NO170926B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-HYDROXYPROPYLAMINE ARYLESTER DERIVATIVES - Google Patents

Description

The invention relates to an analogue method for the preparation of compounds having valuable pharmaceutical properties and the formula

where Ar denotes a phenyl or naphthyl group which may be unsubstituted or substituted with one or more lower alkyl groups with 1-10 carbon atoms, alkenyl with 2-10 carbon atoms, alkynyl with 2-10 carbon atoms, alkoxy where the alkyl group contains 1-10 carbon atoms, halogen, acetamido, amino, nitro, alkylamino with 1-10 carbon atoms, hydroxy, hydroxyalkyl with 1-10 carbon atoms, cyano, aryl alkoxy where the alkyl group contains 1-6 carbon atoms and the aryl group denotes unsubstituted phenyl or phenyl which is substituted with halogen, methyl or a or two hydroxy groups, and groups with the formula where R4 denotes lower alkyl, aryl or aralkyl and A is a direct bond, the alkylene with 1-10 carbon atoms or the alkenylene with 2-10 carbon atoms, W denotes the alkylene with 1-10 carbon atoms, and B denotes -NR2COR1 , -NR^CONR^R^, -NR2SO2R1, -NR2SO2NR1R3 or -NR2C00R1 kv°r Ri» R2 °3 R3» can be the same or different and can be hydrogen, alkyl, alkoxyalkyl, cycloalkyl, alkenyl, alkynyl, phenyl , thiophenyl, imidazole, oxazole, indole or aralkyl, or when B is -NR2CONR1R3 or -NR2SO2NR1R3, R]_ and R3 together with N may form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine group, except that R ]_ cannot be hydrogen when B is -NR2SO2R1 or -NR2COOR1 as well as the pharmaceutically acceptable salts thereof. The compounds are produced by reacting an amine with the formula H2N-W-B with a compound of the formula

The compounds prepared according to the present invention are useful because of their valuable pharmaceutical properties. They exhibit (3-adrenaline-blocking action and are also useful in the treatment of glaucoma. The compound can also be used for the treatment or prophylaxis of heart disorders.

There is good documentation for therapeutic and prophylactic uses of compounds that block stimulation of B-adrenaline receptors caused by the sympathetic nervous system in the heart, pulmonary vascular system and other organs.

Typically, such compounds are administered therapeutically to patients suffering from ischemic heart disease or heart muscle infarction, in order to reduce the work of the heart, i.e. heart rhythm and force of contraction. Reduction of the heart's work reduces the need for oxygen and can actually also increase the oxygen supply. Reduction of the heart's work can thus help to prevent further damage to tissue and alleviate angina pectoris.

γ-adrenaline stimulation may also exacerbate or cause arrhythmias due to elevated levels of catecholamines. Thus $-blocking can. means are used to reduce the risk of rhythm disturbances.

Some of the compounds produced according to the invention selectively block γ-adrenaline receptors in various organs. g-receptors.in the heart.are generally referred to as (^-receptors, and such as.are associated with dilation of vessels and bronchi, are .(^"receptors• Selective β-blocking agents are preferred for the treatment of heart disorders, because they can have less tendency to cause high blood pressure or bronchoconstriction A number have been found

B-^-selective epinephrine blocking agents [Smith, L. H., J. Appl. Chem. Biotechnol., 28, 201-202 (1978)]. Most

such compounds are structural variants of 1-amino-3-aryloxy-2-propanol.

In the past, research into 8-blocking agents has focused on developing compounds that can be administered to heart patients over longer periods of time. However, it is often desirable for treatment in critical situations to quickly reduce the heart's work or improve its rhythm during a cardiac crisis, e.g. during or shortly after a cardio-muscular infarct. Conventional B-blocking agents can be used for such treatment, but the duration of their action may be much longer than the doctor wishes. B-blocking agents that have a long duration of action,., do not allow precise control of the heart's work or rapid cancellation of the B-blocking effect, which may be required in treatment in critical situations. Does the heart's pumping action e.g. dangerously weak, it is desirable to quickly weaken or cancel the B-blocking effect. The persistent effect of available B-blocking agents will be able to counteract the healing and greatly complicate

the therapeutic decisions the doctor must make during such critical treatment of cardiac patients.

There is therefore a need for a pharmaceutical preparation and a treatment method using a B-adrenaline blocking agent which has a short duration of action.

Compounds produced.; according to . the invention is -new B-blockers. means... The presence of a. ester function

in these compounds ensures a predictable metabolism of these compounds into metabolites which are without B-blocking effect, . and ■,which is. strongly polar, and easy going. out in the stool.

Some of the compounds produced according to the invention are quickly metabolised after infusion into the circulatory system and therefore have a short-term β-blocking effect. Such compounds are particularly advantageous since they allow precise control during the treatment of certain cardiovascular disorders by "intravenous" administration of the compound.

Compounds prepared according to the invention are also useful for treating glaucoma or lowering intraocular pressure by topical administration of the compounds to the eye. Compounds that last a short time in the circulatory system, but have good stability in ocular fluid, are particularly useful, since they are unlikely to cause side effects in the system.

Glaucoma is an eye condition characterized by increased intraocular pressure. In the absence of treatment, the condition can eventually lead to irreversible retinal damage and blindness. Conventional treatment of glaucoma has included topical administration of pilocarpine and/or epinephrine which is applied to the eye several times a day.

The use of various B-blocking agents to lower intraocular pressure is well documented. E.g. US Patent No. 4,195,085 issued to Stone describes a method of treating glaucoma by optically administering a B-blocking compound, timolol maleate. US patent no. 4,127,674 describes another method. to treat glaucoma with labetalol, a. known antagonist to both alpha- and beta-adrenaline receptors. However, these methods also have obvious disadvantages, in that absorption of the B-blocking compound in the circulatory system can cause unpleasant side effects. Such side effects result from prolonged B-blocking action on the heart, tracheal system and blood vessels. E.g. According to the Physicians Desk Reference, Charles E. Baker, Jr., 35th ed., 1981, p. 1233, adverse reactions to the use of timolol maleate may include respiratory spasm and heart failure, as well. as.deficient .circulation in the heart. There is therefore a need for a procedure for the treatment of Glaucoma : or, to lower intraocular. pressure .with.significantly less tendency.to side effects in the form.of system disorders.

