Pyrazolo - and pyrrolopyridine

 

(57) Abstract:

The invention relates to a compound of formula I and pharmaceutically acceptable acid additive salts, where: a Is N or CH; b is-NR1R2-NHCHR1R2, -OCHR1R2. The compounds exhibit antagonistic activity against corticotropinreleasing factor (CRF). It is known that CRF antagonists are effective in treating a wide spectrum of diseases caused by stress, such as depression, fear, headache, symptoms of inflamed colon cancer, inflammatory diseases, immune deficiency, Alzheimer's disease, gastrointestinal diseases, neurotic anorexia nervosa, hemorrhagic stress, drug withdrawal syndrome, drug and alcohol addiction to the excessive use of drugs and infertility. 6 C.p. f-crystals, 1 table.

b refers to pyrazolopyrimidines and pyrrolopyridines, pharmaceutical compositions containing these compounds, and methods for their introduction to a subject that needs their antagonistic activity against factor contributing to the release of adrenocorticotropic hormone (corticotropinreleasing factor (CRF).

CRF-anagnosti antagonists is indicated in the literature, for example, it is discussed in U.S. patent N 5063245 that is entered in the reference list of this invention. A modern description of the various activities that have a CRF antagonist, appears in the publication M. J. Owens et al., Pharm.Rev., Vol.43, pages 425-473 (1991), which is also entered in the reference list of this invention. Based on the research described in these and other references, I believe that CRF antagonists are effective in the treatment of diseases associated with stress, such as depression, fear, headache, irritable bowel syndrome, inflammatory disease, immune deficiency, Alzheimer's disease, gastrointestinal disorders, neurotic anorexia nervosa, hemorrhagic stress, drug withdrawal syndrome, drug and alcohol addiction to the excessive use of drugs and infertility.

This invention relates to the compound of the formula

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and its pharmaceutically acceptable acid additive salts,

where A Is N or CH;

B IS-NR1R2, -NHCHR1R2, -OCHR1R2;

R1- C1-C6alkyl, which optionally may contain one or two substituent independently selected from the group comprising hydroxyl is>C4alkyl;

R4is hydrogen, C1-C6alkyl;

R5- phenyl, containing three deputies, which represents a C1-C6alkyl;

R7is hydrogen, C1-C4alkyl.

Group specific embodiments of the present invention includes compounds of formula I, where (a) R1represents a C1-C4alkyl, which may optionally contain as Deputy C1-C2alkoxygroup, R2represents C1-C4alkyl; or (b) R1represents a C1-C4alkyl, substituted hydroxyl group.

Another group of more specific embodiments of this invention relate to compounds of formula I in which: (a) R3represents methyl; (b) R4represents hydrogen, methyl; and (C) R5represents a phenyl containing three substituent independently selected from C1-C6the alkyl.

Other more specific embodiments of this invention relate to compounds of the formula I, in which R3represents methyl; R4is hydrogen, C1-C3alkyl; and R5is a substituted phenyl.

Examples of specific embodiments daleiden-4-yl]ethylamine;

[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-piraro[3,4-b] pyridine-4-yl] -(1-methoxymethyl)amine;

4-(1-methoxymethylethoxy)-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-b] pyridine;

(1-ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-b]pyridine-4-yl]amine.

