HUT77002A - Tachykinin antagonists - Google Patents

Description

The present invention relates to novel compounds having tachykinin antagonistic activity, to processes for their preparation, to pharmaceutical compositions containing them, and to their use as pharmaceuticals.

More particularly, the invention relates first to novel compounds of formula (I)

R1 represents one or two substituents selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, hydroxy, methoxy, hydroxymethyl, methoxymethyl, methoxycarbonyl, carbamoyl and / or N-methyl phenyl substituted with carbamoyl;

- n is 0 or 1;

- X 1 is oxygen, sulfur or = NCN;

X ₂ and X ₃ are each independently oxygen or sulfur;

- R ₂ is hydrogen or methyl;

- R ₃ is phenyl, halophenyl, 2-naphthyl, 1H-indol-3-yl or 1-methyl-indol-3-yl;

- Z is -N (CH ₃ ) - or -CH ₂ -;

R 2 is phenyl, 3,5-bis (trifluoromethyl) phenyl or pyridyl; and

- _R5 is hydrogen, phenyl, 3,5-bis (trifluoromethyl) phenyl or pyridyl, with the proviso that when X ₃ is S, Z is -N (CH ₃₎ group.

The invention also relates to acid addition salts of the compounds of formula (I).

Halogen may be chlorine, fluorine, bromine and iodine.

In the case where R 1 is a doubly substituted phenyl group, the substituents may be the same or different.

CLAIMS 1. A group of compounds of the present invention are those compounds of formula (I) wherein R1 is nitro, cyano, trifluoromethyl, hydroxymethyl, methoxymethyl, carbamoyl and / or N-methyl. phenyl substituted with one or two carbamoyl groups.

2. Another class of compounds of the invention are those compounds of formula (I) wherein n = 0.

2a. When n = 0, R 1 is preferably - nitro, cyano, methoxymethyl, methoxycarbonyl, carbamoyl and / or N-methylcarbamoyl (e.g. nitro), cyano, methoxymethyl, carbamoyl and / or N-methylcarbamoyl), in particular phenyl, mono- or di-substituted with nitro and / or methoxymethyl, most preferably nitro.

2, b) In the case where n = 0, R 1 is preferably a monosubstituted phenyl group, in particular a monosubstituted phenyl group in the 2-position.

2.c) When n = 0, R 1 is most preferably a phenyl group which in the 2-position has any of the substituents listed in 2 a), in particular 2-nitrophenyl or 2- (methoxymethyl) phenyl. monosubstituted phenyl, especially 2-nitrophenyl.

3. A further class of compounds of the invention are those compounds of formula (I) wherein n is 1.

3.a) When n = 1, R 1 is preferably phenyl mono- or di-substituted with halogen, trifluoromethyl and / or methoxy, in particular halogen and / or trifluoromethyl.

3.b) When n = 1, R 1 is - preferably phenyl substituted in the 2-position or in the 2-and 6-position.

3. (c) When n = 1, R 1 is most preferably phenyl substituted singly at position 2 or twice at positions 2 and 6 with any of the substituents listed in (3a); first and foremost

A monosubstituted phenyl group in the 2-position, in particular 2-halophenyl or 2-trifluoromethylphenyl, particularly preferably 2-chlorophenyl or 2- (trifluoromethyl) phenyl, is most preferred. in this case, the compounds of formula I containing 2-chlorophenyl are preferred.

In the general formula (I)

4. It is preferred that n = 0.

5. Xi is preferably oxygen or sulfur, particularly preferably oxygen.

6. X ₂ and X ₃ are each preferably oxygen.

7. R-2 is preferably hydrogen.

8. When R ₃ represents a halogen substituted phenyl group, a halogen disubstituted phenyl group is preferred, in particular a halogen atom.

3 and 4 disubstituted phenyl. The halogen atom is preferably chlorine, so it is particularly preferred that the R ₃ substituent is 3,4-dichlorophenyl.

9. The substituent R ₃ is preferably 2-naphthyl or halogen substituted phenyl, for example one of the groups defined in claim 8, in particular 2-naphthyl.

10. Z is preferably -N (CH ₃ ) -.

11. In the case when R ₅ is not hydrogen, _R4 and R5 are the same.

12. The pyridyl group at the R ₄ and / or R ₅ substituent is preferably 2-pyridyl.

13. R ₄ is preferably phenyl.

14. R ₅ is preferably hydrogen.

15. Most preferably, R ₄ is phenyl and R 5 is hydrogen.

The compounds of the present invention include all compounds having the meaning given to the general chemical symbols in formula (I) by any combination or sub-combination of the meanings given in the interpretation of formula (I) and / or in claims 1 to 15. a combination of meanings defined by one or more of these points.

A) A subgroup of the compounds of the present invention are compounds having the general formula (I)

R1 is 2-halophenyl or 2-nitrophenyl;

- n is 0;

- X ₂ and X 3 is an oxygen atom;

- R ₄ is phenyl or pyridyl;

- R5 is hydrogen, phenyl or pyridyl; and

- X 1, R ₂ , R 3 and Z have the same meaning as in the interpretation of formula (I).

B) Another subgroup of compounds of the present invention are compounds of formula (I)

R1 represents a group of the formula (a)

- Rja is trifluoromethyl, halogen, methoxy or nitro; and

Rib is hydrogen, trifluoromethyl, halogen, methoxy or nitro;

- n is 1;

- X ₂ and X ₃ are both oxygen;

- R ₃ is halophenyl, 2-naphthyl, 1H-indol-3-yl or 1-methyl-indol-3-yl;

- Z is -N (CH ₃ ) -; and

- X 1, R ₂ , R ₄ and R ₅ have the same meaning as in the interpretation of formula (I).

With respect to the subgroups defined in A) and B), the preferred meanings of each substituent are the same as those set forth in Sections 1 to 15. .

R ₄ and / or R ₅ containing pyridyl group (I)

V

The compounds of Formula 7 may be both free bases and acid addition salts. The present invention relates to compounds of formula I in both free base and acid addition salts. Examples of pharmacologically acceptable acid addition salts for use in the present invention include the hydrochloride salts.

The compounds of the present invention contain at least two asymmetric carbon atoms represented by (a) and (b) in formula (I). In the case where R ₄ and R 5 are the various different meanings and R5 represents hydrogen, a further asymmetric carbon atom [(c)] is present. Accordingly, the compounds of the invention may exist in the form of optical isomers.

The individual isomers may be prepared by conventional methods, for example by synthesis using optically active starting materials or by separation of the first mixture of isomers. Separation of the isomeric mixtures is accomplished by chromatography on a chiral support or by recrystallization of diastereomeric salts.

Unless otherwise stated, the present invention relates to both pure or substantially pure individual isomers as well as to various mixtures such as racemic and diastereomeric mixtures.

It is preferred that the carbon atom represented by (a) or (b) in the formula (I) has the (S) configuration. More preferably, both the carbon atoms represented by (a) and (b) have the (S) configuration. Accordingly, in a preferred embodiment of the invention, compounds of formula (I) as hereinbefore defined which are composed exclusively or predominantly of molecules having both (a) and (b) carbon atoms are prepared. (S) -configuration. (For example, the amount of other isomers is less than 10%, preferably less than 5%, for example less than 2%.)

The present invention also provides a process for the preparation of the compounds of formula I as hereinbefore defined and the acid addition salts thereof. According to a process according to the invention

- Compounds of formula (II) - wherein R ₂ to R 5, X ₂ , X ₃ and Z in formula (II) are as defined above - are reacted with compounds of formula (III): phenyl substituted singly or twice with a hydroxy group, a protected hydroxy group, a methoxy group, a protected hydroxymethyl group, a methoxymethyl group and / or a methoxycarbonyl group, and n and Xi are as defined for the interpretation of formula I; and then, if desired

- releasing the compound of formula (I) containing the resulting Rf-protected hydroxy group and / or protected hydroxymethyl group from the protecting group (s) and / or the resulting Rf-substituted methoxycarbonyl phenyl group; converting a compound of formula (I) wherein Rf is a phenyl substituted by a carbamoyl group or an N-methylcarbamoyl group; and

- recovering the compounds of formula (I) thus obtained in the form of the free base or of an acid addition salt.

• ··· ···· ·

The compounds of formula (II) and (III) are suitably reacted with one another in an inert organic solvent such as dioxane at a temperature between 20 ° C and reflux temperature.

Protected hydroxy groups or hydroxymethyl groups in the R 1 substituent are known and commonly used for protecting hydroxyl groups in peptide chemistry. An example of such a protecting group is tert-butyldimethylsilyloxymethyl. The protecting groups may be removed by conventional methods such as those described in Examples 18 and 19.

