ALLENYL AMINES

Abstract: The present invention relates to compounds which are allenyl amines, more specifically, β-ethenylidene-­ (substituted)ethanamines, possessing antihypertensive activity. They are prepared by a novel reaction of a protected N,N-bis-(trimethylsilyl)-4-methoxy-2-­ butynylamine compound with a metallo-organic compound, with subsequent removal of the silyl protecting groups to provide the desired compound.

Description: This invention relates to a process for preparing allenyl amines, and the intermediates useful for this process. More specifically, this invention relates to a process for preparing allenyl amines of the general formula wherein Het is furyl, pyridyl, thiazolyl, imidazolyl, pyrazolyl, benzo/b/thienyl or a thienyl moiety; n is the integer 0, 1 or 2; each X independently is a substituent selected from (C₁-C₆)alkyl, halo, -O-(C₁-C₆ )alkyl,-S-(C₁-C₆)alkyl, -SO-(C₁-C₆)alkyl,-SO₂-(C₁-C₆)alkyl,-CO₂R and -CH₂OR, wherein halo is chloro, bromo or fluoro and R is H or (C₁-C₆)alkyl, and the therapeutically-acceptable acid addition salts thereof. β-Methylene furanethanamines are described in EPA-186915 as possessing dopamine-β-hydroxylase (DBH)-inhibiting activity while β-methylenethiophenethaamines are described in EP-A-187390 for the same activity. The Het moieties, which can optionally be substituted with 1-2 substituents as defined by X, are illustrated as follows: wherein n and X are as above defined. Where n is 2, the X substituents on each Het group can be the same or different, although they preferably are the same. Preferably, n is O or 1. R is preferably H. The term "alkyl" in each occurrence means from to 1 to 6 carbon atoms, and includes methyl, ethyl, propyl, butyl, pentyl and hexyl groups, which can be straight- or branched-chain. Preferably, alkyl groups of from 1 to 4 carbon atoms are employed. The following represent preferred embodiments of the compounds prepared by the process of invention: (1) n is 0 or (2) a is 1, (3) n is 2; (4) n is 1 and X is selected from the group consisting of halo and (C₁-C₆)alkyl; thienyl (5) the embodiment of (4) wherein Het is thienyl or benzo[b]thienyl; (6) the embodiment of (2) wherein X is -O- or -S-(C₁-C₆)alkyl; (7) the embodiment of (2) wherein X is -CO₂R; (8) the embodiment of (2) wherein X is -CH₂OR; (9) the embodiment of (1) wherein Het is thienyl; (10) the embodiment of (2) wherein X is alkyl of from 1 to 4 carbon atoms, and (11) the embodiment of (1) wherein Het is benzo[b]thienyl. Illustrative examples of the compounds prepared by the process of this invention include β-ethenylidene-2-thiopheneethanamine,β-ethenylidene-2-furaneethanamine, β-ethenylidene-2-benzo-[b]thiophene-ethanamine; β-ethenylidene-2-pyridineethanamine, β-ethenylidene-2-thiazoleethanamine, β-ethenylidene2-imidazoleethanamine,β-ethenylidene-3-pyrazoleethanamine β-ethenylidene-5-chloro-2-thiopheneethanamine, β-ethenylidene-5-methoxy-2-thiopheneethanamine, β-ethenylidene-5-carboxy-2-thiopheneethanamine, β-ethenylidene-5-methylsulfinyl-2-thiopheneethanamine, β-ethenylidene-5-methyl-2-furanethanamine, β-ethenylidene-3-bromo-2-benzo[b]thiopheneethanamine, β-ethenylidene-5-bromo-2-benzo[b]thiopheneethanamine, β-ethenylidene-3,5-dibromo-2-benzo[b]thiopheneethanamine, β-ethenylidene-5-chloro-2-pyridineethanamine, β-ethenylidene-5-methyl-2-thiazoleethanamine, β-ethenylidene-5-methoxy-2-imidazoleethanamine and β-ethenylidene-5-chloro-2-pyrazoleethanamine and the therapeutically acceptable acid addition salts thereof. Representative salts are those salts formed with nontoxic organic or inorganic acids, such as, for example, those formed from the following acids: hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, itaconic and benzenesulfonic. The process of the invention allows the ready preparation of the allenyl amines (I) by-a series of reaction steps which are illustrated by the following reaction scheme: In essence, the foregoing reaction scheme shows that the allenyl amines (I) are prepared by the novel reaction of a protected amine, N,N-bis(trimethylsilyl)-4-alkoxy-2-butynylamine (III), with a metallo-organic compound of formula (IV) wherein Het, X and n are as defined above and M is a metal containing moiety, such as for example, -MgBr, a trimethylstannyl or a tri-n-butylstannyl group. In formula III, R′ is an alkoxymethyl group of 1-4 carbon atoms, and is preferably methoxymethyl. The reaction is carried out in an inert solvent, such as diethylether, at room temperature in the presence of a nickel catalyst, such