Pharmaceutical formulation comprising pyrazolo[4,3-d]pyrimidines and nitrates or thienopyrimidines a

专利摘要:
Eczema, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart, right heart failure, atherosclerosis, reduced cardiovascular condition, peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma A pharmaceutical formulation comprising at least one phosphodiesterase V inhibitor and at least one nitrate for the manufacture of a medicament for the treatment of allergic rhinitis, glaucoma, irritable bowel syndrome, tumor, renal failure and cirrhosis.
公开号:KR20030070149A
申请号:KR10-2003-7010043
申请日:2001-12-27
公开日:2003-08-27
发明作者:에겐바일러한스-미카엘；아이어만폴커；쉘링피에르
申请人:메르크 파텐트 게엠베하；
IPC主号:

专利说明:

PHARMACEUTICAL FORMULATION COMPRISING PYRAZOLO [4,3-D] PYRIMIDINES AND NITRATES OR THIENOPYRIMIDINES AND NITRATES}
[44] Pharmaceutical compositions composed of nitrates with other phosphodiesterase V (PDE V) inhibitors are described in WO 00/15228.
[45] It is for example described in WO 00/10542 that administration of nitrate with PDE V inhibitors at the onset of erectile dysfunction is a known contraindication. At the same time, however, it is disclosed that even if a phosphodiesterase V inhibitor is used for the treatment of erectile dysfunction, nitrate can be administered simultaneously with anti-eyeginase.
[46] The specification also describes pharmaceutical formulations comprising both nitrate and phosphodiesterase inhibitors for simultaneous use in the treatment of erectile dysfunction and / or cardiovascular disease due to the presence of each other indication. .
[47] The present invention is based on the object of providing novel medicaments in the form of pharmaceutical formulations which have better properties than known medicaments which can be used for the same purpose.
[48] This object was achieved with the discovery of new formulations.
[49] Compounds of formula (I), (I-I) and (I-II) and salts thereof have very useful pharmacological properties and good resistance. In particular, they exhibit specific inhibition of cGMP phosphodiesterase (PDE V).
[50] Quinazolin with cGMP phosphodiesterase-inhibiting activity is described, for example, in J. Chem. Med. Chem. 36 , 3765 (1993) and ibid. 37 , 2106 (1994).
[51] The biological activity of the compounds of the formulas (I), (II) and (I-II) can be identified, for example, by methods as described in WO 93/06104. The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterases is confirmed by measuring their IC ₅₀ values (the concentration of such inhibitors necessary to achieve 50% inhibition of enzyme activity). It can be identified using enzymes isolated by known methods (eg, WJ Thompson et al., Biochem. 1971, 10 , 311). Experiments can be made using the modified batch method of WJ Thompson and MM Appleman (Biochem. 1979, 18 , 5228).
[52] Thus, the compounds are suitable for the treatment of cardiovascular diseases, in particular heart failure, and for the treatment and / or treatment of potency diseases (erectile dysfunction).
[53] The use of substituted pyrazolopyrimidinones for the treatment of impotes is described, for example, in WO 94/28902.
[54] The compound is effective as an inhibitor of phenylephrine-induced contraction in rabbit cavernous specimens. Such biological actions are described, for example, in F. Holmquist et al. in J. Urol., 150 , 1310-1315 (1993)}. Inhibition of contraction demonstrates the effectiveness of the treatment and / or treatment of the potency of the compounds according to the invention.
[55] The efficacy of the pharmaceutical compositions according to the invention, in particular against pulmonary hypertension, can be demonstrated as described in E. Braunwald in Heart Disease 5 ^th edition, WB Saunders Company, 1997, Chapter 6: Cardiac Catheterisation, 177-200. Can be.
[1] The present invention is an eye, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart, right heart failure, atherosclerosis, reduced cardiovascular condition, peripheral vascular disease, stroke, bronchitis, allergic asthma At least one phosphodiesterase V inhibitor of formula (I) for the manufacture of a medicament for the treatment of chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumor, renal failure and cirrhosis:
[2]
[3] (Wherein
[4] R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
[5] R ¹ and R ² together may optionally be alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —CH ₂ —O—CH ₂ —, —O—CH ₂ —O— or —O—CH; ₂ -CH ₂ -O-,
[6] R ³ and R ⁴ are each independently H or A,
[7] X is each R ⁵ , R ⁶ or R ⁷ monosubstituted by R ⁸ ,
[8] R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms, in which one or two CH ₂ groups may be replaced by a —CH═CH— group, O, S or SO,
[9] R ⁶ is cycloalkyl or cycloalkylalkylene having 5 to 12 carbon atoms,
[10] R ⁷ is phenyl or phenylmethyl,
[11] R ⁸ is COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,
[12] A is alkyl having 1 to 6 carbon atoms,
[13] Hal is F, Cl, Br or I)
[14] And / or physiologically acceptable salts and / or solvates thereof and one or more nitrates.
[15] The present invention also relates to eye or nausea, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart, right heart failure, atherosclerosis, reduced cardiovascular condition, peripheral vascular disease, stroke, bronchitis, allergic At least one phosphodiesterase V inhibitor of formula (II) for the manufacture of a medicament for the treatment of asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumor, renal failure and cirrhosis:
[16]
[17] (Wherein
[18] R ¹ and R ² are each independently of each other H, A or Hal, and one of the radicals R ¹ and R ² is not always H,
[19] R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms,
[20] R ³ and R ⁴ are each independently of each other H, A, OH, OA or Hal,
[21] R ³ and R ⁴ together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[22] X is each R ⁵ or R ⁶ monosubstituted by R ⁷ ,
[23] R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms, or one of two CH ₂ groups, which may be replaced with a —CH═CH— group, or —C ₆ H ₄ — (CH ₂ ) _m −,
[24] R ⁶ is cycloalkylalkylene having 6 to 12 carbon atoms,
[25] R ⁷ is COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,
[26] A is alkyl having 1 to 6 carbon atoms,
[27] Hal is F, Cl, Br or I,
[28] m is 1 or 2,
[29] n is 0, 1, 2 or 3)
[30] And / or physiologically acceptable salts and / or solvates thereof and one or more nitrates.
[31] The present invention also relates to eye or nausea, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart, right heart failure, atherosclerosis, reduced cardiovascular condition, peripheral vascular disease, stroke, bronchitis, allergic At least one phosphodiesterase V inhibitor of formula (I-II) for the manufacture of a medicament for the treatment of asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumor, renal failure and cirrhosis:
[32]
[33] (Wherein
[34] R ¹ and R ² are each independently of each other H, A, OA, OH or Hal,
[35] R ¹ and R ² together may optionally be alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —CH ₂ —O—CH ₂ —, —O—CH ₂ —O— or —O—CH; ₂ -CH ₂ -O-,
[36] X is each R ⁴ , R ⁵ or R ⁶ monosubstituted by R ⁷ ,
[37] R ⁴ is straight or branched chain alkylene having 1 to 10 carbon atoms, in which one or two CH ₂ groups may be replaced by a —CH═CH— group,
[38] R ⁵ is cycloalkyl or cycloalkylalkylene having 5 to 12 carbon atoms,
[39] R ⁶ is phenyl or phenylmethyl,
[40] R ⁷ is COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,
[41] A is alkyl having 1 to 6 carbon atoms,
[42] Hal is F, Cl, Br or I)
[43] And / or physiologically acceptable salts and / or solvates thereof and one or more nitrates.
[56] The compounds of formulas (I), (I-I) and (I-II) can be used as pharmaceutically active ingredients of human and animal medicines. They can also be used as intermediates for the preparation of other pharmaceutical active ingredients.
[57] Compound of formula (I)
[58] The compound of formula (I) and salts thereof according to claim 1,
[59] a) a compound of formula (II):
[60]
[61] (Wherein
[62] R ³ , R ⁴ and X are as defined above,
[63] L is Cl, Br, OH, SCH ₃ or a reactive esterified OH group)
[64] To the compound of formula III:
[65]
[66] (Wherein
[67] R ¹ and R ² are as defined above)
[68] Or react with
[69] b) converting radical X in the compound of formula I to another radical X, for example, by hydrolyzing an ester group with a COOH group or by converting a COOH group with an amide or cyano group,
[70] And / or converting the compound of formula (I) into one of its salts.
[71] The term solvate of a compound of formula (I) is considered to mean an adduct of inert solvent molecules to the compound of formula (I) formed due to their mutual attraction. For example, the solvate is a monohydrate or dihydrate or alcoholate.
[72] Above and below, unless stated otherwise, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X and L are as defined in formulas I, II and III .
[73] A is alkyl having 1 to 6 carbon atoms.
[74] In the above formula, alkyl is preferably straight chain and has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl or propyl, and also preferably isopropyl, butyl, isobutyl, secondary- Butyl or tert-butyl, also n-pentyl, neopentyl, isopentyl or hexyl.
[75] X is R ^5, R ⁶ or R ⁷ radical to be substituted by R ^7.
[76] R ⁵ is preferably an alkylene radical, for example methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary-butylene, pentylene, 1-, 2- or 3-methylbutyl Ethylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2 -, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methyl Linear or branched alkylene having 1 to 10 carbon atoms, which is propylene, 1,1,2- or 1,2,2-trimethylpropylene, straight or branched heptylene, octylene, nonylene or decylene. R ⁵ is also, for example, but-2-enylene or hex-3-enylene. One CH ₂ group in R ⁵ may preferably be replaced by oxygen. Very particular preference is given to ethylene, propylene, butylene or CH ₂ -O-CH ₂ .
[77] R ⁶ is cycloalkylalkylene having 5 to 12 carbon atoms, preferably cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
[78] R ⁶ is optionally cycloalkyl having 5 to 7 carbon atoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
[79] Hal is preferably F, Cl or Br, and also I.
[80] The radicals R ¹ and R ² are the same or different and are preferably present in the 3- or 4-position of the phenyl ring. These are for example, independently of each other in each case, H, alkyl, OH, F, Cl, Br or I, or together alkylene such as propylene, butylene or pentylene, also ethyleneoxy, methylenedi Oxy or ethylenedioxy. These are optionally preferably each alkoxy such as, for example, methoxy, ethoxy or propoxy.
[81] The radical R ⁸ is preferably, for example, COOH, for example COOA, CONH ₂ , CON (CH ₃ ) ₂ , CONHCH ₃ or CN, such as COOCH ₃ or COOC ₂ H ₅ , in particular COOH or COOA.
[82] For the whole invention, all radicals which occur more than once may be identical or different, ie independent of one another.
[83] The present invention particularly relates to pharmaceutical compositions in which the nitrate and at least one of said radicals comprises at least one compound of formula (I) having one of the preferred meanings set forth above. Preferred groups of the compound can be represented by the following partial formulas Ia to If, which are consistent with formula I, radicals not specified in more detail are as defined in formula I,
[84] In Ia,
[85] X is R ⁵ , phenyl or phenylmethyl, each substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN;
[86] In Ib,
[87] R ¹ and R ² together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O—, or —O—CH ₂ —CH ₂ —O,
[88] X is R ⁵ , phenyl or phenylmethyl, each substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN;
[89] In Ic,
[90] R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
[91] R ¹ and R ² together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O—, or —O—CH ₂ —CH ₂ —O,
[92] X is R ⁵ , phenyl or phenylmethyl, each substituted with COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN;
[93] In Id,
[94] R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
[95] R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[96] X is alkylene, cyclohexyl, phenyl or phenylmethyl having 2 to 5 carbon atoms monosubstituted by R ⁸ ,
[97] R ³ is alkyl having 1 to 6 carbon atoms,
[98] R ⁴ is alkyl having 1 to 6 carbon atoms,
[99] R ⁸ is COOH or COOA,
[100] A is alkyl having 1 to 6 carbon atoms,
[101] Hal is F, Cl, Br or I;
[102] In Ie,
[103] R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
[104] R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[105] R ³ is alkyl having 1 to 6 carbon atoms,
[106] R ⁴ is alkyl having 1 to 6 carbon atoms,
[107] X is-(CH ₂ ) _2-5 -R ⁸ , 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -methyl) phenyl;
[108] In If,
[109] R ¹ and R ² are, independently from each other, H, A, OH, OA or Hal,
[110] R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[111] R ³ is alkyl having 1 to 6 carbon atoms,
[112] R ⁴ is alkyl having 1 to 6 carbon atoms,
[113] X is — (CH ₂ ) _2-5 —R ⁸ where one CH ₂ group may be replaced by O, or 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -methyl) Phenyl;
[114] R ⁸ is COOH or COOA.
[115] The present invention preferably provides [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl-meth Oxy] acetic acid and its physiologically acceptable salts and / or solvates and nitrates. In addition to the free acid, ethanolamine salts are also preferred.
[116] Preference is given to nitrates selected from the group consisting of pentaerythritol tetranitrate, trinitrate, dinitrate and mononitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate.
[117] Particular preference is given to nitrates selected from the group consisting of pentaerythritol tetranitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate, with very particular preference to pentaerythritol tetranitrate .
[118] Compounds of formula (I) and starting materials for their preparation are also described in the literature (for example, standard workbooks such as Houben-Weyl, Methoden der organischen Chemie, Georg-Tieme-Verlag, Stuttgart). It is known to the reaction by methods known per se as described and prepared precisely under suitable reaction conditions. Modifications known per se but not mentioned in detail herein may also be used.
[119] In the compounds of formula (II) or (III), R ¹ , R ² , R ³ , R ⁴ and X have the meanings indicated, in particular the preferred meanings indicated.
[120] When L is a reactive esterified OH group, it is preferably alkylsulfonyloxy (preferably methylsulfonyloxy) having 1 to 6 carbon atoms or arylsulfonyloxy (preferably phenyl- or p-) having 6 to 10 carbon atoms. Tolylsulfonyloxy, also 2-naphthalenesulfonyloxy).
[121] The compound of formula (I) can preferably be obtained by reacting a compound of formula (II) with a compound of formula (III).
[122] If necessary, the starting material can be formed in situ by it not being separated from the reaction mixture but instead immediately converted further to the compound of formula (I). On the other hand, sequential reactions can also be carried out.
[123] Starting compounds of the compounds of formulas (II) and (III) are generally known. If they are not known, they can be produced by methods known per se. Compounds of formula (II) can be prepared, for example, from 4-amino-3-alkoxycarbonylpyrazoles by cyclization using nitriles by methods known from the literature and then reacting the cyclization products with phosphorus oxychloride. {In a similar manner to Houben Weyl E9b / 2}.
[124] Specifically, the compound of formula (II) is reacted with the compound of formula (III) at a temperature of about -20 to 150 degrees, preferably 20 to 100 degrees, in the presence or absence of an inert solvent.
[125] Addition of acid-binding agents, for example alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of weak acids of alkali or alkaline earth metals, preferably potassium, sodium or calcium, or triethylamine, dimethylamine, pyridine or The addition of quinoline or excess amine compound may be advantageous.
[126] Examples of suitable inert solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, or mixtures of these solvents.
[127] It is also possible, for example, to hydrolyze an ester or cyano group to produce a COOH group, thereby converting radical X in the compound of formula (I) to another radical X. For example, at temperatures from 0 to 100 °, NaOH or KOH in water, water / THF or water / dioxane can be used to saponify ester groups. For example, thionyl chloride can be used to convert the carboxylic acid to the corresponding carbonyl chloride, which can be converted to the carboxamide. Water is removed by known methods to obtain carbonitrile.
[128] For example, the base can be used to convert the acid of formula (I) to the relevant acid-addition salt by reacting an equal amount of acid with a base in an inert solvent such as ethanol and then evaporating. Suitable bases for this reaction are, in particular, bases which give physiologically acceptable salts.
[129] Thus, a base (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) can be used to convert the acid of formula (I) to the corresponding metal salt, in particular alkali or alkaline earth metal salts, or corresponding ammonium salts. Also particularly suitable are organic bases which produce physiologically acceptable salts such as, for example, ethanolamine.
