MXPA01010544A - Carbamic acid derivatives and their use as metabotropic glutamate receptor ligands - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein X signifies O, S or two hydrogen atoms not forming a bridge;A1/A2 signify, independently from each other, phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms;B is a group of formula (A), wherein Y signifies -O-, -S- or a bond;Z signifies -O- or -S-;or B is a 5-membered heterocyclic group of formulas (a, b, c or d). These compounds may be used as metabotropic glutamate receptor ligands in the control or prevention of acute and/or chronic neurological disorders.

Description

DERIVATIVES OF CARBAMIC ACID AND THEIR USES AS LIGANDS OF THE METABOTROPIC GLUTAMATE RECEPTOR DESCRIPTION OF THE INVENTION The present invention relates to ester derivatives of carbamic acid, of the general formula wherein R 1 signifies hydrogen or lower alkyl; R2, R2 'signify, independently of each other, hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; X means O, S or two hydrogen atoms that do not form a bridge; Ax / A2 signify, independently of one another, phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms; REF: 133201 B is a group of formula wherein R3 signifies lower alkyl, lower alkenyl, lower alkynyl, benzyl, lower alkyl-cycloalkyl, lower alkyl-cyano, lower alkyl-pyridinyl, lower alkyl-lower alkoxy-phenyl, lower alkyl-phenyl, which is optionally substituted with alkoxy lower, or phenyl, which is optionally substituted by lower alkoxy, or lower alkyl-thienyl, cycloalkyl, lower alkyl-trifluoromethyl or lower alkyl-morpholinyl; And it means -O-, -S- or a link; Z means -O- or -S-; or B is a 5-membered heterocycle group, of formulas (b) JX (c) < d) wherein R4 and R5 mean hydrogen, lower alkyl, lower alkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with the proviso that at least one of R4 or R5 must be hydrogen; as well as its pharmaceutically acceptable salts. In particular, the invention relates to compounds of the following structures: I was going in which the definition of substituents has been given above. These compounds and their salts are new and are distinguished by valuable therapeutic properties. It has surprisingly been found that the compounds of general formula I are antagonists of the metabotropic glutamate receptor and / or agonists. In the central nervous system (CNS) the transmission of stimuli takes place through the interaction of a neurotransmitter, which is emitted by a neuron, with a neuroreceptor. L-glutamic acid, the neurotransmitter that is most commonly found in the CNS, plays a critical role in a large number of physiological processes. The receptors for glutamate-dependent stimuli are divided into two main groups. The first major group forms ion channels controlled by ligands. The metabotropic glutamate receptors (mGluR) belong to the second main group, and also belong to the family of receptors coupled with G-proteins. At present, eight different members of mGluRs are known and of these, some even have subtypes. Based on the structural parameters, the different paths indicated by the second messenger, and the different affinity to low molecular weight chemical compounds, these eight receptors can be subdivided into three subgroups: mGluRl and mGluR5 that belong to group I, mGluR2 and mGluR3 belonging to group II and mGluR4, GluRβ, mGluR7 and mGluRd belonging to group III. Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and / or chronic disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as pain chronic and acute. Other indications that can be treated, related to the described, are the restricted brain function caused by deviation or transplant operations, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia Other treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye lesions, retinopathy, idiopathic parkinsonism or parkinsonism caused by medications as well as conditions that lead to glutamate-deficient functions such as example, muscle spasms, seizures, migraine, urinary incontinence, nicotine addiction, opioid addiction, anxiety, vomiting, dyskinesia and depression. Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their preparation, medicines based on a compound according to the invention and their preparation as well as the use of the compounds according to the invention. invention in the control or prevention of diseases of the aforementioned kind, and respectively, for the preparation of the corresponding medicaments. Preferred compounds of formula I within the scope of the present invention are those in which, A means phenyl, X means 2 hydrogen atoms that do not form a bridge, and B means the group wherein Z is 0 and R3 and Y have been described above The following are examples of these compounds: butylated diphenylacetylcarbamic acid ester, diphenylacetylcarbamic acid ethyl ester or penta-4-ynyl ester of diphenylacetylcarbamic acid.

The compounds of formula I, wherein A means phenyl, X means -O- or -S- and B, mean the group they are also preferred, in which Z is O and R3 and Y have been described above.

Examples of these compounds are: (9H-xanten-9-carbonyl) -carbamic acid ethyl ester, (9H-xanten-9-carbonyl) -carbamic acid butyl ester, or butyl ester. (9H-thioxanten-9-carbonyl) -carbamic acid. Preferred compounds of formula I in the scope of the present invention are those in which A means phenyl, X means 2 hydrogen atoms that do not form a bridge, and B means a heterocycle group of formulas: Where R4 and R * have the meaning given above. Examples of said compounds are: N- (5-ethyl-oxazol-2-yl) -2, 2-diphenyl-acetamide, N- (5-methyl-oxazol-2-yl) -2, 2-diphenyl-acetamide, 2, 2-diphenyl-N- (5-propyl- [1,3,4] oxadiazol-2-yl) -acetamide, N- [5- (2-methoxy-ethyl) - [1, 3, 4] oxadiazole -2-yl] -2, 2-diphenyl-acetamide, N- (3-methyl- [1,2,4] oxadiazol-5-yl) -2, 2-diphenyl-acetamide, N- (3-cyclopropyl- [1, 2, 4] oxadiazol-5-yl) -2, 2-diphenyl-acetamide, or N- (5-methyl- [1,2,4] oxadiazol-3-yl) -2, 2-diphenyl- acetamide. Other compounds of formula I are also preferred, wherein A means phenyl, X means -O- or -S-; and B means a heterocycle group of formulas: a) (b) (c) (d) for example, the following compounds: 9H-xanten-9-carboxylic acid oxazol-2-yl-amide, 9H-xanthenic acid (5-propyl- [1, 3, 4] oxadiazol-2-yl) -amide 9-carboxylic acid, 9H-xanten-9-carboxylic acid (5-ethyl-oxazol-2-yl) -amide, 9H-xanthen-9-carboxylic acid (5-methyl-oxazol-2-yl) -amide, 9H-xanten-9-carboxylic acid (5-propyl-oxazol-2-yl) -amide, 9H-xanten-9 (9-ethyl- [1, 3, 4] oxadiazol-2-yl) -amide) -carboxylic acid, 9H-xanten-9-carboxylic acid (5-cyclopropylmethyl- [1, 3, 4] oxadiazol-2-yl) -amide, 9H-xanten-9-carboxylic acid (4-methyl-oxazol-2-yl) -amide xanten-9-carboxylic acid, 9H-xanten-9-carboxylic acid (3-methyl- [1, 2, 4] oxadiazol-5-yl) -amide, (5-trifluoromethyl- [1, 3, 4] oxadiazole- 2-yl) -amide of 9H-xanthen-9-carboxylic acid, 9H-xanthen-9-carboxylic acid (5-methoxymethyl- [1, 3, 4] oxadiazol-2-yl) -amide, (3-cyclopropyl) - [1, 2, 4] oxadiazol-5-yl) -amide of 9H-xanthen-9-carboxylic acid, or (5-methyl- [1, 2, 4] oxadiazol-3-yl) -amide of the 9H-xanten-9-carboxylic acid. The invention comprises all stereoisomeric forms in addition to the racemates.

