HK1019327B - Novel aryl glycinamide derivatives, method of producing said derivatives and pharmaceutical compositions containing these compounds - Google Patents

Description

Arylglycinamide derivatives, process for their preparation and pharmaceutical compositions containing them

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The invention relates to novel arylglycinamide derivatives of general formulaAnd pharmaceutically acceptable salts thereof, processes for their preparation, and pharmaceutical compositions containing them. These compounds are valuable neurokinin (tachykinin) antagonists.

Abbreviations used in the specification and claims are as follows: CDI = carbonyldiimidazole DCCI = dicyclohexylcarbodiimide HOBt = 1-hydroxybenzotriazole THF = tetrahydrofuran DMF RT = room temperature DMAP = 4-dimethylaminopyridine TBTU = O-benzotriazolyl-tetramethyl * tetrafluoroborate

Each structural formula is represented in a simplified manner. In the representation of the compounds, for example, all CH₃The substituents are all represented by a short lineCH represents ≡ such that, for example:means that

The invention relates to novel arylglycinamide derivatives of general formula (I)Or a pharmaceutically acceptable salt thereof, wherein Ar is unsubstituted or mono-to penta-substituted phenyl, or unsubstituted or mono-to di-substituted naphthyl [ wherein the substituents of phenyl and naphthyl are independently of each other halogen (F, Cl, Br, I), (C)_{1- 4}) Alkyl, O- (C)_1-4) Alkyl radical, CF₃,OCF₃Or NR¹²R¹³(wherein R is¹²And R¹³Independently of one another, H, methyl or acetyl)]Or Ar is-O-CH₂-O-or-O- (CH)₂)₂-O-substituted phenyl; r¹And R²Together with the N to which they are bonded form a ring of the formulaOr

Wherein r, s and t are 2 or 3; r⁶Is H, (C)_1-5) Alkyl radical (C)_3-5) Alkenyl, propynyl, hydroxy (C)_2-4) Alkyl, methoxy (C)_2-4) Alkyl, di (C)_1-3) Alkylamino radical (C)_2-4) Alkyl, amino (C)_2-4) Alkyl, oxy, di (C)_1-3) Alkylamino, monofluoro-to perfluoro (C)_1-2) Alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CH₂-C(O)NR¹⁴R¹⁵Group, wherein R¹⁴Is H or (C)_1-4) Alkyl and R¹⁵Is H, (C)_1-4) Alkyl radical (C)_3-6) Cycloalkyl, hydroxy (C)_2-4) Alkyl, alkoxy (C)_2-3) Alkyl, phenyl (C)_1-4) Alkyl, or R¹⁴And R¹⁵Together with the N bonded thereto form a ring (1-pyrrolidinyl, 1-piperidinyl, N-morpholinyl or 1-methylpiperOxazin-4-yl); r⁷Having the definitions in (a) to (d),

