DD204480A1 - PROCESS FOR THE PREPARATION OF 10-BASED SUBSTITUTED 5,5-DIMETHYL-5,10-DIHYDRO-BENZO (B) (1,8) NAPHTHYRIDINES - Google Patents

Abstract

Basic 10-substituted-5,5-dimethyl-5,10-dihydro-benzo (b) (1,8) naphthyridines d. general formula I can be prepared by cyclization of 2-phenylamino-3- (1'-methyl-1'-hydroxy-ethyl) -pyridinen of general formula II to 5,5-dimethyl-5,10-dihydrobenzo (b) ( 1,8) naphthyridines of the general formula III by means of Lewis acids and subsequent reactions of the resulting compounds of the general formula III with esters of basic alcohols of the general formula IV in inert organic solvents and in the presence of basic condensing agents. The compounds of the general formula I have antirheumatic properties.

Description

A process for the preparation of basically substituted in 10-position of 5,5-Dim8thyl-5,10-dihydro-benzo ^ "b _- 7 /" i, 8-naphthyridines 7 _iM

Field of application of the invention

The invention relates to a process for the preparation of basic 1Q-substituted in the 5Q-dimethyl-5,1Q ~ dihydro-benzo ^ 'bji ^ "* 1,8_7 ^ aphthyridinen the general formula I wherein Hj and R ₂ , ie may be the same or different and is a hydrogen, chlorine or bromine atom or a methyl, methoxy or Ithoxy group, R ^ is a hydrogen atom or a methyl group and R, and Hc, which may be the same or different and an alkyl radical having 1 to 4 C atoms or the benzyl radical and R and Rr together with the 3J atom to which they are attached, a piperidine, morpholine, S-methylpiperazine, H- {ß-Hydrosyäthyl) -piperazin-, 4 Osopiperidine or an 8-aza-1,4-dioxo-spiro ^ 4,5- _{i (} 7- ^de -ring and η is one of the numbers 0 or 1 The compounds of the general formula I possess valuable pharmacological properties and can be used, for example, for the treatment of rheumatic diseases.

Characteristic of the known technical solutions

From the series of structurally related 2-anino-nicotinic acids, i.a. the well-known »Uiflamic acid« meaning

238934 1

as an anti-inflammatory drug. However, there are considerable lifting effects on the gastric mucosa, which are alleviated by salt formation, complex formation and special galenic processing. »

10-substituted 5,5-dimethyl acridans (Dimetacrin, US Pat. No. 3,431,342) which are similar to the compounds according to the invention are used as heuroleptics or thymoleptics. Other patents of this substance class also mention antiviral, locally anesthetic, anticonvulsant and water-quenching properties (US Pat. No. 3,043,842, GH-PS 460,010).

Object of the invention

The invention makes it possible to produce new orally active analgesics and anti-inflammatory drugs in a technically simple manner, which has the disadvantages described, such as

cera, the previously known active ingredients do not have * So show the compounds of general formula I kaolin and Carragjseninödem; _s antiphlogistic efficacy in adjuvant arthritis and cotton wool granuloma. They inhibit peroxidase activity in vitro and leave the hyaluronidase activity unaffected. Anaectin effects were detected in the hot-plate-Sest, and are stronger than those of phenylbutazone * In prophylactic and therapeutic oral administration, the compounds of general formula I show a safe antipyretic effect in lower dosages than phenylbutazone · Thus, the compounds of the general formula I for the treatment of rheumatic diseases.

In the spasmolytic activity test in vitro according to Janasen specific inhibitory effects were observed in other compounds of the invention, which were stronger than in imported anticholinergics.

238934

Presentation of the essence of the invention

The invention has the object, aufaufindes and produce new highly effective pharmaceuticals, especially anti-inflammatory drugs,

According to the present invention, this is achieved by reacting appropriately substituted 2-phenylaiaino-3- {1'-methyl-1'-hydroxymethyl) -pyridines of the general formula II in which R 1 and R _{2 have} the abovementioned meaning, cyclized by means of Lewis acids, preferably polyphosphoric acids and the obtained 5 »5-dimethyl-5,10-dihydro-benzo ^" * b_7Z "" ^! , 8_7Eaphthyridine the general formula III, wherein the radicals R-, and R _{2 is} the have the abovementioned meaning, with reactive esters of basic alcohols of the general formula I ', in which Rj »Ra»% ^ ³³ ^ ⁿ ^ ^{0 have the} abovementioned meaning and 2 is a halogen atom or the radical of a sulfonic acid, ζ · Β · the benzene or p-toluenesulfonic acid, reacting in an inert organic solvent and in the presence of a basic condensing agent and the resulting compounds of the general formula (I) if necessary with physiologically compatible inorganic or organic acids, such as · Β · hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, fumaric acid or tartaric acid, are converted into their acid addition salts or the compounds of general formula I from the obtained acid addition salts of compounds of general formula I with alkalis.