Conversion of the methoxycarbonyl moieties may also be accomplished by methods known in the art, such as hydrolyzing the methoxycarbonyl group to a carboxyl group, converting the carboxyl group into a reactive functional derivative such as a carbonyl halide or a mixed anhydride. and reacting the resulting derivative with ammonia or methylamine, for example as described in Examples 15 and 16.

Starting materials of formula (III) are known in the art, are commercially available, or may be prepared in a manner analogous to known compounds. For example, compounds of formula (III) wherein X is = NCN can be prepared by the general procedures described in Example 4.

Compounds of formula (II) may be prepared according to Scheme 1. In the scheme, R _{p is a} protecting group for amino, R is _a carboxyl activating group, Hal is chlorine, bromine or iodine, especially bromine, and R _{2 is} -R 5, X ₂ , X 3 and Z are as defined above.

The amino groups to protect corresponds R _p substituted by any method known in peptide chemistry, and the protection group, such as t-butoxycarbonyl (Boc) group, which is particularly suitable for the (IV) and the compound of formula (VIII) in connection with good results.

Reaction of compounds of formula (IV) with compounds of formula (Va) and (Vb) leads to the formation of compounds of formula (VI), and thus of formula (II), wherein the Z substituent, in the order mentioned, is -N (CH _3). ) - and -CH ₂ -.

The compounds of formula (IV) to react with a compound of formula (Va) and (c), step R _the carboxyl suitable activating group such as groups derived from mixed anhydrides, such as i-butoxy-carbonyloxy group. These reactions can be performed using any of the methods known and used in peptide chemistry, such as those described in FIG. according to general solutions according to example.

The starting materials of formulas (Va) and (Vb) are known in the art or may be prepared in a manner analogous to known compounds, for example as described in Examples 5, 20 and 24.

For the reaction of the compounds of formula (IV) and (Vb) with R, _the appropriate carboxyl activating group is, for example, pyridyl and picolyl ester groups such as 2-pyridyloxy. The reaction is known to those skilled in the art by in situ formation of (Vb) Grignard reagents,

For example, 11 may be repeated as described below in connection with Example 28.

The starting materials of formula (IV) are known, described in the literature, or can be prepared by known methods, for example by activating the appropriate acids having a protecting group on their nitrogen atom, preferably in situ, e.g. in the same manner as in Example.

Compounds of formula R ₂ is methyl (II) from compounds of the formula R ₂ is hydrogen (IV) can be prepared, e.g., Olsen method [J. Org. Chem., 35, 1912-1915 (1970)] by introducing a methylation step before step (d), for example methylating the compound of formula (IX). This solution is illustrated in Figures 27-29. Examples.

Steps (b) and (d) are conventional deprotection procedures commonly used in peptide syntheses, as exemplified below in Example I.B.

The following examples illustrate various embodiments of the process for preparing the compounds of the present invention.

Example 1

Preparation of 2-Nitrophenylcarbamoyl - [(S) -propyl] - [(S) -3- (2-naphthyl) -anyl] -N-benzyl-N-methylamide [Formula I = 2-nitrophenyl; n = 0; the

X ₁ , X ₂ and X ₃ are each oxygen 12; R ₂ = H; R ₃ = 2-naphthyl; Z = -N (CH ₃ ) -; R ₄ = phenyl and R 5 = H; and 1.39 g of (S) -prolyl- (S) -3- (2-naphthyl) -alanyl-N- are dissolved in ethyl acetate (S) with both carbon atoms (a) and (b). benzyl N-methylamide and 551 mg of 2-nitrophenyl isocyanate are added to the resulting solution. The resulting yellow solution was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated. The orange evaporation residue was purified by flash chromatography. Elution was carried out with a 2: 1 by volume mixture of ethyl acetate and hexane. The resulting yellow foam was dissolved in ethyl acetate (20 mL) and added dropwise to a stirred solution of hexane (200 mL). The yellow precipitate was filtered off and dried. thereby obtain the title compound, mp 79-82 ° C, thin layer chromatography (silica, cyclohexane: ethyl acetate 1: 2 by volume) _Rf 0.36 and Rf specified.

Example 2

Preparation of 2-Chloro-benzothiocarbamoyl - [(S) -propyl] - [(S) -3- (2-naphthyl) -anyl] -N-benzyl-N-methyl-amide [Formula I = 2-chlorophenyl; n = 1; X 1 = sulfur; X ₂ and X ₃ are each oxygen; R ₂ = H; R ₃ = 2-naphthyl; Z = -N (CH ₃ ) -; R ₄ = phenyl and R 5 = H; furthermore, 1.03 g of (S) -propyl (S) -3-13- (2-naphthyl) -alanyl are dissolved in (S) -configuration] methylene chloride in both (a) and (b) carbon atoms. N-benzyl-N-methylamide and 455 mg of 2-chlorobenzyl isothiocyanate were added and the resulting solution was stirred at ambient temperature for 18 hours. The solvent was then removed in vacuo. The residue was purified by flash column chromatography. The carrier is silica and the eluent is a 1: 2 by volume mixture of cyclohexane and ethyl acetate. The product was then recrystallized from ethyl acetate to give tiny white needles which were filtered and dried at 75 ° C for 18 hours at 13 Pa. This gave the title compound, m.p. 129-131 ° C, with an Rf value of 0.3 as determined by thin layer chromatography (silica; cyclohexane: ethyl acetate = 1: 2).

The compounds (Table I) wherein R ₂ is hydrogen, R ₃ is 2-naphthyl, and Z is -N (CH ₃ ) - in the formula (Ia) in the example 1, η = In one case, it can be prepared in a manner similar to that described in Example 2:

. spreadsheet

Physical constants op (° C) / R _f X tf © CN I 00 H *She © SALT ANCESTOR 1 CN Ancestor m OO θ ' CN ANCESTOR 1 © ANCESTOR m -Ή She <© r- ANCESTOR salt C l She © ' © She 00 Ancestor ΤΓ SHE © ' 00 Ancestor 1 tt Ancestor © * CN θ ' Ancestor CN t-H salt CN x CN © salt CN 1 tt CN X θ ' Γ- © 1 uc She oo CM θ ' Γ- oo X 00 rc <N θ ' © © © X * x CN © —H © ob ANCESTOR cn ANCESTOR ι-H © CN © 1 © ANCESTOR CN © * © X 1 Ancestor © 7 CN She CN © 1 00 X 98-104 / 0.24 ⁽¹⁾ CN © * CN © © OO 1 X 00 cn 'ancestor © θ r · Ancestor X ANCESTOR tt 1-H © She" Γ- ΟΟ 1 X 00 'ancestor © ~ © Γ- 1 QC r- OO H θ ' rc · r * I 125-127 / 0.1 1 ⁽⁴⁾ 102-104 / 0.15 ⁽⁴⁾ X tf © X ΤΓ H 1 CM lake £ • - * - 'S. 1 CM K X £ £ X z X X £ £ K K K -3 • FF J- hh 1 CM z K £ £ p 4) uh X * Rt · lake p <u C ω < « S ι- Ο- ι CM u " SHE- CM • F * Ό • w * t • fX P- CN P 1.) 'W P ω c. * - c <L> P <u q • FF P <u + - • FF P <u «Η, Ι P 4) • fH P ω stl • fF P She <+ H P 1.) q ~ l • FF P <u P <U • fF Ό • X 1- • ff P. CN * 3 1 • fF P. 1 CN P <u s (U <M- ó o S ΓΞ c .: p • U <U 1- Uh HH | 5 · £ ¹ <u S rc » P 1.) q-i P 4> <+ H > < tZ) z SHE z II She She t / 3 CZ3 SHE She SHE SHE SHE She SHE She She She She CZ1 (Z) OO She 0Q CZ3 CZ5 c She © © © © She She © She She © © © © © © © -c f- F- - F- - Λ lake 1 CM She z 1 ol 1 CM She z 1 CM CM She z 1 CM CM She z 1 CM CM She z 1 CM 1 u CM CM She z t d Z u CN Z u rc uh 1 She u She m She CN 1 CM She z rc She She K z £ u CM SHE U CM ffi z CN 1 CM ffi u She ΓΊ ffi u CN 1 She K CN CM ffi u She X CN U CN 1 u CN 1 m U. SHE cl 1 u CN 1 ύ CM 1 u CN Λ CQ CN The serial number of the example CC -x d ^- x salt Γ- 00 Ancestor © CN rc d -X -X X H X -X © r · + * -X 00 -X -X -X ANCESTOR © CN H CN CN CN rc CM d cl X CN © CN

• ·

Compounds (Table II.), (Ia), R _t ^represents 2NO ₂ wherein - a hydrogen atom, R ₃ is 2-naphthyl, _R4 is phenyl and _R5 is, for n = 0 is the first and for η = 1 as described in Example 2:

II. spreadsheet

The serial number of the example n Xi r ₂ z Physical constants op (° C) / R _f 27th 0 0 ch ₃ - -N (CH ₃ ) - 71-74 / 0.55 ^{1 (2) *} 28th 0 0 H -ch ₂ - 106-10 8 / 0.3 5 ⁽⁴⁾ 29th 1 s ch ₃ - -N (CH ₃ ) - 84-85 / 0.19 ⁽⁴⁾

Compounds (Table III) wherein R ₂ is hydrogen, Z is -N (CH ₃ ) -, R ₄ is phenyl and R 5 is hydrogen, n = 0

May be prepared as described in Example 1 and, for η = 1, as described in Example 2;

III. spreadsheet

The serial number of the example Ria n Xi r ₃ Physical constants op (° C) / R _f 30th 2NO ₂ - 0 0 H-indol-3-yl 96-98 / 0.36 ⁽²⁾ 31st 2NO ₂ - 0 0 3,4-dichlorophenyl 151-152 / 0.54 ⁽²⁾ 32nd 2C1- 1 s 3,4-dichlorophenyl 185-186 / 0.59 ⁽²⁾ 33rd 2C1- 1 s l-methyl-indol-3-yl 160-162 / 0.6 ⁽⁴⁾

(1) = silica; a 1: 2 by volume mixture of cyclohexane and ethyl acetate.