The term "lower alkyl" used in the present disclosure means saturated straight or branched chain hydrocarbon radicals, with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like. The term "lower alkoxy" means a lower alkyl residue in the sense of the above definition, linked through an oxygen atom. The term "halogen" encompasses fluorine, chlorine, bromine and iodine. The compounds of general formula I and their pharmaceutically acceptable salts can be obtained by processes which consist of: a) reacting a compound of formula with a compound of the formula R ~ * YH III to obtain a compound of formula wherein the substituents have the meaning given above, or b) reacting a compound of formula with a compound of the formula to give a compound of formula wherein G is a suitable leaving group, such as Cl, Br or acyloxy, or an equivalent of carbonyl chloride such as a carbonyl-pyrazolide, carbonyl imidazole, carbonyl benzotriazole, carbonyloxysuccinimide, or activated esters such as an ester of p- nitrophenyl, pentachlorophenyl ester and the like, and the other substituents have the meanings given above, c) or reacting a compound of formula with a compound of formula to obtain a compound of formula OR d) reacting a compound of formula with a compound of formula to obtain a compound of formula IA wherein the substituents have the meanings indicated above, or e) reacting a compound of formula with a heterocyclic compound of formula B-NH2 IX to give a compound of formula IB (a-d) where B is a 5-membered heterocycle, of the formulas and wherein the remaining substituents have the meanings indicated above, and if desired, a functional group is converted to a compound of formula I in another functional group, and, if desired, a compound of formula I is converted to a salt pharmaceutically acceptable. According to variant a) of the process, a compound of formula III is added, for example, an alcohol (1-butanol, benzyl alcohol, alkyl alcohol, isopropyl alcohol) in dichloromethane, a compound of formula II, for example isocyanate diphenylacetyl and the mixture is stirred at room temperature. The compounds of formula IA can be prepared according to variant b) of the process. A compound of formula V, for example a corresponding urethane or an alkyl carbamic acid ester, is reacted with a compound of formula IV, for example with 9H-xanthen-9-carbonyl chloride or bromide, or with an acyloxy derivative of formula IV, or with an equivalent carbonyl chloride of formula IV, which compounds contain a carbonyl-pyrazolide group, a carbonyl imidazole group, a carbonylbenzotriazole group, a carbonyloxysuccinimide group or an activated ester such as the p-nitrophenyl ester, pentachlorophenyl ester and the like. This reaction is carried out in a solvent, such as pyridine, at room temperature, by methods known in the art. In addition, the compounds of formula IA-1 and IA can be prepared according to the process variant c) and d), wherein a compound of formula VI is reacted with a compound of formula VII or VIII. This reaction is carried out in a manner similar to those described for variant b) of the process. The compounds of formula IB can be prepared by a reaction of a heterocyclic compound of formula IX with a compound of formula IV in the presence of N, N-dimethylamino pyridine at a temperature of 0 ° C. The preferred solvent is methylene chloride. The pharmaceutically acceptable salts can be obtained easily according to the methods already known, and taking into consideration the nature of the compound to be converted into a salt. Inorganic and organic acids, such as for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-Toluenesulfonic acid and the like, are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. The compounds containing alkali or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids, they are suitable for the formation of pharmaceutically acceptable salts of acidic compounds. The reaction scheme 1 provides an overview of the preparation of the compounds of formula IA. The preparation of representative compounds of formula I is described in detail in Examples 1-30. 32 and 34-43. The reaction scheme 2 describes the process for obtaining the compounds of formula IB, which process is described in more detail in examples 31, 33 and 44-69.

Reaction Scheme 1 Substituents have the meaning given above.

Reaction scheme 2 IB (a-d) where B is a 5-membered heterocyclic compound, of formulas A) (b) (c) (d) and the remaining definitions of the substituents are given above. The starting materials used in the reaction schemes 1 and 2 are already known compounds or can be prepared by methods already known per se. The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, agonists and / or antagonists of the metabotropic glutamate receptor, and can be used for the treatment or prevention of acute and / or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficit, as well as acute and chronic pain. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Other treatable indications are Alzheimer's disease, Huntington's chorea, ALS, dementia caused by AIDS, ocular lesions, retinopathy, idiopathic parkinsonism or parkinsonism caused by medications as well as conditions that lead to glutamate-deficient functions, such as, for example, muscle spasms, seizures, migraine, urinary incontinence, nicotine addiction, psychosis, opioid addiction, anxiety, vomiting, dyskinesia and depression.

The compounds of the present invention are agonists and / or antagonists of the mGlu receptor of group I. For example, it has been shown that the compounds of examples 1-22 and 30-69 show agonistic activities, and those of examples 23- 29 are antagonists. The compounds show activities, as measured in the assay described below, of 50 μM or less, typically 1 μM or less, and ideally 0.5 μM or less.

The following table details some specific activity data: Test Description The cDNA encoding the mGlu rat receptor, obtained by Professor S. Nakanishi (Kyoto, Japan), was transiently transferred to EBNA cells using a procedure described by Schlaeger et al., New Dev. New Appl. Anim. Cell Techn., Proc. ESACT Meet., 15 (1998), 105-112 and 117-120. Measurements of [Ca2 +] i were made on EBNA cells transfected with mGlu la after incubation of the cells with Fluo-3 AM (final concentration 0.5 μM) for 1 hour at 37 ° C followed by 4 washes with buffer (stabilizer) (DMEM supplemented with Hank's salt and 20 mM HEPES.) [Ca2 +] i measurements were made using a fluorometric plate imaging reader (FLIPR, Molecular Devices Corporation), La Jolla, CA , USA) When the compounds were evaluated as antagonists, they were tested against 10 μM glutamate as agonist.

The inhibition (antagonist) or activation (agonist) curves were plotted with a four-parameter logistic equation that gave the EC50. and the Hill coefficient using the Origin (non-linear iterative curves) software set (Microcal Software Inc., Northampton, MA, USA). The compounds of formula I and the pharmaceutically acceptable salts thereof can be used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, lacquered tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injectable solutions. The compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert inorganic or organic carriers for the preparation of pharmaceutical preparations. Lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like may be employed, for example, as carriers for tablets, lacquered tablets, dragees and hard gelatin capsule. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance, no carrier is normally required, however, it is required in the case of soft gelatine capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous solutions for injection of water-soluble salts of the compounds of formula I, but as a general rule, it is not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers (stabilizers), sequestering agents or antioxidants. They may also contain other therapeutically valuable substances. As it mentioned above, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof, and a therapeutically inert excipient, are also an object of the present invention, as well as a process for the preparation of said medicaments, which comprises the conversion of one or more compounds of formula I or pharmaceutically acceptable salts thereof, and if desired, one or more therapeutically valuable substances, in a galenic dosage form together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will of course be adjusted to the individual requirements of each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01 and 20 mg / kg / day, with a dosage of 0.1 to 10 mg / kg / day being preferred for all the indications described. The daily dosage for an adult human with a weight of 70 kg is between 0.7 and 1400 mg per day, preferably between 7 and 700 mg per day. Finally, as mentioned above, the use of compounds of formula I and pharmaceutically acceptable salts thereof, for the preparation of medicaments, especially for the control or prevention of acute and / or chronic neurological disorders of the aforementioned kind , it is also an object of the invention.

