HU0104218A2 - New esters derived from substituted phenyl-cyclohexyl compounds - Google Patents

New esters derived from substituted phenyl-cyclohexyl compounds Download PDF

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HU0104218A2
HU0104218A2 HU0104218A HU0104218A HU0104218A2 HU 0104218 A2 HU0104218 A2 HU 0104218A2 HU 0104218 A HU0104218 A HU 0104218A HU 0104218 A HU0104218 A HU 0104218A HU 0104218 A2 HU0104218 A2 HU 0104218A2
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hydroxy
phenyl
compounds
formula
ch
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HU0104218A
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HU0104218A3 (en
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Juan Carlos Castillo Nieto
Maria Chalaux Freixa
Joan Huguet Clotet
Marisabel Mourelle Mancini
Elisabet Ramon Amat
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Vita-Invest S.A.
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Priority to PCT/ES1999/000352 priority patent/WO2000027799A1/en
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Publication of HU0104218A3 publication Critical patent/HU0104218A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/40Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C219/30Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Abstract

The present invention relates to compounds of formula (I) wherein R1 is a group of formula (B); R2 is hydroxy; R3 is hydrogen or R2 and R3 together form a double bond; R8 is hydroxy, -O-CO-N (CH3) 2 or NH-R11; R11 is phenyl, optionally mono- or polysubstituted, wherein the substituent is halogen, nitro, C1-6alkyl, C2-6 alkenyl, hydroxyl or amino, salts and optical isomers. The invention also encompasses a process for the preparation of compounds and the use of compounds thereof. The atramadol derivatives of the compounds of the present invention also have analgesic activity. (B) Oh

Description

COPIES

The present invention relates to compounds of formula (I) wherein

Rt is a group of formula B;

R 2 is hydroxy;

R 3 is hydrogen

R 2 and R 3 together form a double bond;

R 8 is hydroxy, -O-CO-N (CH3) 2-NH-Rn group;

Rn is phenyl, optionally mono- or polysubstituted, wherein the substituent is halogen, nitro, C1-6alkyl, C2-6 alkenyl, hydroxyl or amine, salts and optical isomers.

The invention also encompasses a process for preparing the compounds and the use of the compounds.

- : - - · '·' · .'x.

Ad id ·· · ·

NEW SUBSTITUTES FROM SUBSTITUTED FENIL CYCLOHEXIL COMPOUNDS

DISCLOSURE EXAMPLE

The present invention relates to novel ester derivatives of substituted phenylcyclohexyl compounds derived from tramadol. The compounds have a greater analgesic effect, lower toxicity and longer duration of action than tramadol.

Pain management is extremely important in medicine. The pharmaceutical agents currently used to treat pain can be divided into two major groups; opium derivatives and non-steroidal anti-inflammatory drugs (NSAIs). NSAIs can only be used for mild to moderate pain. High pain is usually treated with opium derivatives. However, these opioid compounds have a number of undesirable side effects, such as constipation, difficulty in breathing, tolerance issues and the possibility of becoming addicted.

U.S. Patent No. 3,652,589 discloses analgesic compounds having a substituted cycloalkanol phenol ether structure having a basic amino group in the cycloalkyl ring. Of these, the above-mentioned patent specifically emphasizes and claims it (1R, 2R)

94370-2940-BÉ / fa ·· · ·

-2 ·· or 1S, 2S) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol, commonly known as tramadol. Tramadol can be represented by formula (IV).

NL 6 610 Ö22 discloses compounds derived from the foregoing by dehydrating the cycloalkanol ring and demethylating the methoxy group at the 3-position of the phenyl ring. These compounds are represented by formula (V).

This patent also discloses a group of compounds derived from the compounds described in the above-mentioned U.S. Patent, where the methoxy group at position 3 of the phenyl ring is demethylated. These compounds may be represented by formula (VI).