(2) = silica; 1: 4 by volume of cyclohexane: ethyl acetate.

··· «« · «·

- 16 (3) - silica; methylene chloride: methanol (25: 1).

(4) = silica; a 1: 1 by volume mixture of cyclohexane and ethyl acetate.

To prepare the compound of Example 4, the compound of formula III is prepared in situ as follows:

Dissolve 44 mg of cyanamide in 1 ml of dimethylformamide and add 1 ml of 1 M potassium tert-butoxide in 1 M tetrahydrofuran. The reaction mixture, which forms a white precipitate, is stirred for 20 minutes at ambient temperature. 180 mg of solid 2-nitrophenyl isothiocyanate were added and the resulting mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was cooled in ice and treated with triethylamine (0.42 mL) followed by (S) -prolyl- (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methyl-amide (415 mg) and 300 mg mercury (II) chloride. Hereinafter, the reaction proceeds as described in Example 1 and the reaction mixture is worked up as in Example 1.

Examples 15 and 16 were prepared from Example 13 in the following manner:

The compound of Example 13 is hydrolyzed to give the corresponding acid of formula (Ia) Ria = 2 (HOCO) -. The acid thus obtained is then reacted under standard conditions (keeping the temperature below -15 ° C) with isobutyl chloroformate and N-methylmorpholine in ethyl acetate, while the compound of Example 15 is slowly added to the reaction flask for 30 minutes. to prepare anhydrous methylamine and to prepare the compound of Example 16.

- 17 ammonia gases. The resulting crude products were processed in a similar manner to that described in Example 1.

The compounds of Examples 18 and 19 are prepared via an oxygen protected intermediate, as follows:

(S) -prolyl- (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methyl-amide, as in Example 1, is 2- (tert-butyldimethylsilyloxy) phenyl isocyanate and 2- (tert-butyldimethylsilyloxymethyl) phenyl isocyanate to give tert-butyldimethylsilyl protected forms of Example 18 and Example 19 respectively. compound. Examples 18 and 19 are prepared by treating said protected compounds with tetrahydrofuran under standard conditions with tetrabutylammonium fluoride.

For the procedure of Example 1, the starting material was prepared as follows.

Example 1A) [Process Step (a)]

1A) 1. Boc- (S) -3- (2-Naphthyl) -alanine isobutoxy-formyl anhydride (Formula IV: R _p = Boc, R ₂ = H, R ₃ = 2-naphthyl), X ₃ = O, R _a = isobutoxycarbonyloxy]

Dissolve 480 mg of Boc- (S) -3- (2-naphthyl) alanine and 170 μΐ (156 mg) of N-methylmorpholine in 5 ml of anhydrous methylene chloride and stir under nitrogen with ice and salt. cool in a bath to -15 ° C. The temperature was then added dropwise, keeping the temperature below -10 ° C, dissolved in 2 ml of anhydrous methylene chloride, 200 μΐ (20 mg) of chlorine ··· »· t * *

18-Formic acid isobutyl ester and the resulting mixture was stirred for 30 minutes.

IA2. Boc- (S) -3- (2-Naphthyl) -alanyl-N-benzyl-N-methylamide (Formula VI: R _p = Boc, R ₂ = H, R ₃ = 2-naphthyl) , X ₃ = Ο, Z = -N (CH ₃ ) -, R ₄ = phenyl, R ₅ = H]

The l.A.l. To a solution of the product of Example 1b in 2 ml of anhydrous methylene chloride was added dropwise 185 mg of N-benzylmethylamine (Va) while maintaining the temperature below -10 ° C. The reaction mixture was stirred until TLC analysis confirmed that the reaction was complete. The reaction mixture was diluted to 75 mL with methylene chloride and washed first with 50 mL of dilute aqueous hydrochloric acid, then with 50 mL of water, and finally 25 mL of aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography over silica. The eluent was a 4: 1 by volume mixture of cyclohexane and ethyl acetate. This gives the title compound as a colorless foamy solid. TLC (silica; 1: 1 by volume cyclohexane: ethyl acetate) Rf 0.54.

Example IB (Process step b) Preparation of (S) -3- (2-naphthyl) alanyl-N-benzyl-N-methylamide (Compound VII)

The product prepared in Example 1A (600 mg) was dissolved in 10 mL of 4.0 M hydrochloric acid in dioxane and the resulting solution was circulated. · · ·· ·· · · ····

Stir at 19 ° C for about 30 minutes. The hydrochloric acid and dioxane were removed in vacuo and the residue was dissolved in water (100 mL). The aqueous solution was made basic with 2N aqueous sodium hydroxide solution and extracted with methylene chloride (2 x 75 mL). The organic phase was dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was evaporated to give the title compound as a yellow oil, m.p. 90-9: 1 by TLC (silica; methylene chloride: methanol: acetic acid).

Example 1C [Process Step (c)]

Preparation of Boc- (S) -prolyl- (S) -3- (2-naphthyl) -alanyl-N-benzyl-N-methyl-amide (Formula IX: R _p = Boc)]

The title compound is prepared according to the method described in I.A. Prepared in the same manner as in Example 1b: 310 mg of Boc- (S) -proline is reacted with 460 mg of the product of Example 1B). The title compound is obtained in the form of a viscous oil, which has an Rf of 0.18 as determined by thin layer chromatography (silica; cyclohexane: ethyl acetate = 1: 1).

Example 1D (Process step (d)) Preparation of (S) -prolyl- (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methyl-amide (Compound II)

Starting from 740 mg of the product of Example 1C), the title compound was prepared as described in Example 1B).

20 are prepared in a similar manner. to give the title compound as a colorless foamy solid having the thin layer chromatography (silica; methylene chloride: methanol: acetic acid 90: 9: 1 by volume) as defined _Rf 0.29.

The product of Example 1D) is also used as starting material for the preparation of Examples 2-4, 8-19, 22, 23 and 26. 6, 7, 21, 25 and 30-33. The compounds of formula (II) used as starting materials in Examples 1 to 8 are prepared in a similar manner.

5, 20, 24 and 27-29. The compounds of formula (II) used as starting materials in Examples 1 to 8 are prepared in a manner similar to that described in Examples 1 (A) to 1 (D) to give the starting compounds (Va) by the methods described below or as modified versions thereof:

For Examples 5 and 20:

N-methyldi (2-pyridyl) methylamine (Formula Va): R ₄ and

Preparation of both Rs 2-pyridyl groups] Dissolve 2.00 g of di (2-pyridyl) ketone in methylene chloride. To the resulting solution was added first 1.90 g of heptamethyldisilazane followed by 0.12 g of trimethylsilyl trifluoromethanesulfonate. The reaction mixture was refluxed for 12 hours and the solvent removed in vacuo. The residue was obtained as an evaporation residue

2.14 g of an oily crude product are dissolved in 20 ml of anhydrous ethanol. Then 0.65 g of acetic acid is added followed by 0.68 g of sodium [cyano · · ·

21-trihydroborate] (1 -) and the reaction mixture was stirred at ambient temperature for 1 hour. Subsequently, potassium bisulfate solution is added until the pH of the mixture is 2 and then 2M sodium hydroxide solution is added until the pH is 12. The ethanol was removed in vacuo and the residue was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and hydrogen chloride gas was bubbled through the filtrate. The title compound obtained as the trihydrochloride salt is filtered off and dried, as described in Examples 1A) -1D, for further direct reaction.

