WO2003068734A1

WO2003068734A1 - Carbamide esters for treating pain

Info

Publication number: WO2003068734A1
Application number: PCT/EP2003/001320
Authority: WO
Inventors: Helmut Buschmann; Claudia Pütz; Dieter Enders; Stefan OBERBÖRSCH
Original assignee: Grünenthal GmbH
Priority date: 2002-02-14
Filing date: 2003-02-11
Publication date: 2003-08-21
Also published as: DE10206405A1; AU2003208830A1

Abstract

The invention relates to carbamide esters of general formula (I) wherein R1 is selected from H, substituted or non-substituted, branched or linear, saturated or unsaturated C1-6 alkyl, and aryl or heteroaryl which are respectively substituted at least once or non-substituted. The invention also relates to a method for producing said carbamide esters, to medicaments containing the same, and to the use of the inventive carbamide esters for producing medicaments for treating pain.

Description

CARBAMIDE STAR TREATMENT OF PAIN

The invention relates to carbamide esters, a process for their preparation, medicaments containing carbamide esters according to the invention and the use of carbamide esters according to the invention for the production of medicaments for the treatment of pain.

The treatment of chronic and non-chronic pain conditions is of great importance in medicine. There is a worldwide need for well-effective pain therapies for a patient-oriented and goal-oriented treatment of chronic and non-chronic pain conditions, which means the successful and satisfactory pain treatment for the patient. This can be seen in the large number of scientific papers that have recently appeared in the field of applied analgesics or basic research on nociception.

A well-known therapeutic agent for the treatment of severe pain is tramadol hydrochloride - (1 RS, 2RS) -2 - [(dimethylamino) methyl] -1 - (3-methoxyphenyl) cyclohexanol, hydrochloride. Aminomethyl-aryl-cyclohexanol derivatives such as tramadol ((1 RS, 2RS) -2-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclo-hexanol, hydrochloride) can have an analgesic effect, but also hydroxylated tramadol Derivatives as described, for example, in EP 753506 A1, or they can be used as intermediates for the preparation of analgesically active substances (such as, for example, 4- or 5-substituted tramadol analogs which are described in EP 753 506 A1 or EP 780 369 A1). Tramadol, in particular, occupies a special position among the centrally active analgesics in that this active ingredient causes strong pain relief without the side effects known for opioids (J. Pharmacol. Exptl. Ther. 267, 331 (1993)), both the enantiomers of tramadol and the enantiomers of the tramadol metabolites are involved in the analgesic effect (J. Pharmacol. Exp. Ther. 260, 275 (1992)).

But there is still a need for other pain relievers.

The invention therefore relates to carbamide esters according to general formula I.

, in which

Ri is selected from

H, C-ι- ₆ alkyl, substituted or unsubstituted, branched or unbranched, saturated or unsaturated; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in represented form or in the form of their acids or their bases or in the form of their salts, in particular the physiologically tolerable salts, or in the form of their solvates, in particular the hydrates.

The compounds shown are effective analgesics.

For the purposes of this invention, alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. C-ι _-2 alkyl for C1- or C2-alkyl, C _1-3 -alkyl for C1-, C2- or C-3-alkyl, Cι _-4 -alkyl for C1-, C2-, C3- or C4-alkyl, Ci.s-alkyl for C1-, C2-, C3-, C4- or C5-alkyl, Cι _-6 -alkyl for C1-, C2-, C3-, C4-, C5- or C6- Alkyl, C _1-7 -alkyl for C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, C _1-8 -alkyl for C1-, C2-, C3-, C4-, C5, C6, C7 or C8 alkyl, d-io-alkyl for C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl and C _1-18 alkyl for C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15 -, C16, C17 or C18 alkyl. Next is C ₃ . ₄ cycloalkyl for C3 or C4 cycloalkyl, C _3-5 cycloalkyl for C3, C4 or C5 cycloalkyl, C _3-6 cycloalkyl for C3, C4, C5 or C6 cycloalkyl, C _{3 -7-} cycloalkyl for C3-, C4-, C5-, C6- or C7-cycloalkyl, C _3-8 -cycloalkyl for C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl, C _{4- 5-} cycloalkyl for C4- or C5-cycloalkyl, C _4-6 -cycloalkyl for C4-, C5- or C6-cycloalkyl, C _4-7 -cycloalkyl for C4-, C5-, C6- or C7-cycloalkyl, C _{5 -6-} Cycloalkyl for C5- or C6-cycloalkyl and C - -cycloalkyl for C5-, C6- or C7-cycloalkyl. With regard to cycloalkyl, the term also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O. The term cycloalkyl also includes, in particular, one or more, preferably mono-, unsaturated cycloalkyls without a hetero atom in the ring, as long as the cycloalkyl is not an aromatic system. The alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, Pentyl, 1, 1-di methylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF2, CF3 or CH2OH as well

Pyrazolinone, oxopyrazolinone, [1, 4] dioxane or dioxolane. In the context of alkyl and cycloalkyl - as long as this is not expressly defined otherwise - the term substituted in the sense of this invention means the substitution of at least one (possibly also several) hydrogen radicals by F, Cl, Br, I, NH ₂ , SH or OH, where “multiply substituted” or “substituted” is to be understood in the case of multiple substitution that the substitution takes place both on different and on the same atom several times with the same or different substituents, for example three times on the same carbon atom as in the case of CF ₃ or in different places as in the case of -CH (OH) -CH = CH-CHCI ₂ . Particularly preferred substituents here are F, Cl and OH. With regard to cycloalkyl, the hydrogen radical can also be substituted by OCι _-3 alkyl or Cι _-3 alkyl (each one or more times substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF ₃ , methoxy or ethoxy , be replaced.

