Method for inhibiting neoplastic cells and related conditions by exposure to 2,8-disubstituted quinazoline derivatives

A method for inhibiting neoplastic cells and related conditions by exposing them to 2,8 disubstituted quinazolinone compounds.

TECHNICAL FIELD
 This invention relates to a method for the inhibition of neoplastic cells,
 for example, for the treatment or prevention of precancerous lesions or
 other neoplasias in mammals.
 BACKGROUND OF THE INVENTION
 Each year in the United States alone, untold numbers of people develop
 precancerous lesions, which is a form of neoplasia, as discussed below.
 Such lesions exhibit a strong tendency to develop into malignant tumors,
 or cancer. Such lesions include lesions of the breast (that can develop
 into breast cancer), lesions of the skin (that can develop into malignant
 melanoma or basal cell carcinoma), colonic adenomatous polyps (that can
 develop into colon cancer), and other such neoplasms. Compounds that
 prevent or induce the remission of existing precancerous or cancerous
 lesions or carcinomas would greatly reduce illness and death from cancer.
 For example, approximately 60,000 people die from colon cancer, and over
 150,000 new cases of colon cancer are diagnosed each year. For the
 American population as a whole, individuals have a six percent lifetime
 risk of developing colon cancer, making it the second most prevalent form
 of cancer in the country. Colon cancer is also prevalent in Western
 Europe. It is believed that increased dietary fat consumption is
 increasing the risk of colon cancer in Japan.
 In addition, the incidence of colon cancer reportedly increases with age,
 particularly after the age of 40. Since the mean ages of populations in
 America and Western Europe are increasing, the prevalence of colorectal
 cancer should increase in the future.
 To date, little progress has been made in the prevention and treatment of
 colorectal cancer, as reflected by the lack of change in the five-year
 survival rate over the last few decades. The only cure for this cancer is
 surgery at an extremely early stage. Unfortunately, most of these cancers
 are discovered too late for surgical cure. In many cases, the patient does
 not experience symptoms until the cancer has progressed to a malignant
 stage.
 In view of these grim statistics, efforts in recent years have concentrated
 on colon cancer prevention. Colon cancer usually arises from pre-existing
 benign neoplastic growths known as polyps. Prevention efforts have
 emphasized the identification and removal of colonic polyps. Polyps are
 identified by x-ray and/or colonoscopy, and usually removed by devices
 associated with the colonoscope. The increased use of colon x-rays and
 colonoscopies in recent years has detected clinically significant
 precancerous polyps in four to six times the number of individuals per
 year that acquire colon cancer. During the past five years alone, an
 estimated 3.5 to 5.5 million people in the United States have been
 diagnosed with adenomatous colonic polyps, and it is estimated that many
 more people have or are susceptible to developing this condition, but are
 as yet undiagnosed. In fact, there are estimates that 10-12 percent of
 people over the age of 40 will form clinically significant adenomatous
 polyps.
 Removal of polyps has been accomplished either with surgery or fiber-optic
 endoscopic polypectomy--procedures that are uncomfortable, costly (the
 cost of a single polypectomy ranges between $1,000 and $1,500 for
 endoscopic treatment and more for surgery), and involve a small but
 significant risk of colon perforation which can be fatal. Overall, about
 $2.5 billion is spent annually in the United States in colon cancer
 treatment and prevention.
 In the breast, breast cancer is often treated surgically, often by radical
 mastectomy with its painful and emotional aftermath. Such surgery is
 costly, too.
 As indicated above, each lesion carries with it a chance that it will
 develop into a cancer. The likelihood of cancer is diminished if a
 precancerous lesion is removed. However, many of these patients
 demonstrate a propensity for developing additional lesions in the future.
 They must, therefore, be monitored periodically for the rest of their
 lives for reoccurrence.
 In most cases (i.e. the cases of sporadic lesion formation, e.g., so-called
 common sporadic polyps), lesion removal will be effective to reduce the
 risk of cancer. In a small percentage of cases (i.e. cases where numerous
 lesions form, e.g. the so-called polyposis syndromes), removal of all or
 part of the effected area (e.g. the colon) is indicated. For example, the
 difference between common sporadic polyps and polyposis syndromes is
 dramatic. Common sporadic polyp cases are characterized by relatively few
 polyps which can usually be removed leaving the colon intact. By contrast,
 polyposis syndrome cases can be characterized by many (e.g. hundreds or
 more) of polyps--literally covering the colon in some cases--making safe
 removal of the polyps impossible short of surgical removal of the colon.
 Because each lesion carries with it a palpable risk of cancerous
 development, patients who form many lesions (e.g. polyposis syndrome
 patients) invariably develop cancer if left untreated. Surgical removal of
 the colon is the conventional treatment in polyposis patients. Many
 polyposis patients have undergone a severe change in lifestyle as a result
 of the disfiguring surgery. Patients have strict dietary restrictions, and
 many must wear ostomy appliances to collect their intestinal wastes.
 The search for drugs useful for treating and preventing cancer is
 intensive. Indeed, much of the focus of cancer research today is on the
 prevention of cancer because chemotherapy for cancer itself is often not
 effective and has severe side effects. Cancer chemoprevention is important
 for recovered cancer patients who retain a risk of cancer reoccurrence.
 Also, cancer prevention is important for people who have not yet had
 cancer, but have hereditary factors that place them at risk of developing
 cancer. With the development of new genetic screening technologies, it is
 easier to identify those patients with high-risk genetic factors, such as
 the potential for polyposis syndrome, who would greatly benefit from
 chemopreventative drugs. Therefore, finding such anti-cancer drugs that
 can be used for prolonged preventive use is of vital interest.
 Known chemopreventative and chemotherapeutic drugs are believed to kill
 cancer cells by inducing apoptosis, or as sometimes referred to as
 "programmed cell death." Apoptosis naturally occurs in virtually all
 tissues of the body, and especially in self-renewing tissues such as bone
 marrow, gut, liver and skin. Apoptosis plays a critical role in tissue
 homeostasis, that is, it ensures that the number of new cells produced are
 correspondingly offset by an equal number of cells that die. For example,
 the cells in the intestinal lining divide so rapidly that the body must
 eliminate cells after only three days in order to prevent the overgrowth
 of the intestinal lining.
 Recently, scientists have realized that abnormalities of apoptosis can lead
 to the formation of precancerous lesions and carcinomas. Also, recent
 research indicates that defects in apoptosis play a major role in other
 diseases in addition to cancer. Consequently, compounds that modulate
 apoptosis could be used to prevent or control cancer, as well as used in
 the treatment of other diseases.