(a) hydroxy radical

(b) 4-piperidylpiperidinyl group in a nitrogen-containing hydrocarbon,

wherein R is¹⁶And R¹⁷Independently of each other are

H,

(C_1-4) An alkyl group, a carboxyl group,

(C_3-6) A cycloalkyl group,

hydroxy (C)_2-4) An alkyl group, a carboxyl group,

(C_1-3) Alkoxy (C)_2-4) An alkyl group, a carboxyl group,

phenyl (C)_1-4) Alkyl or

Two (C)_1-3) Alkylamino radical (C)_2-4) An alkyl group, a carboxyl group,

or as R¹⁶Is H or (C)_1-4) An alkyl group, a carboxyl group,

then R is¹⁷Or may be-CH₂C(O)NR¹⁸R¹⁹Wherein R is¹⁸And R¹⁹Is as defined for R¹⁴

And R¹⁵；

Wherein R is²⁰Is that

H,

(C_1-4) An alkyl group, a carboxyl group,

(C_4-6) Cycloalkyl radicals or

-CH₂C(O)NR²¹R²²，

Wherein R is²¹And R²²Is as defined for R¹⁴And R¹⁵；R⁸Is HR⁹And R¹⁰Each independently is (C)_1-4) Alkyl radical, R¹¹Is H, (C)_1-5) Alkyl radical (C)_3-5) Alkenyl, propynyl, hydroxy (C)_2-4) Alkyl, methoxy (C)_2-3) Alkyl, di (C)_1-3) Alkylamino radical (C)_2-3) Alkyl, amino (C)_2-3) Alkyl, amino, di (C)_1-3) Alkylamino, monofluoro-to perfluoro (C)_1-2) Alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CH₂-C(O)NR²³R²⁴Group, wherein R²³And R²⁴Is as defined for R¹⁴And R¹⁵；R³Is H, (C)_1-4) Alkyl, unsubstituted or mono-to trisubstituted phenyl, wherein the substituents are independently of one another halogen (F, Cl, Br, I), (C)_1-4) Alkyl, O- (C)_1-4) Alkyl radical, CF₃,OCF₃Or NR²⁵R²⁶(wherein R is²⁵And R²⁶Independently of one another, H, methyl or acetyl); r⁴Is phenyl (C)_1-4) Alkyl or naphthyl (C)_1-4) Alkyl, wherein phenyl may be substituted with from l to 3 substituents, wherein each of said substituents is independently (F, Cl, Br, I), (C)_1-4) Alkyl, O- (C)_1-4) Alkyl radical, CF₃,OCF₃Or NR²⁷R²⁸(wherein R is²⁷And R²⁸Independently of one another, H, methyl or acetyl); and R⁵Is H, (C)_1-4) Alkyl radical (C)_3-6) Cycloalkyl radical, CH₂COOH,CH₂C(O)NH₂OH or phenyl (C)_1-4) An alkyl group. Preferred compounds of the formula I are; wherein Ar is unsubstituted or mono-or disubstituted phenyl, or unsubstituted naphthyl, or Ar is-O-CH₂-O-or-O (CH)₂)₂-O-substituted phenyl;

R¹and R²And N bonded thereto together form a ring of the formulaOrWherein r is 2 or 3 and s and t is 2; r⁶,R⁷,R⁸,R⁹,R¹⁰And R¹¹The definition of (A) is as previously described; r³Is H or (C)_1-4) Alkyl radical, R⁴Is phenyl (C)_1-4) Alkyl or naphthyl (C)_1-4) Alkyl, wherein the phenyl group may be substituted with 1 or 2 substituents, and wherein each of these substituents is independently halogen (F, Cl, Br, I), (C)_1-4) Alkyl, O- (C)_1-4) Alkyl radical, CF₃Or OCF₃(ii) a And R⁵Is H, (C)_1-4) Alkyl radical (C)_3-6) Cycloalkyl, OH or (C)_1-4) An alkyl phenyl group.

Preferred compounds of the formula I are those in which Ar is unsubstituted or mono-or disubstituted phenyl or unsubstituted naphthyl [ in which the substituents of the phenyl are each independently halogen (F, Cl, Br, I), methyl, methoxy, CF₃Or OCF₃]Or Ar is a-O-CH₂-O-or-O- (CH)₂)₂-O-substituted phenyl; in particular those of the formula I in which Ar is phenyl, naphthyl, phenyl which is substituted in the 3-and/or 4-position by methoxy or halogen, or in the 2-and 3-or 3-and 4-positions by-O-CH₂-O-linked phenyl, particularly preferred compounds are those in which Ar is phenyl, phenyl substituted in the 3 and 4 positions by methoxy or in the 3 and 4 or 2 and 3 positions by-O-CH₂-an O-linked phenyl group.

Of the above compounds, particularly preferred are those in which, in the lower ringR is 2 or 3 and R⁶Is H, (C)_1-5) Alkyl radical (C)_3-5) Alkenyl, propynyl, hydroxy (C)_2-4) Alkyl, methoxy (C)_2-4) Alkyl, di (C)_1-3) Alkylamino radical (C)_2-4) Alkyl, amino (C)_2-4) Alkyl, amino, di (C)_1-3) Alkylamino, monofluoro-to perfluoro (C)_1-2) Alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, orParticularly preferred compounds are those in which R is 3 and R⁶Is methyl; and wherein R is 2 and R⁶Is H, (C)_1-4) Alkyl, propenyl, propynyl, hydroxy (C)_2-3) An alkyl group, a carboxyl group,methoxyethyl, di (C)_1-2) Alkylamino radical (C)_2-3) Alkyl, aminoethyl, amino, dimethylamino, CH₂CF₃N-methylpiperidinyl, pyridyl, pyrimidinyl, orPreferred compounds are those wherein R is 2 and R⁶Is H, (C)_1-3) Alkyl, allyl, 2-propynyl, -CH₂CH₂OCH₃,-CH₂-CH₂N(CH₃)₂N-methylpiperidinyl, 2-pyrimidinyl orIn particular those compounds, wherein R is 2 and R⁶Is H, CH₃,C₃H₇,CH(CH₃)₂,CH₂CH₂OH,CH₂CH₂OCH₃Or CH₂CH₂N(CH₃)₂。