Under the term (CH ₂ ) ₃ - ₆ is -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ - CH ₂ -CH ₂ -CH ₂ -CH ₂ - and CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - to be understood, (CH ₂ ) _1-4 is -CH ₂ - _, -CH ₂ -CH ₂ -, -CH ₂ - CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ -CH ₂ - to understand, etc.

An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted.

A heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur contain and can also be mono- or polysubstituted. Examples include from the group of heteroaryls furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo [1, 2.5] thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole , Indole and quinazoline listed.

In connection with aryl and heteroaryl, substituted - if not expressly defined otherwise - means the substitution of aryl or heteroaryl with R ²³ , OR ^23, a halogen, preferably F and / or Cl, a CF3, a CN, a NO2, one NR ²⁴ R ² ^, one

(saturated), a C-μ-alkoxy, a C .ß-cycloalkoxy, a

C.G-cycloalkyl or a C2_ß-alkylene.

The rest is there preferably one

C- _j _SS-alkyl, an aryl or heteroaryl, or for a via C - ^ - alkyl, saturated or unsaturated, or

bound

Aryl or heteroaryl radical, where these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals,

the residues R ²⁴ and

preferably a C- _j .g-alkyl, an aryl, a heteroaryl or one via C- _j . -Alkyl, saturated or unsaturated, or a C < _| _3-alkylene group means aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals,

or the radicals R ²⁴ and R ²⁵ together mean CH2CH2OCH2CH2,

CH ₂ CH2NR ²⁶ CH ₂ CH2 or (CH ₂ ) ₃ . ₆ , and the radical R ² ^ for H, a C- _j ^ g-alkyl, preferably a C _η .g-alkyl, an aryl or heteroaryl radical or for a via C- _j _3-alkyl, saturated or unsaturated , or a C « _| _3-alkylene group bound aryl or

Heteroaryl radical, where these aryl and heteroaryl radicals themselves may not be substituted with aryl or heteroaryl radicals.

The term salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions. In particular, this means physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids.

For the purposes of this invention, the term “physiologically compatible salt with cations or bases” means salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which is physiologically - in particular when used in humans and / or mammal - are compatible. The salts of the alkali and alkaline earth metals are also particularly preferred, however, with NH ⁺ , but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

For the purposes of this invention, the term “physiologically compatible salt with anions or acids” is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which especially when used in humans and / or mammals - are compatible. For the purposes of this invention, this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals. Examples of physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2-dihydrol λ ⁶ -benzo [d] isothiazol-3-one (saccharic acid),

Monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid,

Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. The hydrochloride salt is particularly preferred.

It is particularly preferred if the following applies to the carbamide esters according to the invention:

Ri is selected from

H; Phenyl or heteroaryl, each mono- or polysubstituted or unsubstituted;

especially from

H, furyl or pyridinyl; or unsubstituted phenyl; or in para position with OCι- alkyl or C-ι- alkyl (each substituted or unsubstituted, branched or unbranched, saturated or unsaturated) or halogen substituted

phenyl;

preferably from H, unsubstituted furyl or pyridinyl; or unsubstituted phenyl; or in the para position with OCH ₃ , CF ₃ t-butyl or CH ₃ substituted phenyl.

Carbamide esters according to the invention are also preferably selected from:

Tert-butyl pyridin-2-yl- (toluene-4-sulfonyl) methyl] -carbamic acid,

Furan-2-yl- (toluene-4-sulfonyl) -methyl] carbamic acid tert-butyl ester,

(Toluene-4-sulfonyl) -p-tolyl-methyl] -carbamic acid tert-butyl ester;

Phenyl- (toluene-4-sulfonyl) -methyl] -carbamic acid tert-butyl ester,

(4-tert-butylphenyl) toluene-4-sulfonyl) methyl] carbamic acid tert-butyl ester,

(Toluene-4-sulfonylmethyl) carbamic acid tert-butyl ester,

(Toluene-4-sulfonyl) - (4-trifluoromethyl-phenyl) -methyl] -carbamic acid tert-butyl ester or

(4-methoxyphenyl) - (toluene-4-sulfonyl) methyl] tert-butyl carbamate;

optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, in particular the physiologically tolerable salts, or in the form of their solvates, in particular the hydrates.

