IE83705B1 - 6- OR 7- (2-imino-2-imidazolidine)-1,4-benzoxazines as alpha adrenergic agents - Google Patents

Description

BACKGROUND OF THE INVENTION . Field of the Invention The present invention is directed to novel 6- or 7- (2- imino—2—imidazolidine)—l,4—benzoxazines which are active as alpha adrenergic agents, and particularly which are useful for treatment of glaucoma, renal and gastrointestinal disorders, vasoconstrictors and other diseases and conditions mediated by alpha—1 and alpha—2 receptors. The nomenclature “2—imino—2— imidazolidine” should be read throughout the description as “imidazolidin—2—ylideneamino”. In another aspect, the present invention is directed to pharmaceutical formulations or compositions which incorporate the novel compounds of the invention. In still another aspect, the present invention is directed to administering such formulations and compositions for the purpose of reducing or maintaining intraocular pressure (anti—glaucoma) and as vasoconstrictors, for example for controlling ocular bleeding, in mammalian species, including humans.

. Brief Description of the Prior Art Alpha adrenergic agents are known in the art. Whereas alpha—l agonists are known to include compounds which have vasoconstrictor activity and are thus useful for controlling intraocular bleeding, alpha—2 agonist are known to include compounds useful for reducing intraocular pressure (anti- glaucoma effect), for increasing renal flow (diurectics) and for altering the rate of fluid transport in the gastrointestinal tract (anti—diarrheals).

In an article titled “Heteroaromatic Analogues of the alpha2—Adrenoreceptor Partial Agonist Clonidine” J.Med. Chem. 1989, 32, l627—1630, Chapleo et al. 4—dihydro—(2H)l, —dihydro—(2H)-l, 4- describe 6~(2—imino— imidazolidine)—3—oxo—3, 4—benzoxazine and 7- (2—imino—imidaZolidine)-3—oxo—3, benzoxazine compounds as partial alpha-2 agonists.

United States Patent No. 3,890,319 discloses (2—imidazolin— —ylamino— substituted quinoxalines as regulators of the cardiovascular system.

United States Patent No. 4,515,800 describes 2- (trisubstituted phenylimino) imidazoline compounds [also known as 2-(trisubstituted—anilino)—l,3—diazacyclopentene—(2) compounds} in pharmaceutical compositions, preferably in eye drops, for the treatment of glaucoma.

United States Patent No. 4,587,257 discloses 2— (trisubstituted phenylimino) imidazoline compounds capable of controlling ocular bleeding; United States Patent No. 3,636,219 discloses 2- (substituted—phenylamino)—thiazolines and imidazolines having anticholinergic activity.

SUMARY OF THE INVENTION This invention covers compounds of Formula 1 HN ; NH Q m /R. 0 R.

FORMULA 1 where Rlis independently H, or lower alkyl of 1 to 6 carbons, R2 is independently H, or lower alkyl of l to 6 carbons or the two R2 symbols jointly represent a carbonyl oxygen; R3 is H, lower alkyl of 1 to 6 carbons; [M and R5 independently is H, Br, Cl or lower alkyl of 1 to 6 carbons, lower alkenyl of 2 to 6 carbons or lower alkynyl of 2 to 6 carbons with the proviso that at least one of R4 ,R5 and R6 cannot be hydrogen and further that the R2 groups must represent carbonyl when R4 and R6 are both hydrogen and R5 is n—propyl and attaches at the 7-position or when R5 is Br and attaches at the 6—position; R6 is hydrogen, Br, Cl, or lower alkyl of 1 to 6 carbons, lower alkenyl of 2 to 6 carbons or lower alkynyl of 2 to 6 carbons, and the R5 and the imidazolidin—2—ylideneamino substituents are connected mutually exclusively to the 6 and 7 positions of the ,4—benzoxazine nucleus.

One group of preferred compounds are those where R1 is H, R3 is H or lower alkyl of 1 to 6 carbons, R4 and R5 independently is H, Br, lower alkyl of l to 6 carbons, or lower alkenyl of 2 to carbons, and R6 is H, Br or lower alkyl of l to 6 carbons or lower alkenyl of 2 to 6 carbons. Preferably, R4, R5 and R6 are independently selected from a group consisting of hydrogen, bromine, lower alkyl of 1 to 3 carbons and allyl groups.

A second group of preferred compounds are those wherein R1 is H, R3 is H or lower alkyl of 1 to 6 carbons, R4 and R5 independently is H, Br, lower alkyl of 1 to 6 carbons, or lower alkenyl of 2 to 6 carbons and R5 is H, Br or lower alkyl of 1 to 6 carbons or lower alkenyl of 2 to 6 carbons and the imidazolidin—2—ylideneamino group is attached to the 6- position of the benzoxazine nucleus.

A third group of preferred compounds are those where R1 is H, R3 is H or lower alkyl of 1 to 6 carbons, R4 and R5 independently is H, Br, lower alkyl of 1 to 6 carbons or lower alkenyl of 2 to 6 carbons and R6 is hydrogen, Br or lower alkyl of 1 to 6 carbons or lower alkenyl of 2 to 6 carbons and the imidaZolidin+2~ylideneamino group is attached to the 7- position of the benzoxazine nucleus. ln the second and third groups the two R2 symbols may jointly represent a carbonyl oxygen. R5 may then represent 'LKV'/41/‘/<—I*lr\V* /\'\r\ V‘V\/‘4—L‘Vv-‘ -a n 4” L.,4.5.~»« viz — ,“, ..Jo.i_o:,cii or lALK_/\,AAj_L on no lo AA_y\J.L\J\j\';:11. rxltclixacivcly, 1\z may be lower alkyl, with R5 representing hydrogen or methyl and R5 being hydrogen. In such compounds one of R4 and R5 may be hydrogen with the other symbol being bromine. Alternatively, both R4 and R5 are bromine, or both may be hydrogen. In yet another alternative, one of R4 and R5 is hydrogen and the other is lower alkyl of 1 to 3 carbons or allyl, or both R4 and R5 are lower alkyl of 1 to 3 carbons.

In the second group of preferred compounds, R2, R3, R5 and R6 may be H and R4 is lower alkyl of 1 to 3 carbons, with methyl being the most preferred. Alternatively, the R2 groups may jointly represent a carbonyl oxygen, R3, R5 and R5 are H and R4 is lower alkyl of 1 to 3 carbons, with methyl being the most preferred. n the third group of preferred compounds, R3 is preferably methyl or hydrogen, both R4 and R5 are hydrogen, and R5 is bromine, lower alkyl of l to 3 carbons or is allyl.

In a second aspect, the present invention relates to the use of the compounds of Formula 1 for reducing or maintaining the intr—aocular pressure in a mammalian eye by administering directly to the mammalian eye a pharmaceutical composition containing an effective amount of one or more compounds of Formula 1.

The compounds of Formula 1, or more precisely pharmaceutical compositions containing one or more of such compounds, are par—ticularly useful for treating mammalian, for example human, eyes affected with glaucoma.

In this regard the present invention also relates to pharmaceutical formulations comprising one or more compounds of Formula 1 admixed with a pharmaceutically acceptable excipient or carrier.

In a third aspect, the present invention also relates to the use of one or more compounds of Formula 1 admixed with suitable pharmacenutically acceptable excipients or as vasocon—strictors in a mammalian carriers, (for example human) species, and parti—cularly as agents for controlling intraocular bleeding.

In still further aspects, the present invention relates to the use of one or more compounds of Formula 1 admixed with suit—able pharmaceutically acceptable excipients or carriers, as agents for increasing renal flow (diuretics) and as agents for controlling secretion of fluids in the gastro—intestinal tract (anti—diarrhoea agents).

As is known in the field, some of the above—noted therapeutic effects are attributed to alpha 1 adrenegic type biological activity, whereas other ones of the above~ noted effects are attributed to alpha 2 type of biological activity. Some of the compounds of the present invention have both alpha 1 and alpha 2 type biological activity but most ones are selectively alpha 2 type agents.

General Embodiments Definitions The terms "ester" ind "amide" as used here refer t , ‘ d »'~ and branch chained alkyl groups as well as cyclo-alkyl groups The term "lower alkyl", unless specifically stated otherwise includes normal alkyl of 1 to 6 carbons, branch chained alkyl of 3 to 6 carbons and cyclo—groups having 3 to 6 carbon atoms. similarly, the terms “alkeny1" and "alkynyl" include normal and branch chained as well as cyc1o— alkenyl and alkynyl groups, respectively, having 2 to 6 carbons when the chains are normal, and 3 to 6 carbons when the chains are branched or cyclic.

A pharmaceutically acceptable salt may be prepared for any compound of this invention having a functionality capable of forming such salt, for example an acid or an amine functionality.

A pharmaceutically acceptable salt may be any salt which retains the activity of the parent compound and does not impart any effect on the subject to which it is deleterious or untoward administered and in the context in which it is administered. derived from any organic or inorganic Of Such a salt may be acid or base. The salt may be a mono or polyvalent ion. particular interest where the acid function is concerned are the inorganic ions, sodium, potassium, calcium, and magnesium.

Organic amine salts may be made with amines, particularly ammoni— um salts such as mono—, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or Any of a number of simple organic acids such as phosphoric acid. mono—, di— or tri-acid may also be used.

The preferred compounds of this invention, with reference to Formula 1, and with reference to the substituents in the 2- position of the l,4—benzoxazine nucleus (R1) are those where R1 is hydrogen- (Conventional numbering of the positions in the 1,4—benzoxazine nucleus is illustrated for the sake of clarity Of this description in Formula 2.) H 6 N 3 7 I 2 O a 1 Formula 2 With reference to the substituents in the 3 position of the 1,4—benzoxazine nucleus (R2), in the preferred compounds of the present invention R2 is either hydrogen, or the two R2 groups In other words, compounds of the invention either are 2,3-dihydro-1,4- benzoxazines unsubstituted in the 2, and 3 positions, or are 2,3- jointly represent an oxo function. the preferred dihydro—3—oxo-1,4~benzoxazines unsubstituted in the 2 position.

With respect to the 5-substituent (R3) in the 4 position of of the present invention, R3 is preferably the 1,4-benzoxazines H, even more to 6 carbons: preferably R3 is H or lower alkyl of or CH3.

The substituent benzoxazines of the present invention is preferably hydrogen, bromine or lower alkyl or alkenyl group; among the lower alkyl and alkenyl groups those having 1 to 3 carbons (such as methyl, ethyl, Q-propyl, 2—propy1 and allyl) are preferred. with respect to the 6 and 7 positions of the benzoxazine (R4) in the 5 position of the 1,4- nucleus of the compounds of the present invention, one of these positions is substituted with a 2—iminoimidazolidine group, as is shown in the structural Formula 1, and the other is preferably substituted with hydrogen, bromine or lower alkyl of 1 to 3 carbons, or lower alkenyl of 3 carbons. ~ The 8 position of the 1,4—benzoxazine nucleus of the com- pounds of the present invention is preferably substituted with hydrogen, bromine, lower alkyl group of 1 to 3 carbons, or lower alkenyl group of 3 carbons (allyl group).

Alternatively, particularly preferred are compounds of the invention where, with reference to Formula 1, the 6.or 7 position bears the 2—imino—2~imidazolidine substituent, the carbon in the 3 position is unsubstituted or is oxo substituted, the nitrogen in the 4—position is either methyl substituted or is unsubstitut- ed, and where the 5, 6, 7 and 8 positions of the l,4—benzoxazine nucleus jointly have a total of 1 to 3 substituents, in the form of bromo, lower alkyl group of 1 to 3 carbons, or lower alkenyl group of 3 carbons. In this regard, mono—bromo compounds where the bromine is in the S, 6, 7 or 8 position, dibromo compounds in the 5 and 7 or in the 6 where the bromines are in the S and 6, and 8 positions, are preferred. Similarly, mono lower C—a1kyi or lower g—alkenyl compounds are also preferred, where the alkyl or For maintaining intraocular pressure in a mammalian eye, and particularly for reducing such pressure as for treatment of glaucoma in humans suffering from that condition, the compounds ‘ of the present invention (or mixtures or salts thereof) are administered to the eye admixed with an qthalmically acceptable Any suitable, e. g. , conventional, ofifihalmically A carrier is oflkhalmically carrier. acceptable carrier may be employed. acceptable if it has substantially no long term or permanent detrimental effect on the eye to which it is administered.

