M⁺ 548.6.

Example 125: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q, Q¹ = H; Q² = 7-CH₃; m = 0; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 182-183°C

M⁺ 515.3.

Example 126: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q, Q¹, Q² = H; m = 1; p = 1;

R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 222-223°C

M⁺ 515.3. Example 127: X = 6-CH₃O; X = 7-CH₃O; X² = H; R, R₅ = H; Q, Q¹, Q² = H; m = 1; p = 1;

R₃R₄N = 2-ClC₆H₄(CH₂)₂NH

m.p. 218-219°C M⁺ 489.2.

Example 128: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R,

R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 3,4,5- (CH₃O)₃C₆H₂(CH₂)₂NH

m.p. 142-150°C

M⁺ 591.4.

Example 129: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R = H;

R₅ = 3,4-(CH₃O)₂C₆H₃CH₂; Q = 6-CH₃O; Q¹ = 7-CH₃O;

Q = H; m = 0; p = 1; R₃R₄N = 2-ClC₆H₄ (CH₂)₂NH

m.p. 234-235°C

M⁺ 671.2.

Example 130: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R = H;

R₅ = 3,4-(CH₃O)₂C₆H₃CH₂; Q = 6-CH₃O; Q¹ = 7-CH₃O;

Q² = H; m = 0; p = 1; R₃R₄N = 2, 3- (CH₃O)₂C₆H₃ (CH₂)₂NH m.p. 144-145°C

M⁺ 697.3.

Example 131: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R = CH₃O; R₅ = H; Q, Q¹, Q² = H; m = 0; p = 1;

R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 120-123°C

M⁺ 531.2.

Example 132: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R = CH₃O; R₅ = H; Q, Q¹, Q² = H; m = 0; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 206-208°C

M⁺ 531.6. Example 133: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q, Q¹, Q² = H; m = 1; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 217-219°C M⁺ 515.5.

Example 134: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q, Q² = H; Q¹ = 7-NH₂; m = 1; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 213-217°C (free base) M⁺ 530.2.

Example 135: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R = H; R-. = 3,4-(CH₃O)₂C₆H₃CH₂; Q = 6-CH₃O; Q¹ = 7-CH₃O;

Q² = H; m = 0; p = 1; R₃R₄N = 3 ,4- (CH₃O)₂C₆H₃ (CH₂)₂NH m.p. 208-209°C

M⁺ 711.4.

Example 136: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R = CH₃O; R₅ = H; Q = H; Q¹ = 7-CH₃O; Q² = 8-CH₃O; m = 0; p = 1; R₃R₄N = 3, -(CH₃O)₂C₆H₃CH (CH₃O) (CH₂)₂NH m.p. 159-161°C (free base)

M⁺ 621.4.

Example 137: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q = 5-OH; Q¹ = 6-CH₃O; Q² = H; m = 0; p = 1; R₃R₄N = 2,3-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 190-200°C

M⁺ 547.0.

Example 138: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R, R₅ = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1; R₃R₄N = 2-Br-4,5-(CH₃O)₂C₆H₂(CH₂)₂NH

m.p. 176-179°C

M⁺ 641.0. Example 139: X = 5-CH₃; X¹, X² = H; R, R₅ = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; m = 0; p = 1;

R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH

m.p. 141-142°C M⁺ 515.0.

EXAMPLES 140-147

Using the procedure of Example 107 and starting with the necessary reagents, the following compounds were prepared:

Example 140: X-CH₃O; X¹ - 7-CH₃O; X² = H; R₁R₂N R₃R₄N =

m.p. 204-207°C M⁺ 545.2. Example 141: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N =

C₂H₅O(CH₂)O R₃R₄ = 2, 4- (CH₃O)₂C₆H₃CH₂NH;

m.p. 117-119° (free base) M⁺ 527.0.

Example 142: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N =

R₃R₄N = 2,4-(CH₃O)₂C₆H₃CH₂NH;

m.p. 146-147°C (free base) M⁺ 621.4.