For example 24:

N-methyl-3,5-bis (trifluoromethyl) benzylamide [(Va) wherein R ₄ = 3,5-bis (trifluoromethyl) phenyl, R = H] Preparation of

Step I: Preparation of N-Boc-3,5-bis (trifluoromethyl) -benzylamine Dissolve 5.00 g of 3,5-bis (trifluoromethyl) benzylamine in 5 ml of N, and 5.12 g of N. - (benzyloxycarbonyloxy) succinimide and the resulting mixture was stirred at ambient temperature for 3 hours. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride. The resulting solution was washed with water (50 mL) followed by brine (50 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. In this way, the title compound is obtained.

• «

- 22 II. step; Preparation of N-Boc-N-methyl-3,5-bis (trifluoromethyl) -benzylamine

6.87 g of the product obtained in Step I are dissolved in 50 ml of anhydrous tetrahydrofuran and the solution is cooled to -78 ° C. To the solution was added 14 ml of a 1.5 M solution of LDA in tetrahydrofuran, and the resulting mixture was stirred at -78 ° C for 30 minutes. Then, 2.98 g of methyl iodide is added slowly. The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography over silica. Elution was carried out with a 9: 1 by volume mixture of cyclohexane and ethyl acetate. This gives the title compound.

III. Step: Preparation of N-methyl-N-3,5-bis (trifluoromethyl) -benzylamine

II. The product (2.00 g) obtained in Step (a) above is dissolved in ethanol (100 ml) and deprotected by the addition of a catalytic amount of 10% palladium on charcoal and the solution being pressurized with hydrogen. After 4 hours, the catalyst was filtered off and the solvent was evaporated in vacuo. The title compound thus obtained is reacted further as described in Examples 1A-1D.

For Examples 27 and 29:

Boc- (S) -prolyl- (S) - (N-methyl) -3- (2-naphthyl) -allyl-N-benzyl-N-methyl-amide [Formula IX: R _p = Boc, R ₂ = • · · · · · · · · · · · · · · · · · · · · · · · · · ···

- 23 methyl, R 3 = 2-naphthyl, Z = -N (CH ₃ ) -, R ₄ = phenyl, R ₅ = H)

1.08 g of the product obtained in Example 1C and 1.04 ml (2.38 g) of iodomethane are dissolved in 30 ml of dimethylformamide.

To the solution was added 1.95 g of silver oxide. The resulting reaction mixture was heated to 60 ° C and stirred until the starting material was detected by high performance liquid chromatography (HPLC). The reaction mixture was cooled to ambient temperature, diluted with chloroform to 200 mL and washed with 5% potassium cyanide (2 x 100 mL), water (2 x 100 mL), and brine (50 mL), and dried over anhydrous magnesium sulfate. , filtered and the solvent removed in vacuo. This gives the title compound as a clear, colorless glass.

The title compound is further reacted in a manner similar to that described in Example 1D below.

For Example 28:

28.A.1. Boc- (S) -3- (2-naphthyl) -alanine-2-pyridyl ester (IV). R _p = Boc, R ₂ = H, R ₃ = 2-naphthyl, Ra = 2-pyridyloxy] 1.00 g of Boc- (S) -3- (2-naphthyl) are dissolved in ml of anhydrous pyridine. ) -alanine and 0.33 g of 2-hydroxypyridine, and the resulting solution was cooled to 0 ° C. To the cooled solution was added 0.72 g of dicyclohexylcarbodiimide and the reaction mixture was stirred at 0 ° C for 6 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution is filtered and the solution is filtered.

24 solvents were removed in vacuo. The residue was purified by flash column chromatography over silica. The eluent was a 2: 1 by volume mixture of cyclohexane and ethyl acetate. In this way, the title compound is obtained, which has an Rf of 0.41 as eluent by TLC on silica, cyclohexane and ethyl acetate (1: 1).

28.A.2. Boc- [1- (S) -Naft-2-ylmethyl-2-oxo-4-phenyl-butyl] -amine [(VI): R _p = Boc, R ₂ = H, R ₃ = 2 naphthyl, Z = methylene; R ₄ = phenyl, Rs = H]

In a flame-dried flask, add 10 ml of anhydrous tetrahydrofuran and dissolve in 29.A.1. 0.85 g. The resulting solution was stirred under a nitrogen atmosphere. The solution was cooled to -78 ° C and 2 mL of 2 M phenethylmagnesium bromide was added slowly. The reaction mixture was stirred for 1 hour at -78 ° C. Saturated ammonium chloride solution (20 mL) was added and the product was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography over silica. Elution was carried out with a 9: 1 by volume mixture of cyclohexane and ethyl acetate. In this way, the title compound was obtained, which had an Rf of 0.66 as a eluent by thin layer chromatography (silica, cyclohexane: ethyl acetate = 4: 1).

The title compound is hereinafter referred to as Examples 1B) - 1D).

- Process in the same way as described in 25 Ban.

For larger scale production, see l.A) -1. The procedures of Examples 1 to 4 can be used with appropriate results, as illustrated in Example 34 below.

Example 34

Preparation of 2-Nitrophenylcarbamoyl - [(S) -propyl] - [(S) -3- (2-naphthyl) -anyl] -N-benzyl-N-methylamide

Step I [= Example I.A]

Into a 0.5 L three-necked round bottom flask equipped with mechanical stirrer, digital thermometer, addition funnel, nitrogen inlet and outlet, and cooling bath, 187.4 g of N-benzylmethylamine are weighed and the internal temperature of the flask is cooled to 1 ° C to 5 ° C. reduced to. To the flask was added dropwise 7.5 g of ethyl trifluoroacetic acid over 15 minutes while maintaining the internal temperature between 1 ° C and 5 ° C. The funnel was washed with ethyl acetate (3 x 2.5 mL, 7.5 mL total) and the washings were added to the reaction mixture. The cooling bath was removed and the reaction mixture was allowed to return to ambient temperature over a period of 30 minutes at 21-23 ° C. The reaction mixture was stirred at ambient temperature for 30 minutes and the oily portion of the mixture was maintained.

In a 12-liter round-bottomed flask equipped with a mechanical stirrer, digital thermometer, addition funnel, nitrogen inlet and outlet, and a cooling bath, 394.0 g of Boc- (S) -3- (2-naphthyl) -alanine and 5.6 liters of ethyl- acetate. So • · · · · ·

The resulting 26 solutions were cooled to -15 ° C (internal temperature) and 174.4 g of 4-methylmorpholine was added over 5 minutes. The addition funnel was washed with ethyl acetate (25 mL) and the wash was added to the reaction mixture. After stirring for 10 minutes, a solution of 125 ml of ethyl acetate and 172.0 ml (181.12 g) of isobutyl chloroformate was added over 30 minutes, keeping the internal temperature between -14 ° C and -16 ° C. between. The addition funnel was washed with ethyl acetate (2 x 25 mL, 50 mL total) and the washings were added to the reaction mixture. The resulting slurry was stirred at -14 ° C to -15 ° C for an additional 30 minutes and then a solution of the benzylmethylamine derivative prepared in the preceding paragraph in 125 ml ethyl acetate was added at a constant rate over a period of 40 minutes. the temperature is maintained between -14 ° C and -15 ° C. The addition funnel was washed with ethyl acetate (2 x 25 mL, 50 mL total) and the washings used in two portions were added to the reaction mixture. The reaction mixture was stirred at the same temperature for an additional hour and a solution of ethyl acetate (25 ml) and isobutyl ester of chloroformate (34.4 ml, 36.22 g) was added over 10 minutes. the temperature is maintained between -14 ° C and -16 ° C. The addition funnel was washed with ethyl acetate (2 x 5 mL, total 10 mL) and the washings used in two portions were added to the reaction mixture. The resulting suspension was stirred for an additional 15 minutes at -14 ° C to -16 ° C. A solution of 25 ml of ethyl acetate and 1.5 g of N-benzylmethylamine pre-treated with 1.5 g of trifluoroacetic acid in ethyl acetate is then added at a constant rate while maintaining the internal temperature. It is kept between -14 ° C and -15 ° C. Dosing funnel 2x5 ml - 10 total

Wash with 27 mL of ethyl acetate and add two portions of the wash to the reaction mixture. The reaction mixture was warmed to ambient temperature - 21-22 ° C over 1 hour. The reaction mixture was stirred at ambient temperature - 21-22 ° C for an additional 1 hour. Water (2.5 L) was added and stirring continued for 5-10 minutes. The organic layer was separated and washed first with 1.876 L of 1 N hydrochloric acid and then with 1.8 L of water. The organic layer was washed with 1.5 L of 5% w / w aqueous sodium bicarbonate. The organic layer was washed with water (1.5 L), brine (1.0 L), and vacuum filtered through a Buchner funnel. 6.1 L of a solution of Boc- (S) -3- (2-naphthyl) alanyl-N-benzyl-N-methylamide in ethyl acetate are obtained. This solution was kept under nitrogen at ambient temperature overnight before being used in the next step.

