AU5233473A

AU5233473A - Nitro-imidazolyl-pyrimidines

Info

Publication number: AU5233473A
Application number: AU52334/73A
Authority: AU
Inventors: Clemens Dr Rufer; Eberhard Dr Schroder; Hans-Joachim Dr Kessler
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1972-02-19
Filing date: 1973-02-19
Publication date: 1974-08-22
Also published as: AT328455B; US3920655A; FR2183670B1; CH577995A5; JPS4886881A; GB1425261A; DD105226A5; ATA141973A; NL7302292A; BE795636A; FR2183670A1; CA974242A

Description

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TEST CHART RESOLUTION MICROCOPY OFSTANDOARS-196 NATIOA 9UREAU

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Al Si RALIA PATIN'I' API I C(ATl ON "ON N) -CN~i~ Form '1

('OMNONWkLIi OF AUSTIRALLA

CONVEN4TION APPLICATION FOR A PATENT

in-1r.11 r

.ddress(es) of 1. B3fr1in ML'ull1erstrausse 19O-lr7?, Germany

hereby apply for the grant of a Patent for an inventionl entitled tt In,.;t sti. NITR-IM1IDAZLYL-PY TL 31

which is described it' the accompanying comlplete specification. This application is a convention application and is based Oil the. pqdbUaDtocv applications for aXPOMc~Datcnts or similar protection mtade in thie folwn~mcr;cu re on the followinig dlate or dates:

In-?r in on) 9.AR1922......No. 22 OB 51.8.3 ht zermany No(. 6pp Insetl in

a epIis-ct(s in ott No.

a n- t in on No.

in on No.

bM)Otr address for service is care of ARTHUR S. CAVE3 CO., Patent and Trade Mark Attortinys, I Alfred Street. Sydney, New Suth Waltes, Australia 2000. W) Ion-t d.1, Dated this t of) 19 day o

S) -CJRING AKTIENESEL "'3CHAF T C (oC,'n p per:

I, p JALIS' 7 EIY FIP A.A To. 5 TW T IA4L ON 1 0LL L

Thei Co nrnhissi n~~pe? )t 'nits. U Ill0l. US FR 1A ARTHU- aA-VE Cc.(qTE:41 PA TL N I AN.'L) i ALL MARK I OR

A.S .C.-2

For 8 AUSTRALIA PATENT.DECLA RATION FORM (CONVENTiON) Fr COMMONWEALTH OF AUSTRALIA Patents Act 1952- 1969

DECLARATION INSUPPORT OF ACONVENTION APPLICATION UNDER PART XVI FOR APATENT OR PATENT OF ADDITION To be signed by the applicantts) or in thc. cas of a Company, to be signed by a person authorised by the Company In support of the Convntion application made for apatentfoanivtoneild of~oraI invention entitled4 Of(T.

Isert fuil 1 ~b It.trdarn..y namols)Of decI rart (s

Insert of .ddres(sIl of

r1;iy

do solemnly and sincerely declare as follows:

(OR, IN THlE CASE OF AN APPLIC'ATION BY A BODY CORPORATE.) r. 1 am/we are authorised by 1EIG AKI.EZ0-LL U applicant for the patent to make this declaration

on its behalf. The basic application(s) as defined by Section 141 of the Act was/were made in the following :country or countries on the following date(s) namely:- a lot nsrt in (d r m a MY Pe on Jl 2q2 19.7 2 No (0 P 2 2 0.8 51 ,8 wirctirosc by E3CH7,RING AKTI-,NGESELLE3CHAFT in1 baicid by S3CH:-RT NG AKTTBNGEGELLSCJHkFT isiCfi~~ in onl ro.

num,r of b g

asophe~nlisi (OR, WHERE A PERSON OTHER THAN THE INVENTOR IS THE APPLICANT)

IN rhoa.. ~b.d is acua I n, of l Bexrlin 3,...Ciinbernst 2o: ioio 1 Berlin etrch deuLatr

is/are the actual inventor(s) of the invention and the facts upon which ac entitled to make the application are as follows: the Company is W(SetThet how is the assi (le

ssirionof tireinvention from threactoal 4. The basic application(s) rp:i-ed to in paragraph 2 of this Declaration x'jt/were the first oventorii application(s) made in a Convention country in respect of the invention the subject of the application. Attestation or

-1aulo Declared at G3yDI1E1 this 15th day or February, 19 To: The Commissioner of Patents, COMMONWEALTH OF AUSTRALIA AF' I HUR S. CAVE CO. (Signature of Declarant) PATEfi f AND TRADE MARK ATTORNEYS IES G. SIELY, F.I.P. A. A. SYDNEY C (,NM h llVWEALTH A.S CF-

COMMONWL:ALJ I OF~ AUSTRALIA Vorm P~ATENTS AC'T 19524,2

(ORIG;INAL)

Application Number c lass 11 62 Ihit. Class Locl"de:~ 1

Complete Specifictition Lodged~-

Published: I I1

A21 3 Frioi-"- ?lei 1 &7 (t~

TO BE C(MPLETHD 13Y APPLICANT

Name of' Applicant' "kIME A2!~ EN'iA

A~ldress of' Applicant: Mul i r~it-'nt. 170-19,) Actual li VejitOT. IDr. :.trb'ird ;ichrodtr, ItT

Address 1or Smnice X Pittet A4 tcrneyr) IAl fred~~ot ~ie iAutrilia.