The invention also includes a pharmaceutical composition for treating a disease, the treatment of which can be made or treatment which may contribute to antagonistic activity with respect to CRF, including but not limited to, diseases induced by CRF, or disease, the occurrence of which contributes to the CRF, or (b) a disease selected from the group of inflammatory diseases such as rheumatoid arthritis or osteoarthritis, pain, asthma, psoriasis and allergies; diseases caused by fear; panic, phobias; obsessive compulsive disorder; post-traumatic stress; sleep disorders, including due to stress; pain, such as fibromyalgia; diseases related to mood, such as depression, including General depression, episodic depression, recurrent depression, depression, stress, moved in kindergartens is Ohm fatigue; headaches caused by stress; cancer; irritable bowel syndrome; granulomatous disease, Crohn's disease; mucous colitis; infection of human immunodeficiency virus (HIV); dementia, such as Alzheimer's disease, Parkinson's disease and Huntington's disease (Huntington''s disease); gastrointestinal diseases; eating disorders, such as neurotic anorexia and bulimia nervosa; hemorrhagic stress; dependence on chemicals and drugs (such as alcohol dependence, cocaine, heroin, benzodiazepines or other drugs); withdrawal symptoms of drugs and alcohol; psychoticism episode, caused by stress; syndrome weakening arteriosa syndrome inconsistencies of antidiuretic hormone (ADH); obesity; infertility; head traumas; spinal-cord trauma; ischemic neuronal lesions (for example, cerebral ischemia such as cerebral ischemia hippocampus (cerebral hippocampal ischemia)); excitotoxic neuronal lesions; epilepsy; seizure; compromised immune function, including dysfunction caused by stress (such as stress syndrome in pigs (porcine stress syndrome), vyzyvayushaya fever cow (bovine shipping fever), convulsive atrial horses (equine paroxysmal fibrillation) and di is lonene (sheering stress in sheep or stress in dogs, caused by the interaction of the "man-animal" (humananimal interaction related stress in dogs)); muscular spasms; urinary incontinence; senile dementia Alzheimera type (senile dementia of Aizheimer's type); dementia caused by multiple infarcts (multiinfarct dementia); amyotrophic lateral sclerosis; and hypoglycemia in a mammal, including man; the composition includes a compound of formula I or a pharmaceutical salt in an amount to provide effective treatment of such disease, and a pharmaceutically acceptable carrier.

The invention also includes methods of treating a disease, the treatment can be performed or treatment which promotes antagonistic activity against CRF, including but not limited to the list only by them, diseases caused by CRF, or disease, the occurrence of which contributes to the CRF, or (b) a disease selected from the group of inflammatory diseases such as rheumatoid arthritis or osteoarthritis, pain, asthma, psoriasis and allergies; diseases caused by fear; panic; phobias; obsessive compulsive disorder; post-traumatic stress; sleep disorders induced by stress; pain, such as a fiber optic scope the processes, recurring depression, depression, stress, childhood, postpartum depression; dysthemia; bipolar disorders; cyclotomy; fatigue syndrome; headache due to stress; cancer; irritable bowel syndrome; granulomatous disease, Crohn's disease (Crohn); mucous colitis; infection of human immunodeficiency virus (HIV); dementia, such as Alzheimer's disease, Parkinson's disease and Huntington's disease (Huntington''s disease); gastrointestinal diseases; eating disorders, such as neurotic anorexia or bulimia nervosa; hemorrhagic stress; psychotic episode, caused by stress; syndrome weakening arteriosa; syndrome inconsistencies of antidiuretic hormone (ADH); obesity; infertility; head traumas; spinal-cord trauma; ischemic neuronal lesions (for example, cerebral ischemia such as cerebral ischemia hippocampus); excitotoxic neuronal tumors; epilepsy; seizure; impaired immune function, including dysfunction of the immune system caused by stress (e.g. stress syndrome in pigs, vyzyvayushaya fever cows, convulsive atrial horses and dysfunction caused by restriction of the movement" the chicken, the stress in sheep, the mod who I urine; senile dementia Alzheimera type; dementia caused by multiple infarcts; amyotrophic lateral sclerosis; dependence on chemicals and drugs (e.g., alcohol dependence, cocaine, heroin, benzodiazepines or other drugs); withdrawal symptoms of drugs and alcohol; and hypoglycemia in a mammal, including humans; treatment includes an introduction to the subject who is in need of said treatment, the compounds of formula I or its pharmaceutically acceptable salt in an amount which provides effective treatment of such diseases.

The invention also includes intermediates of the formula

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where D represents chlorine, hydroxyl or cyano;

R9- C1-C4alkyl, chlorine; and

A, R4, R5and R7take the values specified above for formula I.

In this description, the term "C1-C6alkyl", unless a different value is used to denote a straight or branched alkyl chain containing from one to six carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl or hexyl.

Compounds of formulas I and II mouthbreathing relates to all optical isomers and stereoisomers of the compounds of formulas I and II and their mixtures.