II. Step [ξ Example 1B]

Into a 12-liter round-bottomed flask equipped with a mechanical stirrer, a digital thermometer, a addition funnel, a drying tube and a cooling bath, a solution of 455.75 g of hydrochloric acid gas and 2.2 liters of ethyl acetate were weighed. The solution was cooled to 10 ° C (internal temperature) and a solution of the product of Step I (6.1 L) in ethyl acetate (6.1 L) was added over 25-30 minutes while maintaining the internal temperature below 20 ° C. The mixture was warmed to ambient temperature - 22-23 ° C and stirred at this temperature for a further 3 hours. The reaction mixture was evaporated under reduced pressure (40-45 ° C and 13.3 - 14.7 kPa) until 5.0 L of solvent was collected. The evaporation residue was cooled to 20-22 ° C and stirred for 15-30 minutes. The resulting solid was collected by vacuum filtration on a Buchner funnel and washed with ethyl acetate (4 x 300 mL, 1.2 L total). The solid was dried at 50-55 ° C and 102 kPa for 24 hours to a constant weight. This yields pure (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methylamide hydrochloride, which has a purity by high performance liquid chromatography of 98.4% by weight.

[α] D = + 24.8 ° (c = 1, methanol).

III. Step [Ξ Example l.c)]

A 5 L round bottom flask equipped with a mechanical stirrer, a digital thermometer, a addition funnel and a cooling bath was charged with 2.0 L of isopropyl acetate and 332.0 g of the product of Step 2. The resulting slurry was cooled to 10-12 ° C (internal temperature) with an ice-water bath. Under vigorous stirring, 1.4 L of 5% w / w aqueous sodium hydroxide solution is added over 10 minutes while maintaining the internal temperature at 10-12 ° C. The mixture was heated to 21-22 ° C over 30 minutes. The organic layer was separated and washed first with 0.7 L of water and then with 0.25 L of aqueous sodium chloride. The organic layer was dried over 100 g of anhydrous sodium sulfate and vacuum filtered on a Buchner funnel. The solid was washed with isopropyl acetate (3 x 30 mL, 90 mL total). The organic layer was evaporated under reduced pressure (4-10 kPa; 43-45 ° C) until no more solvent was removed. In this way, (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methyl-amide is obtained as the free base in the form of an oily substance, which is preserved.

One 12-liter four-neck with mechanical stirrer, digital thermometer, dosing funnel, nitrogen inlet and nitrogen outlet

- Weigh into a round-bottomed flask with 29 holes and a cooling bath

205.4 g of Boc- (S) -proline and 3.2 L of ethyl acetate. The mixture was stirred for 5 minutes and 125.6 g of 4-methylmorpholine were added over 10 minutes while maintaining the internal temperature at 20-22 ° C. The addition funnel was washed with ethyl acetate (25 mL) and the wash was added to the reaction mixture. The solution was cooled to -15 ° C (internal temperature) and then 132.9 g of chloroformic acid isobutyl ester dissolved in 75 ml of ethyl acetate was added over 25-30 minutes while maintaining an internal temperature of -14 ° C and -16 ° C. ° C. The addition funnel was washed with ethyl acetate (3 x 20 mL, 60 mL total) and the individual washings were added to the reaction mixture. The resulting suspension was stirred for an additional 30-35 minutes at -14 ° C to -15 ° C. Prepare a solution of (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methyl-amide (0.35 L) in ethyl acetate (0.35 L) and then steady at about 10 mL / min. at about 60 minutes while maintaining the internal temperature between -14 ° C and -15 ° C. The addition funnel was washed with ethyl acetate (3 x 25 mL, 75 mL total) and the individual washings were added to the reaction mixture. The reaction mixture was warmed to ambient temperature - 21-22 ° C over 1 hour and stirred at this temperature for an additional hour. Water (3.0 L) was then added at 21-23 ° C and the whole was stirred for 5-10 minutes. The organic layer was separated and washed first with 1.5 L of 1 N hydrochloric acid and then with 1.5 L of water. The resulting organic layer was washed with 1.5 L of 5% w / w aqueous sodium bicarbonate solution, 1.5 L of water and 1.0 L of aqueous sodium chloride, respectively. The organic layer was vacuum filtered through a Buchner funnel. This gives 3.93 liters of Boc- (S) -prolyl9 · 9 ·

30- (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methyl-amide. This solution was kept under nitrogen at ambient temperature overnight before being used in the next step.

ARC. step [= Example I.C]

Into a 12-liter round-bottomed flask equipped with a mechanical stirrer, a digital thermometer, a addition funnel, a drying tube and a cooling bath, was added a solution containing 335.3 g of hydrochloric acid gas and 1.63 liters of ethyl acetate. The solution is cooled to 6 ° C (internal temperature) and 3.93 liters of the crude solution of Step 3 are added over 25-30 minutes while maintaining the internal temperature below 20 ° C. The addition funnel was washed with ethyl acetate (3 x 60 mL, total 180 mL) and the individual washings were added to the reaction mixture. The reaction mixture was warmed to ambient temperature - 22-23 ° C and stirred at this temperature for a further 2 hours. The reaction mixture was concentrated under reduced pressure (40-44 ° C, 10.7 to 14.7 kPa) until 4.7 liters of solvent were collected. The resulting oil (0.66 L) was dissolved in water (1.4 L) and extracted with ethyl acetate (1.0 L). The organic layer was extracted with 0.2 L of water. The aqueous layers were combined and transferred to a 5-liter round bottom flask equipped with a mechanical stirrer, digital thermometer, dosing funnel and a cooling bath. The aqueous layer was cooled to 15 ° C (internal temperature) with an ice-water bath, and a solution cooled to 20-21 ° C containing 120 g of sodium hydroxide and 1.2 liters of water was added over 20-30 minutes. , and during the addition the internal temperature is kept below 18 ° C (pH should be between 9 and 10). The mixture is heated to ambient temperature (21-23 ° C) for 10 minutes, «* · ·

Extract with 31 L of 3 L isopropyl acetate. The organic layer was separated and the aqueous layer was extracted with isopropyl acetate (2x0.5 L, 1.0 L total). The combined organic layers were washed first with 0.75 L of water and then with 0.5 L of aqueous sodium chloride. The organic layer was dried over 125 g of anhydrous sodium sulfate and vacuum filtered on a Buchner funnel. The solid was washed with isopropyl acetate (2 x 50 mL, 100 mL total). In this way, (S) -prolyl- (S) -3- (2-naphthyl) -anyl-N-benzyl-N-methyl-amide is obtained in an amount of 5.02 liters. This solution was kept under nitrogen pressure until used in the next step.

Step V (ξ Example 1)

Into a 12-liter round-bottomed flask fitted with a mechanical stirrer, a digital thermometer, a dosing funnel, a nitrogen inlet and a nitrogen outlet and a cooling bath, weigh 5.02 liters into a IV flask. isopropyl acetate. The solution is cooled to 6- 11 ° C (internal temperature) in an ice-water bath at 6-7 ° C, and a solution of 156 g of 2-nitrophenyl isocyanate and 0.5 g of sodium hydroxide is added over 20-30 minutes. of isopropyl acetate, and the internal temperature is maintained below 17-18 ° C during the addition. The addition funnel was washed with isopropyl acetate (2 x 25 mL, 50 mL total) and the individual washings were added to the reaction mixture. The mixture was warmed to ambient temperature - 22-23 ° C and stirred at this temperature for a further 1 hour. The reaction mixture is filtered and concentrated under reduced pressure (40-45 [deg.] C., 9.3-13.3 kPa) until no more solvent is distilled off. About 0.64 kg of crude product obtained by evaporation 40 ···· ···· ·

After heating to 32 ° C (bath temperature), it is dissolved in 0.5 L of a mixture of ethyl acetate and hexane (60:40 by volume). The solution was cooled and poured onto a chromatography column containing 8.5 kg of silica gel. The column is eluted until the liquid level reaches silica gel. The flask was washed with 3 x 0.3 liters of a mixture of ethyl acetate and hexane (60:40 by volume) and the individual washings were poured onto the column. In each case, the column is eluted until the liquid level reaches silica gel. The column was eluted first with 36.5 liters of a 60:40 by volume mixture of ethyl acetate and hexane and then with 3 8 liters of ethyl acetate. 16 to 24 containing the product fractions were combined and the solvent was evaporated (39-44 ° C, 9.3 to 14.7 kPa) until no further solvent was distilled off. The resulting oily material was suspended in 1.8 liters of 190 degree ethanol and the solvents were evaporated (39-44 ° C, 9.3-14.7 kPa). The residue was dissolved in 3.1 L of alcohol at 190 ° C with heating (bath temperature: 40-45 ° C). The resulting solution (3.6 L) was cooled to 29-30 ° C (internal temperature) and added over 30 minutes to a 13 L, pre-12 l, four neck, mechanical stirrer, digital thermometer, addition funnel, nitrogen inlet and nitrogen outlet. in a round-bottomed flask equipped with an opening and a cooling bath, cooled to 7-8 ° C [internal temperature, bath temperature 0 - -2 ° C]. The internal temperature was maintained at 7-9 ° C during the addition. The addition funnel was washed with 2x50 mL of a total of 100 mL ethanol at 190 and both washings were added to the suspension. The suspension was kept at the same temperature for a further t · · · · · · · · · · · · · · · · · · ·

.........