Of the above compounds, particularly prominent are the compounds wherein R¹And R²And N bonded thereto together form the following ringWherein R is⁸Is H and R⁷Is OHWherein R is¹⁶And R¹⁷Independently of one another are: h (C)_1-3) An alkyl group, a carboxyl group,(CH₂)_nOH wherein n is 2,3 or 4 (CH)₂)₂OCH₃-(CH₂)_nPh wherein n is 2 or 4 (CH)₂)₂N(CH₃)₂OrIn particular these compounds, wherein R¹⁶And R¹⁷Are all CH₃Or C₂H₅Or R¹⁶Is H or CH₃And R¹⁷Is (C)_1-3) An alkyl group, a carboxyl group,(CH₂)₂OH,(CH₂)₄OH orR⁷Is thatN(CH₃)₂OrIn particular those compounds, wherein R¹And R²And N bonded thereto together form a ring as followsWherein (a) R⁸Is H and

R⁷is thatWherein R is¹⁶And R¹⁷Both of which are CH₃,C₂H₅Or CH₂CH₂OH or R¹⁶Is H or CH₃And R is¹⁷Is (C)_1-3) An alkyl group, a carboxyl group,(CH₂)₂OH or (CH)₂)₄OH or (b) R⁸Is H and R⁷Is that

Of the above compounds, the more prominent ones are those wherein R is¹And R²And N bonded thereto together form a ring as follows

Of the above compounds, the more prominent ones are those wherein R is¹And R²And N bonded thereto together form a ring as followsWherein R is¹¹Is H or (C)_1-3) Alkyl radicals, in particularAre those compounds wherein R¹¹is-CH (CH)₃)₂。

Of the above-mentioned compounds, particularly preferred are those compounds wherein R is³Is H; and/or R⁴Is phenyl (C)_1-4) Alkyl, where the phenyl radical may be substituted by 1 or 2 substituents, and where the substituents are each independently of the other and are halogen (F, Cl, Br, I), (C)_1-4) Alkyl, O- (C)_1-4) Alkyl radical, CF₃Or OCF₃(ii) a And/or R⁵Is H, (C)_1-4) Alkyl radical (C)_3-6) Cycloalkyl, -OH or phenyl (C)_1-4) Alkyl radicals, especially those compounds in which R is⁴Is phenyl (C)_2-4) Alkyl, wherein the substituents are in the 3 and/or 5 position of the phenyl ring and/or R⁵Is H, methyl, OH or phenethyl, preferably those compounds in which R is⁴Is thatAnd R⁵Is methyl.

The compounds of the formula I may have acid groups, predominantly carboxyl groups, and/or basic groups, such as amino groups, and may therefore be present in the form of their internal salts, for example salts with pharmaceutically acceptable mineral acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid, or organic acids, such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid, or with pharmaceutically acceptable bases, such as alkali metal or alkaline earth metal hydroxides or carbonates, or with organic amines, such as dimethylamine, triethylamine, triethanolamine, etc.

The compounds according to the invention may exist as racemates, but the pure enantiomers, i.e. (R) -or (S) -forms, may also be prepared.

The term "naphthyl" as used above includes 1-naphthyl and 2-naphthyl.

Test results for compounds according to the invention:

receptor affinity for the NK 1-receptor (P-receptor substance) is determined using clonally propagated NK₁The receptor is on the human lymphoblastoid cells (IM-9) by measurement¹²⁵I-displacement of the labeled substance P. K thus obtained_iValues indicate the effectiveness of these compounds:

Ki[nM]

example 11.2

Example 21.0

Example 319

Example 41.4

Example 51.5

Example 81.8

Example 92.5

Example 113.8

Example 125.0

Example 132.4

Example 150.98

Example 160.90

Example 177.75

Example 180.96

Example 191.17

Example 202.0

Example 222.2

Example 232.5

Example 242.2

Example 256.0

Example 261.6

Example 281.3

Example 301.8

Example 321.3

Example 337.4

Example 342.9

Example 471.7

Example 551.25

Example 631.4

Example 641.1

Example 655.7

Example 732.0

Example 741.5

Example 750.44

Example 762.0

The compounds according to the invention are valuable neurokinin (tachykinin) antagonists having not only substance P antagonistic but also neurokinin A or neurokinin B antagonistic properties. These compounds are useful for the treatment and prevention of diseases caused by neurokinins:

for the treatment or prophylaxis of inflammatory and allergic diseases of the respiratory tract, such as asthma, chronic tracheitis, respiratory allergies, emphysema, rhinitis and cough, and for the treatment or prophylaxis of eye diseases, such as conjunctivitis and iritis, for the treatment or prophylaxis of skin diseases, such as contact dermatitis, urticaria, psoriasis, sunburn, insect bites, itching, sensitive or allergic skin, for the treatment or prophylaxis of gastrointestinal diseases, such as gastric and duodenal ulcers, ulcerative colitis, Crohn's disease, colepsy and Hirschsprung's disease.