 Unfortunately, even though known chemotherapeutic drugs may exhibit such
 desirable apoptosis effects, most chemotherapeutic drugs have serious side
 effects that prohibit their long-term use, or use in otherwise healthy
 individuals with precancerous lesions. These side effects, which are a
 result nonspecific cytotoxicity of the drugs, include hair loss, weight
 loss, vomiting, immune suppression and other toxicities. For this reason,
 there is a need to identify new drug candidates for therapy of patients
 with precancerous lesions that do not have such serious side effects in
 humans.
 In recent years, several nonsteroidal anti-inflammatory drugs ("NSAIDs"),
 originally developed to treat arthritis, have shown effectiveness in
 inhibiting and eliminating colonic polyps. Polyps virtually disappear when
 the patients take such drugs, particularly when the NSAID sulindac is
 administered. However, the prophylactic use of currently available NSAIDs,
 even in polyposis syndrome patients, is marked by severe side reactions
 that include gastrointestinal irritations and ulcerations. Once NSAID
 treatment is terminated due to such complications, the polyps return,
 particularly in polyposis syndrome patients.
 Sulindac has been particularly well received among the NSAIDs for the polyp
 treatment. Sulindac is a sulfoxide compound that itself is believed to be
 inactive as an anti-arthritic agent. The sulfoxide is reportedly converted
 by liver enzymes to the corresponding sulfide, which is acknowledged to be
 the active moiety as a prostaglandin synthesis inhibitor. The sulfide,
 however, is associated with the side effects of conventional NSAIDs. The
 sulfoxide is also known to be metabolized to sulfone compound that has
 been found to be inactive as an inhibitor of prostaglandin synthesis but
 active as an inhibitor of precancerous lesions.
 SUMMARY OF THE INVENTION
 This invention includes a method of inhibiting neoplastic cells by exposing
 those cells to a pharmacologically effective amount of those compounds
 described below. Such compounds are effective in modulating apoptosis and
 eliminating and inhibiting the growth of neoplasias such as precancerous
 lesions.
 The compounds of that are useful in the methods of this invention include
 2,8-disubstituted quinazolinones of Formula I:
 ##STR1##
 wherein A is an oxiranyl group, optionally substituted by straight-chain or
 branched alkyl with up to 8 carbon atoms, which in turn may be substituted
 by phenyl, or A is selected from the group consisting of
 ##STR2##
 wherein R.sup.1 is selected from the group consisting of hydrogen or a
 straight-chain or branched alkyl with up to 6 carbon atoms;
 R.sup.2 is selected from the group consisting of a straight-chain or
 branched alkyl with up to 8 carbon atoms, which is optionally substituted
 by phenyl;
 R.sup.3 is selected from the group consisting of a straight-chain or
 branched alkyl with up to 5 carbon atoms or a group with the formula
 --OR.sup.6,
 wherein R.sup.6 is selected from the group consisting of hydrogen, a
 hydroxy-protecting group, or a straight-chain or branched alkyl with up to
 5 carbon atoms;
 R.sup.4 is selected from the group consisting of a straight-chain or
 branched alkyl with 2 to 10 carbon atoms, which is optionally substituted
 by phenyl;
 L is selected from the group consisting of --CO--, --CH(OH), --CH.sub.2,
 --CH(N.sub.3), or --CH(OSO.sub.2 R.sup.7);
 wherein R.sup.7 is selected from the group consisting of a straight-chain
 or branched alkyl with up to 4 carbon atoms or phenyl;
 R.sup.5 is selected from the group consisting of a straight-chain or
 branched alkyl with 3 to 8 carbon atoms, which is optionally substituted
 by phenyl, or benzyl or 2-phenylethyl;
 D is selected from the group consisting of hydrogen or a group with the
 formula --SO.sub.2 --NR.sup.8 R.sup.9;
 wherein R.sup.8 and R.sup.9 are the same or different and are selected from
 the group consisting of hydrogen, phenyl, or straight-chain or branched
 alkyl with up to 6 carbon atoms, which is optionally substituted by
 hydroxy, or R.sup.8 and R.sup.9 together with the nitrogen atom they form
 a 5- to 6-membered heterocyclic ring with up to 2 other hetero atoms
 selected from the group consisting of S, N, and/or O, which is optionally
 also substituted through a free N function by straight-chain or branched
 alkyl with up to 6 carbon atoms, which in turn may be substituted by
 hydroxy;
 E is a straight-chain or branched alkyl with up to 8 carbon atoms; and
 their tautomers and salts.
 The present invention is also a method of treating individuals with
 neoplastic lesions by administering a pharmacologically effective amount
 of an enterically coated pharmaceutical composition that includes
 compounds of this invention.
 Preferably, such compounds are administered without therapeutic amounts of
 an NSAID.
 In still another form, the invention is a method of inducing apoptosis in
 human neoplastic cells by exposing those cells to an effective amount of
 compounds of Formula I, to those neoplastic cells sensitive to such a
 compound.
 As used herein, the term "precancerous lesion" includes syndromes
 represented by abnormal neoplastic, including dysplastic, changes of
 tissue. Examples include dysplasic growths in colonic, breast, bladder or
 lung tissues, or conditions such as dysplastic nevus syndrome, a precursor
 to malignant melanoma of the skin. Examples also include, in addition to
 dysplastic nevus syndromes, polyposis syndromes, colonic polyps,
 precancerous lesions of the cervix (i.e., cervical dysplasia), esophagus,
 prostatic dysplasia, bronchial dysplasia, breast, bladder and/or skin and
 related conditions (e.g., actinic keratosis), whether the lesions are
 clinically identifiable or not.
 As used herein, the term "cancerous" refers to lesions that are malignant.
 Examples include malignant melanomas, breast cancer, prostate cancer and
 colon cancer.
 As used herein, the term "neoplasm" refers to both precancerous and
 cancerous lesions and hyperplasia.
 The substances pursuant to the invention may also be in the form of salts.
 Physiologically acceptable salts are preferred in the context of the
 invention.
 Physiologically acceptable salts can be salts of the compounds pursuant to
 the invention with inorganic or organic acids. Preferred salts are those
 with inorganic acids, for example hydrochloric acid, hydrobromic acid,
 phosphoric acid, or sulfuric acid, or salts with organic carboxylic acids
 or sulfonic acids, for example acetic acid, maleic acid, fumaric acid,
 malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or
 methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
 toluenesulfonic acid, or naphthalenedisulfonic acid.
 The compounds pursuant to the invention with the general Formula I can
 occur in various stereochemical forms, which have the nature either of
 image and mirror image (enantiomers) or which are not mirror images of one
 another (diastereoisomers). The invention relates both to the antipodes
 and to the racemic forms, and to mixtures of diastereoisomers. The racemic
 forms can be separated, as can the diastereoisomers, into their
 stereoisomerically pure components, by known methods.
 A 5- to 6-membered saturated heterocyclic ring bonded through the nitrogen
 atom, which also may contain up to 2 oxygen, sulfur, and/or nitrogen atoms
 as hetero atoms, generally stands for piperidyl, morpholinyl, or
 piperazinyl. Morpholinyl is preferred.
 Preferred compounds of Formula I for practice of this invention are those