EXAMPLE 1 Diphenyl acetylcarbamic acid butyl ester To a stirred solution of 1-butanol (0.32 ml, 3.49 mmol) in dichloromethane (4 ml), was added to a solution of diphenylacetyl isocyanate (2.33 ml, 0.5 M in CH2C12, 1.16 mmoles) and the mixture was stirred at RT for 1 hour. Removal of the solvent in vacuo gave a yellow oil, which was purified by column chromatography on silica gel (ethyl acetate / hexane 1: 2) obtaining the title compound (0.3 g, 83%) as a a light yellow solid, mp 82-84 ° C and MS: m / e = 334 (M + Na +).

EXAMPLE 2 Benzyl Ester of Diphenylacetyl Carbamic Acid The title compound, a white solid, m.p. 100-101 ° C and MS: m / e = 345 (M +), was prepared according to the general method of Example 1 from the diphenylacetyl isocyanate and benzyl alcohol.

Example 3 Allyl ester of diphenylacetyl carbamic acid The title compound, a white solid, m.p. 118-120 ° C and MS: m / e = 295 (M +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and alcoolic alcohol.

EXAMPLE 4 Isopropyl Ester of Diphenylacetyl Carbamic Acid The title compound, a white solid, m.p. 122-124 ° C and MS: m / e = 297 (M +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and isopropyl alcohol.

Example 5 Ester tere. diphenyl acetyl carbamic acid butyl The title compound, a yellow solid, m.p. 160-162 ° C and MS: m / e = 334 (M + Na +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and alcohol tere. -butyl EXAMPLE 6 (9H-xanten-9-carbonyl) -carbamic acid ethyl ester To a stirred solution of urethane (0.82 g, 9.21 mmol) and DMAP (0.05 g, 0.41 mmol) (10 mL) in pyridine was added at 0 ° C, 9H-xanthen-9-carbonyl chloride (1.50 g, 6.13 mmol). Stirring was continued at RT for 17 hours, the reaction mixture was evaporated and water (50 ml) / saturated NaHCO solution (20 ml) was added. The solid was separated by filtration and crystallized from water and then from EtOH / hexane to give the product (1.22 g, 67%) as a white solid, m.p. 228 ° C (decomposition) and MS: m / e = 298.2 (M + H +).

Example 7 (RS) - (2-Bromo-9H-xanthen-9-carbonyl) -carbamic acid ethyl ester The title compound, a light brown solid, m.p. 203 ° C and MS: m / e = 375 (M +), was prepared according to the general method of Example 6 from urethane and 2-bromo-9H-xanthene-9-carbonyl chloride.

Example 8 (9H-xanthen-9-carbonyl) -carbamic acid butyl ester The title compound, a white solid, m.p. 180-183 ° C and MS: m / e = 325.4 (M + H +), was prepared according to the general method of Example 6 from the 9H-xanthen-9-carbonyl chloride and the butyl ester of carbamic acid.

EXAMPLE 9 Diphenyl acetylcarbamic acid ethyl ester The title compound, a white solid, m.p. 133 ° C and MS: m / e = 284.2 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and ethanol.

Example 10 Cyclopropylmethyl ester of diphenylacetycarbamic acid The title compound, a white solid, m.p. 108 ° C and MS: m / e = 309.4 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and cyclopropyl ethanol.

EXAMPLE 11 Pent-4-ynyl ester of diphenylacetylcarbamic acid The title compound, a white solid, m.p. 109 ° C and MS: m / e = 321.4 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and pent-4-in-1-ol.

EXAMPLE 12 2-Cyano-ethyl ester of diphenylacetyl carbamic acid The title compound, a white solid, m.p. 113 ° C and MS: m / e = 308.3 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and 3-hydroxy-propionitrile.

Example 13 3-pyridin-4-yl-propyl ester of diphenylacetycarbamic acid The title compound, a brown solid, m.p. 147-50 ° C and MS: m / e = 374.4 (M + H +), was prepared according to the general method of example 1 from diphenylacetyl isocyanate and 3-pyridin-4-yl-propan-l- ol.

EXAMPLE 14 3-Benzyloxypropyl Ester of Diphenylacetycarbamic Acid The title compound, a colorless oil, MS: m / e = 403.5 (M + H +), was prepared according to the general method of Example 1 from isocyanate of diphenylacetyl and 3-benzyloxy-propan-l-ol.

EXAMPLE 15 2- (3,4-dimethoxy-phenyl) ethyl ester of diphenylacetylcarbamic acid The title compound, a white solid, m.p. 144 ° C and MS: m / e = 419.5 (M + -H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and 2- (3,4-dimethoxy-phenyl) -ethanol.

Example 16 (RS) -2-phenylpropyl ester of diphenylacetycarbamic acid The title compound, a white solid, m.p. 131 ° C and MS: m / e = 373.5 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and (RS) -2-phenyl-propan-1-ol.

Example 17 Diene-2-yl methyl ester of diphenylacetyl carbamic acid The title compound, a white solid, m.p. 116 ° C and MS: m / e = 351.4 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and thien-2-yl-methanol.

EXAMPLE 18 Cyclopentyl Ester of Diphenylacetyl Carbamic Acid The title compound, a white solid, m.p. 120-123 ° C and MS: m / e = 323.4 (MH +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and cyclopentanol.

EXAMPLE 19 Cyclohexyl Ester of Diphenylacetyl Carbamic Acid The title compound, a white solid, m.p. 117-119 ° C and MS: m / e = 337.4 (M + Ht), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and cyclohexanol.

Example 20 4-phenyl-butyl ester of diphenylacetylcarbamic acid The title compound, a light yellow solid, m.p. 118 ° C and MS: m / e = 387.5 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and 4-phenyl-butan-1-ol.

Example 21 3, 5-dimethoxy-phenyl ester of diphenylacetycarbamic acid The title compound, a white solid, m.p. = 150-152 ° C and MS: m / e = 391.4 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and 3,5-dimethoxy-phenol.

EXAMPLE 22 2, 2, 2-trifluoroethylester of diphenylacetycarbamic acid The title compound, a white solid, m.p. = 125-127 ° C and MS: m / e = 337.3 (M + H +), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and 2,2,2 trifluoro-ethanol.

EXAMPLE 23 (2, 2-Diphenyl-propionyl) -carbamic acid methyl ester The title compound, a colorless gum, MS: m / e = 297.4 (M + H +), was prepared according to the general method of Example 1 from 2,2-diphenylpropionyl isocyanate and ethanol.

Example 24 (2, 2-Diphenyl-propionyl) -carbamic acid allyl ester The title compound, a white solid, m.p. = 89 ° C and MS: m / e = 309.4 (M + H +), was prepared according to the general method of Example 1 from 2,4-diphenylpropionyl isocyanate and prop-2-en-1-ol .

Example 25 (2, 2-Diphenyl-propionyl) -carbamic acid butyl ester The title compound, a white solid, m.p. = 83 ° C and MS: m / e = 325.4 (M + H +), was prepared according to the general method of Example 1 from 2,4-diphenylpropionyl isocyanate and butan-1-ol.

Example 26 (2, 2-Diphenylpropionyl) -carbamic acid cyclopropyl methyl ester The title compound, a white solid, m.p. = 125 ° C and MS: m / e = 323.4 (M + H +), was prepared according to the general method of Example 1 from 2,4-diphenylpropionyl isocyanate and cyclopropyl-methanol.