[130] On the other hand, the base of formula (I) can be converted to the relevant acid-addition salt using the acid, for example by reacting and then evaporating the acid with an equivalent amount of base in an inert solvent such as ethanol. Suitable acids for this reaction are, in particular, acids which produce physiologically acceptable salts. Thus, for example, hydrofluoric acid such as sulfuric acid, nitric acid, hydrochloric acid or bromic acid, phosphoric acid such as orthophosphoric acid, inorganic acids such as sulfamic acid, and also organic acids, especially aliphatic, cycloaliphatic, aromatic aliphatic, aromatic or heterocyclic monobasics or poly Base carboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid Acids, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and -disulfonic acid, or lauryl sulfate. For example, salts with physiologically unacceptable acids such as picrates can be used for the separation and / or purification of the compounds of formula (I).
[131] The invention also relates to a pharmaceutical composition comprising one or more nitrates of one or more compounds of formula (I), and / or physiologically acceptable salts thereof, and comprising one or more excipients and / or adjuvants. will be.
[132] The pharmaceutical preparations are prepared in particular by non-chemical means and the active ingredient is converted into a suitable dosage form together with one or more solid, liquid and / or semi-liquid excipients or adjuvants.
[133] Such agents may be used as medicaments in human or animal medicine. Suitable excipients are suitable for enteral (eg oral), parenteral or topical administration and include, for example, water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, lactose Or organic or inorganic materials that do not react with new compounds such as carbohydrates such as starch, magnesium stearate, talc or petrolatum. In particular, tablets, pills, tablets, capsules, powders, granules, syrups, juices or drops are suitable for oral administration, suppositories are suitable for rectal administration, solutions, preferably oil-based solutions or aqueous solutions, also suspensions, Emulsions or implants are suitable for parenteral administration, and ointments, creams or powders are suitable for topical administration. The new compound may be lyophilized and the injection may be prepared, for example, using the resulting lyophilized product. The formulation is sterilized and / or a number of additional active ingredients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, osmotic pressure adjusting salts, buffers, coloring agents, flavoring agents and / or one or more vitamins, for example. It may include an adjuvant such as They can also be administered by nasal spray.
[134] In general, the substance is preferably administered at a dosage of about 1 to 500 mg, in particular 5 to 100 mg, per dosage unit. The daily dosage is preferably about 0.02 to 10 mg per kg of body weight. However, the specific dosage for each patient is, for example, the efficacy, age, weight, general state of health, sex, diet, time and method of administration, rate of excretion, combination of medications and therapies to which the particular compound used is applied. This depends on a variety of factors, such as the severity of the particular disease. Oral administration is preferred.
[135] The present invention relates in particular to the use of a composition according to the invention for the preparation of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[136] The components of the novel pharmaceutical formulations above are preferably administered in combination. However, they may be administered separately or simultaneously or sequentially.
[137] The invention also
[138] (a) an effective amount of [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] Acetic acid, ethanolamine salt,
[139] And
[140] (b) effective amount of nitrate
[141] A set (kit) consisting of individual packages of.
[142] The present invention is particularly intended for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[143] (a) an effective amount of [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid Ethanolamine salts,
[144] And
[145] (b) effective amount of nitrate
[146] A set (kit) consisting of individual packages of.
[147] The set comprises a suitable container, such as a box, individual bottle, box, bag or ampoule. This set is for example an effective amount of each [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] -pyrimidine-5 -Ylmethoxy] acetic acid, ethanolamine salts, and individual ampoules containing nitrate in dissolved or lyophilized form.
[148] Above and below, all temperatures are given in degrees Celsius. In the examples which follow, "normal reaction finishing" is carried out by adding water if necessary, adjusting the pH to 2 to 10 if necessary according to the composition of the final product, extracting the mixture with ethyl acetate or dichloromethane, and Is separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography and / or crystallization on silica gel.
[149] Mass Spectrometry (MS): Electron Impact Ionization (EI) M ⁺
[150] Fast Atomic Impact (FAB) (M + H) ⁺
[151] Example 1
[152] 3 g of methyl 3- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionate in 50 ml of dimethylformamide (DMF) and 1.9 g of 3-chloro-4-methoxybenzylamine ("A") are stirred at 60 ° for 12 hours in the presence of potassium carbonate. After filtration, the solvent was removed and the product was subjected to the usual reaction to give 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazol as colorless oil. 4.6 g of [4,3-d] pyrimidin-5-yl] propionate is obtained.
[153] Similarly, "A" is reacted with methyl 2- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] acetate to yield methyl 2- [ 7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] acetate is obtained.
[154] Similarly, 3,4-methylenedioxybenzylamine is converted to methyl 3- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propio By reacting with methylate to methyl 3- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] pro Obtain cypionate.
[155] Similarly, "A" is reacted with methyl 4- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyrate to react methyl 4- [ 7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyrate is obtained.
[156] Similarly, 3,4-methylenedioxybenzylamine is combined with methyl 4- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyrate Reaction gives methyl 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyrate .
[157] Similarly, "A" is reacted with methyl 5- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valerate to give methyl 5- Obtain [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric.
[158] Similarly, 3,4-methylenedioxybenzylamine is substituted with methyl 5- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valerate Reacted with methyl 5- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valerate Get
[159] Similarly, "A" is reacted with methyl 7- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoate to give methyl 7 -[7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoate is obtained.
[160] Similarly, 3,4-methylenedioxybenzylamine is substituted with methyl 7- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptano React with methyl to give 7- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] hep Get tanoate.
[161] Similarly, "A" is methyl 2- [4- (7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl) -cyclohex-1 Methyl- {4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyridine by reaction with -yl] acetate Midin-5-yl] -cyclohexyl-1-yl} acetate.
[162] Similarly, 3,4-methylenedioxybenzylamine is converted to methyl 2- [4- (7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl ) -Cyclohex-1-yl] acetate to react with methyl 2- {4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4, 3-d] pyrimidin-5-yl] cyclohexyl-1-yl} acetate.
[163] Similarly, benzylamine
[164] Methyl 3- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionate to react with methyl 3- [7-benzylamino- Obtaining 1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionate;
[165] Methyl 4- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyrate by reaction with methyl 4- [7-benzylamino-1- Obtaining methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyrate;
[166] Methyl 5- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valerate to react with methyl 5- [7-benzylamino-1 -Methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric is obtained.
[167] Similarly, "A" is reacted with methyl 4- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylate Methyl 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxyl The rate was obtained and 3,4-methylenedioxybenzylamine was reacted to give methyl 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4, 3-d] pyrimidin-5-yl] cyclohexanecarboxylate is obtained.
[168] Example 2
[169] 4.3 g of methyl 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl- 1H -pyrazolo [4,3-d] pyrimidin-5-yl] propionate Is dissolved in 30 ml of tetrahydrofuran (THF), 10 ml of 10% NaOH is added and the mixture is stirred at 60 ° for 8 hours. After addition of 10% HCl, the precipitated crystals were separated and recrystallized from methanol to give 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H − 3.7 g of pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid (mp 178 °) are obtained.
[170] Evaporation with an equal amount of potassium hydroxide methanol solution affords the potassium salt of the acid as an amorphous powder.
[171] In a similar reaction with the esters listed in Example 1, the compound:
[172] 2- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] acetic acid,
[173] 3- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
[174] 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 152 ° ;
[175] 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 172 °;
[176] 5- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 159 °;
[177] 5- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, ethanolamine salt , mp 160 °;
[178] 7- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,
[179] 7- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,
[180] 2- {4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl -1-yl} acetic acid,
[181] 2- {4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl- 1-yl} acetic acid,
[182] 3- [7-benzylamino-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
[183] 4- [7-benzylamino-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,
[184] 5- [7-benzylamino-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 185 °;
[185] 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylic acid ,
[186] 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylic acid
[187] Get
[188] In a similar reaction, the compound:
[189] 5- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-isopropyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, cyclo Hexylamine salt, mp 148 °;
[190] 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-ethyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 176 ° ;
[191] 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-ethyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 187 °;
[192] 4- [7- (3-chloro-4-methoxybenzylamino) -1-ethyl-3-methyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 206 ° ;
[193] 4- [7- (3,4-methylenedioxybenzylamino) -1-ethyl-3-methyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 177 °;
[194] 4- [7-benzylamino-1-methyl-3-ethyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 208 °;
[195] 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-methyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 250 ° ;
[196] 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-methyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 225 °;
[197] 4- [7-benzylamino-1-methyl-3-methyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 201 °;
[198] 5- [7- (4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 160 °;
[199] 5- [7- (3-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 141 °;
[200] 5- [7- (4-chlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 148 °;
[201] 5- [7- (3-chlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid, mp 151 °;
[202] Example 3
[203] Methyl 4- [7-chloro-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] phenylcarboxylate in 20 ml of N-methylpyrrolidone (" B ″) a mixture of 1.8 g and 1.5 g of 3-chloro-4-methoxybenzylamine is heated at 110 ° for 4 hours. After cooling, the mixture was finished with a conventional reaction to afford methyl 4- [7- (3-chloro-4-methoxybenzylamino-1-methyl-3-propyl-1 H -pyrazolo [4,3-d 2.2 g of] pyrimidin-5-yl] benzoate is obtained.
[204] Similar to Example 2, 4- [7- (3-chloro-4-methoxybenzylamino-1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidine with 1.2 g of ester -5-yl] benzoic acid, ethanolamine salt, mp 139 °, 1.0 g.
[205] Similar to Example 1, methyl 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H − with “B” and 3,4-methylenedioxybenzylamine Obtain pyrazolo [4,3-d] pyrimidin-5-yl] benzoate, which is ester hydrolyzed to 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl -1 H - pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid is obtained.
[206] In a similar reaction, the compound:
[207] 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid, glucamine Flame, mp 114 °
[208] And
[209] 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid is obtained.
[210] Example 4
[211] 1 equivalent of 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid and tee 1.2 equivalents of onyl chloride are stirred in dichloromethane for 2 hours. Remove the solvent, 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] Obtain propionyl chloride.
[212] The product was transferred into an aqueous ammonia solution and the mixture was stirred for one hour and the usual reaction finish was completed, 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H − Pyrazolo [4,3-d] pyrimidin-5-yl] propionamide is obtained.
[213] Example 5
[214] At 0 ° 1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile. Then 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionamide 1 Add equivalent weight. The mixture is stirred for an additional hour. Finishing the usual reaction, 3- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl ] Propionitrile is obtained.
[215] Example 6
[216] Similar to Examples 1, 2 and 3, the corresponding chloro-pyrimidine derivatives were reacted with 3,4-ethylenedioxybenzylamine to yield the following carboxylic acids:
[217] 4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,
[218] 3- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
[219] 5- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,
[220] 7- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,
[221] 2- {4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl- 1-yl} acetic acid,
[222] 4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylic acid,
[223] 4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
[224] 4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
[225] 4- [7- (3,4-ethylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid is obtained.
[226] Similarly, by reacting with 3,4-dichlorobenzylamine, the following compounds:
[227] 4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid, mp 209 °;
[228] 3- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
[229] 5- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,
[230] 7- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,
[231] 2- {4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl-1- Acetic acid,
[232] 4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylic acid,
[233] 4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
[234] 4- [7- (3,4-dichlorobenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid
[235] Get
[236] Similarly, by reacting with 3-chloro-4-ethoxybenzylamine, the following compounds:
[237] 4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,
[238] 3- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
[239] 5- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,
[240] 7- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,
[241] 2- {4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexyl -1-yl} acetic acid,
[242] 4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxylic acid ,
[243] 4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
[244] 4- [7- (3-chloro-4-ethoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid
[245] Get
[246] Similarly, by reacting with 3-chloro-4-isopropoxybenzylamine, the following compounds:
[247] 4- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid,
[248] 3- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] propionic acid,
[249] 5- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] valeric acid,
[250] 7- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] heptanoic acid,
[251] 2- {4- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclo Hexyl-1-yl} acetic acid,
[252] 4- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] cyclohexanecarboxyl mountain,
[253] 4- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid,
[254] 4- [7- (3-chloro-4-isopropoxybenzylamino) -1-methyl-3-propyl- 1H -pyrazolo [4,3-d] pyrimidin-5-yl] phenylacetic acid
[255] Get
[256] Example 7
[257] Compounds [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidine-5 in a similar reaction to Examples 1 and 2 -Ilmethoxy] acetic acid, ethanolamine salt, mp138 °.
[258] The following examples pertain to pharmaceutical formulations:
[259] Example A: Vials for Injection
[260] Using 2N hydrochloric acid, the pH of 100 g of the active ingredient of formula I, 100 g of nitrate and 5 g of sodium diphosphate in 3 l of secondary distilled water was adjusted to 6.5, sterile filtered, transferred to an injectable vial, sterile conditions Lyophilized under and sealed under sterile conditions. Each injectable vial contains 5 mg of active ingredient.