Example 143: X, X¹, X² = H; R₁R₂N = C₆H₁₁NH-;

R₃R₄N = C₆H₁₁NH;

m.p. 162-165°C (free base)

M⁺ 325.0.

Example 144: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N =

m.p. 215-217°C (free base) M⁺ 591.0. Example 145: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N = 3₄

v

m.p. 220°C;

M⁺ 507.0.

Example 146: X = 6-N(CH₃)₂; X¹ X² = H; R₁R₂N =

; R₃R₄N = 3,4-(CH₃O)₂C₆H₃(CH₂)₂NH; m.p. 193.5-194.5°C M⁺ 544.3.

Example 147: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N =

R₃R₄N = ;

m.p. 156-158°C M⁺ 579.3.

PREPARATION A

Employing the procedure of Example 1A and starting with appropriate reagents, the following intermediates were prepared:

Compound 1: X = 6-CH₃O; X¹ = 7-C₃H₇O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p.

120-121°C.

Compound 2: X = 6-C₂H₅O; X ¹ = 7-C₂H₅O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p.

161-162°C.

Compound 3: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q, Q¹,

Q² = H; R, R₅ = H; m.p. 169-171°C.

Compound 4: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p.

183-186°C.

Compound 5: X, X¹, X² = H; Q = 6-CH₃O; Q¹ = 7-CH₃O;

Q² = H; R, R₅ = H;; m.p. 126-126.5°C. Compound 6: X = 6-CH₃O; X¹ = 7-CH₃O; X² = 8-CH₃O;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p.

130-131°C.

Compound 7: X = 6-CH₃O X¹ = 7-C-H₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O Q² = H;

R₅ = 3,4-(CH₃O)₂C₆H₃CH₂ R = H; m.p. 154-156.5°C.

Compound 8: X = 6-CH₃O X¹ = 7-CH₃O; X² = H; Q = H;

Q¹ = 7-CH₃O; Q² = 8-CH₃O; R, R₅ = H ; m.p . 162-163 ºC . Compound 9 : X = 6-CH₃O; X¹ , X² = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² - H; R, R₅ = H ; m.p . 132-134 °C.

Compound 10: X = 6-CH₃; X¹, X² = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p. 133-135°C.

Compound 11: X, X¹, X² = H, Q, Q¹, Q² = H; R, R₅ = H; m.p. 130-131°C.

Compound 12: X = 6-F; X¹ = 7-F; X² = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p. 219-220°C.

Compound 13: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q,

Q² = H; Q¹ = 7-NO₂; R, R₅ = H; m.p. 210-212°C.

Compound 14: X, X¹ = H; X² = 8-CH₃O; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p. 147-149°C.

Compound 15: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹, Q² = H; R, R₅ = H; m.p. 181-184°C.

Compound 16: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 5-CH₃O; Q¹ = 6-CH₃O; Q² = 7-CH₃O; R, R₅ = H; m.p.

152-153°C.

Compound 17 : X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 5-CH₃O; Q¹ , Q² = H; R, R₅ = H; m. p . 144. 5-146 °C .

Compound 18 : X = 6-CH₃O; X¹ = 7-CH₃O ; X² = H;

Q = 7-NH₂ ; Q¹ , Q² = H; R, R₅ = H; m. p . 123-126 °C . Compound 19: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 7-Cl; Q¹, Q² = H; R, R₅ = H; m.p. 187-189°C.

Compound 20: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = 8-CH₃O; R = C₂H₅O;

R₅ = H; m.p. 150-153°C.

Compound 21: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q = H;

Q¹ = 7-CH₃O; Q² = 8-CH₃O; R = CH₃O; R₅ = H; m.p.

138-140ºC.

Compound 22: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹, Q² = H; R = C₂H₅O; R₅ = H; m.p.

140-142°C.

Compound 23: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q = H;

Q¹ = 7-CH₃O; Q² = 8-CH₃O; R = C₂H₅O; R₅ = H; m.p.