Examples of oflflfialmically acceptable carriers include water (distilled or deionized water) saline and other aqueous media.

The compounds of the invention are preferably soluble in the carrier which is employed for their administration, so that the compounds are administered to the eye in the form of a solution.

Alternatively, a suspension of the active compound or compounds (or salts thereof) in a suitable carrier may also be employed.

The compounds of the invention (or mixtures or salts there- of) are administered in an ophflalmically acceptable carrier in sufficient concentration so as to deliver an effective amount of the active compound or compounds to the eye. Preferably, the opthalmic, therapeutic solutions contain one or more compounds of the invention in a concentration range of approximately 0.0001 % to approximately 1 % (weight per volume) and more preferably ap- proximately 0.05 % to approximately 0.5 % (weight per volume).

Any method of administering drugs directly to a mammalian eye may be employed to provide the presently useful compound or comounds to the eye to be treated. By the term "administering directly" is meant to exclude those general systemic drug admin- istration modes, e.g., injection directly into the patient's blood vessels, oral administration and the like, which result in the compound or compounds being systemically available. The primary effect on the mammal resulting from the direct adminis- tering of the presently useful compound or compounds to the mammal's eye is preferably a reduction in intraocular pressure.

More preferably, the presently useful compound or compounds are applied topically to the eye or are injected directly into the eye. Particularly useful results are obtained when the compound~ or compounds are applied topically to the eye.

Topical ophthalmic preparations, for example ocular drops, gels or creams, are preferred because of ease of application, ease of dose delivery, and fewer systemic side effects, such as An exemplary topical ophthalmic The abbreviation q.s. cardiovascular hypotension. formulation is shown below in Table I. means a quantity sufficient to effect the result or to make volume.

TABLE I Ingredient Amount (% wgv) Compound of the invention, for about 0.0001 to about 1_O example the compound of Example 30 Preservative 0—0.1O Vehicle O-40 Tonicity Adjustor 1-10 Buffer 0.01-10 pH Adjustor q.s. pH 4.5-7.5 as needed as needed to make 100 % antioxidant Purified Water Various preservatives may be used in the ophthalmic prepara- tion described in Table I above. Preferred preservatives in- clude, but are not limited to, benzalkonium chloride, chlorobuta- nol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Likewise, various preferred vehicles may be used in These vehicles include, but are not such ophthalmic preparation. limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl hydroxyethyl cellulose, carboxymethyl cellulose, poloxamers, cellulose, and purified water.

Tonicity adjustors may be added as needed or convenient.

They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so - long as the resulting preparation is ophthalmically acceptable.

Accordingly, buffers include but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers.

Acids or bases may be used to adjust the pH of these formulations as needed. _ In a similar vein, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and buty- _lo_ lated hydroxytoluene.

Other excipient components which may be included in the exemplary ophthalmic preparation described in Table I are chelat- ing agents which may be added as needed. The preferred chelating agent is edetate disodium, although other chelating agents may also be used in place of or in conjunction with it.

For treatment of ocular bleeding, which occurs, for example during conventional "invasive" qmthalmic surgery, and also during certain type of ocular surgery conducted with laser, the com- pounds of the present invention are also administered to the eye in a pharmaceutical composition which comprises, in addition to an effective concentration of one or more compounds of the inven- tion (or of salts thereof), a suitable, pharmacologically accept- able carrier. Oflfihalmic solutions and suspensions are preferred as carriers, and the concentration of the active compound or compounds of the invention may be typically in the same range as for their use as anti-glaucoma agents. The oflfihalmic solutions or suspensions are typically adjusted to isotonicity with sodium chloride, and thickening agents such as carboxymethylcellulose, or carbopol may also be employed to enhance delivery. The pH of the oghfialmic solution or suspension is typically also adjusted to be within ofifihalmically acceptable range. of United States Patent No. 4,587,257, as it pertains to the The specification utilization of compounds capable of treating or controlling intraocular bleeding, is hereby expressly incorporated by refer- ence.

The anti-glaucoma activity (ability to maintain or reduce intaocular pressure) of the compounds of the present invention is established by the following assay procedure. This assay proce- dure is generally recognized in the art to provide pertinent information with respect to the anti-glaucoma activity of the formulations assayed. Thus, each of the compounds of the inven- tion to be tested was dissolved in distilled water at a concen- tration of 0.3% (W/V). topically and unilaterally to one eye of a drugnaive, unanesthe- Each of these solutions was administered tized monkey or New Zealand white rabbit in a single 50 micro liter drop. The contralateral eye received an equal volume of saline prior to determining the intraocular pressure after the mixture was administered. Also, approximately 10 micro liters of 0.5% (W/V) proparacaine (topical anesthetic) was applied to the corneas of each of the animals before determining intraocular pressure. As a control test, six (6) other drug-naive, unanes~ thetized animals were treated and tested as described above except that no compound of the invention was included in the solutions administered to the eyes.

The intraocular pressure was determined in both eyes of each animal both before and after the solutions were administered.

Such intraocular pressure determinations were made in the conven- tional manner using conventional equipment.

Results of these IOP determinations were as follows: Maximum Difference in Intraocular Pressure After Solution Administration % Decrease in IOP from Control (Duration hours) Example Ipsilateral Contralateral (Treated) Eye (Untreated) Eye Control 0.0:1.4 0.S:1.2 Example 30 l4:2.5 6.8il.8 ‘ (1 - 6 h) (1 h) Example 21 11.5:2.7 5.7j'_2.0 (1 — 2 h) (lh) N.S. refers to no significant change in the intraocular pressure.

These results demonstrate the effectiveness in reducing intraocular pressure achieved by directly administering the compounds of the invention to mammalian eyes.

The vasoconstrictive properties of the compounds of the present invention, i. e. their ability to reduce or control intraocular bleeding, are established by the rabbit aorta: alpha 1 adrenergic receptors in vivo assay procedure, which is recog- nized in the art to be indicative of the in vivo activity of the tested compounds as vaso—constrictors or as anti intraocular bleeding agents.

Thoracic aorta specimens were obtained frdm albino rabbits that were killed by C02 inhalation. The aorta was cut into 3 mm rings. Tissues were placed in Krebs—Hensleit solution of the following composition (millimolar): Nacl 119; KCl 4.7; MgSO4 1.5, KHZ P04 1.2; CaCl2 2.5; NaHCO3 25 and glucose 11.0. also contained cocaine (0.1 millimolar) to block neuronal uptake The solution and EDTA (30 micromolar) and ascorbic acid (5 micromolar) to prevent oxidation of the compound being tested. hung in 10 ml organ baths and tension was measured via Grass FTO3 Tissues were force—displacement transducers. Resting tension was 2g for the The solution was gassed with 95% O2 and 5% CO2 and main- Tissues were allowed to equilibrate for 2 hours aorta. tained at 37°C. before stimulation and the cumulative addition of the compound to be tested (aryl oxazoline) was started. Tissue stimulation was performed using a square wave stimulator (WPI A310) Accupulser with A385 stimulus) at 0.1 Hz, 2 ms pulse width at 90 mA.

The results of these tests with regard to some examples of the compounds of the invention, are indicated as follows: Rabbit Aorta: Alpha 1 adrenergic receptor assay EC50 (nm) Example 4 1120: 457 Example 5 3.41: 0.5 .0: 6.36 Illustrative Example Example 13 > 100,000 Example 30 2740: 1430 Example 21 1430i 891 Example 55 1120: 94.1 Example 49 940: 18.5 Example 38 5690: 956 182.1 L—pheny1ephrine* * control substance, Shayes and Green Journal of Pharmacology and Experimental Therapeutics; Vol 180 pp 317-325 The test procedure for alpha-2 adrenergic receptor activity of the compounds of the present invention is the rabbit vas deferens assay which is described as follows: New Zealand white rabbits (2-3 kg) were killed by C02 inha- lation and the vasa deferentia removed. The prostatic ends of the vasa deferentia (2-3 cm lengths) were mounted between plati- num ring electrodes in 9 ml organ baths and bathed in Krebs bicarbonate solution of the following composition (millimo1ar): NaCl 118.0; KCl 4.7; CaCl2 2.5; MgSO4 1.2; KHZ P04 1.2; glucose 11.0; NaHCO3 25.0; which solution was maintained at 35 degrees C and bubbled with 95% O2 and 5% C02.

The tissues were left to equilibrate for The initial tension of the vas deferens was 0.5 g. minutes before stimulation was started. stimulated (0.1 Hz, 2 ms pulse width at 90 mA) using a square The ‘ Vasa were then field wave stimulator (WPI A310 Accupulser with A385 stimulus). contractions of the tissue were recorded isometrically using Grass FTO3 force-displacement transducers and displayed on a Grass Model 7D polygraph. Cumulative concentration-response curves were obtained for the compounds being tested with a 4 minute contact time at each concentration. The reduction in response height was measured and expressed as a percentage of the height of the response before the addition of the compounds.

Concentration response curves for each of the compounds were _l4_ plotted. The effective concentration required for a 50% reduc- tion in response height, expressed as EC50 were obtained from these curves.

Rabbit Vas Deferens Assay EC50 (nm) Qomment Example 4 167: 56.1 o{2 Selective Example 5 0.591 0.14 Non—Selective Potent- Vasoconstrictor Illustrative Example > 10,000 Ci 1 Selective Example 13 48.5: 20.6 0&2 Selective Example 30 41.5: 24.4 CQ 2 Selective Example 21 105: 35.5 C1 2 Selective Example 55 18.1i 1.21 C9 2 Selective Example 49 8.92: 3.11 04 2 Selective Example 38 74.6: 43.6 CY 2 Selective Specific Embodiments The compounds of this invention can be made by a number of different synthetic chemical pathways. To illustrate this inven- tion, there is here outlined a series of steps which have been proven to provide the compounds of Formula 1 when such synthesis is followed in fact and in spirit. The synthetic chemist will readily appreciate that the conditions set out here are specific embodiments which can be generalized to any and all of the com- pounds represented by Formula 1. Furthermore, the synthetic chemist will readily appreciate that the herein described syn- thetic steps may be varied and or adjusted by those skilled in the art without departing from the scope and spirit of the inven— tion.

Thus, the 1,4—benzoxazine derivatives of the present inven- tion (compounds of Formula 1) can be made in accordance with the generalized synthetic procedures illustrated below. *Specifical- ly, the 1,4—benzoxazine derivatives of the present invention which are substituted with the 2—iminoimidazolidine group in the 7 position of the l,4—benzoxazine nucleus are made in accord- ance with Reaction Scheme 1. In accordance with this procedure, 2—amino-5—nitrophenol (available commercially) is reacted with ethyl 2-bromoacetate to provide 7-nitrooxo-3,4—dihydro—(2H)— 1,4-benzoxazine (compound 1). (In the present description the terms "compound" and "example" are sometimes used interchange- ably, with the proper meaning being readily ascertainable from the context. The numerals following these terms are not used in duplicate, so that the term "Compound 1" refers to the same compound as "Example 1".) 7-nitro-3—oxo—3,4-dihydro—(2H)—1,4- benzoxazine (Compound 1) is reduced to provide 7—amino—3—oxo—3,4— dihydro—(2H)—1,4-benzoxazine (Compound 2). 7—aminooxo—3,4- dihydro-(2H)—1,4—benzoxazine (Compound 2) is a compound described in J. Med. Chem. 1989, 32, 1627-1630. dine group is then introduced into the 7 position of the 1,4- The 2—imino—2-imidazoli— benzoxazine nucleus by reacting Compound 2 with 2-imidazoline sulfonic acid to provide 7-2(2-iminoimidazolidine)—3—oxo—3,4- Compound 3 is also Although its preparation dihydro-(2H)—1,4-benzoxazine (Compound 3). mentioned in the above-noted J. Med. Chem. reference. 2-imidazoline-sulfonic acid is a known compound, from 2-imidazolidinethione is described in detail below.

