DE2939998A1 - N-SUBSTITUTED CYCLIC AMINES, THEIR PRODUCTION AND MEDICINES CONTAINING THEY - Google Patents

Description

SANDOZ Patent GmbH. Case 100-5101

Loerrach

N-SUBSTITUTED CYCLIC AMINES, THEIR MANUFACTURING AND MEDICINAL PRODUCTS

ORIGINAL INSPECTED

030018/0662

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N-SUBSTITUED CYCLIC AMINES, THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM

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

The invention relates to the new compounds of formula I, _RR

X is an oxygen atom, a sulfur atom or a radical NR, in which R is hydrogen or alkyl with 1-4 carbon atoms means

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A stands for ethylene, trimethylene or tetramethylene, which, if X is a group NR, 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 of 9 to 35,

R. denotes hydrogen, alkyl with 1-4 carbon atoms or alkenyl with 3-5 carbon atoms, where the double bond is not in the α-position to the nitrogen atom to which R, is bound,

R _{2 represents} hydrogen or alkyl with 1-4 carbon atoms,

R and R. 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 of 9 to 35 and

either m the number 0 and η the number 1 or 2 or m and η both the number 1, with the Provided that,

if X is a group NR, 25 A is unsubstituted, m is the number 0 and
η mean the number 1,

then R. does not stand for hydrogen.

ORIGINAL INSPECTED

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293 ^ 38

X preferably denotes a sulfur atom or an NR radical, in particular a sulfur atom. A stands preferably for ethylene. A is preferably unsubstituted. If it is substituted, it is preferably substituted by alkyl. If it is substituted by phenyl, it is preferably by unsubstituted phenyl substituted. If phenyl is substituted, it is preferably monosubstituted. The substituent is preferably in the para position.

10 If phenyl is disubstituted, they are

Substituents are preferably identical. If phenyl is disubstituted, the substituents are preferably in meta, para position. If phenyl is substituted, it is preferably substituted by halogen. R.

preferably denotes hydrogen. If it is not hydrogen, it is preferably alkyl. If it is alkyl with more than 2 carbon atoms, it is preferably straight-chain. R ₂ preferably denotes hydrogen. R- can be bonded to any methylene residue on the nitrogen-containing ring. R- is preferably bonded to a methylene radical which is not adjacent to the ring nitrogen atom. R and / or R. are preferably hydrogen. If they are not hydrogen, they are preferably attached to a position on the phenyl ring which is adjacent to the linked nitrogen-containing ring. If R and / or R are not hydrogen, they are preferably alkyl, alkoxy or halogen, in particular alkyl or halogen. If they are not both hydrogen, they are preferably identical. ta preferably denotes the number 0. η preferably denotes the number 1.

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293S398

Alkyl and / or alkoxy and / or alkylthio preferably contain 1 or 2, in particular 1, carbon atom (s). Halogen is preferably chlorine or bromine, in particular chlorine. Alkenyl preferably contains 3 carbons atoms.

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

Ipa

wherein

R, R, R and R have the above meaning,

A for ethylene, trimethylene or tetramethylene

el

stands, and

R ^ ^a denotes alkyl with 1-4 carbon atoms or alkenyl with 3-5 carbon atoms, the double bond not being in the σ-position to the nitrogen atom to which the radical R ^ is attached.

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

030018/0662

" ^lu " 100-5101

293P998

wherein

R and R to R have the above meaning and

A for one 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 of 9 to 35 mono- or identically or differently disubstituted phenyl monosubstituted ethylene, trimethylene or Tetramethylene residue.

10 Another group of compounds of the formula I consists of the compounds of the formula lpe, R-

Ipc

wherein A and R ₁ to R. have the above meaning and

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

03G01S / G662,. ° *> GINAL INSPECTED

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2 9 3 H 9 9

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

Ipd

wherein

R and R- to R have the above meaning and

Aj ₃ for an ethylene 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 of 9 to 35, Trimethylene or tetramethylene radical.

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

lpe

030018/0662

"* ¹² " 100-5101

2 9 3 Γ? 3

wherein

A and R to R. have the above meaning and a j_ 4

X 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,, R and R. to R. have the above meanings.