Treating or preventing joint diseases such as rheumatoid arthritis, reactive joint disease and Reiter syndrome; for the treatment of central nervous system disorders such as dementia, pre-senile dementia, schizophrenia, psychosis, depression, headache (e.g., migraine or tension headache), epilepsy, Parkinson's disease and stroke;

for the treatment of herpes zoster and post-herpetic pain, tumors, collagenous diseases, disorders of the urinary tract in the case of spermatorrhea, hemorrhoids, nausea and vomiting, for example as a result of radiation or cytostatic therapy or exercise and various pains.

The invention also relates to the use of the compounds of the invention as therapeutic agents and pharmaceutical preparations containing these compounds. These compounds are preferably used in humans. The compounds of the invention may be administered intravenously, subcutaneously, intramuscularly, intraperitoneally or intranasally, by inhalation, transdermally, by iontophoresis or known enhancers in the literature, or orally, as desired.

For parenteral administration, the compounds of the formula I or their physiologically acceptable salts can be present in solution, suspension or emulsion in combination with the substances customary for this purpose, such as solubilizers, emulsifiers or other adjuvants. Useful solvents include: water, physiological saline solution or alcohol, such as ethanol, propylene glycol or glycerol, sugar solution such as glucose or mannose solution or mixture of several solvents.

Furthermore, such compounds may be administered via implants, such as polylactide, polyethylene glycol ester or polyhydroxybutyric acid, or intranasal formulations.

The oral effect of the compounds of formula I can be demonstrated by the following standard tests: anesthetic-inhibiting guinea pig agent NK₁Resulting in a decrease in blood pressure.

300-500 g guinea pigs were anesthetized with pentobarbital (50 mg/kg, given intra-abdominally), intubated, and breathed. The artificial respiration is 10 ml/kg air, 60 times per minute. The carotid artery was cannulated and arterial blood pressure was recorded. A polyethylene tube was inserted into the jugular vein for intravenous administration of the substance.

Every 10 minutes NK was given intravenously₁-agonist [ beta Ala⁴,Sar⁹,Met(O₂)¹¹]SP(4-11)The blood pressure was temporarily lowered and the dose given was 0.2. mu. mol/kg. After measuring the blood pressure thus generated, the test compound was introduced into the duodenum, and further NK was injected every 10 minutes₁-an agonist.

Results to suppress specific NK₁% of blood pressure decrease induced by agonist.

Example 1 Compounds for NK at a dose of 1 mg/kg (administered to human duodenum)₁Inhibition of the decrease in blood pressure by agonist was 80%.

The compounds of the present invention can be prepared by generally known methods.

These compounds can be prepared by various methods. The two most common preparation methods are described below:method A. Reacting carboxylic acids with amines HN (R) in various ways⁵)R⁴And (7) connecting. The usual methods are coupling methods, such as those used in peptide chemistry. To coupling participants (coupling partners) in nearly equal amounts of coupling reagents, e.g., TBTU, DCCI/HOBt, CDI, etc. Suitable solvents are DMF, THF, CH₂Cl₂,CHCl₃Acetonitrile or other inert solvent or mixtures thereof. Suitable temperatures are from-50 ℃ to +120 ℃ and preferably from 0 ℃ to 40 ℃.

The carboxylic acids can also be used first in a known manner with SOCl₂,SO₂Cl₂,PCl₃,PCl₅Or PBr₃Or mixtures thereof, with an amine HN (R)⁵)R⁴In an inert solvent, e.g. CH₂Cl₂The reaction is carried out in THF or dioxane at a temperature of-50 ℃ to +100 ℃, typically 0 ℃ to 20 ℃.

Another method is to convert the carboxylic acid into an alkyl ester, generally a methyl ester, by known methods and then to react the ester with an amine HN (R)⁵)R⁴The reaction is carried out in an inert solvent, such as DMF, dioxane or THF. The reaction temperature is 20 ℃ to 150 ℃, generally 50 ℃ to 120 ℃. The reaction can also be carried out in a pressurized vessel. Process B. the process is carried out by reacting an alpha-halogeno-arylacetamide derivative prepared by known process with an amine R¹(R²) The NH reacts under the cleavage of the hydrogen halide. Using inorganic bases, e.g. K₂CO₃，NaHCO₃Or CaCO₃Or organic bases, e.g. triethylamine, henig's (Hunig) base, pyridine or DMAP, it also being possible to use an excess of the amine R¹(R²) The NH scavenges the cracked (or excess) hydrogen halide. DMF, THF, dioxane or other inert solvents were used. The reaction temperature is from 0 ℃ to 100 ℃, generally from 10 ℃ to 80 ℃. Process C. Compounds of the invention, wherein R⁵Instead of H, it can also be prepared as follows: first, R is synthesized according to method A or B⁵Is the corresponding compound of H. Then, the following method is used for N-alkylation to introduce alkyl, cycloalkyl or CH₂COOH. According to the invention R⁵The compound is H with equivalent amount of NaH, NaNH₂,KOH,NaOCH₃Or other strong base for deprotonation. The reaction uses an anhydrous inert solvent such as THF, dioxane or diethyl ether. The alkylating agent is then slowly added in the form of the corresponding halide, tosylate or mesylate. The reaction is carried out at-50 ℃ to +100 ℃, typically 0 ℃ to +50 ℃.