'\,"| Referring now to Reaction Bcheme 2, the 7—2(2—imino imidazolidine) compounds of the invention which are bromo substituted can be made by bromination of 7-2(2—imino—2— imidazolidine)oxo-3,4-dihydro-(2H)—1,4~benzoxazine (Compound 3) to provide a 6—monobromo derivative (Compound 4) and a 6,8- dibromo derivative (Compound 5). 8—Bromo-7—2(2-imino \ imidazolidine)—3—oxo—3;4-dihydro-(ZH)-1,4-benzoxazine (Compound 6, not shown on Reaction Bcheme 2) can be made by reacting 8- Bromo-7—amino-3—oxo—3,4—dihydro-2H—1,4-benzoxazine with 2- as well as its bromo imidazoline—su1fonic acid. Compound 3, derivatives, such as Compounds 4, 5 and 6 are reduced with LiAlH4 to remove the 3—oxo Group. and to provide the compounds, (for example Compounds 7* and 7) where, with reference to Formula 1, R2 is hydrogen. (Compound 7* refers to the compound of the Illustrative Example).

Readion Scheme 2 H B TO N O HN/fl\NH HN NH 3 U 1 £1 3 UAIH4 L/ 5 LIAIH4 [V H N N 03 I HN NH with reference to Reaction scheme 3, in order to obtain the alkyl substituted 7-2(2—iminoimidazolidine)-sntstituted compounds of the invention, 7-nitro-3—oxo—3,4—dihydro-(2H)-1,4- benzoxazine (compound 1) is alkylated in the presence of strong .lg_ base (such as NaH). The resulting 4—fl—alkyl derivative (compound 18)when the alkyl group is methyl) is reduced to provide 7-amino- 4-methyl-3—oxo—3,4—dihydro—2H—l,4-benzoxazine (Compound 19) which is then reacted with 2—imidazoline—sulfonic acid to give 4- methyl2(2—imino-2—imidazolidine)oxo-3,4—dihydro—(2H)-1,4- benzoxazine (Compound7ni,. It will be readily understood by those skilled in the art that whereas Reaction Scheme 3 shows CH3I as the alkylating agent, the alkylation reaction disclosed here by this example is not so limited. 4-methyl2(2—imino imidazolidine)oxo-3,4—dihydro—(2H)-1,4-benzoxazine (Compound ) is brominated to yield 6-bromo—4—methyl—7—2(2-imino—2— imidazolidine)—3—oxo—3,4—dihydro-(2H)—1,4-benzoxazine (Compound 91} and 6,8—dibromo—4-methyl—7—2(2—imino—2—imidazolidine)—3—oxo— 3,4—dihydro—(2H)-1,4—benzoxazine (Compound 23) The 4-g—alkyl 2(2—iminoimidazolidine)oxo-3,4-dihydro—2H-1,4-benzoxazines, such as 4—methyl2(2—iminoimidazolidine)oxo—3,4—dihydro— 2H—l,4—benzoxazine, (Compound WW are reduced with lithium alumi- num hydride (or similar reagent) to remove the 3—oxo function and yield the compounds, where, with reference to Formula 1, R2 are hydrogen. when the 4-5 substituent is methyl, dazolidine)-3,4-dihydro-(2H)-l,4—benzoxazine is obtained in this —methyl—7—2(2—imino-2—imi- reaction. Similar removal of the 3-oxo groups by reduction with LiAlH4 can be performed on the 4-E-alkyl bromo derivatives; for example reduction with LiAlH4 of compound Zland‘ compound ,23 provides 6-bromo-4—methyl—7-2(2—imino—2-imidazolidine)—3,4-dihy~ dro-(2H)—1,4—benzoxazine (Compound22)and‘ 6,8-dibromo—4—methyl2(2—iminoimidazolidine)-3,4-dihydro- (2H)-1,4—benzoxazine (compoundjuo respanjvely. r‘ J L,'1 _19._ Reaction Schernea C”: :4‘ 0 Na” pl; 0 (|:HI ———-————————> OET LIT "= " ° CH3! M T 02'“ 1 O OZN 0 H2” 0 K 50:” cu. A I N NH \__/ N o;Té 3% I HN/KN” 21 vi EH’ 0 U QT UAH. 7 o Hm:E>H 20 (IN: 3'2 TEE") N O H’ UAIH‘ ca, LWH4 (EH: °' "' / Li‘) N 0) .. /ll\ 8, Wk ~ A . m 24 an 16838 The 2-alkyl substituent can be introduced into the compounds of the present invention by using, in the condensation reaction involving 2-amino-5—nitropheno1 (Reaction Scheme 1) an appropri- ate "alkylated" derivative of ethyl bromoacetate. For example, by using ethyl 2-bromopropionate in this reaction the 2-methyl derivatives of the compounds of the invention can be obtained. _20_ The 1,4—benzoxazine derivatives of the present invention which are substituted with the 2-imino—2—imidazolidine group in the 6 position of the 1,4-benzoxazine nucleus are made in syn- thetic steps which are analogous to the synthetic steps generally Thus, 2~ amino-4—nitropheno1 (available commercially) is reacted with described above. in accordance with Reaction Scheme 4, ethyl 2-bromoacetate to‘provide 6—nitro—3-oxo—3,4—dihydro—(2H)— 6—Nitro-3—oxo—3, 4-dihydro—(2H)— ,4~benzoxazine (Compound 9).

'L4-b€flZOX3ZhK3 (Compound 9) is reduced to provide » _ _ 6-amino-3—oxo-3,4-dihydro—(2H)—1,4-benzoxazine(cmmmund10) which is thereafter reacted with 2-imidazoline sulphonib acid to yield 6-2(2—imino—2—imidazolidine)oxo-3,4—dihydro—(2H)-1,4- benzoxazine (Compound 11). ‘Compound 9, Compound 10 and Compound 11 per se, are known (see the above—cited J. Med. Chem. article). -2] _ Reaction Scheme 4 H ' o N (|3OOEt 2 N 0, .__?..?)..

CH28r (compoundlé).

Reaction Scheme 5 ::f¢° amyLMgBr ______________ CbN 0 H 3”(Y1 NTO OZN 0 H ~:j¢¢o cgu’ :;: :0 akfl akfi ‘\ arkyx-Mgar 02,, ‘J 0 (Z7 + . ?;_ H . °2"I:E"T° Ikfi 0 ‘J akfi H 0,»: N)/0 arkyl-MgBr ‘<*—-———————-—_ my! o The R‘, R5 and R6 substituents (preferably lower alkyl of 1- 3 carbons or lower alkenyl of 1-3 carbons such as allyl) are introduced into the compounds of the invention by reacting the 7- nitrooxo—3,4—dihydro-(2H)—1,4—benzoxazine intermediate (Com- pound 1) and the 6-nitrooXo—3,4—dihydro-(ZH)-1,4-benzoxazine intermediate (Compound,9), with an excess of a Grignard reagent.

(Reaction Scheme 5). when the starting material is compound 93, then 5 and 7 Q- The 5,7 dial-- These alkyl substituted reaction products are obtained. kyl substitued product is obtained by further alkylation.

Q-alkyl substituted compounds are carried through the reaction sequences described above (to wit: reduction of nitro group to amino group, subsequent condensation with 2-imidazoline sulphon— ic acid, and reduction of the 3-oxo group or in the alternative fi—alkylation followed by reducthmiof the nitro group etc.) to provide the Q-alkyl and dialkyl substituted compounds of the invention. when the starting material is 7—nitro—3—oxo—3,4— THF/Hexane (1:5). dihydro—2H-1,4-benzoxazine intermediate (compound 1), then the reaction with the Grignard reagent yields 6 and 8 mono g—alkyl derivatives, which can also be carried through the above—noted reaction sequences to yield the 6 or 8 alkyl (or alkenyl) substi- tuted 7-2(2—imino—2-imidazolidine)-3,4-dihydro-(ZH)-l,4- benzoxazine derivatives of the present invention.

Specific Examples Example 1 -nitrooxo-3.4 dihvdro-(2H)~l.4-benzoxazine Under argon, ethyl bromoacetate (7.2 ml, 65 mmol) was added to a solution of anhydrous potassium fluoride (10 g, 172.1 mmol) in 50 ml anhycunus DMF. at room temperature. 2-Aminonitrophenol (Aldrich, 10g, 65 mmol) was then disssolved in 25 ml of DMF and added dropwise to After the final addition the reac- The The solution was stirred for 30 minutes the reaction with stirring. tion was warmed to 70 degrees and stirred for 16 - 24 hours. reaction was then poured into 300 mls of an ice/water mixture The with stirring. A yellow precipitate was formed immediately. solid was filtered off and dried in vacuo. The product was Collected 8.3 g (72.5%) of tan m.p. 227-230; ‘H NMR (300 MHZ, DMSO) & 4.752 (s, 2H, CH2), 7.0835 (d, J 8.73, Hz, 1H, ACH), 7.769 (d, J 2.44 Hz, 1H) 7.9185 (dd, J = 2.525, 8.705 Hz, 1H, ACH); 13c NMR (300 MHZ, DMSO) & 66.560, 111.344, 115.776, 118.738, 134.464, 142.643, 142.861, 164.891. Mass spectrum (EI) m/z 194 14''’ Example 2 -amino-3—oxo—3,4-dihydro-(2H)-1,4-benzoxazine .

Under argon, 10% palladium on carbon (350 mg, 5% w/w) was recrystallized from hot THF. crystals: added to a suspension of 7-nitrooxo-3,4-dihydro-(2H)-l,4- benzoxazine (7g, 39.3 mmol) in 50 ml of MeOH. The reaction mixture was hydrogenated at 40 psi for 16 hours. mixture was then diluted with THE (-200 mls) and the reaction was The reaction filtered through celite. The solvent was evaporated, leaving a brown solid as the residue. Product was recrystallized from Collected 4.2 g (72%) of a tan solid: m.p. -215, ‘H NMR (300 M Hz, Dnso) & 4.410 (s, 2H), 4.869 (s, 2H) 6.141 (d, 1H, J = 2.44) 5.175 (dd, 1H, J = 2.25, 4.59), 6.553 (d, 1H, J = 8.19), 9.535 (brs, 1H)7 13c NMR (300 MHZ, DMSO) & 55.9495, 102.2081, 108.1369, 115.5779; 116.8982, 144.5502, 145.4287, 164.389; Mass spectrum M+ at m/z 164 Example 3 -2(2—imino-2—imidazo1idine)-3,4~dihvdro—2H-1.4—benzoxazine 7—amino—3—oxo-3,4-dihydro-(ZH)—1,4—benzoxazine (50 mg, 0.205 mmol) was combined with 2—imidazoline sulfonic acid (62 mg, 0.410 mmol) in 5 ml isobutanol. The reaction was heated to 50 degrees for 16 hours. The solvent was evaporated leaving a yellow solid.

