HU176621B - Process for preparing new omega-amino-alkoxyalkanes and pharmaceutically acceptable salts thereof - Google Patents

Abstract

This invention relates to novel omega-aminoalkoxyalkanes. The compounds of the invention are compounds of the general formula: </ P>

Description

The present invention relates to novel ω-aminoalkoxyalkanes and their pharmaceutically acceptable salts.

No. 3,254,083. U.S. Pat. No. 4,198,125 describes a process for the preparation of 1-arylalkylcyclohexane esters by reacting substituted 1-phenyl or 1-benzylcycloalkanol with an alkyl halide.

The novel compounds are characterized by the general formula I wherein

R ¹ and R ^{2 are the} same or different C 1-6 alkyl groups,

R ^{3 is} cyclohexyl or phenyl optionally substituted with C 1-4 alkyl or halogen,

R ^{4 is} hydrogen or C 1-3 alkyl, R ⁵ and R ^{6 are the} same or different C 1-3 alkyl, n is 2,3 or 4 and m is 0,1,2,3 or 4.

R ¹ and R ² groups are preferably straight chain alkyl groups. Alkyl groups are preferably C 1 -C 6 groups such as methyl, ethyl, n-propyl, i-propyl, butyl, e.g. n-butyl or tert-butyl, pentyl such as π-pentyl, tert.-pentyl or neopentyl and hexyl such as η-hexyl or isohexyl. It is particularly preferred that R ¹ and R ^{2 have from} 1 to 4 carbon atoms, especially when R ¹ and R ² together contain 5.6 or 7 carbon atoms, such combinations being, for example, ethyl / propyl, ethyl / pentyl, and especially propyl / propyl. . R ^{3 is} phenyl or naphthyl, preferably phenyl. Cyclo2 is pentyl and hexyl and aryl, naphthyl and phenyl with halogen, e.g. they may be substituted by bromine or iodine, preferably fluorine or chlorine, or by a C 1-4 alkyl group, preferably a methyl or ethyl group. The substituents are preferably attached to the aromatic group in the 4 or para position.

When R ⁴ is alkyl, it is preferably unbranched and contains from 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl or isopropyl. R ⁵ and R ⁶ include methyl, ethyl, η-propyl, isopropyl, butyl, such as n-butyl or tert-butyl, pentyl, such as n-pentyl, tert-pentyl or neopentyl, hexyl - or n-hexyl or isohexyl.

R ⁵ and R ^{6 are} preferably C 1-4 alkyl, especially methyl, m is preferably 0, 1 or 2, especially 0 and n is preferably 2 or 3, preferably 3.

The compounds of formula I can be prepared by known methods. Compounds of formula I may be prepared, for example, from a compound of formula II wherein R ¹ , R ² , R ³ , R ⁴ , m and n are as defined above and X is a leaving group, preferably a sulfonyloxy group or a halogen with a secondary amine of formula III. or with an acid addition salt thereof, wherein R ⁵ and R ⁶ are as defined above.

The complete synthesis is illustrated in Scheme 1. The synthesis consists of the following reaction steps:

Step 1: Reagents are heated to reflux in a suitable solvent such as dry benzene and a small amount of a strong acid such as toluene.

sulfonic acid until the calculated amount of water is liberated.

Step 2: The Grignard compound is prepared in the usual manner from the corresponding halogen compound and magnesium in dry ether and then reacted with the cyclic ketal of the alkanone. For example, the resulting compound is quenched with aqueous ammonium chloride solution and the reaction mixture is extracted with an organic solvent and the desired ω-hydroxyalkoxyalkane is isolated from the organic phase.

Step 3: The hydroxy group of the ω-hydroxyalkoxyalkane obtained in the previous step is protected by a leaving group, which may be an ether, ester or halogen. Sulfonyloxy groups such as methylsulfonyloxy or p-toluenesulfonyloxy groups are preferably used as leaving groups, but other leaving groups such as chlorine, bromine or iodine are also suitable. The ω-hydroxyalkoxyalkane is dissolved in a suitable solvent, such as dry pyridine, and then, for example, tosyl chloride is added at low temperature. The reaction mixture was allowed to stand at this temperature for a while.

Step 4: The resulting sulfonyl ester or other compound in which the sulfonyl group is replaced by another leaving group is heated under reflux in a suitable solvent such as dry toluene.

