DE2514558A1 - NEW ORGANIC COMPOUNDS AND PROCEDURES FOR THEIR PRODUCTION - Google Patents

Description

25H558

SANDOZ - PATENT- GMBH Case 600-6641

76-, ΰ Loerrach

New organic compounds and processes for their

Manufacturing

The invention relates to new diaminopyridines of the formula I,

^R 2

R-HN

wherein R and R 'are the same or different and each represent a secondary or tertiary alkyl group with up to 7 carbon atoms, R _{1 represents} hydrogen or an alkyl group having 1-4 carbon atoms, and either R _{2 represents} hydrogen if R represents hydrogen , or R is hydrogen, chlorine or bromine, if R

^ 1

represents an alkyl group with 1-4 carbon atoms, R

609843/0903

600-6641

Hydrogen, a cyano group or a radical of the formula -COR. means in which R. is amino, an alkyl group with 1-4 carbon atoms or a radical of the formula II,

^R 5

E ₇

means in which either R ₁ -, R _fi or R_ are identical or different and each mean hydrogen, fluorine, chlorine, bromine or an alkyl or an alkoxy group each having 1-3 carbon atoms, with the proviso that R ~, R , or R_ does not represent halogen in the ortho position of the phenyl radical, or 2 of the substituents R _1. , R ^ and R _n , provided they are located on adjacent carbon atoms, together represent a methylenedioxy group, and the other of these substituents has the above meaning, with the proviso, if R_ stands for a cyano group, R and R ^{1 are} identical or different and each have a tert. Alkyl radical with 4-7 carbon atoms mean «

The compounds of the formula I can be converted into their salts and vice versa.

According to the invention, either a) compounds of the formula Ia are obtained,

509843/0903

25H55S

- 3 - 600-6641

Yes

^; N '
R-HN "NH-R '

in which R, R ¹ and R _{1 have the} above meaning, and R 'has the same meaning as R _f with the exception that it cannot stand for an alkanoyl group, by using compounds of the formula III,

III

where R ₁ and R 'have the above meaning and either X and X ^{1 are} identical or different and each represent chlorine or bromine, or one of the substituents X and X ^{1 is} chlorine or bromine and the other is R-NH- or R ¹ -NH-, in which R and R 'have the above meaning, with an amine or an amine mixture of the formula IV,

R / R'-NH ₂ IV

where R / R ^{1 have the} above meaning, converts, b) to compounds of the formula Ib,

Ib

R-HN

509843/0903

25H558

- 4 - 600-6641

in which R and R ^{1 have the} above meaning, R ₁ 'denotes an alkyl group with 1-4 carbon atoms and R' denotes an alkyl group with 1-4 carbon atoms or a radical of the formula II by using compounds of the formula Va,

R '- C-CH = C = N-R Va

wherein R and R ₁ 'have the above meaning, with compounds of the formula VI,

R '-C = CH-C = N-R' VI

⁴ I.

NH ₀ .

wherein R ¹ and R 'have the above meaning, reacts in the presence of a strong base,

c) to compounds of the formula Ic,

Ic

R-St.

wherein R, R ¹ , R and R "have the above meaning by adding compounds of the formula Id,

509843/0 903

600-6641

R-H

"CORJ

Id

wherein R, R ¹ , R. and R have the above meanings, and R, "stands for an alkyl group with 1-4 carbon atoms, hydrolyzed,

d) to compounds of the formula Ie,

R-H

Ie

in which R, R ¹ , R 'and R have the above meanings, and R' stands for chlorine or bromine, by using compounds of the formula If,

R-HN

If

wherein R, R ¹ , R 'and R have the above meanings, chlorinated or brominated in an inert organic solvent, or

509843/0903

600-6641

e) to compounds of the formula Ig,

^R l

R-HN

NH-R ¹

ig

in which R _r R ¹ and R have the above meaning, and R '"is an alkyl group having 1-4 carbon atoms or phenyl, by using compounds of the formula VIII,

R-HN

VIII

NH-R '

V7orin R, R ¹ , R- and R '"have the above meaning, hydrolyzed.

The procedure specified under a) can be carried out as described below:

The reaction of compounds of the formula III with compounds of the formula IV is expediently carried out at temperatures from 20 to 200 ° C, preferably from 160 to 180 ° C, it is preferred to carry out the reaction at higher Carry out temperatures, if large-volume and sterically hindered amines of the formula IV, for example

509843/0903

25H558

- 7 - 6U0-6641

tert. Alky! Amines, can be used. The implementation takes place conveniently in an inert organic solvent, for example an alkanol with 1-4 carbon atoms, for example ethanol. Instead of an inert organic solvent, an excess of the Amine form the reaction medium.

With the aid of the reaction, two amino groups can be introduced if X and X ¹ each represent chlorine or bromine in the compounds of the formula III, or a single amino group if one of these substituents is already an amino group. If two amino groups are introduced, at least two equivalents of compounds of the formula IV are used and, if an amino group is to be introduced, at least one equivalent of compounds of the formula IV. A small excess, for example of 10%, of the amino component should advantageously be used as an acid-binding agent be used.

In the compounds of the formula III, X and X ¹ , if they are halogen, are preferably chlorine. ^{If R and R 1 are} different in the desired end products and X and X ¹ in the starting compounds of the formula III are each chlorine or bromine, a mixture of amines of the formula IV is used, a mixture of end products being obtained. These can be separated in a manner known per se. To make such mixed

509843/0903

25H558

COO-6641

substituted connecting rods, however, it is advisable to as starting compounds, compounds of the formula IHa,

HIa

₁ and R 'have the above meaning, and either

X for chlorine or bromine and X * for R'-NH- or X for

JL al JL

R-NH- and X ¹ stand for chlorine or bromine, to be used. However, these starting compounds can also be used to prepare compounds of the formula Ia in which R and R 'are the same.