 wherein:
 A is selected from the group consisting of oxiranyl, which is optionally
 substituted by straight-chain or branched alkyl with up to 7 carbon atoms,
 which in turn may be substituted by phenyl, or A is selected from the
 group of the formula:
 ##STR3##
 wherein R.sup.1 is selected fom the group consisting of stands for hydrogen
 or for a straight-chain or branched alkyl with up to 5 carbon atoms;
 R.sup.2 is selected from the group consisting of a straight-chain or
 branched alkyl with up to 6 carbon atoms, which is optionally substituted
 by phenyl,
 R.sup.3 is selected from the group consisting of a straight-chain or
 branched alkyl with up to 4 carbon atoms or a group with the formula
 --OR.sup.6
 wherein R.sup.6 is selected from the group consisting of hydrogen, benzyl,
 acetyl, or a straight-chain or branched alkyl with up to 4 carbon atoms;
 R.sup.4 is selected from the group consisting of a straight-chain or
 branched alkyl with 2 to 8 carbon atoms, which is optionally substituted
 by phenyl;
 L is selected from the group consisting of --CO--, --CH(OH), --CH.sub.2,
 --CH(N.sub.3), or --CH(OSO.sub.2 R.sup.7);
 wherein R.sup.7 is selected from the group consisting of a straight-chain
 or branched alkyl with up to 3 carbon atoms or phenyl;
 R.sup.5 is selected from the group consisting of a straight-chain or
 branched alkyl with 3 to 7 carbon atoms, which is optionally substituted
 by phenyl, or benzyl or 2-phenylethyl;
 D is selected from the group consisting of hydrogen or a group with the
 formula --SO.sub.2 --NR.sup.8 R.sup.9 ;
 wherein R.sup.8 and R.sup.9 are the same or different and are is selected
 from the group consisting of hydrogen, phenyl, or straight-chain or
 branched alkyl with up to 5 carbon atoms, which is optionally substituted
 by hydroxy; or R.sup.8 and R.sup.9 together with the nitrogen atom they
 form a morpholinyl, piperidinyl, or piperazinyl ring, which is optionally
 also substituted through a free N function by straight-chain or branched
 alkyl with up to 4 carbon atoms, which in turn may be substituted by
 hydroxy;
 E is selected from the group consisting of straight-chain or branched alkyl
 with up to 6 carbon atoms; and their tautomers and salts.
 Especially preferred are compounds useful in the practice of this invention
 are those of Formula I wherein
 A is selected from the group consisting of oxiranyl, which is optionally
 substituted by straight-chain or branched alkyl with up to 6 carbon atoms,
 which in turn may be substituted by phenyl, or a group of the formula
 ##STR4##
 wherein R.sup.1 is selected from the group consisting of hydrogen or for a
 straight-chain or branched alkyl with up to 3 carbon atoms,
 R.sup.2 is selected from the group consisting of a straight-chain or
 branched alkyl with up to 6 carbon atoms, which is optionally substituted
 by phenyl;
 R.sup.3 stands for a straight-chain or branched alkyl with up to 4 carbon
 atoms or a group with the formula --OR.sup.6 ;
 wherein R.sup.6 is selected from the group consisting of hydrogen, benzyl,
 acetyl, or a straight-chain or branched alkyl with up to 3 carbon atoms;
 R.sup.4 is selected from the group consisting of a straight-chain or
 branched alkyl with 2 to 7 carbon atoms, which is optionally substituted
 by phenyl;
 L is selected from the group consisting of --CO--, --CH(OH), --CH.sub.2,
 --CH(N.sub.3), or --CH(OSO.sub.2 R.sup.7);
 wherein R.sup.7 is selected from the group consisting of a straight-chain
 or branched alkyl with up to 3 carbon atoms or phenyl;
 R.sup.5 is selected from the group consisting of a straight-chain or
 branched alkyl with 3 to 6 carbon atoms, which is optionally substituted
 by phenyl, or benzyl or 2-phenylethyl;
 D is selected from the group consisting of hydrogen or for a group with the
 formula --SO.sub.2 --NR.sup.8 R.sup.9 ;
 wherein R.sup.8 and R.sup.9 are the same or different and are selected from
 the group consisting of hydrogen, phenyl, or straight-chain or branched
 alkyl with up to 3 carbon atoms, or R.sup.8 and R.sup.9 together with the
 nitrogen atom form a morpholinyl or piperidinyl ring;
 E is selected from the group consisting of straight-chain or branched alkyl
 with up to 4 carbon atoms; and their tautomers and salts.
 Compounds of this invention may be formulated into pharmaceutical
 compositions together with pharmaceutically acceptable carriers for oral
 administration in solid or liquid form, or for intraveneous, rectal or
 topical administration, although carriers for oral administration are most
 preferred.
 Pharmaceutically acceptable carriers for oral administration include
 capsules, tablets, pills, powders, troches and granules. In such solid
 dosage forms, the carrier can comprise at least one inert diluent such as
 sucrose, lactose or starch. Such carriers can also comprise, as is normal
 practice, additional substances other than diluents, e.g., lubricating
 agents such as magnesium stearate. In the case of capsules, tablets,
 troches and pills, the carriers may also comprise buffering agents.
 Carriers such as tablets, pills and granules can be prepared with enteric
 coatings on the surfaces of the tablets, pills or granules. Alternatively,
 the enterically coated compound can be pressed into a tablet, pill, or
 granule for administration to the patient. Preferred enteric coatings
 include those that dissolve or disintegrate at colonic pH such as shellac
 or Eudraget S.
 Pharmaceutically acceptable carriers include liquid dosage forms for oral
 administration, e.g., pharmaceutically acceptable emulsions, solutions,
 suspensions, syrups and elixirs containing inert diluents commonly used in
 the art, such as water. Besides such inert diluents, compositions can also
 include adjuvants such as wetting agents, emulsifying and suspending
 agents, and sweetening, flavoring and perfuming agents.
 Pharmaceutically acceptable carriers for topical administration include
 DMSO, alcohol or propylene glycol and the like that can be employed with
 patches or other liquid-retaining material to hold the medicament in place
 on the skin so that the medicament will not dry out.
 Pharmaceutically acceptable carriers for rectal administration are
 preferably suppositories that may contain, in addition to the compounds of
 this invention excipients such as cocoa butter or a suppository wax, or
 gel.
 The pharmaceutically acceptable carrier and compounds of this invention are
 formulated into unit dosage forms for administration to a patient. The
 dosage levels of active ingredient (i.e., compounds of this invention) in
 the unit dosage may be varied so as to obtain an amount of active
 ingredient effective to achieve lesion-eliminating activity in accordance
 with the desired method of administration (i.e., oral or rectal). The
 selected dosage level therefore depends upon the nature of the active
 compound administered, the route of administration, the desired duration
 of treatment, and other factors. The therapeutically active compound
 should be present in each case at a concentration of about 0.5 to 90 wt. %
 of the total mixture, i.e., in amounts that are sufficient to reach the
 indicated dosage range. If desired, the unit dosage may be such that the
 daily requirement of the active compound is in one dose, or divide d among
 multiple doses for administration, e.g., two to four times per day.
 It is recommended with intravenous administration to administer amounts of
 about 0.01 to 10 mg/kg of body weight, preferably about 0.1 to 10 mg/kg,