Example 27 (2, 2-Diphenyl-propionyl) -carbamic acid cyclohexyl ester The title compound, a white solid, m.p. = 126 ° C and MS: m / e = 351.4 (M + H +), was prepared according to the general method of Example 1 from 2,4-diphenylpropionyl isocyanate and cyclohexanol.

Example 28 (2, 2-Diphenyl-propionyl) -carbamic acid 4-phenyl-butyl ester The title compound, a yellow oil, MS: m / e = 401.5 (M + H +), was prepared in accordance with the general method of Example 1 from 2,4-diphenylpropionyl isocyanate and 4-phenyl-butan-1-ol.

Example 29 (2, 2-Diphenyl-propionyl) -carbamic acid 2, 2, 2-trifluoro-ethyl ester The title compound, a white solid, m.p. = 143-145 ° C, MS: m / e = 351.3 (M + H +), was prepared according to the general method of Example 1 from 2,4-diphenylpropionyl isocyanate and 2,2,2-trifluoroethanol .

Example 30 (9H-thioxanten-9-carbonyl) -carbamic acid ethyl ester The title compound, a white solid, m.p. = 179-182 ° C, MS: m / e = 314.2 (M + H +), was prepared according to the general method of Example 6 from the 9H-thioxanten-9-carbonyl chloride [US patent 3,284,449] and the urethane.

EXAMPLE 31 Oxazole-2-ylamide of 9H-thioxanthen-9-carboxylic acid To a stirred solution of (0.048 g, 0.575 mmol) of 2-amino-oxazole [Cockerill & col., Synthesis 591 (1976)], and DMAP (0.003 g, 0.03 mmol), in pyridine (2 ml) was added at 0 ° C (0.100 g, 0.384 mmoles), of 9H-thioxanthen-9-carbonyl chloride . Stirring was continued at RT for 16 h, the reaction mixture was evaporated and water (5 ml / saturated NaHCO 3 solution (2 ml) was added.The solid was filtered off, dissolved in dichloromethane, dried (MgSO4), and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (methylene chloride / methanol 40: 1) to obtain the product (0.022 g, 18%) as a white solid, m.p. 188-191 ° C and MS: m / e = 309.1 (M + H +).

Example 32 (9H-thioxanten-9-carbonyl) -carbamic acid butyl ester The title compound, a white solid, m.p. = 151-154 ° C, MS: m / e = 342.2 (M + H +), was prepared according to the general method of example 6 from 9H-thioxanten-9-carbonyl chloride and carbamic acid butyl ester .

EXAMPLE 33 Oxazol-2-yl-amide of 9H-xanthen-9-carboxylic acid The title compound, a white solid, m.p. = 232-235 ° C, MS: m / e = 292 (M +), was prepared according to the general method of Example 31 from 9H-xanthen-9-carbonyl chloride and 2-amino-oxazole.

EXAMPLE 34 2-Morpholin-4-yl-ethyl ester of diphenylacetycarbamic acid The title compound, a white solid, m.p. = 135-137 ° C and MS: m / e = 369.3 (H + H "), was prepared according to the general method of Example 1 from diphenylacetyl isocyanate and 2-morpholin-4-yl-ethanol.

Example 35 S-Butyl Ester of Diphenylacetyl Thiocarbamic Acid The title compound, a white solid, m.p. = 99 ° C and MS: m / e = 327 (M +), was prepared according to the general method of example 1 from diphenylacetyl isocyanate and butanethiol.

Example 36 [(3-Chloro-5-trifluoromethyl-pyridin-2-yl) -m-tolyl-acetyl] -carbamic acid ethyl ester 97 μl (95 mg, 0.80 mmol) of diethyl carbonate and 38 μl (30 mg 0.50 mmoles) of isopropanol were dissolved in 2 ml of absolute THF. The solution was cooled to 0 ° C and 29 mg (0.67 mmoles) of a sodium hydride dispersion (55% in mineral oil) were added. Then, 164 mg (0.50 mmol) of 3-chloro-5-trifluoromethyl-2-pyridyl-3-methylphenylacetamide was added in portions, at 0 ° C. After stirring for 1 hour at 0 ° C, the reaction was allowed to warm to room temperature and was stirred overnight. Treatment in the usual way with a solution of ammonium chloride and ethyl acetate gave a yellow oil which was purified by flash chromatography on silica gel using a 5: 1 mixture of hexane and ethyl acetate as eluent. 14.1 mg (0.035 mmol, 7%) of [(3-chloro-5-trifluoromethyl-pyridin-2-yl) -m-tolyl-acetyl] -carbamic acid ethyl ester, as a white solid, m.p. 146-147 ° C, MS: m / e = 401.3 (M + H +).

Example 37 (9H-xanthen-9-carbonyl) -carbamic acid cyclopropylmethyl ester The title compound, a white solid, m.p. = 183-185 ° C, MS: m / e = 323 (X), was prepared according to the general method of example 36 from the 9-xanthan-9-carbonyl chloride and the cyclopropylmethyl ester of carbamic acid.

Example 38 (4-Trifluoromethyl-9H-xanthen-9-carbonyl) -carbamic acid ethyl ester The title compound, a white solid, m.p. = 196-198 ° C, MS: m / e = 365 (M +), was prepared according to the general method of Example 36 from the 4-trifluoromethyl-9H-xanthene-9-carbonyl chloride and the ethyl ester of carbamic acid.

Example 39: Cyclopropanecarboxylic acid diphenylacetylamide To a stirred and cooled (0 ° C) solution of 2,2-diphenylacetamide (500 mg, 2.36 mmole) in THF (20 ml), sodium hydride (95 mg, 2.36 mmol) was added. 60%), and the mixture was stirred at RT for 0.5 hours. Next, cyclopropanecarboxylic acid chloride (247 mg, 2.36 mmol), dissolved in THF (5 ml), was added dropwise at RT, and the solution was stirred at RT for 20 hours. The reaction mixture was poured into saturated NaHCO 3 solution (50 ml) and extracted with ethyl acetate (2 x 70 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO 4) and evaporated. Subsequent purification by column chromatography (toluene / ethyl acetate 19: 1) gave the product, which was recrystallized from ethyl acetate / hexane to give a white solid (133 mg, 20%), m.p. 178 ° C and MS: m / e = 279 (M +).

Example 40 Butyryl-a-ida of 9H-xanthen-9-carboxylic acid The title compound, a white solid, m.p. 222 ° C and MS: m / e = 295 (Mt), was prepared according to the general method of Example 39 from 9H-xanthen-9-carboxylic acid amide and propancarboxylic acid chloride.

Example 41 N-diphenylacetyl-butyramide The title compound, a white solid, m.p. 205 ° C and MS: m / e = 281 (M +), was prepared according to the general method of Example 39 from the 2, 2-diphenylacetamide and propancarboxylic acid chloride.

Example 42 Pentanecarboxylic acid diphenylacetylamide The title compound, a white solid, m.p. 87 ° C and MS: m / e = 309 (M +), was prepared according to the general method of Example 39 from the 2, 2-diphenylacetamide and pentanecarboxylic acid chloride.

Example 43 Pentanoic acid diphenylacetylamide The title compound, a white solid, m.p. 83 ° C and MS: m / e = 296.3 (M + H +), was prepared according to the general method of Example 39 from 2, 2-diphenylacetamide and butanecarboxylic acid chloride.