Suitable inert organic solvents are, for example, aromatic hydrocarbons, such as toluene or jylene. Suitable basic condensing agents are, for example, aluminum hydride such as potassium hydroxide, alkali metal such as sodium amide or alkali metals such as sodium.

2Λ Λ Λ ^ / J U ν y = ΐ

alkali metal hydroxides used condensation agent can be used both in solid form as well as in the two-phase system with the organic solvents in the form of alkali metal in the presence of phase transfer catalysts.

The applied temperatures can be within wide limits. · In general, temperatures may be varied between room temperature and 15O ⁰ C are applied _·}

Insofar as dihydro halides are obtained in the preparation of salts of the compounds of general formula I, they can be converted into the pure monohydrohalides by thermal treatment, for example by heating for several hours at 100 to 150 ^° C. in a drying oven.

The cyclization of the compounds of the general formula II to the compounds of the general formula III can conveniently be carried out at temperatures between 100 and 200 ^° C.

Exemplary embodiments Example 1

General procedure for the preparation of 5,5-dimethyl-1O-dialkylaminoalkyl-5,1O-dihydrobenzG ^ fb ^ / Ti, 8_7aaphthyridines (formula I)

To 70 ml of toluene is added with stirring 0.02 to 0.05 mol of substituted 5,5-dimethyl-5,1Q-dihydro-benzo _</ b_7 ~ ^ ""1> ~ 8_7

naphthyridine (formula III) and 15 g of finely-hydrolyzed ka3am-The suspension is refluxed for 2 hours

238934 1

heated, where daa potassium salt precipitates. It is cooled to 50 ⁰ C, veraetat with 50 ml of a toluene solution of the equivalent amount of Dialkylamiaoalkylhalogenids or, set the corresponding hydrohalide directly. After 0.5 hours, the temperature is increased to 100-11O ⁰ G and refluxed for 4 hours. After cooling to room temperature, the product is filtered off with suction, the filtrate is washed twice with water, dried over sodium sulphate and concentrated. The oily residue is distilled one in an oil pump vacuum. The distillates are converted in the customary manner into the corresponding salts. The compounds obtained in this way are listed in table 1.

Example 2

Preparation of _5> 5-Dim8thyl-5j10-dlhyäro.benzo ^ "" b _-p 7 ^ "''" 8.7-naphthyridine (Formula III)

20 g of 2-? -Lenylamino-3- (1'-methyl-1'-hydroxy-ethyl) -pyridine (ΡογβθΙ II) are added in 200 g of P-olyphosphorsäure and slowly heated with stirring to 120 ⁰ G. The clear solution remains at this temperature for 1 hour. Then pour on Sia and added dropwise 20 ml of concentrated sodium hydroxide solution. The precipitated aqueous solution is discarded. The deposited phosphate greases are dissolved in 50 ml of warm ethanol and, while cooling and stirring with dilute sodium hydroxide solution, are added to a strongly alkaline reaction. Then dilute with enough water that all product precipitates. "The crystalline crude product is filtered off with suction and recrystallized from ethanol. Yield: 84 % of theory on S, -dimethyl-Si-O-dihydrobenzoyl, 8-7aaphthyridine,. 119.5-120 ⁰ G. C ₁₄ H ₁₄ N ₂

Table 2 lists further compounds of the general formula III which have been prepared in the same way.