161-164°C.

Compound 24: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = H; Q² = 8-CH₃O; R, R₅ = H; m.p.

159-161°C.

Compound 25: X = H; X¹ = 7-CH₃O; X² = 8-CH₃O;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p.

143-143.5°C.

Compound 26: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 6-CH₃O; Q¹ = 7-CH₃O; Q² = 8-CH₃O; R, R₅ = H; m.p.

152-153°C.

Compound 27: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 7-CH₃; Q¹, Q² = H; R, R₅ = H; m.p. 169-170°C.

Compound 28: X = 5-Cl; X¹, X² = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p. 161-162°C.

Compound 29 : X = 6-Cl ; X¹ , X² = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; R, R₅ = H ; m. p . 144-145°C . Compound 30: X = 6-CH₃O; X ¹= 7-CH₃O; X² = H;

Q = 5-CH₃O; Q¹ = 6-CH₃O; Q² = H; R, R₅ = H;

m.p. 138.5-139°C.

Compound 31: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

Q = 5-OH; Q¹ = 6-CH₃O; Q² = H; R, R₅ = H;

m.p. 221-223°C.

Compound 32: X = 5-CH₃; X¹, X² = H; Q = 6-CH₃O;

Q¹ = 7-CH₃O; Q² = H; R, R₅ = H; m.p. 174-175°C.

Compound 33: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q = H;

Q¹ = 7-CH₃O; Q² = 8-CH₃O; R = CH₃O; R,. = H;

m.p. 138-140°C.

Compound 34: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q,

Q¹ = H; Q² = 8-CH₃O; R, R₅ = H; m.p. 204-205°C.

Compound 35: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q, Q¹,

Q² = H; R = CH₃O; R₅. = H; m.p. 162-165°C.

Compound 36: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q = 6-F;

Q¹, Q² = H; R = CH₃O; R₅ = H; m.p. 155-157°C.

Compound 37: X = 6-N(CH₃)₂; X¹, X² = H; Q = 6-CH₃O; Q¹ = 7-CH₃O; Q = H; R, R₅ = H; amorphous.

Compound 38: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; Q = 6-F;

Q¹, Q² = H; R = CH₃O; R₅ = H; m.p. 195-197°C.

PREPARATION B

The procedure of Example 1A was repeated starting with the required materials to give the following intermediates:

Compound 39: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N =

m.p. 241-243°C.

Compound 40: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H;

R₁R₂N = C₂H₅O(CH₂)₂ m.p. 91-94°C.

Compound 41: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N=

m.p. 149-150°C Compound 42: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N =

Compound 43: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N = m.p. 174-176°C.

Compound 44: X = 6-CH₃O; X¹ = 7-CH₃O; X = H; R₁R₂N = m.p. 300°C.

Compound 45: X = 6-CH₃O; X¹ = 7-CH₃O; X² = H; R₁R₂N =

Compound 46: X, X¹, X² = H, R₁R₂N = C₆H₁₁NH; m.p. 85-89°C.

Claims

1. A compound of the formula

and a pharmaceutically acceptable acid addition salt thereof wherein X and X¹ are each hydrogen, alkyl having one to four carbon atoms, alkoxy having one to four carbon atoms, bromo, iodo, nitro, amino, alkylamino having one to three carbon atoms, (CH₃)₂S^⊕, aminomethyl, methylsulfinyl, dialkylaminomethyl having three to seven carbon atoms, methylthio, hydroxymethyl, benzoylamino, substituted benzoylamino wherein said substituent is azido, methoxy, methyl, fluoro, chloro or trifluoromethyl, alkanoylamino having two to four carbon atoms, 4-methylpiperazino, morpholino, thiomorpholino, piperazino, piperidino, pyrrolidino, dialkylamino having two to six carbon atoms, fluoro or chloro; X² is hydrogen, alkyl having one to four carbon atoms or alkoxy having one to four carbon atoms; X and X¹ together are ethylenedioxy or methylenedioxy; R₁ is alkoxylalkyl said alkoxy having from one to three carbon atoms and said alkyl having two to three carbon atoms, cycloalkyl having three to seven carbon atoms, alkyl having one to four carbon atoms or benzodioxan-2-ylmethyl; R₂ is hydrogen, alkyl having one to eight carbon atoms or benzyl; R₁ and R₂ when taken together with the nitrogen atom to which they are attached form