The invention relates to an analogous method for the preparation of compounds of the general formula

where Ar, W and B are as indicated above. The compounds described herein are not limited to any particular stereoisomeric configuration. They can be administered in the form of their pharmaceutically acceptable acid addition salts, e.g. such as hydrochloride, sulfate, phosphate, oxalate, gluconate, tartrate, etc.

Compounds prepared according to the invention occur as two stereoisomers due to the presence of an asymmetric carbon atom. The compounds include each of the stereoisomeric forms, as well as racemic mixtures. In the case of compounds where R 1 , R 2 or R 3 denotes alkenyl, both cis and trans isomers are within the scope of the invention. In the case of compounds where Ar is a substituted aromatic ring, the substituents can be in the ortho-, meta- or para-position to the propoxy-carbonyl side chain.

The compounds described herein can be prepared by any available method. Compounds which are in the form of acid addition salts can be converted into the free base by reaction with a suitable base such as sodium carbonate or sodium bicarbonate. The connections are preferably made by one of the following methods:

1) As illustrated in scheme I, a suitable acyl chloride is reacted with glyeidol in the presence of a base such as pyridine. The resulting product is then reacted with a suitable amine in the presence of dimethylformamide:

where Ar, W and B have the same meaning as above.

Alternatively, as illustrated in Scheme III, the aminodiol is reacted with p-methoxybenzyloxycarbonyl azide in the presence of sodium bicarbonate and dioxane to protect the amine group. The resulting compound is reacted with a suitable acyl chloride, and the protecting group is removed by reaction with a suitable acid.

where Ar, W and B have the same meaning as above.

The amines, fL^N-W-B, where W and B have the same meaning as coran, can be prepared by the following methods:

(a) For amidoalkylamines (B=NR2COR1):

.where W, R2 and R^ have meanings as before.

(b) For Alkoxycarbonylaminoalkylamines (B=NR2COOR^)

one or the other of two methods was used.

iivor W, R2 and R^ have meanings as above.

(c) For ureidoalkylamines (B=NR2CONR^R3) one used any of four methods: where W, R 2 and R 3 have meanings as above. where W, R^, R2 and R3 have the meaning as before. where W, R 2 and R 3 have meanings as above.

where W and R2 have. meaning as before.

(d) For sulfonamidoalkylamines (B=NR2SO2R3):

where W, R 2 and R 3 have meanings as above.

(e) For sulfamidoalkylamines (B=NR2S02NR^R3) one or the other of two methods was used:

where W, R3_ and R3 have meanings as above.

The production of part of the starting materials is described in the concurrent US application serial no. 211,341; which is hereby incorporated by.reference..

When used for the treatment of cardiac disorders, the compounds prepared according to the invention are advantageously administered orally or parenterally, e.g. by intravenous injection or intravenous infusion. Prescriptions for intravenous injection preferably include the active compound as a soluble acid addition salt in a properly buffered isotonic solution.

The dosage administered to a patient and the duration of the infusion will depend on the patient's needs and the particular compounds used. For short infusion periods, e.g. less than approx. 3 hours, the duration of action is considered to be determined by both metabolic effects and distribution phenomena. For relatively long infusion periods, e.g. more than approx. 3 hours, the duration of action is believed to depend largely on metabolic effects. Therefore, although the present methods and compounds are applicable generally for short-term* infusion therapy, certain compounds are preferred for longer infusion times. The compounds have been found to be generally non-toxic within conventional dosage ranges. Generally, doses of about 0.0001 to about 100 mg;pr. kg body weight per hour, preferably within the area from. about 0.01 to about 10 mg per kg body weight per hour.

When the compounds are used for be-

action of glaucoma, they are advantageously administered topically to the eye in the form of a solution, ointment or solid insert as described in US patent no. 4,195,085. Formulations may contain the active component, preferably in the form of a soluble acid addition salt, in amounts ranging from about 0.01 to about 10 percent by weight, preferably about 0.5 to about 5 percent by weight. Unit doses of the active compound may be in the range of from about 0.01 to about 5.0 mg, preferably from about 0.05 to about 2.0 mg.The dose administered to a patient will depend on the needs of the patient and the particular compounds employed.

Carriers used in the preparations are preferably non-toxic pharmaceutical and inorganic;

or inorganic compounds such as water, mixtures of water and water-miscible solvents, e.g. lower alcohols, mineral oils, petroleum jelly, ethyl cellulose, polyvinylpyrrolidone and other conventional carriers. The pharmaceutical preparations may also contain additional components/ such as. emulsifying, preserving, wetting and sterilizing agents. These include polyethylene glycols 200, 300, 400 and 600, carb waxes 1,000,

1,500, 4,000, 6,000 and 10,000, bactericidal components such as quaternary ammonium compounds, phenylmercuric salts which are known for. to have cold sterilizing ability and are harmless in use, thimerosal,.. methyl and propylparaben, benzyl alcohol, phenylethanol, beef ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene, sorbitan monopalmitylate > dioctyl sodium sulfosuccinate , monothio-glycerol, thiosorbitol, ethenediamine-tetraacetic acid. and such.

In addition, ophthalmic carrier fluids can be used as carrier media for the present purpose, including conventional phosphate buffer fluid tanks, isotonic boric acid fluids, isotonic sodium chloride fluids, isotonic sodium borate fluids and the like.

