KR800000411B1 - Process for preparing derivatives of quinazoline - Google Patents

Abstract

Quinaxolines (I, R2 = C1-4 alkoxy; Y = N(R4)-CO- NHR6, N(R4) CSNHR6, O-CO-NHR6 or O-CS-NHR6; R4 = H, C1-4 alkyl, benzyl, pyridylmethyl; R6 = C1-6 alkyl, phenyl, pyrideyl, ethoxycarbonylemthyl) were prepd. by reaction of quinazoline(II, A = NHR4, OH) and isocyanate(R6-N=C=O) or thioisocyanate(R6-N=C=S) at 25-200≰C in inert solvent Thus, 2.9 g 1-(6,7-dimethoxyquinazoline-4-yl)piperido-4-one and 1.19 g 2-amino-methylpyridine were refouxed in 50ml benzene for 2 hr to give 4-[4-(2-pyridylethyl-amino)piperidine -6,7- dimethoxyquinazoline.

Description

Method for preparing quinazoline derivatives

The present invention relates to a therapeutic agent which is a new derivative of quinazoline, especially a derivative having a heterocyclic ring substituted at the 4-position.

Compounds of the present invention are cardiac agents, a preferred class of which selectively increases myocardial contractility without significantly increasing heart rate. This compound is useful for treating or preventing heart conditions such as congestive heart failure, angina pectoris, cardiac iris myas and acute heart failure.

According to the present invention there is provided a new quinazoline compound of the general formula and pharmacologically usable acid salts thereof.

Wherein (i) R ¹ is a hydrogen atom or a lower alkyl group:

(R ² ) _n is a suitable substitution of 1-3, each R ² is a hydrogen atom or hydroxy or lower alkoxy, n is 1-3, or any two of the groups R ² are adjacent to ring A Constituting attached methylenedioxy or ethylenedioxy groups:

(ii) X is one (CH ₂ ) p-wherein P is 1-3, -CH = CH- or-CH ₂ .CH = CH-:

(Iii) Y is attached at the 3- or 4-position of ring C,

Any one of (b) or (c) is shown.

(a) -Z ¹ -COR ³

-이고Where Z ¹ is -CH ₂一 or-

-ego

R ³ is a lower alkyl group optionally substituted with amino (as defined below), hydroxy, lower alkoxy, aryl or isoaryl group: lower alkenyl- or lower alkynyl-methyl group: amino, aryl, isoaryl, lower alkoxy or A lower alkoxy group substituted with a hydroxy group: amyl group: amyloxy group: or isoaryl group

R ⁴ is a lower alkyl group substituted with a hydrogen atom, amino, lower alkoxy, hydroxy, carbetoxy, aryl or isoaryl group: lower alkenyl or lower alkynyl-methyl group: aryl group or isoaryl group.

-SO₂R⁵의 기(b) General formula

Group of -SO ₂ R ⁵

Wherein R ⁵ is a group defined by R ³ or a one-off-

As a group R ⁷ is a hydrogen atom or a lower alkyl group, R ⁶ is as defined for R ⁴ above, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a saturated monocyclic ring.

Where Z ² is Z ^l or -O-, R ⁶ and R ⁷ are as defined above,

- 이면 R⁴와 R⁷은 함께 -(CH₂)₂-,-(CH₂)₃- 또는 0-페닐렌기를 나타낸다.Where Z ² is-

-Then R ⁴ and R ⁷ together represent a-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -or 0-phenylene group.

(iv) R is a hydrogen atom or a lower alkyl group attached to the same carbon atom as Y, provided that when X is -CH = CH- or -CH ₂ CH = CH- then R is absent and Y is -CH ₂ COR ³ , —CH ₂ CON (R ⁶ ) (R ⁷ ) or —CH ₂ CSN (R ⁶ ) (R ⁷ ), wherein R ³ , R ⁶ and R ⁷ are as defined above and Y is attached to the carbon atom of the unsaturated ring have.