Example 44 (9H-xanthen-9-carboxylic acid 5-propyl- [1, 3, 4] oxadiazol-2-yl] -amide) A) to a solution of 76 mg (0.60 mmol, 1.2 equiv.) Of 5- propyl- [1, 3, 4] oxadiazol-2-ylamine and 6 mg (0.05 mmol, 0.01 equiv.) of N, N-dimethylamino pyridine in 2 ml of anhydrous pyridine, a solution of 122 mg (0.5 mmol. The mixture was stirred 3-4 hours at 0 ° C and then at room temperature overnight. It was poured into a well stirred mixture of 50 ml of ethyl acetate and 50 ml of water.The organic phase was separated.The aqueous phase was extracted twice with 25 ml of ethyl acetate.The combined organic phases were washed twice with ethyl acetate. ml of water, and concentrated The residue was treated in about 25 ml of ethyl acetate and evaporated to dryness The crude product (167 mg, light yellow solid) provided after recrystallization with ethanol, 62 mg (0.185 mmol, 37%) of 9H-xanthen-9-carboxylic acid (5-propyl- [1, 3, 4] oxadiazol-2-yl) -amide, in the form of white crystals, m.p. 215-216 ° C and MS: m / e = 335 (M +). 44b) The 5-propyl- [1, 3, 4] oxadiazol-2-ylamine used in the above reaction was obtained as follows: To a solution of 5.0 g (47.0 mmol) of cyanogen bromide in 50 ml of methanol a solution of 4.80 g was added dropwise over a period of 30 minutes. (47.0 mmoles), of butyric acid hydrazide in 50 ml of methanol. The mixture was then heated to reflux for 15 minutes, and then concentrated in vacuo until crystallization started. The crystals (9 g) were removed by filtration, treated in 60 ml of ethanol. Then, 5 g of finely divided potassium carbonate was added, and the suspension was stirred for 5 minutes at room temperature. The resulting orange suspension was filtered, and the filtrate was concentrated in vacuo. The resulting orange powder (5.5 g) was purified by flash chromatography on silica gel with an 80: 10: 1 mixture of methylene chloride / methanol / 28% ammonia as eluent to obtain 3.95 g (31.1 mmol, 66%). of 5-propyl- [1, 3, 4] oxadiazol-2-ylamine in the form of white crystals, MS: m / e = 127 (M +). Example 45 2, 2-diphenyl-N- (5-propyl- [1,3,] oxadiazol-2-yl] -acetamide The title compound, a viscous oil and MS: m / e = 322.4 (M + H +) , was prepared according to the general method of example 44a from 5-propyl- [1, 3, 4] oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.

Example 46 [1, 3, 4] Oxadiazol-2-ylamide of 9H-xanthen-9-carboxylic acid The title compound, a white solid, m.p. 239-240 ° C and MS: m / e = 293 (M +), was prepared according to the general method of Example 44a from [1, 3, 4] oxadiazol-2-ylamine and 9-xanten-carboxylic acid chloride. [1, 3, 4] Oxadiazol-2-ylamine, a white solid, MS: m / e = 85 (M +) used in the above reaction, was prepared according to the general method of example 44b from the hydrazide of formic acid and the cyanogen bromide.

EXAMPLE 47 N- [1, 3, 4] oxadiazol-2-yl-2, 2-diphenyl acetamide The title compound, a light yellow solid, m.p. 131-132 ° C and MS: m / e = 279.2 (M "), was prepared according to the general method of example 44a from [1, 3, 4] oxadiazol-2-ylamine and 2-acid chloride, 2-diphenylacetic Example 48 (9H-xanten-9-carboxylic acid 48a) 5-ethyl- [1, 3, 4] oxadiazol-2-yl) -amide) 500.5 mg (1.64 mmol) of (3,5-dimethylpyrazol-1-yl) ) - (9H-xanten-9-yl) -methanone and 186.8 mg (1.64 mmol) of 5-ethyl- [1, 3, 4] oxadiazol-2-ylamine were suspended in 1.5 ml of DMF and stirred for 6 hours. hours at 130 ° C. The reaction mixture was allowed to cool to room temperature and 5 ml of acetone was added. After stirring for 5 minutes, the product was filtered, washed with acetone and dried in vacuo to obtain 219.5 mg of 9H-xanthenic acid (5-ethyl- [1, 3,] oxadiazol-2-yl] -amide. 9-carboxylic acid, in the form of a white solid, mp 256-257 ° C and MS: m / e = 321.2 (M +). 48b) 5-Ethyl- [1, 3, 4] oxadiazol-2-ylamine used in the above reaction, it was obtained as follows: To a solution of 6.3 g of the propionic acid hydrazide (72 mmol) in 50 ml of water, 34 g of saturated potassium bicarbonate solution (75 mmoles) and a solution of 7.7 g (72 mmol) of cyanogen bromide in 60 ml of water. The temperature rose from 22 ° C to 32 ° C with evolution of carbon dioxide. After 30 minutes some white crystals began to appear. The white suspension was stirred for 3 hours and allowed to stand overnight. The reaction mixture was evaporated to dryness in vacuo. The crude product was recrystallized with 20 ml of water. The product was filtered, washed with a small amount of ice / cold water and dried in vacuo. 6.1 g (54 mmol, 75%) of 5-ethyl- [1, 3, 4] oxadiazol-2-ylamine were obtained, as a white solid, m.p. 174-175 ° C and MS: m / e = 113.1 (M +). 48c) The (3,5-dimethylpyrazol-1-yl) - (9H-xanten-9-yl) -methanone used in the above reaction was obtained as follows: 2.6 g (11 mmol) of the hydrazide of 9-xantencarboxylic acid , they were suspended in 2.5 ml of water, and 10 ml of 2N HCl solution was added. To the white slurry was added 30 ml of ethanol and the suspension was heated to 65 ° C and then allowed to cool to room temperature. To the resulting light yellow solution, 1.1 g (11 mmol) of acetylacetone was added while stirring vigorously. The temperature rose to 30 ° C with formation of white crystals after about 2 minutes. Stirring was continued for 15 minutes at room temperature and another 15 minutes at 0 ° C.

The product was filtered and washed with ethanol at -20 ° C. The crude product was recrystallized from 15 ml of ethanol to obtain 2.80 g (9.2 mmol, 84%) of (3,5-dimethylpyrazol-1-yl) - (9H-xanten-9-yl) -methanone in the form of white crystals, pf 114-115 ° C and MS: m / e = 304.1 (M +).

Example 49 N- (5-ethyl- [1,3,4] oxadiazol-2-yl) -2, 2-diphenyl-acetamide The title compound, a white solid, m.p. 123-125 ° C and MS: m / e = 308.2 (M + H +) was prepared according to the general method of Example 48a from 1- (3,5-dimethyl-pyrazol-1-yl) -2 , 2-diphenyl ethanone and 5-ethyl- [1,4,4] oxadiazol-2-yl-amine. 1- (3,5-Dimethyl-pyrazol-1-yl) -2,2-diphenyl-ethanone, a white solid, m.p. 91-92 ° C and MS: m / e = 291.2 (M + H +), used in the above reaction, was prepared according to the general method of Example 48c from the 2,2-diphenylacetic acid hydrazide [Chem. . Zentralblatt. 100, 2414 (1929) and acetylacetone.

