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    • 专利摘要:
    The present invention relates to thienopyrimidines of formula (I) and their physiologically acceptable salts: Formula I Where R 1 , R 2 and X are as defined in claim 1. Since the compounds of the present invention inhibit phosphodiesterase V, they can be used to treat diseases of the cardiovascular system and to treat and / or treat foot dysfunction.
    公开号:KR20020010719A
    申请号:KR1020017016275
    申请日:2000-06-07
    公开日:2002-02-04
    发明作者:조나스로쿠스；쉘링피에르；클룩센프란츠베르너；크리스타틀러마리아
    申请人:플레믹 크리스티안；메르크 파텐트 게엠베하；
    IPC主号:
    专利说明:

    Thienopyrimidine as phosphodiesterase inhibitor {THIENOPYRIMIDINES AS PHOSPHODIESTERASE INHIBITORS}
    [13] Pyrimidine derivatives are disclosed, for example, in EP 201 188 or WO 93/06104.
    [14] The present invention is based, in particular, on the purpose of finding novel compounds with useful properties that can be used for the manufacture of medicaments.
    [15] It has been found that the compounds of formula (I) and salts thereof have very useful pharmacological properties with good resistance.
    [16] In particular, they specifically inhibit cyclic guanosin monophosphate (cGMP) phosphodiesterase (Phosphodiesterase, PDE V).
    [17] Quinazolin with cGMP phosphodiesterase-inhibiting activity is described, for example, in J. Med. Chem ., 36 , 3765, 1993 and ibid ., 37 , 2106, 1994.
    [18] The biological activity of the compounds of formula (I) can be measured by the methods described in WO 93/06104. The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterases is determined by identifying their IC 50 (concentration of inhibitors necessary to inhibit 50% enzyme activity) values. To carry out the measurements, enzymes isolated according to known methods can be used (see, eg, WJ Thompson et al . Biochem ., 10 , 311, 1971). To carry out the experiment, W. second. Thompson and M. M. A "batch" method modified by MM Appleman ( Biochem ., 18 , 5228, 1979) can be used.
    [19] Therefore, the compounds are suitable for treating cardiovascular disorders, in particular heart failure, and for treating and / or treating impotence (erectile dysfunction).
    [20] The use for the treatment of impotence of substituted pyrazolopyrimidinones is described, for example, in WO 94/28902.
    [21] The compound is effective as an inhibitor of phenylephrine-induced contraction in rabbit corpus cavernosum tissue samples. Such biological activity is for example f. This can be demonstrated according to the method described in F. Holmquist et al., J. Urol ., 150 , 1310-1315, 1993. Inhibition of such contractions indicates the efficacy of the compounds according to the invention for treating and / or treating foot dysfunction.
    [22] The compounds of formula (I) can be used as pharmaceutically active compounds in humans and veterinary medicine. They may also be used as intermediate products for the preparation of further pharmaceutically active compounds.
    [1] The present invention relates to compounds of formula (I) and their physiologically acceptable salts:
    [2]
    [3] Where
    [4] R 1 and R 2 are each independently of each other H, A, OH, OA or Hal;
    [5] X is R 4 , R 5 or R 6 monosubstituted with R 7 ;
    [6] R 4 is a linear or branched alkylene having 1 to 10 carbon atoms, in which one or two CH 2 groups may be substituted with a —CH═CH— group;
    [7] R 5 is cycloalkyl or cycloalkyl alkylene having 5 to 12 carbon atoms;
    [8] R 6 is phenyl or phenylmethyl;
    [9] R 7 is COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN;
    [10] A is alkyl having 1 to 6 carbon atoms;
    [11] Hal is F, Cl, Br or I;
    [12] At least one of the radicals R 1 and R 2 is OH.
    [23] Accordingly, the present invention relates to compounds of formula (I); And
    [24] (a) reacting a compound of formula II with a compound of formula III;
    [25] (b) in the compound of formula (I), radical X is converted to another radical X by hydrolyzing the ester group with a COOH group or by converting the COOH group with an amide or cyano group; or
    [26] (c) In the compounds of formula I, by converting an alkoxy group hydroxyl radicals R 1 and / or the other radicals R 2 to R 1 and / or converted into R 2, and / or
    [27] A process for the preparation of compounds of formula (I) according to claim 1 and salts thereof, characterized in that the compounds of formula (I) are converted to one of their salts:
    [28]
    [29]
    [30] In the above formulas,
    [31] R 1 and R 2 and X are as defined above;
    [32] L is Cl, Br, OH, SCH 3 or a reactive esterified OH group.