Another object of the invention is a process for the preparation of carbamide esters of the general formula I according to the following reaction scheme:

IV

, the reaction taking place in an aqueous alcoholic medium at acidic pH. It is particularly preferred if the alcohol added for the reaction is EtOH or MeOH, preferably EtOH, and / or carboxylic acid, preferably formic acid, is added to achieve the acidic pH, and / or the reaction is carried out at temperatures between room temperature and 80-90 ° C takes place.

This synthesis was based on methods known from the literature (AM Kanazawa; J.-N. Denis, AE Greene, J. Org. Chem. 1994, 59, 1238; JBFN Engberts, J. Strating, Recueil 1965, 84, 942; JBTN Engberts , J. Strating, Recueil 1964, 83, 733; WH Peason, AC Lindbeck, JW Kampf, J. Am. Chem. Soc. 1993, 115, 2622; R. Ballini, M. Petrine, Tetrahedron Lett. 1999, 40, 4449).

The substances according to the invention are toxicologically harmless, so that they are suitable as active pharmaceutical ingredients in pharmaceuticals. The invention therefore furthermore relates to medicaments comprising at least one carbamide ester according to the invention and optionally further active ingredients, auxiliaries and / or additives.

In addition to at least one substituted compound according to the invention, the medicaments according to the invention optionally contain suitable additives and / or auxiliaries, including carrier materials, fillers, solvents, diluents, dyes and / or binders and can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of excipients etc. and the amounts to be used depend on whether the medicinal product is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local, for example on the skin, mucous membranes or in the eyes to be applied. Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration. Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration, are suitable percutaneous application preparations. Formulations which can be used orally or percutaneously can release the compounds according to the invention with a delay. In principle, other active substances known to the person skilled in the art can be added to the medicaments according to the invention.

The amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. Usually 0.005 to 1000 mg / kg, preferably 0.05 to 5 mg / kg, of at least one compound according to the invention are applied.

The invention further relates to the use of a carbamide ester according to the invention for the manufacture of a medicament for the treatment of pain, anxiety, depression or epilepsy, in particular pain. In the following, the invention is further generally explained in particular by examples, without being restricted thereto.

Examples

Example 1: Synthesis

The synthesis was based on methods known from the literature (AM Kanazawa; J.-N. Denis, AE Greene, J. Org. Chem. 1994, 59, 1238; JBFN Engberts, J. Strating, Recueil 1965, 84, 942; JBTN Engberts , J. Strating, Recueil 1964, 83, 733; WH Peason, AC Lindbeck, JW Kampf, J. Am. Chem. Soc. 1993, 115, 2622; R. Ballini, M. Petrine, Tetrahedron Lett. 1999, 40, 4449th

IV

The carbamates are prepared by adding a solution of the carbamic acid ester II and the p-toluenesulfonic acid sodium salt III in methanol and water as the solvent, the aldehyde IV and 88% formic acid. The reaction solutions are stirred for 24 hours at room temperature or alternatively heated at 80-90 ° C. for 1.5-2 hours. The aldehydes are used to achieve as complete a conversion as possible and to maintain the carbamates in as high a purity as possible used in excess of 1.5 - 2.0 equivalents in the reaction. The liquid aldehydes used in excess can be removed by washing the solid carbamates with n-pentane.

Example 2:

General working instructions:

To a solution of one equivalent of carbamic acid tert-butyl ester and 2.5 equivalents of p-toluenesulfinic acid sodium salt in water (200 ml per 0.1 mol carbamic acid fatty butyl ester) and methanol (75 ml per 0.1 mol carbamic acid te / f-butyl ester) are added with stirring two equivalents of aldehyde (diluted with 12.5 ml of methanol per 0.1 mol of aldehyde) and two equivalents of 88% formic acid and stirred for 24 hours at room temperature. Due to the formation of an emulsion in some aldehydes, ethanol is added and the mixture is stirred at room temperature and / or warmed to the homogeneous reaction solution (see individual description of the experiments). The precipitated colorless solids are worked up by filtration and washing with water and n-pentane.

Example 3:

Compounds synthesized according to Example 1 and / or 2

[Pyridin-2-yl (toluene-4-sulfonyl) methyl] carbamic acid tert-butyl ester terι

According to AAV 1, 5.85 g (50 mmol) of fatty butyl carbamic acid, 21.38 g (120 mmol) of p-toluenesulfinic acid sodium salt and 10.70 g (100 mmol) of pyridine-2-aldehyde reacted with the addition of 6.0 ml of formic acid. The product is obtained as a colorless solid.

Yield: 15.56 g

(86% of theory) Melting point: 167-170 ° C

¹ H NMR Spectrum (300 MHz, CDCI ₃ ): δ = 1.27 (s, 9H, OC (CH ₃ ) ₃ ), 2.42 (s, 3H, C ₆ H ₄ CH ₃ ), 6.00 (d, 1 H , J = 9.3, CHNH), 6.78 (d, 1 H, J = 9.3, CHNH), 7.60 - 7.81 (kB, 7H, CH ^Ar -C ₅ H ₄ N, CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 8.61 (d, 1 H, J = 3.8, CH ^Ar -C ₅ H ₄ N) ppm.