The treatment method involves

beneficial...topical administration of eye drops containing the active compound. Formulations for eye drops preferably include the active compound as a soluble acid addition salt in a properly buffered, sterile, aqueous isotonic solution.

The compounds produced according to the invention are beta-blocking agents that contain ester groups and have a selective, localized g-blocking effect in the eye after topical administration. Such compounds are believed to be rapidly metabolised by plasma and/or liver esterases into inactive by-products after entering the circulatory system. It has been discovered that these same compounds are relatively stable in eye fluids, i.e. tear fluids and aqueous humor. Such compounds are therefore useful for treatment of glaucoma or for the reduction of intraocular pressure, ago. they remain stable when administered topically to the eye, but quickly undergo metabolism when they are then absorbed into the circulatory system.

Some of the compounds break down faster than others in the aqueous humor. - Such compounds can be advantageously used when only a temporary lowering of the intraocular is desired. pressure, e.g. for diagnostic processes. Compounds with a more long-lasting effect are generally used to cause more long-lasting reductions in intraocular pressure, as is desired in the treatment of chronic glaucoma. Thus, the compounds represent a very useful therapeutic alternative when it comes to treating glaucoma or lowering intraocular pressure.

The rate of hydrolysis of the ester function in compounds prepared according to the invention depends on the type of amine substituent used. By changing the amine substituent, it is possible to change the duration of the compound's presence in the body. The presence of the amine substituent also makes the compounds less lipophilic. Compounds that are less lipophilic are less likely to act on the central nervous system, since there is less opportunity for CNS penetration.

The in vitro studies that will be described in the following indicate that the compounds produced by the method according to the invention will undergo enzymatic hydrolysis to varying degrees, depending on their location in the body (see table III). E.g. the compound according to example VII is completely hydrolysed within 60 minutes in both dog blood and liver homogenate, although only 31% is hydrolysed after one hour in aqueous humor, and only 54% hydrolysed after two hours. The compound according to example II is less stable in aqueous humor, hydrolyzing 42% after one hour and 68% after two hours.

The effect of several compounds produced according to the invention in terms of blocking beta-adrenaline receptors has been demonstrated in vitro (table I) and in vivo (table II).

A. Beta-blocker monitoring in vitro

Several of the compounds prepared according to the invention were tested for B-blocking activity in vitro, using right heart atria from guinea pigs and tracheal strips from guinea pigs placed in a tissue bath containing oxygenated (95% 02 - 5% C02) physiological Krebs- saline solution at 37°C. Each tissue sample was suspended between a fixed glass rod and a Statham Universal Transducer connected to a Beckman recorder. The anterior chamber was allowed to beat spontaneously under a loading stretch of approximately 0.5 g. Intrinsic inhibitory or stimulatory activity was determined for each compound by successively increasing concentrations in the tissue baths at 60 min intervals. The tissue samples were not washed between the concentration increases.

The maximum concentration showing little or no cardiac depressant effect was chosen for blocking experiments. Differences in rate in response to isoproterenol, a standard B-receptor agonist, were measured in the absence and presence of test compounds. Spiral strips of guinea pig trachea were suspended under permanent tension of 5 g and incubated with phentolamine, tropolone and cocaine. Active stretch was produced by the addition of carbachol (3.0 x .10 7M), and reductions in stretch in response to isoproterenol were determined quantitatively. Cumulative concentration-response curves were established with isoproterenol both before and after 60 minutes of incubation of test compounds with anterior chamber and tracheal samples. Compounds with B-blocking effect shifted the concentration-response curves to the right. The blocking ability of test compounds was estimated by calculating pA2~ values (-log K ) according to the Furchgott method according to the article Pharmacological.Differentiation of Adrenergic Receptors, Ann.

N. Y. Acad. Sci., 139: 553-570 (1967). Comparison between the blocking action of right atrial and tracheal response to isoproterenol makes it possible to judge cardiac selectivity of test compounds, cardiac selective compounds being relatively more effective at blocking atrial rate than tracheal force response to isoproterenol. The degree of cardiac selectivity is estimated from the ratio .KB trachea/

Kg atrial chamber (10(pA2atrial chamber<r-P>A2trachea))# A ratio higher than one indicates cardiac selectivity. Test drugs were dissolved in distilled water and added to the bath (30 ml) in a volume of 10 or 100 µl. The results of the in vitro tests are listed in Table I. All test compounds are active B-blocking agents.

B. Duration: dg strength of beta blocker. effect in vivo

The duration of β-blockade was determined in vivo using pentobarbital-anesthetized dogs equipped to measure heart rate using a Beckman cardiotachometer electronically triggered by a phase-variable aortic blood pressure signal. Both cranial nerves were severed in the neck area, and the animals were ventilated mechanically. The experimental setup used used a 3 hour infusion of test compound. Tablet doses of isoproterenol (0.5 ug/kg) were used to assess the degree of 8-blockade and recovery from B-blockade after determination of the infusion. The doses were given at intervals of 10 minutes, both before, during and after the infusion of the test compounds. The rate of infusion was adjusted so that the degree of isoproterenol inhibition at the end of the infusion time of 3 hours averaged approximately 50% of the control value. After completion of infusion of blocking agent, percentage recovery from 3-blocking was calculated and the time for 80% recovery was estimated. The results are listed in Table II. C. Enzymatic hydrolysis of beta-blocking agents using dog blood, liver homogenate and aqueous humor

Chemicals - Acetonitrile was "HPLC" grade. Distilled water was used to dissolve compounds and 0.01 N HCl to dissolve compounds as needed. an acidic pH value to dissolve.

Enzyme Source - Fresh aqueous humor was collected from dog eyes using a 23 gauge needle, while fresh dog blood was collected in heparinized Vacutainer tubes. Fresh liver was homogenized in 0.9% NaCl using a Potter-Elvehjem Teflon rammer and glass homogenizer to form a 25% (W/V) homogenate.