Compounds of the formula IiIa can be prepared by adding compounds of the formula IHb,

IHb

where R and R 'have the above meaning, and X_ and X' are identical or different and each represent chlorine or bromine, is reacted with an amine of the formula IV.

509 8 4 3/0903

25H558

- 9 - COO-6641

The reaction of compounds of the formula IUb with compounds of the formula IV is conveniently carried out at temperatures from 20 to 25 ° C., conveniently in an inert organic solvent such as an alkanol having 1-4 carbon atoms, in particular ethanol. The reaction, in which the compounds of the formulas IHb and IV are expediently used in a ratio of 1: 1, leads to a mixture of compounds of the formula IHa in which either X represents an amino group which corresponds to the compound IV used, or to a compound of the formula HIa, in which X 'represents an amino group which corresponds to the compound of the formula IV used. The composition of this mixture depends on the nature of the amine used. For example, relatively sterically unhindered amines, preferably the hydrogen atom in position 2, will replace. In any case, the individual isomers for use in process a) can be separated and purified in a manner known per se,

The procedure given in section b) can be carried out as follows carried out as described:

The strong bases used in the reaction of compounds of the formula Va with compounds of the formula VI are for example a lower-alkyllithium, for example methyl- or n-butyl-lithium, sodium or potassium lower alkoxides, for example sodium methoxide or potassium t-butoxide, alkali metal hydroxides, for example

509843 / -0903

- 10 - 60U-6641

Lithium, sodium or potassium hydroxides, metal hydrides, for example sodium or calcium hydride, and lithium diisopropyl amides, preferably the latter or n-butyllithium. One equivalent of the base is preferably used, based on compounds of the formula VI. The reaction is expediently carried out at temperatures from 15 to 60 ° C., preferably from 20 to 30 ° C., under an inert gas atmosphere, preferably a nitrogen atmosphere. The reaction is conveniently carried out in an inert organic solvent, for example an acyclic ether with 5-10 carbon atoms, a cyclic ether, for example p-dioxane or tetrahydrofuran, a 2-lower alkoxyethyl ether, for example bis-2-methoxyethyl ether or bis-2- ethoxyethyl ether, and a lower alkyl ether of ethylene glycol, for example 1,2-diinethoxyethane _? I ^ 2-diethoxyethane or l-ethoxy-2-methoxyethano tetrahydrofuran and p-dioxane are preferred. Mixtures of these solvents with alkanes, for example of 6 × 10 carbon atoms, can also be used. The reaction time can be, for example, from 30 to 180 minutes, in particular from 30 to 120 minutes. The molar ratio of the amidine of the formula VI to the ketoketonimide of the formula V is expediently 1: 1, although a small excess, for example up to 10% of the latter, can also be used.

When carrying out process b) one often arrives at unidentifiable by-products. The desired

509843/0503

25H558

- 11 - S00--6641

However, compounds of the formula Ib can be isolated from the mixture in a manner known per se. The by-products can, however, conveniently also be converted into compounds of the formula Ib after isolation are ^ conveniently heated for this purpose, the by-products to temperatures of 35 to 70 ° C, preferably from 40 to 60 ° C, in an inert organic solvent, for example a solvent as described above for the Process b) has been described, or a lower alcohol such as ethanol, methanol or isopropanol, or an aqueous mixture thereof. The heating should preferably last for 1 to 60, preferably 5 to 30 minutes, take place.

The starting compounds of the formula VI can conveniently be obtained by adding compounds of the Formula V,

R ₄ '-C-CH = C = NR ¹ V

wherein R 'and R' have the above meanings, or a compound of formula VII,

VII

509843/0903

25U558

- 12 ~ 60C-6641-

where R ¹ and R 'have the above meaning and A is an anion which does not participate in the reaction, for example a perchlorate, tetrafluoroborate, methyl sulfate, ethyl sulfate, bisulfate, chloride, bromide, iodide or p-toluenesulfonate, is reacted with ammonia.

The reaction of compounds of the formula V or of compounds of the formula VII with ammonia is expedient in an inert organic solvent, for example methylene chloride, carried out, where anhydrous liquid ammonia is used for this. The reaction is conveniently carried out at temperatures of -40 ° to -60 ° C with stirring, for example for 5 to 60 minutes. The implementation can expediently in an inert gas atmosphere, e.g. nitrogen atmosphere, take place.

The compounds of the formula V, including those of the formula Va, used in the process of section b) as starting compounds are either known or can be used in a manner known per se from known starting compounds getting produced. A convenient method is that you have appropriate connections of Formula VII with a base using the method described by Woodward et al., in J. Am. Chem. Soc "jB_8, 3169-3170 Process implements. The process is preferably carried out in such a way that a triethylamine is used as the base and used as an inert organic solvent, methylene dichloride. Temperatures of

509843/0903

25H558

- 13 - 600-6641

-10 ° to 0 ° C is appropriate, and the reaction time can be, for example, between 15 minutes and 4 hours. Ammonia can also be used for this purpose, but this is not preferred, the compounds if desired of the formula V to isolate, because ammonia reacts with those as described above and delivers here Compounds of Formula VI.

The compounds of the formulas V and VI obtained can be isolated and purified in a manner known per se.

