WO1980000840A1

WO1980000840A1 - N-substituted cyclic amines,their preparation and pharmaceuticals containing them

Info

Publication number: WO1980000840A1
Application number: PCT/CH1979/000126
Authority: WO
Inventors: R Berthold; G Bormann
Original assignee: Sandoz Ag
Priority date: 1978-10-12
Filing date: 1979-10-02
Publication date: 1980-05-01
Also published as: NL7907458A; AU5165579A; DE2939998A1; FR2438656A1; DK415479A; PT70299A; IL58429A0; GB2031427A; FI793063A

Abstract

Compounds of formula I (FORMULA) exhibiting vasoconstrictive properties. They can be utilised as pharmaceuticals. They are obtained by cyclisation.

Description

N-SUBSTITUTED CYCLIC AMINES, THEIR PRODUCTION AND THE MEDICINES CONTAINING THEY

The invention relates to N-substituted cyclic amines, their preparation and medicaments containing them.

The invention relates to the new compounds of the

wherein

X is an oxygen atom, a sulfur atom or one

Radical NR _o , where Ro is hydrogen or alkyl with

1-4 carbon atoms means A stands for ethylene, trimethylene or tetramethylene, which, if X represents a group NR _o , is optionally monosubstituted. by alkyl with 1-4 carbon atoms, phenyl or phenyl mono- or identically or differently disubstituted by alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or halogen with an atomic number from 9 to 35,

R _{1 is} hydrogen, alkyl of 1-4 carbon atoms or alkenyl of 3-5 carbon atoms. means, where the double bond is not in the α-position to the nitrogen atom to which R _{1 is} bonded,

R _{2 stands} for hydrogen or alkyl with 1-4 carbon atoms, R ₃ and R ₄ independently of one another hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkylthio with 1-4 carbon atoms or halogen with an atomic number from 9 to Are 35 and either m is the number 0 and n is the number 1 or 2 or m and n are both the number 1, with the proviso that if X is a group NR, A is unsubstituted, m is the number 0 and n is the number 1, then R _{1 is} not hydrogen. X preferably denotes a sulfur atom or a residue NR _o , in particular a sulfur atom. A preferably represents ethylene. A is preferably unsubstituted. If it is substituted, it is preferably substituted by alkyl. If it is substituted by phenyl, it is preferably substituted by unsubstituted phenyl. If phenyl is substituted, it is preferably monosubstituted. The substituent is preferably in the para position. If phenyl is disubstituted, those are

Substituents are preferably identical. If phenyl is disubstituted, the substituents are preferably in the meta, para position. If phenyl is substituted, it is preferably substituted by halogen. R ₁ is preferably hydrogen. If not. Means hydrogen, it is preferably alkyl. If it is alkyl with more than 2 carbon atoms, it is preferably straight-chain. R ₂ preferably means

Hydrogen. R ₂ can be attached to any methylene residue of the nitrogen containing ring. R ₂ is preferably bonded to a methylene radical which is not adjacent to the ring nitrogen atom. R ₃ and / or R _{2 are} preferably hydrogen. If they are not hydrogen, they are preferably attached at a position on the phenyl ring which is adjacent to the linked nitrogen-containing ring. If R ₃ and / or R _{4 are} not hydrogen, they are preferably alkyl, alkoxy or halogen, in particular alkyl or halogen. If both of them are not hydrogen, they are preferably identical, m is preferably the number 0. n is preferably the number 1. Alkyl and / or alkoxy and / or alkylthio preferably contain 1 or 2, in particular 1 carbon atom (s). Halogen preferably means chlorine or bromine, in particular chlorine. Alkenyl preferably contains 3 carbon atoms.

A group of compounds of the formula I consists of the compounds of the formula Ipa,

wherein R _o R ₂ , R ₃ and R _{4 have the} above meaning, A _{a stands} for ethylene, trimethylene or tetramethylene, and

Alkyl with 1-4 carbon atoms or alkenyl with

3-5 carbon atoms means that the double bond is not in the α-position to the nitrogen atom to which the rest is attached.

Another group of compounds of the formula I consists of the compounds of the formula Ipb,

wherein R _o and R ₁ to R _{4 have the} above meaning and

A ^pb for an ethylene or trimethylene monosubstituted by alkyl with 1-4 carbon atoms, phenyl or by alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or halogen with an atomic number from 9 to 35 mono- or identically or differently disubstituted phenyl - or tetramethylene residue.