as 1,3-bis(diphenylphosphinopropane)-nickel(II)chloride [henceforth NiCl₂(dppp)], to yield the silyl-protected amines (III). The reaction product is then treated with a deprotecting agent, e.g., such as ammonium hydroxide and silica gel (column chromatography), or ethanolic hydrochloric acid or sodium fluoride, to remove the silyl protecting groups and give the desired product (I). The free bases can be converted into acid addition salts, or the acid addition salts can be converted into the free bases by conventional chemical methodology. The trimethylsilyl starting material (III) is prepared by the addition of ethylmagnesium bromide to a mixture of methylpropargyl ether (II) and tetrahydrofuran (THF), after which N,N-bis(trimethylsilyl) methoxymethylamine is added. After dilution with ether, filtration through celite and washing with sodium hydroxide, Kugelrohr distillation yields bis(trimethylsilyl) protected 4-methoxy-2-butynylamine (III). When the metallo-organic starting compound in the above reaction is a Grignard reagent, it is obtained by converting the appropriate brominated heterocycle (see Het above), for example, 2-bromothiophene, by reactions with magnesium according to standard Grignard conditions to yield, 2-thienylmagnesium bromide; or by converting the appropriate lithiated heterocycle, for example 2-benzo[b]thienyllithium lithium, with magnesium bromide to yield, 2-benzo[b]thienylmagnesium bromide according to standard Grignard conditions. When M in the above reaction is a tin derivative, it can be obtained in a manner consistent with the procedure of T. Bailey, Tetrahedron Letters , 27, 37, 4407 (1986). The foregoing reaction scheme is further illustrated by the following specific exemplifications. EXAMPLE 1 N,N-bis(trimethylsilyl) 4-methoxy-2 butynylamine (III) Methylpropargyl ether (36.4g,0.52M) and dry tetrahydrofuran (300 ml) were added to a dry 100 ml 3-necked flask with mechanical stirrer, thermometer, and addition funnel with a nitrogen bubbler. The solution was cooled in an ice bath and ethylmagnesium bromide (262 ml, 0.52M) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 10 minutes and N,N-bis(trimethylsilyl) methoxymethylamine was added. The reaction mixture was heated at reflux for 16 hours until complete by C G analysis. The thick slurry was diluted with ether, filtered through a celite pad and the filtrate washed with 1 liter 30% NaOH. The product was dried over K₂CO₃/Na₂SO₄ and concentrated into an oil. Kugelrohr distillation at 80°C (2 mmHg) gave 91 g. (77%) of III. EXAMPLE 2 β-Ethenylidene-2-thiopheneethanamine NiCl₂ (dppp) catalyst (170 mg; 3M %) was added to dry ether (30 ml) in a 100 ml 3-necked flask with mechanical stirrer, thermometer and nitrogen bubbler. III (2.47g, 10.2 mM) was added via syringe with stirring and immediately thereafter 3M 2-thienylmagnesium bromide (7 ml, 21 mM) was added via syringe. After stirring at room temperature for 20 hours the reaction was complete as shown by C G Analysis. The silylated product was isolated by shaking with dilute NH₄OH and extraction into ethylacetate (three times, each into 100 ml). After drying over K₂CO₃ and concentration, 2.68 g crude product was obtained. Purification and desilylation by flash chromatography (300 g silica gel, eluted with CHCl₃, then CHCl₃:MeOH:conc. NH₄OH 100:10:1) gave 1.22 g (87%) of the desired product as a light tan oil after drying under high vacuum. Treatment of an etheral solution of the free base with one equivalent of 1M ethanolic p-toluenesulfonic acid or with one equivalent of an ethanolic solution of oxalic acid gave the tosylate and oxalate salts respectively. The tosylate salt was a 76% conversion from the free base, Mp 126-127°C (isopropanol). The oxalate salt was a 72% conversion from the free base, Mp 188-190°C (isopropanol). Anal. Calc'd for C₈H₉NS: C, 55.71; H, 5.30; N, 5.30. Found: C, 55.75; H,5.44; N, 4.28. EXAMPLE 3 β-Ethenylidene-2-benzo[b]thiophene-ethanamine 2-Benzo[b]thienylmagnesium bromide was prepared by adding butyllithium (5.1 ml, 15.8 mM) to benzo[b]thiophene (1.7 g., 12.7 mM) in a 3-necked, 100 ml flask with septum stir bar, thermometer, and nitrogen inlet, in the presence of ether (15 ml), allowing reaction to reflux about 15 minutes, and then cooling to 0°C in ice. Magnesium bromide etherate (12.7 mM) was added all at once and was allowed to warm to 20°C over about 15 minutes. Then NiCl₂(dppp) (30 mg) was added and, following the procedure described in Example 2, III (12.7 mM) was added and stirred overnight to produce