The compounds disclosed in NL 6 610 022 include O-demethyltramadol, which is described as one of the metabolizing products of tramadol (see W. Lintz et al., Arzneim-Forsch (Drug Rés) 31 (II)); 1932-43 (1981). The analgesic effect of tramadol is attributed to its (+) isomer [see Lars Poulsen et al., Clin. Pharmacol. Ther (St. Louis) 60: 636-644 (1996). However, no data are available on the clinical use of the O-demethyltramadol metabolite.

Recently, EP 753506 describes novel tramadol derivatives that are O-demethyl substituted at the 1-position with halo-3 and / or cyclohexyl at position 3.

Tramadol has an opioid agonist effect. However, according to clinical experience with tramadol, however, the compound does not have some side effects characteristic of opioid agents, such as respiratory depression (see W. Vogel et al., Arzneim. Forsch (Drug Rés) 28, (1), 183 (1978)] with constipation [see Arend et al., Arzneim. Forsch (Drug Rés) 28 (I), 199 (1978)] with tolerance problems [see L. Flohe et al., Arzneim. Forsch (Drug Rés) 28 (I), 213 (1978)] and with the possibility of becoming addicted (see T. Yenagita et al., Arzneim. Forsch (Drug Rés) 28 (I), 158 (1978)). Tramadol-specific side effects that it causes then are injected intravenously (iv) and rapidly injected, such as red spots and sweating.

Another disadvantage of tramadol is the short duration of the effect [see T. Metthiesen, T. Wohrmann, TP Coogan, H. Uragg, "The Exposure Toxicology of Tramadol: An Overview", Toxicology Letters 95: 63-71 (1998).

U.S. Pat. No. 5,733,936 discloses some 6-dimethylaminomethyl-1-phenylcyclohexane ester having a analgesic effect and low toxicity within the general formula.

The aim of US-A-5,733,936 is 6-dimethylaminomethyl 1-1-phenyl-1-chloro-hexane derivatives ··· · ·

-4-esters, phosphonates, ethers, phenols, carbonates, carbamates, etc. wherein said derivatives may be substituted at the 5-position of the cyclohexyl ring (as defined in R 2 and R 3 ) and are intended to produce their dehydroxylated chlorinated fluorinated analogue derivatives.

In addition, although some of the 6-dimethylaminomethyl-1-phenylcyclohexane esters are disclosed in US-A-5,733,936, no example of the document relates to the O-demethyltramadol ester. None of the examples contain a compound containing the tertiary hydroxyl group typical of O-demethyltramadol. Example 13 describes an ester of an analogue of O-demethyltramadol with acetylsalicylic acid and not the ester of O-demethyltramadol. Thus, in U.S. Pat. No. 5,733,936 there is no mention of an O-demethyltramadol ester having a typical hydroxyl group at position 1. U.S. Pat. No. 5,733,936 does not contain an example of an O-demethyltramadol ester. The three esters of Examples 14, 15 and 16 do not contain tertiary hydroxyl groups.

Thus, data on the stability, activity and side effects of such compounds cannot be inferred from this document.

Therefore, as mentioned above, there would be a need for compounds that have the analgesic effect of tramadol.

They have similar or greater analgesic effects, lower toxicity, and longer duration.

The invention is based on the surprising finding that the compounds of formula (I) to be defined later have such an effect.

The present invention relates to novel esters of O-demethyltramadol or its 1,2-dehydrated derivative. It has been found that these compounds have a greater analgesic effect than tramadol, but have lower toxicity and longer duration of oral administration than tramadol (shown in Figure 1).

More particularly, the invention relates to compounds of formula (I), salts and optical isomers thereof, and to a process for the preparation of compounds.

