DE1720031A1 - Biologically active 5-benzylpyrimidine derivatives and processes for their preparation - Google Patents

Description

DR. EULE DR. BERG DIPL.-ING. STAPF

PATENTANWÄLTE 8 MÜNCHEN 2. HIUBLESTRASSE

Dr. Owl dr Barg Dipl.-Ing. Stopf, 8 Munich 2, HilbiestraBe 20

Our sign date

%, Febr. 1968 Attorney File 16 994 Be / Be "'" ~~

Addendum to patent

(German patent application W 43 385 IVd / i2p)

The Welioome Foundation limited London N.W.1 / England

Biologically Active 5-Benzylpyrimidine Derivatives and Processes for their manufacture

This invention relates to a method of producing biologically more effective 5-benzylpyrimidine derivatives and new ones 5-benzylpyrimidine derivatives.

The present invention provides a process for the preparation of a compound of formula (i)

B 208. - ■ '■■' '. '-2-

209832/1173

(D

where X and Y are the same or different and each is an amino or hydroxyl group, Z is a hydrogen atom, an alkyl group with no more than 4 carbon atoms, a hydroxyl group or a substituted or unsubstituted amino group, the substituted amino group being a cyclic one Amino group, such as a piperidino or morpholino group

2 "5
includes the radicals E and E, the same or different and each being a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, wherein the alkyl and alkoxy groups each contain no more than 4 carbon atoms and R is an alkyl group having no more than 10 carbon atoms, a Halogen-substituted alkyl group with not more than 4 carbon atoms, an unsaturated, aliphatic hydrocarbon radical with not more than 4 carbon atoms or an aralkyl group which is unsubstituted or substituted with one or more alkoxy or alkyl groups, each containing not more than 4 carbon atoms,

and the method reacting a compound of the formula

(H)

—3—

209832/1173

where X, Y, Z, E and ß- ^ have the same meaning as ollen, with a compound EQ, where E is given above Has meaning and Q is a reactive atom or a Group such as halogen under basic conditions. This Eeakt ion is suitably effected in an alcoholic or in an aqueous, alcoholic solvent. A suitable alcohol is, for example, methanol. The ba-.sische Conditions can be created, for example, by dissolving potassium hydroxide in the solvent. It it was generally found that the reaction at room temperature progresses satisfactorily, however, the rate of reaction can be adjusted if desired by application be increased by heat.

A compound of formula (II) can according to the British Patent application Kr. 7376/66 described process, that is, by reacting a compound of formula (IV), getting produced,

(IV)

with a Mannich base of the formula (III).

(III)

209832/1173 -4-

wherein NRp is a dialkylamino or a cyclic amino group is.

The compounds of the formula (I) are particularly valuable because of their remarkable antibacterial activity. For example, 2,4-diamino-5- (3 ', 4 ¹ , 5 ^f -trimethoxybenzyl) pyrimidine, also known as trimethoprim, is very effective as an antibacterial compound and has proven its practical value. The present invention also provides a new compound of formula (I) wherein X, X, Z, R and

• Ζ Λ

R ^ have the meanings given above and R is an alkyl group with of between 5 and 10 carbon atoms, a halogen substituted alkyl group with not more than 4 carbon atoms, an unsaturated, aliphatic hydrocarbon radical having no more than 4 carbon atoms or an aralkyl group that is unsubstituted or substituted with one or more alkoxy or alkyl groups, each having no more than 4 carbon atoms. These new ones Compounds of formula (i) are particularly effective against Staphylococcus aureus, Aerobaoter aerogenes and Esoherioia coli. The new compounds of formula (I) have also proven to be antibacterial agents in combination with sulfonamide compounds proven useful. The benzylpyrimidine and sulfonamide compound act in combination synergistisoh and form an overall improved effect against the bacterial infection to be treated.

-5- 209832/1173

The above process for the preparation of a compound of the formula (I) is remarkable when it is used for the preparation a special subgroup within the formula (I) is used, i.e. a compound of the formula (V)

NH ₂

(V)

wherein Z is a hydrogen atom or an alkyl group with no more than 4 carbon atoms and R is an alkyl group with not more than 10 carbon atoms, a halogen substituted alkyl group with not more than 4 carbon atoms, an unsaturated, aliphatic hydrocarbon radical with no more than 4 carbon atoms or an aralkyl group is that is unsubstituted or with one or more Alkyl or alkoxy groups, each having no more than 4 carbon atoms, is substituted.

