DE1470275C - Oxazohdon (2) derivatives and processes for their preparation - Google Patents

Description

2. A method for producing a compound according to claim 1, characterized in that an acid chloride of the cis or trans form of the general formula II

II

HO-CH, -CH ₂ -N

CH,

CH,

III

N — C — O — CH, —CH, —N

a chlorine atom or a low molecular weight alkyl or alkoxy group with up to 5 carbon atoms or in 2,3-, 3,3-, 3,4- or 3,5-position by methyl- " groups disubstituted cyclohexane ring forms, the unsubstituted cycloheptyl, cyclooctyl or the Decahydronaphthylrest means, as well as their salts and the process for their preparation.

The lower alkyl radicals are those with a straight or branched chain, for example methyl, ethyl, Propyl, butyl, amyl, isopropyl and isobutyl groups, as lower alkoxy groups, for example Methoxy, ethoxy, propoxy, butoxy and amyloxy groups into consideration.

All compounds of the general formula I in which the radical Z is a decahydronaphthalene radical, can come in two isomeric forms, hereinafter arbitrarily referred to as form "a" and form "b" will exist. Since the decahydronaphthalene residue itself exists in two isomeric forms, so there are for each of the forms "a" and "b" an cis and a trans isomer.

The inventive method for the preparation of the new oxazolidone (2) derivatives consists in that an acid chloride of the cis or trans form of the general formula II

in which Z has the meaning given above, with dimethylaminoethanol of the formula III

in a known manner in an organic solvent at a temperature of 20 to 70 ° C. and, if appropriate, the base of the general formula I obtained in a manner known per se Way converted into a salt with an acid.

The invention relates to new oxazolidone (2) derivatives of the general formula I.

in the Z together with the carbon atom of the oxazolidine ring through one in the 2-, 3- or 4-position N — C — Cl

in which Z has the meaning given above, with dimethylaminoethanol of the formula III

HO-CH ₃ -CH ₂ -N

CH,

CH,

III

in a manner known per se in an organic solvent at a temperature of 20 to 70.degree reacts and optionally the base of the general formula I obtained in a manner known per se converted into a salt with an acid. An aromatic hydrocarbon is advantageous as the organic solvent, for example benzene, or an aliphatic or heterocyclic ether, for example Tetrahydrofuran, used and in the presence of an excess of dimethylaminoethanol or one tertiary base as hydrogen halide acceptor, for example triethylamine or pyridine, worked.

It is advantageous to use a solution of the dimethylaminoethanol in the preferred solvent, which optionally contains the above-mentioned tertiary bases, the acid chloride dissolved in the same Solvent to be added.

The new oxazolidone (2) derivatives, which are strong bases, can by physical methods, for example Crystallization, chromatography, or by chemical methods such as education of salts with inorganic or organic

Acids, crystallization from a suitable solvent and decomposition in an alkaline medium will. In these operations, the type of anion does not matter, provided that it results in a well-defined and easily crystallizable salt. The bases are used for storage expediently converted into the salts.

The salts with mineral acids are the hydrochlorides, hydrobromides, sulfates, phosphates and methanesulfonates and as salts with organic acids the acetates, propionates, maleinates, fumarates, succinates, Benzoates, tartrates, malates and oxalates can be considered.

The compounds according to the invention have valuable therapeutic, in particular analgesic, ones and anti-inflammatory properties.

The toxicity of the new derivatives was determined as DL ₅₀ in the mouse when administered intraperitoneally.

The products according to the invention are in terms of their anti-inflammatory properties known, equally effective, commercially available 4-butyl-1,2-diphenyl-pyrazoIidin-3,5-dione (Phenylbutazone) or the 2,3-dimethyl-4-dimethylamino-1-phenyl-pyrazolone- (5) (aminophenazone) with regard to superior to analgesic effectiveness. The results of the comparative tests are in The table below shows the anti-inflammatory effectiveness due to the edema was determined on the rat paw evoked by injection of kaolin. The ones to be examined Compounds were used in a total of 600 mg / kg buccally in five Single doses of 120 mg / kg each administered within 48 hours. The analgesic effect was using the heated plate method according to Wo ο 1 f and McDonald (J. Pharmacol., 80 [1944], p. 300) definitely. '. .