Incubation condition - A 0.5 ml sample of aqueous canine humor, blood or liver homogenate was incubated with 12.5 µg

(0.5 ml) B-blocking agents in a shaking metabolic Dubnoff incubator at 37°C for 60 and 120 min. Denatured control tissue was prepared by adding 2.0 ml of acetonitrile to 0.5 ml of aqueous humor, blood or liver homogenate to eliminate esterase effects prior to addition of 8-blocking agent. These control tissues were then incubated at 37°C for 120 min. After

60 and 120 min, the incubations were terminated by the addition of

2 ml of acetonitrile and immediately mixed using a "Vortex" to stop esterase effects.

Processing and data analyzes of samples _ All samples were centrifuged at 4000 rpm for 10 min to precipitate denatured proteins. The resulting non-settled portions were transferred to "WISP" bottles and analyzed using an HPLC assay developed for B-blocking agents. The hydrolysis of the B-blocking agents by means of aqueous humor, blood and liver homogenate was determined by the disappearance of the compounds. The degree of enzymatic hydrolysis for each tissue was determined by comparing the amount of each compound (absolute peak area) recovered at each time point with the amount of each compound (absolute peak area) in denatured control tissue and aqueous control samples. The results of these tests are shown in - table III.

D. Half-life of B-blocking agents in whole dog Slocr and dog liver homogenate

These examples describe experiments which show the disappearance of the compounds produced according to the invention in vitro in whole human blood, whole dog blood and dog liver homogenate. The rate at which a compound disappears is expressed by the half-life (Tl/2), which is the time it takes for half of the original quantity of the tested compound to disappear. In each experiment, 1 ml of a solution containing 50 µg of the test compound was added to 1 ml of whole blood or 1 ml of a 33% (w/v) liver homogenate. The samples were incubated in a shaking metabolic Dubnoff incubator for 2.5, 5.0, 10.0, 20.0, 30.0 and 60.0 min. at 37°C. For the specified time periods, the sample mixtures were removed from the incubator and transferred to an ice bath at 0°C. Acetonitrile (2 mL) was immediately added and the mixtures were mixed to stop enzymatic hydrolysis. Zero-time samples were prepared by adding 2 ml of acetonitrile to denature the proteins prior to the addition of the test compounds. After centrifugation to deposit* denatured proteins, 2 ml of the residual liquid was removed and analyzed by high pressure liquid chromatography using a mobile phase of 60% acetonitrile/40% 0.05 m sodium phosphate buffer (pH 6.6), a U.V.- detector and Waters u Bondapak phenyl column. The half-life: for each test compound was determined graphically by plotting the decrease in concentrations as a function of time. The results of the experiments are shown in Table III.

The present invention is further illustrated by the following examples

Example I

This example describes the synthesis of a compound of the following formula via Scheme III:

(a) 3- /*( 2- isopropyl Icarbony lamino) ethyl lamino/ l, 2- propanedio 1

To 39 g (0.3 mol) of 2-(isopropylcarbonylamino)ethylamine in 150 ml of isopropyl alcohol was added 22.2 g (0.3 mol) of glycidol. The reaction mixture was stirred at 25°C for 24 hours and evaporated in vacuo. The remaining oil was chromatographed (silica gel/ethanol) to give 18.6 g (30%) of product. This compound was identified by NMR and IR spectroscopy.

(b) 3-/N-( 4- methoxybenzyloxycarbonyl)-N-/*( 2- isopropylcarbonylamino)- ethyl7amino- 1, 2- propanediol

A mixture of 18.6 g (91 mmol) of 3-(2-(isopropyl-carbonylamino)ethylamino)-1,2-propanediol, 20 g (97 mmol) of p-methoxybenzyloxycarbonyl-azide and 24 g (280 mmol) of sodium bicarbonate in 66 ml of dioxane and 33 ml of water was stirred at room temperature for 3 days.

The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was chromatographed, silica gel/10% ethanol in chloroform to give 16 g (47.6%) of product. The compound was identified by NMR and IR spectroscopy.

(c) 2- hydroxy- 3-/ N-/^- methoxybenzyloxycarbonyl7- N-/'( 2-isopropylcarbonylamino) ethyl77aminopropyl- 2- fluorobenzoate

• To a mixture containing 8 g (2.2 mmol) of

the diol from the previous experiment in 50 ml of methylene chloride-pyridine (1:1), 3.5 g (2.2 mmol) o-fluoro-benzoyl chloride was added there at 25°C. The reaction mixture was stirred at 25°C for 2.5 hours and evaporated to dryness in vacuo at 60°C. The residue was partitioned between water and methylene chloride. The methylene chloride was washed with 5% aqueous

sodium bicarbonate solution and evaporated to dryness. The product was purified by chromatography; silica gel/10% ethanol in chloroform. The yield was 75%, and the compound was identified by NMR and IR spectroscopy.

(d) 3-/2- ( isopropyl Icarbonylamino )_ 7ethyl 17amino- 2- hydroxypropyl 1

2-fluorobenzoate hydrochloride

Hydrogen chloride gas was introduced for 5 min into a mixture of 8 g of the ester from the previous experiment in 150 ml of methylene chloride-ethanol (99:1). The reaction mixture was stirred at 25°C for 3 hours, and the precipitate was filtered and recrystallized from isopropanol to give 3.3 g (56%) of product. Melting point 162.5-163°C. NMR and IR spectra were consistent with the intended structure, and the elemental analysis was consistent with the empirical formula <C>^<gH>^^O^FCl.