The compounds of Formula I may also be prepared by reacting a compound of Formula IV wherein R ¹ , R ² , R ³ and R ⁴ are as defined above and R is hydroxy with a compound of Formula V or an acid addition salt thereof, wherein R ⁵ , R ⁶ and n are as defined above and Y is halogen.

Preferably, a compound of formula IV wherein R is hydroxy is reacted with a compound of formula V wherein Y is halogen.

Prior to reaction with the compound of formula V, the compound of formula IV, wherein R is hydroxy, is preferably converted into a salt, preferably an alkali metal salt thereof, by reaction with a base such as sodium hydroxide, potassium hydroxide or especially sodium amide. The salt does not need to be isolated.

The starting material of Formula IV can be quite readily prepared by the Grignard reaction known from the ketone starting material in the Scheme, by reacting the ketone with HalMg (CH 2) _m CHR ³ R ⁴ - where Hal is halogen, and then the resulting alcohol is halogenated.

Pharmaceutically acceptable salts of the compounds of formula I include acid addition salts obtained by reacting the free base of the formula with an organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, citric acid, ascorbic acid, malonic acid, succinic acid, fumaric acid or tartaric acid. The compound of formula I is usually dissolved in its free base in alcohol and added to an alcoholic hot solution of the acid of interest.

Preferably, hydrochlorides, hydrobromides, tartrates or fumarates are prepared. Hydrogen fumarates are particularly preferred.

The compounds of the present invention have significant vasodilator activity.

They have very low toxicity and side effects that usually accompany coronary and / or peripheral vasodilator effects such as the indotropic effects, the blood pressure lowering effect, the heart rate changing effect, surprisingly mild. They also show antispasmodic and antithrombotic effects.

Effect of ω-Amino-alkoxyalkanes on the Heart and Circulation of Narcotic Dogs

Male and female mongrels weighing 8-15 kg were used for the experiment, and the dogs were kept awake 16 hours prior to the experiment. Dogs were dosed with 75 mg / kg α-chloralose and 750 mg / kg urethane i. v. narcotized.

The femoral artery and femoral vein of the two hind limbs were excised for blood pressure measurement and for insertion of a catheter and PVC tube.

Test compounds were injected slowly in 0.9% saline over 30 seconds. The volume injected corresponds to half the body weight. Allow at least 40 minutes between dosages. The substances were tested at doses of 1 and 3 mg / kg.

Arterial blood pressure was measured with a Statham P 23 Db pressure gauge attached to the right femoral artery and connected to an electrometer. The catheter-manometer signal was differentiated to measure the rate of pressure increase. At the time of maximum effect, the diastolic blood pressure was dp / dt _max .

Statistical evaluation

From the absolute and relative values, we calculated the mean x and the mean error value (s;).

In a control experiment, the administration of 0.9% saline did not cause a notable change in the above parameters. Thus, the changes listed in Tables 1 and 2 refer to the immediate baseline values prior to application of the substance and are relative to all doses of Bencyclan = 100%.

Table 1

Diastolic blood pressure reduction in narcotic dogs

Material number Decrease in diastolic blood pressure (rel.%) 1 mg / kg dose 3 mg / kg dose B ¹ 100 ± 39 100 ± 22 (115% at 1 mg / kg) First 140 ± 22 142 ± 5 Second 133 ± 34 254 ± 17 4th 163 ± 14 276 ± 20 5th 128 ± 31 250 ± 31 6th 165 ± 43 268 ± 59 7th 165 ± 41 _2 9th 115 ± 13 170 ± 20 10th 158 ± 13 260 ± 22

¹ = B = Bencyclan as reference ² = 3 mg / kg was not measured

The data listed in Tables 1 and 2 show that aminoalkoxyalkanes have a stronger diastolic blood pressure lowering effect and a stronger positive inotropic effect (dp / dt ^) than the comparator Bencyclan.

Table 2

Increase in pressure increase rate (dp / dt _max ) in narcotic dogs

Pressure increase rate (rel.%)

number 1 mg / kg dose 3 mg / kg dose B ¹ 100 ± 15 100 ± 13 (ie 184% of 1 mg / kg) 1 184 ± 15 165 ± 20 Second 157 ± 32 101 ± 22 Third 143 ± 28 114 ± 23 4th 100 ± 20 _2 5th 187 ± 51 123 ± 26 6th 171 ± 70 117 ± 54 7th 134 ± 61 _2 8th 146 ± 11 169 ± 20 9th 128 ± 17 101 ± 13 10th 209 ± 49 150 ± 42

¹ = B = Bencyclan as reference ² = 3 mg / kg was not measured

Particularly noteworthy is the strong reduction in diastolic blood pressure, given that the comparator increases the reduction in blood pressure only from 100% to 115% at a dose increase of 1 to 3 mg / kg, whereas the test compounds increase at 115 mg to 165 mg / kg. % pressure drop. From this, the superior antihypertensive properties and the circulatory properties of the compounds can be deduced.