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

030018/0662

" ¹³ " 100-5101

wherein

A and R. to R. have the above meaning and PQ

X represents an oxygen atom or a sulfur atom.

According to the invention one arrives at the compounds of Formula I by adding corresponding compounds of the formula II,

II

wherein

A, R. to R, m and η have the above meaning and

either X ^{1 represents} an oxygen atom or a sulfur atom,

χ ¹¹ a leaving group and

R ^{1 is} hydrogen,

or X ¹ together with a hydrogen atom represents a leaving group,

X ¹¹ represents a group NR ^11, and

ORIGINAL INSPECTED

030018/0662

^lq 100-5101

293V Ι98

one of R 'and R ¹ ' is hydrogen and the ο ο

others are hydrogen or alkyl of 1-4 carbon atoms mean,

with the proviso that,

if X ¹ represents 'is a group NR ^1',

A is unsubstituted, m stands for the number 0 and 10 η for the number 1, then R. does not mean hydrogen, cyclized.

The reaction according to the invention can be carried out analogously to known ones Methods for the cyclization of analogous amino derivatives can be carried out.

If X ¹ 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 its absence an additional solvent. The reaction is preferably carried out in the presence of a mineral acid such as hydrochloric or hydroiodic acid. The temperature can vary from about room temperature to about 150 ° C., it is preferably at least 50 ° C., for example the reaction mixture is operated at the reflux temperature.

0 300 18/06 62 .ORIGiNALiNSPECTED

_: - 15 - 100-5101

If X ^{1 is} an oxygen atom, the reaction is preferably carried out in water, if X ^{1 is} 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 'stands for a sulfur atom, it is preferred to work at room temperature.

If X ¹ together with a hydrogen atom stands for a leaving group, X ¹ zP denotes a group NP. ,

el

where R is alkyl with 1-4 carbon atoms, especially

el

special methyl, or hydrogen.

If X ' ^{1 is} a leaving group, it is, for example, halogen or a group F -S0-0-, in which P. is phenyl, tolyl or lower alkyl, in particular chlorine or bromine.

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

The compounds of the formula I can be in free form as a base or in acid addition salt form. From the Compounds in free form can be in a known manner 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, i.e. in the form in which the double

ORIGINAL INSPECTED 030018/0662

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2930: J98

bond with the other nitrogen atom or with the X is bonded to the extent that this other nitrogen atom or this X is not fully substituted. Such tautomeric forms are also included in the scope of formula I.

The starting products can be produced analogously to known methods.

The compounds of the formula Ha,

Ha

wherein
R to R, A, m and η have the above meaning

X ^{1 represents} an oxygen atom or a sulfur atom

stands and

X '' is a leaving group _f ei

is obtained, for example, by reacting corresponding compounds of the formula III,

0300 18/0662

ORIGINAL INSPECTED

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29 3 '- Γ)

III

with corresponding compounds of the formula IV,

X ¹ X ¹ '
aa

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

χ · ¹ is identical to X ¹ 'if the latter group is a leaving group. Compounds of the formula III in which R. is not hydrogen are obtained, for example, by N-substitution of corresponding compounds of the formula III in which R. is hydrogen.

Compounds of the formula Hb,

ORIGINAL INSPECTED

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293 ^ 98

Man

NH-Rj ¹ "

before in

A ,, R. to R, m and n have the above meaning,

Χ, ¹ together with a hydrogen atom denotes a leaving group and

one of P. ' '' and R "" hydrogen and the other

ο ο

Denote hydrogen or alkyl with 1-4 carbon atoms,

with the proviso that,

if A, is unsubstituted,
rc the number 0 and
η mean the number 1,

then R. does not stand for hydrogen,

is obtained, for example, by reacting corresponding compounds of the formula V,

030018/0662 _ΛΟ1 ^

ORIGINAL INSPECTED

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29 3 ^f ) 9 9

in which the radical SY is a leaving group,
where S is a sulfur atom, with corresponding compounds of the formula VI,

fill °

NH-R "" ο

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

The reaction conditions for the preparation of compounds of the formula Ha, in particular if X ^{1 stands} for a sulfur atom, and of compounds of the formula
Hb, can be selected so that they are identical to the reaction conditions for the cyclization according to the invention.