[261] Example B: Suppositories
[262] A mixture of 20 g of the active ingredient of formula I-II and 20 g of nitrate is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into a mold and cooled. Each suppository contains 20 mg of active ingredient.
[263] Example C: Solution
[264] In 940 ml of secondary distilled water, 1 g of active ingredient (I), 1 g of nitrate, 9.38 g of NaH ₂ PO ₄ 2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ O and 0.1 g of benzalkonium chloride were added to the solution. Manufacture. The pH is adjusted to 6.8 and the solution is brought to 1 L and sterilized by irradiation. This solution can be used in the form of eye drops.
[265] Example D: Ointment
[266] Under aseptic conditions 500 mg of the active ingredient of formula I and 500 mg of nitrate are mixed with 99.5 g of petrolatum.
[267] Example E: Tablets
[268] A mixture of 1 kg of active ingredient of formula I, 1 g of nitrate, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate, is compressed in a conventional manner so that each tablet contains 10 mg of active ingredient To obtain tablets.
[269] Example F: Tablets
[270] Similar to Example E, the tablets are compressed and then coated by coating with sucrose, potato starch, talc, tragacanth and dye in a conventional manner.
[271] Example G: Capsule
[272] 2 kg of the active ingredient of formula (I) and 2 kg of nitrate are introduced into the hard gelatin capsule in a conventional manner such that each capsule contains 20 mg of the active ingredient.
[273] Example H: Ampoules
[274] A solution of 1 kg of the active ingredient of formula I and 1 kg of nitrate in 60 l of secondary distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
[275] Example I: Inhalation Spray
[276] 14 g of the active ingredient of formula (I) and 14 g of nitrate are dissolved in 10 l of NaCl isotonic solution and the solution is transferred into a commercial spray vessel having a pump mechanism. The solution may be sprayed into the mouth or nose. One spray (about 0.1 mL) corresponds to an active ingredient dose of about 0.14 mg.
[277] Compound of Formula I-I
[278] Compounds of formula (I-I) and salts thereof,
[279] a) a compound of formula II-I:
[280]
[281] (Wherein
[282] R ¹ , R ² and X are as defined above,
[283] L is Cl, Br, OH, SCH ₃ or a reactive esterified OH group)
[284] To the compound of formula III:
[285] [Formula III]
[286]
[287] (Wherein
[288] R ³ , R ⁴ and n are as defined above)
[289] Or react with
[290] b) converting radical X in the compound of formula (I-I) to another radical X, for example by hydrolyzing an ester group with a COOH group or converting a COOH group with an amide or cyano group,
[291] And / or by converting the compound of formula (I-I) to one of its salts.
[292] The term solvate of a compound of formula (I-I) is understood to mean an adduct of inert solvent molecules to the compound of formula (I-I) formed due to their mutual attraction. For example, the solvate is a monohydrate or dihydrate or alcoholate.
[293] Above and below, unless stated otherwise, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, L and n are as defined in Formulas II, II-I and III same.
[294] A is alkyl having 1 to 6 carbon atoms.
[295] In the above formula, alkyl is preferably straight chain and has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl or propyl, and also preferably isopropyl, butyl, isobutyl, secondary- Butyl or tert-butyl, also n-pentyl, neopentyl, isopentyl or hexyl.
[296] X is an R ⁵ or R ⁶ radical mono-substituted by R ⁷ .
[297] R ⁵ is preferably an alkylene radical, for example methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary-butylene, pentylene, 1-, 2- or 3-methylbutyl Ethylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2 -, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methyl Straight or branched carbon atoms of 1 to 10, preferably 1 to 8, being propylene, 1,1,2- or 1,2,2-trimethylpropylene, straight or branched heptylene, octylene, nonylene or decylene Chain alkylene.
[298] R ⁵ is also, for example, but-2-enylene or hex-3-enylene.
[299] R ⁶ is cycloalkylalkylene having 6 to 12 carbon atoms, preferably cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
[300] One of the radicals R ¹ and R ² is preferably H and the other is preferably propyl or butyl, particularly preferably ethyl or methyl. In addition, R ¹ and R ² together are optionally preferably propylene, butylene or pentylene.
[301] Hal is preferably F, Cl or Br, optionally I.
[302] R ³ and R ⁴ are the same or different and are preferably present in the 3- or 4-position of the phenyl ring. These are, for example, independently of each other in each case, H, OH, alkyl, F, Cl, Br or I, or together, for example, alkylene such as propylene, butylene or pentylene, also ethyleneoxy, methylenedi Oxy or ethylenedioxy. These are optionally preferably each alkoxy such as, for example, methoxy, ethoxy or propoxy.
[303] The radical R ⁷ is preferably, for example, COOH, COOCH ₃ , COOC ₂ H ₅ , CONH ₂ , CON (CH ₃ ) ₂ , CONHCH ₃ or CN.
[304] For the whole invention, all radicals which occur more than once may be identical or different, ie independent of one another.
[305] The invention particularly relates to pharmaceutical compositions in which the nitrate and at least one of said radicals comprises at least one compound of the formula (I-I) having one of the preferred meanings set forth above. Preferred groups of the compound may be represented by the following partial formulas Ia to Ie, which are consistent with formulas I-I, and radicals not specified in more detail are as defined in formulas I-I,
[306] In Ia,
[307] X is R ⁵ or R ⁶ , each substituted by COOH or COOA;
[308] In Ib,
[309] R ¹ and R ² are each independently of each other H, A or Hal, and at least one of the radicals R ¹ and R ² is not always H,
[310] R ³ and R ⁴ together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[311] X is R ⁵ or R ⁶ , each substituted by COOH or COOA;
[312] In Ic,
[313] R ¹ and R ² are each independently of each other H, A or Hal, and at least one of the radicals R ¹ and R ² is not always H,
[314] R ³ and R ⁴ are each independently of each other H, A, OA or Hal,
[315] R ³ and R ⁴ together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[316] X is R ⁵ or R ⁶ , each substituted with COOH or COOA;
[317] n is 1 or 2;
[318] In Id,
[319] R ¹ and R ² are each independently of each other H, A or Hal, and one of the radicals R ¹ and R ² is not always H,
[320] R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms,
[321] R ³ and R ⁴ are each independently of each other H, A, OA or Hal,
[322] R ³ and R ⁴ together are optionally —O—CH ₂ —O—,
[323] X is R ⁵ monosubstituted by R ⁷ ,
[324] R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms or —C ₆ H ₄ —CH ₂ —,
[325] R ⁷ is COOH or COOA,
[326] A is alkyl having 1 to 6 carbon atoms,
[327] Hal is F, Cl, Br or I,
[328] m is 1,
[329] n is 1 or 2;
[330] In Ie,
[331] R ¹ and R ² are each independently of each other H, A or Hal, and one of the radicals R ¹ and R ² is not always H,
[332] R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms,
[333] R ³ and R ⁴ are each independently of each other H, A, OH, OA or Hal,
[334] R ³ and R ⁴ together are optionally —O—CH ₂ —O—,
[335] X is R ⁵ monosubstituted by R ⁷ ,
[336] R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms or —C ₆ H ₄ —CH ₂ —,
[337] R ⁷ is COOH or COOA,
[338] A is alkyl having 1 to 6 carbon atoms,
[339] Hal is F, Cl, Br or I,
[340] m is 1,
[341] n is 1 or 2.
[342] The present invention is preferably 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyridine Midin-2-yl] valeric acid and its physiologically acceptable salts and / or solvates and one or more nitrates. In addition to the free acid, ethanolamine salts are also preferred.
[343] Preference is given to nitrates selected from the group consisting of pentaerythritol tetranitrate, trinitrate, dinitrate and mononitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate.
[344] Particular preference is given to nitrates selected from the group consisting of pentaerythritol tetranitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate, with very particular preference to pentaerythritol tetranitrate .
[345] Compounds of formula (I) and starting materials for their preparation are also described in the literature (for example, standard workbooks such as Houben-Weyl, Methoden der organischen Chemie, Georg-Tieme-Verlag, Stuttgart). It is known to the reaction by methods known per se as described and prepared precisely under suitable reaction conditions. Modifications known per se but not mentioned in detail herein may also be used.
[346] In the compounds of the formulas II-I or III, R ¹ , R ² , R ³ , R ⁴ , X and n have the meanings indicated, in particular the preferred meanings given.
[347] When L is a reactive esterified OH group, it is preferably alkylsulfonyloxy (preferably methylsulfonyloxy) having 1 to 6 carbon atoms or arylsulfonyloxy (preferably phenyl- or p-) having 6 to 10 carbon atoms. Tolylsulfonyloxy, also 2-naphthalenesulfonyloxy).
[348] The compound of formula (I-I) may preferably be obtained by a method of reacting a compound of formula (II-I) with a compound of formula (III).
[349] If necessary, the starting material can be formed in situ by it not being separated from the reaction mixture but instead immediately converted further to the compound of formula (I). On the other hand, sequential reactions can also be carried out.
[350] Starting compounds of the compounds of formulas II-I and III are generally known. If they are not known, they can be produced by methods known per se. Compounds of formula II-I can be prepared, for example, by reacting POCl ₃ with compounds prepared from thiophene derivatives and CN-substituted alkylenecarboxylic acid esters. (Eur. J. Med. Chem. 23 , 453 (1988).
[351] Specifically, the compound of formula II-I is reacted with a compound of formula III at a temperature of about -20 to 150 degrees, preferably 20 to 100 degrees, in the presence or absence of an inert solvent.
[352] Addition of acid-binding agents, for example alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of weak acids of alkali or alkaline earth metals, preferably potassium, sodium or calcium, or triethylamine, dimethylamine, pyridine or The addition of quinoline or excess amine compound may be advantageous.
[353] Examples of suitable inert solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, or mixtures of these solvents.
[354] It is also possible, for example, to hydrolyze an ester or cyano group to produce a COOH group, thereby converting radical X in the compound of formula I-I to another radical X. For example, at temperatures from 0 to 100 °, NaOH or KOH in water, water / THF or water / dioxane can be used to saponify ester groups. For example, thionyl chloride can be used to convert the carboxylic acid to the corresponding carbonyl chloride, which can be converted to the carboxamide. Water is removed by known methods to obtain carbonitrile.
[355] For example, the base can be used to convert the acid of formula (I-I) to the relevant acid-addition salt by reacting an equal amount of acid with a base in an inert solvent such as ethanol and then evaporating. Suitable bases for this reaction are, in particular, bases which give physiologically acceptable salts.
[356] Thus, a base (eg, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) can be used to convert the acid of formula (I-I) to the corresponding metal salt, in particular alkali or alkaline earth metal salts, or corresponding ammonium salts. Also particularly suitable are organic bases which produce physiologically acceptable salts such as, for example, ethanolamine.
[357] For example, the base can be used to convert the acid of Formula I-I to the related acid-addition salt by reacting an equal amount of acid with a base in an inert solvent such as ethanol followed by evaporation. Suitable bases for this reaction are, in particular, bases which give physiologically acceptable salts.
[358] Thus, a base (eg, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) can be used to convert the acid of formula (I-I) to the corresponding metal salt, in particular alkali or alkaline earth metal salts, or corresponding ammonium salts. Also particularly suitable are organic bases which produce physiologically acceptable salts such as, for example, ethanolamine.
[359] On the other hand, the base of formula (I-I) can be converted to the relevant acid-addition salt using acid by, for example, reacting and then evaporating the acid with an equivalent amount of base in an inert solvent such as ethanol. Suitable acids for this reaction are, in particular, acids which produce physiologically acceptable salts. Thus, for example, hydrofluoric acid such as sulfuric acid, nitric acid, hydrochloric acid or bromic acid, phosphoric acid such as orthophosphoric acid, inorganic acids such as sulfamic acid, and also organic acids, especially aliphatic, cycloaliphatic, aromatic aliphatic, aromatic or heterocyclic monobasics or poly Base carboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid Acids, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and -disulfonic acid, or lauryl sulfate. For example, salts with physiologically unacceptable acids such as picrates can be used for the separation and / or purification of the compounds of formula (I).
[360] The present invention also relates to a pharmaceutical composition comprising one or more nitrates and one or more excipients and / or adjuvants, comprising one or more of at least one compound of Formula II and / or a physiologically acceptable salt thereof. .
[361] The pharmaceutical preparations are prepared in particular by non-chemical means and the active ingredient is converted into a suitable dosage form together with one or more solid, liquid and / or semi-liquid excipients or adjuvants.
[362] Such agents may be used as medicaments in human or animal medicine. Suitable excipients are suitable for enteral (eg oral), parenteral or topical administration and include, for example, water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, lactose Or organic or inorganic materials that do not react with new compounds such as carbohydrates such as starch, magnesium stearate, talc or petrolatum. In particular, tablets, pills, tablets, capsules, powders, granules, syrups, juices or drops are suitable for oral administration, suppositories are suitable for rectal administration, solutions, preferably oil-based solutions or aqueous solutions, also suspensions, Emulsions or implants are suitable for parenteral administration, and ointments, creams or powders are suitable for topical administration. The new compound may be lyophilized and the injection may be prepared, for example, using the resulting lyophilized product. The formulations are sterilized and / or a number of additional active ingredients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for controlling osmotic pressure, buffers, colorants and flavors and / or for example one or more vitamins. It may include an adjuvant such as They can also be administered by nasal spray.
[363] In general, the substance is preferably administered at a dosage of about 1 to 500 mg, in particular 5 to 100 mg, per dosage unit. The daily dosage is preferably about 0.02 to 10 mg per kg of body weight. However, the specific dosage for each patient is, for example, the efficacy, age, weight, general state of health, sex, diet, time and method of administration, rate of excretion, combination of medications and therapies to which the particular compound used is applied. This depends on a variety of factors, such as the severity of the particular disease. Oral administration is preferred.
[364] The present invention relates in particular to the use of a composition according to the invention for the preparation of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[365] The components of the novel pharmaceutical formulations above are preferably administered in combination. However, they may be administered separately or simultaneously or sequentially.
[366] The invention also
[367] (a) an effective amount of 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine -2-yl] valeric acid, ethanolamine salt,
[368] And
[369] (b) an effective amount of prostaglandin or prostaglandin derivative
[370] A set (kit) consisting of individual packages of.
[371] The present invention is particularly intended for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[372] (a) an effective amount of 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine -2-yl] valeric acid, ethanolamine salt,
[373] And
[374] (b) effective amount of nitrate
[375] A set (kit) consisting of individual packages of.
[376] The set comprises a suitable container, such as a box, individual bottle, box, bag or ampoule. This set is for example an effective amount of 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3- d] pyrimidin-2-yl] valeric acid, ethanolamine salt, and individual ampoules containing nitrate in dissolved or lyophilized form.
[377] Above and below, all temperatures are given in degrees Celsius. In the examples which follow, "normal reaction finishing" is carried out by adding water if necessary, adjusting the pH to 2 to 10 if necessary according to the composition of the final product, extracting the mixture with ethyl acetate or dichloromethane, and Is separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography and / or crystallization on silica gel.