Example 1

Melting point: 105-115C

FAB-MS:(M+H)⁺=516.3. first step: 0.71 g of 1-isopropylpiperazine was dissolved in 55 ml of anhydrous DMF, and 0.64 g of Na was added₂CO₃Mix and stir at room temperature for 20 minutes and then cool to 5 ℃. 1.15 g of methyl (R, S) - α -bromophenylacetate are added and the suspension is stirred at room temperature overnight. The precipitate was filtered off and the filtrate was evaporated. The residue was dissolved in ethyl acetate and treated with 10% KHCO₃The solution was extracted twice and then once with saturated NaCl solution. Organic phase in Na₂SO₄Drying, filtering and evaporating to obtain 1.23 g of (R, S) -1-isopropyl-4- (2-phenylacetic acid) methyl ester piperazine as viscous oil. Yield: about 89%. A second step; 1.23 g of the product of the first step are dissolved in 10ml of methanol and 10ml of THF, mixed with 10ml of 1N NaOH and the mixture is stirred at room temperature overnight. The clear reaction solution was neutralized with 10ml of 1N HCl, evaporated to dryness, the residue was treated with DMF and the solid was filtered off with suctionThe filtrate was evaporated to dryness, the residue was triturated with ether, the solid was filtered off with suction and dried in a desiccator. This gave 1.1 g of (R, S) -1-isopropyl-4- (2-phenylacetic acid) -hexahydropiperazine as a white solid. Yield: 92% of a third step: 0.37 g of the product of the second step and 0.42 g of N-methyl-3.5-bis (trifluoromethyl) -phenylethylamine were dissolved in 14 ml of DMF and adjusted to pH8.5 by adding about 0.4 ml of TEA. 0.48 g of TBTU was added and the mixture was stirred at room temperature overnight. The clear solution was evaporated in vacuo. The residue is taken up in NaHCO₃The solution was stirred and extracted twice with ethyl acetate. The combined organic phases were filtered and the filtrate was evaporated. The residue is chromatographed on silica gel using CH₂Cl₂MeOH (9: 1) as eluent. The same portion obtained was evaporated and dissolved in a small amount of MeOH, acidified with etherified HCl and evaporated again. The residue was triturated with ether and dried in a desiccator. To obtain 0.58 g of (R, S) -1-isopropyl-4- [ 2-phenylacetic acid-N-methyl-N- (3, 5-bistrifluoromethylphenylethyl)]Amide dihydrochloride, as a white solid. Yield: 75 percent. Other compounds of the invention can be prepared in a similar manner, as in the following examples:

example 2:melting point: 141-146 ℃ FAB-MS (M + H)⁺=474.3

Example 3:melting point: 122-132 ℃ FAB-MS (M + H)⁺=552,4

Example 4:melting point: 138-148 ℃ FAB-MS (M + H)⁺=502,3

Example 5:melting point: 231 ℃ 241 ℃ (Zers.) FAB-MS (M + H)⁺=516.4

Example 6:melting point: 122-132℃FAB-MS:(M+H)⁺=518.1

Example 7:melting point: 168 + 174 deg.C (Zers) FAB-MS: M⁺=502.3

Example 8:melting point: 240 ℃ C

Example 9:melting point: more than 230 DEG C

Example 11:boiling point: 130 ℃ and 160 ℃ melting point: 215 at 218 deg.C (decomposition)

Example 12:melting point: more than 230 DEG C

Example 13:melting point: more than 230 DEG C

Example 15:boiling point: 143 ℃ C. -120-

Example 16Melting point: 168 ℃ C

Example 17:melting point: 142 ℃ C. and 150 ℃ C

Example 18:melting point: more than 230 DEG C

Example 19:melting point: 202-204 deg.C

Example 20:melting point: 178-180 deg.C

Example 22:melting point: 191-193 deg.C

Example 23:melting point: 162-164 deg.C

Example 24:melting point: 220 ℃ and 224 ℃ (decomposition); FAB-MS (M + H)⁺=514.3

Example 25:melting point: 102-117 ℃; FAB-MS (M + H)⁺=512.4

Example 26:melting point: 225-232 ℃ (decomposition); FAB-MS (M + H)⁺=518.3

Example 28:melting point: 242 ℃ 245 ℃ (decomposition) FAB-MS (M + H)⁺=545.2

Example 29:

example 30:melting point: 115-124 ℃; FAB-MS (M + H)⁺=532.3

Example 31:

example 32:melting point: 107-112 ℃; FAB-MS (M + H)⁺=530.2

Example 33:melting point: 133-143 ℃; FAB-MS (M + H)⁺=530.4

Example 34:melting point: 178-182 ℃; FAB-MS (M + H)⁺=488.3

Example 35:

example 36:

example 37:

example 38:

example 39:

example 40:

example 41:

example 42:

example 43:

example 44:

example 45:

example 46:melting point: 149-159 ℃ FAB-MS (M + H)⁺=534.3

Example 48:

example 49:

example 50:

example 51:

example 53:

example 54:

example 55:melting point: 115 ℃ and 119 DEG C

Example 56:

example 57:

example 58:

example 59:

example 60:

example 61:

example 63:melting point: 218 ℃ 228 ℃ (decomposition) FAB-MS (M + H)⁺=516.3

Example 64:melting point: FAB-MS (M + H) at 92-96 deg.C⁺=488.2

Example 65:melting point: 132-142 ℃ FAB-MS (M + H)⁺=576.5

Example 66:melting point: 131-141 ℃ FAB-MS (M + H)⁺=560.1.

Example 67:melting point: 228 ℃ 231 ℃ (decomposition) FAB-MS (M + H)⁺=502.3

Example 68:

example 69:

example 70:

example 71:

example 72:

example 73:melting point: 108 ℃ 118 ℃ FAB-MS (M + H)⁺=560.4

Example 74:melting point: 138-]_D ²⁰=+45.5°(MeOH)

Example 75:melting point: 166-]_D ²⁰=+19.0°(DMSO).Melting point: 132 ℃ and 134 DEG C

Of these compounds, the compounds of examples 1 and 8 are preferred.

In the above structural formula, CH is used herein₃The radicals are not shown.

For example, compound 1 contains a methyl group as R⁵. Pharmaceutical preparation injection solution

200mg of active substance^*

1.2mg monopotassium phosphate = KH₂PO₄ )

0.2mg disodium hydrogen phosphate = Na₂HPO₄₂H₂O =) (buffer)

94mg sodium chloride) (isotonic solution)

520mg glucose)

4mg Albumin (protective protease)

Appropriate amount of sodium hydroxide solution

Hydrochloric acid in proper amount) to a pH of 6

Adding water for injection to 10ml

Injection solution

200mg of active substance^*

94mg of sodium chloride

Or 520mg of glucose

4mg Albumin

Appropriate amount of sodium hydroxide solution

Hydrochloric acid in proper amount) to a pH of 9

Adding water for injection to 10ml

Freezing desiccant

200mg of active substance^*

520mg mannose (isotonic agent/structure-forming agent (Gerustbilder))

4mg Albumin

Solvent for freezing desiccant 1

10ml of water for injection

Solvent for freezing desiccant 2

20mg polysorbate * 80= tween * 80 (surfactant)

10ml of water for injection

^*Active substance: compounds of the invention, for example one of examples 1 to 76

Adult dose weighing 67 kg: 1 to 500 mg

Claims (25)