In this process the starting material of formula (II) is restricted accordingly. Therefore, the new compounds of formula (V), wherein Z is a hydrogen atom or a Alkyl group with not more than 4 carbon atoms and R an alkyl group with between 5 and 10 carbon atoms, a halogen substituted alkyl group with not more than 4 carbon atoms, an unsaturated, aliphatic hydrocarbon radical with no more than 4 carbon atoms or an aralkyl group which is unsubstituted or

209832/1173 -6-

ner or more alkoxy groups, each not more than Containing 4 carbon atoms, substituted is just as remarkable. .

Examples of compounds of the formula (ν) are those where, when Z is a hydrogen atom, R is an allyl group, ß-chloroethyl group, γ-chloropropyl group, butyl group, Heiyl group, Ootyl group, benzyl group or 3,4,5-trimethoxybenzyl group

B. ' 1

^ and when Z is methyl, R is methyl.

All of these compounds are new except for the compound in which Z is hydrogen and R is butyl.

The compounds of formula (I) can be used for antibacterial use, along with a pharmaceutically acceptable one Carrier. The compounds can advantageously be in separate units, such as tablets, capsules, Ampoules or suppositories are presented, each Unit contains a predetermined amount of the compound. The compound can also be used as a powder or granules Solution or suspension in aqueous, non-aqueous or emulsified liquid form or as an ointment are presented. For parenteral use, the preparations of this invention can be prepared by any pharmaceutical method and they can contain one or more of the following additional ingredients: diluent or Extenders, solvents, buffers, flavorings

209832/1173 ~ ⁷ ~

substances, binders, dispersants, surface-active agents Agents, thickeners, lubricants and coating materials, Protective agents, antioxidants, bacteriostatioa, Suppository and ointment bases and any others acceptable other excipients.

The present invention therefore provides a pharmaceutical composition comprising a novel compound ■ 'M of the formula (I) as an active ingredient in admixture with a pharmaceutically acceptable carrier in other respects. The present invention further provides a process for the manufacture of such a pharmaceutical preparation, the process comprising mixing a novel compound of formula (I) with a pharmaceutically acceptable carrier.

The following examples illustrate the invention.

example 1

Methyl iodide (1.42 g) was added to a solution of 2,4-Dlamino-5- (3 ^r ^ »- dimethoxy - ^ '- hydroxybenzylJ-pyrimidine (2.76 g) in 40 # aqueous methanol (35 ml) plus a 3.2 H methanolic solution of potassium hydroxide (4.5 ml) was added The mixture was allowed to stand in a sealed flask at room temperature for 72 hours, after which the solvent was removed and the residue was extracted with water to remove impurities Recrystallize

from ethanol gave crystals of 2,4-diamino-5- (3 ^t f4 ^l »5 ^! - 209832/1173 _ ₈ _

trimethoxybenzyl) pyrimidine with a melting point of 197-199 ⁰ C.

Example 2

A mixture of 2,4-diamino-5- [3 ^t , S'-dimethoxy - ^ '- hydroxybenzyl] pyrimidine (2.76 g), allyl bromide (1.21 g) and potassium hydroxide (0.6 g) was added dissolved in a mixture of methanol (30 ml) and water (10 ml) by heating on a steam bath for 30 minutes. The mixture was then allowed to stand in a sealed flask at room temperature for three days. A white precipitate could be seen, which was isolated and recrystallized from an ethanol-water mixture. This gave 2,4 ~ diamino-5- [3 ^f 5 ^{t-dimethoxy-4 t} -allylbenzyl] pyrimidine having a melting point of 193-194 ⁰ C.

Example 3

2,4-Diamino-5- [3 ^f , 5 '-dimethoxy ^' - hydroxybenzylj-pyrimidine was treated with benzyl bromide in the manner described in Example 1 to prepare 2,4-diamino-5- [3 ^t , 5 ^r - dimethoxy-4 ^t -benzyloxybenzyl] pyrimidine treated, this had a melting point at 162 to 164 ⁰ C after recrystallization from dilute ethanol.