The term lower used in an alkyl, alkenyl, alkynyl or alkoxy group refers to a group having up to 6, preferably up to 4 carbon atoms, which group may be straight or optionally branched.

As used herein, "aryl" and "heteroaryl" include unsubstituted aryl and isoaryl groups, and aryl and heteroaryl groups substituted with lower alkyl, lower alkoxy, hydroxy, halogen or acet amido groups.

의 기를 의미하여, 이때 R⁸은 수소나 저급알킬을 나타내고, R⁹은 수소, 저급알킬, 또는 저급알킬로 치환된 아릴이머, 또는 R⁸과 R⁹은 이들이 부착된 질소원자와 더불어 포화 단일 이성환상의 기(즉 피페리디노)를 형성한다.The term amino, as used herein, is general formula-

By the means a group, wherein R ⁸ may represent hydrogen or lower alkyl, R ⁹ is hydrogen, lower alkyl, or aryl timer substituted with lower alkyl, or R ⁸ and R ⁹ is saturated with the nitrogen atom to which they are attached form a single binary Form cyclic groups (ie piperidino).

Halogen represents fluorine, chlorine, cancellation or oxo.

Compounds of the present invention containing one or more asymmetric centers exist as one or more coliform pairs, and such pairs or individual isomers are subjected to physical methods, i.e. fractional crystallization or chromatography of free bases or suitable salts. Can be separated by The present invention includes discrete pairs as well as mixtures thereof as racemic mixtures or as optically active isomeric forms of D- and L-.

Pharmacologically usable acid addition salts of the compounds of the present invention include non-toxic acid addition salts containing pharmacologically available anions such as hydrochloride, sulphate, iodo salt, sulfate or sulfite, phosphate or acid phosphate, vinegar salt, male acid salt, fumarate salt. And acid forming a oxalate, lactate, tartarate, citrate, gluconate, saccharide, and P-toluenesulfonate salt.

It is to be understood that the compound of formula (I) in which ring C is unsaturated may exist in the form of tautomers.

Cardiac activity of the compounds of the present invention is manifested in effectiveness in one or more of the following tests.

(a) Increases contractile force in bicentroidal adiposity of isolated, unconsciously beating marsupials (mormot).

(b) increase myocardial contractility (left ventricular dp / dtmax) in rats anesthetized by implanted left ventricular catheter;

(c) Increased myocardial contractility in conscious dogs by implanted left ventricular transducers.

In test (a), atrial positive inotropic and chronotropic responses to test compounds were measured at various doses and compared with those from isoprenin. Comparing the used reaction curves, the force on the rate selectivity of the test compound can be measured.

In the test (b), the positive inotric action of the test compound after intravenous administration was measured in anesthetized dogs and compared with isoprenin. Selective versus frequency for the increase in potency and potency of innotropic action and the duration of action of the positive compound innotropic effect of the test compound were obtained and were identical to their peripheral neuronal effects, ie, to the pressure of the hull.

In test (c), the positive inotropic action of the test compound was measured and compared with isoprenaline after intravenous or oral administration in a conscious dog with implanted left ventricular tmenducers. Both the efficacy of innotropic action and the selectivity to increase in strength versus the frequency of measurement and the duration of action of the innotropic effect of the test compound were obtained.

Other compounds preferred by the potency of the compounds of the present invention in the above tests were identified as follows: (R ² ) _n is preferably 6,7-di (lower alkoxy), most preferably 6,7-dimethoxy Indicates.

X preferably represents -CH ₂ -,-(CH ₂ ) ₂ -or -CH = CH-, most preferably -H _2- .

R ¹ preferably represents a hydrogen atom.

When ring C is saturated, R is preferably hydrogen.

Preferred Y group is as follows.

(i) -CH ₂ COR ₃ , wherein R ³ is lower alkyl or lower alkoxy.