Another group of compounds of the formula I consists of the compounds of the formula Ipc,

wherein A _a and R ₁ to R _{4 have the} above meaning and X ^{pc represents} an oxygen atom or a sulfur atom. Another group of compounds of the formula I consists of the compounds of the formula Ipd,

wherein

R _o and R ₁ to R _{4 have the} above meaning and

A _b for an optionally mono- or identically or differently disubstituted by alkyl having 1-4 carbon atoms, phenyl or phenyl by alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms or halogen with an atomic number of 9 to 35 monosubstituted ethylene, Trimethylene or tetramethylene residue.

Another group of compounds of the formula I consists of the compounds of the formula Ipe,

wherein

A _a and R ₁ to R _{4 have the} above meaning and X ^{pe represents} an oxygen atom or a sulfur atom.

Another group of compounds of the formula I consists of the compounds of the formula Ipf,

wherein

A _b , R _o and R ₁ to R _{4 have the} above meaning.

Another group of compounds of the formula I consists of the compounds of the formula Ipg,

wherein

A _a and R ₁ to R _{4 have the} above meaning and

X ^{pg represents} an oxygen atom or a sulfur atom.

According to the invention, the compounds of the formula I are obtained by corresponding compounds of the formula II,

wherein

A, R ₁ to R ₄ , m and n have the above meaning and either X 'represents an oxygen atom or a sulfur atom, X''is a leaving group and

R ₀ 'is hydrogen, or X' together with a hydrogen atom represents a leaving group,

X means "a group NR" and one of R _o 'and R _o "is hydrogen and the other is hydrogen or alkyl of 1-4 carbon atoms, with the proviso that if X" is a group NR _o ",

A is unsubstituted, m is the number 0 and n is the number 1, then R _{1 is} not hydrogen, cyclizes.

The reaction according to the invention can be carried out analogously to known methods for the cyclization of analog amino derivatives.

If X 'together with a hydrogen atom represents a leaving group, the reaction is preferably carried out in an inert solvent, such as methanol or ethanol, or, if the compound of the formula VI used (see below) is liquid at the reaction temperature, optionally in the absence of an additional one Solvent. The reaction is preferably carried out in the presence of a mineral acid such as hydrochloric acid or hydroiodic acid. The temperature can vary from about room temperature to about 150 ° C, it is preferably at least 50 ° C, for example, one works at the reflux temperature of the reaction mixture. If X 'represents an oxygen atom, the process is preferably carried out in water, if X' represents a sulfur atom, preferably in an organic solvent such as ether. The temperature can vary from about room temperature to about 100 ° C. If X 'represents a sulfur atom, it is preferred to work at room temperature.

If X 'together with a hydrogen atom represents a leaving group, X' means, for example, a group NR _a , in which R _{a represents} alkyl with 1-4 carbon atoms, in particular methyl, or hydrogen.

If X ″ is a leaving group, it is, for example, halogen or a group R _b -SO ₂ -O-, where R _{b is} phenyl tolyl or lower alkyl, in particular chlorine or bromine.

The compounds of the formula I can be isolated and purified from the reaction mixture analogously to known methods.

The compounds of the formula I can be in free form as a base or in acid addition salt form. Acid addition salts, e.g. the hydrochloride or hydrogen fumarate or maleate, and vice versa.

The compounds of the formula I can also be in tautomeric form, ie in the form in which the double bond with the other nitrogen atom or with the radical X, insofar as this other nitrogen atom or this radical X is not fully substituted. Such tautomeric forms also fall within the scope of Formula I.

The starting products can be prepared analogously to known methods.

The compounds of formula IIa

in which R ₁ to R ₄ , A _a , m and n are as defined above,

X _a 'represents an oxygen atom or a sulfur atom and

X _a ″ denotes a leaving group, is obtained, for example, by reacting corresponding compounds of the formula III,

with corresponding compounds of the formula IV,

preferably in a solvent such as ether, e.g. at a temperature of about 0 ° to about 50 ° C, preferably at room temperature.

X _a '' is identical to X '' if the latter group is one

Leaving group means. Compounds of the formula III in which R _{1 is} not hydrogen are obtained, for example, by N-substitution of corresponding compounds of the formula III in which R _{1 is} hydrogen.