The product was purified by flash chromatography (70:30, CHCl3: MeOH sat. with NH3) and product was isolated as a white solid (23.2 mg, 49%) m.p. 271-275 (decomp.); H NMR (300 MHZ, DMSO) & 3.587 (S, HH, 4.560 (S, 2H, 6.755 (m, 2H), 6.918 (d, 2H, J = 8.03) 13c NMR (300 MHZ, DMSO) & 42.7154, 66.9089, 111.6185, 116.6721, 117.4629, 125.5162, 132.0013, 144.0188, 158.6280, 164.9108; mass spectrum (EI) M+ observed at m/z 232.

Example 4 6—Bromo—7-(2—imino—2—imidazolidine)—3—oxo—3.4—dihvdro-(ZH)-1,4- benzoxazine. hydrobromide A solution of 7-(2—imino—imidazolidine)oxo—3,4-dihydro- (2H)-1,4—benzoxazine (100 mg; 0.430 mmol) in acetic acid (2 ml) at room temperature was treated with H2804 (1 drop) followed by dropwise addition of bromine (688 mg, 4.30 mmol).

The title compound The reaction was stirred at room temperature for 16 hours. was obtained as a yellow crystalline solid which was washed with ether and dried in vacuo. Yield: 164.3 mg (100%); mp 220-230 degrees c, decomp; 1H NMR (300 MHz, DMSO) 5. 10.51 (br, 38); 6.98 (S, 1H); 6.52 (S, IH).

Example 5 6,8—dibromo(2-imino—2—imidazolidine)oxo—3.4-dihvdro-(2H)- 1,4—benzoxazine Procedure: 7-(2—imino-2—imidazolidine)—3—oxo-3,4—dihydro- (2H)—1,4-benzoxazine (100 mg, .430 mmol) was dissolved in 2 ml of Ac0H. One drop of H2804 was added and the reaction mixture was heated to reflux for 16 hours. basified to pH 14 with 2.5 N NaOH and extracted with ethyl ace- The reaction mixture was cooled, tate. Extracts were dried and evaporated leaving a tan solid.

Purified by flash chromatography (Si02, NH3 sat. Me0H: CHCl3, Collected 115.4 mg(69%) of + :95) to give a yellow solid. product; mp 254-255; Mass spectrum m/z, M and 392; High resolution Mass spectrum calculated for CllH10N402Br2 387.9170, found 387.9152; calc'd for CllH10N40281BrBr 339.9150, found 389.9145; calc'd for 81 CllH10N4O2 Brz 391.9129, found 391.9138. observed at 388, 390 Example 6 8—bromo(2-iminoimidazolidine)oxo-3,4—dihydro—(2H)—1,4— benzoxazine Procedure: 8—bromo—7—amino—3-oxo—3,4—dihydro-(2H)—1,4— (100 mg, 0.616 mmol) was suspended in .411 mmol) and 2-imidazoline—2-sulfonic mls of i-BuOH and The reaction mixture was basified The combined benzoxazine acid (92 mg, heated to reflux for 16 hours. to pH 14 with 2N NaOH and extracted with EtoAC. extracts were dried (MgS04) and evaporated leaving a tan solid.

Product was purified by flash chromatography (SiO2, NH3 sat.

Me0H: CHCl3, 5:95) collected 66.4 mg (50%) of an off—white solid. mp 205-215 (decomp); 1H NMR (300 MHZ, DMSO) & 10.4 (brs, lH)7 6.63 (d, 1H); 6.40 (d, 1H): 5.10 (brs, 2H); 4.55 (s, 2H); 3.31 (s, 4H); Mass spectrum m/z, M+ 310, 312; High resolution mass spectrum, calculated for C11H11N4O2Br 310.0055, found 310.0065.

Illustrative Example 6-bromo—7-(2-imino—2-imidazolidine1~3.4—dihvdro-(2H1~1,4- benzoxazine A solution of 6-bromo(2-imino-2—imidazolidine)- —oxo-3,4-dihydro-(2H)—1,4-benzoxazine (310 mg, 1 mmol) in tet- rahydrofuran (4 ml) is treated with LiA1H4 (38 mg, 1 mmol) and the reaction mixture is heated at reflux for 1 hour.‘ The reac- tion is cooled to room temperature, filtered through celite and concentrated in vacuo to yield a residue which is chromatographed ...27_ (3102; CHCI3/CH3OH saturated with NH3) to yield the title comc pound which is characterized spectroscopically.

Example 7 ,8—Dibromo—7—(2—iminoimidazolidine)—3L4-dihvdro-(2H)—1,4— benzoxazine The title compound is prepared by LiAlH4 mediated reduction of 6,8—dibromo—7-(2-imino—2—imidazolidine)—3foxo-3,4-dihydro—(2H)-1,4- benzoxazine in tetrahydrofuran using the procedure described in the Illustrative Example- Example 8“ -bromo—7—(2—imino-2—imidazolidine)-3.4-dihvdro-(2H)—1,4— benzoxazine The title compound is prepared by LiAlH4 mediated reduction of 8—bromo~7—(2—imino—2-imidazolidine)—3—oxo—3,4-dihydro—(2H)—1,4—benz- OX3.ZlIlE in tetrahydrofuran using the procedure illustrated inljm lflmstfimive Example Example.

The title compound was prepared using the method illustrated in Example 1.

Yield 8.2 g (73.2%) tan crystals: m.p. 233-235; 1H NMR (300 MHZ, DMSO) & 4.754 (s, 1H), 7.12 (d, J = 8.9 Hz, 2H), 7.714 (d, J = 2.66, 1H) 7.8155 (dd, J = 2.71, 8.9 Hz, 1H), 11.064 (brS, lH); 13C NMR (300 MHZ, DMSO) & 66.8619, 110.9932, 116.7802, 119.3719, 127.9445, 142.1591, 149.0456, 164.1843; mass spectrum (EI) m/z at 194. _‘ Example 10 - 6-amino-3—oxo—3.4-dihvdro-(2H)benzoxazine Procedure: 10% Pd/C (20 mg, to a suspension of 6~nitrooxo—3,4-dihydro-(ZH)—1,4-benzoxazine (4 9, at 40 psi for 4 hours. (150 mls) and filtered through celite.

The product was purified by recrystalli— under argon, 5% w/w) was added .6 mmol) in 100 ml MeOH.

The reaction mixture was diluted with THF The reaction was hydrogenated The solvent was evaporat- ed leaving a tan solid. _28._. zation from THF/Hexane (1:5). Collected 2.4 g (70.5%) of product as a tan solid: m.p. 221-223; 1H NMR (300 MHZ, DMSO) 6 4.360 (3, H), 4.823 (s, 2H), 6.102 (dd, 1H, J = 2.55, 8.41), 6.159 (d, 13, J = 2.49), 6.609 (d, 1H, J = 8.41), 10.461 (brS, 1H); 130 NMR (300 MHZ, DMSO) & 67.0407, 101.4395, 108.2861, 116.3699, 127.6622, 134.1601, 144.1535, 165.7326; Mass spectrum M+ at M/Z 164.

Example 11".

Procedure: 6—amino-3—oxo—3,4—dihydro-(2H)-1,4—benzoxazine (3.5 g, 21.3 mmol) was combined with 2-imidazoline sulphonic acid (6.4 g, 42.6 mmol) in 10 mls of i-BuOH. The reaction was heated Ether was added and a white precipitate The to reflux for 16 hours. was formed. The solid was filtered and dried in vacuo. solid is very hygroscopic so filtration was done quickly. solid was then dissolved in NH3 sat. MeOH and purified by flash chromatography (SiO2, NH3 sat. MeOH: CHC13, 30:70). Collected .05 g (82%) of product as a white solid; mp 225-230 (decomp); ‘H MHZ, DMSO) & 9.85 (br, 1H}; 8.25 (br, 2H)7 6.85 (d, IH); 1H), 6.60 (m, 1H); 4.50 (s, 2H); 3.42 (s, 4H); 130 NMR DMSO) & 165.439, 158.417, 139.647, 127.929, 117.468, 116.667, 110.652, 66.900, 42.847; MS, M+ found at m/z 232.

Example '12.,“ 7—bromo(2—imino~2-imidazolidine)oxo-3,4-dihvdro—(2H)-1,4- NMR (300 6.71 (d, (75 MHz, benzoxazine hvdrobromide Procedure: 6-(2—imino-imidazolidine)—3—oxo—3,4-dihydro-(2H)= 1,4-benzoxazine (60 mg, 0.258 mmol) was dissolved in 2 ml ACOH.

Brz (412 mg, 2.58 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. added, and an oil precipitated out from the reaction mixture.

The diethyl ether was decanted off and the oil was dissolved in MeOH. Diethyl ether was added and the product precipitated as a yellow solid. No further purification was necessary. m.p. 230- 235 decomp; 13c NMR (75 MHz, DMSO) & 164.624, 158.856, 143.900, Diethyl ether was 128.219, 128.024, 120.524, 116.205, 114.283, M+ was found at m/z 310/312; High resolution mass spectrum: .794, 42.732; MS calc'd for C11H1lN4O281Br 312.0045, found 312.0044.

Example :13‘, ,7-dibromo—6—(2—imino-2—imidazo1idine)oxo-3,4—dihydro-2H—1,4— benzoxazine The title compound was prepared using the method illustrated in Example 5.

Yield 92.3 mg (55.6%); mp, 215-230 decomp: ‘H NMR (300 MHZ, DMSO)& 9.7 (br s, 1H), 7.2 (s, 1H), 6.1 (br s, 1H), 4.50 (s, 2H), 3.326 (s, 4H); 13cNMR (75MHz, DMSO) s 165.794, 157.755, 144.183, .402, 126.761, 118.923, 111.097, 107.440, 67.133, 41.743; Mass spectrum: M+ found at m/z 388/390/392 Example ,_ 14:» —bromo—6—(2-imino—2—imidazolidine)-3—oxo-3.4-dihydro-(2H)-1.4- benzoxazine The title compound is prepared by debromination of 5,7- dibromo—6—(2-imino—2—imidazolidine)-3—oxo—3,4-dihydro—(2H)-1,4- benzoxazine (75 mg, 0.192 mmol) using (Ph3P)4Pd (236 mg, 0.19 0.46 mmol) and sodium formate (32 mg, in dimethylformamide The reaction mixture is heated to 125 degrees C for 4 mmol) (4 ml). hours before cooling to room temperature and quenching with saturated NaHC03. The reaction mixture is extracted with ethyl acetate. The combined organic extracts are dried over MgSO4 and concentrated in Vacuo. The residue is chromatographed (Si027 CHCI3; CH3OH saturated with NH3) to yield the title compound which is characterized spectroscopically. — Example -46} 7-bromo—6—(2-imino-2—imidazolidine)-3,4—dihvdro-(2H)-1.4- benzoxazine Procedure: 7—bromo—6—(2-iminoimidazolidine)—3—oxo-3,4- dihydro-(ZH)-1,4-benzoxazine (112.7 mg, 0.362 mmol) was dissolved in 5 mls THF. LiA1H4 (6.3 mg, 0.181 mmol, 2 equiv. of hydride) was added with stirring. The reaction mixture was heated to reflux and stirred for 16 hours whereafter it was cooled, (85%) of a tan solid. m.p. 150-152: ‘H NMR (300 MHZ, CDCI3) & $6.945 (S, 1H), 6.306 (S, 1H), 4.188 (t, 2H), 3.501 (5, 4H) 3.374 ,(t, 2H); 13c NMR (300 MHZ, CDC13) & 40.889, 42.529, 55.112, 5105.678, 110.424, 120.239, 133.521, 142.015, 147.2204, 158.006; The title compound is prepared by LiAlH4 mediated reduction of ,7-dibromo(2—imino—2-imidazolidine)-3—oxo¥3,4—dihvdro—(2H)-1,4- in tetrahydrofuran using the procedure illustrated inthe Ilhxmratiwe Example.