    [33] Above and below, 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 and III unless otherwise indicated.
    [34] A is alkyl having 1 to 6 carbon atoms. Wherein the alkyl is not branched and preferably has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl or propyl, more preferably isopropyl, butyl, isobutyl, secondary -Butyl, tert-butyl, n-pentyl, neopentyl, isopentyl or hexyl.
    [35] X is a R 4 , R 5 or R 6 radical monosubstituted with R 7 .
    [36] R 4 is a linear or branched alkylene radical having 1 to 10 carbon atoms, wherein the alkylene radical is preferably, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary-butylene , Pentylene, 1-, 2- or 3-methylbutylene, 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-methylpropylene, 1,1,2- or 1,2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene. R 4 is more preferably, for example, but-2-eneene or hex-3-enylene. Very particularly preferably ethylene, propylene or butylene.
    [37] R 5 is cycloalkylalkylene having 5 to 12 carbon atoms, preferably cyclopentyl methylene, cyclohexyl methylene, cyclohexylethylene, cyclohexylpropylene or cyclohexyl butylene. In addition, R 5 is preferably cycloalkyl having 5 to 7 carbon atoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
    [38] Hal is preferably F, Cl, Br or I.
    [39] The radicals R 1 and R 2 may be the same or different and are preferably present at position 3 or 4 of the phenyl ring. These are each independently H, alkyl, alkoxy, hydroxyl, F, Cl, Br or I, for example. Preferably, they are independently of each other Hal and hydroxyl. At least one of the radicals R 1 and R 2 is hydroxyl.
    [40] The radical R 7 is preferably COOH, COOCH 3 , COOC 2 H 5 , CONH 2 , CON (CH 3 ) 2 , CONHCH 3 or CN, for example.
    [41] All radicals resulting from numerous recovery are the same or different, ie independent of one another, apply to all inventions.
    [42] The present invention therefore relates in particular to compounds of formula (I), in which one or more of the radicals mentioned above is one of the preferred meanings defined above.
    [43] Some preferred groups of formulas may be represented by the following subgroups of Formulas Ia to Id and their physiologically acceptable salts, which subgroups correspond to Formula I and radicals not shown in more detail are as defined in Formula I:
    [44] Formula Ia, wherein X is R 4 , phenyl or phenylmethyl, substituted with COOH, COOA, CONH 2 , CONA 2 , CONHA or CN;
    [45] R 1 and R 2 are each independently of each other H, A, OH, OA or Hal; X is R 4 , phenyl or phenylmethyl, substituted with COOH, COOA, CONH 2 , CONA 2 , CONHA or CN; At least one of R 1 and R 2 is OH;
    [46] R 1 and R 2 are each independently of each other H, A, OA or Hal; X is C2-C5 alkylene, cyclohexyl, phenyl or phenylmethyl monosubstituted with R 7 ; R 7 is COOH or COOA; A is alkyl having 1 to 6 carbon atoms; Hal is F, Cl, Br or I; At least one of R 1 and R 2 is OH; And
    [47] R 1 is Hal; R 2 is OH; X is C2-C5 alkylene, cyclohexyl, phenyl or phenylmethyl monosubstituted with R 7 ; R 7 is COOH or COOA; A is alkyl having 1 to 6 carbon atoms; Hal is F, Cl, Br or I.
    [48] In addition, compounds of formula (I) and starting materials for these preparations are alternatively described in standards such as, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart. By methods known per se, ie under reaction conditions suitable for the reactions known and mentioned. It can also be used in this modified case known per se but is not mentioned in more detail here.
    [49] In the compounds of formula (II) or (III), R 1 , R 2 , R 3 , R 4 , X and n are as defined above, in particular as defined above preferably.
