JPH0140828B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 3-aminopropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them. According to the invention, the formula where R ₁ is hydrogen or methyl, R ₂ is methyl, alkoxycarbonyl having 2 to 5 carbon atoms, carbamoyl or cyano, and R is a group -B-CO-R _h , where and B is the base

[Formula], where R ₁ is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl monosubstituted with halogen of atomic number 9 to 35, and R h is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl monosubstituted with halogen of atomic number 9 to 35, and R _h is phenylalkyl or diphenylalkyl having 13 to 17 carbon atoms, or b group

[Formula], where R _n is -COR _o or -R _p , where R _o and R _p are diphenylalkyl having 13 to 17 carbon atoms; Aminopropoxyaryl derivatives or pharmaceutically acceptable salts thereof are provided. One group of compounds of the invention has the general formula _p where R ₁ and R ₂ are as defined above and R _p is a group —B—CO—R _h , as defined above; b group

Compounds of the formula p', where R _o is as defined above, are Another group of compounds of the invention are compounds of the general formula _p ' where R ₁ and R ₂ are as defined above and R ^p ′ is a group

A compound of the formula: wherein R _p is as defined above, and including the conditions of the foregoing proviso. Another group of compounds of the invention are those of the general formula _a where R ₁ is as defined above, R ^a ₂ is methyl, alkoxycarbonyl of 2 to 5 carbon atoms or cyano, and R ^a is a group -B ^a -CO-R ^a _h , where B ^a is the base

[Formula], where R ^a _i is hydrogen, methyl or halophenyl, and R ^a _h is benzyl or diphenylmethyl; b group

[Formula] Here, R ^a _n is -COR ^a _o or -R ^a _p , where R ^a _o
is diphenylmethyl, and R ^a _p is diphenylmethyl or 2,2-diphenylethyl. Another group of compounds of the invention are those of formula _b where R ₁ and R ₂ are as defined above and R ^b is a group B ^b —CO— ^h , where B ^b is

[Formula] where R ^b _i is hydrogen or alkyl of 1 to 4 carbon atoms, and R _h is as defined above, or b group

where R _n is -COR _o or -R _p , where R _o and R _p are as defined above. It is. It is a compound of In one subgroup, R _h in formula _b is diphenylalkyl. In other subgroups R ₂ is cyano. In other subgroups, R ₁ is hydrogen.
In other subgroups, R ^b is the radical

[Formula]. Another group of compounds of the invention are those of formula _c where R ₁ and R ₂ are as defined above and R ^c is a group B ^b —CO—R ^b _h , where B ^b is as defined above and R ^b _h is Diphenylalkyl having 13 to 17 carbon atoms, b group

[Formula] where R ^b _n is -COR ^b _o or -R ^b _p , where R ^b _o and R ^b _p have the meanings given above for R ^b _h , is a compound of . In one subgroup, R ₂ in formula _c is other than hydrogen. In other subgroups, R ₂ is cyano.
In other subgroups, R ^c is the base

[Formula]. In other subgroups, R ₁ is hydrogen. R ₁ is preferably hydrogen. R ₂ is preferably alkoxycarbonyl, carbamoyl or cyano, especially cyano. R is preferably a group

[Formula]. R _i is preferably hydrogen or alkyl, especially hydrogen. R _h , R _o and/or R _p are diphenylalkyl.
R _n is preferably -R _p . Phenyl alkyl preferably has 7 to 7 carbon atoms.
9, especially 7 or 8 carbon atoms. When it is more than 8, the alkylene moiety is preferably in particular in the α-position, e.g.
Part - CαH (CH ₃ ) CH ₂ -, -Cα (CH ₃ ) ₂ CH ₂ -
or branched, as in -Cα(CH ₃ ) ₂ (CH ₂ ) ₂ -. Diphenylalkyl preferably has 13 carbon atoms
~15, especially 13 carbon atoms. The phenyl rings are preferably attached to the same carbon atom. The rings are preferably attached to a carbon atom in the ω-position, eg 3-diphenylpropyl. Diphenylalkyl is preferably diphenylmethyl. Alkyl and/or alkoxy preferably has 1 or 2 carbon atoms, especially 1 carbon atom.
Alkoxycarbonyl preferably has 2 carbon atoms
Or three, especially two. If it is based on more than two carbon atoms, it is preferably branched at position alpha to the carbonyl moiety, as in isopropoxycarbonyl. The halogen is preferably chlorine or bromine, especially chlorine. According to the invention, the compounds of the invention have the formula where R ₁ and R ₂ are as defined above and R _x is a group capable of reacting with a primary or secondary amine to form a 2-amino-1-hydroxyethyl group. , with a suitable compound of the formula R--H, in which R is as defined above, and optionally the resulting compound of the formula is reacted singly in free or salt form. It can be obtained by a method consisting of separating. This amination method is based on the analogous 3-amino-2-
It can be carried out by conventional methods for the production of hydroxypropoxyaryl compounds. For example, R _x is the formula