Example 17. 5-bromo—6~(2—iminoimidazolidine)-3,4—dihydro-(2H)-1,4- benzoxazine The title compound is prepared by LiAlH4 mediated reduction of —bromo(2—imino-2—imidazolidine)-3—oxo—3,4-dihydro~(2H)—1,47benz in tetrahydrofuran using the procedure illustrated infihe Iyhstnmjve Example.

Example T8. 4-methvl—7—nitro-3—oxo-3.4*dihYdro-(ZH)—1.4-benzoxazine Procedure: 7—nitro‘3-oxo—3,4—dihydro-(ZH)-1,4-benzoxazine _3l_ solid (2.6 g 68%). M.P. 183—185; ‘H NMR (300 MHZ, DMSO) & 7_96 (dd, J = 9.01 Hz, 1H), 7.781 (d, J = 2.49 Hz, 1H), 7.36 (d, J = 8.95, 1H), 4.796 (s, 1H), 3.322 (s, 3H); 13c NMR (300 MHZ, DMSO) & 28.047, 66.923, 111.469, 115.768, 118.778, 135.870, 142.813, 144.731, 164.282. Mass spectrum: M+ observed at m/z 208; HRMS calculated for C9H8N2O4 208.0000, found 208.0484.

Example 19 7—aminomethv1—3—oxo-3,4-dihydro-(ZH)-1.4-benzoxazine Procedure: 4—methy1nitrooxo—3,4-dihydro—2H-1,4- benzoxazine (2g, 10.4 mmol) was dissolved in 50 ml Me0H. The solution was purged with argon for 15 minutes. 10% Pd/C (200 mg, % w/w) was added and the mixture was hydrogenated for 16 hours at 20 psi. The reaction mixture was filtered through celite and evaporated leaving a yellow oil. Product was purified by flash chromatography (SiO2, NH3, MeOH: CHCI3, 5:95). Collected 1.4 g (78%) of a tan solid. MP 143-145; ‘H NMR (300 MHZ, DMSO) & 6.81 (d, J = 8.47, 1H) 6.237 (m, 2H), 5.000 (S, 2H), 4.490 (s, 2H), 3.170 (S, 3H) 13C NMR (300 MHZ, DMSO & 27.4673, 67.2261, 116.0754, 119.2791, 145.7760, 145.9278, observed a m/z 178; HRMS, .2182, 163.4086. ed for CoH1ON202, 178.000, found 173.0742. .0221, Mass spectrum: M+ calculat- Examplezo 4—methyl—7-(2—imino-imidazolidine)—3-oxo—3,4-dihydro-(2H)— 1,4-benzoxazine.

Procedure: 4—methyamino-3—oxo-3,4-dihydro—(2H)-1,4- benzoxazine (55 mg, 0.285 mmol) was combined with 2-imidazoline sulfonic acid (88.5 mg, 570 mmol) in 5 ml of i—BUOH. The reac-- tion was heated for 125 degrees C for 16 hours. The reaction mixture was cooled, basified with 2.5 N NaOH to pH 14, and ex- tracted with EtoAC. The combined extracts were dried and evapo- rated leaving a yellow oil. chromatography (S102, CHCl3; NH3, Me0H, 90:10). mg (34 %) of a white solid. MP 251-254 (decomp): ‘H NMR (300 MHZ, DMSO) & 6.95 (a, in): 6.62 (m, 2H); 6.20 (br, 2H)7 4.52 (s, 2H); 3.30 (s, 4H); 3.20 (s, 3H); Mass spectrum: M+ m/Z 246: High Product was purified by flash Collected 58.6 -32..

Resolution Mass spectrum: calculated for C12H14N4O2 246.1116; found 246.1106.

Example 21 ‘ ~methyl-6—bromo—7~(2—imino-imidazolidine)-3—oxo—3,4— dihydro—2H-1,4—benzoxazinehydrobromide Procedure: 4-methyl~7—(2-imino—imidazolidine)—3~oxo—3,4- dihydro—(2H)—1,4—benzoxazine (100 mg, 0.406 mmol) was dissolved in 5 ml ACOH.

A drop of H2804 was added and the reaction was stirred at Brz (77 microliter, 0.812 mmol) was added drop- wise. room temperature for 16 hours. The reaction mixture was cooled to 0 degrees and diethyl ether was added. lated as the HBr salt.

The product was iso- The product was recrystallized from MeOH: Et2O (5:1). Collected 132 mg (80%) of a white solid. M.P. > 300 -: ‘H NMR (300 MHz, DMSO) & 10.180 (brs, 1H), 8.240 (br s, 2H), 7.524 (s, 1H), 7.176 (S, 1H), 4.707 (s, 2H), 3.632 (5, 4H), 3.284 (s, 3H); Mass spectrum: M+ m/z 324.326; High Resolution Mass Spectrum ca1c'd for C12H13N4O2Br 324.0222; found 324.0220; calc'd for Cl2H13N4O2 lBr 326.0201; found 326.0202.

Example 22 —bromo—4—methyl—7—(2—imino-imidazolidine)-3,4—dihydro-(2H)— 1,4-benzoxazine.

Procedure: 6-bromo—4-methy1—7-(2-imino—imidazo1id1ne) oxo—3,4—dihydro-(2H)-1,4-benzoxazine (100 mg, 0.308 mmol) was dissolved in 10 ml of THF. LiAlH4 (5.8 mg 0.154 mmol, 2 equiv. of hydride) was added with stirring at room temperature. The reaction was then heated to reflux for 4 hours. The reaction was quenched with H20 and extracted with EtoAc. The combined ex- tracts were dried (MgSO4) and evaporated leaving a tan 011. product, was purified by flash chromatography (90:10, CHC13: NH3, MeOH). Collected 42.8 mg (44.8%) of a tan solid. MP 194-198 decompi 1H NMR (300 MHZ, CDC13) & 6.809 (S, 1H), 6.518 (s, 1H), 4.580 (br s), 4.263 (t, 2H), 3.507 (s, 4H), 3.178, (t, 2H), 2.817 (s, 3H); 13c NMR (300 MHZ, CDCI3) & 158.8009, 114.3704, 138.4333, 133.4388, 116.2412, 111.986, 109.7393, 65.0111, 48.8641, 42.3351, 33.3533; MS, M+ found at m/z 310; HRMS calcu- lated for Cl2Hl5N4OBr 310.0429, found 310.0436.

Example 23 6,8—Dibromo—4—methyl(2-imino—2—imidazolidine)—3—oxo—3,4_ dihydro-(2H)—1,4—benzoxazine, hydrobromide.

The title compound is prepared by treating a solution of 4- methyl(2—imino—2-imidazolidine)-3—oxo-3,4—dihydro—(2H)—1,4- benzoxazine in acetic acid with bromine and a catalytic amount of H2504, using the method illustrated in Example 5.

Examplezg ' ,8—Dibromo—4-methyl—7-(2—imino—2-imidazolidine)-3,4-dihy~ dro—(2H)-1,4—benzoxazine. The title compound is prepared by LiAlH4 mediated reduction of 6,8-dibromo-4—methyl(2—imino imidazolidine)—3—oxo—3,4—dihydro-(2H)—1,4—benzoxazine in tetrahy— drofuran, using the procedure illustrated intjm iflustnfiiveemampka Example 25’ ‘ —Bromo—4-methyl(2—imino-2—imidazolidine)oxo—3,4— dihydro-(2H)-1,4—benzoxazine.

The title compound is prepared by debromination of 6,8- dibromo—4—methy1»7—r2~imino—2-imidazolidine)-3—oxo-3,4-dihydro— (2H)-1,4-benzoxamine using the procedure illustrated in Example14 Erample Ai 8—Bromomethyl(2—imino—2-imidazolidine)-3,4-dihydro- (2H)—1,4—benzoxazine.

The title compound is prepared by reduction of 8—bromo methyl(2-imino—2-imidazolidine)—3—oxo-3,4-dihydro-(2H)-1,4- benzoxazine using the procedure illustrated in tm3i1hmtmNive}kamfle_ Example 27_ 4-methyl—6-nitro~3-oxo-3,4-dihydro-(ZH)—1,4—benzoxazine The title compound was prepared from 6—nitro—3-oxo—3,4— dihydro—(2H)—1,4-benzoxazine using the method described in Exam- Yield: 3.01 g (56%) of product as a yellow solid. mp 185-187; ‘H NMR (300 MHZ, DMSO) & 7.968 (dd, J = 8.9'Hz, 2H), 7.78 (d, J = 2.5H 1H), 7.363 (d, J = 8.9 2H), 4.799 (s, 2H), 3.32 (s, 3H); 13C NMR (75 MHZ, DMSO) & 164.430, 144.77, 135.913, ple 19. ..34.._ 118 .824, 115.808, 111.5142, 66.944, 20.82; Mass spectrum: M+ m/z 208.

Example 28 6—amino—4—methy1—3-oxo—3,4-dihydro—(2H)—1,4—benzoxazine.

The title compound was prepared from 4-methyl—6-nitro—3—oxo— 3,4-dihydro—(2H)—1,4-benzoxazine using the method described in Examp1e19 7 Yield: 1.3 g (72%) of a tan solid; mp 143—145;"H NMR (300 MHZ, DMSO) & 6.811 (d, J = 8.46, 1H), 6.250 (m, 2H), 5.002 (s, 2H), 4.492 (s, 2H), 3.172 (s, 3H): 13c NMR (25MHz, DMSO) & .958, 145.813, 119.296, 116.114, 108.043, 102.237, 27.494; Mass spectrum: M+ m/z 178. .442, 67,251, Examp1eZ9 4—Methy1—6—(2-imino—2-imidazolidine)oxo-3,4—dihydro—(2H)— 1,4-benzoxazine.

The title compound was prepared from —6—amino~4—methy1oxo-3,4—dihydro—(2H)—1,4—benzoxazine using the method described in Examph2ZO. Yieh174i3mg(58£%%)(asa white solid) M.P. 262-264; ‘H NMR (300 MHz, DMSO) & 6.939 (d, J 2 8.9, 1H), 6.633 (m, 2H), 4.537 (s, 2H), 3.302 (s, 4H), 3.215 (s, 3H); 130 NMR (300 Mmz, DMSO) & 27.5584, 43.0360, 67.1992, 109.5818, 115.5611, 115.7735, 122.6263, 145.3208, 158.2961, .8386; MS, M+ found at m/z 246; HRMS, calculated for Cl2Hl4N4O2 246.1116 found 246.1131.

Example 3p 7—bromomethy1(2—imino—imidazo1idine)-3—oxo-3,4-dihy- dro—(2H)-1,4—benzoxazine 4—methy1—6—(2—imino-imidazolidine)-3—oxo-3,4~dihydr0-(2H)- l,4—benzoxazinewas brominated, collected 110 mg (67%) of the product as a tan solid; mp 210—220 decomp; ‘H NMR (300 MHz, DMSO) & 10.244 (s, 1H), 8.253 (8, 2H), 7.525 (5, 1H), 7.182 (S, 1H), 4.708 (S, 2H), 3.636 (s, 4H), 3.284 (s, 3H); 13C NMR 475 MHZ, 158.687, 144.789, 130.851, 129.086, 119.227, 66.153, 66.986, 42.741, 27.960. Mass spectrum DMSO) & 164.027, 117.115, 114.153, M* m/z 324.

Example 3L S,7-Dibromo—4-methy1—6(2-imino—2-imidazolidine)-3—oxo~3,4_ dihydro—(2H)~1,4—benzoxazine, hydrobromide.

The title compound is prepared by treating a solution of 4- methyl(2—imino—2—imidazolidine)oxo-3,4-dihydro—(2H)—1,4— benzoxazine in acetic acid with bromine and a catalytic amount of H2504 using the method illustrated in Example 5.

Example 32 -Bromomethyl(2-imino—2—imidazolidine)—3—oxo-3,4- dihydro—(2H)—l,4—benzoxazine.