 to produce effective results.
 The pharmaceutical compositions of this invention are preferably packaged
 in a container (e.g., a box or bottle, or both) with suitable printed
 material (e.g., package insert) containing indications, directions for
 use, etc.
 A general method for preparing the compounds of Formula I employs compounds
 of Formula II as a starting material
 ##STR5##
 wherein D and E have the meanings given above; T is a C.sub.1 -C.sub.4
 -alkyl; and R.sup.10 stands for halogen, preferably bromine or iodine.
 A compound of Formula II is first cyclized with formamide to give a
 compound of the general Formula III
 ##STR6##
 wherein D, E, and R.sup.10 have the meanings given above.
 In a last step, a compound of Formula III is converted with a compound with
 the general Formula IV
EQU R.sup.1 --CH.dbd.CH--R.sup.2
 wherein R.sup.1 and R.sup.2 have the meanings given above in an inert
 solvent, in the presence of a base, and in the system
 tri-o-tolylphosphine/palladium(II) acetate to a compound with the general
 Formula Ia
 wherein D, E, R.sup.1, and R.sup.2 have the meanings given above, and the
 double bond is optionally hydrogenated. If A is a substituted oxiranyl,
 the double bond is optionally oxidized by an oxidizing agent by
 conventional methods in inert solvents to the corresponding epoxy
 compounds, and these are converted by ring-opening reactions into the
 corresponding hydroxy compounds. Starting with the hydroxy compounds,
 optionally after activation, nucleophilic substitution reactions can be
 carried out, or the hydroxy compounds are oxidized to the oxo compounds.
 The method pursuant to the invention can be illustrated by he following
 schematic diagram by way of example:
 ##STR7##
 [KEY to diagram]
 ##STR8##
 Bortrifluorid-Etherat=boron trifluoride etherate
 Inert organic solvents that do not change under the reaction conditions are
 suitable for the method. Preferred examples include diethyl ether,
 dioxane, tetrahydrofuran, ethylene glycol mono- or dimethyl ether,
 halogenated hydrocarbons such as di-, tri-, or tetrachloromethane,
 dichloroethylene, trichloroethylene, ethyl acetate, toluene, acetonitrile,
 dimethylformamide, hexamethylphosphoric triamide, and acetone. It is
 possible to use mixtures of solvents. Dichloromethane and
 dimethylformamide are preferred.
 The reaction temperature can generally be varied within a broad range: in
 the range of -20.degree. C. to 200.degree. C., preferably from 0.degree.
 C. to 25.degree. C. The cyclization can be carried out in a temperature
 range of +50.degree. C. to 200.degree. C., preferably from +160.degree. C.
 to +180.degree. C.
 The compounds with the general Formula Ia can be prepared in one of the
 solvents listed above, preferably dimethylformamide, and in the presence
 of a base. Inorganic or organic bases in general can be used. Preferred
 examples are alkali metal carbonates such as sodium carbonate, potassium
 carbonate, or cesium carbonate, or alkali metal or alkaline earth
 alkoxides or amides such as sodium or potassium methoxide, sodium or
 potassium ethoxide, potassium t-butoxide, or potassium amide, or organic
 amines (trialkyl(C.sub.1 -C.sub.6)amines) such as triethylamine or
 tributylamine. Tributylamine is especially preferred. The base is usually
 used in an amount of 0.05 mole to 10 moles, preferably from 1 mole to 2
 moles per mo e of compound of Formula III. The reaction can be carried out
 in a temperature range of 0.degree. C. to +80.degree. C., preferably from
 +30.degree. C. to +150.degree. C.
 The steps can be carried out at atmospheric pressure. However, it is also
 possible to operate under elevated or reduced pressure (e.g., in a range
 from 0.5 to 5 bar).
 The epoxidation is carried out in one of the solvents listed above,
 preferably dry trichloromethane, in the presence of an oxidizing agent,
 for example m-chlorobenzoic acid [sic] or H.sub.2 O.sub.2.
 m-Chloroperbenzoic acid is preferred. The epoxidation s generally carried
 out in a temperature range of -20.degree. C. to +50.degree. C., preferably
 from 0.degree. C. to +30.degree. C.
 The hydrogenation is usually done in one of the alcohols listed above,
 preferably methanol. Palladium compounds are generally suitable as
 catalyst. Pd/C is preferred.
 The catalyst is used in an amount of 0.01 mole to 0.4 mole, preferably from
 0.05 mole to 0.2 mole per mole of the corresponding alcohol.
 The hydrogenation is generally carried out in a temperature range of
 -20.degree. C. to +50.degree. C., preferably from 0.degree. C. to
 +30.degree. C. The hydrogenation is generally carried out at atmospheric
 pressure. However, it is also possible to operate under elevated or educed
 pressure (e.g., in a range of 0.5 to 5 bar).
 The epoxides are opened by methods described in the literature [cf. Takano
 et al., Heterocycles 29, (1989), 249], and likewise in one of the alcohols
 listed above, preferably methanol, in the presence of boron trifluoride
 etherate.
 The reaction with alkylsulfonyl chlorides, starting with the corresponding
 free hydroxy compounds, is carried out in one of the solvents listed above
 and one of the bases, preferably with dichloromethane and triethylamine,
 in a temperature range of -20.degree. C. to +20.degree. C., preferably
 0.degree. C., at atmospheric pressure.
 The azide group is introduced generally by reacting the corresponding
 alkylsulfonyloxy-substituted compounds with sodium azide in one of the
 solvents listed above, preferably dimethylformamide, in a temperature
 range of 50.degree. C. to +120.degree. C., preferably at 100.degree. C.
 and atmospheric pressure.
 The ketones are prepared from the corresponding hydroxy compounds by known
 methods (Swern Oxidation).
 The enantiomerically pure compounds are accessible by conventional methods,
 for example by chromatography of racemic compounds with the general
 Formula I on chiral phases.
 Some of the compounds with the general Formula II are known and some are
 new, and they can then be prepared by reacting compounds with the general
 Formula V
 ##STR9##
 wherein R.sup.10 and T have the meanings given above with 2-n-alkoxybenzoyl
 chlorides with the Formula VI
 ##STR10##
 wherein D and E have the meanings given above. This reaction is carried out
 in inert solvents and in the presence of a base. Suitable solvents are the
 solvents listed above, with dichloromethane being preferred. Suitable
 bases are cyclic amine for example, piperidine, pyridine, pyrimidine,
 dimethylaminopyridine, or C.sub.1 -C.sub.4 -alkylamines, for example
 triethylamine. Triethylamine and pyridine are preferred.
 The base is employed in an amount of 0.5 mole to 2 moles, preferably 1 mole
 to 1.2 moles per mole of the compounds with the general Formula V. The
 reaction temperature is in the range of -20.degree. C. to 200.degree. C.,
 preferably from 0.degree. C. to 25.degree. C.
 Compounds of Formula IV are known. Compounds of Formula (V) are also known
 (see, e.g., J. Heterocyclic Chem., 26(5), 1989, 1405-1413), as are those
 of Formula VI (see, e.g. EP-0 526 004 A1).
 The compounds of Formula III can be prepared as describe above.
 The foregoing may be better understood from the following examples that are
 presented for the purposes of illustration and are not intended to limit
 the scope of the invention. Examples I-IV illustrate the systhesis of
 certain starting materials useful in synthesizing compounds such as those
 referenced in Examples 1-30 below that can be used in the methods
 according to this invention.

