KR900005954B1 - 2-amino-3-formyl-furanes processes for preparing them and pharmaceutical compositions containing them - Google Patents

Abstract

Cpds. of formula (I), where A is (a), are prepd. by the cyclization of a cpd. of formula (I), where A is (b), in the presence of H2O and protonic acid. In the formulas, A is a gp. of (a) or (b); B is a gp. of (c); R1 and R2 are each methoxy; R3 is H; R4 is methyl, ethyl, C3-6 cycloalkyl or phenyl; R5 is H. (I) and their acid addn. salts have cardioprotective activity, and are useful for treating coronary heart disease and acute myocardial infarct.

Description

2-amino-3-formyl-furan, preparation method thereof and pharmaceutical composition containing same

The present invention relates to compounds of formula (I) and acid addition salts thereof, methods for their preparation and pharmaceutical compositions containing these compounds.

Wherein A is a group of formula (la), (lb) or (lc),

B represents an aromatic system of the general formula (Id), (Ie), (If), (Ig) or (Ih) with two adjacent carbon atoms,

or

X represents sulfur or NR ₅ , wherein R ₅ is hydrogen, methyl or benzyl; Y represents sulfur, oxygen or NR ₆ , wherein R ₆ is the same as defined for R ₅ ; R ₁ and R ₂ are independently from each other hydrogen, C ₁ - ₄ alkoxy, mercapto, methyl mercapto, or represents the amino, or, R ₁ and R ₂ together are a group -O- (CH _{2) n} -O- ( It represents where n is 1 or 2), R ₃ and R ₄ each independently represent hydrogen, or straight-chain or saturation of the side chain (C ₁ - ₁₂₎ hydrocarbon group, or an unsaturated (C ₂ - ₁₂₎ hydrocarbon group, or cyclic (C ₃ - ₆₎ represents a hydrocarbon group, where these groups are hydroxy, methoxy, amino, (C ₁ - ₅₎ alkylamino, di - (C ₁ - ₅₎ - alkylaminocarbonyl, phenyl ( Which is optionally mono- or polysubstituted by hydroxy, methoxy or halogen), or 5- or 6-membered or unsaturated heterocyclic groups, which contain one or two N, S or O heteroatoms and (C ₁ - ₃₎ can be substituted by alkyl or substituted one or all may be substituted by, R ₃ and R ₄ with the nitrogen atom To, to form a optionally further nitrogen, oxygen or sulfur, 5-or 6-membered ring containing a hetero atom; And R ₇ is the same as defined for R _3, R ₈ is hydrogen, (C ₁ - ₃₎ alkyl or (C ₃ - ₆₎ represents a cycloalkyl or -SCH _3.

Halogen atoms may be four conventional halogen atoms, of which chlorine, bromine and fluorine atoms are preferred.

Preferably, R ₁ and R ₂ represent methoxy.

Preferably, R ₃ represents hydrogen R ₄ is methyl, ethyl, allyl, propargyl, straight-chain or branched (C ₃ - ₅₎ alkyl, methoxy (C ₁ - ₄₎ alkyl, hydroxy (C ₁ - ₄ ) represents an alkyl, or R ₃ and R ₄ are (C ₁ - ₅₎ represents an alkyl or R ₃ and R ₄ represents a pyrrolidinyl group with a modifying atom.

Preferred groups of compounds of general formula (I) can be summarized as follows: Compounds (I), in particular R ₁ and R ₂ , each of which B represents a group of the following general formula (Id) with adjacent carbon atoms And a compound at position 7, preferably a compound of formula (I) wherein R ₁ and R ₂ represent methoxy