    [50] When L is a reactive esterified OH group, these are alkylsulfonyloxy (preferably methylsulfonyloxy) having 1 to 6 carbon atoms, or arylsulfonyloxy (preferably phenyl- or p-tol) having 6 to 10 carbon atoms. Rylsulfonyloxy, and 2-naphthalenesulfonyloxy) are preferred.
    [51] The compound of formula I can preferably be obtained by reacting a compound of formula II with a compound of formula III.
    [52] If desired, starting materials may also be formed at that position so that they can be further reacted immediately without isolation from the reaction mixture to afford compounds of formula (I). On the other hand, the reaction can be carried out stepwise.
    [53] In general, starting compounds of the formulas (II) and (III) are known. If they are not known, they can be prepared by methods known per se. Compounds of formula (II) can be obtained, for example, by reacting corresponding hydroxypyrimidines synthesized from thiophene derivatives and CN-substituted alkylene carboxylic acid esters with POCl 3 ( Eur. J. Med. Chem , 23 , 453, 1988]. Hydroxypyrimidines are conventionally used to prepare pyrimidine derivatives (eg Houben Weyl E9b / 2), ie dehydrogenating the corresponding tetrahydrobenzo-thienopyrimidine compounds, or by aldehydes or nitriles. Prepared by cyclizing an aminobenzothiophene-3-carboxylic acid derivative.
    [54] Specifically, the compound of formula (II) is reacted with the compound of formula (III) at a temperature of about -20 to about 150 ° C, preferably 20 to 100 ° C, in the presence or absence of an inert solvent.
    [55] Adding acid-binding agents such as 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; It may be advantageous to add organic bases such as triethylamine, dimethylamine, pyridine or quinoline, or excess amine components.
    [56] Suitable inert solvents include, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, 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 (methyl glycol or ethyl glycol), 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; And esters such as ethyl acetate or mixtures of the above solvents.
    [57] In the compounds of the formula (I), it is also possible to convert radical X to another radical X, for example by hydrolyzing an ester or cyano group with a COOH group. Ester groups can be hydrolyzed, for example, using NaOH or KOH, water-THF or water-dioxane in water at a temperature of 0 to 100 ° C.
    [58] Carboxylic acids can be converted to the corresponding carboxylic acid chlorides, for example using thionyl chloride, which can be converted to carboxamides. Carbonnitrile is obtained from these by removing water by a known method. Compounds of formula (I) in which R 1 and / or R 2 are OA can be converted to the corresponding compounds in which R 1 and / or R 2 are hydroxyl according to known methods of ether cleavage.
    [59] The acid of the compound of formula (I) can be converted to the associated acid addition salt using a base, for example by reacting the same amount of acid with the base in an inert solvent such as ethanol and then evaporating. Suitable bases for the reaction are, in particular, those which produce physiologically acceptable salts. Therefore, the acid of the compound of formula (I) is converted to the corresponding metal salt, in particular alkali metal or alkaline earth metal salt, or to the corresponding ammonium salt using a base (eg sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate) Can be switched. Suitable organic bases for the reaction are, in particular, those which produce physiologically acceptable salts, such as ethanolamine.
    [60] On the other hand, the base of the compound of formula (I) can be converted to the associated acid addition salt using an acid, for example by reacting the same amount of base with the acid in an inert solvent such as ethanol and then evaporating. Acids suitable for this reaction are those which produce, inter alia, physiologically acceptable salts. Thus, inorganic acids include, for example, sulfuric acid, nitric acid, hydrochloric acid (eg hydrochloric acid or hydrobromic acid), phosphoric acid (eg o-phosphoric acid), sulfamic acid, or organic acids, in particular aliphatic, cycloaliphatic, Araliphatic, aromatic or heterocyclic single or polybasic carboxylic acids, sulfonic acids 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, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono And disulfonic acid, laurylsulfuric acid can be used. Salts with physiologically unacceptable acids, such as picric acid salts, can be used to isolate and / or purify compounds of formula (I).
    [61] The invention furthermore relates to the use of the compounds of formula (I) and / or their physiologically acceptable salts, in particular for the preparation of pharmaceutical preparations by non-chemical routes. In this regard, they may be prepared in suitable dosage forms together with one or more solid, liquid and / or semi-liquid vehicles or excipients, and optionally in combination with one or more further active compounds.