A group of the formula or a derivative of this group, for example a group of the formula -CH(OH)-CH ₂ Y, where Y is chlorine, bromine or R _y -SO ₂ -
O--, where R _y can be phenyl, tolyl or lower alkyl. Y is especially chlorine. This reaction is preferably carried out in isopropanol or a suitable ether such as dioxane. Excess amine can be used as a solvent if necessary. Alternatively, the reaction can be carried out in the form of a fusion melt. A suitable reaction temperature is approximately 20
to about 200°C, conveniently the reflux temperature of the reaction mixture when a solvent is present. The free form of the compounds of the invention can be prepared in the conventional manner by
It can be converted into salt form and vice versa. Suitable acids for the formation of acid addition salts include maleic acid, malonic acid or fumaric acid. In the compounds of the invention, for example, the carbon atom at the 2-position of the 3-aminopropoxy side chain is asymmetrically substituted. Thus, the compounds of the invention can exist in the form of racemates or individual optical isomers. The preferred optical isomer has the S configuration at this asymmetrically substituted carbon atom of the 3-aminopropoxy side chain. Individual optical isomers can be obtained, for example, by using optically active starting materials or by fractional crystallization using optically active acids. The compounds used as starting materials can be obtained by conventional methods. In particular, compounds _{of formula} In the formula, R ₁ and R ₂ are as defined above. The compounds of formula are preferably reacted in anionic form. formula _a where R _i and R _h are as defined above, a compound of formula where S is a protecting group, for example a benzyl group, is reacted with hydroxylamine, the resulting oxime is reduced, the resulting amine is suitably monoacylated, and optionally subsequently the group R _i can be obtained by introducing into a monoacylated derivative produced by N-alkylation and finally removing the protecting group S from the resulting derivative. formula _b where R _o is as defined above, a compound of formula where S' is a protecting group, for example benzyl, can be obtained by suitably acylating the compound and deprotecting the resulting acyl derivative, for example by debenzyl. Unless the preparation of a particular starting material is specifically described, the preparation of this starting material can be carried out in a conventional manner. The invention is further illustrated by the following examples. In these examples, all temperatures are uncorrected. Example 1 4-[3-(4-diphenylmethylpiperazin-1-yl)-2-hydroxypropoxy]-1H-indole-2-carbonitrile 4g of 4-(2,3-epoxypropoxy)-
1H-indole-2-carbonitrile and 3.7 g of 1-diphenylmethylpiperazine are dissolved in methanol and the solvent is evaporated to dryness. 70 residue
Heat to ℃ for 10 minutes. After cooling to room temperature, the resulting yellow oil is dissolved in ethanol and 1 equivalent of Romain is added. After adding ether to the ethanol solution, crystallization begins. The title compound in the form of hydrogen malonate salt is obtained in the form of crystals containing ethanol (mp 124 °C [decomposition]; after removal of ethanol mp 140
(°C; melting point of methanesulfonate form: 188°C; melting point of free base form: 163-164°C). R _x

From suitable compounds of the formula, the following compounds of the formula can be obtained by reaction with suitable compounds of the formula in a manner analogous to Example 1:

【table】

Table: Compounds of the invention exhibit pharmacological activity in animals. In particular, the compounds have cardiotonic activity as shown by standard tests.
For example, in normally tonic Numal anesthetized dogs, the increase in left ventricular contractility is approximately
Observed with intravenous doses of 0.2 to about 2 mg/Kg and intraduoduole doses of about 0.02 to about 2 mg/Kg. The test method is as follows: Dogs of both sexes weighing 10-15 Kg are used. 65
Numal in an intravenous dose of mg/Kg is used as anesthetic. Mount the animal in supine position on the operating table. After the usual preparations, a heparinized catheter is introduced into the left ventricle along the right carotid artery under radiologic control, and the pressure transfer is applied to the donor.
Record with membrane (Gould Statham p23Gb). The increase in pressure as a function of time is calculated and recorded with an HSE-physiodifferentiator.
The left ventricular pressure increase is a measure of the heart's contractile force. The magnitude of the pressure difference is expressed in mmHg/sec. Maintain a constant appropriate body temperature (approximately 36-37°C). After a control period of approximately 40 minutes, the test substance is injected into the femoral vein and its effect observed on recorded or calculated parameters. The compounds are therefore indicated for use as cardiotonic agents, for example for the treatment of heart failure. The compound of Example 1 is preferred in this application. The applied daily dose is about 1 mg to about 500 mg,
1 in unit dosage form containing about 0.25 mg to about 250 mg.
It is convenient to administer in divided doses 2 to 4 times a day or in delayed release form. An example of a daily dosage is 10-500 mg. The compounds also exhibit antiarrhythmic activity as shown in standard tests.
For example, the compound is described by N. Reuter and E Heeg.
According to the principle of [ Arch.Pharmakol. 268 (1971) 323-333], the functional refractory period in the left atrium of the guinea pig is 10 ^-6 ~
Extend at a concentration of 10 ^-4 molar. The compounds are therefore suitable for use as antiarrhythmic agents, for example in the treatment of heart rhythm disorders.
disorder). The compounds also exhibit α-adrenoceptor blocking activity as shown in standard tests. For example, inhibition of alpha-adrenoceptors occurs in isolated spirals and strips of the dog's femoral vein.
strip) (E. MU¨ller-Schweinitzer and E. Stu¨mer, Br. J. Pharmacol. [1974] 51 ,
441-446), can be observed at bath concentrations of about 10 ^-7 molar to about 10 ^-5 molar. Therefore, the compound is an α-adrenoceptor.
Use as a blocker is indicated, for example for the prophylaxis and treatment of disorders relating to paralysis of the intestine motility of the intestines, such as paralytic ileus. The compounds also have β-adrenoceptor blocking activity as shown in standard tests. For example, an isolated spontaneously sliding guinea pig atrium (K. Saameli, Helv. Physiol. Acta 25
[Method of 1967/CR219-CR221], the positive inotropic effect of adrenaline
inotropic effect) is suppressed from approximately 10 ^-9 mol to approximately 10 ^-6
observed at molar bath concentrations. The compounds are therefore suitable for use as β-adrenoceptor blockers, for example in coronary artery diseases, such as angina pectoris, in conditions resulting from sympathetic overstimulation, such as neurogenic cardiac discomfort. (nervous
heart ailment), myocardial infarction (myocardial infarction)
in fact), for the treatment of interval migraine, and for the prevention and treatment of glaucoma and thyreotoxicosis.
toxicosis). The applied daily dose is about 0.1 mg to about 1000 mg,
1 in unit dosage forms containing about 0.025 mg to about 500 mg.
It is convenient to administer in divided doses 2 to 4 times a day or in delayed release form. An example of daily dosage is
It is 0.1-100 mg. Generally, the 2(S) optical isomer of the compound is β
-More active as an adrenoceptor blocker than the 2(R) optical isomer. Before carrying out the aforementioned in vitro tests to demonstrate activity, it may be necessary to convert compounds with a substituent in the 2-position of the 3-aminopropoxy side chain to the corresponding free hydroxy compound. . Use as a cardiotonic agent is a preferred mode of use of the compound. The compounds can be administered in the form of pharmaceutically acceptable salts. Such salt forms exhibit similar activity to the free form and are easily prepared by conventional methods. The invention also provides a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form and a pharmaceutical carrier or diluent. Such compositions can be in the form of solutions or tablets, for example.

Claims (1)

[Claims] 1 formula where R ₁ is hydrogen or methyl, R ₂ is methyl, alkoxycarbonyl having 2 to 5 carbon atoms, carbamoyl or cyano, and R is a group -B-CO-R _h , where and B is a group [formula], where R _i is phenyl monosubstituted with hydrogen, alkyl having 1 to 4 carbon atoms, or halogen having atomic number 9 to 35, and R _h is a carbon phenylalkyl of 7 to 11 atoms or diphenylalkyl of 13 to 17 carbon atoms, or b group [formula], where R _n is -COR _o or -R _p , where: A 3-aminopropoxyaryl derivative or a pharmaceutically acceptable salt thereof, wherein R _o and R _p are diphenyl alkyl having 13 to 17 carbon atoms. 2 4-[3-(4-diphenylmethylpiperazin-1-yl)-2-hydroxypropoxy]-
The compound according to claim 1, which is 1H-indole-2-carbonitrile or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, which is a 2(S) optical isomer. 4 formula In the formula, R ₁ is hydrogen or methyl, R ₂ is methyl, alkoxycarbonyl of 2 to 5 carbon atoms, carbamoyl or cyano, and R _X is a group [formula] or a group [formula], where Y is chlorine, bromine or R _y —SO ₂ —O, where R _y is phenyl, tolyl or lower alkyl, is a compound of the formula R—H where R is a group —B—CO—R _h , where B is a group [formula], where R _i is hydrogen, alkyl having 1 to 4 carbon atoms, or phenyl monosubstituted with halogen having atomic number 9 to 35, and R _h is phenylalkyl of 7 to 11 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms; or b group [formula], where R _n is -COR _o or -R _p , where R _o and R _p are diphenylalkyl of 13 to 17 carbon atoms, and optionally the resulting compound in free form or as a salt. Formulas characterized by isolation in the form A method for producing a 3-aminopropoxyaryl derivative or a pharmaceutically acceptable salt thereof, wherein R ₁ , R ₂ and R are as defined above.