After stirring for 35 minutes, the solids were collected by vacuum filtration through a polypropylene cartridge fitted in a Buchner funnel. The solid was washed with 3 x 1 liter of water (3 liters in total). The solid was dried in a kilo-plant SS vacuum disk dryer on polyethylene pads in trays at 42-43 ° C (42.5 kPa) until constant weight (44 hours) was achieved. In this way, 2-nitrophenylcarbamoyl [(S) -propyl] - [(S) -3- (2-naphthyl) -anyl] -N-benzyl-N-methyl is obtained as a yellow solid. amide having a purity of 99.4% by weight as determined by high performance liquid chromatography (HPLC 951068).

[α] D = -59.8 ° (c = 1, methanol).

The compounds of formula I and their pharmacologically acceptable acid addition salts, hereinafter collectively referred to as the active compounds of the invention, exhibit tachykinin antagonist activity. More particularly, the agents of the invention are potential antagonists of the NK-1 tachykinin receptor (substance P). Accordingly, the active compounds of the invention may also be used as medicaments, for example, in the forms described below.

Affinity for NK-1 receptor binding can be demonstrated by the ability to reposition the [ ³ H] P substance, for example by the following assay.

Test I

Transfer of [ ³ H] P Binding from Membranes Derived from Cos-7 Cells Transfected with Cloned Human NK-1 Receptor (hNK-1R) 34 Preparation of membranes containing hNK-1R

Transient expression of recombinant DNA in Cos-7 cells and subsequent cell harvesting is accomplished using conventional techniques [Sambrook et al., 1989; Kriegler, 1990],

Membranes are prepared from transfected Cos-7 cells by homogenizing the cells in a Kinematica homogenizer for 30 minutes at 10,000 rpm. The resulting suspension is centrifuged at 28,000 g for 30 minutes. The particulate material was washed and resuspended two more times in 50 mM Tris hydrochloride (pH 7.4) and centrifuged again. At the end, the particulate material is resuspended in 50 mM Tris hydrochloride (pH 7.4) containing 5% glycerol to give a protein concentration of 2 to 8 mg / ml. 500 μΙ aliquots of the suspension were pipetted, and the pipetted material was rapidly frozen on dry ice.

Binding of [ ³ H] P to hNK-1R receptor containing membranes

The membranes prepared as described above were suspended at -70 ° C. Binding assays are performed in 1.2 ml polypropylene test tubes containing a final volume of 0.5 ml with the following components:

- Binding buffer with the following composition in pg / ml: chymostatin 2, leupeptin 4, bacitracin 40, 2 mM manganese (II) chloride, · · · ·

35 0.1 wt% bovine serum albumin, 20 mM Hepes, pH 7.4;

- 400 μΐ membrane suspension (0.019 ± 0.03 mg protein per tube);

- 50 μΐ 6 nM [ ³ H] P; and

- 50 μΐ 50% by weight of dimethylsulfoxide (to determine the total amount of binder);

- 50 μΐ CP96, 345 (10 μΜ) (Snider et al., 1991) (to determine non-specific binding); obsession

- various test compounds at concentrations of 50 μΐ.

Test compounds are prepared in 10 mM stock solutions using 100% dimethylsulfoxide (DMSO). The stock solutions were further diluted with 50% (w / w) dimethylsulfoxide to a concentration of 1mM before use. Six test concentrations of each test compound were used to record inhibition curves. Each assay is performed using three samples. Specific binding to NK1 receptors is defined as the difference between the results obtained for total binding test tubes and those for non-specific binding assays. The reaction is initiated by the addition of the radioactive ligand and incubated at 24 ° C for 45 minutes. The reaction was quenched by the addition of 500 μΐ ice-cold 50 mM Tris hydrochloride buffer, pH 7.4. The binding mixture was rapidly filtered through Whatman GF / B filter plates previously soaked in 0.3% polyethyleneimine solution at ambient temperature for 2-3 hours. The test tubes and filters were washed with 6x1 ml ice-cold wash buffer. The radioactivity of the material bound to the filter was determined in a Canberra Packard TopCount instrument by liquid scintillation. Microscint-40 is used as the liquid scintillant fluid. Binding parameters were calculated using LIGAND according to Munson and Rodbard (1980).

First protein experiments with Cos-7 cell membranes transfected with the human NK-1 receptor showed that, per test tube! Up to 80-100 pg of protein, the specific binding of [ ³ H] P increases with the protein concentration. For routine assays, 19 ± 3 pg of protein is used per tube. At a concentration corresponding to this amount, the amount of specific binding of [ ³ H] P is generally more than 70% of the total amount of binding. 3% of the total amount of radioactive material added to the incubation medium is bound.

[ ³ H] P binds rapidly to Cos-7 cell membranes transfected with human NK-1 receptor: equilibrium is reached at ambient temperature for 20 minutes and remains stable for 90 minutes. Binding was measured after 45 minutes in each successive assay.

The data required to record the saturation curves for binding of [ ³ H] P to Cos-7 cell membranes transfected with human NK-1 receptors are determined by measuring after incubation at ambient temperature for 45 minutes. The equilibrium dissociation constant (K _D = 85 + 12 pM) and the number of binding sites (B _max = 537 ± 139) for each transfection were determined using LIGAND (Munson et al., 1980) simultaneously from at least three series of data by nonlinear iteration curve fitting. , and calculate the arithmetic mean for all 10 transfections.

• · ···· · · · ·

- 37 References:

- Kriegler et al., Gene Transfer and Expression, Laboratory Manual, Stockton Press, 1990;

Munson et al., Anal. Biochem. 107: 220 (1980);

- Sambrook et al., Molecular Cloning, Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory Press. Refs., 1989; and

Snider et al., Science 251: 435-436 (1991).

The active compounds of the invention tested by the method described are K; =? 0.01-10.0 nM effectively displaces [ ³ H] -P.

The pharmacological utility of the active compounds of the invention as NK-1 receptor antagonists, for example as analgesics, may also be demonstrated by conventional assays, such as:

II. Study: A model based on strong pain

Six test groups of approximately 250 g of male Dunkin-Hartley guinea-pigs were formed. Guinea pigs are injected with 100 μΐ of 1% w / w carrageenan. Mechanically induced severe pain sensation is measured using a Ugo Basile Analgesymeter (up to 250 g pressure on the paw) and the threshold at which the animal withdraws the paw as the first sign of distress is determined. The intense heat-induced pain sensation is determined by placing the animals in a perspex box (poly (methyl methacrylate)) and stimulating the soles of the paws with increasing heat.

Measure the time to paw retraction (Hargreaves et al., Pain, 32, 77-88 (1988)). The withdrawal thresholds for mechanical and thermal stimuli are determined for both inflamed and non-inflamed paws.

Excessive pain sensation for heat and mechanical action was measured 24 hours after carrageenan injection. The test substance, the active ingredient according to the invention, is then administered orally in various doses in the form of a 10% w / w solution of dimethyl sulfoxide containing 1% by weight of tragacanth gum, and after a further 3 hours the severe sensation of heat and mechanical action is again determined. .

By the test method described above, it has been found that the compounds of the present invention, when administered orally at a dose of about 0.5 to 5.0 mg / kg body weight, are effective in reducing intense mechanical pain and about 0.5 to 5.0 mg / kg orally. When used at a dose of 1 kg of body weight, it is effective in reducing excessive pain induced by heat.

Thus, the active compounds of the present invention may be used as a medicament such as a tachykinin antagonist, in particular as an NK-1 antagonist (substance P antagonist), for example in the treatment of diseases or clinical conditions characterized by extremely high levels of substance P-mediated or unwanted activity.

The active compounds of the present invention are particularly useful as anesthetic and analgesic agents for the treatment of pain of different origins or pathologies. These agents are anti-inflammatory or anti-edema

They can also be used as 39 agents for the treatment of inflammatory reactions, diseases and conditions.

It has been found that the active ingredients of the present invention exhibit remarkably good or greater post-oral anesthetic activity compared to tachykinin antagonists known in the art, such as NK-1 antagonists. Following systemic administration, it has also been found that, following systemic administration, these agents exhibit remarkably potent analgesic activity in the central nervous system, compared to other tachykinin antagonists known in the art, such as NK-1 antagonists.