(ii) -NR ⁴ · COR ³ , wherein R ³ is a lower alkyl group: lower alkoxy group substituted with an amino or alkoxy group: lower alkoxy group: lower alkoxy group substituted with an aryl group: aryloxy group: or a heteroaryl group; R ⁴ is a hydrogen atom: lower alkyl group: or lower alkyl group substituted with a hydroxy group.

이때 R⁴는 수소원자 또는 저급알킬기 이고, R⁵는 저급알킬, 아릴 또는 이성아릴기 또는 일반식 -N(R⁶)(R⁷) 인 기이며 이때의 R⁶는 저급알킬기이고, R⁷은 수소원자 또는 저급알킬기 이다.(Ⅲ)

Wherein R ⁴ is a hydrogen atom or a lower alkyl group, R ⁵ is a lower alkyl, aryl, or aryl group or a rational formula ^{-N (R 6) (R 7} ) group wherein the R ⁶ is a lower alkyl group, R ⁷ is Hydrogen atom or lower alkyl group.

이때 R⁶는 저급알킬기 이고 R⁷은 수소원자 이다.(Ⅳ)

R ⁶ is a lower alkyl group and R ⁷ is a hydrogen atom.

, 이때 R⁴는 수소원자:저급알킬:이성아릴, 아릴, 아미노 또는 하이드록시기로 치환된 저급알킬기:또는 이성아릴기 이고:R⁶는 수소원자:저급알킬기:하이드록시나 카베톡시나 이성아릴기로 치환된 저급알킬기:저급알케닐-메틸기:저급알키닐-에틸기:아릴기 또는 이성아릴기 이고:R⁷은 수소원자 또는 저급알킬기 이거나:또는 R⁴와R⁷은 함께 취해지는 경우 0-페닐렌기를 나타내고:또는 R⁶와 R⁷은 함께 취해져서 -(CH₂)₅-를 나타낸다.(Ⅴ)

R ⁴ is a lower alkyl group substituted with a hydrogen atom: lower alkyl: isoaryl, aryl, amino or hydroxy group: or a heteroaryl group: R ⁶ is a hydrogen atom: lower alkyl group: hydroxy, carbetoxy or isoaryl group Substituted lower alkyl group: lower alkenyl-methyl group: lower alkynyl-ethyl group: aryl group or isoaryl group: R ⁷ is a hydrogen atom or a lower alkyl group; or R ⁴ and R ⁷ are taken together, 0-phenylene Or R ⁶ and R ⁷ are taken together to represent-(CH ₂ ) _5- .

이때 R⁶는 수소원자, 저급알킬 또는 이성아릴기 이고, R⁷은 수소원자 이다.(Ⅵ)

R ⁶ is a hydrogen atom, a lower alkyl or a heteroaryl group, and R ⁷ is a hydrogen atom.

이때 R⁶는 수소원자, 또는 저급알킬기 이고:(Ⅶ)

Wherein R ⁶ is a hydrogen atom or a lower alkyl group:

R ⁶ is a lower alkyl group: R ⁷ is a hydrogen atom.

Y is most preferably selected from the following groups.

(저급알킬 또는 알콕시) 이때 R⁴는 수소원자 또는 저급알킬기 이다.(Ⅰ)

(Lower alkyl or alkoxy) wherein R ⁴ is a hydrogen atom or a lower alkyl group.

(ii) -OCONH. (Lower alkyl)

(저급알킬), 이때 R⁴는수소원자, 저급알킬기 또는 2-,3-또는4-피리딜가로 치환된 저급알킬기 이다.(Ⅲ)

(Lower alkyl) wherein R ⁴ is a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a 2-, 3- or 4-pyridyl number.

(iv) -N.SO ₂ NH. (Lower alkyl), wherein R ⁴ is a hydrogen atom or a lower alkyl group.