The compounds of this invention are represented by formula (Γ) wherein the * represents the asymmetric carbon atoms, and R (A), (B) or a group of formula (C), R 2 is hydroxy,

R 3 is hydrogen or R 2 and R 3 together form a double bond,

R 4 is hydrogen or C 1-3 alkyl;

R 5 is hydrogen, NH 2, NH or O Rn-Rn group of the formula

R 6 is hydrogen, CO-R 1b is O-R 11

-6 or halogen;

R 7 is hydrogen, C 1-5 alkyl, C 2-5 O-alkenyl or phenyl, or R 6 and R 7 together form -CH = CR 12 -CR 13 = CH- forms a fused aromatic ring,

R s is OH, -O-CO-N (CH3) 2-NH-Rn group of the formula

R g and R 10 are hydrogen or C 1-4 alkyl, which may be the same or different, or -CH 2 -CH 2 -,

Rm is phenyl; phenyl optionally substituted with one or more of the following groups: halogen, such as chloro, bromo or iodo, nitro, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl or amino;

R 12 and R 13 are hydrogen or C 1-3 -alkyl, which may be the same or different.

When Rt is a group of formula (A), preferably R 4 is methyl or hydrogen, R 5 is amino or 2,5-dichlorophenylamino or hydrogen, R 6 is substituted CO-phenyl or hydrogen, R 7 is isobutyl or hydrogen, or R 6 and R 7 together form a fused aromatic ring.

When Rt is a group of formula (A), the following compounds are particularly preferred:

-7 • · ·

- 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl-2- (4-isobutyl-phenyl) -propion,

- 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl-2- (6-methoxy-naphthalen-2-yl) -propionate,

- 3- (2-Dimethylaminomethyl-cyclohex-1-ene) -phenyl 1-2- (4-isobutyl-en en) I, p.

- 3- (2-Dimethylaminomethyl-cyclohex-1-enyl) -phenyl-2- (6-methoxy-naphthalen-2-yl) -popone.

When R 1 is a group of formula B, it is preferred that R 8 is hydroxy or -O-CON (CH 3 ) 2 .

When Rt is a group of formula B, the following compounds are particularly preferred:

- 3- (2-dimethylmethyl-1-hydroxy-cyclohexyl) -phenyl-2-hydroxy-benzoate,

- 3- (2-dimethylaminomethyl-cyclohex-1-enyl) -phenyl-2-hydroxy-benzoate,

- 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl-2-dimethylcarbamoyloxybenzoate,

- 3- (2-dimethylmethylcyclic ex-1-ene) phenyl-2-dimethylcarbamoyloxybenzoate.

When R is group (C) formula, it is preferred, when R g is methyl or hydrogen, or R 10 together with razor blade and eluted -CH 2 CH 2 - to form a radical. When Rt is a group of formula C, the following compound is particularly preferred:

3- (2-Dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxyl.

• · · ·

A compound -8a formula (I) may be prepared in general (II) compound with the appropriate acid or acid derivative of formula (III L). The reaction is

Scheme 1 illustrates where R 1, R 2 and R 3 are as defined above;

L is hydroxyl, halogen, (a) a group of formula O-R14 or -CO-R15 group, wherein

R 14 is C 1-6 alkyl, phenyl or optionally substituted phenyl, and

R 15 is alkyl or optionally mono- or polysubstituted phenyl or optionally mono- or polysubstituted heterocyclic ring.

L is preferably hydroxy or halogen.

The reaction is carried out in an inert solvent, preferably dichloromethane, tetrahydrofuran or the like, at a temperature in the range of -20 ° C to 120 ° C, preferably 0 ° C to 35 ° C, and preferably a condensation promoting agent such as carbonyldiimidazole, diisocoalcicarbobenzimidazole, etc. . presence.

Compounds of Formula II are prepared by methods known in the art (e.g., U.S. Patent No. 6,610,222 or Flick et al.

-9 • ·

Awl. Forsch / Drug Slot. 28 (1), 107-113 (1978).

The pharmacological properties of the compounds were investigated.

The analgesic effect was investigated by the following procedures. The pharmacological activity of the compounds according to the invention was investigated by several experimental methods known for the evaluation of pain in animals. These are the following.

a) Hot plate process

The method used is known (see J. Pharm. Exp. Ther. 107: 385-393 (1953). The analgesic activity of the compounds was evaluated by analyzing the behavior of the animals on a hot surface heated to 55 ° C + 1 ° C.