Due to their anesthetic and anti-inflammatory properties, the active compounds of the present invention are particularly effective in the treatment of inflammation-induced pain, intense pain sensation and, above all, chronic pain, such as severe chronic pain. They are useful, for example, in the treatment of pain, inflammation and / or edema following injuries such as burns, sprains, fractures and the like, and in the treatment of pain following surgical procedures such as surgery. They are also well suited for treating inflammatory pain of various origins, such as arthritis, rheumatic diseases, tendonitis, vasculitis and rheumatoid arthritis (e.g., arthritis with deformity), and gout.

The active compounds of the present invention can also be used successfully in the treatment of pain associated with angina, cramps, gallstones, and menstruation.

The active compounds of the present invention are useful in the treatment of migraine ···· · · · · · »

- 40 for pain associated with the disease. They may also be used as anti-emetic agents, for the treatment of nausea, such as those associated with chemotherapy, poisoning, pregnancy or migraine, as well as for incontinence and gastrointestinal disorders such as delayed gastric emptying, indigestion, and esophageal reflux.

The active compounds of the present invention are also effective in treating chronic or obstructive airways diseases, for example, by reducing or preventing their use, bronchial edema, amount of substance secreted by the lung mucosa, and airway hyperresponsiveness, such as in the treatment or prevention of asthma. The active compounds of the invention are atopic and nematic asthma, such as allergic asthma, exercise-induced asthma, occupational asthma, asthma following bacterial infection, drug-induced asthma, such as aspirin, and wheezing symptoms. are equally suitable for treatment.

Further, among the diseases of the airways which are inflammatory or obstructive and which can be treated with the active compounds of the invention are pneumoconiosis of various types or origins, e.g. such as lime pneumoconiosis, hair loss, iron powder inhaled pneumoconiosis, silicosis, tobacco and, most importantly, cotton pneumoconiosis.

Other Diseases and Conditions Associated with Inflammation or Airway Blockage and Treatable with the Agents of the Invention

Among the 41, adult respiratory distress syndrome (ARDS), chronic pulmonary or airway obstruction (COPD or COAD), and bronchitis are also mentioned. The active compounds of the present invention may also be used to treat allergic and vasomotor rhinitis.

The active compounds of the present invention are also indicated for the treatment of the following diseases and disorders:

central nervous system disorders, in particular anxiety states such as anxiety, depression, psychosis, schizophrenia, panic disorder, phobias such as loneliness, somatic disorders stress and addiction disorders such as alcohol;

- neurodegenerative disorders such as dementia, including senile dementia, Alzheimer's disease and Down's syndrome;

- myelopathic disorders such as MS and ALS and other neuropathological disorders such as peripheral neuropathy such as diabetes and neuropathy induced by chemotherapy.

The agents of the invention are also indicated for the treatment of diseases or conditions associated with dysfunction of the immune system, such as autoimmune diseases, in particular autoimmune diseases associated with inflammation, edema or pain transmission. Typical diseases and conditions in this group include: autoimmune haematological disorders (including Crosby's syndrome, aplastic anemia, erythrocytes) • ♦

- 42 anemia and essential platelet counts), systemic cutaneous tuberculosis, polychondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, autoimmune goiter, gonorrhea ulcerative bowel disease and Crohn's disease), endocrine-related eye disease, Grace's disease, sarcoidosis, multiple sclerosis, primary liver cirrhosis, juvenile diabetes (type I diabetes mellitus), uveitis (anterior and posterior), - and conjunctivitis, intercellular fibrous degeneration of the lung tissue, psoriasis and arthritis, glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minor lesions) (kidney problems) and inflammation of the blood vessels. The active compounds of the present invention may be used as an immunosuppressive agent or as an immunosuppressive adjuvant, for example in combination with other immunosuppressive agents, for example in the treatment of cyclosporin or macrolide immunosuppressive drugs, for the suppression of non-human organs or , liver, cornea, heart, lungs or heart and lung transplantation.

The active compounds of the present invention may also be indicated for the treatment of allergic diseases and conditions of, for example, the skin, eyes, nose and throat, and the gastrointestinal tract, especially when these diseases and conditions are inflammatory, edema or they are accompanied by pain-relieving reactions. Examples of such diseases and conditions include eczema and disorders caused by hypersensitivity, such as catarrh allergy, contact dermatitis, conjunctivitis, conjunctivitis of the eye, dermatitis of the cornea and conjunctivitis, dermatitis and others.

The active compounds of the present invention are also useful in the treatment of circulatory disorders caused by vasodilation and vascular spasms such as angina, migraine and Reynaud's disease.

In addition, the compounds of the present invention have been found to have P-glycoprotein blocking activity. Accordingly, the active compounds of the invention, together with those of other therapeutic groups, may be indicated as adjuvants or co-agents, for example for the following applications:

- increasing or extending the efficacy of, or sensitivity to, other chemotherapeutic agents, in particular antimicrobial agents such as antimicrobial, antiviral, antifungal or anti-protozoal, anti-AIDS or anti- such as antineoplastic or cytostatic chemotherapy. Accordingly, they may be indicated, for example, as agents for lowering conventional chemotherapy dose levels, such as antineoplastic or cytostatic chemotherapy, agents for reducing the overall toxicity of active ingredients, and, in particular, restoring susceptibility to chemotherapeutic treatment. ·

44 as an agent for reducing resistance, whether it is congenital or acquired resistance;

- to enable the central nervous system to be treated with other active substances or to enhance the effect of the treatment, for example, to increase the amount of active substance that crosses the blood / CSF barrier, to enable, to enhance or extend the effectiveness of or, for example, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, etc. - in combination with therapeutic agents and chemotherapeutic agents for the treatment of brain tumors;

as an antiparasitic agent, in particular an anti-protozoal agent, for example against organisms of the genus Toxoplasma such as Toxoplasma gondii and organisms of the genus Plasmodia such as Plasmodium falciparum.

For the above indications, the dosage of the active compounds of the invention will, of course, vary depending upon, for example, the patient being treated, the mode of administration, the nature and severity of the condition being treated, and the relative efficacy of the active ingredient. In general, however, it is worth mentioning that animals can provide satisfactory pain relief and satisfactory treatment of migraine and nausea when the compounds of the invention are orally administered in an amount of about 0.1 to 10 mg / kg orally. ·· ·

- 45 body weight daily doses. For oral administration to larger mammals, such as humans, the oral dose is about 7.0 to 700 mg / day, for example about 100 mg / day, which can be administered up to four times a day or in divided doses or as a sustained release drug. to relieve pain, migraine and nausea. Suitable oral dosage forms thus contain from about 1.5 mg to about 150 mg or 700 mg, for example from about 25 to 100 mg, of the active compound of the invention in admixture with a pharmaceutically acceptable diluent or carrier.

Because of the relatively low solubility of the active compounds of the invention for oral use, it is desirable to formulate a composition comprising a hydrophilic phase (e.g., a mixture of propylene glycol and ethanol), a hydrophobic phase (e.g., mono-, di- and triglycerides derived from vegetable such as a commercially available MAISINE trademark) and a surfactant (e.g., a polyoxyhydrogenated vegetable oil such as CREMOPHOR). Intravenous injection formulations may be prepared by dissolving the selected active compound of the invention together with the appropriate surfactant such as CREMOPHOR RH 40 in ethanol. The following example illustrates the preparation of galenic formulations suitable for oral use:

• «• · · · · · ·

Component amount per unit dose ·· «·

- 46 Identifying the component

1. An agent of the invention, such as the compound of Example 1

2. Propylene glycol

3. Mono-, di-, and triglycerides derived from corn oil, such as MAISINE®

4. Polyoxyl 40 (hydrogenated castor oil, e.g.

100.00 mg 94.70 mg

19.90 mg

CREMOPHOR RH 40) 383.70 mg

5. Anhydrous ethanol 94.70 mg

Total: 993.00 mg

Component 4 is maintained at 40 ° C until it becomes liquid. Components 2, 3 and 5 are added to component 4 and the whole mixture is stirred in a conventional manner until a clear solution is obtained. To the solution thus obtained, if necessary, at low temperature, add component 1 in finely divided form, e.g.

The amorphous compound of Example 1 in the form of the free base was stirred and the whole was stirred until a clear solution was obtained. The product thus obtained is a drinkable solution. The composition may also be formulated in soft gelatin or hard gelatin capsules. The capsules thus prepared contain, for example, 50 or 100 mg of component 1.

The active compounds of the invention may optionally be applied topically in the form of creams, gels, and the like.

- 47, for example, for the treatment of the skin conditions previously described. The active compounds of the present invention may also be inhaled, for example, in the form of a dry powder, for example, for the treatment of obstructive or inflammatory diseases of the respiratory tract, or otherwise, for example, by injection or infusion.