Example II

This example describes the synthesis of a compound of the following formula via Method I:

3-/L,1-dimethyl-2-(1-morpholinecarbonylamino)^7ethylamino-2-hydroxypropyl-2-'flubrobehzbate-hydrochloride

A mixture containing 37 g (0.5 mol) glycidol, 500 ml anhydrous ethyl ether, 500 ml pyridine and 80 g (0.5 mol) o-fluorobenzoyl chloride was stirred at 0°C for 1 hour and at 25°C for 2 hours. The mixture was filtered, and the ethanol filtrate was washed with 100 ml of 5% hydrochloric acid. Evaporation of the ethyl ether gave an oil which was distilled to give 69.5 g (71%) of the product, 2,3-epoxypropyl-2-fluorobenzoate, which had a boiling point of 115°C/0.5 mmHg. NMR and IR spectra were consistent with the intended structure.

To 8.5 g (0.043 mol) of 2,3-epoxypropyl-2-fluorobenzoate in 100 ml of dimethylformamide was added 8.74 g (0.043 mol) of 1,1-dimethyl-2-(1-morpholinecarbonylamino)ethylamine. The reaction mixture was stirred at 25°C for 4 hours, and the dimethylformamide was evaporated in vacuo at 60°C. The product was purified by column chromatography - silica gel/ethyl ether-ethanol (4:1) - to give a colorless oil which was dissolved in ether and acidified with ethereal hydrochloric acid. The precipitate was filtered and recrystallized in isopropanol-ethyl ether to give 4.1 g (24%) of product. Melting point 58.5 - 59.5°C. NMR and IR spectra were consistent with the proposed structure, and the elemental analysis was consistent with the empirical formula C₂₂₂₂N-₂O₂FCl.

Example III

This example describes the synthesis of a compound of the following formula:

3 -/l-methyl-2-( methylcarbonylamino)_ 7ethylamino- 2- hydroxypropyl 2- fluorobenzoate

The procedure of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1-methyl-2-(methylcarbonylamino)ethylamine was substituted for 1,1-dimethyl-2-(1-morpholinocarbonylamino) the ethylamine. The product, which was recovered as a semi-solid, had a melting point of 30°C. It was identified by NMR and IR spectroscopy and elemental analysis.

Example IV

This example describes the synthesis of a compound of the following formula:

3-/ l, l- dimethyl- 2- ( methylcarbonylamino^ ethyl lamino- 2-hydroxypropyl- 2- fluorobenzoate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-(methylcarbonyl-amino)ethylamine was substituted for 1,1-dimethyl-2-(1 -morpholinocarbonylamino) the ethylamine. The product, which was recovered as an oil, was identified by NMR and IR spectroscopy and elemental analysis.

Example V

This example describes the synthesis of a compound of the following formula:

3-/ 1,1- Dimethyl- 2-( isopropylcarbonylamino) J7ethylamino- 2- hydroxypropyl- 2- fluorobenzoate- oxalate- monohydrate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-isopropylcarbonylaminoethylamine was substituted for 1,1-dimethyl-2-(1-morpholinocarbonylamino )ethylamine. The product, which was crystallized from isopropanol, had a melting point of 134.5 - 137.5°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example VI

This example describes the synthesis of : a. connection with the following formula:

3-/ 1, 1- dimethyl 1- 2- (cyclohexylcarbonylamino} 7ethylamino- 2- hydroxypropyl- 2- fluorobenzoate- oxalate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-cyclohexylcarbonylaminoethylamine was substituted for 1,1-dimethyl-2-(1-morpholinocarbonylamino )ethylamine. The product, which was crystallized from ethyl acetate-propanol, had a melting point of 187-188°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example VII

This example describes the synthesis of a compound of the following formula:

3-/ 1, 1- dimethyl 1- 2- ( benzyl Icarbonyl lamino )^ ethyl lamino- 2- hydroxypropyl- 2- fluorobenzoate- hydrochloride

The procedure of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-benzylcarbonylaminoethylamine was substituted for the 1,1-dimethyl-2-(morpholinocarbonylamino)ethylamine. The product; which was crystallized from isopropanol, had a melting point of 145.5-146.5°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example VIII

This example describes the synthesis of a compound of the following formula:

3-/ 1, 1- dimethyl 1- 2- ( phenylsulfonylamino jethylamino- 2- hydroxypropyl- 2- fluorobenzoate- oxalate

The procedure of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-(phenylsulfonylamino)ethylamine was substituted for 1,1-dimethyl-2-(morpholinocarbonylamino) the ethylamine. The product, which was crystallized from isopropanol, had a melting point of 152.4-153°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example IX

This example describes the synthesis of a compound of the following formula:

3-/ 1 , l- dimethyl- 2- ( ethoxycarbonylamino)^ 7ethylamino- 2- hydroxypropyl- 2- fluorobenzoate- hydrochloride

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-ethoxycarbonylaminoethylamine was substituted for 1,1-dimethyl-2-(1-morpholinocarbonylamino )ethylamine. The product, which was crystallized from ethyl acetate, had a melting point of 137°C

and was identified by NMR and IR spectroscopy and elemental analysis.

Example X

This example describes the synthesis of a compound of the following formula:

3-/ 1, 1- dimethyl 1- 2- ( aminocarbonylamino)/ ethylamino- 2- hydroxypropyl- 2- fluorobenzoate

The procedure of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-(aminocarbonylamino)ethylamine was substituted for 1,1-dimethyl-2-(1 -morpholinocarbonylamino)ethylamine. The product, which was recrystallized from water, had a melting point of 58-62°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example XI

This example describes the synthesis of a compound of the following formula:

3-/ 1, l- dimethyl- 2-( methylaminocarbonylamino)./ ethylamino- 2-hydroxypropyl- 2- fluorobenzoate- hemioxalate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-(methylaminocarbonylamino)ethylamine was substituted for 1,1-dimethyl-2-(1 -morpholinocarbonylamino)ethylamine. The product, which was crystallized from isopropanol, had a melting point of 149.5°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example XII

This example describes the synthesis of a compound of the following formula:

3-/ 1,1-dimethyl-2- (phenylaminocarbonylamine)_/ ethylamino- 2- hydroxypropyl- 2- fluorobenzoate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-(phenylaminocarbonylamino)ethylamine was substituted for 1,1-dimethyl 1-2-( 1-morpholinocarbonylamino) ethylamine. The product, which was recovered as an oil, was identified by NMR and IR spectroscopy and elemental analysis.