Male Swiss mice of 20-25 g were used. The test compounds were administered orally or intraperitoneally 1 hour or 30 minutes before the start of the study.

The test consists in placing the animals on a plate and holding a 25 cm tall and 21 cm tall plexiglass cylinder. Determine the time that elapses until the animals jump from the hot surface. Animals are selected prior to the start of the study so that those that jump after more than 10 seconds are not included in the treated group.

30 minutes after the test compound was administered, the test was repeated and recorded again

- 10 • · ·:

. ··· ··· · The maximum time it takes for animals to jump. Animals that do not jump after 60 seconds are removed from the hot plate to avoid injury, and recorded with a 100% effect.

The results are expressed as a percentage of the jump! time increase from the following equation:

(treatment time of treated animals - baseline jump time) jump time increase% = ------- x 100 base jump time

In order to determine the duration of analgesic activity of the orally administered compounds, the analgesic effect is measured on the hot plate at 1, 3, 6, 8 and 24 hours after administration of the compound, and measurements are also made with the comparator group which only received vehicle. The basic reactions were measured 30 minutes and 5 minutes before the addition of the compounds.

b) Determination of DL50 values

See CEUDRA / S / 87/011, Single Dose Toxicity, European Directive 75/318 / EEC (ICH S4, toxicity studies, single dose and repeated dose, CPMP vol III, February 1987, Single dose toxicity).

Male Swiss mice of 20 to 25 g are simultaneously used to determine the acute toxicity of the compounds.

-11 • · »* ·· ·

Prior to administration of the compounds, the animals were kept for 12 hours without food and water could be consumed arbitrarily. A subset of 10 animals is randomly selected, and the test compounds are administered orally at an increasing dose, followed by 14 days of free water and food intake. We then count the dead animals in each subgroup and calculate the DL50.

The results of the hot plate assay in mice are shown in Figure 1, and the duration of the increased reaction is plotted as a function of the time in hours after administration of the compound. The results obtained with tramadol are gray, the compound of Example 6 according to the invention is striped and the compound of Example 1 is black.

The invention is illustrated by the following examples.

1.1. First, some compounds of the invention are prepared.

Example 1

Preparation of 3- (2-Dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl-2- (4-isobutyl-phenyl) -propionate [compound represented by formula (1 P)]

Carbonyldiimidazole (0.76 g, 4.8 mmol) was added to (+) - ibuprofen (60 ml), anhydrous tetrahydrofuran (1 g, 4.8 mmol).

- 129 · ··· to «4» »« * ·· »· with furan. After 2 hours at room temperature, 0.59 g (2.4 mmol) of sodium hydride (RR, SS) -3- (2-dimethylaminomethyl- a solution of hydroxy-cyclohexyl-phenol in 60% mineral oil.

After 16 hours at room temperature, the reaction mixture was evaporated to dryness, dichloromethane (100 ml) was added and the mixture was washed with 1N sodium hydroxide (2 x 50 ml) and water (100 ml).

The organic layer was dried and evaporated. The residue was purified by chromatography on silica gel using a mixture of methylene chloride / ethanol (98: 2 to 96: 4) as eluent. 0.65 g of the title compound is obtained as a colorless oil. Yield: 62%.

1 H-NMR (CDCl 3 ): 0.90 (d, 6H); 1.20-2.20 [m, 21H including 1.6 (d, 3H) and 2.05 (s, 6H)]; 2.32-2.44 (dd, 1H); 2.47 (d, 2H); 3.92 (c, 1H); 6.78-6.86 (m, 1H); 7.12 (d, 2H); 7.18 (sa, 1H); 7.22-7.34 (m, 4H).

Example 2

Preparation of 3- (2-Di-methyl-aminomethyl-1-hydroxy-cyclohexyl) -phenyl-2- (6-methoxy-naphthalen-2-yl) -propionate [compound represented by formula (2P)]

Example 1 was used except that (+) - ibuprofen (+) - 6-methoxy-α-methyl-2-naphthylacetic acid (naproxen) was used. The title compound was obtained as an oil in a yield of 40%.