[378] Mass Spectrometry (MS): Electron Impact Ionization (EI) M ⁺
[379] Fast Atomic Impact (FAB) (M + H) ⁺
[380] Example 1
[381] Methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] -pyrimidin-2-yl) in 20 ml of N-methylpyrrolidone Propionate [methyl-2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate is cyclized using methyl 3-cyano-propionate, followed by phosphorus oxychloride Prepared by chlorination with dimethylamine] 1.9 g and 2.3 g of 3-chloro-4-methoxybenzylamine (“A”) are stirred at 110 ° for 5 hours. The solvent was removed and the product was subjected to the usual reaction to give methyl 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1]-as colorless oil. 2.6 g of benzothieno [2,3-d] pyrimidin-2-yl] propionate are obtained.
[382] Similarly, "A"
[383] Methyl 3- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) propionate to react with methyl 3- [4- ( 3-chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionate;
[384] Methyl 3- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) propionate to react with methyl 3- [4- ( 3-chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionate;
[385] Methyl 3- [4- (3-chloro-4-methoxybenzylamino by reacting with methyl 3- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) propionate ) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionate;
[386] Methyl 3- [4- (3-chloro-4-methoxy by reaction with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) propionate Benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionate;
[387] Methyl 3- [4- (3-chloro-4-methoxybenzylamino by reacting with methyl 3- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) propionate ) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionate;
[388] Methyl 3- [4- (3-chloro-4-methoxybenzylamino)-by reaction with methyl 3- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) propionate Obtaining 6-chlorothieno [2,3-d] pyrimidin-2-yl] propionate;
[389] Methyl 2- [4- by reacting with methyl 2- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) acetate (3-Chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] acetate is obtained.
[390] Similarly, 3,4-methylenedioxybenzylamine
[391] Methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) propionate to react with methyl 3- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionate Getting;
[392] Methyl 3- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) propionate to react with methyl 3- [4- ( 3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionate;
[393] Methyl 3- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) propionate to react with methyl 3- [4- ( 3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionate;
[394] Methyl 3- [4- (3,4-methylenedioxybenzylamino) by reaction with methyl 3- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) propionate -6-methylthieno [2,3-d] pyrimidin-2-yl] propionate;
[395] Methyl 3- [4- (3,4-methylenedioxybenzyl by reaction with methyl 3- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) propionate Obtaining amino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionate;
[396] Methyl 3- [4- (3,4-methylenedioxybenzylamino) by reaction with methyl 3- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) propionate -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionate;
[397] Methyl 3- [4- (3,4-methylenedioxybenzylamino) -6 by reaction with methyl 3- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) propionate -Chlorothieno [2,3-d] pyrimidin-2-yl] propionate is obtained.
[398] Similarly, "A"
[399] Methyl 4- [4 by reacting with methyl 4- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate -(3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
[400] React with methyl 4- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate to methyl 4- [4- (3- Chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
[401] Methyl 4- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate was reacted with methyl 4- [4- (3- Chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
[402] Methyl 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyrate to react with methyl 4- [4- (3-chloro-4-methoxybenzylamino)- Obtaining 6-methylthieno [2,3-d] pyrimidin-2-yl] butyrate;
[403] Methyl 4- [4- (3-chloro-4-methoxybenzylamino by reaction with methyl 4- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) butyrate ) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyrate;
[404] Methyl 4- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) butyrate to react with methyl 4- [4- (3-chloro-4-methoxybenzylamino)- Obtaining 6-ethylthieno [2,3-d] pyrimidin-2-yl] butyrate;
[405] Methyl 4- [4- (3-chloro-4-methoxybenzylamino by reacting with methyl 4- (4,6-chloro-6-chlorothieno [2,3-d] pyrimidin-2-yl) butyrate ) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyrate.
[406] Similarly, 3,4-methylenedioxybenzylamine
[407] Methyl 4- [4 by reacting with methyl 4- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate -(3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
[408] Methyl 4- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate to react with methyl 4- [4- (3, 4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
[409] Methyl 4- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate to react with methyl 4- [4- (3, 4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyrate;
[410] Methyl 4- [4- (3,4-methylenedioxybenzylamino) -6 by reaction with methyl 4- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) butyrate -Methylthieno [2,3-d] pyrimidin-2-yl] butyrate;
[411] Reaction with methyl 4- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) butyrate to methyl 4- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyrate;
[412] Methyl 4- [4- (3,4-methylenedioxybenzylamino) -6 by reaction with methyl 4- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) butyrate -Ethylthieno [2,3-d] pyrimidin-2-yl] butyrate;
[413] React with methyl 4- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) butyrate to methyl 4- [4- (3,4-methylenedioxybenzylamino) -6-chloro Obtain thieno [2,3-d] pyrimidin-2-yl] butyrate.
[414] Similarly, "A"
[415] Methyl 5- [4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valerate to react with methyl 5- [ 4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valerate Getting;
[416] Methyl 5- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valeric acid reacted with methyl 5- [4- (3 -Chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valerate;
[417] React with methyl 5- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valeric acid to react with methyl 5- [4- (3 -Chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valerate;
[418] Reaction with methyl 5- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl 5- [4- (3-chloro-4-methoxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric;
[419] Methyl 5- [4- (3-chloro-4-methoxybenzyl by reaction with methyl 5- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) valeric Amino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valerate;
[420] Reaction with methyl 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl 5- [4- (3-chloro-4-methoxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric;
[421] Reaction with methyl 5- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) valeric acid methyl 5- [4- (3-chloro-4-methoxybenzylamino) -6 Obtain chlorothieno [2,3-d] pyrimidin-2-yl] valeric.
[422] Similarly, 3,4-methylenedioxybenzylamine
[423] Methyl 5- [4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valerate to react with methyl 5- [ 4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric was obtained ;
[424] Methyl 5- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valeric acid reacted with methyl 5- [4- (3 , 4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valerate;
[425] React with methyl 5- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valeric acid to react with methyl 5- [4- (3 , 4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric;
[426] Reaction with methyl 5- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl 5- [4- (3,4-methylenedioxybenzylamino)- Obtaining 6-methylthieno [2,3-d] pyrimidin-2-yl] valeric;
[427] Reaction with methyl 5- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) valericate to give methyl 5- [4- (3,4-methylenedioxybenzylamino ) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valerate;
[428] Reaction with methyl 5- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) valeric acid methyl 5- [4- (3,4-methylenedioxybenzylamino)- Obtaining 6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric;
[429] Reaction with methyl 5- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) valericate methyl 5- [4- (3,4-methylenedioxybenzylamino) -6- Chlorothieno [2,3-d] pyrimidin-2-yl] valeric is obtained.
[430] Similarly, "A"
[431] Methyl 7- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) heptanoate to react with methyl 7- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptano Obtaining an eight;
[432] Methyl 7- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) heptanoate was reacted with methyl 7- [4- ( 3-chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoate;
[433] Methyl 7- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) heptanoate was reacted with methyl 7- [4- ( 3-chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoate;
[434] Methyl 7- [4- (3-chloro-4-methoxybenzylamino by reaction with methyl 7- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) heptanoate ) -6-methylthieno [2,3-d] pyrimidin-2-yl] heptanoate;
[435] Methyl 7- [4- (3-chloro-4-methoxy by reaction with methyl 7- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) heptanoate Benzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoate;
[436] Methyl 7- [4- (3-chloro-4-methoxybenzylamino by reaction with methyl 7- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) heptanoate ) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoate;
[437] Methyl 7- [4- (3-chloro-4-methoxybenzylamino by reaction with methyl 7- (4-chloro-6-chlorothieno [2,3-d] pyrimidin-2-yl) heptanoate ) -6-chlorothieno [2,3-d] pyrimidin-2-yl] heptanoate is obtained.
[438] Similarly, 3,4-methylenedioxybenzylamine
[439] Methyl 7- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) heptanoate to react with methyl 7- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoate Getting;
[440] Methyl 7- (4-chloro-5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) heptanoate was reacted with methyl 7- [4- ( 3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoate;
[441] Methyl 7- (4-chloro-5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl) heptanoate was reacted with methyl 7- [4- ( 3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoate;
[442] Methyl 7- [4- (3,4-methylenedioxybenzylamino) by reaction with methyl 7- (4-chloro-6-methylthieno [2,3-d] pyrimidin-2-yl) heptanoate -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric;
[443] Methyl 7- [4- (3,4-methylenedioxybenzyl by reaction with methyl 7- (4-chloro-5,6-dimethylthieno [2,3-d] pyrimidin-2-yl) heptanoate Amino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoate;
[444] By reaction with methyl 7- (4-chloro-6-ethylthieno [2,3-d] pyrimidin-2-yl) heptanoate methyl 7- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoate;
[445] Reaction with methyl 7- (4,6-dichlorothieno [2,3-d] pyrimidin-2-yl) heptanoate methyl 7- [4- (3,4-methylenedioxybenzylamino) -6 -Chlorothieno [2,3-d] pyrimidin-2-yl] heptanoate is obtained.
[446] Similarly, "A"
[447] Methyl 2- [4- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) -cyclohexyl-1- Reacted with yl) acetate to methyl 2- {4- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3 -d] pyrimidin-2-yl] cyclohexyl-1-yl} acetate;
[448] Methyl 2- [4- (4-chloro-6-ethylthieno [2,3-d] -pyrimidin-2-yl) -cyclohexyl-1-yl] acetate to react with methyl 2- {4- [ 4- (3-chloro-4-methoxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetate;
[449] Similarly, 3,4-methylenedioxybenzylamine
[450] Methyl 2- [4- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) -cyclohexyl-1- Reacted with one] acetate to methyl 2- {4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3- d] pyrimidin-2-yl] cyclohexyl-1-yl} acetate.
[451] Similarly, benzylamine
[452] Methyl 3- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) propionate to react with methyl 3- Obtaining (4-benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) propionate;
[453] Methyl 4- (4 by reaction with methyl 4- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate -Benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) butyrate;
[454] Methyl 5- (4-chloro-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valerate to react with methyl 5- ( 4-benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl) valerate;
[455] React with methyl 4- (4-chloro-6-methylthieno [2,3-d] -pyrimidin-2-yl) butyrate to methyl 4- [4-benzylamino-6-methylthieno [2,3 -d] pyrimidin-2-yl] butyrate;
[456] By reaction with methyl 5- (4-chloro-6-ethylthieno [2,3-d] -pyrimidin-2-yl) valericate methyl 5- [4-benzylamino-6-ethylthieno [2, 3-d] pyrimidin-2-yl] valerate is obtained.
[457] Example 2
[458] Methyl 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl ] 2.2 g propionate is dissolved in 20 ml ethylene glycol monomethyl ether, 10 ml 32% NaOH are added and the mixture is stirred at 110 ° for 5 hours. After addition of 20% HCl, the mixture is extracted with dichloromethane. Petroleum ether is added to 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- 2.0 g of [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid (mp 229 °) are obtained.
[459] The precipitated crystals are dissolved in 30 ml of isopropanol and 0.5 g of ethanolamine is added. 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2 via crystallization 1.3 g of -yl] propionic acid, ethanolamine salt (mp 135 °) are obtained.
[460] In a similar reaction with the esters listed in Example 1, the following carboxylic acids
[461] 3- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid;
[462] 3- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid;
[463] 3- [4- (3-chloro-4-methoxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
[464] 3- [4- (3-chloro-4-methoxybenzylamino) -5,6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
[465] 3- [4- (3-chloro-4-methoxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
[466] 3- [4- (3-chloro-4-methoxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionic acid;
[467] 2- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] Acetic acid, ethanolamine salt, mp 126 °;
[468] 3- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid ;
[469] 3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid;
[470] 3- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid;
[471] 3- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
[472] 3- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
[473] 3- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] propionic acid;
[474] 3- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] propionic acid;
[475] 4- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] Butyric acid;
[476] 4- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;
[477] 4- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;
[478] 4- [4- (3-chloro-4-methoxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, m.p. 142 °;
[479] 4- [4- (3-chloro-4-methoxybenzylamino) -5,6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
[480] 4- [4- (3-chloro-4-methoxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, m.p. 170 °;
[481] 4- [4- (3-chloro-4-methoxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyric acid;
[482] 4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyric acid , Ethanolamine salt, mp 114 °;
[483] 4- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;
[484] 4- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyric acid;
[485] 4- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, m.p. 170 °;
[486] 4- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
[487] 4- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
[488] 4- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] butyric acid;
[489] 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] Valeric acid, mp 165 °; Ethanolamine salt, m.p. 112 °;
[490] 5- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric acid;
[491] 5- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric acid;
[492] 5- [4- (3-chloro-4-methoxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, m.p. 156 °;
[493] 5- [4- (3-chloro-4-methoxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
[494] 5- [4- (3-chloro-4-methoxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, m.p. 156 °;
[495] 5- [4- (3-chloro-4-methoxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valeric acid;
[496] 5- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] baller mountain;
[497] 5- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric acid;
[498] 5- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric acid;
[499] 5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, m.p. 167 °;
[500] 5- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
[501] 5- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
[502] 5- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] valeric acid;
[503] 7- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] Heptanoic acid, ethanolamine salt, mp 130 °;
[504] 7- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[505] 7- [4- (3-chloro-4-methoxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[506] 7- [4- (3-chloro-4-methoxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[507] 7- [4- (3-chloro-4-methoxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[508] 7- [4- (3-chloro-4-methoxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[509] 7- [4- (3-chloro-4-methoxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[510] 7- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptane Acid, ethanolamine salt, mp 137 °;