ORIGINAL INSPECTED 030018/0662

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293CD38

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 Ha or Ub.

The compounds of the formula Va,

R ^ R-s \ . j ³ \ Sr T, 2 η ^R 4 "K * S ^ (CH ₂ ) \ ^R i ^c

Va

wherein

R ₁ to R., m and η have the above meaning and

Y _a denotes alkyl with 1-4 carbon atoms,

is obtained, for example, starting from the corresponding compounds of the formula VII
R.

VII

through possible monosubstitution of the primary arcino

030018/0662 _ __

INSPECTED

100-5101

29 3 Γ- '-) 9

radicals with a suitable radical R. 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 also apply mutatis mutandis to those described above Starting products and such tautomerism are therefore of also includes the above formulas.

If the production of the required starting materials is not described, these are known or by processes known per se or analogously to those described here or analogously to those known per se Process producible.

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

Q- ^ Al »NSPtCTED

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Example 1 ; N- (4,5-dihydrothiazol-2-yl) -2,3-dihydro-IH-i nd ο1-1-ami n

With slight cooling, one drips into a solution of 15 g of l-amino-2,3-dihydro-lH-indole in 60 ml of ether, 18.6 g of 2-bromoethyl isothioxyanate diluted with 50 ml Ether. The temperature rises from about 15 ° to. Stirring is continued for a further 2 hours, with the initially greasy bodice gradually becomes crystalline. The crystals are sucked off and taken in Water on. The aqueous solution is made alkaline with 10% sodium hydroxide solution and irit Extracted methylene chloride. On evaporation of the methylene chloride solution dried over magnesium sulfate The title compound is obtained (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) methylaminol-dimethyl indole in

10 g of l- (4-methylindolin-l-yl) -l, 2-dimethylisothiourea hydroiodide are dissolved in 50 ml of ethanol and, after adding 5.6 ml of ethylenediamine, heated to boiling for 10 hours while stirring. The reaction solution is evaporated to dryness and shakes out the vapor residue between ethyl acetate and IN sodium hydroxide solution. Evaporation of the ethyl acetate solution, dried over magnesium sulfate, gives the title compound (melting point of the hydrochloride 259-260 ° - from methanol / ether).

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2933998

The starting material is obtained as follows:

The urethane obtained by reacting l-amino-4-methylindoline with ethyl chloroformate is converted into 4-methyl-l-methylaminoindoline _{with LiAlH 4 in dioxane}

reduced (m.p. of the hydrochloride 154-155 ° - from methanol / ether). From this one obtains with benzoyl isothiocyanate in boiling tetrahydrofuran and subsequent saponification with dilute sodium hydroxide solution the l- (4-methylindolin-l-yl) -l-methylthiourea under reflux for 30 minutes {M.p. 152-153 ° - from methanol). This thiourea is converted into l- (4-methylindolin-l-yl) -l, 2-dimethylisothiourea hydroiodide by boiling with methyl iodide for 1 hour (M.p. 193-195 ° - from

15 methanol / ether) transferred.

Example 3 : N- (4,5-pihydrooxazol-2-yl) -2,3-dlhydrolH-indol-1-amln

The l- (2-chloroethyl) -3- (2,3-dihydro-lH-indol-l-yl) urea obtained as described below it is slurried in 30 parts of water and heated to the boil for minutes. The aqueous solution is with conc. Ammonia solution made alkaline and extracted with ethyl acetate. When evaporating the over magnesium sulfate dried ethyl acetate solution gives the title compound (melting point of the hydrogen maleate 125-127 ° - methanol / ethyl acetate).

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The starting product is obtained as follows:

In a solution of 2.5 g of 1-ainino-2,3-dihydro-1H-indole 1.95 g of 2-chloroethyl isocyanate, diluted with, are added dropwise to 15 ml of ether with stirring in the course of 10 minutes 15 ml of ether. The temperature rises to about 35 °. Stirring is continued for a further 2 hours, with crystallization he follows. The crystals are filtered off with suction and 1- (2-chloroethyl) -3- (2,3-dlhydro-1H-indol-lyl) urea is obtained (M.p. 103-104 ° - from ether).