N — C — O — CH, —CH, —N

Investigated connection example Z DL ₅₀ mouse Analgesic increase Anti-infl.
Effect, Therapeutic index 1 Cycloheptyl effect the rat tox. dose I. P. mg / kg at the mouse oLnmcrz-
threshold 600 mg /
ks PO act. dose 2 S-chloro-cyclohexyl 518.3 I. P. mg / kg % %. (571 to 470) 150 71.2 33 0.86 anti-infl. 3 4-methoxy-cyclohexyl 691.2 4th 3-methoxy-cyclohexyl (762 to 626) ■ - - 28.4 1.15 anti-infl. 7th 2-methyl-cyclohexyl > 1500 ~ 1000 - - 26.7 2.5 anti-infl. O 10 Cyclooctyl 1037 - - . 32 1.66 anti-infl. (1144 to 940). - - 60.3 1.73 anti-infl. 13th 3,5-dimethyl-cyclohexyl 462 ' (507 to 421) 150 '128 - ■ ■ ■ 3.08 anaig. 14th 3,3-dimethyl-cyclohexyl 813 (897 to 737) 150 47.8 - 5.42 anaig. 15th Decahydro-ct-naphthyl 522. trans (591 to 451) - - 39. 0.87 anti-infl. 16 Decahydro- / 9-naphthyl 263 trans (286 to 241) 100 98.6 -. 2.63 anaig. 17th Decahydro-a-naphthyl 439 ice cream (551 to 350) 150 45 - 2.93 anaig. 18th Decahydro- / S-naphthyl 492 ice cream (501 to 481) 150 136 - 3.7 anaig. 4-butyl-1,3-diphenylpyrazolidine 158 3,5-dione (phenylbutazone) (173 to 140) 50 68 - 3.16 anaig. 2,3-dimethyl-4-dimethylamino 311 1-phenyl-3-pyrazolone- (5) (355 to 273) - - · 37 0.52 anti-infl. (Aminophenazone) 210 (234 to 189) 100 57 - 2.1 anaig.

The new oxazolidone (2) derivatives can be buccal, rectal or parenteral with appropriate pharmacological carriers.

The following examples illustrate the invention. The melting points given were on the Definitely Kofier bench. The yields are given based on the acid chloride used.

example 1

Spiro [cycloheptane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine]

IO

A solution of 14.5 g of spiro [cycloheptanl, 5 '- (2'-oxo-3'-chloroformyl) oxazolidine] in 300 cm ^{3 of} anhydrous benzene is added dropwise over the course of 20 minutes at a temperature of 10 ° C. 11 , 2 g of dimethylaminoethanol in 30 cm ^{3 of} benzene. When the addition is complete, the temperature is allowed to rise to 23 ° C., during which time a small precipitate forms. After stirring for 2 hours, the mixture is left to stand for 24 hours at laboratory temperature. After this period of time, 100 cm ^{3 of} water are added and the benzene part is then decanted off. This latter is extracted several times with 10% hydrochloric acid, and the acidic extracts are made alkaline with potassium carbonate. After several extractions with ether and drying of the ether extracts over anhydrous potassium carbonate, the solvent was evaporated under reduced pressure at a temperature of about 4O ⁰ C. are thus obtained 15 g of crude oily base.

Obtained by adding dry hydrogen chloride to the base dissolved in anhydrous ethanol 15 g of the hydrochloride. Mp = 205 ° C. Yield: 72%.

The carboxylic acid chloride used as the starting substance (not isolated) in a benzene solution was saved by reacting an excess of phosgene with the sodium derivative of Spiro [cycloheptane - 1,5 '- (2' - oxo) - oxazolidine], melting point = 93 ° C., which in turn was made according to Newman and K u t η e r (Journal Am. Chem. Soc, 73 [1961], 4202).