[511] 7- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclopenteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[512] 7- [4- (3,4-methylenedioxybenzylamino) -5,6-cyclohepteno- [1] -benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[513] 7- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
[514] 7- [4- (3,4-methylenedioxybenzylamino) -5,6-dimethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[515] 7- [4- (3,4-methylenedioxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[516] 7- [4- (3,4-methylenedioxybenzylamino) -6-chlorothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[517] 2- {4- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2 -Yl] cyclohexyl} acetic acid;
[518] 2- {4- [4- (3-chloro-4-methoxybenzylamino) -6-ethylthieno [2,3-d] pyrimidin-2-yl] cyclohexyl} acetic acid;
[519] 2- {4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2- General] cyclohexyl} acetic acid;
[520] 3- (4-benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionic acid, ethanolamine salt, m.p. 126 °;
[521] 4- (4-benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, m.p. 133 °;
[522] 5- (4-benzylamino-5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, mp 135 ° ;
[523] 4- [4-benzylamino-6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid, ethanolamine salt, m.p. 165 °;
[524] 5- [4-benzylamino-6-ethylthieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, m.p. Get 162 °.
[525] Example 3
[526] 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] 1 equivalent of propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. Remove the solvent, 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine 2-yl] propionyl chloride is obtained.
[527] The product was transferred into an aqueous ammonia solution and the mixture was stirred for one hour and the usual reaction finishes to yield 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] propionamide is obtained.
[528] Example 4
[529] At 0 ° 1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile. Then 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2- 1 equivalent of general] propionamide is added. The mixture is stirred for an additional hour. Finishing the usual reaction, 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyridine Midin-2-yl] propionitrile is obtained.
[530] Example 5
[531] Similar to Examples 1 and 2, the following compounds:
[532] 6- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] Hexanoic acid, mp165 °;
[533] 2- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] Propionic acid, ethanolamine salt, mp150 °;
[534] 4- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] 2,2-dimethylbutyric acid, ethanolamine salt, mp130 °;
[535] 4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] 2 , 2-dimethylbutyric acid, ethanolamine salt, mp126 °;
[536] 5- [4- (3-chloro-4-hydroxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] Valeric acid, mp179 °;
[537] 5- [4- (3,4-dichlorobenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, Ethanolamine salt, mp136 °;
[538] 5- [4- (3-chloro-4-isopropyloxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidin-2-yl Valeric acid, ethanolamine salt, mp118 °;
[539] 2- [4- (4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2 -Yl) phenyl] acetic acid, ethanolamine salt, mp119 °;
[540] 2- [4- (4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2- (I) phenyl] acetic acid, mp214 °.
[541] The following examples pertain to pharmaceutical formulations:
[542] Example A: Vials for Injection
[543] Using 2N hydrochloric acid to adjust the pH of 100 g of the active ingredient of formula II, 100 g of nitrate and 5 g of sodium diphosphate in 3 l of secondary distilled water to 6.5, sterile filtered, transferred to an injection vial, sterile conditions Lyophilized under and sealed under sterile conditions. Each injectable vial contains 5 mg of active ingredient.
[544] Example B: Suppositories
[545] A mixture of 20 g of the active ingredient of formula (I-II) and 20 g of nitrate is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into a mold and cooled. Each suppository contains 20 mg of active ingredient.
[546] Example C: Solution
[547] In 940 ml of secondary distilled water, 1 g of active ingredient of formula II, 1 g of nitrate, 9.38 g of NaH ₂ PO ₄ 2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ O, and 0.1 g of benzalkonium chloride were added to the solution. Manufacture. The pH is adjusted to 6.8 and the solution is brought to 1 L and sterilized by irradiation. This solution can be used in the form of eye drops.
[548] Example D: Ointment
[549] Under aseptic conditions 500 mg of the active ingredient of formula I-I and 500 mg of nitrate are mixed with 99.5 g of petrolatum.
[550] Example E: Tablets
[551] A mixture of 1 kg of active ingredient of formula II, 1 g of nitrate, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate, is compressed in a conventional manner so that each tablet contains 10 mg of active ingredient To obtain tablets.
[552] Example F: Tablets
[553] Similar to Example E, the tablets are compressed and then coated by coating with sucrose, potato starch, talc, tragacanth and dye in a conventional manner.
[554] Example G: Capsule
[555] 2 kg of the active ingredient of formula (I-I) and 2 kg of nitrate are introduced into the hard gelatin capsule in a conventional manner such that each capsule contains 20 mg of the active ingredient.
[556] Example H: Ampoules
[557] A solution of 1 kg of the active ingredient of Formula I-I and 1 kg of nitrate in 60 l of secondary distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
[558] Example I: Inhalation Spray
[559] 14 g of the active ingredient of formula (I-I) and 14 g of nitrate are dissolved in 10 l of NaCl isotonic solution and the solution is transferred into a commercial spray vessel with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (about 0.1 mL) corresponds to an active ingredient dose of about 0.14 mg.
[560] Compound of Formula I-II
[561] The compound of formula (I-II) and salts thereof according to claim 1,
[562] a) a compound of formula II-II:
[563]
[564] (Wherein
[565] X is as defined above,
[566] L is Cl, Br, OH, SCH ₃ or a reactive esterified OH group)
[567] To the compound of formula III:
[568] [Formula III]
[569]
[570] (Wherein
[571] R ¹ and R ² are as defined above)
[572] Or react with
[573] b) converting radical X in the compound of formula (I-II) to another radical X, for example by hydrolyzing an ester group with a COOH group or by converting a COOH group with an amide or cyano group,
[574] And / or converting a compound of formula (I-II) to one of its salts.
[575] The term solvate of a compound of formula (I-II) is considered to mean an adduct of inert solvent molecules to the compound of formula (I-II) formed due to their mutual attraction. For example, the solvate is a monohydrate or dihydrate or alcoholate.
[576] Above and below, unless stated otherwise, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X and L are as defined in formulas I-II, II-II and III same.
[577] A is alkyl having 1 to 6 carbon atoms.
[578] In the above formula, alkyl is preferably straight chain and has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl or propyl, and also preferably isopropyl, butyl, isobutyl, secondary- Butyl or tert-butyl, also n-pentyl, neopentyl, isopentyl or hexyl.
[579] X is a R ⁴ , R ⁵ or R ⁶ radical mono-substituted by R ⁷ .
[580] R ⁴ is preferably an alkylene radical, for example methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary-butylene, pentylene, 1-, 2- or 3-methylbutyl Ethylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2 -, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methyl Linear or branched alkylene having 1 to 10 carbon atoms, which is propylene, 1,1,2- or 1,2,2-trimethylpropylene, straight or branched heptylene, octylene, nonylene or decylene.
[581] R ⁵ is also, for example, but-2-enylene or hex-3-enylene.
[582] Very particular preference is given to ethylene, propylene or butylene.
[583] R ⁵ is cycloalkylalkylene having 5 to 12 carbon atoms, preferably cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
[584] R ⁵ is optionally preferably cycloalkyl having 5 to 7 carbon atoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
[585] Hal is preferably F, Cl or Br, optionally I.
[586] R ¹ and R ² are the same or different and are preferably present in the 3- or 4-position of the phenyl ring. These are, for example, independently of each other in each case, H, hydroxyl, alkyl, F, Cl, Br or I, or together, for example, alkylene such as propylene, butylene or pentylene, also ethyleneoxy, methylene Dioxy or ethylenedioxy. These are optionally preferably each alkoxy such as, for example, methoxy, ethoxy or propoxy.
[587] The radical R ⁷ is preferably, for example, COOH, COOCH ₃ , COOC ₂ H ₅ , CONH ₂ , CON (CH ₃ ) ₂ , CONHCH ₃ or CN.
[588] For the whole invention, all radicals which occur more than once may be identical or different, ie independent of one another.
[589] The present invention particularly relates to pharmaceutical compositions in which the nitrate and at least one of said radicals comprises at least one compound of formula (I-II) having one of the preferred meanings indicated above. Preferred groups of the compound may be represented by the following partial formulas Ia to Ie, which are consistent with formulas I-II, and radicals not specified in more detail are as defined in formulas I-II,
[590] In Ia,
[591] X is R ⁴ , phenyl or phenylmethyl, each substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN;
[592] In Ib,
[593] R ¹ and R ² together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O—, or —O—CH ₂ —CH ₂ —O,
[594] X is R ⁴ , phenyl or phenylmethyl, each substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN;
[595] In Ic,
[596] R ¹ and R ² are each independently H, A, OA or Hal,
[597] R ¹ and R ² together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O—, or —O—CH ₂ —CH ₂ —O,
[598] X is R ⁴ , phenyl or phenylmethyl, each substituted by COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN;
[599] In Id,
[600] R ¹ and R ² are each independently H, A, OA or Hal,
[601] R ¹ and R ² together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[602] X is each alkylene, cyclohexyl, phenyl or phenylmethyl having 2 to 5 carbon atoms monosubstituted by R ⁷ ,
[603] R ⁷ is COOH or COOA,
[604] A is alkyl having 1 to 6 carbon atoms,
[605] Hal is F, Cl, Br or I;
[606] In Ie,
[607] R ¹ and R ² are each independently H, A, OA or Hal,
[608] R ¹ and R ² together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
[609] X is each alkylene, cyclohexyl, phenyl or phenylmethyl having 2 to 5 carbon atoms monosubstituted by R ⁷ ,
[610] R ⁷ is COOH or COOA,
[611] A is alkyl having 1 to 6 carbon atoms,
[612] Hal is F, Cl, Br or I.
[613] The present invention preferably provides [4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexane-carboxylic acid and its physiology. It relates to a composition comprising a scientifically acceptable salt and / or solvate and one or more nitrates. In addition to the free acid, ethanolamine salts are also preferred.
[614] Preference is given to nitrates selected from the group consisting of pentaerythritol tetranitrate, trinitrate, dinitrate and mononitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate.
[615] Particular preference is given to nitrates selected from the group consisting of pentaerythritol tetranitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate, with very particular preference to pentaerythritol tetranitrate .
[616] Compounds of formula (I-II) and starting materials for their preparation can also be found in standard workbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie, Georg-Tieme-Verlag, Stuttgart. The reaction is known by the method per se and is accurately prepared under suitable reaction conditions as described in < RTI ID = 0.0 > Modifications known per se but not mentioned in detail herein may also be used.
[617] In the compounds of the formulas II-II or III, R ¹ , R ² , R ³ , R ⁴ , X and n have the meanings indicated, in particular the preferred meanings given.
[618] When L is a reactive esterified OH group, it is preferably alkylsulfonyloxy (preferably methylsulfonyloxy) having 1 to 6 carbon atoms or arylsulfonyloxy (preferably phenyl- or p-) having 6 to 10 carbon atoms. Tolylsulfonyloxy, also 2-naphthalenesulfonyloxy).
[619] The compound of formula (I-II) can preferably be obtained by a method of reacting a compound of formula (II-II) with a compound of formula (III).
[620] If necessary, the starting material can be formed in situ by it not being separated from the reaction mixture but instead immediately further converted to the compound of formula (I-II). On the other hand, sequential reactions can also be carried out.
[621] Starting compounds of the compounds of the formulas II-II and III are generally known. If they are not known, they can be produced by methods known per se. Compounds of formula II-II can be prepared, for example, by reacting POCl ₃ with a corresponding hydroxypyrimidine prepared from thiophene derivatives and CN-substituted alkylenecarboxylic acid esters. (Eur. Med. Chem. 23 , 453 (1988)).
[622] The hydroxypyrimidines dehydrogenate the corresponding tetrahydrobenzothienopyrimidine compounds or ring 2-aminobenzothiophene-3-carboxylic acid derivatives using common aldehydes or nitriles for the production of pyrimidine derivatives. Is prepared by, for example, Houben Weyl E9b / 2.
[623] Specifically, the compound of formula II-II is reacted with a compound of formula III at a temperature of about -20 to 150 °, preferably 20 to 100 °, in the presence or absence of an inert solvent.
[624] Addition of acid-binding agents, for example alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of weak acids of alkali or alkaline earth metals, preferably potassium, sodium or calcium, or triethylamine, dimethylamine, pyridine or The addition of quinoline or excess amine compound may be advantageous.
[625] Examples of suitable inert solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, or mixtures of these solvents.
[626] It is also possible, for example, to hydrolyze an ester or cyano group to produce a COOH group, thereby converting radical X in the compound of formula I-II to another radical X.
[627] For example, at temperatures from 0 to 100 °, NaOH or KOH in water, water / THF or water / dioxane can be used to saponify ester groups. For example, thionyl chloride can be used to convert the carboxylic acid to the corresponding carbonyl chloride, which can be converted to the carboxamide. Water is removed by known methods to obtain carbonitrile.
[628] For example, the base can be used to convert the acid of Formula I-II to the related acid-addition salt by reacting an equal amount of acid with a base in an inert solvent such as ethanol and then evaporating. Suitable bases for this reaction are, in particular, bases which give physiologically acceptable salts.
[629] Thus, a base (eg, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) can be used to convert the acid of formula (I-II) to the corresponding metal salt, in particular alkali or alkaline earth metal salts, or corresponding ammonium salts. have. Also particularly suitable are organic bases which produce physiologically acceptable salts such as, for example, ethanolamine.
[630] For example, the base can be used to convert the acid of Formula I-II to the related acid-addition salt by reacting an equal amount of acid with a base in an inert solvent such as ethanol and then evaporating. Suitable bases for this reaction are, in particular, bases which give physiologically acceptable salts.
[631] Thus, a base (eg, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) can be used to convert the acid of formula (I-II) to the corresponding metal salt, in particular alkali or alkaline earth metal salts, or corresponding ammonium salts. have. Also particularly suitable are organic bases which produce physiologically acceptable salts such as, for example, ethanolamine.
[632] On the other hand, the base of formula (I-II) can be converted to the related acid-addition salt using the acid by, for example, reacting and then evaporating the acid with an equivalent amount of base in an inert solvent such as ethanol. Acids suitable for this reaction are, in particular, acids which produce physiologically acceptable acids. Thus, for example, hydrofluoric acid such as sulfuric acid, nitric acid, hydrochloric acid or bromic acid, phosphoric acid such as orthophosphoric acid, inorganic acids such as sulfamic acid, and also organic acids, especially aliphatic, cycloaliphatic, aromatic aliphatic, aromatic or heterocyclic monobasics or poly Base carboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid Acids, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and -disulfonic acid, or lauryl sulfate. For example, salts with physiologically unacceptable acids such as picrates may be used for the separation and / or purification of the compounds of formula (I-II).
[633] The present invention also comprises a pharmaceutical composition comprising one or more nitrates and one or more excipients and / or adjuvants, comprising one or more compounds of formula (I-II), and / or physiologically acceptable salts thereof. It is about.