The compounds of formula I, where B represents-NR1R2, -NHCHR1R2or-OCHR1R2can be obtained by the coupling of compounds of formula II, where D is Cl, and R4, R5, R7and A take the values defined above for formula I, with a compound of the formula BH, where B takes the values defined in the paragraph above, or with the compound of the formula R1NH2. The reaction is carried out in a solvent in the presence of a base at a temperature in the range of from about room temperature to about 230oC in the presence or without organohalogens, such as bromide, iodide or chloride of copper, or magnesium bromide, in the presence of or without an acid catalyst such as p-toluensulfonate. Suitable solvents are organic solvents, such as tetrahydrofuran (THF), acetonitrile, dimethylsulfoxide (DMSO), acetone, C1-C5alkilany alcohol, chloroform, benzene, xylene, dioxane, toluene, sulfolane, pyridine or 1-methyl-2-pyrrolidinone. Preferably, the solvent is dimethyl sulfoxide or 1-methyl-2-pyrrolidinone.

In the case when B target compounds of formula I represents a-NR1R or-NHCHR1R2in to the of, other than BH, such as potassium carbonate and three (C1-C6) alkylamine. This reaction is usually carried out at a temperature of from about 75oC to about 230oC. Organohalogen, such as copper bromide, can be used to facilitate the reaction. In the case when the reaction proceeds very passively, the compounds of formula I, where B represents-NR1R2or-NHCHR1R2you can get in two stages, as described below. The reaction of compounds of formula II with an excess of R1NH2or NH3or equivalent NH3the precursor (for example, NaN3n-BuN+N3N-or NH2OH) at a temperature of from about 75oC to approximately 250oC and a pressure of from about 0 to about 300 psi in a suitable solvent, as described above, leads to the formation of compounds of formula I, where B is an-other11, -NH2, -NH2OH or-N3. The conversion of compounds of formula I, where B represents-N3or-NH2OH, into the corresponding compounds of formula I, where B represents-NH2can be carried out by known methods, such as hydrogenation or recovery. The alkylation of compounds of formula I, gouania, such as bis-trimethylsilyl lithium or sodium, or diisopropylamide lithium or sodium, or tert-piperonyl n-utility or sodium, in a suitable solvent, such as THF, dioxane or methylene chloride, to yield the corresponding compounds of formula I, where B represents-NR1R2. In accordance with another method, the acylation of compounds of formula I, where B is an-other1or-NH2with the subsequent recovery borohydride (e.g. sodium borohydride), will lead to the formation of compounds of formula I, where B represents-NR1R2.

In the case where the reaction of BH and the appropriate compounds of formula II is very passive, can be used in acidic conditions, obtained using p-toluensulfonate acid or phenol or its derivatives.

When B represents-OCHR1R2you can get the base that has the ability to deprotonate BH, such bases are hydrides of alkali metals, such as sodium hydride or potassium, or an ORGANOMETALLIC base such as Diisopropylamine sodium bis(trimethylsilyl)-amide sodium, diisopropylamide lithium bis(trimethylsilyl)amide or n is telengard, toluene, sulfolane or 1-methyl-2-pyrrolidinone and the reaction is usually carried out at a temperature in the range of from about room temperature to 180oC, preferably in the range of from about 50oC to about 130oC.

The compounds of formula II, where D is cyano, R4, R5and R7take the values defined above, and R9is a (C1-C4) alkyl or chlorine (hereinafter referred to their mark as the compounds of formula IIA) can be obtained by the interaction of the corresponding compounds of formula II, where D is chlorine, potassium cyanide or copper cyanide in the presence of or without p-toluensulfonate sodium or methanesulfonate sodium as a catalyst in dimethyl sulfoxide or N, N-dimethylformamide.