1. An arylglycinamide derivative of the general formula i or a pharmaceutically acceptable salt thereof:wherein Ar represents an unsubstituted mono-to penta-substituted phenyl group, or an unsubstituted mono-to di-substituted naphthyl group; wherein the substituents of phenyl and naphthyl are, independently of one another, halogen of F, Cl, Br, I, C_1-4Alkyl, O-C_1-4Alkyl radical, CF₃,OCF₃Or NR¹²R¹³(ii) a Wherein R is¹²And R¹³Independently of one another, H, methyl or acetyl, or Aris-O-CH₂-O-or-O- (CH)₂)₂-O-substituted phenyl; r¹And R²Together with the N to which they are bonded form a ring of the formulaOrWherein r, s and t are 2 or 3; r⁶Is H, C_1-5Alkyl radical, C_3-5Alkenyl, propynyl, hydroxy C_2-4Alkyl, methoxy C_2-4Alkyl, di (C)_1-3) Alkylamino radical C_2-4Alkyl, amino C_2-4Alkyl, amino, di (C)_1-3) Alkylamino, monofluoro-to perfluoroC_1-2Alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CH₂-C(O)NR¹⁴R¹⁵Group, wherein R¹⁴Is H or C_1-4Alkyl and R¹⁵Is H, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy C_2-4Alkyl, alkoxy C_2-3Alkyl, phenyl C_1-4Alkyl, or R¹⁴And R¹⁵Together with the N to which it is bonded, form a ring, to 1-pyrrolidinyl, 1-piperidinyl, N-morpholinyl or 1-methylpiperazin-4-yl; r⁷Having the definitions of (a) to (d), (a) hydroxy (b) 4-1-piperidinylpiperidinyl,wherein R is¹⁶And R¹⁷Independently of one another are H, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy C_2-4Alkyl radical, C_1-3Alkoxy radical C_2-4Alkyl, phenyl C_1-4Alkyl or di (C)_1-3) Alkylamino radical C_2-4Alkyl, or if R is¹⁶Is H or C_1-4Alkyl, then R¹⁷Or may be-CH₂C(O)NR¹⁸R¹⁹Wherein R is¹⁸And R¹⁹Is as defined for R above¹⁴And R¹⁵The definition of (1);wherein R is²⁰Is H, C_1-4Alkyl radical, C_4-6Cycloalkyl or-CH₂C(O)NR²¹R²²Wherein R is²¹And R²²As described above for R¹⁴And R¹⁵Defining; r⁸Is HR⁹And R¹⁰Each independently is C^1-4Alkyl radical, R¹¹Is H, C_1-5Alkyl radical, C_3-5Alkenyl, propynyl, hydroxy C_2-4Alkyl, methoxy C_2-3Alkyl, di (C)_1-3) Alkylamino radical C_2-3Alkyl, amino C_2-3Alkyl, amino, di (C)_1-3) Alkylamino, monofluoro-to perfluoroC_1-2Alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or-CH₂-C(O)MR²³R²⁴Group, wherein R²³And R²⁴As described above for R¹⁴And R¹⁵Defining; r³Is H, C_1-4Alkyl, unsubstituted mono-to trisubstituted phenyl, wherein the substituents are independently of one another F, Cl, Br, halogen of I, C_1-4Alkyl, O-C_1-4Alkyl radical, CF₃,OCF₃Or NR²⁵R²⁶Wherein R is²⁵And R²⁶Independently of one another, H, methyl or acetyl; r⁴Is phenyl C_1-4Alkyl or naphthyl C_1-4Alkyl, wherein phenyl may be substituted with 1 to 3 substituents,

wherein the substituents are each independently halogen, C, F, Cl, Br, I_1-4Alkyl, O-C_1-4Alkyl radical, CF₃,OCF₃Or NR²⁷R²⁸Wherein R is²⁷And R²⁸Independently of one another, H, methyl or acetyl; and R⁵Is H, C_1-4Alkyl radical, C_3-6Cycloalkyl radical, CH₂COOH,CH₂C(O)CH₂OH or phenyl C_1-4An alkyl group.

2. A compound according to claim 1, wherein Ar is unsubstituted mono-or disubstituted phenyl, or unsubstituted naphthyl, or Ar is-O-CH₂-O-or-O (CH)₂)₂-O-substituted phenyl; r¹And R²Together with the N to which they are bonded form a ring of the formulaOrWherein r is 2 or 3 and s and t are 2; r⁶,R⁷,R⁸,R⁹,R¹⁰And R¹¹As defined in claim 1; r³Is H or C_1-4Alkyl radical, R⁴Is phenyl C_1-4Alkyl or naphthyl C_1-4Alkyl, wherein the phenyl group may be substituted with 1 or 2 substituents, and wherein these substituents are each independently halogen, C being F, Cl, Br, I_1-4Alkyl, O-C_1-4Alkyl radical, CF₃Or OCF₃(ii) a And R⁵Is H, C_1-4Alkyl radical, C_3-6Cycloalkyl, OH or phenyl C_1-4An alkyl group.

3. A compound according to claim 1 or 2, wherein Ar is unsubstituted mono-or disubstituted phenyl, or unsubstituted naphthyl; wherein the substituents of the phenyl radicals are, independently of one another, halogen, methyl, methoxy, CF of F, Cl, Br, I₃Or OCF₃(ii) a Or Ar is a-O-CH₂-O-or-O- (CH)₂)₂-O-substituted phenyl.

4. A compound according to claim 3, wherein Ar is phenyl, naphthyl, phenyl substituted in the 3 and/or 4 position with methoxy or halogen, or in the 2 and 3 or 3 and 4 positions by-O-CH₂-an O-linked phenyl group.

5. A compound according to claim 4, wherein Ar is phenyl, phenyl substituted with methoxy in the 3 and 4 positions, or through-O-CH in the 3 and 4 or 2 and 3 positions₂-an O-linked phenyl group.