Example 2

Spiro [2-chlorocyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine]

45

This compound is prepared according to Example 1 with a yield of 55%. The corresponding hydrochloride melts at 215 ° C (ethanol). The unisolated acid chloride used as the starting material was obtained according to Example 1 from spiro [2-chlorocyclohexane-1,5 '- [2'-oxo) oxazolidine], melting point. = 150 ° C., which in turn was produced by cyclization of l-aminomethyl-2-chloro-cyclohexanol- (1) (hydrochloride: melting point = 186 ° C.) with phosgene in the presence of potassium hydroxide. 1-Aminomethyl-2-chlorocyclohexanol- (l) was obtained by catalytic reduction of l-nitromethyl- (2-chloro) -cyclohexanol- (l) (bp ₁₅ = 115 to 119 ° C; n ?, ⁵ = 1.5030 ) receive.

Example ^

Spiro [4-methoxycyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine]

This product is prepared according to the procedure of Example 1 with a yield of 42%. The corresponding acidic fumarate melts at 144 ° C.

65 The unisolated acid chloride used as the starting substance was prepared from spiro [4-methoxycyclohexane-1,5 '- (2'-oxo) -oxazolidine], melting point = 135 ° C., which in turn was produced by Curtius degradation of 2- [ 4'-methoxy-l'-hydroxycyclohexyl (r)] - acethydrazide, mp = 86 ⁰ C, was obtained.. The hydrazide was prepared from 4 '- methoxy - Γ - hydroxycyclohexyl (l') - acetic acid _{ethyl ester (bp. 0> 4} = 92 to 98 ° C; n "= 1.4623), which by reaction according to Reformatzki with 4-methoxycyclohexane had been received.

B e i s ρ i e 1 4

Spiro [2-methoxycyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine]

This product is prepared according to the procedure of Example 1 in a yield of 40%. The corresponding acidic fumarate melts at 160 ^° C.

The starting materials were prepared as from 2'-methoxy-l'-hydroxycyclohexyl (r) -acetate described in Example 3; manufacturer (Kp _{0, 5} = 80 to 85 ° C n% = 1.4598.). placed. (C.

Example 5

Spiro ^ -methylcyclohexane-l ^ '- ^' - oxo ^ '- dimethylaminoethoxycarbonyl) -oxazolidine] (Form a)

• This product is produced according to the procedure of Example 1 with a yield of 67%. The corresponding hydrochloride melts at 207 ° C. The starting substances were processed in the same way produced as in example 3. The acid chloride used as the starting substance was not isolated.

Spiro [2 - methylcyclohexane - 1,5 '- (2' - oxo) - oxazolidine], mp = 110 ° C (Forma); 2'-Methyl-l'-hydroxycyclohexyl- (l ') -acetic acid ethyl ester _{: bp 6} = 105 to 107 ⁰ C, η% = 1.4588.

Examples

Spiro [4-methylcyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine] (Form a)

This product is prepared according to the procedure of Example 1 ι with a yield of 89%, v The corresponding acid fumarate melts at 161 ° C.

The starting materials were in a procedure which was analogous to that of Example 3. The acid chloride used as the starting product was not isolated.

Spiro [2 - methylcyclohexane -1,5 '- (2' - oxo) - oxazolidine], mp = 110 ° C (Forma); 2'-methyl-1'-hydroxycyclohexyl- (1) -acetylhydrazide: mp = 121 ° C; 4'-Methyl-l'-hydroxycyclohexyl- (l ') -acetic acid ethyl ester _{: bp 8} = 112 to 116 ° C, n ² i = 1.4552.

Example 7

Spiro [3-methylcyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine] (Form a)

This compound was prepared following the procedure of Example 1 in a yield of 61%. The acidic fumarate melts at 151 to 152 ° C.