EXAMPLE I
 Methyl 2-(2-n-Propoxybenzamido)-3-Iodobenzoate

##STR11##
 27.9 g (0.1 mole) of methyl 2-amino-3-iodobenzoate and 15.4 ml (0.11 mole)
 of triethylamine are dissolved in 170 ml of absolute CH.sub.2 Cl.sub.2.
 solution,) of 20 g (0.1 mole) of 2-n-propoxybenzoyl chloride in 80 ml of
 absolute CH.sub.2 Cl.sub.2 is added dropwise at 0.degree. C. The mixture
 is stirred overnight at 20.degree. C., the precipitate is filtered off,
 and the solution is extracted with 100 ml of 1 N HCl, 100 ml of 1 N NaOH,
 and 100 ml of saturated NaCl solution. The organic phase is dried over
 Na.sub.2 SO.sub.4, and evaporated under vacuum, and the residue is
 purified by chromatography on silica gel (eluant:toluene/ethyl acetate
 95:5).
 Yield: 36 g (81.4%)
 R.sub.f =0.25 (toluene/ethyl acetate 10:1)
 EXAMPLE II
 Methyl 2-(2-n-Propoxybenzamido)-3-Bromobenzoate

##STR12##
 The title compound is prepared analogously to the method for Example I,
 starting with methyl 2-amino-3-bromobenzoate.
 Yield: 60.4%
 R.sub.f =0.19 (toluene/ethyl acetate 5:1)
 EXAMPLE III
 2-(2-n-Propoxyphenyl)-8-Iodoquinazolin-4(3H)-One