    [62] The invention also relates to a medicament of the formula (I) and physiologically acceptable salts thereof as phosphodiesterase V inhibitors.
    [63] The present invention also relates to pharmaceutical preparations comprising one of formula (I) and / or its physiologically acceptable salts.
    [64] The formulations can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances suitable for intestinal (eg oral) or parenteral administration or for topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, Carbohydrates such as polyethylene glycol, glyceryl triacetate, gelatin, lactose or starch, magnesium stearate, talc and petrolatum. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are administered orally, suppositories are administered rectally, solutions, preferably oily or aqueous solutions, or suspensions, emulsions or Inserts are administered parenterally and ointments, creams or powders are applied topically. In addition, the novel compounds are lyophilized and the lyophilized obtained is used for preparing injection formulations, for example. Designated formulations may be sterile and / or excipients (e.g., lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, osmotic salts, buffer materials, colorants, flavors and / or one or more additional active materials (e.g., One or more vitamins)).
    [65] The compounds of formula (I) and their physiologically acceptable salts can be applied to control diseases in which inflammation and muscle relaxation are inhibited or prevented by increasing cGMP levels. The compounds according to the invention can be used, in particular, to treat diseases of the cardiovascular system and to treat and / or treat foot dysfunction.
    [66] In this regard, the substance is generally 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 / kg body weight. However, the specific dosage for an individual patient may vary with all kinds of factors, e.g., efficacy, age, weight, general health, sex, diet, time and route of administration, rate of release, pharmaceutical combination and treatment of the specific compound used. It depends on the severity of the particular disorder that will be. Oral administration is preferred.
    [67] Above and below, all temperatures are expressed in degrees Celsius. In the following examples, "normal work-up" means: adding water as needed to adjust the pH and optionally adjusting the mixture to a value of 2 to 10 depending on the final product composition, ethyl acetate or dichloro Extract with methane, separate organic phase, evaporate to dryness with sodium sulfate and purify the residue by silica gel chromatography and / or crystallization.
    [68] Mass spectrometry (MS): EI (electron impact ionization) M +
    [69] FAB (fast atom bombardment) (M + H) +
    [70] Example 1
    [71] Methyl 3- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) propionate [methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylic acid salt Can be obtained by cyclization with methyl 3-cyanopropionate, dehydrogenation with sulfur, followed by chlorination with phosphorus acid chloride / dimethylamine] and 3-chloro-4-methoxybenzylamine (hereinafter referred to as "A") Was stirred in N-methylpyrrolidone at 110 ° C. for 5 hours. The solvent was removed and the residue was worked up in the usual way. Methyl 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionate was obtained as a colorless oil.
    [72] Methyl 2- [4- (3-chloro-4-methoxybenzylamino by reacting “A” with methyl 2- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) acetate ) Benzothieno [2,3-d] pyrimidin-2-yl] acetic acid salt was obtained in a similar manner.
    [73] Methyl 4- [4- (3-chloro-4-methoxybenzylamino by reacting “A” with methyl 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) butyrate ) Benzothieno [2,3-d] pyrimidin-2-yl] butyrate was obtained in a similar manner.
    [74] Methyl 5- [4- (3-chloro-4-methoxybenzylamino by reacting “A” with methyl 5- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) valeric acid ) Benzothieno [2,3-d] pyrimidin-2-yl] valeric acid salt was obtained in a similar manner.
    [75] Methyl 7- [4- (3-chloro-4-methoxybenzylamino by reacting “A” with methyl 7- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) heptanate ) Benzothieno [2,3-d] pyrimidin-2-yl] heptanate was obtained in a similar manner.
    [76] "A" is reacted with methyl 2- [4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) cyclohex-1-yl} acetic acid methyl 2- {4- [ 4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} acetic acid salt was obtained in a similar manner.
    [77] Methyl 4- [4- (3-chloro-4-methoxy by reacting “A” with methyl 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) cyclohexanecarboxylic acid salt Benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid salt was obtained in a similar manner.