Example 4

The reaction of 2,4-diamino-5- [3 ^l ^ '- dimethoxy ^^ - hydroxybenzylj-pyrimidine with i-bromo-2-chloroethane was essentially

2 0 9 8 3 2/1173 -9-

union in the same manner as described in Example 3 carried out. In this way, 2,4-diamino-5- [3 ^f »5 ^r -dimethoxy-4- (ß-chloroethoxy) benzyl] pyrimidine was prepared. When this was recrystallized from dilute ethanol, it had a melting point of 177 to 178 ⁰ O.

Example 5

Hexyl bromide was allowed to stand with 2,4-diamino-5- [3 ^l , 5 ^t -diπlethoxy-4 ^t -hydroxybenzyl] ~ pyrimidine for 7 days in the manner described in Example 1, after which it was heated for a short time on the steam bath of 2,4-diamino-5- [3 ^t »5'-dimethoxy ^ '- hexyloxybenzyl] pyrimidine. This had a melting point of 158 to 159 ^° C. after recrystallization from dilute ethanol.

Example 6

In a reaction similar to that described in Example 3, octyl bromide was used as the alkylating agent and 2,4-diamino-5- [3 ^l >5'-diamino-4 ¹ -octyloxybenzyl] pyrimidine was obtained. This substance had a melting point at 163 ⁰ C after recrystallization from ethanol.

Example 7

A mixture of 2,4-diamino-5- [3 ^f , S'-dimethoxy ^ '- hydroxybenzyl] -pyrimidine (2.76 g), i-bromo-3-chloropropane (1.73 g)

^! -10-

209832/1 173

- ίο -

and potassium hydroxide (0.6 g) was refluxed with methanol (40 ml) and water (10 ml) for two hours. A trace of insoluble material was filtered off from the mixture and the solvent removed. The residue was washed with cold water, recrystallized from dilute ethanol to give pure 2,4-diamino ~ 5- [3 ^f , 5'-dimethoxy-4 ^! - (Y-chloropropyloxy) -benzyl] -pyrimidine with a melting point of 179 to 18O ⁰ C.

Example 8

The alkylation of 2,4-diamino-5- [3 ^? , 5 * -dimethoxy-4 ^f hydroxybenzylj-pyrimidine with 3 »4r5-trimethoxybenzyl chloride was carried out in a manner similar to that in Example 7, and thus 2,4-diamino-5- [3 ^f , 5 ' -dimethoxy-4 ^l - (3 ", 4", 5 "-trimethoxybenzyloxy) - benzyl] pyrimidine. This had a melting point of 164 to 165 ^° C. after recrystallization from ethanol.

Example 9

2,4-diamino-5- (3 ', 5-dimethoxy-4 * ^r -but oxybenzyl) -pyrimidine (m.p. 163-164 ⁰ C) was in a similar manner as described in the preceding examples were prepared.

Example 10

2,4-diamino-6-methyl-5- (3 ', 5'-dimethoxy-4'-hydroxybenzyl) -

-11-

209832/1173

pyrimidine (1.90 g) was added in a 2: 1 methanol-water mixture (90 ml) containing potassium hydroxide (0.6 g) and methyl iodide (1.5 g). The mixture was allowed in a sealed flask for 96 hours to stand at 4O ⁰ C. Some of the solvent was then removed. After quenching the residue, the product was crystallized out. This was extracted with alkali to remove starting material, after which it was recrystallized from ethanol. The product 2,4-diamino-6-methyl-5- (3 ^l , 4 * ^ - trimethoxybenzyl) -pyrimid1n had a melting point of 190 to 192 ° 0.

Example 11

A mixture of 2,4-diamino-5- [3 ^t »^ 5 ¹ ImCthoxy-4 * -liydroxybenzyl] pyrimidine (2.76 g), allyl bromide (1.21 g) and potassium hydroxide (0.6 g) was dissolved in a mixture of methanol (30 ml) and water (10 ml) with heating on the steam bath for 30 minutes. The mixture was then allowed to stand in the sealed flask at room temperature for three days. A white precipitate could be seen, which was isolated and recrystallized from an ethanol-water mixture. In this way, 2,4-diamino-5- [3 ', 5 ^t -dimethoxy-4 ^l -allyloxybenzyl] pyrimidine with a melting point of 193 to 194 ° C. was obtained.