¹³ C NMR spectrum (75 MHz, CDCI ₃ ): δ = 21.7 (C ₆ H ₄ CH ₃ ), 28.0 (OC (CH ₃ ) ₃ ), 74.4 (CHNH), 80.7 (OC (CH ₃ ) ₃ ) , 124.4 (CH ^Ar -C ₅ H ₄ N), 125.6 (CH ^Ar -C ₅ H ₄ N) 129.6 (CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 129.9 (CH ^Ar - CH ₃ C ₆ H ₄ S0 ₂ ), 133.5 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 136.6 (CH ^Ar -C ₅ H ₄ N), 145.0 (C ^Ar - CH ₃ C ₆ H ₄ S0 ₂ ), 148.0 (C ^Ar -C ₅ H ₄ N), 149.5 (CH ^Ar -C ₅ H ₄ N), 153.7 (C = 0) ppm.

IR spectrum (KBr pellet): v = 3418 (m), 3092 (m), 3069 (w), 3008 (s), 2969 (m), 2930 (w), 2729 (w), 2304 (w) , 1924 (f), 1713 (s), 1670 (f), 1593 (m), 1571 (m), 1491 (s), 1474 (m), 1437 (m), 1394 (m), 1372 (s) , 1334 (s), 1321 (s), 1304 (m), 1294 (w), 1255 (m), 1226 (m), 1176 (s), 1148 (s), 1118 (m), 1086 (m) , 1049 (m), 1019 (m), 997 (m), 961 (w), 892 (w), 850 (m), 810 (m), 775 (m), 749 (m), 722 (m) , 699 (w), 669 (m), 630 (m), 622 (w), 571 (m), 521 (s), 491 (m), 464 (m) cm ^-1 .

Mass spectrum (Cl, isobutane): m / z (rl%) = 363 (19, M ⁺ +1), 209 (25), 208 (18), 207 (95), 206 (8), 195 (5), 163 (4), 159 (5), 158 (9), 157 (100), 156 (5), 153 (10), 152 (10), 151 (95), 150 (5), 145 (4), 141 (5), 139 (5), 107 (35). Elemental analysis (Cι ₈ H ₂₂ N ₂ 0 ₄ S, 362.444): calc .: C = 59.65 H = 6.12 N = 7.73 found: C = 59.64 H = 6.10 N = 7.67

[Furan-2-yl (toluene-4-sulfonyl) methyl] carbamic acid tert-butyl ester 19h

According to AAV 1, 4.69 g (40 mmol) of carbamic acid tetτ-butyl ester, 17.81 g (100 mmol) of p-toluenesulfinic acid sodium salt and 7.68 g (80 mmol) of 2-furylaldehyde are reacted with the addition of 6.0 ml of formic acid. The product is obtained as a colorless solid.

Yield: 9.83 g

(70% of theory) Melting point: 145-147 ° C

¹ H NMR Spectrum (400 MHz, CDCI ₃ ): δ = 1.29 (s, 9H, C (CH ₃ ) ₃ ), 2.42 (s, 3H, C ₆ H ₄ CH ₃ ), 5.86 (d, 1 H , J = 10.4,

CHNH), 6.00 (d, 1 H, J = 10.4, CHNH), 6.44 (m, 1 H, CH ^Ar -C ₄ H ₃ 0), 6.57 (m,

1 H, CH ^Ar -C ₄ H ₃ 0), 7.29 - 7.80 (kB, 5H, CH ^Ar -C ₄ H ₃ 0, CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ) ppm.

¹³ C-NMR spectrum (100 MHz, CDCI ₃ ): δ = 21.6 (C ₆ H ₄ CH ₃ ), 27.9 (C (CH ₃ ) ₃ ), 68.9 (CHNH), 81.2 (C (CH ₃ ) ₃ ) , 111.0 (CH ^Ar -C ₄ H ₃ 0), 112.0 (CH ^Ar -C ₄ H ₃ 0), 129.4 (CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 129.5 (CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 133.2 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 143.0 (C ^Ar -C ₄ H ₃ 0), 144.0 (CH ^Ar -C ₄ H ₃ 0), 145.0 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 153.7 (C = 0) ppm. IR spectrum (KBr pellet): v = 3383 (m), 3268 (m), 3148 (w), 3049 (w), 3028 (w), 2978 (m), 2923 (w), 1936 (w) , 1703 (s), 1596 (m), 1539 (m), 1510 (m), 1496 (m), 1476 (w), 1460 (w), 1393 (m), 1367 (m), 1314 (s) , 1306 (s), 1289 (m), 1269 (m), 1250 (m), 1224 (w), 1179 (m), 1143 (s), 1085 (m), 1071 (w), 1047 (w) , 1018 (m), 955 (w), 933 (w), 874 (w), 818 (m), 764 (s), 703 (m), 686 (w), 666 (m), 630 (w) , 597 (m), 548 (m), 565 (s), 525 (m), 479 (w) cm ^-1 .