Example XIII

This example describes the synthesis of a compound of the following formula:

3-/ 2-( Benzylcarbonylamino) ethyl/ amino- 2- hydroxypropyl- 2-fluorobenzoate- hydrochloride

The method of Example I was repeated in all essential details to give the above compound, except that an equivalent amount of 2-(benzylcarbonylmono)ethylamine was substituted for the 2-(isopropylcarbonylamino)ethylamine. The product crystallized from isopropanol had a melting point of 140.5°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example XIV

This example describes the synthesis of an amine melioma product with the following formula:

1,1-dimethyl-2-(methylcarbonylamino)ethylamine

A mixture of 26.4 g (0.3 mol) ethyl acetate and 79.2 g (0.9 mol) 1,2-diamino-2-methylpropane was heated to 100°C in a pressure flask for 36 hours. The reaction mixture was evaporated in vacuo and distilled to give 22.4 g (57.4%) of product. Boiling point 100°C/0.1 mmHg. This product was identified by NMR and IR spectroscopy.

Example XV

This example describes the synthesis of an amine intermediate of the following formula:

2-(isopropylcarbonylamino)ethylamine

The method of Example XIV was repeated in all essential details to give the above compound, except that "equivalent amounts of ethylenediamine and ethyl 2-methylpropionate were substituted for the 1,2-diamino-2-methylpropane and ethyl acetate, respectively." The product, which was recovered as an oil, was identified by NMR and IR spectroscopy and elemental analysis.

Example XVI

This example describes the synthesis of an amine intermediate of the following formula:

2-(Benzylcarbonylamino)ethylamine

The method of Example XIV was repeated in all essential details to give the above compound except that equivalent amounts of ethylenediamine and ethylphenylacetate were substituted for the 1,2-diamino-2-methylpropane and ethylacetate respectively. The product, which had a melting point of 37-38°C, was identified by NMR and IR spectroscopy.

Example XVII

This example describes the synthesis of an amine intermediate of the following formula:

1-methyl-2-(methylcarbonylamino)ethylamine

The method of Example XIV was repeated in all essential details to give the above compound, except that an equivalent amount of 1,2-diaminopropane was substituted for 1,2-diamino-2-methylpropane. The product, which had a boiling point of 90-95°C at 0.1 mraHg, was identified by NMR and IR spectroscopy.

Example XVIII

This example describes the synthesis of an amine intermediate of the following formula:

2-(methylcarbonylamino)ethylamine

The method of Example XIV was repeated in all essential details to give the above compound, except that an equivalent amount of ethylenediamine was substituted for 1,2-diamino-2-methylpropane. The product, which had a melting point of 51-52°C, was identified by NMR and IR spectroscopy.

Example IXX

This example describes the synthesis of an amine intermediate product. with the following formula:

1,1-Dimethyl-2-(isopropylcarbonylamino)ethylamine

The method of Example XXV was repeated in all essential detail to give the above compound, except that an equivalent amount of ethyl 2-methylpropionate was substituted for ethyl acetate. The product, which had a boiling point of 110°C at 0.1 mmHg, was identified by NMR and IR spectroscopy.

Example XX

This example describes the synthesis of an amine intermediate of the following formula:

1,1-dimethyl-2-(cyclohexylcarbonylamino)ethylamine

The method of Example XIV was repeated in all essential details to give the above compound, except that an equivalent amount of ethyl cyclohexyl carboxylate was substituted for ethyl acetate. The product, which had a boiling point of 100-110°C at 0.1 mmHg, was identified by NMR and IR spectroscopy.

Example XXI

This example describes the synthesis of an amine intermediate of the following formula:

1., 1-Dimethyl-2-(benzylcarbonylamino)ethylamine

The method of Example XIV was repeated in all essential details to give the above compound, except that an equivalent amount of ethyl phenyl acetate was substituted for ethyl acetate. The product, which had a melting point of 46.5°C, was identified by NMR and IR spectroscopy.

Example XXII

This example describes the synthesis of an amine with the following formula:

1, 1- dimethyl- 2-<ethoxycarbony 1) aminoethylamine

To a mixture of 88.2 g (1 mole) of 1,2-diamino-2-methyl-propane, 50 ml of triethylamine. and 500 ml of diethyl ether, a solution of 27.1 g (0.25 mol) ethyl chloroformate in 100 ml of ether was added dropwise. The reaction mixture was stirred for 16 hours at 25°C and filtered. Evaporation of the filtrate to dryness gave 38 g (95%) of product which was identified by NMR and IR spectroscopy.

Example XXIII

This example describes the synthesis of an amine with the following formula:

1,1-Dimethyl-2-(methylaminocarbonylamino)ethylamine

A reaction mixture of 5.7 g (1 mol) methyl isocyanate and

20 ml of pyridine was stirred at 0°C for 5 minutes and slowly added to a solution of 20 g (0.23 mol) of 1,2-diamino-2-methyl-propane in 30 ml of pyridine. The reaction mixture was warmed to 20°C and stirred for 1 hour. Evaporation of the solvent in vacuo gave 11.6 g (90%) of product which was identified by NMR

and IT spectroscopy.

Example XXIV

This example describes the synthesis of an amine with

following formula:

1,1-dimethyl-2-(aminocarbonylamino)ethylamine

The method of Example XXIII was repeated in all essential details to give the above compound, except that an equivalent amount of cyanic acid was substituted for methyl isocyanate. The product was recovered as a semi-solid.