The compounds of formula II where a is N, D is OH, and R9represents C1-C4alkyl, can be obtained in accordance with Scheme 1, the interaction of the compounds of formula IV with the compound of the formula III in the presence of an acid catalyst such as p-toluensulfonate, HCl, or H2SO4, in a suitable solvent, such as toluene, benzene or xylene, with a trap Dean-stark, at a temperature in the range of from about 60 to 150o

Suitable acids are 85% phosphoric acid, aqueous HCl and water (H2SO4. The compounds of formula V can be obtained as described in concurrently filed November 26, 1993, the patent application Serial N PCT/US 93/11333, registered in the United States, or by known methods. International application PCT/US 93/11333 entered in the reference list of this invention.

Scheme 1.

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The compounds of formula I, where R7is an alkyl group, can be obtained via the intermediate product of formula IIB or a compound of formula ID, where R7is-COOR, -COR, or CN, as shown in Scheme 2, the conversion of the group R7in other groups of R7using well-known methods. For example, the hydrolysis of compounds in which R7is an ester with a base (e.g. lithium hydroxide in a mixture of water: dioxane 1:1 water: methanol 1: 1 or aqueous LiOH or NaOH) at a temperature in the range of from about 80oC to 100oC, followed by quenching the reaction of acid and boiled under reflux for implementation decarboxylation leads to the corresponding compound of formula ID, where R7- H. Recovery of compounds in which R7is difficult-ether is to obtain the corresponding compounds in which R7represents CH2OH or CHO. Alkylation of CH2OH group with a base, such as NaH, sodium alkoxide or organolithium derivative, followed by alkylation with methyliodide or ethyliodide, leads to the formation of compounds of formula ID, where R7- -CH2OCH3or-CH2OC2H5. The reaction of Grignard group-CO2CH3, -CO2C2H5, -COCH3or-COC2H5with the subsequent elimination and hydrogenation leads to the formation of compounds of formula ID, where R7represents an alkyl group. In the above-described synthesis to obtain the target compounds can be used a method of introducing protective groups and their subsequent removal.

Scheme 2.

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Another method of preparing compounds of the formula IIB, in which D represents a hydroxyl group, chlorine or cyano, is shown in figure 3.

Scheme 3.

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The compounds of formula VIII, where L and L' are removed by suitable groups such as chlorine, bromine, mesyl, tosyl or methoxy group, can turn into a compound of formula IX, where D is a hydroxyl group, or L', by reaction with an amine of formula R5NH2in Panie, which is able to deprotonate R5NH2such as n-utility or organohalogen, such as bromide, chloride or iodide, copper or magnesium bromide. The reaction can be carried out in the presence of or without a suitable solvent, which can be used alcohol (for example, pentanol), DMSO, sulfolane or dioxane. The alkylation of compounds of formula IX introduction to R4can be convenient ways. Preferably, the process is carried out first by adding a base such as sodium hydride or potassium, placed in an inert solvent such as an ether, e.g. diethyl ether, THF or dioxane, or a polar aprotic solvent, such as DMSO, under the atmosphere of inert gas, for example nitrogen, to obtain the compounds of formula IX, and then add the compound of the formula R4L, where L takes the values defined above. The reaction temperature preferably lies in the range from approximately 0oC to approximately 25oC. In the case when R4- halogen, R4L represents a halogenation agent, such as bromine, chlorine, iodine, diethylamino sulfur TRIFLUORIDE or N-bromosuccinimide. The compounds of formula X, where R4- thiophenyl that can be polucheniyami formula X, where R4- C1-C6alkyl, when interacting with C1-C6alkylation with subsequent restoration tofanelli group Raney Nickel or trimethylsilylpropyne (TMSH) with zinc to obtain selectively monosubstituted compounds of formula X.

The compounds of formula IIB, in which R6represents hydrogen, can be formed from compounds of formula X recovery, for example, lithium aluminum hydride, aluminum hydride, of Diisobutyl, with subsequent elimination or dehydration.

An acid additive salt get the easy way - with a processing solution or suspension of the free base of the compounds of formula I with one chemical equivalent of a pharmaceutically acceptable acid. To highlight salts using methods suitable concentration or recrystallization. Typical suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamony, fumaric, sulfuric, phosphoric, hydrochloric, Hydrobromic, itestosterone, sulfonic acid, such as methanesulfonate, benzolsulfonat, p-toluensulfonate and derived from these acids, Sultanova.