##STR13##
 19.4 g (44.17 mmoles) of the compound from Example I is stirred for 10
 hours at 180.degree. C. in 216 ml of formamide. After cooling, 500 ml of
 water is added and extracted 4 times with 300-ml portions of CH.sub.2
 Cl.sub.2. The combined organic phases are dried over MgSO.sub.4, the
 solvent is evaporated under vacuum, and the residue is stirred in a
 mixture of 100 ml of diethyl ether and 50 ml of petroleum ether. The
 product (17.8 g) is filtered off by suction and recrystallized from 250 ml
 of absolute ethanol.
 Yield: 14.56 g (81.2%)
 M.p.: 174.degree. C.
 EXAMPLE IV
 2-(2-n-Propoxyphenyl)-8-Bromoquinazolin-4(3H)-One

##STR14##
 The title compound is prepared analogously to the method or Example III,
 starting with the compound from Example II.
 Yield: 60%
 R.sub.f =0.7 (toluene/ethyl acetate 10:1)
 EXAMPLE 1
 2-(2-n-Propoxyphenyl)-8-(1-Hepten-1-yl)Quinazolin-4(3H)-One

##STR15##
 5 g (12.31 mmoles) of the compound from Example III, 3.7 ml (15.4 mmoles)
 of tributylamine, 6.6 ml (46.2 mmoles) of 1-heptene, 375 mg of
 tri-o-tolylphosphine (1.23 mmoles), and 138 mg of palladium(II) acetate
 (0.6 mmole) are stirred in 50 ml of dry DMF for 2.5 h at 100.degree. C.
 The mixture is cooled to room temperature, 50 ml of ethyl acetate is
 added, and the mixture is washed 3 times with 50-ml portions of H.sub.2 O.
 After drying over MgSO.sub.4, the organic phase is evaporated under
 vacuum, and the residue is chromatographed on silica gel with
 toluene/ethyl acetate 95:5 as eluant. The fractions containing the product
 are combined and the solvent is evaporated under vacuum. The initially
 oily residue is crystallized by stirring with 35 ml petroleum ether.
 Yield: 2.2 g (47.5%)
 M.p.: 94.degree. C.
 EXAMPLE 2
 2-(2-n-Propoxyphenyl)-8-(3-Phenyl-1-Propen-1-yl)Quinazolin-4(3H)-One

##STR16##
 The title compound is prepared analogously to the method of Example 1,
 starting with the compound from Example III and 3-phenyl-1-propene.
 Yield: 63.9%
 M.p. 123-126.degree. C. (from diethyl ether)
 EXAMPLE 3
 2-(2-n-Propoxyphenyl)-8-(4-Phenyl-1-Buten-1-yl)Quinazolin-4(3H)-One

##STR17##
 The title compound is prepared analogously to the method of Example 2,
 starting with the compound from Example III and 4-phenyl-1-butene.
 Yield: 49.9%
 R.sub.f =0.27 (toluene/ethyl acetate 10:1)
 EXAMPLES 4 And 5
 2-(2-n-Propoxyphenyl)-8-(5-Phenyl-2-Penten-2-yl)Quinazolin-4(3H)-One and
 2-(2-n-Propoxyphenyl)-8-(5-Phenyl-3-Penten-3-yl)Quinazolin-4(3H)-One

##STR18##
 The title compounds are prepared analogously to the method of Example 1,
 starting with the compound from Example III and 5-phenyl-2-pentene.
 Yield: 64.6%
 EXAMPLE 6
 2-(2-n-Propoxyphenyl)-8-(1-Heptyl)quinazolin-4(3H)-One

##STR19##
 20 mg of Pd/C (10%) is prehydrogenated for 20 minutes in 2 ml of absolute
 methanol. To it are added 200 mg (0.53 mmole) of the compound from Example
 1 in a mixture of 2 ml of absolute methanol and 0.8 ml of ethyl acetate,
 and the mixture is hydrogenated for 1 hour at 20.degree. C. The catalyst
 is filtered off, and the solvent is evaporated under vacuum in a rotary
 evaporator. The residue is pure in TLC and crystallizes upon drying under
 high vacuum.
 Yield: 180 mg (89.6%)
 M.p.: 73.degree. C.
 EXAMPLE 7
 2-(2-n-Propoxyphenyl)-8-(3-Phenyl-1-Propyl)quinazolin-4-(3H)-One

##STR20##
 The title compound is prepared analogously to the method of Example 6,
 starting with the compound from Example 2.
 Yield: 79.7%
 M.p.: 89.degree. C.
 EXAMPLE 8
 2-(2-n-Propoxyphenyl)-8-(4-Phenyl-1-Butyl)Quinazolin-4-(3H)-One

##STR21##
 The title compound is prepared analogously to the method of Example 6,
 starting with the compound from Example 3.
 Yield: 86.2%
 M.p.: 82.degree. C.
 EXAMPLES 9 AND 10
 2-(2-n-Propoxyphenyl)-8-(5-Phenyl-2-Pentyl)Quinazolin-4-(3H)-One and
 2-(2-n-Propoxyphenyl)-8-(5-Phenyl-3-Pentyl)Quinazolin-4-(3H)-One

##STR23##
 1.5 g (3.98 mmoles) of the compound from Example 1 is dissolved at
 0.degree. C. in 40 ml of dry chloroform. To it is added 0.98 g (3.98
 mmoles) of 70% m-chloroperbenzoic acid. The mixture is allowed to come to
 room temperature and is stirred for 3 hours longer. It is washed 3 times
 with 30 ml portions of 10% sodium bisulfite solution and twice with 30 ml
 portions of 1 N NaOH solution, dried over MgSO.sub.4, and evaporated under
 vacuum. The residue (1.6 g) was chromatographed on silica gel with
 toluene/ethyl acetate 95:5 as eluant.
 Yield: 1.06 g (67.8%)
 M.p.: 78.degree. C.
 EXAMPLE 12
 2-(2-n-Propoxyphenyl)-8-(3-Phenyl-1,2-Epoxy-1-Propyl)Quinazolin-4-(3H)-One