Example 50 (9H-xanthen-9-carboxylic acid 5-methyl- [1, 3, 4] oxadiazol-2-yl) -amide The title compound, a white solid, m.p. 261-263 ° C and MS: m / e = 307.1 (M +), was prepared according to the general method of example 44a from 5-methyl [1, 3, 4] oxadiazol-2-ylamine and the chloride of 9-xanten-carboxylic acid. 5-Methyl [1, 3, 4] oxadiazol-2-ylamine, a white solid, MS: m / e = 99 (M +) used in the above reaction, was prepared according to the general method of Example 48b from acetic acid hydrazide and cyanogen bromide.

Example 51 N- (5-methyl- [1,3,4] oxadiazol-2-yl) -2, 2-diphenyl-acetamide The title compound, a white solid, m.p. 160-161 ° C and MS: m / e = 293.1 (M +), was prepared according to the general method of example 44a from 5-methyl [1, 3, 4] oxadiazol-2-ylamine and chloride of the acid 2, 2-diphenylacetic.

Example 52 (9H-xanten-9-carboxylic acid 5-methoxymethyl- [1, 3, 4] oxadiazol-2-yl) -amide The title compound, a white solid, m.p. 233-234 ° C and MS: m / e = 337.1 (M + H +), was prepared according to the general method of example 48a from (3,5-dimethylpyrazol-1-yl) - (9H-xanten -9-yl) -metanone and 5-methoxymethyl- [1,3,4] oxadiazol-2-ylamine. -methoxymethyl- [1, 3, 4] oxadiazol-2-ylamine, a white solid, m.p. 113-114 ° C and MS: m / e = 129.2 (M +) used in the above reaction, was prepared according to the general method of Example 48b from the methoxyacetic acid hydrazide [J. Org. Chem. USSR, 6 (1), 93 (1970) and cyanogen bromide.

Example 53 N- (5-ethyl- [1,3,4] oxadiazol-2-yl) -2, 2-diphenyl acetamide The title compound, a white solid, m.p. 138-140 ° C and MS: m / e = 324.3 (M + H +), was prepared according to the general method of Example 44a from 2, 2-diphenylacetic acid chloride and 5-methoxymethyl [1.3 , 4] oxadiazol-2-ylamine.

EXAMPLE 54 [5- (2-methoxy-ethyl) - [1, 3, 4] oxadiazol-2-yl] -amide of 9H-xanthen-9-carboxylic acid The title compound, a white solid, m.p. 204 ° C and MS: m / e = 351.1 (M + H +), was prepared according to the general method of example 44a from the (3, 5-dimethylpyrazol-1-yl) - (9H-xanten-9-yl) -methanone and [5- (2-methoxy-ethyl- [1,3,4] oxadiazol-2-yl] -amine The [5- (2-methoxy-ethyl) - [1,3,4] oxadiazol-2-yl] -amine, a white solid, mp 105-106 ° C and MS: m / e = 143.1 (M +) employed in the above reaction, it was prepared according to the general method of example 48b from 3-methoxypropionic acid hydrazide [US 3441606] and cyanogen bromide.

Example 55 N- [5- (2-methoxy-ethyl) - [1,4,4] oxadiazol-2-yl] -2, 2-diphenyl acetamide The title compound, a white solid, m.p. 114-115 ° C and MS: m / e = 338.2 (M + H +), was prepared according to the general method of example 44a from 2, 2-diphenylacetic acid chloride and [5- (2-methoxy ethyl) - [1, 3,4] oxadiazol-2-yl] -amine.

Example 56: 9H-xanten-9-carboxylic acid (5-cyclopropyl- [1, 3, 4] oxadiazol-2-yl) -amide The title compound, a white solid, m.p. 246-248 ° C and MS: m / e = 333.1 (M + H +), was prepared according to the general method of example 48a from (3,5-dimethylpyrazol-1-yl) - (9H-xanten -9-yl) -metanone and 5-cyclopropyl- [1, 3, 4] oxadiazol-2-ylamine [J. Med. Pharm. Chem. 5, 617 (1962)].

Example 57 N- (5-Cyclopropyl- [1,3,4] oxadiazol-2-yl] -2, 2-diphenyl acetamide The title compound, a white solid, mp 159-160 ° C and MS: m / e = 320.3 (M + H +), was prepared according to the general method of example 44a from 2, 2-diphenylacetic acid chloride and 5-cyclopropyl- [1,3,4] oxadiazole-2- ilamine.

Example 58: 9H-xanten-9-carboxylic acid (5-cyclopropylmethyl- [1, 3, 4] oxadiazol-2-yl) -amide The title compound, a white solid, p. F. 234-236 ° C and MS: m / e = 347.1 (M + H +), was prepared according to the general method of example 48a from (3,5-dimethylpyrazol-1-yl) - (9H-xanten -9-il) -metanone and the -cyclopropylmethyl- [1,3,4] oxadiazol-2-ylamine. 5-Cyclopropylmethyl- [1,3,4] oxadiazol-2-ylamine, a white solid, m.p. 140-141 ° C and MS: m / e = 139 (M +), used in the above reaction, was prepared according to the general method of Example 48b from the cyclopropanecarboxylic acid hydrazide [J. Chem. Soc. Perkin Trans. 2.1844 (1974)] and cyanogen bromide.

Example 59 N- (5-cyclopropylmethyl- [1,3,4] oxadiazol-2-yl) -2, 2-diphenyl acetamide The title compound, a white solid, m.p. 158-159 ° C and MS: m / e = 334.3 (M + H +), was prepared according to the general method of example 44a from 2, 2-diphenylacetic acid chloride and 5-cyclopropylmethyl- [1, 3,4] oxadiazol-2-ylamine.

Example 60: 9H-xanten-9-carboxylic acid (5-trifluoromethyl- [1, 3, 4] oxadiazol-2-yl) -amide. The title compound, a white solid, m.p. 220-223 ° C (decomposition), and MS: m / e = 362.2 (M + H +), was prepared according to the general method of example 48a from (3,5-dimethylpyrazol-1-yl) - (9H-xanten-9-yl) -metanone and 5-trifluoromethyl- [1,3,4] oxadiazol-2-ylamine [US 2883391].

Example 61 N- (5-trifluoromethyl- [1,3,4] oxadiazol-2-yl] -2, 2-diphenyl acetamide The title compound, a white solid, mp 149-150 ° C and MS: m / e = 347.2 (M +), was prepared according to the general method of Example 44a from 5-trifluoromethyl [1, 3, 4] oxadiazol-2-ylamine and 2, 2-diphenylacetic acid chloride.

Example 62. 9H-xanten-9-carboxylic acid (5-ethyl-oxazol-2-yl) -amide The title compound, a white solid, m.p. 212-213 ° C and MS: m / e = 320.1 (M +), was prepared according to the general method of Example 44a from the -ethyl-oxazol-2-ylamine [Ver. 95, 2419 (1962)] and 9-xanten-carboxylic acid chloride.

Example 63 N- (5-ethyl-oxazol-2-yl) -2, 2-diphenyl-acetamide The title compound, a white solid, m.p. 148-149 ° C and MS: m / e = 307.3 (M + H +), was prepared according to the general method of example 44a from 5-ethyl-oxazol-2-ylamine and 2-acid chloride, 2-diphenylacetic Example 64: 9H-Xanthen-9-carboxylic acid (5-methyl-oxazol-2-yl) -amide The title compound, a white solid, m.p. 217-220 ° C and MS: m / e = 306.1 (M +), was prepared according to the general method of example 44a from 5-methyl-oxazol-2-ylamine [Ver. 9_5, 2419 (1962)] and 9-xanten-carboxylic acid chloride.