Alternatively, the urea in this example was prepared as follows: A mixture of 26.5 g (0.3 mol) of 1,2-diamino-2-methylpropane and 18 g (0.3 mol) of urea in 150 ml of water was refluxed for 4 hours. . The mixture was stirred in vacuo. The residue was dissolved in chloroform, filtered and concentrated to form a solid which was recrystallized in ethyl acetate. to ai 15 a product (38%), m.p. 87-90°C. The NMR and IR spectra were consistent with the intended structure.

Example XXV

This example describes the synthesis of an amine with the following formula:

1,1-dimethyl-2-(1-morpholinocarbonylamino)ethylamine

To 16.2 g (0.1 mol) of N,N'-carbonyldiimidazole in 100 ml of chloroform was added 8.7 g (0.1 mol) of morpholine. The reaction mixture was stirred for 30 minutes at 25°C and slowly added. one. solution of 1,2-diaraino-2-rmethylpropane in 100 ml of chloroform. After stirring for 30 minutes, the reaction product was evaporated to dryness and the product chromatographed - silica gel/ethanol ethyl ether (1:1) - to give 8.74 g (43%) of product. NMR and IR spectra were consistent with the intended structure.

Example XXVI

This example describes the synthesis of an amine with the following formula:

1,1-Dimethyl-2-(phenylaminocarbonylamino)ethylamine

The method of Example XXV was repeated in all essential details to give the above compound, except that an equivalent amount of aniline was substituted for morpholine. The product, which had a melting point of -1SO4-1S104, was identified by NMR and IR spectroscopy.

Example XXVII

This example describes the synthesis of an amine with the following formula:

31

2-(methylaminocarbonylamino)ethylamine

3.23 g (0.057 mol) of methyl isocyanate was added dropwise

to a stirred suspension of 5 g (0.057 mol) of acetylethylenediamine in 100 ml of methylene chloride at 10°C. After the addition of the methyl isocyanate was complete, 100 mL of anhydrous ether was added to the reaction mixture and stirring was continued for an additional 30 minutes. A solid with a melting point of 143-144°C was collected by filtration. This was dissolved in 50 ml of 15% hydrochloric acid and heated to 80°C for 4 hours. Removal of the aqueous acid under reduced pressure gave the product as an oil which was identified by its NMR and IR spectra.

Example XVIII

This example describes the synthesis of an amine with

following formula:

2-(phenylaminocarbonylamino)ethylamine

The method of Example XXVII was repeated in all essential details to give the above compound, except that an equivalent amount of phenyl isocyanate was substituted for methyl isocyanate. The product had a melting point of 190.4°Ci.

Example XXIX"

This example describes the synthesis of an amine with the following formula:

1,1-dimethyl-2-(phenylsulfonylamino)ethylamine

To a:"mixture of 14.97 g (0.169 mol) 1,2-diamino-2-methylpropane in 300 ml chloroform and 80 ml pyridine was added 10 g (0.057 mol) benzenesulfonyl chloride at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and now brought to room temperature. The mixture was evaporated to dryness in vacuo and the residue partitioned between water and chloroform. Evaporation of the chloroform gave 10.3 g (79%) of semi-solid. The product was identified by NMR and IR -spectroscopy and elemental analysis.

Example XXXI

This example describes the synthesis of a compound of the following formula:

3-/ 1, l- dimethyl- 2-/"( 2- methoxy) ethoxycarbonylamino, 77ethylamino- 2-hydroxypropyl- 2- fluorobenzoate- oxalate

The method of Example II was repeated in all essential details to give the above compound except that an equivalent amount of 1,1-dimethyl-2-(2-methoxy)ethoxycarbonylamino)ethylamine was substituted for 1,1-dimethyl- The 2-(1-morph olinocarbonylamino)ethylamine The product, which was crystallized from ethyl acetate, had a melting point of 94-96°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example XXXII

This example describes the synthesis of a compound of the following formula:

3- 3 , l- dimethyl- 2- ( dimethylaminosulfonylaminol7ethylamino- 2-hydroxypropyl- 2- fluorobenzoate- oxalate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of 1,1-dimethyl-2-(dimethylaminosulfonylamino)ethylamine was substituted for 1,1-dimethyl-2-(1- morph olinocarbony lamino) the ethylamine. The product, which ... was crystallized from acetone-ethylamine/ had a melting point of 124-125°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example. XXXIII

This example describes the synthesis of a compound of the following formula:

3 -/ Xr l- dimethyl- 2-( l- morpholinocarbonylamino) J7ethylamino- 2-hydroxypropyl- benzoate- oxalate- hemihydrate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of benzoyl chloride was substituted for o-fluorobenzoyl chloride. The product, which was recrystallized from. ethyl acetate, had a melting point of 141-143°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example. XXXIV •

This example describes the synthesis of a connection with the following formula:

3-/ 1, l- dimethyl- 2-( 1- morpholinocarbonylamino) ./ ethyl lamino- 2-hydroxypropyl- 2- chlorobenzoate- oxalate

The method of Example II was repeated in all essential details to give the above compound, except that an equivalent amount of o-chlorobenzoyl chloride was substituted for o-fluorobenzoyl chloride. The product, which was recrystallized from isopropanol ether, had a melting point of 117-119°C and was identified by NMR and IR spectroscopy and elemental analysis.

Example XXXIX

This example describes the synthesis of an amine with the following formula:

1,1-dimethyl-2-(methoxyethoxycarbonylamino)ethylamine

To 10 g (62 mmol) of N,N'-carbonyldiimidazole in 100 ml of methylene chloride was. 4.7 g (62 mmol) of 2-methoxyethanol were added there. The reaction mixture was stirred at 25°C for 1 hour, and 10.9 g

(124 mmol) of 1,2-diamino-2-methylpropane was added. Stirring was continued for 18 hours and the reaction product was evaporated to dryness. The product was chromatographed on ki gel/EtOH:EtOAc (1:1)

to give 9.5 g (80.5%) product. NMR and IR were consistent with the intended structure.