##STR24##
 The title compound is prepared analogously to the method of Example 11,
 starting with the compound from Example 2.
 Yield: 47%
 R.sub.f =0.27 (toluene/ethyl acetate 10:1)
 EXAMPLE 13
 2-(2-n-Propoxyphenyl)-8-(4-Phenyl-1,2-Epoxy-1-Butyl)Quinazolin-4-(3H)-One

##STR25##
 The title compound is prepared analogously to the method of Example 11,
 starting with the compound from Example 3.
 Yield: 61.4%
 R.sub.f =0.29 (toluene/ethyl acetate 1:1)
 EXAMPLE 14
 2-(2-n-Prooxyphenyl)-8-(1-Methoxy-2-Hydroxy-1-Heptyl)Quinazolin-4(3H)-One

##STR26##
 0.1 ml of boron trifluoride etherate (0.76 mmole) is added to a solution of
 0.2 g (0.51 mmole) of the compound from Example 11 in 6 ml of methanol at
 0.degree. C. After 20 minutes at 0.degree. C., 75 ml of ethyl acetate is
 added, and the mixture is extracted 3 times with 50-ml portions of water.
 The organic phase is chromatographed on silica gel with toluene/ethyl
 acetate 5:1 as eluant.
 Yield: 160 mg (73.9%)
 R.sub.f =0.19 (toluene/ethyl acetate 5:1)
 EXAMPLE 15
 2-(2-n-Propoxyphenyl)-8-(3-Phenyl-1-Methoxy-2-Hydroxy-1-Propyl)Quinazolin-4
 (3H)-One

##STR27##
 The title compound is prepared analogously to the method of Example 14,
 starting with the compound from Example 12.
 Yield: 32.5%
 R.sub.f =0.20 (toluene/ethyl acetate 5:1)
 EXAMPLE 16
 2-(2-n-Propoxyphenyl)-8-(4-Phenyl-1-Methoxy-2-Hydroxy-1-Butyl)Quinazolin-4(
 3H)-One

##STR28##
 The title compound is prepared analogously to the method of Example 14,
 starting with the compound from Example 10.
 Yield: 74.4%
 R.sub.f =0.17 (toluene/ethyl acetate 5:1)
 EXAMPLE 17
 2-(2-n-Propoxyphenyl)-8-(3-Hydroxy-2-Octyl)quinazolin-4(3H)-One

##STR29##
 1.9 ml of 1.6 molar methyllithium solution in diethyl ether (3.06 mmoles)
 is added dropwise at -78.degree. C. to a suspension of 0.14 g (1.53
 mmoles) of Cu(I)CN in 3 ml of absolute diethyl ether. After 1 hour at
 -78.degree. C., the mixture was warmed to -45.degree. C. and 200 mg (0.51
 mmole) of the compound from Example 11 in 2 ml of absolute diethyl ether
 is added dropwise. The mixture is stirred for 1 h at 0.degree. C. and then
 at 20.degree. C. until the reaction was complete (TLC control, about 1
 hour). After adding 50 ml of ethyl acetate, the mixture was washed 3 times
 with 30-ml portions of water. The organic phase is dried over Na.sub.2
 SO.sub.4 and the solvent is evaporated under vacuum in a rotary
 evaporator. The residue is chromatographed on silica gel with
 toluene/ethyl acetate 7:1 as eluant.
 Yield: 80 mg (38.4%)
 R.sub.f =0.22 (toluene/ethyl acetate 5:1)
 EXAMPLE 18
 2-(2-n-Propoxyphenyl)-8-(4-Phenyl-3-Hydroxy-2-Butyl)Quinazolin-4(3H)-One

##STR30##
 The title compound is prepared analogously to the method of Example 14,
 starting with the compound from Example 9.
 Yield: 38.5%
 R.sub.f =0.21 (toluene/ethyl acetate 5:1)
 EXAMPLE 19
 2-(2-n-Propoxyphenyl)-8-(5-Phenyl-3-Hydroxy-2-Pentyl)quinazolin-4(3H)-One

##STR31##
 The title compound is prepared analogously to the method of Example 17,
 starting with the compound from Example 13.
 Yield: 51.4%
 EXAMPLE 20
 2-(2-n-Propoxyphenyl)-8-(4-Hydroxy-3-Nonyl)Quinazolin-4(3H)-One

##STR32##
 1.02 ml of a 3 M solution of C.sub.2 H.sub.5 MgBr (3.05 mmoles) in diethyl
 ether is added at -20.degree. C. to a solution of 240 mg (0.61 mmole) of
 the compound from Example 11 and the mixture is stirred for 45 minutes at
 -20.degree. C. and then for 20 minutes at room temperature. The oily
 precipitate is dissolved by adding 4 ml of absolute tetrahydrofuran and an
 additional 1.02 ml of the 3 M solution of C.sub.2 H.sub.5 MgBr was added
 to complete the reaction. After 15 min at 20.degree. C., 75 ml of ethyl
 acetate is added, and the mixture is extracted 3 times with 50 ml portions
 of water. After drying the organic phase over MgSO.sub.4, the solvent is
 evaporated under vacuum in a rotary evaporator, and the residue is
 chromatographed on silica gel with toluene/ethyl acetate 10:1 as eluant.
 Yield: 40 mg (15.5%)
 R.sub.f =0.24 (toluene/ethyl acetate 5:1)
 EXAMPLE 21
 2-(2-n-Propoxyphenyl)-8-(3-Methanesulfonyloxy-2-Octyl)Quinazolin-4(3H)-One