238934 \

- (CH ₂ ) _n -

II

III

J - CH ₂ --CH- (CH ₂ ) _n -

IY

Table 1

5.5 "dimethyl-5,10-dihydro-benzoate"" _m 7Z""i * 6-naphthyridines according to formula I

Mr. R

R ₃ η R ₄

salt

Bruttof,

· ° σ

AUAB "

1 H H II 0 -CH-

2HHH 0 -C ₂ H ₅

3HHH 0 -C ₂ H ₅

4 H H H 0

5 H H H 0

6. H HH 0

7 H H H 0

CH

-C ₂ H ₅

-IG τΗ> 7 J ι

2HCl x H ₂ O

^Ο 2Ο ^Η 27 ^Ν 3 C ₂₁ H ₂₉ W ₃

methiodide

C ₂₂ H ₃₁ N ₃

methiodide

^C 24 ^H 35 ^N 3

methiodide

-C ₂ H ₅ - (CH ₂ ) ₅ -

-CH ₂ -C ₆ H ₅

8HH HO - (CH ₂ ) 2- ^ο - (ΟΗ ₂ ) ₂ - ° 25 ^Η 29 ^Ν 3 ^C 21 ^H 27 ^N 3

C ₂₀ H ₂₅ H ₃ O

0.05 / 150 196-199

0.05 / 150

0.2 / 170

144-145

0.2 / 175

101-102

0.05 / 175

244-245

78-79

0.4 / 220

79.5 to 81

80-82

64

58 50

43 55

46 50

53

R3 ^η

Salt gross. · Ρρ / Κρ. ° Ο

9 H H H 1

10 HH GH ₃ 0 11 HHH 1

12 H H H 1

-CH

-OH

13 H H H 1

- (CH ₂ ) ₅ -

- (CHg) ₂ -IK CH _{2) 2} -CHO

(CH ₂ ) ₂ -N ~ (CH ₂ ) ₂ -CH ₂ methoiodide Ox al at

HCl oxalate

° 19 ^H 25 ^W 3

° 22 ^Η 29 ^ϊί 3

C ₂₂ H ₃₀ K ₄

OH maleate

2HGIxH ₂ O

Dimaleinate χ H ₂ O

oxalate

0.3 / 185.

201

221 (Zero ·)

0.3 / 163

209-211 _%

0.4 / 209

166-170

0.4 / 220

187-188

220-223

tough oil

148-151

200-201

CM VO

co

CM

CM

CM

CO CM CM

CO

ISS

CM

CM

CM

so ^

CM O-

O I

in

co

co

CVJ

CM CM O

TJ • H

CM O

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CM

CM

M O

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in

CM CO

VO CO

CM

O*

P * O

S3

c-

CM

CM O

CM

CM

CO O

co O

co W O

VO

O O

VQ O

τ- CVJ

m in

oco

CO. co

O O

VO VO CM CM

CM

in

CM

238934

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OO

VD CO

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** C-

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CO

VO

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<T \ CM

 Ρ CO O r-j a) H a CM O & 0 a I Ά O O a CM co a 0 I

a a co CO CM 0 a a O 0 O i I 1 i

co

M O

H [j O H O O I O 1 I C- I C- c- C-

CTv

CM

in in

a "

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K 04 CM

 Ρ

approx

in

CM O

O C-

C-

ro CO

,in

O CM CM

CM O

CM O

co

CM

CM CM O

PQ CM

fO

CM

CM

,O

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H O

H O

CM

a ο

in

CM O

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LFN

ro

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H O O I 1 C- cn CM ro CM CM

ΓΟ

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OJ

co co

VO CO O tn C- vo VO ro O CM ro. cn in cn O C- T- co τ- cn OO CM CM cn O CM T- CM τ- N Ι τ- τ- CM τ- CM τ- CM V ^ 1 I in cn 1 ! i ro C- τ O in VO CM CO CO ·> C- O η τ- co r- O O CM O O O O O CM O CM

ro

1-

CM

CM O

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C-OJ

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CM

No. R ₁ R ₂ R η R ₄ R ₅ Saia Gross. Mp / kg Aust).

7-OGH ₃ HH O -O ₂ H ₅ - ° 2 ^H 5 ° 21 ^Η 29 ^ΪΪ 3 ° .0.4 / 204 59

Metkojodid 101-102

29 7-OC ₂ H ₅ HH 0 -G ₂ H ₅ -G ₂ H ₅ C ₂₁ H ₂₉ H ₃ O 0.05 / 185 83

2HGIxH ₂ O, 168

30 8-Cl H 9-01 0 _r (CH _{2) 5} ~ 22 ^{Ο Η β1} 28 2 ¹ 3 °> ^2/2 1 ° ⁶¹

Methoiodide 168-170

HGIxO, 5H ₂ O 203-208

31 8-Cl 9-Cl H 1 ~ (CH ₂ ) ₂ -N- (GH ₂ ) ₂ - ° 22 ^Η 28 ⁰¹ 2 ^1ϊ 4 123-125 43

CH ₃

32 8-01 9-GH _{3 H} ¹ - (0H ₂ ) ₂ -N- (CH ₂ ) ₂ -HCl C ₂₃ H ₃₁ Cl H ₄ 162 50

33 8-Cl 9-CH ₃ . HO.- (OH ₂ ) ₅ - " ^C 22 ^H 28 ^GlN 3 0.2 / ^210.78

Methododid 168/170 ·.