Both starting compounds of process b) can be obtained by treating compounds of formula VII with ammonia. An alternative to method b) therefore concerns the preparation of these starting materials in situ and perhaps only as a temporary one occurring intermediate. In this variant of the procedure a compound of the formula VII with ammonia is conveniently at temperatures of 15 to 30 ° C, preferably from 15 to 25 ° C. The reaction is expediently using anhydrous Ammonia carried out in an inert organic solvent. Suitable solvents are halogenated lower ones Alkanes, such as methylene dichloride, 1,2-dichloroethane, 1,2-dibromoethane, Chloroform, 1,1,1-trichloroethane and 1-bromo-2-chloroethane, Dialkyl ethers with 5-10 carbon atoms, cyclic ethers such as p-dioxane or tetrahydrofuran, N, N-dimethyl acetamide, and formic acid amides, for example Formamide or its mono- or di-lower-alkyl derivatives,

509843/0903

25U558

- 14 - 600-6641

such as N-ethy! formamide, Ν, Ν-dimethyl or diethy! formamide or N-methyl-N-ethy-formamide. Halogenated lower Alkanes, especially methylene dichloride, are preferred. The reaction is expediently in an inert Gas atmosphere, for example in nitrogen atmosphere, carried out, and the reaction time is, for example, from 2 to 10 days, especially from 3 to 5 days. The ratio of ammonia to compounds of the formula VII can be up to 3: 2, but it is preferred Ammonia in a large 5- to 200-fold excess to add.

The procedure specified under c) can be carried out as follows be carried out as described:

The hydrolysis of compounds of the formula Id can occur on ah known manner, for example using aqueous mineral acids, for example hydrogen chloride acid, or organic acids, for example methanesulfonic acid. The procedure is conveniently carried out in an inert organic solvent, for example a lower alcohol, such as methanol, and conveniently at temperatures of 50 to 70 ° C, preferably at the boiling point of the reaction mixture. The reaction time can, for example, from 90 minutes to 5 hours, in particular from 150 minutes up to 4 hours. Preferably from 1.02 to 1.1 equivalents of acid and 1.2 to 2 equivalents are used Water. The hydrolysis can also expediently

509843/09 0 3

- 15 - 50C - 6641

with a base, for example hydroxylamine hydrochloride, be carried out, the reaction temperature conveniently from 20 to 50 ° C, preferably from 20 to 30 ° C, should be and the reaction time, for example, from 5 to 120 minutes.

The procedure given in section d) can be carried out as follows:

The chlorination or bromination of compounds of the formula If is expediently carried out using N-chloro- or N-bromosuccinimide as the chlorinating or brominating agent. Instead of these chlorinating or brominating agents, a solution of gaseous chlorine or liquid bromine in an inert organic solvent can also be used for this purpose. The reaction temperature is conveniently optionally N-chloro- or N-bromosuccinimide are from 0 ° to 30 ° C, preferably from 20 to 25 ° C ₁ is used, and from 0 ° to 10 ° C, if chlorine or bromine may be used, respectively. Suitable solvents are lower alkanols, such as ethanol and carbon tetrachloride, or, if chlorine or bromine is used, glacial acetic acid. The reaction time can be from half a hour to 12 hours, preferably from 1 to 3 hours.

The procedure given in section e) can be carried out as described below:

509843/0903

25U558

- 16 - 60Ü-6441

The hydrolysis of compounds of the formula VIII can be carried out in a manner customary for the hydrolysis of imines to ketones Wise carried out, for example using an acid, preferably acetic acid. Preferred becomes a dilute acid, especially 0.01 to 0.1N acetic acid. The reaction temperature is preferably 60 to 100 ° C, the reaction times from 5 to minutes.

The compounds of the formula I obtained can be isolated and purified in a manner known per se.

The process described in section b) is preferred for the preparation of compounds of the formula Ib in which one or both of the substituents R and R ^{1 are} tert. Alkyl stand.

The compounds of the formulas III, IV and VII, which are available as Starting compounds used are either known or can be obtained in a manner known per se from known starting compounds, for example as in Example 2a) described below for the compounds of the formula VII.

The compounds of the formula VIII which are used as starting compounds in process e) can, for example be prepared by adding a compound of the formula Ihn,

509843/0903

600-6641

N ' \ NH-R'

Him

wherein R _{1 has the} above meaning, and R ₀ and R ₀ 'are identical or different and each represent a secondary or tertiary alkyl with up to 7 carbon atoms, with compounds of the formula IX,

R ₄ ¹ "- Q

IX

where R "'

Has the above meaning and Q stands for lithium magnesium bromide or magnesium chloride, in one Reacts inert organic solvent and the adduct obtained is then hydrolyzed.

The reaction of compounds of the formula Ihn with compounds of the formula IX can be carried out in one for the conversion a nitrile can be converted into an imine by means of a Grignard reaction. Preferably at least 3, preferably from 3.01 to 20 equivalents of the compounds are used for the reaction of formula IX, and the reaction is conveniently at temperatures from 0 ° to 100 ° C, preferably at Carried out boiling temperature of the reaction mixture. Suitable solvents are ethers, such as tetrahydrofuran, or diethyl ether, especially mixtures thereof, and the reaction time can, for example, from 2 to 24 hours

509843/0903

25 U 558

- 18 - 60Ü-6641

be. The subsequent hydrolysis can, for example, be used for the hydrolysis of lithium or Grignard adducts be carried out in the usual manner, for example with the aid of aqueous ammonium chloride Temperatures of, for example, -10 ° to 0 ° C.

If desired, the compounds of the formula VIII obtained can be isolated and purified in a manner known per se will. However, the compounds are obtained in situ and can also be used in this way without further purification can be used in the next stage of the process.

The compounds of the formula Ihn, which are used to prepare the Starting compounds of section e) are used are outside the scope of protection of formula I. and are either known or can be obtained in a manner known per se from known starting material, for example using a process which is analogous to process a).