[634] The pharmaceutical preparations are prepared in particular by non-chemical means and the active ingredient is converted into a suitable dosage form together with one or more solid, liquid and / or semi-liquid excipients or adjuvants.
[635] Such agents may be used as medicaments in human or animal medicine. Suitable excipients are suitable for enteral (eg oral), parenteral or topical administration and include, for example, water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, lactose Or organic or inorganic materials that do not react with new compounds such as carbohydrates such as starch, magnesium stearate, talc or petrolatum. In particular, tablets, pills, tablets, capsules, powders, granules, syrups, juices or drops are suitable for oral administration, suppositories are suitable for rectal administration, solutions, preferably oil-based solutions or aqueous solutions, also suspensions, Emulsions or implants are suitable for parenteral administration, and ointments, creams or powders are suitable for topical administration. The new compound may be lyophilized and the injection may be prepared, for example, using the resulting lyophilized product. The formulations are sterilized and / or a number of additional active ingredients such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for controlling osmotic pressure, buffers, colorants and flavors and / or for example one or more vitamins. It may include an adjuvant such as They can also be administered by nasal spray.
[636] In general, the substance is preferably administered at a dosage of about 1 to 500 mg, in particular 5 to 100 mg, per dosage unit. The daily dosage is preferably about 0.02 to 10 mg per kg of body weight. However, the specific dosage for each patient is, for example, the efficacy, age, weight, general state of health, sex, diet, time and method of administration, rate of excretion, combination of medications and therapies to which the particular compound used is applied. This depends on a variety of factors, such as the severity of the particular disease. Oral administration is preferred.
[637] The present invention relates in particular to the use of a composition according to the invention for the preparation of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[638] The present invention also provides one or more phosphodiesterase V inhibitors and one or more for the manufacture of a medicament for oral treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure. It relates to the use of a pharmaceutical preparation comprising a prostaglandin or prostaglandin derivative.
[639] The components of the novel pharmaceutical formulations above are preferably administered in combination. However, they may be administered separately or simultaneously or sequentially.
[640] The invention also
[641] (a) an effective amount of [4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid, ethanolamine salt,
[642] And
[643] (b) effective amount of nitrate
[644] A set (kit) consisting of individual packages of.
[645] The present invention is particularly intended for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[646] (a) an effective amount of [4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid, ethanolamine salt,
[647] And
[648] (b) effective amount of nitrate
[649] A set (kit) consisting of individual packages of.
[650] The set comprises a suitable container, such as a box, individual bottle, box, bag or ampoule. This set is, for example, an effective amount of [4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid, respectively, Ethanolamine salts, and individual ampoules containing nitrate in dissolved or lyophilized form.
[651] Above and below, all temperatures are given in degrees Celsius. In the examples which follow, "normal reaction finishing" is carried out by adding water if necessary, adjusting the pH to 2 to 10 if necessary according to the composition of the final product, extracting the mixture with ethyl acetate or dichloromethane, and Is separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography and / or crystallization on silica gel.
[652] Mass Spectrometry (MS): Electron Impact Ionization (EI) M ⁺
[653] Fast Atomic Impact (FAB) (M + H) ⁺
[654] Example 1
[655] Methyl 3- (4-chlorobenzothieno [2,3-d] -pyrimidin-2-yl) propionate [methyl 2-amino-5,6,7,8-tetra in N-methylpyrrolidone Prepared by cyclization of hydrobenzothiophene-3-carboxylate with methyl 3-cyanopropionate, dehydrogenation with sulfur and chlorination with phosphorus oxychloride / dimethylamine] and 3 -Chloro-4-methoxybenzylamine ("A") is stirred at 110 ° for 5 hours. The solvent was removed, and the mixture was finished with a usual reaction to yield methyl 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl as colorless oil. ] Propionate is obtained.
[656] Similarly, "A" is reacted with methyl 2- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) acetate to give methyl 2- [4- (3-chloro-4-meth Obtain oxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] acetate.
[657] Similarly, 3,4-methylenedioxybenzylamine is reacted with methyl 3- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) propionate to methyl 3- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionate is obtained.
[658] Similarly, reacting “A” with methyl 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) butyrate to methyl 4- [4- (3-chloro-4-meth Oxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyrate is obtained.
[659] Similarly, 3,4-methylenedioxybenzylamine is reacted with methyl 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) butyrate to methyl 4- [4- (3 , 4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyrate is obtained.
[660] Similarly, "A" is reacted with methyl 5- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) valeric to give methyl 5- [4- (3-chloro-4- Obtain methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric.
[661] Similarly, 3,4-methylenedioxybenzylamine is reacted with methyl 5- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) valerate to give methyl 5- [4- ( 3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric is obtained.
[662] Similarly, "A" is reacted with methyl 7- (4-chlorobenzothieno [2,3-d] -pyrimidin-2-yl) heptanoate to give methyl 7- [4- (3-chloro-4 -Methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoate is obtained.
[663] Similarly, 3,4-methylenedioxybenzylamine is reacted with methyl 7- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) heptanoate to methyl 7- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoate is obtained.
[664] Similarly, "A" is reacted with methyl 2- [4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -cyclohex-1-yl] acetate to yield methyl 2- { 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetate is obtained.
[665] Similarly, 3,4-methylenedioxybenzylamine is substituted with methyl 2- [4- (4-chlorobenzothieno [2,3-d] -pyrimidin-2-yl) -cyclohex-1-yl]- Reacted with acetate to methyl 2- {4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetate Get
[666] Similarly, benzylamine
[667] Methyl 3- (4-benzylamino-benzothieno [2,3-d] by reaction with methyl 3- (4-chlorobenzothieno [2,3-d] -pyrimidin-2-yl) propionate Obtaining pyrimidin-2-yl) propionate;
[668] Methyl 4- (4-benzylamino-benzothieno [2,3-d] pyrimidine by reaction with methyl 4- (4-chlorobenzothieno [2,3-d] -pyrimidin-2-yl) butyrate 2-yl) butyrate;
[669] Methyl 5- (4-benzylamino-benzothieno [2,3-d] pyridine by reaction with methyl 5- (4-chlorobenzothieno [2,3-d] -pyrimidin-2-yl) valeric Midin-2-yl) valerate.
[670] Similarly, "A"
[671] Methyl 4- [4- (3-chloro-4-methoxy by reaction with methyl 4- (4-chlorobenzothieno [2,3-d] -pyrimidin-2-yl) -cyclohexane-carboxylate Benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylate;
[672] 3,4-methylenedioxybenzylamine is reacted to methyl 4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarbox Obtain a carboxylate.
[673] Example 2
[674] Methyl 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionate is dissolved in ethylene glycol monomethyl ether, 32% NaOH is added and the mixture is stirred at 110 ° for 5 hours. After addition of 20% HCl, the mixture is extracted with dichloromethane. Petroleum ether is added to give 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid (m.p 218 °).
[675] Precipitated crystals are dissolved in isopropanol and ethanolamine is added. Crystallization gives 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid, ethanolamine salt.
[676] In a similar reaction the following compounds:
[677] 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid, m.p.225 °, ethanolamine salt m.p.150 °;
[678] 5- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, m. P. 210 °, ethanolamine salt m. P. 141 °;
[679] 4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid, hydrochloride m.p.245 ° is obtained.
[680] Carboxylic Acids Following Reactions Similarly to the Esters Listed in Example 1
[681] 2- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] acetic acid;
[682] 3- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid,
[683] 5- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid,
[684] 7- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
[685] 7- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
[686] 2- {4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,
[687] 2- {4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,
[688] 3- (4-benzylamino-benzothieno [2,3-d] pyrimidin-2-yl) propionic acid,
[689] 4- (4-benzylamino-benzothieno [2,3-d] pyrimidin-2-yl) butyric acid,
[690] 5- (4-benzylamino-benzothieno [2,3-d] pyrimidin-2-yl) valeric acid,
[691] 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid, ethanolamine salt, m.p. 167 °;
[692] 4- [4- (3,4-methylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid, ethanolamine salt, m.p. Get 143 °.
[693] Example 3
[694] Methyl 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) -phenylcarboxylate ("B") in 20 ml of N-methylpyrrolidone, corresponding to sulfur 1.5 g and 3-chloro-4) prepared by dehydrogenating the 5,6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine compound followed by chlorination with phosphorus oxychloride / dimethylamine) 1.5 g of methoxybenzylamine are heated at 110 ° for 4 hours. After cooling, the mixture was finished with a conventional reaction to afford methyl 4- [4- (3-chloro-4-methoxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidine-2. -Yl] benzoate 2.6 g are obtained (mp 203-204 °).
[695] Similar to Example 2, 4- [4- (3-chloro-4-methoxybenzylamino)-[1] -benzothieno [2,3-d] -pyrimidin-2-yl with 1.2 g of ester ] Benzoic acid, ethanolamine salt, mp 189-190 °, 1.0 g is obtained.
[696] Similar to Example 1, methyl 4- [4- (3,4-methylenedioxybenzylamino)-[1] -benzothieno [2,3 with "B" and 3,4-methylenedioxybenzylamine -d] -pyrimidin-2-yl] benzoate, which is ester hydrolyzed to 4- [4- (3,4-methylenedioxybenzylamino)-[1] -benzothieno [2,3- d] -pyrimidin-2-yl] benzoic acid, sodium salt, mp> 260 °.
[697] In a similar reaction, the compound:
[698] 4- [4- (3-chloro-4-methoxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid, ethanolamine salt, m.p. 130 °;
[699] And
[700] 4- [4- (3,4-methylenedioxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid, ethanolamine salt, mp202 ° Get
[701] Example 4
[702] 1 equivalent of 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid and 1.2 equivalents of thionyl chloride were dichloromethane over 2 hours. Stir in the middle. Remove the solvent to afford 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionyl chloride.
[703] The product was transferred into an aqueous ammonia solution and the mixture was stirred for one hour and the usual reaction finishes to yield 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidine 2-yl] propionamide is obtained.
[704] Example 5
[705] At 0 ° 1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile. Then 1 equivalent of 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionamide is added. The mixture is stirred for an additional hour. Normal reaction is completed to obtain 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionitrile.
[706] Example 6
[707] Similar to Examples 1, 2 and 3, the corresponding chloro-pyrimidine derivatives were reacted with 3,4-ethylenedioxybenzylamine to
[708] 4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,
[709] 3- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid,
[710] 5- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid,
[711] 7- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
[712] 2- {4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,
[713] 4- [4- (3,4-ethylenedioxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid,
[714] 4- [4- (3,4-ethylenedioxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid, decomposed. 220-230 °;
[715] 4- [4- (3,4-ethylenedioxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid, ethanolamine salt, m. P. 252 °;
[716] 4- [4- (3,4-ethylenedioxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid is obtained.
[717] Similarly, by reacting with 3,4-dichlorobenzylamine the following compounds:
[718] 4- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,
[719] 3- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid,
[720] 5- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, m.p. 160 °;
[721] 7- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
[722] 2- {4- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,
[723] 4- [4- (3,4-dichlorobenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid,
[724] 4- [4- (3,4-dichlorobenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid,
[725] 4- [4- (3,4-dichlorobenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid is obtained.
[726] Similarly, by reacting with 3-chloro-4-ethoxybenzylamine the following compounds:
[727] 4- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,
[728] 3- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid,
[729] 5- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid,
[730] 7- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
[731] 2- {4- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,
[732] 4- [4- (3-chloro-4-ethoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid,
[733] 4- [4- (3-chloro-4-ethoxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid, m.p. 185-187 °;
[734] 4- [4- (3-chloro-4-ethoxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid is obtained.
[735] Similarly, by reacting with 3-chloro-4-isopropoxybenzylamine the following compounds:
[736] 4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,
[737] 3- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid,
[738] 5- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid, ethanolamine salt, m.p. 130 °;
[739] 7- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
[740] 2- {4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid,
[741] 4- [4- (3-chloro-4-isopropoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid,
[742] 4- [4- (3-Chloro-4-isopropoxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid, m.p. 240-241 °;
[743] 4- [4- (3-chloro-4-isopropoxybenzylamino)-[1] -benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid is obtained.
[744] The following examples pertain to pharmaceutical formulations:
[745] Example A: Vials for Injection
[746] Using 2N hydrochloric acid, the pH of 100 g of the active ingredient of formula I-II, 100 g of nitrate and 5 g of sodium diphosphate in 3 l of secondary distilled water was adjusted to 6.5, sterile filtered and transferred to an injection vial, Lyophilized under sterile conditions and sealed under sterile conditions. Each injectable vial contains 5 mg of active ingredient.
[747] Example B: Suppositories
[748] A mixture of 20 g of the active ingredient of formula I-II and 20 g of nitrate is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into a mold and cooled. Each suppository contains 20 mg of active ingredient.
[749] Example C: Solution
[750] In 940 ml of secondary distilled water, 1 g of active ingredient of Formula I-II, 1 g of nitrate, 9.38 g of NaH ₂ PO ₄ 2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ O and 0.1 g of benzalkonium chloride were added. Prepare a solution. The pH is adjusted to 6.8 and the solution is brought to 1 L and sterilized by irradiation. This solution can be used in the form of eye drops.
[751] Example D: Ointment
[752] Under aseptic conditions 500 mg of the active ingredient of formula I-II and 500 mg of nitrate are mixed with 99.5 g of petrolatum.
[753] Example E: Tablets
[754] A mixture of 1 kg of active ingredient of Formula I-II, 1 g of nitrate, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate, is prepared in a conventional manner so that each tablet comprises 10 mg of active ingredient Compressed to obtain tablets.
[755] Example F: Tablets
[756] Similar to Example E, the tablets are compressed and then coated by coating with sucrose, potato starch, talc, tragacanth and dye in a conventional manner.
[757] Example G: Capsule
[758] 2 kg of the active ingredient of Formula I-II and 2 kg of nitrate are introduced into the hard gelatin capsule in a conventional manner such that each capsule contains 20 mg of the active ingredient.
[759] Example H: Ampoules
[760] A solution of 1 kg of the active ingredient of formula I-II and 1 kg of nitrate in 60 l of secondary distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
[761] Example I: Inhalation Spray
[762] 14 g of active ingredient of Formula I-II and 14 g of nitrate are dissolved in 10 L of NaCl isotonic solution and the solution is transferred into a commercial spray vessel with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (about 0.1 mL) corresponds to an active ingredient dose of about 0.14 mg.