R ₃ represents hydrogen, R ₄ is methyl, ethyl, allyl, propargyl, straight-chain or branched (C ₃ - ₅₎ alkyl, methoxy-a - - ₍₄ C ₁₎ alkyl, (C _{1 4)} alkyl, hydroxy Displays or, R ₃ represents hydrogen, R ₄ is (C ₃ - ₆₎ indicate the cycloalkyl or phenyl or, R ₃ and R ₄ are independently of each other (C ₁ - ₅₎ general formula (ⅰ represents an alkyl group ), In particular R ₃ represents hydrogen, R ₄ represents CH ₃ -or (CH ₃ ) ₂ -CH- (CH ₂ ) ₂ -or C ₂ H ₄ -CH (CH ₃ ) CH ₂ -or (CH ₃ ) A compound of formula (I) which represents ₃ -C- or R ₃ and R ₄ represent C ₂ H ₅ or together form a group-(CH ₂ ) _4- : A is a general formula (Ia) compound of formula (ⅰ) R ₈ is hydrogen: the group of formula (ⅰ) the compounds of and a is a group of the formula (Ib), R ₇ is a saturated straight or branched chain (C ₁ - ₁₂₎ hydrocarbon group or an unsaturated (C ₂ - ₁₂₎ hydrocarbon group, or cyclic (C ₃ - ₆₎ a hydrocarbon group or Naemyeo, where these groups are hydroxy, methoxy, amino, by alkyl-amino, phenyl (which is optionally hydroxy, methoxy or halogen - (C ₁ - ₅₎ - alkylamino, di - (C ₁ - ₅₎ mono- or multi-substituted), or 5-or 6-membered cyclic saturated or unsaturated heterocyclic group [which (C ₁ - ₃₎ may be substituted by alkyl, and containing one or two nitrogen, sulfur or oxygen heteroatoms A compound of formula (I) which may be mono- or polysubstituted, in particular a compound of formula (I) wherein R ₇ is the same as R ₃ or R ₄ in the same compound.

The compound of general formula (I) according to the invention is a base and can be converted to acid addition salts in a conventional manner using inorganic or organic acids, while the acid addition salts are also converted by other acid addition salts. It can also be manufactured.

Suitable acids for salt formation include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, unsaturated hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid. Acids, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid or methanesulfonic acid.

Compounds of formula (I) and acid addition salts thereof have shown useful therapeutic properties in experiments on animals. They have excellent cardioprotective activity, measured as follows.

As is well known, the Ca ⁺² content of cardiac muscle is a measure of heart damage caused by hypoxic heart damage or toxic doses of catecholamines. See, eg, HIGGINS et al., Cell, Cardiol, 10,427-438,1984: NAKANISHI Et al., Am. J. Physiol. 242: 437-449,1982: FLECKENSTEIN, Vortrage der Erlanger Physiol. Tagung 19700, Ed.keidel, Springer Verlag Berlin, Heidelberg, New York, 1971]. In contrast, inhibition of hypoxic or isoprenin-induced myocardial calcium absorption can be attributed to calcium antagonists (eg FLECKENSTEIN loc, cit), calmodulin inhibitors (eg HIGGINS) and other drugs such as beta-adrenergic blockers. (Ref. ARNDTS, Arz-neimittelforschung 25: 1279-1289,1975).

Cardioprotective activity is measured using the method described by ARNDTS (ARNDTS: cited above) in conscious rats after subcutaneous or oral administration of the active substance, and the efficacy of the test substance is obtained with an H ₅₀ value. This value corresponds to a dose that inhibits the radio-calcium uptake of the myocardial layer by 50% caused by administering 30 mg / kg of isoprenin by the subcutaneous route.

The novel compounds tested proved to be up to five times more effective than the effects of known commercial propranolol. C. Van Breemen, P. Aaranson, R.Loutzenheiser and Meisheri, chest 78: 1575-1655 (1980)] C. Van Breemen, P. Aranson, R. Lawchenheiser and K. Mayshery And R. Castels and C. Drogman's method [R. Castels and c. Droopman, J. Physiol. 317: 263-279 (1981), and in vitro tests on smooth muscle (strip of the aorta) found that the compounds according to the invention are calcium antagonists with new forms of activity.

In view of these results, compounds of formula (I) and acid addition salts thereof are useful as active agents for the treatment of coronary heart diseases such as angina, heart infarction and palpitations. They also improve the circulation of blood through tissues and the supply of oxygen to tissues, especially in the central nervous system. Intraperitoneal administration of the muscarinic-cholinergic antagonist scopolamine 0.6 mg / kg to limit short-term memory or to inhibit the conversion of short-term memory to long-term memory. Psychopharmacology 78, pages 104-111 (1982) ], The compounds of the present invention may exhibit antagonism or therapeutic action against pharmacologically induced cerebral insufficiency.