The title compound is prepared by debromination of 5,7- dibromomethyl—6—(2—imino—2—imidazo1idine)oxo~3,4— dihydro—(2H)-1,4-benzoxazine using the procedure illustrated in Example 14‘? Example33‘ 7;Bromomethyl-6(2-iminoimidazolidine)-3,4-dihy— dro—(2H)—l,4-benzoxazine.

The title compound is prepared by LiAlH4 mediated reduction of 7—bromo~4-methyl(2—imino—2—imidazolidine)oxo—3,4-dihy— dro-(ZH)-l,4—benzoxazine in tetrahydrofuran using the procedure illustrated in ‘the illustrative example.

Example34 ‘ I ,7—uibromo-4—methyl—6—(2-imino—2—imidazolidine)-3,4—dihy— dro-(ZH)-1,4-benzoxazine.

The title compound is prepared by LiAlH4 mediated reduction of 5,7—dibromomethyl(2-imino—2-imidazolidine)-3—oxo-3,4- dihydro-(2H)-1,4-benzoxazine in tetrahydrofuran using the proce~ dure illustrated ingfhe illustrative eggample.

Example 35 ~Bromo—4-methy1—6-(2—imino-2—imidazolidine)—3,4—dihydro— (2H)-l,4—benzoxazine.

The title compound is prepared by LiAlH4 mediated reduction of 5-bromo-4—methyl—6—(2—imino—2—imidazolidine)-3—oxo-3,4—dihy- dro—(2H)-1,4—benzoxazine in tetrahydrofuran using the procedure illustrated in _the illustrative example. _36_ Example 36‘ 7—methyl—6-nitro—3—oxo-3,4-dihydro—(2H)—1,4—benzoxazine and —methyl—6-nitro-3—oxo~3,4-dihydro—(2H)—1,4—benzoxazine.

Procedure: 6—nitrooxo-3,4-dihydro-(2H)-l,4—benzoxazine (5 g, 25.7 mmol) was dissolved in 250 ml of anhydrous THF and cooled to 0 degrees C. CH3MgBr (21 ml, 64.2 mmol) was added dropwise After the final addition, the reaction A so1ution.of KMn04 (2.7 with vigorous stirring. was stirred for 15 min at 0 degrees C. g, 17.2 mmol) in acetone: H20 (1:1) was prepared and cooled to 0 degrees C. The reaction mixture was poured into the KMnO4 solu- The mixture was stirred for 15 min at 0 degrees C, then The The celite was then washed The combined tion. warmed to room temperature and stirred for another 15 min. mixture was filtered through celite. with EtoAC. The reaction was extracted with EtoAC. organic layers were dried over MgSO4 and evaporated leaving a The product was purified using flash Isolated 2.4 g (44.8%) bright yellow solid. chromatography (sioz, EtoAC: Hex, 3:7). of product which comprised a mixture of the title compounds which were not separated at this step.

Example 37 6—Amino—5-methyl—3-oxo-3,4—dihydro-(2H)—1,4-benzoxazine and —Amino—7—methyloxo—3,4—dihydro—(2H)—1,4—benzoxazine.

A mixture of 5-methylnitro—3-oxo—3,4—dihydro—(2H)—1,4— benzoxazine and 7-methyl—6-nitro—3-oxo—3,4-dihydro—(2H)-1,4- benzoxazine (423 mg, 2.03 mmol) was dissolved in 25 ml of MeOH.

The reaction was purged with argon gas, 10 % Pd/C (21 mg, 5% w/w) was added and the mixture was hydrogenated for 16 hours at 40 PSI. The reaction mixture was filtered through celite and con- centrated in vacuo. The residue was recrystallized from 3:1 CHCl3: Hexanes to yield 324 mg (89.7%) of the title compounds.

The title compounds are separated by flash chromatography (S102; 7:3 Hexanes EtoAC). ‘H NMR (DMSO) 5-methyl compound: & 10.41 (br s, 1H),’ 6.59 (d, 1H), 6.11 (d, 1H); 4.80 (br, 2H)”,- 4.32 (s, 2H); 1.91 (s, 3H); 7—methyl compound: & 10.38 (brs, 1H); 6.52 (s, H)7 6.18 (S, lH)7 4.57 (S, 2H)7 4.32 (S, 2H)7 1.92 (S, 3H)7 -37.. 13cNMR (DMSO) & 165.95, 142.08, 134.45, 125.67, 117.61, ll6_Q3, .81. .77, 67.16, Examp1e38, —methyl—6-(2-iminoimidazolidine)—3—oxo—3,4-dihydro-(23)- 1,4—benzoxazine Procedure: 7—methy1aminooxo—3,4—dihydro-(2H)-1,4- benzoxazine (150 mg, 0.842 mmol) and 2—imidazoline sulfonic acid (245 mg, 165 mmol) were suspended in 5 ml i-BuOH and heated to degrees for 16 hours. yellow oil. The product was purified by flash chromatography (SiO2, CHCI3: NH3 Sat. MeoH, 4:6) collected 123.6 mg (59.6%) of a white solid. m.p. 225-230 decomp.; ‘H NMR (DMSO, 300 MHZ) & 6.697 (s, 1H), 6.446 (5, 1H), 4.421 (s, 2H), 3.250 (S, 4H), 1.984 (8, 3H); 13cNMR (DMSO, 75 MHZ) & 165.459, 157.515, 143.076, 137.842, 125.278, 125.206, 117.378, 110.225 67.012, 42.106, 17.3737; MS M+ observed at m/z 246; High Resolution Mass Spectrum calc'd for The solvent was evaporated leaving a C12“14O2N Example 39 .1117 found 246.1101.

-Methyl(2-imino-2—imidazolidine)- 3-oxo-3,4—dihydro— (2H)-1,4—benzoxazine. ,7-Dimethylnitro—3-oxo—3,4-dihydro-(2H)—1,4—benzoxazine.

The title compound is synthesized from 5—methyl—6-nitro—3- oxo-3,4—dihydro-(2H)—l,4—benzoxazine or from 7—methylnitro—3= oxo-3,4-dihydro-(2H)—1,4-benzoxazine and methyl magnesium bromide using the method illustrated in Example 35 Example Q1 —Amino—5—7,dimethyl—3—oxo-3,4—dihydro-(ZH)-1,4—benzoxazine.

The title compound is synthesized from 5,7-dimethyl—6—nitro— 3—oxo—3,4—dihydro-(2H)—l,4—benzoxazine using the method illus- trated in Example 37 1‘ Example 42 1 ,7-Dimethyl(2—imino-ifiimidazolidine)oxo-3,4—dihydro— (2H)—1,4-benzoxazine.

The title compound is synthesized from 6-amino—S,7—dimethyl— 3~oxo—3,4-dihydro-(2H)—l,4—benzoxazine and 2—imidazoline-2—sul- fonic acid using the method illustrated in Example 33 Example 43, -Methyl(iminoimidazolidine)-3,4—dihydro—(2H)~1,4— benzoxazine.

Procedure: 7-methyl—6-(2-imino-imidazolidine)oxo-3,4- dihydro-(2H)-1,4-benzoxazine (100 mg, 0.406 mmol) was dissolved in 10 ml of THF. LiAlH4 (15 mg, 4 equivalent of hydride, 0.406 mmol) was added with stirring at room temperature. mixture was then heated to reflux for 16 hours, and thereafter was quenched with H20 and extracted with EtOAc.

The reaction Extracts were dried and evaporated leaving a tan solid. The product was puri- fied by flash chromatography (SiO2, CHCI3: NH3 sat. MeoH, 95.5).

Collected 52.6 mg (42%) of an off-white solid. MP 200 - 210 (decomp.; ‘H NMR (300 MHZ, CDC13) & 6.573 (s, 1H), 6.228 (s, 1H), 4.195 (t, J = 4.12 Hz, 2H), 3.461 (S, 4H), 3.362 (t, J = 4.4 Hz, 2H), 2.051 (s, 3H); 13c NMR (75 MHZ, CDC13) & 157.541, 147.207, 140.845, 139.877, 131.450, 121.925, 118.161, 110.540, 65.311, 42.570, 41.250, 17.117;.

Examp1e44 —Methyl—6-(2~iminoimidazolidine)-3,4-dihydro—(2H)-1,4- benzoxazine.

The title compound is prepared from 5—methy1—6-(2-imino—2— imidazolidine)oxo—3,4-dihydro-(2H)-1,4-benzoxazine using the ; method described in the Illustrative Example.

Example 45_ ,7-Dimethyl(2-iminoimidazolidine)-3,4—dihydro—(2H)- 1,4—benzoxazine.

The title compound is synthesized from 5,7-dimethyl-6~(2- imino—2-imidazolidine)oxo—3,4-dihydro-(2H)-1,4-bengoxazine using the method illustrated in theifllfistfififiveéfiamphi Example 45, -39.. —ethyl—6—nitro—3—oxo—3,4—dihydro-(ZH)-1,4-benzoxazine and 7—ethylnitro—3—oxo-3,4—dihydro-(2H)—1,4—benzoxazine.

The title compounds were prepared as an inseparable mixture, using the method illustrated in Example 37 except that ethyl magnesum bromide was substituted for methyl magnesium bromide to yield 1.2 g (35.3%) of products as a solid. 'H NMR (DMSO, 300 MHz)& 10.932 (s, 1H), 7.555 (s, 1H), 7.058 (s, 1H): 4.735 (s, 2H), 2.809 (q, J = 7.3 2H) 1.166 (t, J = 6.89, 3H).

ExamplezJ_ _ A 6-Aminoethyl-3—oxo-3,4-dihydro-(2H)-1,4-benzoxazine and 6-Amino—7-ethy1—3—oxo—3,4—dihydro—(2)H-1,4-benzoxazine.

The title compounds were synthesized from the mixture of 5- ethyl-6—nitro—3-oxo—3,4-dihydro-(2H)-l,4~benzoxazine and 7—ethyl— 6-nitrooxo-3,4-dihydro-(2H)-1,4-benzoxazine using the method ‘H NMR (300 lH); 4.65 6—Amino illustrated in Exame 37.} MHZ, DMSO) & 10.42 (br, (br, 2H); 4.36 (s, 2H): Example 53_ -Ethyl(2-imino—2—imidazolidine)—3—oxo—3,4—dihydro—(2H)— 1,4—benzoxazine. The title compound is synthesized from 6—amino— S-ethyl—3-oxo-3,4—dihydro—(2H)—1,4-benzoxazine and 2-imidazoline- 2-sulfonic acid using the method illustrated in Example 38 Example 49. 7-Ethyl(2-iminoimidazolidine)oxo—3,4-dihydro-(2H)— ,4-benzoxazine. The title compound was synthesized from 6-aminoethyloxo-3,4-dihydro-(2H)-1,4-benzoxazine and 2- imidazoline—2—sulfonic acid using the method illustrated in example 38. Yiehi (57%) of title compound as a white crystalline solid, mp 250 - 270 degrees C (decomp); ‘H NMR (300 MHZ, DMSO) & 6.77 (s, 1H); 6.54 (s, IH); 4.49 (s, 2H); 3.42 (s, 4H); 2.40 (q, 2H); 1.03 (t, 3H); 130 NMR (75 MHZ, ouso) & 155.25; 15s;7o; _40_ .247 133.87} 125.62: 116.25; 112.80; 66.95; .54. .62; 42.34; 23.40; Example 5d_ 7 ,7—Diethyl~6—nitro-3—oxo-3,4—dihydro-2H-1,4—benzoxazine.

The title compound is synthesized from either 5-ethyl—6—nitro—3— oxo-3,4—dihydro-(2H)-1,4—benzoxazine or from 7-ethyl—6—nitro—3— oxo—3,4—dihydro-(2H)-1,4-benzoxazine and ethyl magnesium bromide, using the procedure illustrated in Example 35 Example 5L 6—Amino—5,7—diethyloXo—3,4—dihydro—(2H)—1,4—benzoxazine.