权利要求:
Claims (43)
[1" claim-type="Currently amended] Eczema, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart, right heart failure, atherosclerosis, reduced cardiovascular condition, peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma At least one compound of formula (I) for the manufacture of a medicament for the treatment of allergic rhinitis, glaucoma, irritable bowel syndrome, tumor, renal failure and cirrhosis:
[Formula I]
(Wherein
R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
R ¹ and R ² together may optionally be alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —CH ₂ —O—CH ₂ —, —O—CH ₂ —O— or —O—CH; ₂ -CH ₂ -O-,
R ³ and R ⁴ are each independently H or A,
X is each R ⁵ , R ⁶ or R ⁷ monosubstituted by R ⁸ ,
R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms, in which one or two CH ₂ groups may be replaced by a —CH═CH— group, O, S or SO,
R ⁶ is cycloalkyl or cycloalkylalkylene having 5 to 12 carbon atoms,
R ⁷ is phenyl or phenylmethyl,
R ⁸ is COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,
A is alkyl having 1 to 6 carbon atoms,
Hal is F, Cl, Br or I)
And / or a physiologically acceptable salt and / or solvate thereof and one or more nitrates.
[2" claim-type="Currently amended] The method of claim 1,
A pharmaceutical composition comprising at least one compound of formula I according to claim ₁ , wherein X is R ⁵ , phenyl or phenylmethyl, each substituted with COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN .
[3" claim-type="Currently amended] The method of claim 1,
R ¹ and R ² together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
A pharmaceutical composition comprising at least one compound of formula I according to claim ₁ , wherein X is R ⁵ , phenyl or phenylmethyl, each substituted with COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN .
[4" claim-type="Currently amended] The method of claim 1,
R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
A pharmaceutical composition comprising at least one compound of formula I according to claim ₁ , wherein X is R ⁵ , phenyl or phenylmethyl, each substituted with COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN .
[5" claim-type="Currently amended] The method of claim 1,
R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
X is each alkylene, cyclohexyl, phenyl or phenylmethyl having 2 to 5 carbon atoms monosubstituted by R ⁸
R ³ is alkyl having 1 to 6 carbon atoms,
R ⁴ is alkyl having 1 to 6 carbon atoms,
R ⁸ is COOH or COOA,
A is alkyl having 1 to 6 carbon atoms,
Hal is a pharmaceutical composition comprising at least one compound of formula I according to claim 1, characterized in that F, Cl, Br or I.
[6" claim-type="Currently amended] The method of claim 1,
R ¹ and R ² are each independently of each other H, A, OH, OA or Hal,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
R ³ is alkyl having 1 to 6 carbon atoms,
R ⁴ is alkyl having 1 to 6 carbon atoms,
X is — (CH ₂ ) _2-5 —R ⁸ where one CH ₂ group may be replaced with O, or 4-R ⁸ -cyclohexyl, 4-R ⁸ -phenyl or 4- (R ⁸ -methyl) phenyl ego,
R ⁸ is a pharmaceutical composition comprising at least one compound of formula I according to claim 1, characterized in that COOH or COOA.
[7" claim-type="Currently amended] The method of claim 1,
(a) 5- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] pentanoic acid ;
(b) 4- [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] benzoic acid;
(c) 4- [7- (3,4-methylenedioxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] butyric acid;
(d) 5- [7- (benzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl] pentanoic acid;
(e) [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid A pharmaceutical composition comprising one or more compounds of formula (I) according to claim 1 selected from the group consisting of:
[8" claim-type="Currently amended] The method of claim 1,
[7- (3-Chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid, ethanolamine salt Pharmaceutical composition comprising a.
[9" claim-type="Currently amended] The method according to any one of claims 1 to 8,
The nitrate is selected from the group consisting of pentaerythryl tetranitrate, trinitrate, dinitrate and mononitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate Pharmaceutical composition.
[10" claim-type="Currently amended] The method of claim 9,
Pharmaceutical composition, characterized in that the nitrate is pentaerythryl tetranitrate, isosorbide mononitrate, isosorbide dinitrate or glycerol trinitrate.
[11" claim-type="Currently amended] The method of claim 10,
Pharmaceutical composition, characterized in that the nitrate is pentaerythryl tetranitrate.
[12" claim-type="Currently amended] The method according to any one of claims 1 to 11,
A pharmaceutical composition comprising one or more excipients and / or adjuvants.
[13" claim-type="Currently amended] The method according to any one of claims 1 to 12,
Pharmaceutical compositions for the manufacture of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[14" claim-type="Currently amended] (a) an effective amount of [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid Ethanolamine salts,
And
(b) effective amount of nitrate
A set (kit) consisting of individual packages of.
[15" claim-type="Currently amended] For the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure
(a) an effective amount of [7- (3-chloro-4-methoxybenzylamino) -1-methyl-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-ylmethoxy] acetic acid Ethanolamine salts,
And
(b) effective amount of nitrate
A set (kit) consisting of individual packages of.
[16" claim-type="Currently amended] Eczema, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart, right heart failure, atherosclerosis, reduced cardiovascular condition, peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma At least one compound of formula (II) for the manufacture of a medicament for the treatment of allergic rhinitis, glaucoma, irritable bowel syndrome, tumor, renal failure and cirrhosis:
[Formula I-I]
(Wherein
R ¹ and R ² are each independently of each other H, A or Hal, and one of the radicals R ¹ and R ² is not always H,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms,
R ³ and R ⁴ are each independently of each other H, A, OH, OA or Hal,
R ³ and R ⁴ together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
X is each R ⁵ or R ⁶ monosubstituted by R ⁷ ,
R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms, or one of two CH ₂ groups, which may be replaced with a —CH═CH— group, or —C ₆ H ₄ — (CH ₂ ) _m −,
R ⁶ is cycloalkylalkylene having 6 to 12 carbon atoms,
R ⁷ is COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,
A is alkyl having 1 to 6 carbon atoms,
Hal is F, Cl, Br or I,
m is 1 or 2,
n is 0, 1, 2 or 3)
And / or a physiologically acceptable salt and / or solvate thereof and one or more nitrates.
[17" claim-type="Currently amended] The method of claim 16,
A pharmaceutical composition comprising at least one compound of formula (II) according to claim 16, characterized in that X is R ⁵ or R ⁶ , each substituted with COOH or COOA.
[18" claim-type="Currently amended] The method of claim 16,
R ¹ and R ² are each independently of each other H, A or Hal, and one of the radicals R ¹ and R ² is not always H,
R ³ and R ⁴ together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
A pharmaceutical composition comprising at least one compound of formula (II) according to claim 16, characterized in that X is R ⁵ or R ⁶ , each substituted by COOH or COOA.
[19" claim-type="Currently amended] The method of claim 16,
R ¹ and R ² are each independently of each other H, A or Hal, and at least one of the radicals R ¹ and R ² is not always H,
R ³ and R ⁴ are each independently of each other H, A, OA or Hal,
R ³ and R ⁴ together are alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
X is R ⁵ or R ⁶ , each substituted by COOH or COOA,
A pharmaceutical composition comprising at least one compound of formula (I-I) according to claim 16, characterized in that n is 1 or 2.
[20" claim-type="Currently amended] The method of claim 16,
R ¹ and R ² are each independently of each other H, A or Hal, and one of the radicals R ¹ and R ² is not always H,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms,
R ³ and R ⁴ are each independently of each other H, A, OA or Hal,
R ³ and R ⁴ together are optionally —O—CH ₂ —O—,
X is R ⁵ monosubstituted by R ⁷ ,
R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms, or —C ₆ H ₄ —CH ₂ —,
R ⁷ is COOH or COOA,
A is alkyl having 1 to 6 carbon atoms,
Hal is F, Cl, Br or I,
m is 1,
A pharmaceutical composition comprising at least one compound of formula (I-I) according to claim 16, characterized in that n is 1 or 2.
[21" claim-type="Currently amended] The method of claim 16,
R ¹ and R ² are each independently of each other H, A or Hal, and one of the radicals R ¹ and R ² is not always H,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms,
R ³ and R ⁴ are each independently of each other H, A, OH, OA or Hal,
R ³ and R ⁴ together are optionally —O—CH ₂ —O—,
X is R ⁵ monosubstituted by R ⁷ ,
R ⁵ is straight or branched chain alkylene having 1 to 10 carbon atoms, or —C ₆ H ₄ —CH ₂ —,
R ⁷ is COOH or COOA,
A is alkyl having 1 to 6 carbon atoms,
Hal is F, Cl, Br or I,
m is 1,
A pharmaceutical composition comprising at least one compound of formula (I-I) according to claim 16, characterized in that n is 1 or 2.
[22" claim-type="Currently amended] The method of claim 16,
(a) 3- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2 -Yl] propionic acid;
(b) 4- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2- General] butyric acid;
(c) 7- [4- (3,4-methylenedioxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2- Il] heptanoic acid;
(d) 7- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2 -Yl] heptanoic acid;
(e) 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine-2 -Yl] valeric acid;
(f) 5- [4- (3-chloro-4-methoxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid;
(g) 4- [4- (3-chloro-4-methoxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
(h) 4- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] butyric acid;
(i) 2- {4- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-terahydro- [1] -benzothieno [2,3-d] Pyrimidin-2-yl] cyclohexyl-1-yl} acetic acid;
(k) one selected from the group consisting of 5- [4- (3,4-methylenedioxybenzylamino) -6-methylthieno [2,3-d] pyrimidin-2-yl] valeric acid A pharmaceutical composition comprising the compound of formula II according to claim 16.
[23" claim-type="Currently amended] The method of claim 16,
5- [4- (3-Chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] -pyrimidin-5-yl ] Pharmaceutical composition comprising valeric acid, ethanolamine salt.
[24" claim-type="Currently amended] The method according to any one of claims 16 to 23,
The nitrate is selected from the group consisting of pentaerythryl tetranitrate, trinitrate, dinitrate and mononitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate Pharmaceutical composition.
[25" claim-type="Currently amended] The method of claim 24,
Pharmaceutical composition, characterized in that the nitrate is pentaerythryl tetranitrate, isosorbide mononitrate, isosorbide dinitrate or glycerol trinitrate.
[26" claim-type="Currently amended] The method of claim 25,
Pharmaceutical composition, characterized in that the nitrate is pentaerythryl tetranitrate.
[27" claim-type="Currently amended] The method according to any one of claims 1 to 26,
A pharmaceutical composition comprising one or more excipients and / or adjuvants.
[28" claim-type="Currently amended] The method according to any one of claims 16 to 27,
Pharmaceutical compositions for the manufacture of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.
[29" claim-type="Currently amended] (a) an effective amount of 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine -2-yl] valeric acid, ethanolamine salt,
And
(b) effective amount of nitrate
A set (kit) consisting of individual packages of.
[30" claim-type="Currently amended] For the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure
(a) an effective amount of 5- [4- (3-chloro-4-methoxybenzylamino) -5,6,7,8-tetrahydro- [1] -benzothieno [2,3-d] pyrimidine -2-yl] valeric acid, ethanolamine salt,
And
(b) effective amount of nitrate
A set (kit) consisting of individual packages of.
[31" claim-type="Currently amended] Eczema, hypertension, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart, right heart failure, atherosclerosis, reduced cardiovascular condition, peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma At least one compound of formula (I-II) for the manufacture of a medicament for the treatment of allergic rhinitis, glaucoma, irritable bowel syndrome, tumor, renal failure and cirrhosis:
[Formula I-II]
(Wherein
R ¹ and R ² are each independently of each other H, A, OA, OH or Hal,
R ¹ and R ² together may optionally be alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —CH ₂ —O—CH ₂ —, —O—CH ₂ —O— or —O—CH; ₂ -CH ₂ -O-,
X is each R ⁴ , R ⁵ or R ⁶ monosubstituted by R ⁷ ,
R ⁴ is straight or branched chain alkylene having 1 to 10 carbon atoms, in which one or two CH ₂ groups may be replaced by a —CH═CH— group,
R ⁵ is cycloalkyl or cycloalkylalkylene having 5 to 12 carbon atoms,
R ⁶ is phenyl or phenylmethyl,
R ⁷ is COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ or CN,
A is alkyl having 1 to 6 carbon atoms,
Hal is F, Cl, Br or I)
And / or a physiologically acceptable salt and / or solvate thereof and one or more nitrates.
[32" claim-type="Currently amended] The method of claim 31, wherein
A pharmaceutical composition comprising at least one compound of formula I-II according to claim 31, characterized in that X is R ⁴ , phenyl or phenylmethyl substituted with COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN. Composition.
[33" claim-type="Currently amended] The method of claim 31, wherein
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
A pharmaceutical composition comprising at least one compound of formula I-II according to claim 31, characterized in that X is R ⁴ , phenyl or phenylmethyl substituted with COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN. Composition.
[34" claim-type="Currently amended] The method of claim 31, wherein
R ¹ and R ² are each independently H, A, OA or Hal,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
A pharmaceutical composition comprising at least one compound of formula I-II according to claim 31, characterized in that X is R ⁴ , phenyl or phenylmethyl substituted with COOH, COOA, CONH ₂ , CONA ₂ , CONHA or CN. Composition.
[35" claim-type="Currently amended] The method of claim 31, wherein
R ¹ and R ² are each independently H, A, OA or Hal,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
X is each alkylene, cyclohexyl, phenyl or phenylmethyl having 2 to 5 carbon atoms monosubstituted by R ⁷ ,
R ⁷ is COOH or COOA,
A is alkyl having 1 to 6 carbon atoms,
A pharmaceutical composition comprising one or more compounds of formula (I-II) according to claim 31, characterized in that Hal is F, Cl, Br or I.
[36" claim-type="Currently amended] The method of claim 31, wherein
R ¹ and R ² are each independently H, A, OA or Hal,
R ¹ and R ² together are optionally alkylene having 3 to 5 carbon atoms, —O—CH ₂ —CH ₂ —, —O—CH ₂ —O— or —O—CH ₂ —CH ₂ —O—,
X is each alkylene, cyclohexyl, phenyl or phenylmethyl having 2 to 5 carbon atoms monosubstituted by R ⁷ ,
R ⁷ is COOH or COOA,
A is alkyl having 1 to 6 carbon atoms,
A pharmaceutical composition comprising one or more compounds of formula (I-II) according to claim 31, characterized in that Hal is F, Cl, Br or I.
[37" claim-type="Currently amended] The method of claim 31, wherein
(a) 3- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] propionic acid;
(b) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] butyric acid;
(c) 7- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
(d) 7- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
(e) 5- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] valeric acid;
(f) 2- {4- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexyl-1 -Yl} acetic acid;
(g) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid;
(h) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] benzoic acid;
(i) 4- [4- (3,4-methylenedioxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] phenylacetic acid;
(j) selected from the group consisting of 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid A pharmaceutical composition comprising at least one compound of formula (I-II) according to claim 31.
[38" claim-type="Currently amended] The method of claim 31, wherein
A pharmaceutical comprising at least 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid, ethanolamine salt Pharmaceutical composition.
[39" claim-type="Currently amended] The method according to any one of claims 31 to 38,
The nitrate is selected from the group consisting of pentaerythryl tetranitrate, trinitrate, dinitrate and mononitrate, isosorbide mononitrate, isosorbide dinitrate and glycerol trinitrate Pharmaceutical composition.
[40" claim-type="Currently amended] The method of claim 39,
Pharmaceutical composition, characterized in that the nitrate is pentaerythryl tetranitrate, isosorbide mononitrate, isosorbide dinitrate or glycerol trinitrate.
[41" claim-type="Currently amended] The method of claim 40,
Pharmaceutical composition, characterized in that the nitrate is pentaerythryl tetranitrate.
[42" claim-type="Currently amended] The method according to any one of claims 1 to 41,
A pharmaceutical composition comprising one or more excipients and / or adjuvants.
[43" claim-type="Currently amended] The method according to any one of claims 31 to 42,
Pharmaceutical compositions for the manufacture of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), pulmonary heart and / or right heart failure.