34 8-Cl 9-01 H 1 -CH ₃ -CH ₃ ^C 19 ^H 23 ^C1 2 ¹ 3 ° ^"2/2 ° 9 48

Methoiodide 201

2389 3 4 1

Table. 2 7-Cl L-5,10 5, 1 9-01 III 5 -D in the θ t hy I 7-Br R ₂ according to formula 7-CH ₃ H ». 7-OCH ₃ H 1 7-OC ₂ H ₅ H 2 7-Cl H 3 8-Cl H 4 8-Cl H 5 9-Cl 6 , 9-Cl 7 O / "^ TT j / V ^ Xl 8th 9

, 8_7naphthyriaine

gross formula

O Yield % 172 to 173.5 83 0.2 / 150 51 153-158 10 133-134 65 130-131 85 148-150 29 103-105 34 110-112 67 106-109 44

C ₁₆ H ₁₈ IT ₂ O

5 ^η 1

Claims (9)

~ o - 2 3 8 9 2 L 1 Claims LJU J JÄ ^ ' 1. A process for the preparation of basically substituted in 10-position of 5 »5-DiJseth.yl-5,10-dlhydro-ben? · ^ ~ So-b_7Z ~ ^{1» 8} .7naphthyridinen of the general formula I wherein Rj and R ₂ , which may be the same or different and a hydrogen, chlorine or bromine atom or a methyl, methoxy or ethoxy group, R-, a hydrogen atom or a methyl group and R ^ and Rj-, which may be the same or different and an alkyl radical having 1 to 4 C atoms or the benzyl radical and R, and Rj- together with the N-atom to which they are bonded, a piperidine, morpholine, ST-methylpiperazine, H- (S--) radical Hydroxyethyl) piperazine, 4-0xo-piperidine or an S-Asa-1 ^ -dioxo-spiro ^ ^ ^ Zd-ekan ring and η one of the numbers 0 or 1 and their salts with physiologically acceptable inorganic or organic acids, characterized in that correspondingly substituted 2-phenylamino-3- (1'-methyl-1'-hydroxy-ethyl) -pyridines of the general formula II, wherein Rj and R ₂ di e have the abovementioned meaning, cyclized by Lewis acids and the resulting 5,5-dimethyl-5,10-dihydro-ben2o ^ "* b ₎ _7Z""' ⁵ > ⁸ _7-naphthyridines of general formula III, wherein the radicals R ^ and R _{2 have} the abovementioned meaning, with reactive esters of basic alcohols of the general formula IY, wherein R-, R *, Rc and η have the abovementioned meaning and X represents a halogen atom or the radical of a sulfonic acid, in an inert organic solvent and in the presence of a basic condensing agent and the. Compounds of the general formula I obtained are desirably converted into their acid addition salts with physiologically compatible inorganic or organic acids. 2 * Method according to item 1, characterized in that the Ö Q Ό Ö H Ι Heat of a sulfonic acid, an aromatic sulfonic acid residue, e.g. the benzenesulfonic acid or p-toluenesulfonic acid radical, 3. The method according to points 1 to 2, characterized in that are used as the inert organic solvent.aromatic hydrocarbons such as toluene or xylene. 4. The method according to points 1 to 3, characterized in that as basic condensation agent alkali metal hydroxides , such as potassium hydroxide, alkali metal amides such as sodium amide or alkali metals such as sodium are used · Process according to points 1 to 4, characterized in that the alkali hydroxides are used in the form of alkali solutions in the two-phase system with the inert organic solvents in the presence of phase transfer catalysts. 6 · Method according to points 1 to 5, characterized in that the reaction is carried out at temperatures between room temperature and 15O ⁰ C. Process according to items 1 to 6, characterized gekennseishnet that resulting dihydrohalides of compounds of the general formula I are converted by thermal treatment in the monohydrohalides of compounds of general formula I. 8 method according to item 1, characterized in that polyphosphoric acid is used as the Lewis acid, 9 · Process according to items 1 and 8, characterized in that the cyclization of the compounds of general formula
leads « NEN formula II by heating at 100 b; Ls 20O ⁰ C durehge-