The compounds of formula I are characterized by a extremely beneficial therapeutic effect. The compounds of the formula I are particularly notable by an anti-obesity effect and an anti-diabetic effect. The connections can therefore to combat obesity and as anti-diabetic drugs be used. The daily dose to be administered of compounds of the formula I should be from 75 to 1500 mg

50 9 8 43/09 03

25H558

- 19 - 60C - 6641

which may be administered in smaller amounts of 20 to 750 mg 2-4 times a day or in sustained release form can be. A preferred daily dose is from 150 to 450 mg, optionally administered in 3 doses from 50 to 150 mg or in sustained release form.

The compounds of the formula I can be in the form of the free bases or in the form of their pharmaceutically acceptable acid addition salts, which have the same degree of effect as the free bases administered. For salt formation suitable acids are hydrochloric acid and hydrogen bromide acid and methanesulfonic acid.

The compounds of the formula I can be used together with customary pharmaceutically acceptable diluents or carriers and optionally other additives are mixed and administered in the form of capsules.

The preferred meanings of R, R ', R, R_ and R are The following:

R: tert. Alkyl of 4-7 carbon atoms, preferably 4-6 carbon atoms, especially tert. Butyl,

R ¹ : tert. Alkyl with 4-7, preferably 4-6 carbon atoms, especially tert. Butyl,

R-: alkyl with 1-4, preferably 1-3 carbon atoms, especially ethyl or methyl,

509843/0903

25H558

- 20 - 600-6641

R: hydrogen or bromine, preferably hydrogen,

R: hydrogen, cyano or -COR '", where R'" is alkyl with 1-4 carbon atoms, in particular 1-3 carbon atoms, amino or a group of Formula Ha,

Ha

denotes in which R 'and R ₆ ^{1 are} identical or different and each denotes hydrogen, ethyl, methyl, methoxy or ethoxy.

R preferably has the same meaning as R 'and R_ in particular has a different meaning than cyano or carboxymethyl and preferably represents hydrogen Acetyl, propionyl or 4-methoxybenzoyl.

The particularly preferred linking groups are those that combine the above meanings, especially those that combine all of them represent preferred meanings. The particularly preferred compound is 3-acetyl-2,6-di-t-butylamino-4-methylpyridine.

509843/0903

25H558

- 21 - 600-5641

Example 1: 2 , 6-di-t-buty! Amino-3-cyano-4-methylpyridine

1 g of 2,6-dichloro-3-cyano-4-methylpyridine and approx

40 ml of t-butylamine (distilled over sodium hydride) heated in an autoclave to 200 ° C. for 5 hours. Another heating for 4 hours on the same Temperature does not lead to any change in the reaction mixture. The reaction mixture is left to stand overnight and is then evaporated under reduced pressure. A rubbery residue is obtained here. This gummy solid residue is between water, which contains small amounts of sodium carbonate, and chloroform distributed and then the aqueous phase

Extracted 2 times with chloroform. The 3 chloroform phases are combined and dried over anhydrous sodium sulfate and evaporated at reduced pressure. The residue is dissolved in 10 ml of chloroform and the solution diluted to 70 ml with hexane. The small amount of crystals formed in this way is filtered off and the Filtrate in a column, in which there is a slurry of 50 ml of silica gel in hexane containing 20% chloroform, is located, where the elution takes place with the same reading medium mixture. The first 130 ml of the Eluate are discarded and the subsequent 100 ml eluate are evaporated, whereby the 6-t-butylamino-2-chloro-3-cyano-4-methylpyridine of m.p. 109 ° C obtained. The next fractions, which the desired compound contained are combined under reduced pressure

509843/09 03

25U558

- 22 - 60C - 6641

evaporated and mixed with hexane. After removing the The residue crystallizes out under reduced pressure in a refrigerator, where the 2,6-dit-butylamino-3-cyano-4-methylpyridine is obtained of m.p. 134-138 ° C obtained.

Example 2;

using the procedure described in Example 1 and from suitable starting compounds in approximately equivalent proportions one arrives at the following compounds:

a) 2 _/ 6-di-t-butylamino-3- (4'-methoxybenzoyl) -4-methylpyridine of melting point 127-129 ° C,

b) 2,6-di-t-butylamino-4-methylpyridine, its methanesulfonate melts at 179-182 ° C,

c) If 6-di-t-butylaminopyridine,

d) 3-Benzoyl-2,6-di-t-butylamino-4-methylpyridine,

e) 2,6-Di-t-butylamino ~ 3- (4'-methylbenzoyl) -4-methylpyridine,

f) 2,6-di-sec-butylamino-4-methylpyridine _r

g) 2-t-amylamino-6-t-butylamino-4-methylpyridine; and h) 2,6-di-t-butylamino-3-carbamoyl-4-methylpyridine.

509843/0903

25U558

- 23 - OOG ~ 6641

Example 3: 3-Acetyl-2,6-di-t-butylamino-4-methylpyridine

A mixture of 1 kg of 5-methylisoxazole and 892 g t-butanol is stirred under nitrogen at 0 ⁰ C and then 6.37 kg 60% perchloric acid slowly during 2 1/2 hours under vigorous stirring at 0 to 5 ° C offset. The remaining suspension is allowed to come to room temperature and is stirred overnight. The reaction mixture is then slowly added to a mixture of 20 liters of tetrahydrofuran and 10 liters of ether at 0 to 10 ° C. for 2 hours with stirring. The mixture obtained is then cooled to -5 ° C. and stirred for a further 2 hours. The 2-t-butyl-5-methylisoxazolium perchlorate which has precipitated is filtered off and washed with ether. The compound melts at 120 to 122 ° C. Another portion of the compound is obtained from the mother liquor. This portion melts at 118 to 121 ° C.