(2-,3- 또는 4-피리딜), 이때 R₄는 수소원자 또는 저급알킬기 이다.(V)

(2-, 3- or 4-pyridyl), wherein R ₄ is a hydrogen atom or a lower alkyl group.

Preferred aryl groups are phenyl groups and preferred isoaryl groups are 2-, 3- or 4-pyridyl groups. Preferred aryloxy groups are phenoxy groups. Preferred alkenyl and alkynyl groups are -CH = CH ₂ and -C≡CH, respectively.

Most preferred compounds of the present invention have the following structure.

Where Y is as defined above.

Preferred individual compounds of formula (I) have the following structure.

Where Y is

The compounds of the present invention may be administered alone, but are generally administered in admixture with a pharmacological carrier selected for the intended method of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, in capsules alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They are injected parenterally, such as intravenously, intramuscularly or subcutaneously. For parenteral administration, it is most suitable to be used in the form of a sterile aqueous solution containing sufficient salt or other solutes such as glucose to make the solution uniform.

When administered to humans in the treatment or prophylaxis of cardiac symptoms such as impaired heart attack, the most active dose of the compound of the present invention is about 20 mg-lg per day for the average patient (70 kg). It is expected to be taken in four rounds.

Intravenous dosages are expected to be in the range of 1-30 mg per single dose, as desired, for example in the treatment of acute heart failure. Thus, for a typical adult patient, each tablet or capsule may contain about 5-500 mg of the active compound in a suitable pharmacological medium or carrier.

Accordingly, the present invention provides a pharmacological composition consisting of the compound of formula (I) and a pharmacologically water-soluble carrier. ,

The present invention also provides a method for stimulating an animal's heart, wherein the method is administered to the animal in an amount sufficient to stimulate the animal's heart, or a compound of formula (I) as defined above or a pharmacological composition as defined above. ·

A compound of formula (I) wherein X is-(CH ₂ ) _P -and Y is -NR ⁴ CONHR ⁶ or -NR ⁴ CSNHR ⁶ is a compound of formula (V) wherein quinazoline is an isocyanate R ⁶ NCO or isothio By reacting with cyanate R ⁶ NCS, wherein R ⁶ is other than hydrogen, or by preparing R ⁶ is H, sodium or kalium cyanate, or by preparing thiocyanate in the presence of an acid.

Wherein X is-(CH ₂ ) _P- .

In order to prepare compounds wherein R ⁶ is other than hydrogen, this reaction is preferably carried out by leaving the reaction at room temperature for up to about 3 hours in an inert organic solvent such as chloroform. The product is then separated by evaporation of the solvent and the resulting residue is recrystallized from the appropriate solvent by conventional methods. Alternatively, the residue is reacted with an acid to form a salt and then purified as above.

To prepare compounds in which R ⁶ is hydrogen, the reactions are heated together in the presence of an acid under reflux in a suitable solvent such as an ethanol solution. The acid is fed by using acid molar salts of the compound of formula (I) as starting material.

Isocyanate or isocyanate groups, or groups capable of reacting with -NH- groups in -NHR of ring C as well as other cyanates or thiocyanates as required, should be protected by conventional protecting groups before the reaction, and protecting groups after the reaction. It is removed by standard procedures. Groups that need to be protected include hydroxy, primary amino and secondary amino, which may exist as R ² , R ⁴ and R ⁶ .

Compounds of general formula (I) wherein X is-(CH ₂ ) _P -and Y is -OCONHR ⁶ or -OCSNHR ⁶ are formulated with a quinazoline of formula (V): isocyanate R ⁶ NCO or isothiocyanate R ⁶ NCS (Wherein R ⁶ is not hydrogen) or in the presence of an acid to prepare a compound or thiocyanate wherein R ⁶ is hydrogen, sodium or carliumcyanate. The reactions are generally heated together in an inert organic solvent at about 100-200 ° C., for example 24-48 hours in a stainless steel vessel.

Wherein X is-(CH ₂ ) _P- .