(a) a moiety of the formula

wherein Q is hydrogen, alkoxy having one to three carbon atoms, hydroxy, alkanoylamino having two to four carbon atoms, alkyl having one to three carbon atoms, bromo, iodo, fluoro, chloro, nitro, morpholino, amino, alkylamino having one to three carbon atoms or dialkylamino having two to six carbon atoms, Q¹ is hydrogen, fluoro, chloro, bromo, alkyl having one to three carbon atoms or alkoxy having one to three carbon atoms and Q² is hydrogen or alkoxy having one to three carbon atoms, Q¹ and Q² together are ethylenedioxy or methylenedioxy, R is hydrogen, alkyl having one to four carbon atoms or alkoxy having one to three carbon atoms, m is an integer of 0-2, p is an integer of 1-2, R₅ is hydrogen or dialkoxybenzyl said alkoxy having one to three carbon atoms and R and R₅ together are alkylene having one to three carbon atoms,

(b) 1,2,3,4-tetrahydro-beta-carbol-2-yl

(c) piperidino of the formula wherein R₆ is pyridylmethoxy, alkoxyalkyleneoxy said alkoxy having from one to three carbon atoms and said alkylene having from two to three carbon atoms or benzoxazol-2- ylmethyl

(d) octahydroisoindol-2-yl or

(e) decahydroisoquinol-2-yl;

R₃ is

(a) cycloalkyl having three to seven carbon atoms, (b) benzodioxan-2-ylmethyl,

(c) aralkyl of the formula wherein n is an integer of 1 or 0, W is 0, S or a chemical bond, A is alkylene having one to four carbon atoms, Y is hydrogen, alkyl having one to three carbon atoms, alkoxy having one to three carbon atoms, fluoro, chloro, bromo, hydroxy, benzyloxy, nitro, dimethylamino or amino, Y¹ is hydrogen, alkoxy having one to three carbon atoms, chloro, fluoro, hydroxy or benzyloxy, Y² is hydrogen or alkoxy having one to three carbon atoms and Y and Y¹ together are ethylenedioxy or methylenedioxy,

(d) aralkyl of the formula wherein R₇ is hydroxy, alkoxy having one to three carbon atoms or C₆H₅(CH₂)_t-, n is 1, t is an integer of 0 or 1, A is alkylene having one to four caraon atoms, Q³ and Q⁴ are each hydrogen or alkoxy having one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(e) pyridylalkyl said alkyl having from one to four carbon atoms,

(f) alkoxyalkyl said alkoxy having from one to three carbon atoms and said alkyl having two the three carbon atoms,

(g) indolylalkyl of the formula

(h) tetrahydronaphthalene of the formula wherein A is alkylene having one to four carbon atoms, Q³ and Q⁴ are each hydrogen or alkoxy having one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(i) aralkanol of the formula wherein W is O, S or a chemical bond and Q³ is hydrogen or alkoxy having one to three carbon atoms,

(j) 2,3-dihydro-2-hydroxyinden-1-yl,

(k) aracycloalkyl of the formula

(1) indene of the formula wherein Q³ and Q⁴ are each hydrogen or alkoxy having one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(m) naphthyl or (n) 1-methylpyrrol-2-yl;

R₄ is hydrogen or alkyl having one to eight carbon atoms, and R₃ and R₄ when taken together with the nitrogen atom to which they are attached form