    [78] Example 2
    [79] Methyl 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionate was dissolved in ethylene glycol monomethyl ether, 32% NaOH After the addition was stirred for 5 hours at 110 ℃. After addition of 20% HCl, the mixture was extracted with dichloromethane. By adding petroleum ether, 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid at a melting point of 218 ° C was obtained.
    [80] Precipitated crystals were dissolved in isopropanol and treated with ethanolamine. After crystallization, 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid, ethanolamine salt was obtained.
    [81] 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid (melting point 225 ° C) and its ethanolamine salt (melting point 150 ° C) ; 5- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid (melting point 210 ° C) and its ethanolamine salt (melting point 141 ° C) ) Was obtained in a similar manner.
    [82] The following carboxylic acids were obtained in a similar manner from the esters listed in Example 1:
    [83] 2- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] acetic acid,
    [84] 7- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
    [85] 2- {4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} acetic acid, and
    [86] 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid, ethanolamine salt (melting point 167 ° C.).
    [87] Example 3
    [88] Methyl 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl) phenylcarboxylic acid salt (hereinafter referred to as "B") [corresponding 5,6,7,8-tetrahydrobenzothier Prepared by dehydrogenation of a no [2,3-d] pyrimidine compound with sulfur, followed by chlorination with phosphorus acid chloride / dimethylamine] and 3-chloro-4-methoxybenzyl in 20 ml of N-methylpyrrolidone. A mixture of 1.5 g of amines was heated at 110 ° C. for 4 hours. After cooling, the mixture was worked up in a conventional manner. 2.6 g of methyl 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] benzoate at a melting point of 203 to 204 占 폚 was obtained.
    [89] In a similar manner as in Example 2, 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid at a melting point of 189 to 190 ° C, 1.0 g of ethanolamine salt was obtained from 1.2 g of their esters.
    [90] Compounds of 4- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid, ethanolamine salts at a melting point of 130 ° C. were obtained in a similar manner. It was.
    [91] Example 4
    [92] 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 in dichloromethane for 2 hours Stirred. The solvent was removed and 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionyl chloride was obtained. The mixture was stirred in aqueous ammonia for 1 hour and subjected to conventional workup, followed by 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidine- 2-yl] propionamide was obtained.
    [93] Example 5
    [94] One equivalent of DMF and one equivalent of oxalyl chloride were dissolved at 0 ° C. in acetonitrile. Then 1 equivalent of 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionamide was added. The mixture was subsequently stirred for 1 hour. After usual workup, 3- [4- (3-chloro-4-methoxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionitrile was obtained.
    [95] Example 6
    [96] The compounds obtained in Examples 1 to 5 can be converted to the corresponding hydroxyl compounds by known methods of ether cleavage. Thus, the following compounds were obtained:
    [97] Methyl 3- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionate,
    [98] Methyl 2- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] acetate,
    [99] Methyl 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyrate,
    [100] Methyl 5- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid salt,
    [101] Methyl 7- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanate,
    [102] Methyl 2- {4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} acetate,
    [103] Methyl 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid salt,
    [104] 3- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid,
    [105] 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,
    [106] 5- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid,
    [107] 2- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] acetic acid,
    [108] 7- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
    [109] 2- {4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} acetic acid,
    [110] 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid,
    [111] 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] benzoic acid,
    [112] 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] phenylacetic acid,
    [113] 3- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionamide, and
    [114] 3- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionitrile.
    [115] Example 7
    [116] In a similar manner to Example 1, 0.01 mol of methyl 4- (4-chlorobenzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid salt in 40 ml of 1-methyl-2-pyrrolidone After reacting with 0.02 mol of 3-chloro-4-hydroxybenzylamine and carrying out the usual workup, methyl 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3- d] pyrimidin-2-yl] cyclohexanecarboxylic acid salt was obtained:
    [117] Compound Methyl 4- [4- (3-methoxy-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid salt and methyl 4- [4- (4 -Hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid salt was obtained in a similar manner.
    [118] By ester hydrolysis in a manner similar to Example 2, the compound 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidine-2 at a melting point of 200 to 202 캜; -Yl] cyclohexanecarboxylic acid, ethanolamine salt; 4- [4- (3-methoxy-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid; And 4- [4- (4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid.
