NL8203214A - BLOOD PRESSURE REDUCERS. - Google Patents

Description

VO I VO 3657

Blood pressure-lowering drugs.

The invention relates to a series of new antihypertensive agents, preparations for their preparation, compositions containing them. unit doses of these compounds which may be used in human and veterinary practice as well as for treating patients with these compounds and preparations.

koinen Agree

The new compounds / of the formula I or the tautomeric forms thereof, wherein R represents a straight or branched chain, saturated or unsaturated aliphatic hydrocarbon group with 1 to 8 carbon atoms, mono- or bi-cyclic, carbocyclic aryl or aralkyl, wherein aryl is an al or unsubstituted phenyl or naphthyl group and the alkyl group of. the aralkyl group has 1 to 6 carbon atoms,

More specifically, H: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, or one of the isomeric pentyl groups, such as pentyl, isopentyl, tert-pentyl and neopentyl, or a of the isomeric hexyl groups e.g. neohexyl, 1,2,2-trimethyl-propyl or 1-ethyl-1-methylpropyl, then sheet one of the isomeric heptyl groups such as 1,1-diethylpropyl and 1,1,3-trimethylbutyl, then sheet the corresponding alkenyl groups, further While the present invention relates to phenyl, p-chlorophenyl, naphthyl, benzyl or phenethyl, the invention also relates to the pharmaceutically suitable salts of these compounds with strong inorganic or organic acids.

In particular, compounds of formula I, wherein R is a straight or branched chain alkyl group having from k-8 carbon atoms, are valuable for the purposes shown below.

If the subject compounds contain one or more asymmetric carbon atoms *, these compounds may exist in various stereoisomeric forms. The invention relates to all such stereoisomers and mixtures thereof,

The present compounds are basic bases but form highly acceptable salts with strong organic or inorganic acids, such as the hydrogen halides, 8203214 - 2 - sulfuric, nitric or methanesulfonic acids.

Previous publications, such as German Offenlegungs No. 2,557,338 or U.S. Patent No. U,057,636, have described the blood pressure lowering effect of certain 2, 3, or U-pyridyl cyanoguanidine. Further research on these compounds is published in the J. Med. Cbem. 21, 773 (1978).

Although these known compounds generally have a marked antihypertensive activity, the underlying compounds have been found to have certain advantages over these compounds. They are also strong antihypertensive agents, but are better suited to their pharmacokinetic properties. E.g. the blood pressure lowering activity is easier to control because the drop in blood pressure when administering the underlying compounds is more gradual than when administering the known compounds, while the effect is longer lasting.

The cause of this can in some cases be that the under-compounds under the influence of oxidoreductases are partly converted into the corresponding more active pyridyl compounds of the formula II and may therefore be used as prodrugs of the latter. bescbouvd.

This conversion is shown in the following table, which indicates the serum concentrations of yr "-cyano-11-1-oxido-if-pyridinio-N '-1,2,2-trimethyl-propylguanidine (P 1368) and N' T-cy aan-N-1-pyridyl-N '-1,2,2-trimethyipro-pylguanidine (P 113¾} after oral administration of 3 mg / kg P 1368 to dogs.

Table

Hours after application - Dog Ho.1 Dog ETo.2 diemng p p 113 ^ p 1368 P 113¾ 20, ng / cm3. ng / cm3 ng / cm3 ng / cm3 1 65 <5 52 <5 2 330 ^ 5 297 238 3. 22¾ 15 ¾57 1070

3 201 3 ^ 8 579 100Q

35 5 2 ^ 5 851 512 1015 8203214 .., · ...... ..................... ... ...... . .

* - 3 -

Tat (el) 6 288.8l6 46o - 748 7 279 747 357 630 8 271 659 281 438 5 24 126 96 10.4 £ 5

A corresponding in vivo conversion of P 1368 to P 1134 has been observed in human volunteers,

The new underlying compounds are not very toxic and have been found to have a strong and prolonged anti-hypertensive effect on various animal species when administered enterally or parenterally, without other pharmacodynamic effects being observed. These compounds are believed to have a blood pressure lowering effect on the peripheral blood vessels, either on their own or after biological conversion to the corresponding pyridyl analogs with Formula 2.