The compounds listed in the table have the following chemical structure:

The compounds of the present invention may be formulated in conventional manner into liquid or solid pharmaceutical compositions such as dragees, tablets, suppositories, and solutions for injection.

For this purpose, conventional carriers and diluents are used.

The oral dosage unit is 0.5 to 50 mg / kg and the daily oral dose is 1.5 to 150 mg / kg. The parenteral unit dose is 0.1 to 5 mg / kg and the parenteral daily dose is 0.3 to 15 mg / kg.

Hydrogen fumarate of the compound of formula I

Compound number R ¹ R ^! m n R ⁴ R · R ' R · First n-Pr nPr- 0 3 H ph CH ₃ - ch ₃ - Second n-Hexyl Me- 0 3 H CH, Ph ch ₃ - ch ₃ - Third isoamyl Me- 0 3 H ph ch ₃ - ch ₃ - 4th n-Bu Me- 0 3 H CH ₃ Ph— ch ₃ - ch ₃ - 5th i-Bu iBu- 0 3 H ph ch ₃ - ch ₃ - 6th i-Bu Me- 0 3 H cyclohexyl- ch ₃ - ch ₃ - 7th n-Bu @n Bu- 1 3 H ph ch ₃ - ch ₃ - 8th i-He- Me- 0 3 H ph ch ₃ - ch ₃ - 9th n-Pr Me- 0 2 H CH-Ph- ch ₃ - ch ₃ - 10th n-PE Et 0 3 H cyclohexyl- . CH ₃ - ch ₃ -

Preferably, compounds of formula I are prepared wherein

R ¹ and R ^{2 have a} total of 5, 6 or 7 carbon atoms,

R ^{3 is} phenyl optionally substituted with halo or 50 methyl,

R ^{4 is} hydrogen,

R ⁵ and R ⁶ is methyl, n is 2 or 3 and m is 0, 55

In order to avoid the creation of centers of asymmetry (leading optical isomer mixture), a compound of formula I wherein R ¹ and R ² are the same alkyl group such as propyl.

Particularly good compounds are those wherein R ¹ and R ^{2 are} 60 propyl. R ^{3 is} phenyl, p-tolyl or p-fluorophenyl, R ^{4 is} hydrogen, R ⁵ and R ^{6 are} methyl, n 2 or 3, and m is 0.

The following examples illustrate the invention. 65

Example 1

a) 1-Phenyl-2- (3'-toluenesulfonyloxy-n-propoxy) -2-n-propylpentane

Dissolve 0.2 mol of 1-phenyl-2- (3'-hydroxy-n-propoxy) -2-n-propylpentane (η 4 = 1.5017, boiling point: 0.3 ° C, 0.3 ° C) in 200 ml of pyridine. and 0.2 mole of 4-toluenesulfonyl chloride was added at 0 ° C. The reaction mixture was kept at 0-5 ° C overnight and then poured onto 500 g of ice. The oily substance which precipitates is extracted 3 times with 100 ml portions of chloroform and the combined chloroform extracts are washed with 5 x 200 ml water. After drying over calcium chloride, the solution is evaporated to dryness in a water bath at a temperature not exceeding 50 ° C. The oily residue contains 1-phenyl-2- (3'-toluenesulfonyloxy-n-propoxy) -2-n-propylpentane in almost quantitative yield. Can be used in the next step without further treatment.

b) 1-Phenyl-2- (3'-dimethylamino-n-propoxy) -2-n-propyl-n-propyl-n-pentane

0.1 M 1-Phenyl-2- (3'-toluenesulfonyloxy-n-propoxy) -2-n-propyl-n-pentane was refluxed with 0.25 M dimethylamine in 50 mL dry toluene for 2 hours. After cooling, the reaction mixture is washed with 3 x 50 ml portions of water, the organic phase is evaporated to dryness and the residue is distilled under vacuum.