The title compound is synthesized from ,7—diethyl—6—nitro—3—oxo~3,4—dihydro-2H—l,4—benzoxazine using the procedure illustrated in Example 37. i i Exampleffl. ‘- ,740iethyl(2-imino—2-imidazolidine)—3—oxo—3,4—dihydro— (2H)-1,4-benzoxazine.

The title compound is synthesized from 6—amino-5,7-diethyl—3—oxo—3,4-dihydro-(ZH)—1,4-benzoxazine using the procedure illustrated in Example 38.

Example 53.

—Propyl—6-nitro-3—oxo—3,4—dihydro-(ZH)—l,4—benzoxazine and 7—propyl-5—nitro-3~oxo-3,4-dihydro—(2H)—1,4~benzoxazine. The title compounds were prepared from 6—nitrooxo—3,4~dihydro—(2H)-1,4-benzoxazine using the method illustrated in Example 36 For the 5—propylnitro compound: NMR (300 MHZ, DMSO) & 10.65 (br S, 1H)7 7.54 (d, 1H)7 7.00 (d, 1H); 4.80 (s, 2H); 2.78 (distorted t, 2H); 1.50 (m, 2H); 0.90 (t, H). For the 7-propylnitro compound: ‘H NMR (300 MHZ, DMSO) & .95 (br, 1H); 7.55 (s, 1H); 7.00 (s, 1H); 4.70 (s, 2H); 2.78 (distorted t, 2H): 1.50 (m, 2H): 0.90 (t, 3H).

Example 54,_ -Aminopropyl-3—oxo-3,4—dihydro-(2H)-l,4—benxozazine and 6-Amino—7-propyloxo-3,4-dihydro-(ZH)-1,4-benzoxazfne.

The title compounds were prepared from the mixture of S- propylnitro—3—oxo—3,4—dihydro-(ZH)-1,4-benzoxazine and 7- propyl—6—nitro—3—oxo—3,4—dihydro—(2H)—1,4—benzoxazine using the method illustrated in example 37 separated by flash chromatography on silica gel by elution with hexanes: ethyl acetate. For the 6—amino—5-propyl compound: 'H NMR (300 MHZ, DMSO) & 9.98 (br, 1H); 6.51 (d, IH); 6.20 (d, 13); 4.54 (s, 2H), 4.28 (s, 2H); 2.45 (t, 2H); 1.32 (m, 2H); 0.88 (t, H). For the 6-amino—7-propyl compound: ‘H NMR (300 MHz, DMSO) & .41 (br S, 1H); 6.50 (S, 1H)7 6.19 (S, 1H); 4.59 (br S, 2H); 4.34 (S, 2H); 2.29 (t, 2H)7 1.45 (m, 2H); 0.88 (t, 3H); 13C NMR (75 MHZ, DMSO) & 165.51; 141.25; 134.17; 125.34; 120.12, 116.46; 101.97; 67.05; 32.14: 21.67: 13.90.

Example 5? __ -Propyl(2—imino—2—imidazolidine)—3—oxo-3,4-dihydro—(2H)— 1,4-benzoxazine.

The title compound is prepared from 6-amino—5—propy1—3—oxo- 3,4-dihydro—(2H)—1,4-benzoxazine and 2—imidazo1ine—2-sulfonic acid using the method illustrated in Example 38 Example 56 04 —propyl—6-(2—iminoimidazolidine)—3—oxo—3,4—dihydro—(2H)— 1,4—benzoxazine.

The title compound was prepared from 6-amino—7—propyl—?—oxo— 3,4—dihydro—(2H)-1,4-benzoxazine and 2-imidazoline-?—sulfonic acid using the method illustrated in Example 38 ‘Yield: collect- ed 106.7 mg (53%) of product as a white solid; ‘H NMR (300 M2, DMSO) & 6.619 (s, 1H), 6.375 (s, 1H), 4.398 (s, 2H), 3.333 (s, 2H), 3.238 (s, 4H) 2.333 (t, J = 8.09 Hz, 2H), 1.417 (m, 2H), 0.833 (t, 7.33, 3H); 13c NMR (75 MHz, DMSO) & 165.499, 157.446,‘ 144.525, 137.405, 129.750, 125.123, 116.353, 109.998, 67.025, 41.955; 32.840, 22.806, 13.881; MS M+ found at m/z 274; HRMS ca1c'd for C14Hl8N4O2 274.1430, found 274.14_[;}Z_ Example 37 _ ‘ I S,7-Dipropyl—6—nitro—3—oxo-3, —dihydro—(2H)-1,4-benzoxazine.

The title copound is synthesized from either 5;propyl—6- nitro—3-oxo—3,4-dihydro—(2H)—1,4-benzoxazine or 7-propyl—6—nitro— 3-oxo—3,4—dihydro—(2H)-1,4-benzoxazine and propyl magnesium bro- mide using the method illustrated in Examplefm.

Examplegg 6—Amino-5,7—dipropy1—3-oxo—3,4—dihydro-(2H)—l,4—benzoxazine.

The title compound is prepared from 5,7-dipropyl—6—nitro—3— oxo—3,4—dihydro-(ZH)-1,4-benzoxazine using the method illustrated in Example 3L ExampleS9.g ,7-Dipropyi—6~(2—imino~2~imidazoiidine;—3—oxo—J,4—dinydro— (2H)—1,4—benzoxazine.

The title compound is synthesized from 6—amino—5,7—dipropyl- 3-oxo—3,4—dihydro-(2H)-1,4—benzoxazine and 2-imidazoline—2-sul- fonic acid using the method illustrated in Examp1e38.

Example 69. ,7-Dipropyl(2—imino~2-imidazolidine)—3,4-dihydro-(2H)— 1,4-benzoxazine.

The title compound is synthesized from 5,7-dipropyl(2- imino-2—imidazolidine)-oxo-3,4-dihydro-(ZH)—1,4-benzoxazine using the method illustrated in Example 43.

Example 61_ S—A1lyl-6—nitrooxo-3,4—dihydro-(ZH)-1,4-benzoxazine and -al1y1—6-nitro—3-oxo-3,4~dihydro—(2H)-1,4—benzoxazine.

The title compounds are prepared from 6-nitro—3-oxo-3,4- dihydro-(ZH)—1,4-benzoxazine and allyl magnesium bromide using the method illustrated in Example 35f Example 62‘ —Allyl—6-aminooxo-3,4—dihydro-(ZH)—l,4-benzoxazine and 7—allyl—6—amino—3—oxo-3,4—dihydro—(2H)-l,4—benzoxazine.

The title compounds are synthesized by reduction of the mixture of 5—allyl—6-nitro—3-oxo-3,4—dihydro—(2H)—1,4—benzoxazine and 7—allylnitro-3—oxo—3,4—dihydro—(2H)—1,4—benzoxazine using the procedure of Mahood and Schaffner Orq. Svnth. Col. Vol. II . The title compounds are separated by flash chroma- , p. tography.

Example 63 —Allyl—6—(2—iminoimidazolidine)-3—oxo—3,4-dihydro-(2H)— 1,4-benzoxazine.

The title compound is prepared from 5-allyl-6—amino—3-oxo— 3,4-dihydro-(ZH)-1,4—benzoxazine and 2-imidazoline-2—sulfonic acid, using the method illustrated in Example38 7 Example 64 J -allyl—6-(2-imino—2-imidazolidine)—3,4-dihydro—(2H)-1,4— benzoxazine.

The title compound is synthesized from 5-allyl-6—(2—imino-2— imidazolidine)oxo-3,4-(2H)-1,4-benzoxazine using the method illustrated in Example43 Example 65 -Allyl(2-imino—2-imidazolidine)oxo—3,4—dihydro—(2H)— 1,4-benzoxazine.

The title compound is synthesized from 7—allyl-6—amino-3—oxo—3,4—dihydro—(2H)-1,4-benzoxazine and 2- imidazolidine-gfsulfonic acid using the procedure illustrated in~ Example 38 Example 66 -Allyl—6-(2-imino-2—imidazolidine)-3,4-dihydro-(2H)-l,4- benzoxazine.

The title compound is synthesized from 7—allyl-6—(2-imino—2- imidazolidine)-3—oxo-3,4—dihydro-(2H)—1,4-benzoxazine using the method illustrated in Example 43 Example 67 _44_ ~(2—propyl)nitro-3—oxo-3,4-dihydro—(2H)-l,4—benzoxazine and 7-(2-propyl)nitro-3—oxo-3,4-dihydro—(2H)-l,4—benzoxazine.

The title compounds are prepared from 6-nitro—3—oxo-3,4- dihydro—(2H)—1,4—benzoxazine and 2-propyl magnesium bromide using the method illustrated in Example36, The isomers are not sepa- rated at this step.

Example 68. i 6-Amino—5—(2—propyl)oxo-3,4-dihydro-(2H)-1,4—benzoxazine and 6—Amino-7—(2-propyl)oxo—3,4-dihydro-(ZH)—1,4—benzoxazine.

Exampleég. -[(2—propyl)(2—imino—2-imidazolidine)]-3—oxo-3,4—dihy— dro-(2H)—l,4—benzoxazine.

The title compound is prepared from 6-amino-5—(2-propyl)—3— oxo-3,4—dihydro—(2H)—l,4—benzoxazine and 2—imidazoline—2—sulfonic acid, using the method illustrated in Example 3g_ A Example 70. —[(2-Propyl)(2¢iminoimidazolidine)]—3,4—dihydro-(2H)— l,4—benzoxazine.

The title compound is synthesized from 5—[(2-propyl)—6-(2- iminoimidazolidine)]—3-oxo—3,4—dihydro— (2H)—1,4-benzoxazine, using the method illustrated in Example 43" Example 7;_ ~ 7—[(2—Propy1)(2—imino-2—imidazo1idne)]—3-oxo-3,4—dihydro-(2H)- 1,4~benzoxazine.

The title compound is prepared from 6-amino-7—(2—propyl)—3- oxo-3,4—dihydro-(2H)-1,4-benzoxazine and 2—imidazoline—2-sulfonic acid using the method illustrated in Example 38.

Example 72_ 7—[(2—Prdpyl)(2-iminoimidazolidine)]-3,4—dihydro—(2H)- l,4—benzoxazine. _45_ The title compound is synthesized from 7-[(2-propyl)—6—(2— iminoimidazolidine)]—3-oxo-3,4-dihydro-(2H)—1,4—benzoxazine using the procedure illustrated in Example 43.

Example 73, 1 8—methyl—7-nitrooxo-3,4-dihydro-(ZH)—1,4-benzoxazine, and 2 6—methyl—7-nitrooxo-3,4-dihydro—(2H)-l,4—benzoxazine Procedure: 7-nitro—3—oxo-3,4-dihydro-(2H)-1,4-benzoxazine (5 g 25.7 mmol) was dissolved in 200 ml anhydrous THF and cooled to 0 degrees C. CH3MgBr (21 ml, 64.2 mmol) was added dropwise with vigorous stirring. After the final addition, the reaction was stirred for 15 minutes at 0 degrees C and thereafter warmed to A solution of KMnO4 (2.7 g, 17.2 mmol) ace- The reaction mixture was poured into the KMnO4 solution with vigorous room temperature. tone: in H20 (1:1) was prepared and cooled to 0 degrees C. stirring. The mixture was stirred at 0 degrees C for 15 minutes then at room temperature for 15 minutes. The reaction mixture The celite was then washed with was filtered through celite.

EtOAc, and the reaction mixture was extracted with EtOAc. combined organic layers were dried over MgSO4 and evaporated The product was purified using flash 3:7). Isolated 1.2 g (22%) of leaving a yellow solid.