The starting substances were prepared in a manner analogous to that given in Example 3 was. The acid chloride used as the starting product was not isolated.

IO

20th

Spiro [1 - methylcyclohexane -1,5 '- (T - oxo) - oxazolidine]: melting point = 131 ^° C. (Forma); 4'-methyl-l'-hytionized crystallizations from petroleum ether separated from form b); 3'-methyl-Γ-hydroxycyclohexyl- (I ') -acethydrazide: mp = 76 ° C; 3'-Methyl-1 '- hydroxycyclohexyl - (1') - acetic acid ethyl ester : _{b.p. 6} = 109 to 113 ° C, _no ^{9 = 1.4569.}

Examples

Spiro [3-methylcyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine] (Form b)

This compound is prepared according to the procedure of Example 1 in a yield of 50%. The corresponding fumarate melts at 144 to 146 ° C.

The acid chloride used as the starting substance was not isolated.

Spiro [3 - methylcyclohexane -1,5 '- (T - oxo) - oxazolidine]: mp = 53 to 55 ° C (form b).

Example 9

Spiro [3-methylcyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethylcarbamido) oxazolidine] (Form a)

This compound is obtained by following the procedure of Example 1 from dimethylaminoethylamine in one yield produced by 34%. The corresponding acidic fumarate melts at 158 ° C.

Example 10

Spiro [cyclooctane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine]

This compound is prepared according to the procedure of Example 1 in a yield of 70%. The corresponding acidic fumarate melts at 142 to 144 ° C. The one used as the starting substance Acid chloride is not isolated.

Spiro [cyclooctane -1,5 '- (T - oxo) - oxazolidine]: melting point = 127 ^° C .; 1 - Hydroxycyclooctyl - (X) - acetydrazide: mp = 81 ° C; Γ -Hydroxycyclooctyl - (V) - ethyl acetate: b.p. ₄ = 121 to 125 ° C, n | ⁵ = 1.4718.

Example 11

Spiro [cis-3,5-dimethylcyclohexane-1,5 '- (2'-oxo-

3'-dimethyiaminoethoxycarbonyl) oxazolidine]

(Form a)

This compound is prepared according to the procedure of Example 1 in a yield of 82%. The acid fumarate melts at 104 ⁰ C with decomposition and then at 167 ° C. The acid chloride used as starting substance is not isolated.

Spiro [cis - 3,5 - dimethylcyclohexane -1,5 '- (T - oxo) oxazolidine] (Forma): mp = 120 ° C; cis -3 ', 5'-dimethyl - 1' - hydroxycyclohexyl - (V) - acethydrazide: mp = 114 ° C; Eis-3 ', 5'-dimethyl -V-hydroxycyclohexyl - (V) - ethyl acetate: boiling point ₇₅ = 89 ° C. n ^! g = 1.4535.

B e i s ρ i e 1 12.

Spiro P ^ -dimethylcyclohexane-1,5 '- (2'-oxo-

3'-dimethylaminoethoxycarbonyl) oxazolidine]

65

This compound is prepared according to the procedure of Example 1 in a yield of 75%. The acidic fumarate melts at 149 ° C.

60 Spiro [3,4-dimethylcyclohexane-1,5 '- (2'-oxo) oxazolidine]: mp = 103 ° C; 3 ', 4' - Dimethyl - V - hydroxycyclohexyl - (V) - acethydrazide (oil), 3 ', 4' - Dimethyll'-hydroxycyclohexyl- (l ') - ethyl acetate _{: boiling point o} [= 85 to 94 ° C, ni ⁵ = 1.4580.

Example 13

Spiro [3-ethyyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine] (Form a)

The compound is prepared according to the procedure of Example 1 in a yield of 75%. The acidic fumarate melts at 150 ° C. That is the starting product acid chloride used was not isolated.