Example 12

2,4-Diamino-5- [3 *, 5 * -dimethoxy-4'-hydroxybenzyl] -pyrimidine was treated with benzyl bromide in the 209832/1 173 - _g

Wise treated to form 2,4-diamino-5- [3 ^l > 5 methoxy-4'-benzyloxybenzyl] pyrimidine with a melting point of 162 to 164 ° C. after crystallization from dilute ethanol. ·

Example 15

The reaction of 2,4-diamino-5- [3 ', 5 ^! Dimethoxy-4 ^f -hydroxybenzyl] pyrimidine with i-bromo-2-chloroethane was carried out essentially in the manner described in Example 2. 2,4-Diamino-5- [3 ^f , 5 ^t -dimethoxy-4- (ßchlorethoxy) benzyl] pyrimidine was obtained. After recrystallization from dilute ethanol, this had a melting point of up to 178 ⁰ G.

Example 14

Hexyl bromide was allowed to stand with 2,4-diamino-5- [3 ', 5 ^f -dimethoxy-4'-hydroxybenzylj-pyrimidine in the manner described in Example 1 for 7 days, after which it was briefly heated on the steam bath and obtained 2 , 4-diamino-5- [3 ', 5 ^f -dimethoxyH-'-hexyloxybenzylj-pyrimidine. This had a melting point of 158 to 159 ^° C. after recrystallization from dilute ethanol.

Example 15

In a reaction similar to that described in Example 2 Octyl bromide was used as the alkylating agent

209832/1173 -13-

..V-: - 15 - ■■; ■ ■ .. "■;

and 2,4-diamino-5- [3 ^l _f 5 ⁱ -diamino-4 ^l octyloxybenzyl] pyrimide was obtained. This substance had a melting point of "163 ⁰ CHaOh. Recrystallization from ethanol.

Example 16

A mixture of 2,4-diamino-5- [3 ^l , S'-dimethoxy ^ '- hydroxybenzyl] pyrimidine (2.76 g), i-bromo-3-chloropropane (1.73 g) and potassium hydroxide (0 , 6 g) was refluxed with methanol (40 ml) and water (10 ml) for a period of 2 ■ ™

Heated for hours. The mixture was filtered off from a trace of insoluble material and. removed the solvent. The residue was washed with cold water, from dilute ethanol recrystallized to give pure 2,4-diamino-5- [3 ^T, 5'-dimethoxy-4 '.'- (γ-chloropropyloxy) -benzyl] -pyrimidine, m.p. 179 to 18O ⁰ G.

Example 17

The alkylation of 2,4-diamino-5- [3 ^f i5 '-dimethoxy ^' - "

hydroxybenzyl] pyrimidine with 3,4,5-trimethoxybenzyl chloride was prepared in a similar manner as described in Example 6, carried out and in this way there was obtained 2,4-diamino-5- [3 ", 5 ^t ~ 4 ^l -dimebhoxy - (3 ", 4", 5 "- trimethoxybenzyloxy) benzyl] pyrimidine. Melting point 164 to 165 ⁰ G after recrystallization from ethanol.

-H-209832/1173

-H-

Example 18

2,4-diamino-5- (3 ^f, 5 * dimethoxy-4 '-but oxybenzyl) -pyrimidine (m.p. 163-164 ⁰ C) was prepared in a similar manner as in the previous examples.

Example 19

2,4-Diamino-6-methyl-5- (3 ', 5'-dimethoxy-4 * -hydroxybenzyl) -pyrimidine (1.90 g) was in a 2: 1 methanol-water mixture (90 ml), the potassium hydroxide (0.6 g) dissolved and methyl iodide (1.5 g) added. The mixture was allowed to stand in a sealed flask at 40 ° for 96 hours. Some of the solvent was then removed. After the residue had been filtered off with suction, the product crystallized. This was extracted with alkali to remove any starting material, then recrystallized from ethanol. The product 2,4-diamino-6-methyl-5- (3 ', 4', 5 ^f -trimethoxybenzyl) -pyrimidine had a melting point of 190 to 192 ^° C.