The following compounds are obtained in an analogous manner Formula I:

030018/0662

ORIGINAL INSPECTED

CD _Λ CO

cn co

Esp.no. Analogous to
Example No. h ^R 2 4-Me ^R 4 m η A. X hml M.p. 4th 2 H H H H O 1 Methylethylene NH hfu 123-124 ° 5 2 H H 5-Cl H O 1 (3,4-dichloro
phenyl) ethylene NH hfu 181-183 ° 6th 2 H H H H O 1 Phenylene NH hml 209-210 ° 7th 2 H H H H O 2 Ethylene NH b 140-142 ° 8th 3 H H H H O 2 Ethylene O hml 146-147 ° 9 2 H H H 1 1 Ethylene NH 134-135 ° b in free form as a base hfu - in hyarogen fumarate form hml β in hydrogen maleate form

cn

CD

CO co OO

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2930

The compounds of formula I in free form or in The form of salts are characterized by interesting pharma-dynamic properties. You can as Remedies are used.

They have vasoconstrictive properties.

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

The doses to be used naturally vary depending on the type of substance, the administration and the purpose treating condition. In general, however, satisfactory results will be obtained with a daily dose obtained from about 0.0025 to about 1 mg; this dose can if necessary in several, for example can be administered in 2 to 4 portions or as a sustained release form. Suitable dosage forms for

20, for example, oral applications contained in the

generally 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 formula I in free form or in the form of a contain physiologically compatible acid addition salt. These remedies, for example, a solution

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or a tablet, according to known methods, using the usual auxiliaries and carriers, getting produced. The compounds of the formula I or their physiologically tolerated medicinal products can be used as medicaments Salts can be administered alone or in suitable dosage forms.

030018/0662

Claims (5)

100-5101 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 a Radical NR, where R is hydrogen or alkyl with ο ο 1-4 carbon atoms means A stands for ethylene, trimethylene or tetramethylene, which, if X is a group NR, 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 of 15 9 to 35, 030018/0662 100-5101 2939 ^ 98 R. Hydrogen, alkyl of 1-4 carbon atoms or Means alkenyl with 3-5 carbon atoms, the double bond not in the α-position to the nitrogen atom stands to the R, is bound, R _{2 represents} hydrogen or alkyl with 1-4 carbon atoms, R_ and R. 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 35 mean and either m the number 0 and η the number 1 or 2 or m and η both the number 1, with the proviso that,
15 if X is a group NR, A is unsubstituted, m is the number 0 and η mean the number 1, then R ₁ does not represent hydrogen, and their acid addition salts, characterized in that corresponding compounds of the formula II, ρ R. II 030018/0662 100-5101 2939098 wherein A, R to R, m and η have the above meaning and either X ^{1 represents} an oxygen atom or a sulfur atom, 5 X '' is a leaving group and R 'is hydrogen, or X 'together with a hydrogen atom for is a leaving group, X ^{11 is} a group NR ¹¹ and one of R ¹ and R ″ is hydrogen and the other ο ο Denote hydrogen or alkyl with 1-4 carbon atoms, with the proviso that, 15 if X "means a group NR ^ ', A is unsubstituted, in stands for the number 0 and η for the number 1, then R, not hydrogen, 20 cyclizes, and the compounds of the formula I thus obtained in free form as a base or in acid addition salt form wins. 2. The method according to claim 1 for the preparation of N- (4,5-dihydrothiazol-2-yl) -2,3-dihydro-1H-indole-lamin, characterized in that corresponding compounds of the formulas in which R ', R ,, R- 1 R-, and R. are hydrogen, m for the number 0 and η 030018/0662 100-5101 2939398 are the number 1, X ^{1 is} a sulfur atom and X "is a leaving group, cyclized. 3. The new M-substituted cyclic amines of the formula I, wherein X, A, R to F, m and η im Claim 1 have the meaning given, and their acid addition salts. 4. The N- (4,5-dihydrothiazol-2-yl) -2,3-dihydrolH-indol-1-amine and its acid addition salts. 5. Light agents, characterized in that they are compounds of the formula I or their physiological Contain 10 compatible acid addition salts. 0 300 18/06 62