In the test for the survival of the animals in a sealed chamber through which a gas mixture of 96.5% nitrogen and 3.5% oxygen passed (tolerance to hypoxia), animals pre-treated with the new material were treated as control animals or dill There is a statistically significant increase in survival compared to animals pretreated with tiazem, verapamil or nifedipine.

The neuroprotective activity of the substances tested in this way is evident even at oral doses of 5 mg / kg. Thus, the novel compounds are clearly superior to the known materials mentioned above both in terms of effective dose and also improved efficacy achieved in experiments on animals.

In view of these test results, the compound of formula (I) and acid addition salts thereof are useful active agents in the treatment of organic brain psychotic syndrome, posttraumatic and alcoholic brain injury.

The compounds of the present invention can be administered enterally or parenterally. In the case of oral administration the suggested dosage is 1 to 3 times a day, 2 to 20 mg, preferably 5 to 10 mg of active ingredient per kg body weight.

Suitable forms for oral administration include tablets, carlisels, suppositories, solutions, syrups, emulsions, aerosols or disperse solubles. These formulations can be obtained, for example, by mixing the active ingredient or ingredients with known excipients.

The present invention provides a compound of formula (I) in which A is a group of formula (Ia) by ring closing the compound of formula (I) in which A is a group of formula (Ic) in the presence of water and a benign asset. And to other acid addition salts by converting to acid addition salts or re-salting acid addition salts.

The process for preparing compounds of formula (I), wherein A is a group of formula (Ia) and B is a group of formula (Id), is particularly advantageous when compounds of formula (II) are used as starting materials. .

The reaction temperature is not critical and the reaction can be carried out within a wide temperature range, preferably by heating or by heating to the boiling point of the solvent.

The reaction can be carried out in any solvent or mixture of solvents, provided that the solvent has sufficient solubility in reactive components and should not adversely affect the progress of the reaction, examples of suitable solvents include ethanol, methylene chloride, chloroform, Tetrahydrofuran and dioxane.

Any positive asset such as hydrochloric acid, sulfuric acid or phosphoric acid can be used as the acid. Typically, dilute acid, such as 2N hydrochloric acid, is used.

Another object of the present invention is to react a compound of formula (III) with an amine of formula (IV), or a reactive derivative thereof, so that A is a group of formula (Ic). There is a novel method for producing the same.

Wherein B, R ₈ , R ₃ and R ₄ are as defined above.

The reaction of the imidazolide of general formula (III) is carried out in a manner known per se at an inert solvent, at ambient temperature or at elevated temperature. The reaction temperature is not important at this time. The reaction temperature and the choice between reactors will be determined by the reactivity of the amines of general formula (IV) used. The solvent may use all the solvents mentioned in connection with the ring closure reaction, for example methylene chloride. If necessary, the compound of general formula (I) in which A is a group of general formula (Ic) can be separated and subsequently ring-closed. However, preference is given to converting the product formed directly, ie without the intermediate step, to the final product of general formula (I) in which A is a group of general formula (Ia).

Starting materials of formula (III) can be prepared by reacting the furancarboxylic acid of formula (V) with 2 molar equivalents of N, N'-carbonyldiimidazole in a suitable solvent.

Wherein B and R ₈ are as defined above.

The reaction can be carried out at ambient temperature or at temperatures up to the boiling point of the solvent used.

The reaction generally lasts for 1 to 15 hours.

The solvent used may be any of the above-mentioned solvents or mixtures of solvents, provided that they do not adversely affect the progress of the reaction, and suitable solvents are described, for example, as suitable for ring closure reactions. Solvents are included.

Preferably, the reaction is carried out at boiling point, in methylene chloride.