Active ones or in combination with pharmaceutically acceptable carriers, in a single dose or multiple doses. Suitable pharmaceutically acceptable carriers are solid fillers or diluents, sterile aqueous solution and various organic and inorganic solvents. The pharmaceutical compositions obtained in the result of combining the novel compounds of formula I and pharmaceutically acceptable carriers are then readily administered in various dosage forms such as tablets, powders, cakes, syrups, injectable solutions, etc., These pharmaceutical compositions can, if necessary, contain additional ingredients such as flavorings, binders, fillers, etc., Thus, for oral administration may be tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate, various dezinfeciruyuhimi substances such as starch, methylcellulose, alginic acid and certain complex compounds of silicon, in combination with binders, such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, commonly used binding agents such as magnesium stearate, nutriceuticals and talc. Solid compositions of a similar title this include lactose or milk sugar and high molecular weight glycols. In the case when for oral administration, the required aqueous suspensions or elixirs, the main active ingredient can be combined with various sweetening or flavouring additives, dyes and, if desired, emulsifying or suspendresume substances in combination with fillers, such as water, ethanol, propylene glycol, glycerin and mixtures thereof.

For parenteral administration can be used solutions of active substances of the present invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution. Such aqueous solutions should contain a suitable buffer additives, if necessary, and the liquid filler with a sufficient amount of salt or glucose to make the solution isotonicity. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal introduction. Apply a sterile aqueous medium can be easily obtained by standard methods known to the skilled technician.

Effective dose for the active substances of the present invention depends on the selected method of administration, and other factors such as who is it to treat. Daily dose for the treatment of diseases caused by previous stressful situations, will, in General, be in the range of from 0.1 to 50 mg/kg weight of the patient that requires treatment, for the treatment of inflammatory diseases of the required dose is in the range of from about 0.1 to about 50 mg/kg for the treatment of Alzheimer's disease - from approximately 0.1 to approximately 50 mg/kg, for gastrointestinal diseases from about 0.1 to about 50 mg/kg, neurotic anorexia is from about 0.1 to about 50 mg/kg, for the treatment of hemorrhagic stress from about 0.1 to about 50 mg/kg for the treatment of withdrawal symptoms of drugs and alcohol is from about 0.1 to about 50 mg/kg

The active compounds of this invention are, in General, be administered from one to three times per day (i.e., from one to three doses per day) when the value of each dose of from approximately 0.1 to approximately 100 mg/kg weight of the patient, although depending on the weight and condition of the patient, nature and severity of the disease, which the patient suffers, and especially as a way of introduction, it will be necessary to adjust the dose. However, the level goslow dose, will be used most often. However, changes in dosage may occur depending on the type of mammal being treated, and the individual characteristics of the reaction of this subject to the specified medication, as well as the type of the selected pharmaceutical composition, application period and the time interval at which carry out this introduction.

Methods for determining the CRF antagonistic activity of the compounds of formula I and their pharmaceutically acceptable salts are described in Endocrinology, 116, 1653-1656 (1985) and Peptides, 10, 179-188 (1985). Binding activity of compounds of formula I, expressed as values of the IC50shown in the table.

The following examples illustrate the formation of compounds of the present invention. Melting points are uncorrected. Data of NMR are shown in the dimension of "parts per million" (ppm) and refer to the signal of deuterium from the sample solvent (deuterochloroform, unless otherwise stated). The specific rotation was measured at room temperature using sodium line D (589 nm). Commercial reagents were used without additional purification. The abbreviation THF refers to tetrahydrofuran, abbreviated DMF exchange rate 32-63 μm silica gel under an atmosphere of compressed nitrogen (fast chromatography). Room temperature or normal temperature indicated temperature 20-25oC. All non-aqueous reactions carried out under a nitrogen atmosphere for convenience and to obtain maximum yield. Concentration (evaporation) of the solution is carried out using a rotary evaporator.

Example 1. (1-Ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-b]pyridine-4-yl]amine.