Example 20

A mixture of 2,4-diamino-6-methylpyrimidine (8.5 g), 2, δ-dimethoxy ^ -dimethylaminomethylphenol hydrochloride (16.8 g) and sodium methoxide (4.05 g) in ethylene glycol ( (70 ml) was added for 4% hours at 140 ° under nitrogen heated. A white precipitate formed upon cooling. This was isolated, dissolved in alkali and redissolved.

209832/1173 * " ¹⁵ "

■ '■ ■ - ¹⁵ -

falls. Thereafter, was recrystallized from dimethylformamide. 2,4-Diamino-6-methyl-5- (3 ', 5 * -dimeth.oxy-4'-hydroxybenzyl) -pyrimidine was obtained in the form of whitish crystals with gradual disintegration over 250 °. The substance exhibited ultraviolet maxima at 204.5, 225 (sh) and 275 μmji in -O ₁ OOiN HCl and at 218.5, 250 (sh) and 287 to 288 μM in 0.1N NaOH.

Example 21

2,6-Di-tert-butyl-4-dimethylaminomethylphenol. (1.2.7 g) was mixed with 2,4,6-triaminopyrimidine (5.6 g), sodium methoxide (0.25 g) and ethylene glycol (80 ml) and the mixture. Heated for 5 hours at 140 °. After cooling, the solution was poured into water and acidified to pH 1 with hydrochloric acid. The acid-insoluble material was removed and the filtrate was neutralized with ammonium hydroxide. The resulting precipitate was isolated and dissolved from a methanol-lenzene mixture. recrystallized with the formation of 2,4,6-triamino-5- (3 ^l , S'-tert. butyl-4 ^t -hydroxybenzyl) pyrimidinh.ydroch.loridmoriohydrat in the form of white crystals with gradual decomposition above 240 °. The substance exhibited ültraviolettmaxima to 199 »214 (sh) and 280 mu in 0.001 N HGL and at 218, 250 to 260 (sh.), 272 and 300 (sh) in O ₁ mu 1N NaOH.

-16- 209832/1173

Claims (1)