Groups capable of reacting with isocyanate or isothiocyanate groups, and suitably with cyanates or isocyanates other than the -OH group of ring C, should be protected before the reaction as required, i.e. in the same manner as described in Method B. In a similar manner, the end products can typically be separated by the methods described above.

All substituents in R ² and R ⁶ which can react with —CH ₂ COOH or activated ester groups, ie primary and secondary amino groups, are protected before the reaction as required and should be removed after the reaction.

Acid addition salts of compounds of general formula (I) are prepared by conventional methods of reacting free bases with acids in an inert solvent, i.e., by reacting each reactant with an alcoholic solution and collecting the precipitate produced by filtration. It can be prepared from pure free base product. The product is then recrystallized and purified.

In the above method, the carbetoxy-substituted lower alkyl group should be minded of the possibility of being attacked by the primary and secondary amino groups, especially in the case of preparing a compound in which R ⁴ or R ⁶ contains a carboxy group. do.

The invention is illustrated by the following examples in which all temperatures are given in degrees Celsius.

Example l

(A) Preparation of 4- {4- (2-pyridylmethylamino) piperidine} -6,7-dimethoxyquinazoline

1- (6,7-dimethoxyquinazolin-4-yl) piperid-4-one (2.9 g) and 2-amino-methylpyridine (1.19 g) were added to the dean end stark in benzene (50 ml) for 2 hours. (Dean & Stark) were refluxed together into a flask equipped with a trap.

To the ethanol (50 ml) cooled solution was added sodium borohydride (0.76 g) slowly with stirring. Agitation was continued for 2 hours when the addition was complete and then excess vinegar acid was added. The reaction mixture was poured into water, basified with 5N-NaOH and extracted with chloroform. The chloroform layer was evaporated to give yellow oil, which was triturated with ethyl to solidify. Recrystallization from ethyl acetate gave 4- [4- (2-pyridylmethyl-amino) piperidine] -6,7-dimethoxyquinazoline (2 g), and a melting point (151-155 ° C.).

(B) Preparation of 4- [4- {3-n-butyl-1- (2-pyridylmethyl) ureido} piperidino] -6,7-dimethoxquinazoline

N-butyl isocyanate (1 g) in a solution obtained by stirring 4- [4- (2-pyridylmethylamino) piperidine] -6,7-dimethoxy quinazoline (1.4 g) prepared in the above in anhydrous chloroform. ) Was added slowly and left at room temperature for 30 minutes. The solution was evaporated to dryness in vacuo to give a yellow oil which was triturated with ether and crystallized. Recrystallization from ethyl acetate gave 4- [4- {3-n-butyl-1- (2-pyridylmethyl) ureido} piperidine] -6,7-dimethoxy quinazoline as yellow crystals. Melting point, 162-4 ° C., for analysis C ₂₆ H ₃₄ N ₆ O ₃

Example 2

(A) Preparation of 4-4- (methylamino) piperidino-6,7-dimethoxy quinazoline acetate

1- (6,7-dimethoxyquinazolin-4-yl) piperid-4-one (14.35 g) and ethanol methylamine (33% W / W: 23.5 g) overnight in anhydrous ethanol (150 ml) Stirred. Sodium borohydride (2.0 g) was slowly added under nitrogen atmosphere while cooling. The reaction mixture was then refluxed for 1 hour, cooled to room temperature and then treated carefully with excess vinegar acid.

The reaction mixture was diluted with water, basified 5N-NaOH and extracted with chloroform. After separation, the chloroform phase was dried (MgSO ₄ ) and evaporated to give a crude oily product (10 g), which was triturated with a mixture of ethyl acetate and ether and crystallized.