A mixture of 4-chloro-3,5,6-trimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b] pyridine (227 mg, 0.72 mmole), p-TsOH (124 mg) and ethylpropylamine (0.5 ml) in 1 ml of dimethyl sulfoxide (DMSO) is heated and refluxed for 4 hours (thin layer chromatography shows no reaction). To the mixture is added a copper bromide (40 mg) and the reaction mass is refluxed additionally for 15 hours. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (EtOAc). The organic fraction was washed with brine, dried and evaporated to obtain a brown oil. The oil cleanse method column chromatography (silica gel, eluent: chloroform (CHCl3):hexane = 8:3), the result is indicated in the title compound as a colourless oil.

1H-NMR (CDC ptx2">

The compound is obtained in the form of the corresponding salts of hydrochloric acid after recrystallization from a mixture of ethyl ether and ethyl acetate in the form of whitish crystals, so pl. 201-205oC.

Example 2. Butyl-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-b] pyridine-4-yl]ethylamine.

A mixture of 4-chloro-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b]pyridine (98 mg, of 0.33 mmole) and N-boogieman (1 ml) in DMSO (2 ml) is heated on an oil bath to a temperature of 175-180oC and kept at this temperature for 20 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with EtOAc. The organic fraction was washed with brine, dried and evaporated to a brown oil. The remainder in the form of oil cleanse method column chromatography (silica gel; eluent: EtOAc/hexane= 1/9), the result is colourless oil.

1H-NMR (CDCl3) 6.92 (s, 2H), 6.29 (s, 1H), 3.42 (square, 2H), 3.27 (t, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H), 1.91 (s, 6H), 1.57 (m, 2H), 1.33 (m, 2H), 1.13 (t, 3H), 0.90 (t, 3H) h/million

IR (pure) 2960, 2920, 1570 cm-1.

Mass spectrometry (MS) high resolution: calculated 364,2627; found 264,26306.

Example 3. 2-[3,6-Dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b]pyridine-4-ylamino]butane-1-ol.

A mixture of 4-chloro-grebaut in the oil bath to a temperature of 190oC and kept at this temperature for 20 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic fraction was washed with brine, dried and evaporated to a brown oil, which was then purified by the method of column chromatography (silica gel, eluent: EtOAc/hexane= 1/9), the result is indicated in the title compound as a yellow oil, 113 mg

1H-NMR (CDCl3) 6.9 (s, 2H), 5.95 (s, 1H), 4.94 (d, 1H,), 3.70 (m, 2H), 3.52 (m, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 2.28 (s, 3H),1.92 (s, 3H), 1.90 (s, 3H), 2.6-2.8(m, 2H), 1.0 (t, 3H), h/million

Example 4. 2-[3,6-Dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b]pyridine-4-ylamino] butane-1-ol and 3,6-dimethyl-4-phenoxy-1-(2,4,6-trimethyl-phenyl)-1H-pyrazolo[3,4-b]pyridine.

A mixture of 4-chloro-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b] pyridine (300 mg, 1 mmole), (3)-2-amino-1-butanol (107 mg, 1.2 mmole) and phenol (188 mg, 2 mmole) is heated on an oil bath to 190oC and kept at this temperature for 15 hours. The mixture is cooled, quenched with 2N-s ' solution of sodium hydroxide and extracted with chloroform. The organic fraction was separated and neutralized 2N-Noah hydrochloric acid and water. The organic fraction is dried and evaporated to a residue in the form of oil. The residue is purified by the method of column chromatography (silica gel, eluent, chloro[3,4-b]pyridine in the form of beige crystals.

1H-NMR (CDCl3) 7.1-7.45(m, 5H), 6.95 (s, 2H), 6.06 (s, 1H), 2.71 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H), 1.94 (s, 6H) ppm;

and 30 mg of 2-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo- [3,4-b]pyridine-4-ylamino]butane-1-ol in the form of a glassy substance is yellow.

Example 5. [3,6-Dimethyl-1-(2,4,6-trimetilfenil)-1H - pyrazolo[3,4-b]pyridine-4-yl]-(1-methoxymethyl)amine.