6. A compound according to one of claims 1 to 5, wherein in the ringR is 2 or 3 and R⁶Is H, C_1-5Alkyl radical, C_3-5Alkenyl, propynyl, hydroxy C_2-4Alkyl, methoxy C_2-4Alkyl, di (C)_1-3) Alkylamino radical C_2-4Alkyl, amino C_2-4Alkyl, amino, di (C)_1-3) Alkylamino, monofluoro-to perfluoroC_1-2Alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, or

7. A compound according to claim 6, wherein R is 3 and R⁶Is methyl.

8. A compound according to claim 6, wherein R is 2 and R⁶Is H, C_1-4Alkyl, propenyl, propynyl, hydroxy C_2-3Alkyl, methoxyethyl, di (C)_1-2) Alkylamino radical C_2-3Alkyl, aminoethyl, amino, dimethylamino, CH₂CF₃N-methylpiperidinyl, pyridyl, pyrimidinyl, or

9. The compound according to claim 8, wherein R is 2 and R⁶Is H, C_1-3Alkyl, allyl, 2-propynyl, -CH₂CH₂OCH₃,-CH₂CH₂N(CH₃)₂N-methylpiperidinyl, 2-pyrimidinyl or

10. The compound according to claim 9, wherein R is 2 and R⁶Is H, CH₃,C₃H₇,CH(CH₃)₂,CH₂CH₂OH,CH₂CH₂OCH₃Or CH₂CH₂N(CH₃)₂。

11. A compound according to claim 1 or 2, wherein R¹And R²Together with the N to which they are attached form the following ringWherein R is⁸Is H, and R⁷Is OHWherein R is¹⁶And R¹⁷Independently of one another are: HC_1-3An alkyl group, a carboxyl group,(CH₂)_nOH, wherein n is 2,3 or 4 (CH)₂)₂OCH₃-(CH₂)_nPh wherein n is 2 or 4 (CH)₂)₂N(CH₃)₂Or

12. A compound according to claim 11, wherein R¹⁶And R¹⁷Are all CH₃Or C₂H₅Or R¹⁶Is H or CH₃And R¹⁷Is C_1-3An alkyl group, a carboxyl group,(CH₂)₂OH,(CH₂)₄OH or

13. A compound according to claim 11, wherein R⁷Is thatN(CH₃)₂Or

14. A compound according to claim 11, wherein R¹And R²Together with the N to which they are attached form a ringWherein (a) R⁸Is H and R⁷Is thatWherein R is¹⁶And R¹⁷All represent CH₃,C₂H₅Or CH₂CH₂OH or R¹⁶Is H or CH₃And R is¹⁷Is C_1-3An alkyl group, a carboxyl group,(CH₂)₂OH or (CH)₂)₄OH or (b) R⁸Is H and R⁷Is that

15. A compound according to claim 1 or 2 wherein R is¹And R²Together with the N to which it is bonded form a ring

16. A compound according to claim 1 or 2 wherein R is¹And R²Together with the N to which it is bonded form a ring

Wherein R is¹¹Is H or C_1-3An alkyl group.

17. A compound according to claim 16, wherein R¹¹is-CH (CH)₃)₂。

18. A compound according to claim 1 or 2, wherein R³Is H.

19. A compound according to claim 1 or 2, wherein

R⁴Is phenyl (C)_1-4) Alkyl, where the phenyl radical may be substituted by 1 or 2 substituents, where these substituents are, independently of one another, halogen, C being F, Cl, Br, I_1-4Alkyl, O-C_1-4Alkyl radical, CF₃Or OCF₃(ii) a And R⁵Is H, C_1-4Alkyl radical, C_3-6Cycloalkyl, -OH or phenyl C_1-4An alkyl group.

20. A compound according to claim 19, wherein

R⁴Is phenyl C_2-4Alkyl, wherein the substituents are located in the 3-and/or 5-position of the phenyl ring and

R⁵is H, methyl, OH or phenethyl.

21. A compound according to claim 20, wherein R⁴Is that

And R is⁵Is methyl.

22. A process for preparing compounds of the general formula i as claimed in one of claims 1 to 21, characterized in that

(a) Reacting an acid of the formula

Or a halide or alkyl ester thereof with an amine of the formula

(b) Reacting an alpha-haloarylacetamide of the formula

With an amine of the formula

(c) R is to be⁵N-alkylating a compound of formula I which is H;

the compound thus prepared is then isolated as the free compound or as a pharmaceutically acceptable salt thereof.

23. A pharmaceutical preparation comprising a compound according to one of claims 1 to 21 and customary carriers and/or excipients.

24. Use of compounds according to one of claims 1 to 22 for the production of pharmaceutical preparations for the treatment and prophylaxis of diseases which are caused by neurokinins.

25. The use according to claim 24 for the preparation of a pharmaceutical composition for oral administration for the treatment and prevention of depressive disorders.