Surprisingly, it has thus been found that the underlying compounds have a very favorable therapeutic index, both in enteral and parenteral administration, improve a condition of high blood pressure and are well tolerated, while the first trials also do not reveal adverse side effects.

The invention also relates to a process for the preparation of the underlying compounds by oxidation of a compound of the formula 2 to a compound of the formula 1 according to reaction scheme A of the formula sheet, wherein R is the above meaning trembles.

The oxidation process can be carried out according to methods known per se. For example, inorganic and organic peracids, such as perboric acid, peracetic acid, perbenzoic acid, m-chloroberbenzoic acid, perchloric acid, peroxymonovavel acid or persulfate can be mentioned as examples for oxidizing agents. Also molybdenum, tungsten, vanadium and manganese, cbromine and corresponding elements of this type of groups of the Periodic System in a bend or arc arc oxidation stage are useful as oxidizing or catalytic agents in the form of. can contain corresponding oxides or acids, but salts of this kind of acids.

The reaction is carried out in an appropriate solvent or reaction medium, e.g. an inert medium such as chloroform, for a sufficient time and at an appropriate temperature to carry out the desired reaction, usually at 0 - 30 ° C. According to a preferred embodiment, the peracids can also be used as solvents and thus be used in excess. In other cases, the oxidizing agent is used in equimolar or substantially equimolar amounts, which may be added portionwise during the reaction.

According to a suitable embodiment, the oxidation is carried out with perhydrol (30% hydrogen peroxide) in isopropanol as reaction medium using sodium tungstate as catalytic agent. In another embodiment, m-chloroperbenzoic acid as an oxidizing agent with e.g. chloroform, ethanol or isopropanol used as reaction medium. You can use a mixture of perhydrol and glacial acetic acid as the oxidizing agent and reaction medium. In a further embodiment, the oxidation can be carried out as electrolytic oxidation.

The starting materials of the formula II are known from Offenlegungsschrift 2,557, 38 and J. Med. Chem. 21, 773, 20 (1978).

In a further embodiment, the intermediates used in preparing compounds of the formula II described in Offenlegungsschrift 2,557,38 can be oxidized as described above, after which the corresponding N-oxides in the desired compounds can be the formula I according to the invention are converted according to methods described in Offenlegungsschrift 2,557.-38. The compounds of the formula I can be converted into their acid addition salts by customary methods.

In the above methods, a desired stereoisomer 30 can be obtained by using a corresponding isomer of the starting material in the preparation.

A racemate can also be used as the starting material, after which the resulting mixture can be subjected to a racemate cleavage, e.g. by crystallization of an appropriate salt with an optically active strong acid, as known per se.

8203214 ..- 5-

The invention relates to pharmaceutical formulations useful in treating excessive blood pressure and similar conditions.

These preparations can contain 0.1 - 99% of the compounds of the formula 1, mixed with organic or inorganic, solid or liquid carriers and / or auxiliaries, which are suitable for preparing various pharmaceutical forms for oral or enteral administration, including extended-stretch preparations.

The compositions may further contain other therapeutically active compounds used in the treatment of excessive blood pressure, and corresponding conditions, such as diuretics, reserpine, met-metbyldopa, and in particular β-adrenergic blocking agents.

The compositions of the invention may be presented in various pharmaceutical forms, such as tablets, pills, dragees, capsules, extended-stretch tablets, suspensions, suppositories, injection fluids containing the compounds of formula I or non-toxic salts .

In human therapy, the compounds and bun salts can only be administered to patients in single doses, each containing no less than 0.5 mg and at most 500 mg, most preferably 5-250 mg.

By the term "unit dose" is meant a single dose which can be administered to a patient and remains appropriately treated as a physically stable monocell by appropriate treatment, and each dose is either active material as such or a mixture thereof with solid or liquid pharmaceutical diluents or carriers.