One preferred active compound of the invention is the compound of Example 1. The described II. In this test, an ED ₅₀ value of 0.73 ± 0.09 mg / kg bw for mechanical hyperalgesia was determined for this compound and 1.75 ± 0.64 mg / kg b.w. for thermal hyperalgesia. The estimated ED ₅₀ value for aspirin by the same test method is approximately 30 mg / kg body weight for mechanical hyperalgesia and 100 mg / kg body weight for thermal hyperalgesia. Thus, when the compound of Example 1 is administered orally as an anesthetic, the amount of active ingredient indicated is 40-50 times less than that of aspirin.

Another preferred active ingredient of the invention is the compound of Example 17. The described II. In this test series, an ED ₅₀ of 1.0 mg / kg body weight was determined for this compound in oral treatment of mechanical hyperalgesia. Thus, when the compound of Example 17 is administered orally as an anesthetic, the amount of active ingredient indicated is 30 times less than that of aspirin.

Accordingly, the present invention provides:

· «» ·. «« »» ** ·· • · «*« r · · · · ♦ · «· · · · · · · · · · · ·

The active compounds of the present invention for use as a medicament, such as an NK-1 antagonist (substance P antagonist), for example in any of the specific indications described above, in particular as anesthetic, anti-inflammatory, anti-edema or allergic conditions or reactions. as an agent for treating colds or nausea.

Pharmaceutical compositions containing the compounds of the invention as active ingredients in admixture with pharmaceutically acceptable diluents or carriers.

Claims (10)

Claims Compounds having the general formula (I) - R.! with one or two substituents selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, hydroxy, methoxy, hydroxymethyl, methoxymethyl, methoxycarbonyl, carbamoyl and / or N-methylcarbamoyl. phenyl substituted with; - n is 0 or 1; - X 1 is oxygen, sulfur or = NCN; X ₂ and X ₃ are each independently oxygen or sulfur; - R ₂ is hydrogen or methyl; - R ₃ is phenyl, halophenyl, 2-naphthyl, 1H-indol-3-yl or 1-methyl-indol-3-yl; - Z is -N (CH ₃ ) - or -CH ₂ -, - R ₄ is phenyl, 3,5-bis (trifluoromethyl) phenyl or pyridyl; and - R ₅ is hydrogen, phenyl, 3,5-bis (trifluoromethyl) phenyl or pyridyl, provided that when X ₃ is sulfur, Z is -N (CH ₃ ) - and Acid addition salts of compounds of formula (I). Compounds according to claim 1, which are of formula (I) - R _t is 2-halophenyl or 2-nitrophenyl; - n = 0; • · X ₂ and Χ 3 are both oxygen; - R ₄ is phenyl or pyridyl; - _R5 is hydrogen, phenyl or pyridyl; and X 1, R ₂ , R 3 and Z are as defined in claim 1 and the acid addition salts of these compounds. Compounds according to claim 1, wherein R 1 in formula (I) is is 2-nitrophenyl, n = 0; X ₁₅ X ₂ and X ₃ are both oxygen, R ₂ is hydrogen, R ₃ is 2-naphthyl, Z is -N (CH ₃ ) -, R ₄ is phenyl and R ₅ is hydrogen. Compounds according to claim 1, wherein, in the formula (I), R 1 is 2- (methoxymethyl) phenyl, R ₂ is hydrogen, n = 0; X ₁ , X ₂ and X ₃ are both oxygen, R ₃ is 2-naphthyl, Z is -N (CH ₃ ) -, R ₄ is phenyl and R ₅ is hydrogen. Compounds according to claim 1, which are of formula (I) a) R 1 is 2-nitrophenyl, n = 0; X ₂ and X ₃ are both oxygen atoms, R ₂ is hydrogen, R ₃ is 2-naphthyl, Z is -N (CH ₃ ) and - X 1 is sulfur, R ₄ is phenyl and R ₅ is hydrogen; - X 1 = NCN, R ₄ is phenyl and R ₅ is hydrogen; - X 1 is oxygen and R ₄ and R ₅ are both 2-pyridyl; - X 1 is oxygen, R ₄ is 2-pyridyl and R ₅ - 51 is hydrogen; obsession - X 1 is sulfur, R ₄ is 2-pyridyl and R ₅ is hydrogen; obsession b) n = 0; X ₂ and X ₃ are both oxygen, R ₂ is hydrogen, R ₃ is 2-naphthyl, Z is -N (CH ₃ ) -, R ₄ is phenyl, R 5 is hydrogen, and R 1 is 2-chlorophenyl. a group, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-fluorophenyl, 2- (methoxycarbonyl) phenyl, 3-nitro-, phenyl, 2- (methylcarbamoyl) -phenyl, 2-carbamoyl-phenyl, 2-hydroxyphenyl or 2-hydroxymethylphenyl; obsession c) R 1 is 2-nitrophenyl, n = 0; X ₁ , X ₂ and X ₃ are both oxygen, R ₃ is 2-naphthyl, R ₄ is phenyl, R ₅ is hydrogen, and - R ₂ is methyl and Z is -N (CH ₃ ) -; obsession - R ₂ is hydrogen and Z is -CH ₂ -; obsession d) R 1 is 2-nitrophenyl, n = 0; X _B X ₂ and X ₃ are both oxygen, R ₂ is hydrogen, R ₃ is 2-naphthyl, Z is -N (CH ₃ ) -, R 5 is hydrogen, and R ₄ is 1H-indol-3-yl. or 3,4-dichlorophenyl; obsession e) n = 1; X ₁ is sulfur, X ₂ and X ₃ are both oxygen, R ₂ is hydrogen, R ₃ is 2-naphthyl, Z is -N (CH ₃ ) -, R ₄ is phenyl, R ₅ is hydrogen, and R 1 is 2-chlorophenyl, 2- (trifluoromethyl) phenyl or 2-bromophenyl; obsession f) R 1 is 2-chlorophenyl, n = 1; X ₂ and X ₃ are both oxy • · - 52 genes, R ₂ is hydrogen, R ₃ is 2-naphthyl, Z is -N (CH ₃ ) -; and X 1 is sulfur, while R ₄ and R 5 are both 2-pyridyl; - X 1 is sulfur, R ₄ is 2-pyridyl and R ₅ is hydrogen; - X 1 is oxygen, R ₄ is phenyl and R 5 is hydrogen; - X 1 is sulfur, R ₄ is 3,5-bis (trifluoromethyl) phenyl and R 5 is hydrogen; obsession - X 1 is sulfur and R ₄ and R 5 are both phenyl; obsession g) n = 1; X ₁ is sulfur, X ₂ and X ₃ are both oxygen, Z is -N (CH ₃ ) -, R ₄ is phenyl, R ₅ is hydrogen; and - R represents a 2-nitrophenyl group, R ₂ is methyl and R ₃ is 2-naphthyl; obsession R 1 is 2-chlorophenyl, R ₂ is hydrogen and R ₃ is 3,4-dichlorophenyl or 1-methylindolyl-3-yl, and the acid addition salts thereof. 6. A compound according to claim 1 of formula (I) wherein (a) and the carbon atoms (b), and - when R ₄ and R ₅ are different, the _R5 substituent is other than hydrogen - (c ) are both in the (S) -configuration, and R ₁ to R ₅ , X _{1 to} X ₃ , n and Z are as defined in claims 1, 2, 3 or 6 and the acid addition of these compounds. salts. • · · · · · · ········ - 53 Compounds according to claim 1, wherein in formula (I) each of the carbon atoms (a) and (b) is of the (S) -configuration, and R 1 to R ₅ , X _{1 to} X ₃ , n and Z are as defined in claim 4. or as claimed in claim 5. 8. A process for the preparation of a compound of formula (I) as defined in claim 1 or an acid addition salt thereof, wherein the compounds of formula (II) - in formula (II) - R ₂ to R 5, X ₂ , X ₃ and Z with compounds of formula (III) wherein Rf is selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, protected hydroxy, methoxy, protected hydroxymethyl, methoxymethyl and / or methoxycarbonyl mono- or di-substituted phenyl, n and X; and is as defined in formula (I); and then, if desired - releasing the compound of formula (I) containing the resulting Rf-protected hydroxy group and / or protected hydroxymethyl group from the protecting group (s) and / or the resulting Rf-substituted methoxycarbonyl phenyl group; converting a compound of formula (I) wherein Rf is a phenyl substituted by a carbamoyl group or an N-methylcarbamoyl group; and - recovering the compounds of formula (I) thus obtained in the form of the free base or of an acid addition salt. Pharmaceutical compositions comprising, in addition to a pharmacologically acceptable diluent or carrier, a pharmaceutical composition according to any one of claims 1-8. A compound as defined in any one of claims 1 to 4 or a compound thereof. - they contain 54 pharmacologically acceptable acid addition salts. 10. A compound of formula (I), or a pharmacologically acceptable acid addition salt thereof, as defined in any one of claims 1 to 6 for use as a medicament.