- 13 1H-NMR (CDCl3): 1.20-2.20 [m, 20 H including 1.67 (d, 3H) and 2.06 (s, 6H), j; 2.35 (dd, 1H); 3.91 (s, 3H); 4.09 (c, 1H); 6.75-6.85 (m, 1H); 7.00 (sa, 1H); 7.15-7.35 (m, 4H); 7.50 (dd, 1H); 7.70-7.80 (m, 3H).

Example 3

Preparation of 3- (2-Dimethylaminomethyl-1-bridge-hydroxy-chloro-hexyl) -phenyl-5-benzoyl-2,3-dihydro-1H-pyrrolysine-1-carboxylate [compound represented by formula (3P) ]

Example 1 was followed except that (+) - ibuprofen was replaced by (±) -ketorolac (i.e., 5-benzoyl-1,2-dihydro-1H-pyrrolizine-1-carboxylic acid). The title compound is obtained as an oil.

1 H-NMR (CDCl 3): 1.20-2.20 (m, 17H); 2.40 (dd, 1H); 2.80-3.10 (m, 2H); 4.28-4.72 (m, 3H); 6.26 (d, 1H);

6.87 (d, 1H); 6.90-6.98 (m, 1H); 7.30-7.60 (m, 6H); 7.787.88 (m, 2H).

Example 4

Preparation of 3- (2-Di-methyl-N-methyl-cyclohex-1-enyl) -phenyl-1-2- (4-isobutyl-phenyl) -propionate [compound represented by formula (4P)]

Example 1 was followed except that (RR, SS) -3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenol was replaced by 3- (2-dimethylaminomethyl-1-cyclohex-1). -enyl) -phenol. The title compound is obtained as an oil.

- 14 1H-NMR (CDCl3): 0.90 (d, 6H); 1.60 (d, 3H); 1.621.98 (m, 4H); 2.02 (s, 6H); 2.10-2.25 (m, 4H); 2.45 (d, 2H); 2.70 (s, 2H); 3.92 (c, 1H); 6.70 (d, 1H); 6.82-6.90 (m, 2H); 7.12 (d, 2H); 7.20-7.32 (m, + H).

Example 5

Preparation of 3- (2-Dimethylaminomethyl-cyclohex-1-ene) -phen-1-2- (6-methoxy-naphthalen-2-yl) -propionate [compound represented by formula (5P)]

Example 1 was followed except that (+) - ibuprofen was replaced by (+) -6-methoxy-α-methyl-2-naphthalenoyloic acid (naproxen) and (RR, SS) -3- ( 3- (2-Dimethylaminomethylcyclohex-1-enyl) -phenol is used in place of 2-dimethylaminomethyl-1-hydroxy-cyclohexyl-phenol. The title compound is obtained as an oil.

1 H-NMR (CDCl 3 ): 1.60-1.76 (m, 4H); 1.68 (d, 3H); 2.02 (s, 6H); 2.10-2.24 (m, 4H); 2.66 (s, 2H); 3.92 (s, 3H); 4.09 (c, 1H); 6.70 (d, 1H); 2.82-2.92 (m, 2H); 7.127.28 (m, 3H); 7.50 (dd, 1H); 7.70-7.78 (m, 3H).

Example 6

3- (2-Dimethyl-amine methyl-1-bridge-hydroxy-chloro-hexyl) -phenyl- (RR, SS) -2-hydroxybenzoate [compound represented by formula (6P)]

7.3 g (29.3 mmol) of (RR, SS) -3- (2-Dimethylaminomethyl-1-hydroxy-chloro-chloro-1-yl) -phenyl and 2.6 g (32.5 mmol) of pyridine A solution of 5.8 g (29.3 mmol) of acetylsalicylyl chloride in 50 ml of methylene chloride was added dropwise to a solution of methylene chloride (50 ml) at 0 ° C. After 10 hours at 0 ° C, methanol (100 ml) and 1N hydrochloric acid (100 ml) were added and the reaction mixture was heated at 25 ° C for 4 days. The methanol was evaporated, the residue was basified with sodium carbonate to pH 8.5, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases are combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel using a mixture of methylene chloride / methanol / ammonium hydroxide (1000: 30: 3) as eluent. Yield: 1.7 g (16%) as a yellow oil.