Example XL

This example describes the synthesis of an amine with the following formula:

1,1-Dimethyl-2-/Dimethylamino)sulfonylamino_7ethylamine

A mixture of 30.7 g (0.35 mol) 1,2-diamino-2-methyl-propane, 150 ml of ether and 50 ml of triethylamine was cooled to 0°C,

and 20 g (0.14 mol) of dimethylsulfamoyl chloride was slowly added. The reaction mixture was stirred for: 30 minutes and evaporated

JD

dryness. The residue was mixed with water, basified with 1^CO., and evaporated to dryness. Acetone was added and the mixture filtered. Evaporation of the filtrate gave a solid which was recrystallized from toluene to give 16.5 g (60.3%) of product, mp 77-78°C. NMR and IR were consistent with the intended structure.

Example XLI

This example describes the synthesis of a compound of the following formula:

2-/"(Dimethylamino)sulfonylamino7ethylamino hydrochloride

A solution of 14.3 g (0.1 mol) dimethylsulfamoyl chloride in 50 ml methylene chloride was added dropwise to a rapidly stirred solution of 10.2 g (0.1 mol) acetylethylenediamine and 10.1 g (0.1 mol) triethylamine in 150 ml of methylene chloride at 25°C. After the addition was complete, the solution was stirred for 30 minutes and then washed in a separatory funnel with two portions of water on

100 ml. The organic phase was separated and dried over MgSO 4 and then concentrated under reduced pressure to give an N-(2/T(dimethylamino)sulfonylamino/ethyl7acetamide) as an oil. The N-acetyl group was then removed by treating the oil with 100 ml of 15%<*>s HCl at 80°C for 6 hours. This solution was concentrated under reduced pressure to give 12.6 g (73%) of product as an oil. The NMR spectrum was consistent with the proposed structure.

Example XLIII

- The method of Example II is repeated in all essential details to give the compounds specified in the following table, except that an equivalent amount of the reagent indicated in the first column is substituted for o-fluorobenzoyl chloride.

Claims (11)

1. Analogous method for the preparation of a compound having valuable pharmaceutical properties and the formula where Ar denotes a phenyl or naphthyl group which may be unsubstituted or substituted with one or more lower alkyl groups with 1-10 carbon atoms, alkenyl with 2-10 carbon atoms, alkynyl with 2-10 carbon atoms, alkoxy where the alkyl group contains 1-10 carbon atoms, halogen, acetamido, amino, nitro, alkylamino with 1-10 carbon atoms, hydroxy, hydroxyalkyl with 1-10 carbon atoms, cyano, aryl alkoxy where the alkyl group contains 1-6' carbon atoms and the aryl group denotes unsubstituted phenyl or phenyl which is substituted with halogen, methyl or one or two hydroxy groups, and groups of the formula, where R4 denotes lower alkyl, aryl or aralkyl and A is a direct bond, the alkylene with 1-10 carbon atoms or the alkenylene with 2-10 carbon atoms, W denotes the alkylene with 1-10 carbon atoms, and B denotes -NR2COR1, -NR2CONR1R3, -NR2SO2R1" - NR2SO2NR1R3 or -NR2COOR1 where R]_, R2 and R3, may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, cycloalkyl, alkenyl, alkynyl, phenyl, thiophenyl, imidazole, oxazole, indole or aralkyl, or when B is -NR2CONR1R3 or - NR2SO2NR1R3, R]_ and R3 together with N can form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine group, except that Rx cannot be hydrogen when B is -NR2SO2R1 or -NR2C00R1 as well as the pharmaceutical acceptable salts thereof, characterized in that an amine of the formula H2N-W-B is reacted with a compound of the formula 2. Analogous method as stated in claim 1 for the preparation of 3 [1,1-dimethyl-2-(aminocarbonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate with the formula characterized in that correspondingly substituted starting materials are used. 3. Analogous method as stated in claim 1 for the preparation of 3 [1,1-dimethyl-2-(methylcarbonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate with the formula characterized in that correspondingly substituted starting materials are used. 4. Analogous method as stated in claim 1 for the preparation of 3.[ 1,1-dimethyl-2-(isopropylcarbonylamino) ] ethylamino-2-hydroxypropyl-2-fluorobenzoate oxalate monohydrate with the formula characterized in that correspondingly substituted starting materials are used. 5. Analogous method as stated in claim 1 for the preparation of 3[1,1-dimethyl-2-(cyclohexylcarbonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate oxalate with the formula characterized in that correspondingly substituted starting materials are used. 6. Analogous method as stated in claim 1 for the preparation of 3[1,1-dimethyl-2-(benzylcarbonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate hydrochloride with the formula characterized in that correspondingly substituted starting materials are used. 7. Analogous method as stated in claim 1 for the preparation of 3[1,1-dimethyl-2-(phenylsulfonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate oxalate with the formula characterized in that correspondingly substituted starting materials are used. 8. Analogous method as stated in claim 1 for the preparation of 3[1,1-dimethyl-2-(ethoxycarbonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate hydrochloride with the formula characterized in that correspondingly substituted starting materials are used. 9. Analogous method as stated in claim 1 for the preparation of 3[1,1-dimethyl-2-(1-morpholinecarbonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate hydrochloride with the formula characterized in that correspondingly substituted starting materials are used. 10. Analogous method as stated in claim 1 for the preparation of 3[1,1-dimethyl-2-(phenylaminocarbonylamino)]ethylamino-2-hydroxypropyl-2-fluorobenzoate with the formula characterized in that correspondingly substituted starting materials are used. 11. Analogous method as stated in claim 1 for the preparation of 3 [1,1-dimethyl-2-[(2-methoxy)ethoxycarbonylamino]]ethylamino-2-hydroxypropyl-2-fluorobenzoate oxalate with the formula characterized in that correspondingly substituted starting materials are used.