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同族专利:

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公开号 | 公开日

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AR035741A1|2004-07-07|

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BR0116849A|2004-02-25|

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HU0302987A2|2003-12-29|

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WO2002060449A2|2002-08-08|

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WO2002060449A3|2003-01-30|

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SK10762003A3|2004-01-08|

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PL362408A1|2004-11-02|

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JP2004517940A|2004-06-17|

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EP1355649A2|2003-10-29|

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MXPA03006717A|2003-10-24|

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CA2436209A1|2002-08-08|

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CN1499969A|2004-05-26|

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US20040077664A1|2004-04-22|

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CZ20032339A3|2004-09-15|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-01-31|Priority to DE10104096.2

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2001-01-31|Priority to DE10104095.4

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2001-01-31|Priority to DE2001104096

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2001-01-31|Priority to DE2001104095

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2001-01-31|Priority to DE2001104097

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2001-01-31|Priority to DE10104097.0

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2001-12-27|Application filed by 메르크 파텐트 게엠베하

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2001-12-27|Priority to PCT/EP2001/015324

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2003-08-27|Publication of KR20030070149A

优先权:

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申请号 | 申请日 | 专利标题

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DE10104095.4|2001-01-31|

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DE2001104096|DE10104096A1|2001-01-31|2001-01-31|Pharmaceutical composition useful for treating e.g. cardiovascular and pulmonary diseases, comprises a nitrate and a 3-benzylamino-benzothienopyrimidine derivative|

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DE2001104095|DE10104095A1|2001-01-31|2001-01-31|Pharmaceutical composition, useful for treating e.g. cardiovascular and pulmonary diseases, comprises a nitrate and a 3-benzylamino-pyrazolopyrimidine derivative|

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DE2001104097|DE10104097A1|2001-01-31|2001-01-31|Pharmaceutical composition, useful for treating e.g. cardiovascular and pulmonary diseases, comprises a nitrate and a 3-benzylamino-thienopyrimidine derivative|

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DE10104097.0|2001-01-31|

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DE10104096.2|2001-01-31|

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PCT/EP2001/015324|WO2002060449A2|2001-01-31|2001-12-27|Pharmaceutical formulation containing pyrazolo[4,3-d]pyrimidine and nitrates or thienopyrimidines and nitrates|