i) A solution of 100 g of 2-t-butyl-5-methylisoxazolium perchlorate in 200 ml of methylene chloride is under Stir to a mixture of 60 ml of anhydrous ammonia and 240 ml of methylene chloride at -50 ° C in Nitrogen atmosphere added. The reaction mixture is then left to stand until the reaction temperature is adopted and then with a saturated one Washed saline. The methylene

509843/0903

25H558

- 24 - 60C-GS41

chloride phase is over anhydrous magnesium sulfate dried. After removing the methylene chloride under reduced pressure, a residue is obtained. This is recrystallized from ethyl acetate, resulting in N'-t-butyl-3-hydroxybutenamidine with a melting point of 118-120 ° C got. Further recrystallization from ethyl acetate gives a melting point of 126-129 ° C.

ii) A solution of 900 g of 2-t-butyl-5-methylisoxazolium perchlorate in 1.8 liters of methylene chloride, which is about Alumina was dried, a mixture of 900 ml of freshly distilled ammonia and 900 ml Methylene chloride, which was dried over aluminum oxide, was added at -50 ° to -60 ° C. with stirring. Thereafter the reaction mixture is allowed to stand until it has reached room temperature and overnight touched. The excess ammonia is removed with the aid of a suction device at 20 to 25 ° C for 1 Hour away. The precipitate formed is filtered off and washed with methylene chloride. the combined filtrates and washing liquids are 2 times with 2 liters of a saturated aqueous Washed potassium carbonate solution, dried over anhydrous sodium sulfate and filtered off. After removal of methylene chloride under reduced pressure and at a temperature of about 45 ° C is obtained a residue which, after recrystallization from ethyl acetate and washing with ethyl acetate / ether

509843/0903

25U558

- 25 - 600-6641

the Ν'-t-butyl-3-hydroxybutenamidine of m.p. 126-129 ° C. Another portion that can also be obtained melts at 119-125 ° C.

A mixture of 700 ml of triethylamine and 1.5 l of methylene chloride is dried over aluminum oxide and cooled to a temperature of -10 ° to -5 ° C. Afterward 1 kg of 2-t-butyl-5-methylisoxazolium perchlorate is added in small portions over the course of 2 1/2 hours, with the temperature of the reaction mixture is kept at -5 ° to 0 ° C. with vigorous stirring. After completion after the addition, the reaction mixture will purge during a period of time Stirred at -5 ° to 0 ° C. for an hour. The reaction mixture is then dissolved in 38 l of carbon tetrachloride Room temperature entered with vigorous stirring, an oily solid precipitating out. After that, 7 1/2 kg anhydrous sodium sulfate was added and the reaction mixture was stirred for 30 minutes. The suspension will filtered off and the residue obtained washed with carbon tetrachloride. The combined filtrates and Wash liquids are at 50 ° C and reduced pressure evaporated to give a dark orange-yellow oil. By distillation in high vacuum (0.8 mm Hg) at 54-55 ° C., 4-t-butylimino-3-buten-2-one is obtained.

509843/090 3

25U558

- 26 - 600-6541

i) 3.17 g of the N'-t-butyl-3-hydroxybutenamidine obtained in process step b) is dissolved in 20 ml of tetrahydrofuran suspended and the suspension a mixture of 12.7 ml of a 1.6 molar solution of n-Butyllithium in hexane in a nitrogen atmosphere added »The subsequent exothermic reaction results in a solution with a temperature of 40 ° C The solution is stirred at 30 to 40 ° C. for 45 minutes and then with 2.8 g of the 4-t-butylimino-3-buten-2-one obtained in process step c) in 8 ml of tetrahydrofuran at 30 to 38 ° C., followed by a further addition of 2 ml of tetrahydrofuran. A precipitate forms after 10 minutes. Stirring is continued for an additional 35 minutes and the reaction mixture is left to stand overnight Reaction mixture after 45 minutes and the following morning is the same). The reaction mixture is cooled to -5 ° C. and 2 ml of a saturated ammonium chloride solution are added to the mixture. Sufficient chloroform and a trace of methanol are then added, a solution being formed will. This is evaporated under reduced pressure to give a mixture of oil and solids will. The mixture is distributed between chloroform and water and a small portion (approx. 1/2 g) a white insoluble substance is filtered off.

509843/090 3

25U558

600-6641

The aqueous phase is extracted again with chloroform, and the chloroform phase is extracted with the Chloroform phase of the initial distribution combined. The combined chloroform phases are over dried anhydrous magnesium sulfate, filtered and evaporated to a brown oil. The brown one OeI is dissolved in a small portion of methanol at 40 ° C and becomes the resulting solution Water added until the cloud remains cloudy. The 3-acetyl-2,6-dit-butylamino-4-methylpyridine crystallizes here in the form of yellow needles. After washing with small proportions of a 1: 1 mixture of methanol and water, the melts Connect at 127-128 ° C.