Recrystallization from acetonitrile and then from ethyl acetate gave pure 4- [4- (methylamino) pyridino] -6,7-dimethoxyquinazoline acetate. Melting Point 169-l72 ℃

Daebya to the analysis _{C 16 H 22 N 4 O 2} · C 2 H 4 O 2

(B) Preparation of 4- [4- (1-methyl-3-n-propyl-ureido) piperidino] -6,7-dimethoxyquinazoline

4- [4- (methylamino) piperidino] -6,7-dimethoxyquinazoline (1.7 g) was dissolved in chloroform (10 ml) and treated with n-propyl isocyanate (0.5 g). After standing at room temperature overnight the mixture was evaporated to dryness. It was triturated with ethyl acetate and the residue solidified. Recrystallization from ethanol gave pure 4- [4- {1-methyl-3-n-propyl-ureido}] piperidino] -6,7-dimethoxyquinazoline (0.4 g).

Melting point 209-11 ℃

H₂O이 대하여Analytical C ₂₀ H ₂₉ N ₅ O ₃

About H ₂ O

Using the method of Examples 1 and 2, the following compounds were obtained from the appropriate 4-piperidino-quinazolin and isocyanate or isothiocyanate and separated in the indicated form. In Example 9 sodium cyanate was used. Theoretical and actual analytical values of the product are recorded, and the actual analytical values are given in parentheses.

Example 35

4- {4-hydroxypiperidino} -6,7-dimethoxy quinazoline (2.9 g) and 3-pyridyl isocyanate (1.3 g) were stainless steel at 150 ° C. for 24 hours in 40 ml of anhydrous dioxane. Heated in spring vessel The cooled mixture was concentrated in vacuo to give a brown sticky solid which was triturated with ether and filtered. Insoluble residue was crystallized from acetonitrile to give 4- [4- (3-pyridylcarbamoyloxy) piperidino] -6,7-dimethoxy quinazoline (1.4 g).

Melting Point 180-183 ℃

Suitable 4- {4-hydroxypiperidino) -quinazolin (or 4- (3-hydroxypyrrolidin-1-yl) -6,7 in the case of Example 44 using the method of Example 35) From the dimethoxy-quinazolin) and the appropriate isocyanate (or sodium cyanate in example 42) the following compounds were prepared and the product was separated in the indicated form. Theoretical and actual analyzes of the product are given, and the stall analysis is in parentheses.

TABLE IV

Example 45

2.81 kg of 4- (4-amino in a solution of 1.68 kg of triethylamine in 4- [4- (3-n-butylureido) piperidino] -6,7-dimethoxyquinazoline in 35,000 ml chloroform Piperidino) -6,7-dimethoxy quinazoline dihydrochloride was added. After half an hour, 8.30 g of n-butyl isocyanate was added and the reaction mixture was heated to reflux for 4 hours. The cooled mixture was washed with water, the volume was concentrated to 6,000 ml and 25,000 ml hexane was added.

The precipitated solid was collected by filtration to give 2.74 kg (92% yield) of the title compound. The product was recrystallized from aqueous ethanol and then chloroform-ethyl acetate to give a material having a melting point of 203 캜.

Claims (1)

The quinazoline of formula (V) is subjected to a temperature of 25 ° C. to 200 ° C. in an isocyanate of general formula R ⁶ -N = C = O or a thiodlsocyanate of general formula R ⁶ -N = C = S and an inert organic solvent A method for producing a quinazoline compound of formula (I) and acid addition salt thereof, which is characterized in that the product is recovered and then the product is recovered.

Wherein R ² is an alkoxy group having 1 to 4 carbon atoms, A is NHR ⁴ or OH, and Y is N (R ⁴ ) -CO-NHR ⁶ , N (R ⁴ ) -CSNHR ⁶ , O -CO- NHR ⁶ or O-CS-NHR ⁶ , R ⁴ is hydrogen, alkyl having 1 to 4 carbon atoms, benzyl, pyridylmethyl or hydroxylethyl, and R ⁶ is alkyl having 1 to 6 carbon atoms, phenyl. Pyridyl or ethoxycarbonyl methyl.