EtOAc: the product as a mixture of isomers, which were not separate from chromatography (SiO2, Hex, —methyl—7-nitro lH); 7.65 (d, one another but were carried on to next step. compound: 'H NMR (300 MHZ, DMSO) & 11.22 (brs, 1H); 6.88 (d, 1H); 4.67 (s, 2H); 2.45 (s, 3H); 6—methylnitro ‘H NMR (300 MHz, DMSO) & 11.18 (br s, 1H); 7.61 (S, 1H): 4.70 (s, 2H); 2.36 (s, 3H). - compound: 1H); 6.85 (5, Example 74. 7—Amino-6;methyl-3—oxo-3,4-dihydro-(ZH)-1,4-benzoxazine and 7-Aminomethyloxo-3,4-dihydro-(ZH)-1,4-benzoxazine.

A mixture of 6-methylnitro-and 8-methylnitro—3-oxo-3,4-dihydro-(ZH)-1,4-benzoxazines (1 g, The reaction was % w/w) was added and .80 mmol) was dissolved in 25 ml of MeOH. purged with argon gas. .10% Pd/C (100 mg, the reaction was hydrogenated for 16 hours at 40 PSI. The reac- tion mixture was filtered through celite and evaporated leaving a white solid.

For the 7-Amino—6—methyl compound: ‘H NMR (300 MHZ, DMSO) & .23 (brs, lH)7 6.45 (S, 1H)7 6.23 (S, 1H)7 4.64 (brs, 2H); 4.37 (s, 2H); 1.94 (s, 3H). For the 7-Aminomethyl compound: 'H NMR (300 MHz, DMSO) & 10.23 (brs, lH): 6.45 (d, 1H); 6.21 (d, lH): 4.66 (brs, 2H); 4.42 (S; 2H);1.90 (s, 3H). The title compounds are separated using flash chromatography on silica gel by elution with hexanes: ethyl acetate.

Example 71 6-Methyl(2—imino-2—imidazolidine)oxo-3,4-dihydro-(2H)— 1,4-benzoxazine.

The title compound is synthesized from 7—aminomethyl oxo-3,4—dihydro-(2H)-1,4—benzoxazine and 2-imidazoline-2—sulfonic acid using the method illustrated in Example 38.

Example 75‘ 6—Methyl(2~imino—2—imidazolidine)—3,4—dihydro-(2H)-1,4- benzoxazine. The title compound is synthesized from 6-methyl (2-iminoimidazolidine)oxo-3,4-dihydro-(ZH)-1,4—benzoxazine using the method illustrated in Example 43_ Example 77_ ' 8—Methyl(2-iminoimidazolidine)-3—oxo-3,4-dihydro-(2H)- l,4—benzoxazine.

The title compound is synthesized from 7-amino-8—methyl—3- oxo—3,4-dihydro-(ZH)-1,4-benzoxazine and 2—imidazolidine—2-sul- fonic acid using the procedure illustrated in Example ;&, Examp1e78.

-Methyl(2—imino—2-imidazolidine)—3,4-dihydro—(2H)-1,4- benzoxazine.

The title compound is synthesized from 8-methyl(2-iminoimidazolidine)oxo-3,4—dihydro-(2H)-l,4—ben using the method illustrated in Example43. _ Following the procedures outlined above the following compounds can also be synthesized .._47._ Example ¢9. 6—Ethy1—7—(2-imino—2—imidazolidine)—3—oxo—3,4-dihydro—(2H)— 1,4—benzoxazine.

Example £9 6-Ethyl(2-iminoimidazolidine)-3,4-dihydro—(2H)—l,4— benzoxazine.

Example 81 ' 8-Ethyl—7—(2—imino—2—imidazolidine)oxo—3,4—dihydro—(2H)— 1,4-benzoxazine.

Example 82 8-Ethy1—7-(2-iminoimidazolidine)-3,4—dihydro—(2H)—1,4— benzoxazine.

Example 83 6-Propyl(2—imino—2-imidazolidine-3—oxo—3,4—dihydro-(2H)- 1,4-benzoxazine.

Example 8% 6-Propyl—7—(2—imino-2—imidazolidine)-3,4-dihydro—(2H)—l,4— benzoxazine.

-Propyl(2—iminoimidazolidine)—3—oxo—3,4—dihydro- Example (2H)—l,4—benzoxazine. benzoxazine.

Example 87 6-[(2—propyl)(2-imino-2—imidazolidine)]oxo-3,4-dihy- dro—(2H)-1,4-benzoxazine.

Example 88 6-[(2-Propyl)(2—iminoimidazolidine)]—3,4—dihydro~ (2H)—l,4-benzoxazine.

Example 89 I 8—[(2—Propyl)(2-iminoimidazolidine)]—3-oxo-3,4-dihy- dro—(2H)-1,4-benzoxazine. _ Example 90A ( 8-[(-2—Propyl)(2-imino-2—imidazolidine)]-3,4—dihydro- _48_ (2H)-1,4-benzoxazine.

Example91 6-Allyl—7—(2—imino-2—imidazolidine)-3—oxo-3,4—dihydro—(2H)— 1,4—benzoxazine.

Example 92 _ 6-Al1yl(2-imino—2—imidazolidine)-3,4—dihydro—(2H)—1,4— benzoxazine.

Example 93 8-Allyl—7—(2—iminoimidolidine)oxo-3,4—dihydro-2H—1,4— benzoxazine.

Example 94 8—Allyl-742—iminoimidazolidine)-3,4-dihydro-2H—1,4- benzoxazine.

Example 95 Imidazolinesulfonic acid: 2~Imidazolidinethione (Aldrich, 66.3 g, 650 mmol), Na2Mo04(5g, 227 mmol) and Nacl (15 g. 256 mmol) were added to 300 ml H20.

Although some dissolution occurred, a solid residue remained in the liquid of the mixture. The mixture was cooled to -100 C using an immersion cooler. 500 ml of a 30% (w/v) aqueous H202 solution was placed in a jacketed controlled drop rate addition funnel and cooled to 0°C using an ice/H20 bath. solution was added to the mixture at a rate of 60 drops/min. mixture was stirred for 16 hours at -10°C. During this time, the mixture changed from a white suspension to a dark blue solution to a light blue suspension. At the end of 16 hours, a solid was filtered from the suspension and dried in vacuo. No further ~ purification was needed. Yield: 57.8 g (a yield of 52.3%) of the title compound as a white solid mp 157-159°C; H NMR (300 MHz, DMSO d6) & 10.38 (br, 2H); 3.85 (s, 4H). solid was stable when stored in the dark at 0°C for at least 6 months.

The aqueous H202 The

Claims (1)

1. Claims: 1. A compound of the formula HN ' ~' “‘ 1; R, \/ N R2 L\ I RI 0 R‘ Re where: where: Rlis independently H, or lower alkyl of l to 6 carbons; Rgis independently H, or lower alkyl of l to 6 carbons; or the two R2 symbols jointly represent a carbonyl oxygen; R3is H, lower alkyl of l to 6 carbons; R4 and Rgindependently is H, Br, Cl or lower alkyl of l to 6 carbons, lower alkenyl of 2 to 6 carbons or lower alkynyl of 2 to 6 carbons with the proviso that at least one of Rt Rgand R6 cannot be hydrogen and further that the R2 groups must represent carbonyl when R4 and Rgare both hydrogen and R518 n—propyl and attaches at the 7—position or when Rgis Br and attaches at the 6—position; t Rgis hydrogen, Br, Cl, or lower alkyl of l to 6 carbons, lower alkenyl of 2 to 6 carbons or lower alkynyl of 2 to 6 carbons, and the R5 and the imidazolidin—2—ylideneamino substituents are connected mutually exclusively to the 6 and 7 positions of the 1, 4—benzoxazine nucleus. A compound of Claim 1 where: Rlis H; R3iS H, lower alkyl of 1 to 6 carbons; R4and Rgindependently is H, Br, lower alkyl of 1 to 6 carbons, or lower alkenyl of 2 to 6 carbons; and Br, Réis hydrogen, or lower alkyl of 1 to 6 carbons or lower alkenyl of 2 to 6 carbons. A compound of Claim 2 where Rr R5 and R5 are independently selected from a group consisting of hydrogen, bromine, lower alkyl of 1 to 3 carbons and allyl groups. A compound of Claim 1 where: Rlis H; R3iS H, or lower alkyl of 1 to 6 carbons; R4and Rgindependently is H, Br, lower alkyl of 1 to 6 carbons, or lower alkenyl of 2 to 6 carbons; and R5iS hydrogen, Br, or lower alkyl of 1 to 6 carbons or lower alkenyl of 2 to 6 carbons and the imidazolidin—2— ylideneamino group is attached to the 6—position of the benzoxazine nucleus. A compound of Claim 4 where the two R2 symbols jointly represent a carbonyl oxygen. A compound of Claim 5 where R3is hydrogen or methyl and where R6 is hydrogen. A compound of Claim 4 where R2 is lower alkyl. A compound of Claim 7 where R3 is hydrogen or methyl and where R6 is hydrogen. 9. A compound of Claim 6 or Claim 8 where one of R4 and R5 is hydrogen the other is bromine. l0.A compound of Claim 6 or Claim 8 where both R4 and R5 are bromine. ll.A compound of Claim 8 where both R4 and R5 are hydrogen. 12.A compound of Claim 6 or Claim 8 where one of R4and R5iS hydrogen and the other is lower alkyl of l to 3 carbons. 13.A compound of Claim 6 or Claim 8 where both R4 and R5 are lower alkyl of l to 3 carbons. 14. A compound of Claim 6 or Claim 8 where one of R4 and R5 is hydrogen and the other is an allyl group. 15.A compound of Claim 1 where: Rlis H; R3is H, or lower alkyl of l to 6 carbons; R4and Rgindependently is H, Br, lower alkyl of 1 to 6 carbons, or lower alkenyl of 2 to 6 carbons; and Rgis hydrogen, Br, or lower alkyl of l to 6 carbons or lower alkenyl of 2 to 6 carbons and the imidazolidin—2— ylideneamino group is attached to the 7—position of the benzoxazine nucleus. 16.A compound of Claim 15 where the two R2 symbols jointly represent a carbonyl oxygen. 17.A compound of Claim 16 where R3 is hydrogen or methyl and where R6 is hydrogen. 52 18.A compound of Claim 15 where R2 is lower alkyl. 19.A compound of Claim 18 where R3 is hydrogen or methyl and where R5 is hydrogen. 20.A compound of Claim 17 or Claim 18 where one of R4 and R5 is hydrogen the other is bromine. 21.A compound of Claim 17 or Claim 18 where both R4 and R5 are bromine. 22.A compound of Claim 18 where both R4 and R5 are hydrogen. 23.A compound of Claim 17 or Claim 18 where one of R4 and R5 is hydrogen and the other is lower alkyl of 1 to 3 carbons. 24.A compound of Claim 17 or Claim 18 where both R4 and R5 are lower alkyl of 1 to 3 carbons. 25.A compound of Claim 17 or Claim 18 where one of R4 and R5 is hydrogen and the other is an allyl group. 26.A compound of Claim 15 where R3iS methyl or hydrogen, both R4 and R5 are hydrogen and R5 is bromine, lower alkyl of 1 to 3 carbons or is allyl. 27.A compound of Claim 4 where R2, Ry R5 and R5 are H, and R4 is lower alkyl of 1 to 3 carbons. 28.A compound of Claim 27 where R4is methyl. 29.A compound of Claim 4 where the R2 groups jointly represent a carbonyl oxygen, R2, R5 and R4 are H and R4is lower alkyl of 1 to 3 carbons. 53 30.The compound of Claim 29 where R4is methyl. 3l.The compound according to any preceding claim substantially as hereinbefore described and/or with reference to the examples. Tomkihs and Co.