    [119] The following compounds were obtained in a similar manner:
    [120] 4- [4- (3-methoxy-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,
    [121] 5- [4- (3-methoxy-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid,
    [122] 2- [4- (3-methoxy-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] acetic acid,
    [123] 7- [4- (3-methoxy-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
    [124] 2- {4- [4- (3-methoxy-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} acetic acid,
    [125] 4- [4- (4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] butyric acid,
    [126] 5- [4- (4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] valeric acid,
    [127] 2- [4- (4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] acetic acid,
    [128] 7- [4- (4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] heptanoic acid,
    [129] 2- {4- [4- (4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} acetic acid, and
    [130] 3- {4- [4- (4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohex-1-yl} propionic acid.
    [131] The following examples pertain to pharmaceutical preparations.
    [132] Example A Injectable Vial
    [133] A solution of 100 g of the active compound of formula (I) and 5 g of disodium hydrogen phosphate was adjusted to pH 6.5 in 3 L of distilled water using 2N hydrochloric acid, sterile filtered, placed in an injection vial and lyophilized under sterile conditions and sealed aseptically. Each injection vial contains 5 mg of active compound.
    [134] Example B: Suppositories
    [135] A mixture of 20 g of the active compound of formula I was dissolved in 100 g of soy lecithin and 1400 g of cocoa butter, poured into a mold and cooled. Each suppository contains 20 mg of active compound.
    [136] Example C: Solution
    [137] The solution was prepared from 1 g of active compound of formula I, 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 in 940 ml of distilled water. The solution was adjusted to pH 6.8, adjusted to 1 L and sterilized by irradiation. This solution can be used in the form of eye drops.
    [138] Example D: Ointment
    [139] 500 mg of the active compound of formula (I) was mixed with 99.5 g of petrolatum under aseptic conditions.
    [140] Example E: Tablets
    [141] A mixture of 1 kg of active compound of formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate was compressed in a conventional manner to obtain a tablet comprising 10 mg of active compound each.
    [142] Example F: Coated Tablets
    [143] In a similar manner to Example E, the tablets were compressed and then coated by a conventional method with a coating of sucrose, potato starch, talc, tragacanth and colorant.
    [144] Example G: Capsule
    [145] 2 kg of active compound of formula (I) were filled into hard gelatin capsules in a conventional manner such that each capsule contained 20 mg of active compound.
    [146] Example H: Ampoules
    [147] A solution of 1 kg of the active compound of formula I in 60 liters of distilled water was sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active compound.
    [148] Example I: Inhalation Spray
    [149] 14 g of active compound of formula (I) were dissolved in 10 L of NaCl isotonic solution and charged with a commercial nebulizer with a pump mechanism. The solution can be sprayed into the mouth or nose. One injection of the nebulizer (about 0.1 ml) corresponds to a dose of about 0.14 mg.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] A compound of formula (I) or a physiologically acceptable salt thereof:
    Formula I

    Where
    R 1 and R 2 are each independently of each other H, A, OH, OA or Hal;
    X is R 4 , R 5 or R 6 monosubstituted with R 7 ;
    R 4 is a linear or branched alkylene having 1 to 10 carbon atoms, in which one or two CH 2 groups may be substituted with a —CH═CH— group;
    R 5 is cycloalkyl or cycloalkyl alkylene 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;
    At least one of the radicals R 1 and R 2 is OH.
    [2" claim-type="Currently amended] The method of claim 1,
    (a) 3- [4- (3-chloro-4-hydroxybenzylamino) benzo [4,5] -thieno [2,3-d] pyrimidin-2-yl] propionic acid;
    (b) 7- [4- (3-chloro-4-hydroxybenzylamino) benzo [4,5] -thieno [2,3-d] pyrimidin-2-yl] heptanoic acid;
    (c) 5- [4- (3-chloro-4-hydroxybenzylamino) benzo [4,5] -thieno [2,3-d] pyrimidin-2-yl] valeric acid;
    (d) 2- {4- [4- (3-chloro-4-hydroxybenzylamino) benzo [4,5] -thieno [2,3-d] pyrimidin-2-yl] cyclohex-1 -Yl} acetic acid; And
    (e) 4- [4- (3-chloro-4-hydroxybenzylamino) benzothieno [2,3-d] pyrimidin-2-yl] cyclohexanecarboxylic acid
    A compound of formula (I) selected from the group consisting of or a physiologically acceptable salt thereof.