Compounds of the formula IIb,

wherein

A _b , R ₁ to R ₄ , m and n have the above meaning,

X _b 'together with a hydrogen atom means a leaving group and one of R _o ''' and R _o '"is hydrogen and the other

Means hydrogen or alkyl having 1-4 carbon atoms, with the proviso that if A _{b is} unsubstituted, m is 0 and n is 1, then R _{1 is} not hydrogen, for example by reacting corresponding compounds of Formula V,

wherein the radical S-Y is a leaving group, where S is an i-sulfur atom, with corresponding compounds of the formula VI,

The radical X _b 'is identical to the radical X' if the latter together with a hydrogen atom represents a leaving group. Y means, for example, alkyl with 1-4 carbon atoms, preferably methyl.

The reaction conditions for the preparation of compounds of the formula Ila, in particular if X _a 'represents a sulfur atom, and of compounds of the formula IIb, can be selected so that they are identical to the reaction conditions for the cyclization according to the invention. The compounds of the formula III or V are then reacted directly with the compounds of the formula IV or VI to give the corresponding compounds of the formula I, without intermediate isolation of the corresponding compounds of the formula Ila or Ilb.

The compounds of formula Va

in which R ₁ to R ₄ , m and n have the above meaning and Y _{a is} alkyl having 1-4 carbon atoms, is obtained, for example, starting from the corresponding compounds of the formula VII

by possible mono substitution of the primary amino the rest with a suitable radical R ₁ for the preparation of the corresponding compounds in which R _{1 is} not hydrogen, subsequent reaction of the amine with eenzoyl isothiocyanate, subsequent saponification of the product thus obtained and subsequent S-alkylation of the thiourea thus obtained.

The above explanations regarding tautomerism σelten mutatis mutandis also for the starting products described above and such tautomersi are therefore also included in the above formulas.

Insofar as the production of the required starting materials is not described, they are known or can be produced by methods known per se or analogously to the methods described here or analogously to methods known per se.

In the following examples, all temperatures are given in degrees Celsius without corrections.

Example 1: N- (4,5-Dihydrothiazol-2-yl) -2,3-dihydro-1H-indol-1-amine

With gentle cooling, 18.6 g of 2-bromoethyl isothioxyanate diluted with 50 ml are added dropwise to a solution of 15 g of 1-amino-2,3-dihydro-1H-indole in 60 ml of ether

Ether. The temperature rises from about 15 ° to 21 °. Stirring is continued for a further 2 hours, during which the initially greasy precipitate gradually becomes crystalline. The crystals are suctioned off and taken up in water. The aqueous solution is made alkaline with 10% sodium hydroxide solution and extracted with methylene chloride. Evaporation of the methylene chloride solution dried over magnesium sulfate gives the title compound (mp. 177-178 ° - from methylene chloride / petroleum ether; mp. Of the hydrogen maleate 149-150 ° - from methanol / ethyl acetate).

Example 2: 1- [N- (2-Imidazolin-2-yl) methylamino] -4-methylindoline

10 g of 1- (4-methylindolin-1-yl) -1,2-dimethylisothiourea hydroiodide are dissolved in 50 ml of ethanol and, after the addition of 5.6 ml of ethylenediamine, heated to boiling for 10 hours with stirring. The reaction solution is evaporated to dryness and the evaporation residue is shaken out between ethyl acetate and 1N sodium hydroxide solution. Evaporation of the ethyl acetate solution dried over magnesium sulfate gives the title compound (mp. Of the hydrochloride 259-260 ° - from methanol / ether). The starting material is obtained as follows:

The urethane obtained by reacting 1-amino-4-methylindoline with ethyl chloroformate is reduced with LiAlH ₄ in dioxane to 4-methyl-1-methylaminoindoline (mp. Of the hydrochloride 154-155 ° - from methanol / ether). This gives 1- (4-methylindolin-1-yl) -1-methylthiourea with benzoyl rsothiocyanate in boiling tetrahydrofuran and subsequent saponification with dilute sodium hydroxide solution under reflux for 30 minutes

(Mp 152-153 ° - from methanol). This thiourea is converted into 1- (4-methylindolin-1-yl) -1,2-dimethylisothiourea hydroiodide (mp. 193-195 ° - from methanol / ether) by boiling for 1 hour with methyl iodide.

Example 3: N- (4,5-Dihydrooxazol-2-yl) -2,3-dihydro1H-indol-1-amine

The 1- (2-chloroethyl) -3- (2,3-dihydro-1H-indol-1-yl) urea obtained as described below is slurried in 30 parts of water and heated to boiling for 30 minutes. The aqueous solution is concentrated with. Ammonia solution made alkaline and extracted with ethyl acetate. Evaporation of the ethyl acetate solution dried over magnesium sulfate gives the title compound (mp. Of the hydrogen maleate 125-127 ° - methanol / ethyl acetate). The starting product is obtained as follows.