A solution of 2-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b]pyridine-4-ylamino]butane-1-ol (69 mg, 0,196 mmole) in 1 ml of dry tetrahydrofuran is treated with 60% sodium hydride in oil (28 ml, 0.7 mmole). After stirring for 3 minutes add methyliodide (0.3 ml) and the mixture stirred at room temperature for 1.5 hours. The mixture is quenched with water and extracted with ether. The organic fraction was washed with water, dried and evaporated, receiving 61 mg of a technical product. The residue is purified by the method of column chromatography (silica gel, eluent: chloroform), the result is 43 mg specified in the title compound as a glassy substance is yellow.

1H-NMR (CDCl3) 6.91 (s, 2H), 6.00 (s, 1H), 5.05 (d, 1H), 3.4-3.6 (m, 2H), 3.41 (s, 3H), 2.66 (s, 3H), 2.40 (s, 3H), 2.28 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H), 1.6-1.8 (m, 2H), 1.05 (t, 3H) h/million

IR (CHCl3) 2920, 1585 cm-1; MC high resolution: calculated its salt of hydrochloric acid, which is a solid yellow color.

Example 6. 4-(1-Methoxymethylethoxy)-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-b]pyridine.

Sodium hydride (60% in oil, 94 mg of 1.33 mmole) was washed with hexane and suspended in 2 ml of tetrahydrofuran (THF). Add 1-methoxy-2-butanol (0.7 ml) and the mixture is stirred at room temperature for 5 minutes. Then add a solution of 4-chloro-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-b]-pyridine (200 mg, 0,665 mmole) in 1 ml THF and the mixture is refluxed for 15 hours, then the mixture is quenched with water and extracted with EtOAc. The organic fraction is dried and evaporated, receiving a technical product (201 mg) as a solid yellow color. The solid is purified by the method of column chromatography (silica gel, eluent: 1% methanol in chloroform), as a result of receiving 175 mg bright crystals, so pl. 108-108oC. IR (KBr) 2900, 1600, 1580 cm-1. MC high-resolution computed 367,2253 found 367,22754;

1H-NMR (CDCl3) 6.93 (s, 2H), 6.34 (s, 1H), 4.59 (m, 1H), 3.64 (2 series of Awkw. , 2H), 3.41 (s, 3H), 2.64 (s, 3H), 2.48 (s, 3H), 2.29 (s, 3H), 1.91 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H), 1.7 -1.9 (m, 2H), 1.04 (t, 3H) h/million

Example 7. 3,6-Dimethyl-4-(tetrahydrofuran-3-yloxy)-1-(2,4,6-trimetilfenil)-1H-pireo is rageragerage. 3-Hydroxymitragynine (1 ml) is added to the mixture and stirred at room temperature for 5 minutes. Then add a solution of 4-chloro-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0,665 mmole) in 1 ml THF and the resulting mixture is refluxed under stirring for 8 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic fraction is dried and evaporated, getting 334 mg of a technical product, technical product was then purified by the method of column chromatography (silica gel, eluent: 1% CH3OH in CHCl3) the result is 127 mg solid brown, T. pl. 117-119oC. IR (KBr) 2950, 1600, 1580 cm-1. MC high-resolution computed 351,1941 found 351,19386;

1H-NMR (CDCl3) 6.90 (s, 2H), 6.15 (s, 1H), 5.07(m, 1H), 3.9-4.05 (m, 4H), 2.6 (s, 3H), 2.47 (s, 3H), 2.38 (s, 3H), 2.2-2.3(m, 2H), 1.98 (s, 3H), 1.96 (s, 3H) h/million

Example 8. 1-[3,6-Dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b]pyridine-4-yl]propane-1-on.

A solution of 3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo-[3,4-b] pyridine-4-carbonitrile (200 mg, 0,690 mmole) in 1 ml of benzene is added to the solution ethylacetamide (1M, 1.5 ml, 1.5 mmole) in 4 ml of benzene at room temperature after stirring at room temperature in accordance with the comfort 2n. sodium hydroxide and extracted with ethyl acetate. The organic fraction is dried and evaporated, receiving a yellow oil. Yellow oil purified by the method of column chromatography (silica gel, eluent: 5% EtOAc in hexane), the result is 118 mg specified in the title compound in the form of a yellow solid substance, so pl. 117-118oC;

IR (KBr) 2980, 2923, 1691, 1573, 1502.