(a) a tetrahydro isoquinoline of the formula wherein Q³ and Q⁴ are each hydrogen or alkoxy having one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(b) piperidino of the formula

wherein R₈ is benzyl, alkoxyalkyleneoxy said alkoxy having from one to three carbon atoms and said alkylene having two to three carbon atoms or alkyl sulfonamide of the formula wherein R₉ is alkyl having from one to four carbon atoms,

(c) 3-methyl-3-phenylpiperidino or

(d) piperazino of the formula wherein R₁₀ is hydrogen, alkoxycarbonyl having from two to six carbon atoms, acyl having one to six carbon atoms, hydroxyalkoxy carbonyl having three to six carbon atoms, furoyl, benzoxazol-2-yl, pyrimid-2-yl or benzodioxan-2- carbonyl.

2. A compound of claim 1, wherein X and X¹ are each alkoxy having one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

wherein Q¹ is alkoxy having one to three carbon atoms, R and R₅ are each hydrogen, p is 1 and m. is 0, R₃ is aralkyl of the formula

wherein Y¹ and Y² are each methoxy, n is 0, W is a chemical bond and A is ethylene and R₄ is hydrogen.

3. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 5-hydroxy, Q¹ is 6-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 2-methoxy and Y² is 3-methoxy.

4. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 7-methoxy, Q¹ is 8-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4-methoxy.

5. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 7-methoxy, Q¹ is 8-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 2-methoxy and Y² is 3-methoxy.

6. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q and Q² are each hydrogen, Q¹ is 6-methoxy, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4-methoxy.

7. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 5-methoxy, Q¹ is 6-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4-methoxy.

8. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 6-methoxy, Q¹ is 7-methoxy, Q² is hydrogen, Y is 2-bromo, Y¹ is 4-methoxy and Y² is 5-methoxy.

9. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 6-methoxy, Q¹ is 8-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4-methoxy.

10. The compound of claim 2, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 6-methoxy, Q¹ is 7-methoxy, Q² is hydrogen, Y is hydrogen, Y¹ is 3-methoxy and Y² is 4-methoxy.

11. A compound of claim 1, wherein X¹ and X² are each hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

wherein Q and Q¹ are each alkoxy having one to three carbon atoms, Q² is hydrogen, R and R₅ are each hydrogen, p is 1 and m is 0, R₃ is aralkyl of the formula

wherein Y² is hydrogen, n is 0, W is a chemical bond and A is ethylene and R₄ is hydrogen.

12. The compound of claim 11, wherein X is 5-methoxy, Q is 6-methoxy, Q¹ is 7-methoxy, Y is 2-chloro and Y¹ is hydrogen.

13. The compound of claim 11, wherein X is 5-chloro, Q is 6-methoxy, Q¹ 7-methoxy, Y is 2-chloro and Y¹ is hydrogen.

14. The compound of claim 11, wherein X is 5-methyl, Q is 6-methoxy, Q¹ is 7-methoxy, Y is 3-methoxy and Y¹ is 4-methoxy.

15. The compound of claim 11, wherein X is 6-dimethyl- amino, Q is 6-methoxy, Q¹ is 7-methoxy, Y is 3-methoxy and

Y¹ is 4-methoxy.

16. A compound of claim 1, wherein X and X¹ are each alkoxy having one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

wherein Q² is hydrogen, R₅ is hydrogen and p is 1-2, R₃ is aralkyl of the formula

wherein Y and Y¹ are each alkoxy having one to three carbon atoms, Y² is hydrogen, n is 0, W is a chemical bond, A is ethylene and R₄ is hydrogen.

17. The compound of claim 16, wherein X is 6-methoxy, X¹ is 7-methoxy, Q and Q¹ are each hydrogen, p is 1, R is methoxy, m is 0, Y is 2-methoxy and Y¹ is 3-methoxy.

18. The compound of claim 16, wherein X is 6-methoxy, X¹ is 7-methoxy, Q and Q¹ are each hydrogen, p is 2, R is hydrogen, m is 0, Y is 3-methoxy and Y¹ is 4-methoxy.