1.95 g of 2-chloroethyl isocyanate diluted with 15 ml of ether are added dropwise to a solution of 2.5 g of 1-amino-2,3-dihydro-1H-indole in 15 ml of ether with stirring over the course of 10 minutes. The temperature rises to about 35 °.

Stirring is continued for a further 2 hours, with crystallization taking place. The crystals are filtered off with suction and the 1- (2-chloroethyl) -3- (2,3-dihydro-1H-indol-1-yl) urea (mp. 103-104 ° - from ether) is obtained.

The following compounds of the formula I are obtained in an analogous manner:

The compounds of formula I in free form or in the form of salts are distinguished by interesting pharmacodynamic properties. They can be used as a remedy.

They have vasoconstrictive properties.

Because of this effect, the compounds can be used as vasoconstrictors, e.g. for the prophylaxis and treatment of vascular headaches, such as migraines, or of orthostatic disorders, such as orthostatic hypotension and its symptoms, such as dizziness.

The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. In general, however, satisfactory results are obtained with a daily dose of about 0.0025 to about 1 mg; if necessary, this dose can be administered in several, for example in 2 to 4, portions or also as a slow-release form. Suitable dosage forms for oral applications, for example, generally contain about 0.0005 to 0.5 mg in addition to solid or liquid carriers or diluents.

The compound of Example 1 is preferred.

The invention also relates to medicaments which contain a compound of the formula I in free form or in the form of a physiologically tolerable acid addition salt. These remedies, for example a solution or a tablet, can be prepared according to known methods, using the usual auxiliaries and carriers. The compounds of the formula I or their physiologically tolerable salts can be administered as medicinal products on their own or in suitable pharmaceutical forms.

Claims

Claims:

1. Process for the preparation of the new N-substituted cyclic amines of the formula I,

wherein

X is an oxygen atom, a sulfur atom or one

Radical NR _o , where R _{o is} hydrogen or alkyl with

1-4 carbon atoms means

A represents ethylene, trimethylene or tetramethylene, which, if X represents a group NR _o , is optionally monosubstituted by alkyl having 1-4 carbon atoms, phenyl or phenyl, mono- or identically or differently or disubstituted by alkyl having 1-4 carbon atoms, alkoxy with 1-4 carbon atoms or halogen with an atomic number from 9 to 35, R _{1 is} hydrogen, alkyl with 1-4 carbon atoms or alkenyl with 3-5 carbon atoms, the double bond not being in the α-position to the nitrogen atom to which R _{1 is} bonded, R _{2 is} hydrogen or alkyl with 1-4 carbon atoms , R ₃ and R ₄ independently of one another are hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkylthio with 1-4 carbon atoms or halogen with an atomic number from 9 to 35 and either m is the number 0 and n the number 1 or 2 or m and n both represent the number 1, with the proviso that if X represents a group NR,

A is unsubstituted, m is the number 0 and n is the number 1, then R _{1 is} not hydrogen, and their acid addition salts, characterized in that corresponding compounds of the formula II,

^ QREA

OMPI wherein

R _o 'is hydrogen, or X' together with a hydrogen atom represents a leaving group,

X '' means a group NR _o '' and one of Ro 'and R _o ''is hydrogen and the other

Are hydrogen or alkyl with 1-4 carbon atoms, with the proviso that if X '' is a group NR _o '', A is unsubstituted, m is the number 0 and n is the number 1, then R _{1 is} not hydrogen means cyclized, and the compounds of formula I thus obtained in free form as a base or in acid addition salt form.

2. The method according to claim 1 for the preparation of N- (4,5-dihydrothiazol-2-yl) -2,3-dihydro-1H-indol-1-amine, characterized in that corresponding compounds of formula II in which R _o ', R ₁ , R ₂ , R ₃ and R _{4 are} hydrogen, m is the number O and n represent the number 1, X 'is a sulfur atom and X''is a leaving group, cyclized.

3. The new N-substituted cyclic amines of formula I, wherein X, A, R ₁ to R ₄ , m and n have the meaning given in claim 1, and their acid addition salts.

4. The N- (4,5-dihydrothiazol-2-yl) -2,3-dihydro-1H-indol-1-amine and its acid addition salts.

5. Remedies, characterized in that they contain compounds of formula I or their physiologically tolerable acid addition salts.