1 H-NMR (CDCl 3 ): 1.20-2.25 (m, 16H)

2.11 (s, 6H); 2.45 (dd, 1H); 6.90-7.15 (m, 3H); 7.30-7.48 (m, 3H); 7.48-7.62 (m, 1H); 8.08 (dd, 1H); 10.55 (s, 1H, exchanged for D 2 O)

Example 7

3- (2-Dimethylaminomethyl-cyclohex-1-enyl) -phenyl-hydroxybenzoate [compound represented by formula (7P)]

Starting from 3- (2-dimethylaminomethyl-cyclohex-1-enyl) -phenol, the title compound was obtained as a yellow oil according to the procedure of Example 6.

1 H-NMR (CDCl 3): 1.60-1.80 (m, 4H); 2.10 (s, 6H);

2.15-2.35 (m, 4H); 2.75 (s, 2H); 6.90-7.10 (m, 5H); 7.40 (t, 1H); 7.55 (t, 1H); 8.10 (d, 1H); 10.50 (sa, 1H, replaced with D 2 O).

Example 8

3- (2-Dimethylamino-1-1-hydroxy-cyclohexyl) -phenyl- (RR, SS) -2-dimethylcarbamoyloxy-benzoate [Compound (8P)]

A solution of 1.82 g (8.0 nmole) of 2-dimethylcarbamoyloxybenzoyl chloride in 25 ml of methylene chloride was added dropwise at 0 ° C to 1.9 g (7.7 nmol) of (RR-SS) -3- (2- Dimethylaminomethyl-1-hydroxycyclohexyl) -phenol and 0.73 g (9.2 nM) of pyridine in 50 ml of methylene chloride. The mixture was kept at 0 ° C for 10 hours and poured into ice water, the phases were separated, and the aqueous phase was extracted with 100 ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a mixture of methylene chloride / acetone (80:20). 570 mg of the title compound are obtained in the form of an orange oil, yield: 48%.

1 H-NMR (CDCl 3 ): 1.30-1.90 (m, 9H); 2.05 (m, 1H);

2.10 (s, 6H); 2.45 (dd, 1H); 2.95 (s, 3H); 3.05 (s, 3H); 7.00-7.10 (m, 1H); 7.20 (d, 1H); 7.30-7.40 (m, 4H); 7.60 (t, 1H); 8.15 (d, 1H).

Example 9

3- (2-Dimethylamino-1-cyclohex-1-enyl) -phenyl-2-dimethylcarbamoyloxybenzoate [compound of formula (9P)]] · · · · · · · ··· ··· · · · ···· ····· ·· ·· ··· ·· · *

Starting from 3- (2-dimethylaminomethylcyclohex-1-enyl) -phenol (17925 mg, 4.0 mmol), 190 g of the title compound were obtained as a yellow oil. Yield: 32%.

1 H-NMR (CDCl 3 ): 1.70 (m, 4H); 2.07 (s, 6H); 2.102.30 (m, 4H); 2.75 (s, 2H); 2.95 (s, 3H); 3.10 (s, 2H); 6.90 (s, 1H); 6.95 (d, 1H); 7.05 (d, 1H); 7.20 (d, 1H); 7.30-7.45 (m, 2H); 7.65 (t, 1H); 8.20 (d, 1H).

The results of pharmacological studies are given in Tables 1 and 2. Table 1 shows the pharmacological effects of some of the compounds of the invention and of tramadol. The results are expressed as a percentage of the increased reaction time obtained in the hot plate test.