The compound of formula (I), in which A is a group of formula (Ia), was prepared using a method already known as Schiff's base for preparing amine NH ₂ R ₇ (wherein R ₇ is as defined above). Same) or a reactive derivative thereof to produce a compound of formula (I) wherein A is a group of formula (lb).

Example 1

1,4-di- (1-imidazolyl) -3-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -butadiene-2-carboxylic acid imidazolide

5 g (15 mmol) of 4- (3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl) -3-furan carboxylic acid hydrochloride in N, N'-carbonyldi in 100 mg of anhydrous methylene chloride 6 g (37 mmol) of imidazole is heated to the boiling point for 2 hours in a water bath. After the reaction is completed, the yellowish orange solution is carefully evaporated until crystallization begins to occur and anhydrous ether is added to crystallize the reaction product.

Yield: 6.9 g of fine yellow needles (83% of theory) having a melting point of 234 to 236 ° C.

1,4-di- (1-imidazolyl) -3-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -butadiene-2-carboxamide

와 혼합시킨다. 생성된 혼합물을 주위온도에서 4시간동안 증발시켜 농축시키고 잔류물은 에틸 아세테이트로부터 결정화시킨다.1,4-di- (1-imidazolyl) -3-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -butadiene-2-carboxylic acid imidazolide 4.7 g (10 mmol) are dissolved in a sufficient amount of anhydrous methylene chloride and ammonia-saturated methylene chloride solution 20

Mix with The resulting mixture is concentrated by evaporation at ambient temperature for 4 hours and the residue is crystallized from ethyl acetate.

Yield: 3.8 g of yellow needles (93% of theory) having a melting point of 224 to 225 ° C.

In a similar manner the following compounds are obtained:

1) 1,4-di- (1-imidazolyl) -3-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -N- (2-furylmethyl ) -Butadiene-2-carboxamide.

Yield: 67% of theoretical value, yellow needle crystal with melting point 212-217 degreeC.

2) 1,4-di- (1-imidazolyl) -3-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -N, N-di- ( m-propyl) -2-carboxamide.

Yield: 88% of theory, yellow needle crystal with melting point of 125-127 degreeC.

3) 1,4-di- (1-imidazolyl) -3-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -N- (1,5- Dimethylhexyl) -2-carboxamide.

Yield: 84% of theory, yellow needle crystal with melting point of 119-120 degreeC.

Example 2A

2- (furan-2-yl-methylamino) -4-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -furan-3-carbaldehyde

1,4-di- (1-imidazolyl) -3-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -N- (2- in 100 ml of ethanol A solution of furylmethyl) -butadiene-2-carboxamide (5 g: 10 mmol) was mixed with 2N hydrochloric acid (10 mL) and heated to 50 ° C. for about 1 hour, after which the mixture was neutralized with soda solution and produced The reaction product is extracted with methylene chloride and purified on Al ₂ O ₃ column (neutral, active stage III, eluent: CH ₂ Cl ₂ ) and crystallized from ethyl acetate / petroleum ether.

Yield: 3.1 g (82% of theory) of greenish yellow needles with melting points of 163 to 164 ° C.

Example 2B

2- (furan-2-yl-methylamino) -4-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -furan-3-carbaldehyde

a) preparation of starting material

4-[(3,4-dihydro-6,7-dimethoxy) -1-isoquinolinyl] -furan-3-carboxylic acid hydrochloride (5 g: 15 mmol) was dissolved in anhydrous CH ₂ Cl ₂ (100 mL). It is heated to boiling point for 1-2 hours with N, N'-carbonyldiimidazole in water.

b) preparation of the final product

After obtaining imidazolide, 2- (aminomethyl) -furan (1.5 g, 15 mmol) was added and the resulting mixture was stirred at ambient temperature for 6 hours, then diluted with 100 mL of ethanol, which was 2N Mix with hydrochloric acid (10 mL) and heat to 50 ° C. for about 1 hour. The reaction mixture is worked up similarly to Example 1 and then the product is crystallized from ethyl acetate / petroleum ether.

Yield: 4.6 g of yellow needles (76% of theory) having a melting point of 163 to 164 占 폚.

[Examples 3 to 34]

The following compounds are obtained by methods analogous to those described in Example 2A or 2B.