[(Toluene-4-sulfonyl) -p-tolyl-methyl] carbamate te /? - butyl

According to AAV 1, 4.69 g (40 mmol) of carbamic acid / τ-butyl ester, 17.81 g (100 mmol) of p-toluenesulfinic acid sodium salt and 9.60 g (80 mmol) of p-methylbenzaldehyde are reacted with the addition of 6.0 ml of formic acid. The product is obtained as a colorless solid.

Yield: 12.15 g

(81% of theory) Melting point: 187 ° C

¹ H-NMR spectrum (400 MHz, CDCI ₃ ): δ = 1.25 (s, 9H, C (CH ₃ ) ₃ ), 2.36 (s, 3H, C ₆ H ₄ CH ₃ ), 2.42 (s, 3H, C ₆ H ₄ CH ₃ ),

5.84 (m, 2H, CHNH, CHNH), 7.20 - 7.90 (kB, 8H, CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ , CH ^Ar -

C ₆ H ₄ CH ₃ ) ppm.

³ C-NMR spectrum (100 MHz, CDCI ₃ ): δ = 21.2 (C ₆ H ₄ CH ₃ ), 21.9 (C ₆ H ₄ CH ₃ ), 27.9 (C (CH ₃ ) ₃ ), 73.6 (CHNH), 80.9 (C (CH ₃ ) ₃ ), 126.8 (C ^Ar -C ₆ H ₄ CH ₃ ), 128.6 (CH ^Ar -C ₆ H ₄ CH ₃ ), 129.2 (CH ^Ar - CH ₃ C ₆ H ₄ S0 ₂ ), 129.3 (CH ^Ar -C ₆ H ₄ CH ₃ ) , 129.4 (CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 133.5 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 139.7 (C ^Ar -C ₆ H ₄ CH ₃ ), 144.7 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 153.3 (C = 0) ppm.

IR spectrum (KBr pellet): v = 3363 (s), 3065 (w), 3042 (m), 3008 (s), 2979 (m), 2951 (m), 2925 (m), 2767 (w) , 2403 (w), 2302 (w), 2224 (w), 1914 (w), 1796 (w), 1717 (s), 1614 (w), 1596 (m), 1528 (m), 1512 (s) , 1455 (f), 1395 (f), 1372 (m), 1362 (m), 1319 (s), 1283 (m), 1250 (s), 1166 (s), 1143 (s), 1086 (m) , 1049 (m), 1022 (m), 948 (w), 885 (m), 829 (w), 809 (m), 779 (w), 762 (w), 726 (w), 708 (m) , 691 (w), 656 (s), 612 (m), 586 (s), 546 (m), 513 (m), 468 (w) cm ^-1 .

Mass spectrum (El, 70 eV): m / z (rl%) = 220 (4, M ⁺ -S0 ₂ C ₆ H ₄ CH ₃ ), 164 (16), 160 (8), 146 (24), 120

(10), 119 (9), 118 (7), 91 (10), 65 (6), 58 (4), 57 (100).

Elemental analysis (C ₂₀ H ₂₅ NO ₄ S, 375.483): calc .: C = 63.98 H = 6.71 N = 3.73 found: C = 64.07 H = 6.55 N = 3.62

Mass spectrum (El, 70 eV): m / z (rl%) = 196 (4, M ⁺ -S0 ₂ C ₆ H ₄ CH ₃ ), 140 (14), 139 (13), 136 (4), 122

(36), 96 (11), 95 (6), 94 (5), 66 (4), 58 (4), 57 (100).

Elemental analysis (C ₁₇ H ₂₁ N0 ₅ S, 351.417): calc .: C = 58.10 H = 6.02 N = 3.99 found: C = 57.99 H = 5.95 N = 3.88 [Phenyl (toluene-4-sulfonyl) methyl] carbamic acid tert-butyl ester

According to AAV 1, 4.69 g (40 mmol) of carbamic acid fe / τ-butyl ester, 17.81 g (100 mmol) of p-toluenesulfinic acid sodium salt and 8.48 g (80 mmol) of benzaldehyde are reacted with the addition of 6.0 ml of formic acid. The product is obtained as a colorless solid.

Yield: 12.30 g

(85% of theory) Melting point: 171 ° C

[(4-fert-butylphenyl) - (toluene-4-sulfonyl) methyl] carbamic acid fe / - butyl ester

According to AAV 1, 4.69 g (40 mmol) of tert-butyl carbamic acid, 17.81 g (100 mmol) of p-toluenesulfinic acid sodium salt and 12.96 g (80 mmol) p-tetf-butylbenzaldehyde with the addition of 6.0 ml of formic acid heated to 90 ° C for 2 hours and stirred for three days at room temperature. The product is obtained as a colorless solid.

Yield: 10.84 g

(65% of theory) Melting point: 181-185 ° C

¹ H-NMR spectrum (400 MHz, CDCI ₃ ): δ = 1.24 (s, 9H, C ₆ H ₄ C (CH ₃ ) ₃ ), 1.32 (s, 9H, OC (CH ₃ ) ₃ ), 2.42 ( s, 3H, C ₆ H ₄ CH ₃ ), 5.84 (m, 2H, CHNH, CHNH), 7.30 - 7.80 (kB, 8H, CH ^Ar - C ₆ H ₄ C (CH ₃ ) ₃ , CjH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ) ppm.