1. Pyrazolo - and pyrrolopyridine General formula I

< / BR>
in which A Is N or CH;

B IS-NR1R2; -NHCHR1R2; -OCHR1R2;

R1- (C1-C6)alkyl, which optionally may contain one or two substituent independently selected from the group comprising a hydroxyl group and (C1-C4)-alkoxygroup;

R2- (C1-C12)alkyl;

R3- (C1-C4)alkyl;

R4is hydrogen, (C1-C6)alkyl;

R5- phenyl, containing three Vice, which is the (C1-C6)alkyl,

R7is hydrogen, (C1-C4)alkyl,

and their pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, where R1- (C1-C4)alkyl, which optionally may contain one Deputy, selected from hydroxy, or CSUB>1-C4)alkyl containing as a substituent a hydroxyl group.

4. Connection on p. 1, where R3is methyl.

5. Connection on p. 1, where R4is hydrogen or methyl.

6. Connection on p. 1, where: a) R3is methyl; (b) R4is hydrogen or methyl and R5- phenyl, containing three Vice, which stands.

7. Connection on p. 1, representing

butyl-[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo (3,4-b)pyridine-4-yl]ethylamine;

[3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo(3,4-b)pyridine-4-yl] -(1-methoxymethyl)amine;

4-(1-methoxymethylethoxy)-3,6-dimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo(3,4-b)pyridine,

(1-ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6-trimetilfenil)-1H-pyrazolo (3,4-b)pyridine-4-yl]amine.

 

Same patents:

The invention relates to new heterocyclic compounds of the formula I where ring a and ring To represent optionally substituted benzene or cycloalkane ring or optionally substituted 5 - or 6-membered aromatic heterocyclic ring containing one to two heteroatoms selected from nitrogen, sulfur and oxygen

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to new cephalosporins and complexes arbocatalogi/para-aminobenzoic acid, methods of their production and in particular the isolation and purification of antibiotics containing the beta-lactam ring

The invention relates to biologically active compounds, namely cyclohexylamino chinoline[2,1-b]hinzelin-12-he-5-carboxylic acid formula

< / BR>
with antireverse activity, suggesting the possibility of its use in medicine as a drug for the treatment of tick-borne encephalitis

The invention relates to an improved process for the preparation of pyrazole and its derivatives of the formula I

< / BR>
in which the radicals R1-R4have the meanings specified below,

from,- unsaturated carbonyl compounds of the formula II

< / BR>
and hydrazine or hydrazine derivatives of formula III

H2N-OTHER4

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to therapeutically active derivatives of hydroxamic acids, processes for their preparation, pharmaceutical compositions containing them and to the use of such compounds in medicine

The invention relates to pyrazolopyrimidines General formula I and their pharmaceutically acceptable salts, where A is the group NR1R2or CR'1R'2R11, R1- H or C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, F, CL and others, or C2-C6alkenyl; or C2-C6-quinil; R2-C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, C1-C6-alkoxy and others; or C2-C6alkenyl or2-C6-quinil, or furanyl; and (C1-C4-alkylene)phenyl which may be substituted by 1 to 3 substituents: CL, F, C1-C4-alkyl, and one Deputy:1-C6-alkoxy, CF3, NO2, NH2; or (C1-C4-alkylen) hetaryl where hetaryl - thienyl, possibly substituted by CL, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl, possibly substituted benzyl, pyrrolidinyl, possibly substituted by benzyl or HE, the IIR>-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6alkyl), S(C1-C4- alkyl); R4- C1-C6- alkyl, or S(O)n(C1-C6)-alkyl, where n= 0-2, R5- 2,4,6-substituted phenyl CL, C1-C6-alkyl, CF3; R11-N., HE, or COO- (C1-C2alkyl), provided that the group CR'1R'2R11not an alkyl straight chain; and when R3is N, then R4isn't C1-C6the alkyl
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