In the form of dosing units, the compounds can be administered once or several times a day at appropriate intervals, depending on the patient's condition and according to a physician's prescription.

A further object of the invention is a choice of a daily dosage of the present compounds, which may be administered in such a way that the caring activity is achieved without side effects.

In human therapy, the present compounds and 8203214 * w - 6 - salts suitably can be administered to adults in a daily dose of 5 mg to 1000 mg, preferably 20 - 500 mg, calculated as free base, while in veterinary practice the daily doses are usually between 0.0T and lk mg / kg body weight.

The invention is further described by the following non-limiting examples.

Example I

N "-cyano-1T-1-oxido - ^ - pyridinio-N'-1,2,2-trimethylpropylguanidine ♦

A suspension of 10.0 g (^ 0 mmol) anhydrous H "-cyano-N-4-py-

* O

Ridyl-H'-1,2,2-trimethylpropylguanicLine in 60 cur isopropanol was stirred at 0 ° C while 31 g (160 mmol). 90% pure m-chloroperbenzoic acid was added, resulting in a clear solution within 5 minutes. la. The precipitate formed was filtered off at 0 ° C for 3 days. The filtrate was slowly evaporated to dryness in vacuo at 0 ° C. The resulting residue was stirred with 200 cm. Of ether, then the mixture was filtered and washed with ether, leaving the crude product. A further purification was obtained by stirring with 75 cm acetone and filtering.

The solid residue was selectively precipitated by solvation with excess 1 N hydrochloric acid and adjusting the pH to 1.3 by addition of solid sodium acetate.

The pure crystalline product was filtered off, washed with water and air dried.

Mp. 2 ^ 2 - 2i + 3 ° C (dec.}; IR (KBr): strong bands at 2180 cm-1 and at 1560 - 1620 cm "1.

The IMR spectrum ((CD ^ igSO) showed signals at S - 0.93 (s, 9Hj, 1.10 (d, J = 7 Hz, 3H.), 3.93 (q, J = 7 Hz, 1H ), 7.28 (bd, 2H), 7.10 (bs, 1H), 8.15 (bd, 2H), 9.50 (bs, 1H) ppm Tetramethylsilane was used as the internal standard.

30 This connection is. administered orally to conscious dogs, which had previously been made hypertensive by the method of Goldblatt et al. (J. Exp. Med. 59, 3 ^ 7 (193M), in doses of 3, -0 and 10, 0 mg / kg · The drop in blood pressure of h2 + + 12 mm mercury and 79 + 16 mm mercury (mean _ + SEM, 3 animals for each dose 1 was observed. The peak effect was observed for 3 hours after administration 8203214 ----- ------------ ·· -.------ ·· - 7 - -% relit and a blood pressure lowering effect was still present 8 hours after administration.

In dogs with normal blood pressure, 1.0 and 3.0 mg / kg of this compound, administered intravenously, resulted in a drop in blood blood pressure of resp. 15 + T mm of mercury and 28 + 9 mm of mercury. (mean + SEM; 3 animals for each dose). The strongest drop in blood pressure was observed 10 minutes after the administration. The blood pressure lowering effect disappeared 2 hours later.

- Example II

10 N "-cyano-H-1-oxi-pyridinio-K1-tert-pentylguanidine.

A suspension of 2.31 g (10-mmol) of N "-cyano-H-tert-pentyl-H'-h-pyridyl-guanidine in 13 cm 3 of ethanol was stirred at 0 ° C, while first 1.70 g of sodium bicarbonate ( 20 mmol) and then 3 85 g (20 mmol) of 90% pure m-chloroperbenzoic acid was added The slowly diluting suspension was kept at 0 ° C with stirring and left overnight in the refrigerator. was filtered off and washed with 10 ml of cold ethanol and ether, then it was stirred in 10 ml of water, filtered, washed with water and air dried to the crude product.

Selective precipitation by solvation in excess 1 Έ aqueous hydrochloric acid and adjusting the pH to 1.3 with sodium acetate afforded the pure crystalline compound, mp 247 ° C (dec.).