The resulting 1-phenyl-2- (3'-dimethylamino-n-propoxy) -2-n-; -propyl-n-pentane distils at 134 ° C and 0.6 torr, = 1.4958.

The equimolar amount of the fumaric acid salt in alcohol is precipitated with ether after the volume of the solution is reduced by evaporation.

The hydrogen fumarate salt has a melting point of 68-70 ° C. Total amine synthesis and salt formation: 77%.

Example 2

In the same manner as in Example 1, the following compounds were prepared:

R ' R ^J n m í R ³ | R ^{4 5} / R · fp. ° C / torr n ^{20 n} D production % hydrogen fwnarate op. C ethyl- pentyl 3 0 phenyl H methyl- 137 / 0.4 1.4917 83 65-61 propyl propyl 3 0 p-tolyl H methyl- 120-127 / 0.1 1.4948 82 89-90 ethyl- pentyl 3 0 p-tolyl H methyl- 138 / 0.1 1.4940 76 64-69 ethyl- pentyl 3 0 p-F-phenyl H methyl- 138 / 0.1 1.4830 77 78-80 propyl propyl 3 1 phenyl H methyl- 125-130 / .05 1.4950 44 78-79 ethyl- pentyl 2 1 phenyl H methyl- 130 / 0.03 1.4955 34 83-86

Example 3

The following compounds were prepared as described in Example 1:

R ¹ R * R * n m R ' R ⁵ / R " Op. Of salt ° C First methyl- butyl p-tolyl 2 0 H ch ₃ ~ 72-73 Second butyl butyl p-fluorophenyl 3 0 H ch ₃ - 90-91 Third hexyl methyl- phenyl 3 0 H ch ₃ - 65-66 4th hexyl methyl- p-tolyl 3 0 H ch ₃ - 96-97 5th hexyl methyl- p-fluorophenyl 3 0 H ch ₃ - 84-85 6th amyl methyl- phenyl 3 0 H ch ₃ - 100-101 7th amyl methyl- p-tolyl 3 0 H ch ₃ - 97-98 8th amyl methyl- p-fluorophenyl 3 0 H CHj- 100-102 9th methyl- amyl phenyl 3 1 H ch ₃ - 75-77 10th propyl methyl- phenyl 3 0 H ch ₃ - 82-86 11th pentyl ethyl- phenyl 3 1 ch ₃ - ch ₃ - 28-29 12th amyl methyl- cyclohexyl- 3 0 H CH ₃ - 94-95 13th propyl propyl cyclohexyl- 3 0 H ch ₃ - 98-99 14th pentyl ethyl- cyclohexyl- 3 0 H ch ₃ - 89-91 15th butyl butyl cyclohexyl- 3 0 H ch ₃ - 103-104

Example 4

a) 0.1 M 2-phenyl-4-hydroxy-4-ethyl-n-nonane (n = > = 1.5013, b.p. 124 ° C / 0.2 torr) was dissolved in 30 ml dry benzene and added dropwise with vigorous stirring, is added to a suspension of 0.1 molar fine powdered sodium amide in 30 ml of dry benzene for 30 minutes. The reaction mixture was heated at reflux for 2 hours. After cooling to 35-40 ° C, 0.11 mol of dinethylaminopropyl chloride in 60 ml of dry benzene is added. The reaction mixture was heated under reflux for an additional 6 hours and then washed with water, 3 x 50 ml. The solvent was removed by evaporation and the oily residue was purified by distillation under vacuum. . 65

48% yield of 2-phenyl-4- (3'-dimethylamino-n-propoxy) -4-ethyl-n-nonane. m.p. = 1.4868, b.p. 148 ° C / 0.5 torr.

b) 0.1 M 2-phenyl-4- (3'-dimethylamino-n-propoxy) -4-ethyl-n-nonane is dissolved in 50 ml ethyl alcohol and added to a solution of 0.1 mol fumaric acid in 50 ml hot ethyl alcohol. . The solution was concentrated by evaporation, ice-cooled, and the salt precipitated with diethyl ether was 2-phenoxy- (3 '- (dimethylamino-n-propoxy) -4-ethyl-n-nonane hydrogen fumarate).

Yield: 97%, m.p. 28-29 ° C. (The low melting point is due to the presence of a mixture of isomers.)