¹³ C-NMR spectrum (100 MHz, CDCI ₃ ): δ = 21.6 (C ₆ H ₄ CH ₃ ), 28.0 (OC (CH ₃ ) ₃ ), 28.0 (C ₆ H ₄ C (CH ₃ ) ₃ ), 34.7 (C ₆ H ₄ C (CH ₃ ) ₃ ), 73.5 (CHNH), 80.8 (OC (CH ₃ ) ₃ ), 125.7 (CH ^Ar -C ₆ H ₄ C (CH ₃ ) ₃ ), 126.7 (C ^Ar -C ₆ H ₄ C (CH ₃ ) ₃ ), 128.4 (CH ^Ar -C ₆ H ₄ C (CH ₃ ) ₃ ), 129.3 (CH ^Ar - CH ₃ C ₆ H ₄ S0 ₂ ), 129.4 (CH ^Ar - CH ₃ C ₆ H ₄ S0 ₂ ), 133.7 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 144.7 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 152.7 (C ^Ar -C ₆ H ₄ C (CH ₃ ) ₃ ), 153.2 (C = 0) ppm.

IR spectrum (KBr pellet): v = 3676 (w), 3374 (s), 3063 (w), 3043 (w), 2970 (m), 2954 (m), 2871 (w), 2405 (w) , 2294 (w), 1922 (w), 1800 (w), 1711 (s), 1654 (w), 1597 (w), 1577 (w), 1510 (s), 1452 (w), 1397 (w) , 1384 (f), 1368 (m), 1333 (m), 1319 (s), 1307 (s), 1287 (m), 1269 (m), 1247 (m), 1163 (s), 1143 (s) , 1107 (m), 1086 (m), 1049 (m), 1022 (m), 927 (w), 884 (m), 844 (m), 814 (m), 783 (w), 770 (w) , 748 (w), 727 (w), 704 (w), 686 (w), 649 (w), 585 (s), 541 (m), 517 (m), 481 (w) cnrf ¹ .

Mass spectrum (El, 70 eV): m / z (rl%) = 261 (6, M ⁺ -S0 ₂ C ₆ H ₄ CH ₃ ), 206 (20), 202 (13), 190 (5), 188 (23), 172 (6), 162 (10), 161 (8), 160 (4), 158 (4), 156 (8), 146 (24), 118 (5), 92 (8), 91 (15), 65 (6), 57 (100).

Elemental analysis (C ₂₃ H ₃ ιN0 ₄ S, 417.564): calc .: C = 66.16 H = 7.48 N = 3.35 found: C = 66.21 H = 7.75 N = 3.34

(Toluene-4-sulfonylmethyl) carbamic acid tert-butyl ester

3.48 g (120 mmol) of paraformaldehyde and 6 ml of formic acid are added to a solution of 4.92 g (42 mmol) of carbamic acid / τ-butyl ester and 12.47 g (70 mmol) of p-toluenesulfinic acid sodium salt in 80 ml of water and 35 ml of methanol. The reaction mixture is heated at 100 ° C. for 1.5 hours with stirring. After cooling overnight, the product crystallizes as a colorless solid from the reaction solution.

Yield: 8.97 g

(75% of theory) Melting point: 119 ° C

¹ H NMR spectrum (400 MHz, CDCI ₃ ): δ = 1.27 [1.15] (s, 9H, OC (CH ₃ ) ₃ ), 2.43 [2.46] (s, 3H, C ₆ H ₄ CH ₃ ), 4.50 [4.44] (d, 2H, J = 7.1, CH ₂ NH), 5.46 [5.25] (t, 1 H, J = 6.9, CH ₂ NH), 7.34 [7.38] (d, 2H, J = 8.2, CH ^Ar -C ₆ H ₄ ), 7.80 [7.82] (d, 2H, J = 8.2, CH ^Ar -C ₆ H ₄ ) ppm.

13 C-NMR spectrum (100 MHz, CDCI ₃ ): δ = 21.6 (C ₆ H ₄ CH ₃ ), 27.9 [27.6] (OC (CH ₃ ) ₃ ), 62.0 [63.5] (CH ₂ NH), 80.8 (OC (CH ₃ ) ₃ ), 128.8 [129.0] ( CH ^Ar -C ₆ H ₄ ), 129.6 [129.8] (CH ^Ar -C ₆ H ₄ ), 133.6 (C ^Ar -C ₆ H ₄ ), 144.9 (C ^Ar -C ₆ H ₄ ), 153.9 (C = 0 ) ppm.