IE (KBr): absorption bands at 2170, 1620-160Q and 1550-60 cm ~ 1.

Example III

H-benzyl-H "-cyano-H, -1-oxido-U-pyridinio-guanidine.

1.0 µg (+ + mmol) Η-benzyl-H '' - cyano-ir-U-pyridylguanidine & slurried in 5 ml of ethanol. While stirring at 0 ° C, 675 mg (8 npol) of sodium bicarbonate and 1.5 µg (8 mmol) of 90% pure m-chloroperbenzoic acid were added. - Stir at 0 ° C for 10 hours and then leave for 3 days in the refrigerator, where the mixture is at approx.

-20 ° C was cooled to give a precipitate which was then filtered off. Washing with small amounts of cold ethanol and with ether gave the crude product. The pure crystalline substance was obtained by dissolving in an excess of 1 E hydrochloric acid, treating with carbon 35 and adjusting the pH to about 1.3 with solid sodium acetate, whereby an 8203214-8 selective precipitation of the N-oxide was reached.

IR ^ KBr): strong absorption bands at 2180, 161 + 0-30, and 1580 cm \

The HMR spectrum ((CD ^ JgSO) showed signals at $ = 1 +, 1 + 6 (bd, 2H), 7.29 (bd, 2H), 7.32 (s, 5H), 8.10 (bd , 2H), 8.18 (bt, 1H), 9.1 + 8 (bs, 1H) ppm Tetramethylsilane - was used as an internal standard.

Example IV

N "-cyano-N-1-ethyl-1-methylpropyl-N1 -1-oxido-1 + -pyridinio-guanidine.

2.1 + 5 g (10 mmol) of H "-cyano-N-1-ethyl-1-methylpropyl-N'-1 + -pyri-10-dylguanidine was suspended in 20 ml of isopropanol while stirring at 0 ° C; Then, at the same temperature, 81 + 0 mg (10 mmol) of sodium bicarbonate and 3.85 g (20 mmol) of 90% pure m-chloroperbenzoic acid was added. The suspension gradually thickened for a total of 1 h Stirred at 0 ° C, then placed in an ice box for 2 days. The crude product was filtered off and washed with small amounts of cold isopropanol and with ether. The further work-up of the residue was filtered by repeated 15 cm stirring water and 20 cm acetone with intermediate filtration, while a final washing was carried out with acetone and ether.

The pure crystalline compound was obtained by dissolving it in excess 1 N hydrochloric acid (25 cm 3) and adjusting the pH to about 1.5 with solid sodium acetate for a selective precipitation.

Mp. 229-30 ° C (dec. IE; KBr): strong absorption bands at 2165, 1610-1600 and 1565-1550 cm * 1.

25 Examples V-XXIV

In accordance with the method shown in Examples I or II but using compounds of the formula II, wherein R has the meaning shown in the table below, compounds of the formula I are obtained, wherein R shows the values shown in the table. Has 30 ticks.

8203214 - 9 -

Table Formula 1

Example __R _ Example ___R_.

V n-C3HT XV C (Me2) CHMe2 5 VI i-C3HT XVI CH (ffe) CH2CHMe2 VII nC ^ XVII CH (Et) CHMe2 VIII iC ^ XVIII CEt3 IX tC ^ XIX C (Me2) CH2CHife2 X n “e5SU 32 C (Me2) CH2CMe3 10. XI i-C5E1i XXI CH (Me) (GH2) 3CHMe2 XII neo-CgH ^ i XXII CgH, _ ΠΙΙ CHEtg XXIII p-Cl-CgE ^ - XIV C (Me2) (CE2} 2CE3 XXIV CgH ^ CEg-CHg-

Example XXV

Nn-cyaaa-E-1-oxi-pyridinio-K-1,2,2-trimethylpropyl-guanidine.