the crude silylated product, the reaction being complete by G C analysis after that time. 1M ethanolic hydrochloride (0.9 equivalent), was added to the etheral solution to yield 1.7 g (72%) of the desired product as a pale yellow solid, Mp 235°C (dec.) (EtOH). Anal . Calc'd for C₁₂H₁₁NS.HCl: C, 60.63; H, 5.09; N, 5.89. Found: C, 60.86; H, 5.21; N, 5.65. The allenylamines obtained by the process of this invention (I) are dopamine-β-hydroxylase (DBH) inhibitors of a mechanism-based nature, inactivation being time dependent. The enzyme is inactivated directly, i.e., at the active site and thus the compounds of formula I are useful as therapeutic agents in the treatment of hypertension. An embodiment if this invention thus comprises a process for producing a medicament for antihypertensive use which comprises preparing a compound of formula (I) by the process of this invention and then mixing said compound with a pharmaceutically acceptable carrier. The DBH inhibitory properties of the compounds obtained by the process of this invention can readily be determined by standard and well known procedures such as those procedures set forth in U.S. Patent 4,415,591. Determination of whether the DBH inhibition demonstrates time-dependent kinetics is exemplified by a procedure wherein enzymatic oxygenation by DBH is determined in aqueous solution in the presence of molecular oxygen, an electron donor such as ascorbate, and the necessary cofactors for the enzyme at a pH of 4.5 to 5.5, preferably pH 5.0, and at a temperature of 20°C to 40°C, preferably 37°C. The test compound is added at the desired concentration, and the system is incubated. At different time intervals aliquots are taken and DBH activity is measured using tyramine as the substrate. The reaction is followed by measuring oxygen uptake using a polarographic electrode and an oxygen monitor by the method of S. May et al., J. Biol. Chem. 256, 2258 (1981). In tests utilizing the above described procedure, the DBH inhibitory activity of the test compound increased as a function of the time of incubation as indicated in Table I: The ability of compounds obtained by the process of this invention to lower blood pressure can be determined in vivo using hypertensive rats according to standard and well known procedures. The test compound is administered intraperitoneally (ip) to conscious rats and the blood pressure monitored continuously. Since DBH is a major enzyme in the synthetic pathway of the catecholamines, it would be expected that the presence of an inhibitor would act to decrease the amount of catecholamines produced, and thereby have an antihypertensive effect. When tested for antihypertensive activity in the above manner, a decrease in mean blood pressure for a period of time was as indicated for the test compound, as set forth in Table II: Thus, based upon this and other standard laboratory techniques known to evaluate DBH inhibitors, by standard toxicity tests and by standard pharmacological assays for the determination of antihypertensive activity in mammals, and by comparison of these results with known antihypertensive agents the effective antihypertensive the process dosage of the compounds obtained by the process of this invention can readily be determined. In general, the effective antihypertensive results can be achieved at a dose of about 5 to about 100 mg per kilogram of body weight per day. Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the hypertension as determined by the attending diagnostician. In their function as therapeutically useful compounds, it is advantageous to administer the compounds to the host animal as a composition in admixture with a pharmaceutically acceptable carrier suitable for internal administration, said carrier constituting a major portion of the admixture. Such preparations will be apparent to those skilled in the art and may be in such forms as, for example, tablets, capsules and suppositories, or in liquid forms, as for example, elixirs, emulsions, sprays and injectables. In the formulation of pharmaceutical preparations there can be employed such substances which do not react with active substances as, for example, water, gelatin, lactose, starches, magnesium sterate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly and the like. The active ingredient of such pharmaceutical preparations is preferably present in the preparation in such proportions by weight that the proportion by weight of the active ingredient to be administered lies between 0.1% and 50%.