Example 65 N- (5-Methyl-oxazol-2-yl) -2, 2-diphenyl-acetamide The title compound, a white solid, m.p. 166-168 ° C and MS: m / e = 292.2 (Mx), was prepared according to the general method of example 44a from 5-methyl-oxazol-2-ylamine and 2, 2- acid chloride diphenylacetic Example 66 (9H-xanthene-9-carboxylic acid) 66 (5-propyl-oxazol-2-yl) -amide) The title compound, a white solid, m.p. 203-205 ° C and MS: m / e = 334.1 (M +), was prepared according to the general method of Example 44a from 5-propyl-oxazol-2-ylamine [Ber. 95, 2419 (1962)] and 9-xanten-carboxylic acid chloride. 66b) The 5-propyl- [1, 3, 4] oxadiazol-2-ylamine used in the above reaction was obtained as follows: 21.8 g (0.132 mol) of 2-bromobutyraldehyde [Chem. Ver., 70, 1898 (1937)], were dissolved in 67.5 ml of a 4: 3 mixture of DMF and water. 8.77 g (0.145 moles) of urea were addedwith agitation. The clear colorless solution was stirred for 16 hours at 105 ° C. The resulting light yellow solution was cooled to 0 ° C and 10 ml of 45% sodium hydroxide solution was added. The solution turned to a dark yellow color (pH 12). 100 ml of brine was added and the solution was extracted five times with 100 ml of a 9: 1 mixture of methylene chloride and methanol. The combined organic phases were concentrated obtaining 15.62 g of a reddish brown oil which was purified by flash chromatography on silica gel with a 9: 1 mixture of methylene chloride and methanol as eluent. They were obtained 6. 2 g (0.049 mol, 37%) of 5-5-propyl-oxazol-2-ylamine in the form of a yellow oil that was used directly without further purification, MS m / e = 126.1 (M +).

Example 67 2, 2-diphenyl-N- (5-propyl-oxazol-2-yl) -acetamide The title compound, a white solid, m.p. 122 ° C and MS: m / e = 320.2 (M +), was prepared according to the general method of Example 44a from 5-propyloxazol-2-ylamine and 2,2-diphenylacetic acid chloride.

Example 68 (9-methyl-oxazol-2-yl) -amide of 9H-xanthen-9-carboxylic acid The title compound, a light yellow solid, m.p. 219-222 ° C and MS: m / e = 306.1 (M +), was prepared according to the general method of example 48a from (3,5-dimethylpyrazol-1-yl) - (9H-xanten-9 -yl) -metanone and 5-methyl-oxazol-2-ylamine [DE 2459380].

Example 69 N- (4-Methyl-oxazol-2-yl) -2, 2-diphenyl-acetamide The title compound, a white solid, m.p. 209-211 ° C and MS: m / e = 306.1 (M +), was prepared according to the general method of Example 48a from (3,5-dimethylpyrazol-1-yl) - (9H-xanten-9 -yl) -metanone and 5-methyl-oxazol-2-ylamine.

Example 70 N- (3-methyl- [1,2,4] oxadiazol-5-yl) -2,2-diphenyl-acetamide The title compound, a white solid, m.p. 215 ° C and MS: m / e = 293 (M +), was prepared according to the general method of Example 44a from the 3-methyl- [1, 2, 4] oxadiazol-5-ylamine (Helv. Chim. Acta, 49 (1966), 1430-1432), and 2,2-diphenylacetic acid chloride.

Example 71: 9H-xanthen-9-carboxylic acid (3-methyl- [1, 2, 4] oxadiazol-5-yl) -amide The title compound, a white solid, m.p. 208 ° C and MS: m / e = 307 (Mt), was prepared according to the general method of example 44a from the 3-methyl- [1, 2, 4] oxadiazol-5-ylamine and the acid chloride 9H-xanten-carboxylic acid.

Example 72 N- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -2, 2-diphenylacetamide The title compound, a white solid, m.p. 163 ° C and MS: m / e = 219 (M +), was prepared according to the general method of Example 44a from 3-cyclopropyl- [1,2,4] oxadiazol-5-ylamine (Helv. Act, 49 (1966), 1430-1432), and 2,2-diphenylacetic acid chloride.

Example 73: 9H-xanten-9-carboxylic acid (3-cyclopropyl- [1, 2, 4] oxadiazol-5-yl) -amide The title compound, a white solid, m.p. 275 ° C and MS: m / e = 333 (M +), was prepared according to the general method of example 44a from 3-cyclopropyl- [1,4,2-oxadiazol-5-ylamine and the 9H-xanthen-carboxylic acid.

Example 74 N- (5-methyl- [1,2,4] oxadiazol-3-yl) -2, 2-diphenyl-acetamide The title compound, a white solid, m.p. 153 ° C and MS: m / e = 293 (M +), was prepared according to the general method of Example 44a from the -methyl- [1, 2, 4] oxadiazol-3-ylamine (EP 413545) and 2, 2-diphenylacetic acid chloride.

Example 75 (9-methyl-9-carboxylic acid 5-methyl- [1, 2, 4] oxadiazol-3-yl) -amide The title compound, a white solid, m.p. 186 ° C and MS: m / e = 307 (M +), was prepared according to the general method of Example 44a from the -methyl- [1, 2, 4] oxadiazol-3-ylamine and 9H-xanthene carboxylic acid chloride.