Claims: 1. Process for the preparation of a compound of the formula (I) (D wherein X and Y are identical or different and each is an amino or hydroxyl group, Z is a hydrogen atom, an alkyl group having not more than 4 carbon atoms, a hydroxyl group, or a substituted or unsubstituted amino group where the substituted amino group is a cyclic amino group such as a piperidino or morpholino group includes the radicals R and R "^ the same or different and each is a hydrogen atom, a halogen atom, an alkyl or alkoxy group, the alkyl and alkoxy groups each contains no more than 4 carbon atoms and R is an alkyl group with no more than 10 carbon atoms, a halogen substituted alkyl group having not more than 4 carbon atoms, a non-saturated, aliphatic one Is a hydrocarbon radical having not more than 4 carbon atoms or an aralkyl group which is unsubstituted or with one or more alkoxy or alkyl groups, each is substituted with not more than 4 carbon atoms, characterized in that a compound of the formula (II) -17- 209832/1173 (ID where X, ΐ, Z., R and R ^{J have} the same meaning as above 1 x 1 ben, with a compound RQ, wherein R is the above Has meaning and Q is a reactive atom or group, reacts under basic conditions. 2 ο Process for the preparation of a compound of the formula (v) NH ₀ ^ CH ₂ - Ir / V-OR ¹ Z ^ "^ S, pCH ₃ ' wherein Z represents a hydrogen atom or an alkyl group with not • 1 more than 4 carbon atoms and R is an alkyl group with not more than 10 carbon atoms, a halogen substituted alkyl group with not more than 4 carbon atoms, an unsaturated, aliphatic carbon waaeratoffreat having no more than 4 carbon atoms or an aralkyl group that is unsubstituted or substituted with one or more Alkyl or alkoxy groups, each with no more than Carbon atoms, is substituted, characterized in that that a compound of the formula (VI) - 18 -2 0 9 8 32/1173 wherein Z has the meaning given above, with a compound RQ, wherein Q is a reactive atom or a Group and ß has the meaning given above, reacts under basic conditions. 3. A process for the preparation of a compound of the formula (V) in which Z is not a hydrogen atom or an alkyl group more than 4 carbon atoms and R is a saturated or unsaturated one Is a hydrocarbon radical which is optionally substituted by halogen. 4. A process for the preparation of a compound of the formula (V), wherein, when Z is hydrogen, R is allyl, is ß-chloroethyl, γ-chloropropyl, butyl, hexyl and when Z is methyl, R is methyl, characterized in that the method is the reaction of a compound of formula (VI) with a compound RQ, wherein Q is a reactive atom or group and Z and R are those given above Have meaning under basic conditions. 5. The method according to any one of the preceding claims thereby characterized in that Q is a halogen atom. 6. The method according to any one of the preceding claims, characterized in that Z is a hydrogen atom. 7. The method according to one of the preceding claims - 19-209832/1173 characterized in that the reaction in the presence of a Solvent takes place. 8 «The method according to claim 7, characterized in that the solvent is aqueous methanol. 9. Process for the preparation of a compound of formula (I) according to claim 1 essentially as in one of the examples 1 to 10. 10. Compound of Formula (I). (I) L ·. R ' where X and Y are identical or different and each is an amino or a hydroxyl group, Z a hydrogen atom, an alkyl group with no more than 4 carbon atoms, a hydroxyl group or a substituted or unsubstituted amino group where the substituted amino group is a cyclic one Amino group, such as a piperidino or morpholine. 2 ^ group includes the radicals R and R. same or different and each is a hydrogen atom, a halogen atom, is an alkyl or alkoxy group, the alkyl and alkoxy groups each containing no more than 4 carbon atoms and R is an alkyl group with between 5 and 10 carbon -20- 2 0 9 8 3 2/1 173 atoms, a halogen substituted alkyl group with nioht more than 4 carbon atoms, one unsaturated, aliphatic Hydrocarbon radical with no more than 4 carbon atoms or an aralkyl group that is unsubstituted or with one or more alkoxy or alkyl groups, each with not more than 4 carbon atoms. _Ä 11. Compound of formula (V) OCH ₃ ¹ H ₂ N wherein Z represents a hydrogen atom or an alkyl group with not more than 4 carbon atoms and R is an alkyl group with between 5 and 10 carbon atoms, a halogen substituted Alkyl group with not more than 4 carbon atoms, an unsaturated, aliphatic hydrocarbon radical with no more than 4 carbon atoms or an aralkyl group that is unsubstituted or substituted with one or more Alkoxy or alkyl groups, each with not more than 4 carbon atoms, is substituted. 12. Compound of the formula (V) in which, when Z is a hydrogen atom, R is an allyl, ß-chloroethyl, γ-chloropropyl, Hexyl, octyl, benzyl or 5,4,5-trimethoxybenzyl group -21- 209832/1 1 73 and if Z -eine. Methyl group, JEl is a methyl group. 13. 2,4-Diamino-5- (3 '-, 5'-dimethoxy-4 »-allyloxybenzyl) - pyr imid in .. 14. 2,4-Diamino-5- (3 ^l , 5 ^t -dimetlioxy-4 ^t - "benzyloxybenzyl) - pyrimid in. 15 .2,4 - Diamino-5 - C 3 * j 5 ^l -d imethoxy-4'-iiexyloxybenzyl) - pyrimidine. 16 * 2,4-543111 ^ 0-5— (3 *, S ^ -äimet & oxy ^ '- ootyloxy'benzyl} - pyrimidine. 17. 2j4 ^ iäminö-5- (3S5 ^t -dimetnoxy-4 »- (ß-chloroethioxy> -iD pyrimidine .. Benzyl. l- *. t «4 ^ iaffiiai * S * m ^ t% l - i- | 3 S 4 * »5 ^r -trimet 21 *. feE-feiaäimg Itr ΙθϊιπαΙ CE) Gewä! In & prtich · 1 © im borrowed wi & in irfencE one of the examples; 2 Ms 8 lint W le 22 «Iharmacetit iaohe preparation dadtiroii characterized, a ± e comprises a YerMndun-g according to one of claims 10 Ma 21 'in admixture with a pharmaceutically acceptable carrier 23 »Process for the production of a pharmaceutical preparation according to claim 2Z dadux'ch characterized in that it comprising mixing a compound according to any one of claims to 21 with a pharmaceutically acceptable carrier. 209832/1173 BATH