2.1; 5 g (10 mmol) anhydrous E "-cyano-1-pyridyl-1,1-1,2,2-trimethyl-3-methylpropylguanidine was suspended with 25 cm chloroform. With stirring at 0 ° 6 portions of 9% pure m-chloroperbenzoic acid were added thereto to a total of 2.50 g (13 mmol) and sheet in the course of 1 hour.

The mixture was navigated at 0 ° C overnight and evaporated to dryness in vacuo at 0 ° C. The residue obtained was triturated with three 25 ml portions of ether, decanted in between, then the crude product was filtered off and washed several more times with ether. This product was dissolved in 8 din glacial acetic acid by varying gently and then precipitated by adding 32 din water.

The pure compound was filtered off, washed with water and air dried.

Mp. 2U2-2 ^ 3 ° C (dec.).

Example XXVI

30 N "-cyano-K-1-ethyl-1 -methylpropy 1-N1 -1 -oxLdo-i-pyridinio-guani dine,

A solution of 2.5 g (10 mmol] N '- cyano-N-T-ethyl-1-methyl-propyl-E1-4-pyridylguanidine in 50 cur glacial acetic acid was stirred at 10 ° C while 5 cur 30% Hydrogen peroxide was added The mixture was heated to 60 ° C for 5 hours and evaporated to dryness in vacuo at 25 ° C. The pE 35 of the residue was made neutral by addition of an aqueous 8203214

44 V.

* r - - - -. ........... ........... “- 10 - solution of sodium carbonate and the crude product filtered off and washed with water.

A selective precipitation at pH 1.3 and recrystallization from aqueous acetic acid, carried out as in Example 1, gave the pure product with a melting point of 229-230 ° C (dec.).

Example XXVII-N-benzyl-N "-cyan-H-1 -oxy d-k-pyridine o-guani dine.

2.51 g (10 mmol) of N-benzyl-N, -1-cyano-N, -U-pyri <3ylguanidine was dissolved in 20 ml (20 mmol) of TN hydrochloric acid containing 200 mg of sodium-10 tungstate dihydrate. With stirring at 0 ° C, 2.0 cm 2 (20 mmol) of 30 # 's aqueous hydrogen peroxide was gradually added and the mixture was slowly brought to room temperature, the pH was adjusted to 1.5 for 6 hours, and the crude product was filtered off and washed with water. Recrystallization from aqueous acetic acid gave the pure compound which was identical to that of Example III.

Example XXVIII

H "-cyano-H-1-oxido-1-pyridinio-H, tert-pentylguanidine.

A suspension of 2.31 g (10 mmol) of N, - cyano-H-tert-pentyl-N'-pyridy-1-guanidine in 10 cm 3 of water was stirred at 0 ° C, while 3.60 g of potassium persulfate were added portionwise was added resulting in a thin suspension After 5 hours at 0 ° C, the mixture was allowed to warm to room temperature while stirring continued overnight.

The mixture was then cooled to 0 ° C and the crude product filtered off and washed with water. Selective precipitation at pH 1.3 and recrystallization from aqueous acetic acid gave the pure compound, which was identical to that of Example II.

Mp. 2kT ° C (dec.).

• Example XXIX • Capsule: 30 Manufacture of 100,000 capsules IP 1368 1,000 kg lactose 10,000 kg II polyvinylpyrrolidone 0.200 kg 35 water, demineralized 1,000 kg 8203214 - 11 - III silicon dioxide, colloidal 0.050 kg magnesium stearate 0.100 kg I was mixed in a planetary mixer , then I with II was just granulated. The wet mixture was passed through a sieve with 5 1.5 mm openings. After this, the moist granulate was dried in a smooth hed at 60 ° C. The dry granulate was then passed through a sieve with 0.8 mm openings, after which the resulting granulate was provided with the lubricants III.

This granulate was filled into b size 10 capsules weighing 113.5 mg of granulate per capsule, corresponding to 10 mg of P 1368 per capsule.

Example XXX Tablet

Manufacture of 100,000 tablets.