19. The compound of claim 16, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 7-amino, Q¹ is hydrogen, R is hydrogen, m is 0, p is 1, Y is 3-methoxy and Y¹ is 4-methoxy.

20. A compound of claim 1, wherein X and X¹ are each alkoxy having one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

wherein Q and Q¹ are each alkoxy having one to three carbon atoms, Q² is hydrogen, R and R₅ are each hydrogen, p is 1, m is 0, R₃ is aralkyl of the formula wherein Q³ and Q⁴ are each alkoxy having one to three carbon atoms, R₇ is methoxy, n is 1, A is methylene and R₄ is hydrogen.

21. The compound of claim 20, wherein X is 6-methoxy, X¹ is 7-methoxy, Q is 7-methoxy, Q¹ is 8-methoxy, Q³ is 2-methoxy and Q⁴ is 4-methoxy.

22. A compound of claim 1, wherein X and X¹ are each alkoxy having one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

wherein Q¹ and Q² are each hydrogen, R₅ is hydrogen, p is 1, m is 0, R₃ is aralkyl of the formula

wherein Q³ and Q⁴ are each alkoxy having one to three carbon atoms, R₇ is methoxy, n is 1, A is methylene and R₄ is hydrogen.

23. The compound of claim 22, wherein X is 6-methoxy,

X¹ is 7-methoxy, Q is 6-fluoro, R is methoxy, Q³ is 2-methoxy and Q⁴ is 3-methoxy.

24. A compound of claim 1, wherein X¹ is alkoxy having one to four carbon atoms, X² is hydrogen, R₁ and R₂ when taken together with the nitrogen atom to which they are attached form a moiety of the formula

wherein Q and Q¹ are each alkoxy having one to three carbon atoms, Q² is hydrogen, p is 1, m is 0, R₃ is aralkyl of the formula

wherein Y² is hydrogen, n is 0, W is a chemical bond, A is ethylene and R₄ is hydrogen.

25. The compound of claim 24, wherein X is 6-chloro,

X¹ is 7-methoxy, Q is 6-methoxy, Q¹ is 7-methoxy, R and R₅ are each hydrogen, Y is 3-methoxy and Y¹ is 4-methoxy.

26. A method of inhibiting a P-glycoprotein in a mammal in need of such treatment which comprises adminis tering to said mammal a P-glycoprotein inhibiting amount of a compound according to claim 1.

27. A method of claim 26, wherein the mammal is a human suffering from cancer and said compound is administered before, with or after the administration to said human of an anticancer effective amount of a chemotherapeutic agent.

28. A pharmaceutical composition for administration to a mammal which comprises a P-glycoprotein inhibiting amount of a compound of claim 1, a pharmaceutically acceptable carrier and, optionally, an anticancer effective amount of a chemotherapeutic agent.

29. A process for preparing a compound of the formula

and a pharmaceutically acceptable acid addition salt thereof wherein X and X¹ are each hydrogen, alkyl having one to four carbon atoms, alkoxy having one to four carbon atoms, bromo, nitro, iodo, methylsulfinyl, (CH₃)₂S^⊕, amino, alkylamino having one to three carbon atoms, methylthio, aminomethyl, dialkylaminomethyl having three to seven carbon atoms, hydroxymethyl, morpholino, thiomorpholino, piperazino, benzoylamino, substituted benzoylamino wherein said substituent is azido, methoxy, methyl, fluoro, chloro or trifluoromethyl, alkanoylamino having two to four carbon atoms, 4-methylpiperizino, piperidino, pyrrolidino, dialkylamino having two to six carbon atoms, fluoro or chloro; X² is hydrogen, alkyl having one to four carbon atoms or alkoxy having one to four carbon atoms; X and X¹ together are ethylenedioxy or methylenedioxy; R₁ is cycloalkyl having three to seven carbon atoms, alkoxyalkyl said alkoxy having one to three carbon atoms and said alkyl having two to three carbon atoms, alkyl having one to four carbon atoms or benzodioxan-2-ylmethyl; R₂ is hydrogen, alkyl having one to eight carbon atoms or benzyl; R₁ and R₂ when taken together with the nitrogen atom to which they are attached form