Example A Tablets of the following composition were prepared, in a conventional manner: mg / tablet Active ingredient 100 Lactose powder 95 White cornstarch 35 Polyvinylpyrrolidone 8 Carboxymethylstarch Na 10 Magnesium stearate 2 Weight per tablet 250 Example B Tablets of the following composition were made, in a conventional manner: mg / comp imido Active ingredient 200 Lactose powder loo White corn starch 64 Polyvinylpyrrolidone 12 Carboxymethyl starch Na 20 Magnesium stearate Weight per tablet 400 Example C Capsules of the following composition were made: mg / capsule Active ingredient 50 Crystalline lactose 60 Microcrystalline cellulose 34 Talcum 5 Magnesium stearate 1 Weight of the content per capsule 150 The active ingredient, has a suitable particle size, the crystalline lactose and the microcrystalline cellulose, were mixed homogeneously with each other, sieved and then talc and magnesium stearate were incorporated . The final mixture was filled into hard gelatin capsules of suitable size.It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (18)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the general formula characterized in that: R1 signifies hydrogen or alkyl (C? -C7); R? , R2 'signify, independently of each other, hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, halogen or trifluoromethyl; X means O, S or two hydrogen atoms that do not form a bridge; A1 / A2 are independently phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms; B is a group of formula wherein R3 signifies (C1-C7) alkyl / (C1-C7) alkenyl, alkynyl (dC-), benzyl, (C1-C7) -alkyl-cycloalkyl, (C1-C7) -cyano-, alkyl- ( C1-C7) -pyridinyl, (C1-C7) alkyl-(C1-C7) alkoxy-phenyl, (C1-C7) alkyl-phenyl, which is optionally substituted with (C1-C7) alkoxy, or phenyl, which is optionally substituted by (C 1 -C 7) alkoxy, or (C 1 -C 7) alkyl -thienyl, cycloalkyl, (C 1 -C 7) alkyl- trifluoromethyl or (C 1 -C 7) alkyl -morpholinyl; And it means -O-, -S- or a link; Z means -O- or -S-; or B is a heterocycle group. of 5 members, of formulas (a) (b) (c) wherein R4 and R5 mean hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, cyclohexyl, (C1-C7) alkyl-cyclohexyl or trifluoromethyl, with the proviso that at least one of R4 or R5 has to be hydrogen; as well as their pharmaceutically acceptable salts with the exception of N- (diphenylacetyl) thiobenzamide, N-benzoyldiphenylacetamide, N-phenoxycarbonyl-a, a-diphenylacetamide and N-phenoxycarbonyl-a-2-pyridylacetamide.
2. 2. The compounds of formula IA according to claim 1, characterized in that B is a group of formula and the rest of the substituents are defined in claim 1.
3. 3. The compounds of formula IB, according to claim 1, characterized because: B is a heterocyclic group of 5 formula members and the remaining substituents are as defined in claim 1.
4. The compounds of formula IA according to claim 2, characterized in that A means phenyl, X means 2 hydrogen atoms that do not form a bridge and Z is -0-.
5. 5. The compounds according to claim 4, the compounds are characterized in that they are: diphenyl acetylcarbamic butyl ester, diphenylacetylcarbamic acid ethyl ester, or diphenylacetylcarbamic acid pent-4-ynyl ester
6. 6. The compounds of formula IA according to claim 2, characterized in that A means phenyl, X means -0- or -S- and Z is -0-.
7. 7. The compounds of formula IA according to claim 6, the compounds characterized in that they are: (9H-xanten-9-carbonyl) -carbamic acid ethyl ester, butyl ester of (9H-xanthen-9-carbonyl) - carbamic, or butyl ester of (9H-thioxanten-9-carbonyl) -carbamic acid.
8. 8. The compounds of formula IB according to claim 3, characterized in that A means phenyl, X means 2 hydrogen atoms that do not bridge, and Z is -0-.
9. 9. The compounds of formula IB according to claim 8, the compounds characterized in that they are: N- (5-ethyl-oxazol-2-yl) -2, 2-diphenyl-acetamide, N- (5-methyl-oxazole) -2-yl) -2, 2-diphenyl-acetamide, 2,2-diphenyl-N- (5-propyl- [1,3,4] oxadiazol-2-yl) acetamide, N- [5- (2- methoxy-ethyl) - [1, 3, 4] oxadiazol-2-yl] -2, 2-diphenylacetamide, N- (3-methyl- [1,2, 4] oxadiazol-5-yl) -2, 2- diphen1-acetamide, N- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -2, 2-diphenyl-acetamide, or N- (5-methyl- [1,2,4] oxadiazole- 3-yl) -2, 2-diphenyl-acetamide.
10. 10. The compounds of formula IB according to claim 3, characterized in that A means phenyl, X means -O- and Z is -O-.
11. 11. The compounds of formula IB according to claim 10, the compounds characterized in that they are: 9H-xanten-9-carboxylic acid oxazol-2-yl-amide, (5-propyl- [1, 3, 4] oxadiazole -2-yl) -amide of 9H-xanten-9-carboxylic acid, (5-ethyl-oxazol-2-yl) -amide of 9H-xanten-9-carboxylic acid, (5-methyl-oxazol-2-yl) ) - 9H-xanten-9-carboxylic acid amide, 9H-xanten-9-carboxylic acid (5-propyl-oxazol-2-yl) -amide, (5-ethyl- [1, 3, 4] oxadiazole- 2-yl) -amide of 9H-xanthen-9-carboxylic acid, (5-cyclopropylmethyl- [1, 3, 4] oxadiazol-2-yl) -amide of the acid 9H-xanten-9-carboxylic acid, 9H-xanten-9-carboxylic acid (4-methyl-oxazol-2-yl) -amide, (3-methyl- [1, 2, 4] oxadiazol-5-yl) - 9H-xanten-9-carboxylic acid amide, 9H-xanthen-9-carboxylic acid (5-trifluoromethyl- [1, 3, 4] oxadiazol-2-yl) -amide, (5-methoxymethyl- [1, 3 , 4] -oxadiazol-2-yl) -amide of 9H-xanthen-9-carboxylic acid, 9H-xanthen-9-carboxylic acid (3-cyclopropyl- [1,4,2-] oxadiazol-5-yl) -amide , or 9H-xanthene-9-carboxylic acid (5-methyl- [1, 2, 4] oxadiazol-3-yl) -amide.
12. 12. A medicament containing a compound according to any of claims 1-11, as well as pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
13. 13. A medicament according to claim 12 for the control or prevention of acute and / or chronic neurological disorders such as restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, of the head, hypoxia caused by pregnancy, cardiac arrest, hypoglycemia, Alzheimer's disease, Huntington's chorea, ALS, dementia caused by AIDS, ocular lesions, retinopathy, cognitive disorders, memory deficit, schizophrenia, idiopathic parkinsonism or parkinsonism caused by medications as well as conditions that lead to functions with glutamate deficiency, such as, for example, muscle spasms, seizures, migraine, urinary incontinence, nicotine addiction, psychosis, opioid addiction, anxiety, vomiting, acute and chronic pain , dyskinesia and depression.
14. 14. The use of compounds according to any of claims 1-11 as well as pharmaceutically acceptable salts thereof, for the control or prevention of diseases.
15. 15. The use of compounds of formula I according to any of claims 1-11. for the preparation of medicaments containing compounds of formula I, for the treatment of diseases as claimed in claim 13.
16. 16. The compounds according to claims 1-11 as well as the pharmaceutically acceptable salts thereof, for the control or prevention of acute and / or chronic neurological disorders.
17. 17. A process for obtaining compounds according to any of claims 1-11, as well as pharmaceutically acceptable salts thereof, the method is characterized in that it consists of: a) reacting a compound of formula with a compound of formula R 'YH III to obtain a compound of formula wherein the substituents have the meaning given in claim 1, or b) reacting a compound of formula with a compound of the formula V to give a compound of formula wherein G is a suitable leaving group, and the other substituents have the meanings given in claim 1, c) reacting a compound of formula with a compound of formula VII to obtain a compound of formula wherein the substituents have the meanings indicated in claim 1. or d) reacting a compound of formula VI with a compound of the formula VIII to give a compound of formula wherein the substituents have the meanings indicated in claim 1, or d) reacting a compound of formula IV with a heterocyclic compound of formula B- -NH IX to give a compound of formula where B is a 5-membered heterocycle, of the formulas (a) (b) (c) (d) and wherein G is a leaving group and the remaining substituents have the meanings given in claim 1, and, if desired, conversion of a functional group into a compound of formula I into another functional group and, if desired, conversion of a compound of formula I in a pharmaceutically acceptable salt.
18. 18. The compounds according to claims 1-11, characterized in that they have been obtained according to a method according to claim 17. SUMMARY OF THE INVENTION The present invention relates to compounds of formula (I): where X means O, S or two hydrogen atoms that do not form a bridge; A1 / A2 are independently phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms; B is a group of formula (A), where Y means -O-, -S- or a bond; Z means -O- or -S-; or B is a 5-membered heterocycle group, of formulas (a, b, c or d), These compounds can be used as ligands of the matabotropic glutamate receptor in the control or prevention of acute and / or chronic neurological disorders.