NMR (CDCl ₃ ):

1.43 S (9 proton singlet) 1.47 S (9 proton singlet) 2.32 S (3 proton singlet) 2.43 S (3 proton singlet) 4.60 S (1 broad proton band

interchangeable)

5.47 S (1 broad proton singlet) 9.94 δ (1 broad proton band

interchangeable)

IR (CHCl ₃ ):

3440, 2985, 1720 (v. Weak), 1605-1580, 1525, 1450, 1420, 1390,

1360, 1290, 1210, 960 cm

-1

509843/0903

25U558

- 28 - 600-6441

UV (CH ₀ OH): λ 222 mu (<£ = 13.650) 3 max '

λ 267 mu (<5 = 15,000) ^iX max ^r

λ 286 rough (C = 10.670) max

X 368 mu (<£ = 20,500) 'Max " '

ii) A mixture of 468 g of the in the process step b) obtained N'-t-butyl-3-hydroxybutenamidine and 6 l of anhydrous tetrahydrofuran is under nitrogen stirred at room temperature and then added dropwise with 1.92 l of a 1.6 molar solution of n-butyllithium in hexane are added dropwise at such a rate that the reaction mixture remains at a temperature of 20 to 40 ° C. After the addition is complete, the reaction mixture is at room temperature for a further Hour stirred. A solution of 417 g is then obtained in process step c) 4-t-Butylimino-3-buten-2-one in 2 L of anhydrous tetrahydrofuran dropwise with cooling added so that the reaction temperature remains at 20 to 25 ° C. After the addition is complete the reaction mixture is stirred overnight at room temperature and then with about 1.2 a saturated aqueous ammonium chloride solution is added, a voluminous white precipitate arises. 12 l of methanol and 12 kg of anhydrous sodium sulfate are then added and the reaction mixture filtered through diatomaceous earth. The filtrate

509843/0903

- 29 - 600-6641 '

is evaporated to dryness under reduced pressure and the residue is dissolved in 25 1 of chloroform. the Chloroform solution is 2 times with 25 1 parts of water and washed once with 25 l of a saturated aqueous sodium chloride solution, over anhydrous Dried sodium sulfate and filtered through silica gel. The clear yellow filtrate will be at about 50 ° C evaporated to dryness under reduced pressure and treated with 5 l of petroleum ether while cooling. Here 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained from m.p. 127-129 ° C.

The free base of the compound can be converted into its hydrobromide by adding a 1.6 N solution of gaseous hydrogen bromide in ether dropwise to a solution of the free base in ether at 0 to 10 ° C with the following Stirring can be transferred for 1 hour. The precipitate formed is washed with ether and extracted with chloroform. Activated animal charcoal is added to the extract and diatomaceous earth is added to the mixture filtered, the filtrate evaporated under reduced pressure and here the hydrobromide of 3-acetyl-2,6-di-t-butyiamino-4-methylpyridine obtained from m.p. 172-175 ° C.

As described above, but when the ethereal hydrogen bromide solution is replaced by a 5.5N solution of gaseous one Hydrochloride is obtained from hydrogen chloride in ether or a solution of methanesulphonic acid in ether the abovementioned compound with m.p. 164-166 ° C. and the methanesulfonate of the abovementioned compound with mp. 118-121 ° C.

509843/0903

- 30 - 600-6641

Example 4; 3-acetyl-2 , 6-di-t-butylamino-4-n-ethylpyridine

a) Unidentified_by-product

73.6 ml of a 1.622 M solution of n-butyllithium in hexane (119 mmol) is added to a solution of 18.6 g of the in the Process step b) of Example 3 obtained N'-t-butyl-3-hydroxybutenamidine added in tetrahydrofuran at 25 to 40 ° C under nitrogen. After finishing the initial The reaction mixture is allowed to exothermic reaction Cool to room temperature by stirring for 1 hour. A solution of 16.6 g of the 4-t-butylimino-3-buten-2-one obtained in process step c) of Example 3 is then added in tetrahydrofuran added dropwise at room temperature (23-25 ° C). The reaction mixture is stirred overnight. Thereafter, 4 ml of a saturated aqueous ammonium chloride solution is added, followed by enough methanol to make a dark colored solution. This is evaporated under reduced pressure. The residue obtained is partitioned between chloroform and water, and the insoluble white solid is through Filtering isolated. This substance melts at 130 ° C (with decomposition).

Elemental analysis: C 55.8-56%

H 8.3-8.4%
N 11.7%

NMR (CD ₃ OD): £ 1.43 (singlet)

£ 1.47 (singlet)
2.23 S (singlet)
4.80 S (singlet)

509843/09 * 03

25U558

6C0-6641

I.R. (Nujol):

3370, 3280, 3120, 2880-2890, 1605, 1580, 1500, 1460, 1420, 1400, 1385, 1370, 1255, 1240, 1230, 1180, 1125, 1095, 1050, 990, 970 cm " ¹

U.V. (Methanol): 218 mu (£ = 443 1% solution)

264 mu (£ = 638 1% solution) 365 mp (c = 650 1% solution)

The chloroform phase of the chloroform / water partition is dried and evaporated under reduced pressure, whereby a brown solid is obtained. Treatment of the brown solid with methylene chloride gives an insoluble solid with a melting point of 130 ° C. (with decomposition).

b) ^^ AcetYl - ^^ e-di-t-but ^ lamin- ^ methYlgYridin

i) A small proportion of the compound of reaction stage a) is recrystallized from methanol / water, wherein the 3-acetyl-2,6-di-t-butylamino-4-methylpyridine in the form of a yellow precipitate soluble in chloroform of m.p. 127-128 ° C (the m.p. of a mixture of this compound with the same different received connection is not degraded).

ii) The compound obtained in the process materials a) is in aqueous methanol for 5 minutes to Boiling heated. Yellow crystals precipitate, which are filtered off and mixed with a 1: 1 mixture of Me-

509843/0903

25H558

- 32 - 6C0-6641

ethanol. The 3-acetyl 2,6-di-t-butylamino-4-methylpyridine thus obtained melts 127-128 ° C.