IR spectrum (KBr pellet): v = 3376 (m), 3309 (w), 3011 (w), 2978 (w), 2941 (w), 1707 (s), 1598 (w), 1533 (w) , 1473 (m), 1425 (m), 1362 (m), 1315 (m), 1303 (m), 1285 (s), 1251 (m), 1220 (w), 1180 (m), 1143 (s) , 1089 (m), 1042 (w), 1012 (m), 911 (w), 856 (w), 816 (w), 773 (m), 751 (m), 623 (m), 580 (w) , 553 (m), 508 (m), 460 (w) cm ^-1 .

Mass spectrum (El, 70 eV): m / z (rl%) = 285 (1, M ⁺ ), 157 (5), 139 (5), 130 (16), 92 (5), 91 (8), 59 (5)

58 (4), 57 (100), 56 (19).

Elemental analysis (C ₁₃ H ₁₉ N0 ₄ S, 285.360): calc .: C = 54.72 H = 6.71 N = 4.91 found: C = 54.72 H = 6.75 N = 4.86

[(Toluene-4-sulfonyl) - (4-trifluoromethylphenyl) methyl] carbamic acid tert-butyl ester

According to AAV 1, 1.75 g (15 mmol) of fatty acid butyl carbamate, 3.56 g (20 mmol) of p-toluenesulfinic acid sodium salt and 3.20 g (22 mmol) of p- Trifluoromethylbenzaldehyde with the addition of 3.0 ml of formic acid in 55 ml of water, 20 ml of EtOH and 10 ml of MeOH heated at 100 ° C for one hour. After cooling the reaction solution to room temperature, the product crystallizes as a colorless solid.

Yield: 4.80 g

(75% of theory) Melting point: 191 ° C

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ CO): δ = 1.22 (s, 9H, OC (CH ₃ ) ₃ ), 2.45 (s, 3H, C ₆ H ₄ CH ₃ ), 5.84 ( d, 1 H, J = 10.5,

CHNH), 7.40 - 7.00 (kB, 9H, CHNH, CH ^Ar -C ₆ H ₄ CF ₃ , CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ) ppm.

¹³ C NMR spectrum (75 MHz, (CD ₃ ) ₂ CO): δ = 21.5 (C ₆ H ₄ CH ₃ ), 28.2 (OC (CH ₃ ) ₃ ), 74.7 (CHNH), 80.7 (OC (CH ₃ ) ₃ ), 125.9

(CH ^Ar -C ₆ H ₄ CF ₃ ), 126.0 (CH ^Ar -C ₆ H ₄ CF ₃ ), 130.4 (CF ₃ ), 130.5 (CH ^Ar -

CH ₃ C ₆ H ₄ S0 ₂ ), 131.3 (CH ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 135.3 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 136.4

(C ^Ar -C ₆ H ₄ CF ₃ ), 145.8 (C ^Ar -CH ₃ C ₆ H ₄ S0 ₂ ), 154.5 (C = 0), 164.7 (C ^Ar -C ₆ H ₄ CF ₃ ) ppm.

IR spectrum (KBr pellet): v = 3362 (m), 2965 (m), 2191 (w), 1697 (s), 1620 (w), 1597 (w), 1507 (s), 1448 (w) , 1423 (m), 1368 (m), 1331 (s), 1316 (s), 1292 (m), 1252 (m), 1173 (s), 1144 (s), 1127 (s), 1110 (m) , 1086 (m), 1069 (m), 1021 (m), 958 (w), 886 (w), 853 (m), 820 (m), 780 (w), 745 (w), 715 (m) , 698 (w), 672 (m), 644 (m), 606 (m), 574 (m), 528 (w), 502 (w), 460 (w) cm ^-1 .

Mass spectrum (Cl, isobutane): m / z (rl%) = 430 (1, M ⁺ +1), 315 (4), 275 (5), 274 (38), 273 (5), 260 (4),

219 (10), 218 (100), 174 (7), 157 (11), 75 (4), 73 (5). Elemental analysis (C ₂₀ H ₂₂ F ₃ NO ₄ S, 429.453): calc .: C = 55.94 H = 5.16 N = 3.26 found: C = 56.04 H = 5.29 N = 3.13

[(4-Methoxyphenyl) - (toluene-4-sulfonyl) methyl] carbamic acid ferf-butyl ester

According to AAV 1, 4.69 g (40 mmol) of carbamic acid tetf-butyl ester, 17.81 g (100 mmol) of p-toluenesulfinic acid sodium salt and 10.88 g (80 mmol) of p-methoxybenzaldehyde are reacted with the addition of 6.0 ml of formic acid. The product is obtained as a colorless solid.

Yield: 12.98 g

(83% of theory) Melting point: 170-173 ° C

¹ H-NMR spectrum (400 MHz, CDCI ₃ ): δ = 1.25 (s, 9H, OC (CH ₃ ) ₃ ), 2.42 (s, 3H, S0 ₂ C ₆ H ₄ CH ₃ ), 3.81 (s, 3H, OCH ₃ ), 5.84 (m, 2H, CHNH, CHNH), 6.89 - 7.84 (kB, 8H, CH ^Ar -C ₆ H ₄ OCH ₃ , CH ^Ar - S0 ₂ C ₆ H ₄ CH ₃ ) ppm.