(a) a moiety of the formula

wherein Q is hydrogen, alkoxy having one to three carbon atoms, hydroxy, alkanoylamino having two to four carbon atoms, alkyl having one to three carbon atoms, bromo, iodo, fluoro, chloro, nitro, amino, morpholino, alkylamino having one to three carbon atoms or dialkylamino having two to six carbon atoms, Q¹ is hydrogen, fluoro, chloro, bromo, alkyl having one to three carbon atoms or alkoxy having one to three carbon atoms and Q² is hydrogen or alkoxy having one to three carbon atoms, Q¹ and Q² together are ethylenedioxy or methylenedioxy, R is hydrogen, alkyl having one to four carbon atoms or alkoxy having one to three carbon atoms, m. is an integer of 0-2, p is an integer of 1-2, R₅ is hydrogen or dialkoxybenzyl said alkoxy having one to three carbon atoms and R and R₅ together are alkylene having one to three carbon atoms,

(b) 1,2,3,4-tetrahydro-beta-carbol-2-yl,

(d) actahydroisoindol-2-yl or

(e) decahydroisoquinol-2-yl; R₃ is

(a) cycloalkyl having three to seven carbon atoms,

(b) benzodioxan-2-ylmethyl,

(c) aralkyl of the formula

wherein n is an integer of 1 or 0, W is O, S or a chemical bond, A is alkylene having one to four carbon atoms, Y is hydrogen, alkyl having one to three carbon atoms, alkoxy having one to three carbon atoms, fluoro, chloro, bromo, hydroxy, benzyloxy, nitro, dimethylamino or amino, Y¹ is hydrogen, alkoxy having one to three carbon atoms, chloro, fluoro, hydroxy or benzyloxy, Y² is hydrogen or alkoxy having one to three carbon atoms and Y and Y¹ together are ethylenedioxy or methylenedioxy,

(d) aralkyl of the formula wherein R₇ is hydroxy, alkoxy having one to three carbon atoms or C₆H₅(CH₂)_t-, n is 1, t is an integer of 0 or 1, A is alkylene having one to four carbon atoms, Q³ and Q⁴ are each hydrogen or alkoxy having one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(e) pyridylalkyl said alkyl having from one to four carbon atoms,

(f) alkoxyalkyl said alkoxy having from one to three carbon atoms and said alkyl having two to three carbon atoms, (g) indolylalkyl of the formula

(j) 2,3-dihydro-2-hydroxyinden-1-yl,

(k) aracylcoalkyl of the formula

(m) naphthyl or

(n) 1-methylpyrrol-2-yl;

(a) a tetrahydro isoquinoline of the formula

wherein Q³ and Q⁴ are each hydrogen or alkoxy having one to three carbon atoms and Q³ and Q⁴ together are ethylenedioxy or methylenedioxy,

(b) piperidino of the formula wherein R₈ is benzyl, alkoxyalkyleneoxy said alkoxy having from one to three carbon atoms and said alkylene having two to three carbon atoms or alkyl sulfonamide of the formula wherein R₉ is alkyl having from one to four carbon atoms, (c) 3-methyl-3-phenylpiperidino or

(d) piperazino of the formula wherein R₁₀ is hydrogen, alkoxycarbonyl having from two to six carbon atoms, acyl having one to six carbon atoms, hydroxyalkoxy carbonyl having three to six carbon atoms, furoyl, benzoxazol-2-yl, pyrimid-2-yl or benzodioxan-2- carbonyl, which comprises reacting a compound of the formula

wherein R₁, R₂, X, X¹ and X² are defined with a compound of the formula

R₃R₄NH where R₃ and R₄ are defined in a reaction-inert solvent containing one equivalent of an amine-acid scavenger at a reaction temperature of 100-200ºC until the reaction is substantially complete.