    [3" claim-type="Currently amended] (a) reacting a compound of formula II with a compound of formula III;
    (b) in the compound of formula (I), radical X is converted to another radical X by hydrolyzing the ester group with a COOH group or by converting the COOH group with an amide or cyano group; or
    (c) In the compounds of formula I, by converting an alkoxy group hydroxyl radicals R 1 and / or the other radicals R 2 to R 1 and / or converted into R 2, and / or
    A process for preparing a compound of formula (I) or a salt thereof according to claim 1 characterized by converting the compound of formula (I) to one of its salts:
    Formula II

    Formula III

    In the above formulas,
    R 1 and R 2 and X are as defined in claim 1;
    L is Cl, Br, OH, SCH 3 or a reactive esterified OH group.
    [4" claim-type="Currently amended] Pharmaceutically characterized in that one of the compounds of formula (I) according to claim 1 and / or physiologically acceptable salts thereof is prepared in a suitable dosage form together with one or more solid, liquid or semi-liquid vehicles or excipients. Method of preparing the formulation.
    [5" claim-type="Currently amended] A pharmaceutical formulation comprising one or more compounds of formula (I) according to claim 1 and / or physiologically acceptable salts thereof.
    [6" claim-type="Currently amended] The method of claim 1,
    A compound of formula (I) or a physiologically acceptable salt thereof, for use in controlling diseases of the cardiovascular system and for treating and / or treating foot dysfunction.
    [7" claim-type="Currently amended] A medicament of a compound according to claim 1 or a physiologically acceptable salt thereof as a phosphodiesterase V inhibitor.
    [8" claim-type="Currently amended] Use of a compound of formula (I) according to claim 1 and / or a physiologically acceptable salt thereof for the manufacture of a medicament.
    [9" claim-type="Currently amended] Use of a compound of formula I according to claim 1 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment and / or treatment of dysfunction.
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    同族专利:
    公开号 | 公开日
    HK1047434A1|2005-01-28|
    CN1144806C|2004-04-07|
    DE19928146A1|2000-12-21|
    CZ20014422A3|2002-03-13|
    CA2375278A1|2000-12-28|
    AT285412T|2005-01-15|
    CN1355805A|2002-06-26|
    ZA200200440B|2003-06-25|
    UA72256C2|2002-04-15|
    JP2003502429A|2003-01-21|
    AU5220400A|2001-01-09|
    MXPA01013228A|2002-07-02|
    NO20016201D0|2001-12-18|
    HK1047434B|2005-01-28|
    WO2000078767A1|2000-12-28|
    CZ293901B6|2004-08-18|
    SK18222001A3|2002-06-04|
    EP1189907B1|2004-12-22|
    ES2234613T3|2005-07-01|
    BR0011778A|2002-04-23|
    RU2238274C2|2004-10-20|
    PT1189907E|2005-05-31|
    US6787548B1|2004-09-07|
    NO20016201L|2001-12-18|
    EP1189907A1|2002-03-27|
    AR024380A1|2002-10-02|
    AU767273B2|2003-11-06|
    PL351822A1|2003-06-16|
    HU0201730A3|2004-12-28|
    HU0201730A2|2002-09-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-06-19|Priority to DE19928146A
    1999-06-19|Priority to DE19928146.7
    2000-06-07|Application filed by 플레믹 크리스티안, 메르크 파텐트 게엠베하
    2000-06-07|Priority to PCT/EP2000/005278
    2002-02-04|Publication of KR20020010719A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19928146A|DE19928146A1|1999-06-19|1999-06-19|New 3-benzylamino-benzothienopyrimidine derivatives inhibit phosphodiesterase V and are useful for treating cardiac insufficiency and impotence|
    DE19928146.7|1999-06-19|
    PCT/EP2000/005278|WO2000078767A1|1999-06-19|2000-06-07|Thienopyrimidines as phosphodiesterase inhibitors|
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