¹³ C-NMR spectrum (100 MHz, CDCI ₃ ): δ = 21.6 (C ₆ H ₄ CH ₃ ), 28.0 (OC (CH ₃ ) ₃ ), 55.4 (CHNH), 73.5 (OCH ₃ ), 81.0 (OC (CH ₃ ) ₃ ), 114.2 (CH ^Ar -C ₆ H ₄ OCH ₃ ), 121.9 (C ^Ar -C ₆ H ₄ OCH ₃ ), 129.5 (CH ^Ar - S0 ₂ C ₆ H ₄ CH ₃ ), 129.7 (CH ^Ar -S0 ₂ C ₆ H ₄ CH ₃ ), 130.2 (CH ^Ar -C ₆ H ₄ OCH ₃ ), 133.9 (C ^Ar -S0 ₂ C ₆ H ₄ CH ₃ ), 144.9 (C ^Ar -S0 ₂ C ₆ H ₄ CH ₃ ), 153.5 (C = 0), 160.7 (C ^Ar - C ₆ H ₄ 0CH ₃ ) ppm.

IR spectrum (KBr pellet): v = 3649 (w), 3629 (w), 3371 (m), 3041 (w), 3007 (w), 2972 (w), 2960 (w), 2932 (w) , 2834 (w), 2038 (w), 1903 (w), 1714 (s), 1613 (m), 1598 (w), 1512 (s), 1464 (m), 1429 (w), 1396 (w) , 1383 (f), 1370 (m), 1338 (f), 1315 (s), 1291 (m), 1250 (s), 1186 (s), 1169 (s), 1141 (s), 1084 (m) , 1051 (m), 1035 (m), 932 (w), 887 (w), 848 (m), 807 (m), 789 (w), 768 (w), 733 (w), 710 (w) , 689 (w), 658 (m), 635 (w), 605 (w), 585 (w), 553 (m), 514 (m), 463 (w) cm.

Mass spectrum (El, 70 eV): m / z (rl%) = 235 (19, M ⁺ -S0 ₂ C ₆ H ₄ CH ₃ ), 180 (9), 176 (8), 162 (31), 156 ( 9), 135 (22), 134 (14), 107 (6), 92 (11), 91 (11), 77 (8), 65 (6), 63 (4), 58 (4), 57 ( 100).

Elemental analysis (C ₂₀ H ₂₅ NO ₅ S, 391.482): calc .: C = 61.36 H = 6.44 N = 3.58 found: C = 61.00 H = 6.48 N = 3.51

Example 4:

The following explanations partly show general, partly Processes according to the invention and produced compounds according to the invention and not according to the invention and contain various general comments and explanations on the invention.

Claims

claims

1. Carbamide esters according to general formula I

, in which

Ri is selected from

H, Cι- ₆ alkyl, substituted or unsubstituted, branched or unbranched, saturated or unsaturated; Aryl or heteroaryl, each mono- or polysubstituted or unsubstituted;

2. Beta-amino ketones according to claim 1, characterized in that

Ri is selected from

H; Phenyl or heteroaryl, each mono- or polysubstituted or unsubstituted; especially from

H, furyl or pyridinyl; or unsubstituted phenyl; or in para position with OCι _-4 alkyl or C ι _-4 alkyl (each substituted or unsubstituted, branched or unbranched, saturated or unsaturated) or halogen substituted

phenyl;

preferably from

H, unsubstituted furyl or pyridinyl; or unsubstituted phenyl; or phenyl substituted with OCH ₃ , CF ₃ , t-butyl or CH ₃ .

3. Carbamide ester according to one of claims 1 or 2, characterized in that the compounds is selected from:

Tert-butyl pyridin-2-yl- (toluene-4-sulfonyl) methyl] -carbamic acid,

Furan-2-yl- (toluene-4-sulfonyl) -methyl] carbamic acid tert-butyl ester,

(Toluene-4-sulfonyl) -p-tolyl-methyl] -carbamic acid tert-butyl ester;

Phenyl- (toluene-4-sulfonyl) -methyl] -carbamic acid tert-butyl ester,

(Toluene-4-sulfonylmethyl) carbamic acid tert-butyl ester,

(4-methoxyphenyl) - (toluene-4-sulfonyl) methyl] carbamic acid tert-butyl ester;

4. A process for the preparation of carbamide esters of the general formula I according to claim 1, according to the following reaction scheme:

II III IV '

, the reaction taking place in an aqueous alcoholic medium at acidic pH.

5. The method according to claim 4, characterized in that the alcohol added for the reaction is EtOH or MeOH, preferably EtOH, and / or carboxylic acid, preferably formic acid, is added to achieve the acidic pH, and / or the reaction at temperatures between room temperature and 80-90 ° C takes place.

6. Medicament containing at least one carbamide ester according to one of claims 1 to 3 and optionally further active ingredients, auxiliaries and / or additives.

7. Use of a carbamide ester according to one of claims 1 to 3 for the manufacture of a medicament for the treatment of pain, anxiety, depression or epilepsy, in particular pain.