Example 5: 2,6-Di-tert-butylamino-3- (4'-methoxybenzoyl) -4- methylpyridine

The N'-t-butyl-3-hydroxy-3- (4'-methoxyphenyl) propenamidine from m.p. 166-16 8 ° C can be obtained using the in the Examples 3 a) and 3 b) described methods using suitable starting compounds in approximately get equivalent shares.

b) ^^ e-Di-t-butYlamino-S - ^^^ - niethoxYbenzoYl) -4-inet.hy_l £ y_ridin

1.24 ml of a 1.6 molar solution of n-butyllithium in hexane is slowly added to a solution of 500 mg of N'-t-butyl-3-hydroxy-3- (4'-methoxyphenyl) propenamidine in 10 ml of dry tetrahydrofuran, which is stirred under nitrogen, added «, The temperature of the reaction mixture rises by 35 ° C. during the addition. The reaction mixture is left for 15 minutes stirred and then with 2.2 ml of a 1 M solution of the obtained using process step c) of Example 3 4-t-Butylamino-3-buten-2-one in dioxane is slowly added. The reaction mixture is then during stirred for a further hour and treated with 1 ml of a saturated aqueous ammonium chloride solution. The reaction mixture is extracted with chloroform and water and the

5 09843/0903

25U558

- 33 - 600-6641

Chloroform extract dried over anhydrous sodium sulfate. After its evaporation under reduced pressure is obtained one an OeI. This is dissolved in ether and the ethereal solution nLt 2N hydrochloric acid and then twice with Washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from ether / heptane, whereby one to 2,6-di-t-butylamino-3- (4'-methoxybenzoyl) -4-methylpyridine of m.p. 127-129 ° C reached.

Example 6: 3-Acetyl ~ 2,6-di-t-butylamino-4- methylpyridine

Approximately 60 ml of anhydrous ammonia is condensed in a container containing 60 ml of methylene chloride. The reaction mixture is kept under nitrogen at a temperature which should not exceed -30 ° C. A solution of 50 g of 2-t-butyl-5-methylisoxazolium perchlorate is then added added rapidly in 100 ml of methylene chloride. The reaction noise is left to stand until it Has assumed room temperature, and then stirred for 4 days at room temperature. After that, that will Removed methylene chloride at reduced pressure to give a gummy solid which after treatment turns into a yellow solid with water. After recrystallization 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained from methanol / water from m.p. 128-129 ° C.

509843/0903

25 U 558

- 34 -. 6C0-6641

Example 7:

Using the procedures of any one of Examples 3-14 and appropriate starting compounds in approximately equivalents Proportions one arrives at the compounds of the examples (only analogous to example 5), 2a) (analogous to examples 3, and 5), 2 d) and 2 e) and the following connections:

a) 2,6-Di-isopropylamino-4-ethyl ~ 3 ~ propionylpyridine,

b) 3-Acety 1-2,6-di ~ t ~ arnylamino-4 ~ methyl pyridine,

c) 2,6-di-t-butylamino-3- (4'-methylbenzoyl) -4-methylpyridine,

d) 2,6-di-t'-butylamino "4-ethyl-3-propionylpyridine and

e) 3 ~ acetyl-2,5-di- (1,1-diethylpropylamino) ~ 4 ~ methylpyridine.

Example 8 : 2,6-Di-t- butylamino-4- methylpyridine

A mixture of 4.22 g of 3-acetyl-2,6 ~ di-t-butylamino-4-methylpyridine, 1 ml methanesulfonic acid and 0.5 ml water in 50 ml of methanol is heated to boiling for 3 hours. The precipitate formed on cooling is filtered off and the filtrate evaporated. Treatment of the residue with ether gives 2,6-di-t-butylamino-4-methylpyridine methanesulfonate of m.p. 168 ° C (with decomposition). After recrystallization from Ethyl acetate melts the compound at 181-182 ° C. One another portion with a melting point of 179-181 ° C. is obtained from the mother liquor.

5Ό9843 / 0903

25U558

- 35 - 6C0-6641

Example 9;

Using the procedure described in Example 8 and corresponding starting compounds in approximately equivalent Fraction leads to the compounds of Examples 2 c), 2 f) and 2 g).

Example 10: 3-Acetyl-5-bromo-2, G-di- t-butylamine-4-methyl pyridine

534 mg N-bromosuccinimide (recrystallized from water) are added in small portions to a solution of 831 mg of 3-acetyl-2,6-di-t-butylamino ~ 4-methylpyridine in 20 ml Carbon tetrachloride and 5 ml of ethanol are added and the reaction mixture is kept overnight at room temperature The reaction mixture is evaporated under reduced pressure and the residue between ether and Water distributed. The organic phase is dried over anhydrous sodium sulfate and under reduced pressure evaporated. This gives yellow crystals. After recrystallization 3-acetyl-5-bromo-2,6-di-t-butylamino-4-methylpyridine is obtained from methanol / water M.p. 99-100 ° C.

Example 11:

Using the process described in Example 10 and corresponding starting compounds in approximately equivalent proportions, 3-acetyl-5-chloro-2 _/ 6-dit-butylamino-4-methylpyridine is obtained.

509843/0903

25U558

- 36 - 600-OC41

Example 12: 3-acetyl-2,6-di-t-butylaminopyridine

250 ml of a 0.4 molar solution of methyllithium in Diethyl ether is added dropwise to a solution of 6 g of 3-cyano-2,6-di-t-butylaminopyridine in 350 ml of dry Tetrahydrofuran was added at -15 ° C. with stirring and in a nitrogen atmosphere. The mixture is then left to stand until it reaches room temperature and then heated to boiling for 4 hours. After the Boiling is cooled to 0 ° C and the mixture with a solution of 17 g of ammonium chloride in 100 ml of water at -4 offset to -10 ° C. Tetrahydrofuran and ether v / earth removed under reduced pressure and the residue between Methylene chloride and water distributed. The methylene chloride layer is dried over anhydrous sodium sulfate and the methylene chloride is then removed under reduced pressure. The crude imine obtained (compound of Formula VIII) is added to 100 ml of a 0.01 N acetic acid and the mixture is heated to 80 ° C. for 2 hours. The mixture is then allowed to cool and extracted with methylene chloride. The methylene chloride extract is under evaporated under reduced pressure and the resulting crude 3-acetyl-2,6-di-t-butylaminopyridine by chromatography purified on silica gel.