##STR33##
 0.17 ml (2.17 mmoles) of methanesulfonyl chloride is added at 0.degree. C.
 to 740 mg (1.81 mmoles) of the compound from Example 17 and 0.3 ml (2.17
 mmoles) of triethylamine in 18 ml of absolute CH.sub.2 Cl.sub.2. The
 mixture is allowed to come to room temperature and is stirred 30 minutes
 longer. The mixture is first extracted twice with 30 ml portions of 1 N
 NaOH and twice with 30-ml portions of 1 N HCl, the organic phase is dried
 over MgSO.sub.4, and the solvent is evaporated under vacuum in a rotary
 evaporator. The solid residue is stirred with a mixture of 30 ml ethyl
 acetate and 30 ml petroleum ether, and the product is filtered off. Yield:
 650 mg (73.8%).
 M.p.: 195.degree. C.
 EXAMPLE 22
 2-(2-n-Propoxyphenyl)-8-(3-Azido-2-Octyl)Quinazolin-4(3H)-One

##STR34##
 50 mg (0.103 mmole) of the compound from Example 18 and 13.4 ml (0.206
 mmole) of sodium azide in 2 ml of absolute DMF is stirred overnight at
 40.degree. C. 5 ml of ethyl acetate is added, and the mixture is extracted
 3 times with 50-ml portions of water. After drying the organic phase over
 Na.sub.2 SO.sub.4, the solvent is evaporated under vacuum in a rotary
 evaporator, and the residue is purified by flash chromatography on silica
 gel (eluant: toluene/ethyl acetate 5:1).
 Yield: 31 mg (67%)
 R.sub.f =0.59 (toluene/ethyl acetate 5:1)
 EXAMPLE 23
 2-(2-n-Propoxyphenyl)-8-(1-Methoxy-2-Oxo-1-Heptyl)Quinazolin-4(3H)-One

##STR35##
 0.38 ml (5.41 mmoles) of absolute DMSO in 4 ml of absolute CH.sub.2
 Cl.sub.2 is added dropwise to 0.21 ml (2.46 mmoles) of oxalyl chloride in
 13 ml of absolute CH.sub.2 Cl.sub.2 at -70.degree. C. After 30 minutes,
 870 mg (2.05 mmoles) of the compound from Example 14 in 6 ml of absolute
 CH.sub.2 Cl.sub.2 is added dropwise, and after 30 minutes longer, 1.42 ml
 (10.24 mmoles) of N(C.sub.2 H.sub.5).sub.3 is added. The mixture is
 allowed to come to room temperature, and after 10 minutes, 100 ml of water
 is added. The aqueous phase is extracted 3 times with 50 ml portions of
 CH.sub.2 Cl.sub.2, and the combined CH.sub.2 Cl.sub.2 phases are dried and
 evaporated on a rotary evaporator. The residue is dissolved in 10 ml of
 ethanol, 3 ml of 1 N HCl is added, and the mixture is stirred at room
 temperature for 3 hours. The ethanol is evaporated under vacuum, and the
 residue is taken up in 30 ml of ethyl acetate and washed twice with
 H.sub.2 O. After drying over MgSO.sub.4, the solvent is evaporated under
 vacuum in a rotary evaporator, and the residue is purified by
 chromatography on silica gel with toluene/ethyl acetate 98:2 as eluant.
 Yield: 510 mg (58.9%)
 R.sub.f =0.26 (toluene/ethyl acetate 5:1)
 EXAMPLE 24
 2-(2-n-Propoxy-5-Morpholinosulfonylphenyl)-8-(1-Hepten-1-yl)Quinazolin-4(3H
 )-One

##STR36##
 The title compound is prepared analogously to the method of Example 1,
 starting with
 2-(2-n-propoxy-5-morpholinosulfonylphenyl)-8-bromoquinazolin-4(3H)-one and
 1-heptene.
 Yield: 53.2%
 M.p. 112.degree. C. (diethyl ether)
 EXAMPLE 25
 2-(2-n-Propoxy-5-Morpholinosulfonylphenyl)-8-(1
 2-Epoxy-1-Heptyl)Quinazolin-4(3H)-One

##STR37##
 The title compound is prepared analogously to the method of Example 11,
 starting with the compound from Example 24.
 Yield: 90.7%
 M.p.: 96.degree. C.
 EXAMPLE 26
 2-(2-n-Propoxy-5-Morpholinosulfonylphenyl)-8-(1-Methoxy-2-Hydroxy-1-Heptyl)
 Quinazolin-4(3H)-One

##STR38##
 The title compound is prepared analogously to the method of Example 14,
 starting with the compound from Example 25.
 Yield: 20.3%
 R.sub.f =0.42 (toluene/ethyl acetate 2:1)
 EXAMPLES 27 AND 28
 2-(2-n-Propoxy-5-Morpholinosulfonylphenyl)-8-(5-Phenyl-2-Penten-2-yl)Quinaz
 olin-4(3H)-One and
 2-(2-n-Propoxy-5-Morpholinosulfonylphenyl)-8-(5-Phenyl-3-Penten-3-yl)Quinaz
 olin-4(3H)-One

##STR39##
 The title compounds are prepared analogously to the method of Example 1,
 starting with
 2-(2-n-propoxy-5-morpholinosulfonylphenyl)-8-bromoquinazolin-4(3H)-one and
 5-phenyl-2-pentene, respectively.
 Yield: 39%
 EXAMPLES 29 AND 30
 2-(2-n-Propoxy-5-Morpholinosulfonylphenyl)-8-(5-Phenyl-2-Pentyl)Quinazolin-
 4(3H)-One and
 2-(2-n-Propoxy-5-Morpholinosulfonylphenyl)-8-(5-Phenyl-3-Pentyl)Quinazolin-
 4(3H)-One

##STR40##
 The title compounds are prepared analogously to the method of Example 6,
 starting with the mixture of isomers from Example 27. Separation is
 accomplished by medium-pressure chromatography on silica gel with CH.sub.2
 Cl.sub.2 /ethyl acetate (2:1) as eluant.
 Yield Ex. 29: 36.3%; R.sub.f =0.44 (CH.sub.2 Cl.sub.2 /ethyl acetate 4:1)
 Yield Ex. 30: 18.4%; R.sub.f =0.49 (CH.sub.2 Cl.sub.2 /ethyl acetate 4:1)