15 IP 1368 1,000 kg corn starch 2,250 kg lactose 10,825 kg II polyvinylpyrrolidone 0.300 kg 20 water, demineralized 1,500 kg III talc 0.500 kg magnesium stearate 0.075 kg silicon dioxide, colloidal 0.050 kg 25 The ingredients I were mixed in a planetary mixer, then I with II became wet granulated. This wet mixture was passed through a 1.5 mm orifice screen. This granulate was then dried in a smooth hed at 60 ° C. The dry granulate was then passed through a 0.8 mm orifice screen and endowed with the gfcLj-30 means III.

This granulate mixture was crushed into tablets of 0.150 g each with a tahleteer maehine.

Stamp size: 7 mm, round, flat tablets with rounded edge. Tahlet hardness: ^ -5 kg.

8203214

Claims (14)

1. Compounds of the formula (I), or the tautomeric forms thereof, in which R represents a straight or branched, saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms, or a mono- or bycyclic, carbocyclic aryl or aralkyl group -5, and its salts with appropriate zirconium- 2. A compound according to formula 1, characterized in that R is selected from the group of the straight or branched chain alkyl radicals having k-8 carbon atoms; and its salts. 3. A compound according to formula 1, characterized in that R is isobutyl. 10 represents butyl, tert-butyl, the isomeric and branched pentyl, hexyl, heptyl or octyl groups; as well as its salts. k. S'-cyano-Jr-1-oxd do-^ -pyridinio-N'-1,2,2-trimethylpropylguanidine and its salts. 5. R "-cyano-N-1-oxido - pyridinio-H 'tert-pentylguanidine and its salts, 6. R-Benzyl-N "-cyano-11'-T-oxido-pyridinio-guanidine and its salts. 7. H "-cyano-iT- (1-ethyl-1-methylpropyl-N'-1-oxi-do-k-pyridinoguanidine) and its salts. Process for preparing a compound of the formula 1 according to claim 1, characterized in that the compound of the formula 2 according to scheme A of the formula sheet is oxidized to a compound of the formula 1, with R above has a given meaning, which oxidation is carried out in an appropriate medium and for a sufficient time at an appropriate temperature for the purpose of carrying out this reaction, then the compound thus formed as recovered or in the form of a salt analog claim 1. Process according to claim 8, characterized in that as oxidizing agent a. inorganic or organic peracid is used. 30 10.,. Process according to claim 9, characterized in that perchloric acid, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perchloric acid, peroxiomonozavelic acid or persulfates as. oxidizing agents are used. 8 20 3 21 4 - ................................... - 13 - II. Process according to claim 9, characterized in that molybdenum, tungsten, vanadium, manganese or chromium are used as oxidizing agents in a high or the highest oxidation form. 12 * Process according to claim 8, characterized in that the oxidizing agent is also used as a reaction medium. Process according to claim 8, characterized in that perhydrol is used as the oxidizing agent together with isopropanol as reaction medium and sodium tungstate as catalyst. lU. Method according to claim 8, characterized in that the oxidation 10 is carried out in the form of an electrolytic oxidation. 15. A composition containing as active compound at least one compound of the formula 1 or a salt thereof, together with solid or liquid pharmaceutical carriers and / or excipients. 16. A composition according to claim 15, characterized in that it contains at least 0.1% of therapeutically active compound. IJ. A composition having at least one compound of the formula 1 or a salt thereof as the active compound, mixed with other therapeutic compounds used in the treatment of hypertension, as well as solid or liquid pharmaceutical carriers and / or excipients. Preparation according to claim 17, characterized in that a further 3-adrenergic blocking agent, a diuretic, cum, reserpine or o-methyl-dopa is present as a further therapeutic agent. 19. A method of treating patients suffering from hypertension, characterized in that a dose of one or more of the compounds of formula 1 or their salts is administered such that the desired effect is achieved without side effect . 20. Method according to claim 19, characterized in that a compound of formula 1 according to claim 1 is administered to adults in dosage units of not less than 0.5 mg and not more than 500 mg, most preferably 5 - 250 mg, calculated as free base with the formula 1. '8 20ΤΠ4'