Claims: A process for preparing a compound of the general formula wherein Het is a furyl, pyridyl, thiazolyl, imidazolyl, pyrazolyl,benzo[b]thienyl or a thienyl moiety; n is the integer 0, 1 or 2; each X independently is a substituent selected from (C₁-C₆)alkyl, chloro-, bromo-, fluoro-, -O-(C₁-C₆)alkyl, -S-(C₁-C₆)alkyl, -SO-(C₁-C₆)alkyl, -SO₂-(C₁-C₆)alkyl, -CO₂R and -CH₂OR wherein R is hydrogen or (C₁-C₆)alkyl, and the therapeutically acceptable acid addition salts thereof, which comprises reacting a protected amine compound of the general formula R'C≡CCH₂N(SiMe₃)₂ (III) wherein R' is a (C₁-C₄)alkoxymethyl group, with a metallo-organic compound of the general formula wherein Het, X, and n are as above defined, and M is a metal containing moiety, in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A process according to Claim 1 for preparing a compound of the genaral formula wherein Het is as defined in Claim 1, which comprises reacting a protected amine compound of the general formula R'C≡CH₂N(SiMe₃)₂ with a metallo-organic compound of the general formula Het-M wherein Het is as above defined, R' is a (C₁-C₄)alkoxymethyl group and M is a metal containing moiety, in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A process according to Claim 1 for preparing a compound of the general formula wherein X and Het are as defined in Claim 1, which comprises reacting a protected amine compound of the general formula R'C≡CCH₂N(SiMe₃)₂ with a metallo-organic compound of the general formula wherein X and Het are, as above defined, R' is a (C₁-C₄)alkoxymethyl group and M is a metal containing moiety, in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A process according to Claim 1 for preparing a compound of the general formula wherein X is selected from the group consisting of chloro-, bromo-, fluoro- and (C₁-C₆)alkyl, and Het is as defined in Claim 1, which comprises reacting a protected amine compound of general formula R'C≡CCH₂N(SiMe₃)₂ with a metallo-organic compound of the genaral formula wherein X and Het are as above defined, R'is a (C₁-C₄)alkoxymethyl group and M is a metal containing moiety in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A process according to Claim 1 for preparing a compound of the general formula wherein X is -O-(C₁-C₆)alkyl, or -S-(C₁-C₆)alkyl, and Het is as defined in Claim 1, which comprises reacting a protected amine compound of the general formula R'C≡CCH₂N(SiMe₃)₂ with a metallo-organic compound of the general formula wherein X and Het are as above defined R' is a (C₁-C₄)alkoxymethyl group and M is a metal containing moiety, in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A process according to Claim 1 for preparing a compound of the general formula wherein X is -CO₂R or -CH₂OR and R and Het are as defined in Claim 1, which comprises reacting a protected amine compound of the general formula R'C≡CCH₂N(SiMe₃)₂ with a metallo-organic compound of the general formula wherein X and Het are as above defined, R' is a (C₁-C₄)alkoxymethyl group and M is a metal containing moiety, in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A prccess according to Claim 1 for preparing ß- ethenylidene-2-thiopheneethanamine which comprises reacting N,N-bis(trimethylsilyl) 4-methoxy-2-butynylamine with 2-thienylmagnesium bromide in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A process according to Claim 1 for preparing β-ethenylidene-2-benzo[b]thiopheneethanamine which comprises reacting N,N-bis(trimethylsilyl) 4-methoxy-2-butynylamine with 2-benzo[b]thienylmagnesium bromide in the presence of an inert solvent and a nickel catalyst, and further treating the resulting product bearing a silyl protected amine group with a deprotecting agent. A process for producing a medicament for antihypertensive use which comprises preparing a compound of the formula(I) by the process according to any of claims 1 to 8 and then mixing said compound with a pharmaceutically acceptable carrier.

Inventors: BARGAR, THOMAS M., BARNEY, CHARLOTTE L., BROERSMA, ROBERT J., MATTHEWS, DONALD P., MCCARTHY, JAMES R.
Applicants: MERRELL DOW PHARMACEUTICALS INC.
Application year: 1987
Main classification: C07D333
IPC codes: A61K31, C07D333, C07D277, A61P9, C07D213, C07D233, C07D307, C07D231