Spiro [3-ethyleyclohexane -1,5 ' - (T -oxo) -oxazo lidine] (Forma): m.p. = 109 ° C; 3'-Methyl-l'-hydroxycyclohexyl- (1 ') -acethydrazide (oil), 3'-ethyl -1'-hydroxycyclohexyl- (V) -acetic acid ethyl ester: Bp. ₆ = 123 to 126 ⁰ C, n ² S = 1.4582.

Example 14

Spiro [3,3-dimethylcyclohexane-1,5 '- (2'-oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine]

This compound is prepared according to the procedure of Example 1 in a yield of 72.5%. The acidic fumarate melts at 163 ° C. The acid chloride used as the starting product was not isolated.

Spiro [3,3-dimethylcyclohexane-1.5 '- (2'-oxo) oxazolidine]: mp = 148 ° C; 3 ', 3' - dimethyl - V - hydroxycyclohexyl - (V) - acethydrazide (oil), 3 ', 3' - dimethyl-1 '- hydroxycyclohexyl - (1') - ethyl acetate _{: b.p. t} = 88 to 92 ° C .

B e i s ρ i e 1 15

trans-Spiro [decahydronaphthalene-2,5 '- (2'-oxo-

3'-dimethylaminoethoxycarbonyl) oxazolidine]

(Form a)

This compound is prepared according to the procedure of Example 1 in a yield of 25%. The hydrochloride melts at 196 to 198 ° C. The acid chloride used as the starting substance was not isolated.

trans - Spiro [decahydronaphthalene - 2,5 '- (T - oxo) -oxazolidine] (Forma):' Mp. = 200 ° C (from isopropanol), (Form b): Mp. = 165 ° C (from ethyl acetate) .

trans - 2 - hydroxy - decahydronaphthyl - (2) - acethydrazide: mp = 107 ° C; trans - 2 - hydroxy - decahydronaphthyl - (2) acetic acid ethyl ester: boiling point ₇ = 153 to 154 ° C, n ₀ = 1.4820.

Example 16

trans-Spiro [decahydronaphthalene-2,5 '- (2'-oxo-

3'-dimethylaminoethoxycarbonyl) oxazolidine]

(Form b)

This compound is prepared according to the procedure of Example 1 in a yield of 60%. The acidic fumarate melts at 148 ° C.

309 010/133

Example 17

cis-Spiro [decahydronaphthalene-2,5 '- (2'-oxo-

3'-dimethylaminoethoxycarbonyl) oxazolidine]

(Form a)

This compound is prepared according to the procedure of Example 1 in a yield of 76.7%. The corresponding acidic fumarate melts at 154 ^° C.

The acid chloride used as the starting product was not isolated.

cis-spiro [decahydronaphthalene-2,5 '- (2'-oxo) oxazolidin] (Form A). m.p. = 140 ⁰ C (from ethyl acetate) (Form B): mp = 207 ⁰ C (from isopropanol. ).

ice - 2 '- Hydroxydecahydronaphthyl - (2') - acethydrazide: mp = 83 ⁰ C;. Eis - 2 '- Hydroxydecahydronaphthyl - (2') - ethyl acetate: b.p. ₇ = 161 to 164 ° C, no = 1.4865.

Example 18

cis-Spiro [decahydronaphthalene-2,5 '- (2' _: oxo-3'-dimethylaminoethoxycarbonyl) oxazolidine]

(Form b)

This compound is prepared according to the procedure of Example 1 in a yield of 49%. The hydrochloride melts at 176 ° C and then at 185 ⁰ C.

Claims (1)

Patent claims: 1. Oxazolidone (2) derivatives of the general formula I N — C — O — CH, —CH, —N in the Z together with the carbon atom of the oxazolidine ring one in the 2-, 3- or 4-position by a chlorine atom or a low molecular weight alkyl or alkoxy group with up to 5 carbon atoms or in the 2,3-, 3,3-, 3,4- or 3,5-position disubstituted by methyl groups cyclohexane ring forms the unsubstituted cycloheptyl, cyclooctyl or decahydronaphthyl radical means, and their salts.