Example 5

a) 2.6 g of 1-hydroxy-4-oxa-5-benzyl-5-propyl-n-octane are dissolved in 100 ml of toluene and mixed with 3 ml of thionyl chloride. The solution was heated to 80 ° C for 3 hours and then evaporated to dryness in vacuo. The residue was purified on Florisil by purification with methylene chloride. 1.71 g of oily 1-chloro-4-oxa-5-benzyl-5-propyl-n-octane are obtained, the structure of which is confirmed by the following spectroscopic data.

IR: 3080, 3060, 3020 (aroma), 2950, 2920, 2860 (C-H), 1605 (aroma), 1500, 1455, 750 (Cl), 700 cm ^-1 .

Nuclear Magnetic Resonance Spectrum: 3.48 (triplet), 3.65 (triplet) and 7.21 (multiplet benzyl).

Mass Spec: 282-0.1 (M ⁺ ), 239 / 241-3 (C ₃ H ₇ ), 191 / 193-23 (C ₇ H ₇ ), 91-100 (C ₇ H ₇ +), 77-7 , 65-20, 51-5, 39-17 (data m / e - relative intensity).

b) The product 1.7 g) is dissolved in 50 ml of ethanol and mixed with 0.5 g of sodium iodide. Thereafter, 20 ml of a 33% solution of dimethylamine in ethanol were added and the solution was refluxed for 24 hours. After evaporation of the solvent, the product is applied to Florisil and purified with methylene chloride. 0.72 g of oily 4-oxa-5-benzyl-5-propyl-l-dimethylamino-n -octane that boils 0.6 horseradish 134 ° C ng ³ = 1.4958.

c) 0.12 g of the product obtained in b) are mixed with 0.5 g of cyclohexanesulfamic acid in 2 ml of acetone. The solution is stored at -20 ° C overnight. The crystals are then suctioned off, washed with ether and dried in a desiccator. 0.51 g of the salt of 4-oxa-5-benzyl-5-propyl-1-dimethylamino-n-octane-cyclohexanesulfamic acid is obtained, m.p. 112-114 ° C.

Further product can be isolated from the mother liquor.

Claims (5)

A process for the preparation of ω-aminoalkoxyalkanes of the formula I and their pharmaceutically acceptable salts, wherein R ¹ and R ^{2 are the} same or different C 1-6 alkyl groups, R ^{3 is} phenyl or cyclohexyl optionally substituted with halo or C 1-4 alkyl, R ⁴ is hydrogen or C 1-3 alkyl, R ⁵ and R ⁶ are C 1-3 alkyl, m is 0-4 and n is 2-4, characterized in that: a) a compound of formula II, wherein R ¹ , R ² , R ³ , R ⁴ , m and n are as defined above and X is preferably a sulfonyloxy group or a halogen atom, with a secondary amine of formula III or an acid addition salt thereof, wherein R ⁵ and R ⁶ is as defined above, or b) a compound of formula IV, wherein R ¹ , R ² , R ³ and R ⁴ and m are as defined above and R is hydroxy, with a compound of formula V or an acid addition salt thereof, wherein R ⁵ , R ⁶ and n are and Y is halogen, and optionally converting the resulting compound into a pharmaceutically acceptable salt. A process for the preparation of a variant of process a) or b) according to claim 1, which is a compound of the formula Ia and pharmaceutically acceptable acid addition salts thereof, wherein R ¹ and R ² are alkyl groups having 1 to 4 carbon atoms in total, R ^{7 is} hydrogen, methyl or halogen, to form n 2 or 3, characterized in that a) reacting a compound of general formula IIa, which is a narrower group of compounds of formula II, wherein R ¹ , R ² , R ⁷ and n are the leaving group and X is preferably a sulfonyloxy group or a halogen atom, with dimethylamine or its acid addition salt; b) a compound of formula IVa, which is a narrower group of compounds of formula IV, wherein R ¹ , R ² , R ⁷ are as defined herein and R is hydroxy, with a compound of formula Va or an acid addition salt thereof which is a narrower group of compounds of formula V Wherein Y and n are as defined in process variant b) of claim 1. 3. The process of embodiments a) and b) according to claim 1, characterized in that in the compounds of the formulas Ha and IVa, R ¹ and R ^{2 are a} total of 5, 6 or 7 carbon atoms. 4. A process according to claim 3 wherein n is 3 in the compounds of formulas IIa and IVa. 5. The development of any process according to claim 1 for the preparation of a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, wherein the substituents are as defined in claim 1, as an active ingredient in admixture with conventional carriers and carriers. converted.