Compounds of the general formula (I ') in which R ₃ and R ₄ are as described in the table above are obtained in a similar manner as described in Example 1.

By reacting the compounds of Examples 1 to 34 using a method known as the preparation method of the Schiff base, a compound in which the definition of the group corresponds to the general formula (I ″) is as follows.

Claims (15)

Compounds of the following general formula (I) and acid addition salts thereof.

Wherein A is a group of formula (la), (lb) or (lc),

B represents an aromatic system of the following general formula (Id) with two adjacent carbon atoms,

R ₁ and R ₂ are each independently hydrogen or (C ₁ - ₄₎ alkoxy; R ₃ and R ₄ independently represent a hydrogen from each other, a saturated straight or branched chain (C ₁ - ₁₂₎ hydrocarbon group, or an unsaturated (C ₂ - ₁₂₎ hydrocarbon group, or cyclic (C ₃ - ₆₎ a hydrocarbon group, represents, where these groups are hydroxy, methoxy, (C ₁ - ₅₎ alkyl, phenyl (which is optionally is substituted by methoxy), or a 5-or 6-membered cyclic saturated or unsaturated heterocyclic group ( Which may be monosubstituted by one or two nitrogen, sulfur or oxygen heteroatoms), or R ₃ and R ₄ together with the nitrogen atom to form a five membered ring optionally containing another nitrogen; R ₇ is the same as defined above for R ₃ , and R ₈ represents hydrogen. A compound according to claim 1, wherein B represents a group of the following general formula (Id) together with adjacent carbon atoms.

The compound of claim 2, wherein R ₁ and R ₂ are at positions 6 and 7, respectively. The compound of claim 2 or 3, wherein R ₁ and R ₂ are methoxy. The compound of claim 1, wherein R ₃ represents hydrogen, R ₄ is methyl, ethyl, allyl, propargyl, straight or branched chain (C _3-5 ) alkyl, methoxy (C _1-4 ) alkyl or hydroxy (C _1-4 ) a compound representing alkyl. The compound of claim 1, wherein R ₃ represents hydrogen and R ₄ represents (C _3-6 ) cycloalkyl or phenyl. The method of claim 1, wherein, R ₃ and R ₄ are independently of each other (C ₁ - ₅₎ compounds represented by the alkyl group. The compound of claim 1, wherein R ₃ represents hydrogen and R ₄ is CH ₃ or (CH ₃ ) ₂ -CH- (CH ₂ ) ₂ -or C ₂ H ₅ -CH (CH ₃ ) -CH ₂ -or ( CH ₃ ) ₃ -C-. The compound of claim 1, wherein R ₃ and R ₄ represent C ₂ H ₅ , or R ₃ and R ₄ together form a group — (CH ₂ ) ₄ —. A compound according to claim 1, wherein A represents a group of formula (la). A pharmaceutical formulation containing the compound as claimed in claim 1 together with conventional excipients or carriers. A compound as claimed in any one of claims 1 to 10 for use in the treatment of coronary heart disease or cerebral metabolic disorders. A compound of formula (I), wherein A is a group of formula (Ic), is closed in the presence of water and a benign asset to prepare a compound of formula (I), wherein A is a group of formula (Ia). To prepare a compound of formula (I) as claimed in any one of claims 1 to 10.

Wherein B, R ₈ and A are as defined in claim 1. A compound of formula (III) is reacted with an amine of formula (IV) or a reactive derivative thereof to prepare a compound of formula (I) wherein A is a group of formula (Ic). A process for preparing the compound of formula (I) as claimed in claim 10.

Wherein B, R ₈ , A, R ₃ and R ₄ are as defined in claim 1. A compound of formula (I), wherein A is a group of formula (Ia), is reacted with an amine NH ₂ R ₇ (wherein R ₇ is as defined in claim 1) or a reactive derivative thereof so that A is A process for preparing the compound of formula (I) as claimed in any one of claims 1 to 10, characterized by preparing a compound of formula (I) which is a group of (Ib).

Wherein B, R ₈ and A are as defined in claim 1.