5098A3 / 0903

Claims (3)

25U558 - 37 - 6C0-6b-il Claims Process for the preparation of new diaminopyridines of the formula I, RI ¹ R. s 3 R-HN. NHR ¹ where R and R ^{1 are} identical or different and each represent a secondary or tertiary alkyl group with up to 7 carbon atoms, R represents hydrogen or an alkyl group having 1-4 carbon atoms, and either R _{2 represents} hydrogen, if R, is hydrogen, or R _{2 is} hydrogen, chlorine or 3rom, if R is an alkyl group with 1-4 carbon atoms, R is hydrogen, a cyano group or a radical of the formula -COR, in which R. is amino, an alkyl group with 1- 4 carbon atoms or a radical of the formula II, R ₅ denotes in which either R ^, R _ß or R_ are identical or different and each denotes hydrogen, fluorine, chlorine, bromine or an alkyl or an alkoxy group each having 1-3 carbon atoms, with the proviso that R_, R or R_ are not stand for halogen in the ortho position of the phenyl radical, or 2 of the substituents R_, R_ and R_, provided that whether ι 509843/090 3 25U558 - 38 - 6C0-6641 they are located on adjacent carbon atoms, together represent a methylenedioxy group, and the other of these substituents. Has the above meaning, with the proviso, if R _{3 stands} for a cyano group, R and R ^{1 are} identical or different and each have a tert. Alkyl radical with 4-7 carbon fatoir.en mean, characterized in that one a) to compounds of the formula Ia Yes R-HN NH-R ■ arrives, in which R, R ¹ and R have the above meaning, and R ^{r has} the same meaning as R, with the exception that it cannot stand for an alkane group, by using compounds of the formula III, III where R and R ₃ ^{1 have the} above meaning and either X and X ^{1 are} identical or different and each represent chlorine or bromine, or one of the substituents X and X ^{f represents} chlorine or bromine and the other represents R-NH- or R ¹ -NH-, in which R and R ^{1 have the} above meaning, with an amine or an anion of the formula IV, 509843/0903 25U558 - 39 - 600-66 * 1 R / R'-NH ₂ IV where R / R ^{1 have the} above meaning, converts, b) to compounds of the formula Ib, Ib NH-R ' arrives, in which R and R ^{1 have the} above meaning, R ₁ ¹ denotes an alkyl group with 1-4 carbon atoms and R 'represents an alkyl group with 1-4 carbon atoms or a radical of the formula II by using compounds of the formula Va, R '-C-CH = C = N-R Va where R and R. ' have the above meaning with compounds of formula VI, R 1 -C = CH-C = NR ¹ VI wherein R ¹ and R ₄ ^{1 have the} above meaning, reacts in the presence of a strong base, 509843/0903 25U558 600-6641 c) to compounds of the formula Ic, R-H Ic where R, R ¹ , R by using compounds of the formula Id, and R _? have the above meaning, R ₂ RH "COR] J Id where R, R ¹ , R, and R_ have the above meaning, and R. "stands for an alkyl group with 1-4 carbon atoms, hydrolyzed, d) to compounds of the formula Ie, R-H KH-R ' Ie arrives, in which R, R ¹ , R ₁ 'and R _{3 have the} above meaning, and R2' stands for chlorine or bromine, by compounds of the formula If, 509843/0903 25U558 - 41 - 6C0-6641 wherein R, R ¹ , R ₁ 'and R have the above meanings, chlorinated or brominated in an inert organic solvent, or e) to compounds of the formula Ig, R, Ig R-HN " ^iN NH-R ' arrives, in which R, R ¹ and R. have the above meaning, and R ₄ "'is an alkyl group with 1-4 carbon atoms or phenyl, by using compounds of the formula VIII, VIII wherein R, R ', R ₁ and R ₄ " ^{1 have the} above meaning, hydrolyzed. 509843/0903 25U558 - 42 - eOO-6641 Germany 2. New diaminopyridines of the formula I, ^R 2 JL- A I! ■ R-HN "NHR". wherein R and R ^{1 are the} same or different and each represent a secondary or tertiary alkyl group with up to 7 carbon atoms, R _{1 represents} hydrogen or an alkyl group with 1-4 carbon atoms, and either R represents hydrogen if R represents hydrogen> or R ₂ denotes hydrogen, chlorine or bromine, if R ₁ denotes an alkyl group having 1-4 carbon atoms, R_ denotes hydrogen, a cyano group or a radical of the formula -COR, -wherein R. amino, an alkyl group having 1-4 carbon atoms .sn or a radical of the formula II, II denotes in which either R ^ / R _ß or R_ are identical or different and each denotes hydrogen, fluorine, chlorine, bromine or an alkyl or an alkoxy group each having 1-3 carbon atoms, with the proviso that R _c , R or R_ does not represent halogen in the ortho position of the phenyl radical, or 2 of the substituents R_, R and R, provided they are on adjacent carbon atoms 5 09843/0903 25U558 - 43 - 600-6541 Germany are, together mean a methylenedioxy group, and the other of these substituents has the above meaning, with the proviso, if R-. represents a cyano group, R and R ^{1 are} identical or different and each represent a tert. Mean alkyl radical with 4-7 carbon atoms. 3. Therapeutic compositions, characterized by the content of compounds of the formula I. 3700 / ST / SE SANDOZ-PATJENT-GMBH lluA 509843/0903