Table 1

The analgesic effect of compounds on hot plates in mice

Compound (15 mg / kg, intra- Reaction time increase% -
fed by peritoneal administration) bán (n = 20
tramadol 218 + 98
Example 1 568 + 100
Example 2 539 + 50
Example 3 416 + 146

Table 1 continued

Example 4 333 + 134
Example 5 356 + 151
Example 6 546 + 63
Example 7 634 + 42
Example 8 327 + 65
Example 9 465 + 13

Table 2 shows the acute toxicity of tramadol and compounds of the invention. Lower toxicity of the compounds of the invention can be observed.

Table 2

Compound Reaction time increases DL50 is about
(20 pounds / kg oral hot (mg (kg) orally
dosing) zen% (n = 20-40) adding
tramadol 87 + 23 350
Example 6 248 + 72 550
Example 1 210 + 88 900

- 19 • ·

Claims (3)

    Claims
  1. Compounds of formula I wherein
    R 10 is a group of formula B;
    R 2 is hydroxy;
    R 3 is hydrogen
    R 2 and R 3 together form a double bond;
    R g is hydroxy, -O-CO-N (CH 3 ) 2, or NH-R 11;
    Rn is phenyl, optionally mono- or polysubstituted, wherein the substituent is halogen, nitro, C1-6alkyl, C2-6 alkenyl, hydroxyl or amino, salts and optical isomers.
  2. 2/3
    N (6P) (7P)
    DISCLOSURE EXAMPLE
    Compounds according to claim 1, wherein R 8 is hydroxy or -O-CO-N (CH 3 ) 2 .
    3. A compound according to claim 2 wherein:
    - 3- (2-dimethylaminoethyl) -1-bromoethylcyclohexylphenyl-2-hydroxybenzoate,
    - 3- (2-di-methyl-methyl-cyclohex-1-enyl) -phenyl-2-hydroxy-benzoate,
    - 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl-2-dimethyl-carbamoyloxy-benzoate,
    - 3- (2-dimethylaminomethyl-cyclohex-1-enyl) -phenyl-2-dimethylcarbamoyloxy-benzoate.
    -20 * ·
    Process for the preparation of compounds according to claim 1, characterized in that a compound of formula (II) is reacted with a compound of formula (III) in a solvent in a temperature range of -20 to +120 ° C, optionally in the presence of a condensation agent.
    R 2 is hydroxy,
    R 3 is hydrogen
    R 2 and R 3 together form a double bond;
    X is hydroxy, halogen, (a) R, OR-I4, or -CO-R 15 group, wherein
    R 14 is C 1-6 alkyl, phenyl or optionally substituted phenyl, and
    R 15 is alkyl or optionally mono- or poly-substituted phenyl or optionally mono- or poly-substituted heterocyclic ring and
    Rt is a group of formula B
    R s is hydroxy, -O-CO-N (CH3) 2-NH-Rn group; wherein Ru is as defined in claim 1.
    5. A process according to claim 4, wherein the solvent is dichloromethane
    - 21 tetrahydrofuran is used.
    The process according to claim 4, wherein the condensation promoting agent is carbonyldimidazole or dicyclohexylcarbimidazole.
    Process according to claim 4, characterized in that the reaction is carried out at a temperature of from 0 to 35 ° C.
    8. Referring to Figures 1-7. Use of compounds of general formula (I) according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of pain.
    The proxy instead of the notifier
    DANUBIA
    Patent and Trademark Office Ltd.
    Bar ^ r patent / Eve charge d'affaires Λ v u
    DISCLOSURE EXAMPLE
    r ° r Rl J 0 of ° V Rl © ° R2 . LR2 HIFEED J n ~ ch 3 k / J n-ch 3 k 3 ch 3 ch 3 CH 3 -N / (I) / V (L *) ch 3 (II)
    Ri-C (ni)
    X
    DISCLOSURE EXAMPLE
  3. 3/3 (IIIj (I) (II))
HU0104218A 1998-11-06 1999-11-04 New esters derived from substituted phenyl-cyclohexyl compounds HU0104218A3 (en)

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