Colmplete Specification fbr the invention enltitled

0 ti tc~ The following statement is a full description of this invent ion, including the best miethodI of perf'orming it known to me 7 77

m

The Present invention is concerned with new nitro-

imidriolyl-pyrimidines and with their manufacture and use. The activit-y of nitro- imidazo 1e s arainst trichoinonads has

been known since the discovery of the antibiotic azomyc'n

[.7-nitro-imidazole, S. Nakamura and H. Umezawa, J.

Antibiotics (Tokyo), 9 A, 66 (1955)]. However, as compared

with IVetronidazol (see below), -these and other 2-nitro-

imidnzoles have proved to be no better in vitro [cf. G. C.

Lancini, E. Lazzari, R. Pallanea, 11 IFarmaco Ed 3c. 21, 278

(1Q6)3 and the CD 5 0 and LD 5 0 values are considerably less

*fivourable (cf. E. Grunberg. E. Titsworth, Antimicrobial Agents

minl Chemotherapy 19)65, 1966, 478). Among the

the best of a larre number of synthesized compounds [cf. Cosar,

Arznoimittel-forschung 16, 23 (1966)] is the commerical Tnroduct

v.Ptronidazol C5nto2mty--2-ydoyehl-mdzl] see aiFo French Patent Specification No. 1,212,028), having a

minimum inhibiting conc entrat ion of 2-5^y Per ml against Trichom- onruF va-inalis. W-e have now found that known 1-substituted 5-nitro-2-

imid-zolyl-imino-carboxylic acid esters can be reacted with imnonia or ammonium salts to form hitherto unkown, also

trichomonacidally active, 1-substituted 5-nitro-2-imidazolyl-

carboxamid'nes, which react with P -dicarbonyl- compounds or

lorivitives thereof, to form 2-(5'-nitro-2'-imidazolyl)-

pyrimidines. The latter are more strongly active than

Metronidavol.

TIhe Dresent invention accordinFly provides compounds of

thp Reneral formula (1)

~0

R NIN R (I)

02N N/ 2 N-- R2

e** Sand also salts thereof with physiolorically tolerable acids,

i which X represents an alkyl group containing 1 to 4 carbon atoms,

R and R 2 each represents a hydroren atom, an alkyl group containing 1 to 4 carbon atoms, a phenyl group, a

trifluoromethyl group or a monocyclic heterocyclic group, and R5 represents a hydrogen atom, ar alkyl group containing

1 to IL carbon atoms, a free or esterified hydroxy-alkoxy group containing 2 to 4 carbon atoms in the alkoxy group, the ester group being derived from an alkane-carboxylic

S" acid containing 1 to 4 carbon atoms, an oxo-alkyl group

containing a total of 3 to 6 carbon atoms, or, when R1 or R 2 represents a phenyl group, an alkylene group which

is connected to the 2-position of the phenyl ring.

R 1 and R 2 may have the same or different meanings. As physiologically tolerable acids there come into

consideration inorganic acids, for example hydrochloric acid

and sulphuric acid, and organic mono-, di- and tri-carboxylic

acids, for example acetic acid, propionic acid, lactic acid,

citric acid, benzoic acid, succinic acid and heptagluconic

acid.

The new compounds can be prepared by, for example, a

process wherein an amidine of the general formula II

N N

:0 L 0 H (II) 02N N NH X

in which X has the meaning given above, or a salt thereof, is

reacted with a -dicarbonyl compound of the general formula III

R

O=0

CH R (111) SO=C

R2 in which R, R2 and R have the meanings given above, or a derivative thereof, and, if desired, in the resulting compound ny acyloxy group is hydrolysed to form a free hydroxyl group and/or any free hydroxyl group is esterified to form an acyloxy group derived from an alkane-carboxylic acid containing 1 to 4 carbon atoms and/or, if desired, any resulting free compound is converted into a salt thereof with a physiologically tolerable inorranic or organic acid and/or any resulting salt is converted

.into the corresponding free compound.

1b As derivatives of the dicarbonyl-compound there come into consideration reactive derivatives, for example an acetal or,

when R 1 and R2 represent hydrogen atoms, an enamine. The reaction of the amidine (II) or of, for example, its

mixed salt with ammonium chloride with the -dicarbonyl-compounds

l or derivatives thereof may be carried out without solvents or

in solvents (for example acetic acid, acetic anhydride,

dimethylformamide or alcohol), and acid or basic catalysts may

be added.

The new compounds of the present invention exhibit good

anti-microbial actions, especially against protozoa and among

S these esnecially against Trichomonas vaginalis, as is shown by

the following comparison of a few examples of compounds of the

present invention with Metronidazol:

Compound Minimum inhibiting concentration in 1,L grams per ml against Trichomonas vaginalis

-Dime thyl-2-((5'-nitro-l '-methyl-

-imida zo lyI) -pyrimid ine 0.4

P- 5' -Ni tro- l '-me thyl-2'-imidaz olyl) -L-

methyl-5,6-dihydrobenzo- U'hj -quinazoline 0.1

4-Tri f luorome thylI-2- (5 '-nitro- l'-metbyl-

J~ -imidazolyl)-F-(2"-tUhienyl)-pyrimidine 0.2

4 -Methyl-6-phenyl-2-( 5'-nitro-l' -methyl-

Metronidazol (in its own testb, 1.6

The new compounds can be administered in the usual pharmaceutical forms of application, for example pills,

'0 0 0drarrees, capsules, vaginal tablets and syrups. The present invention accordingly further provides a

pharmaceutical preparation which comprises a compro ai of the P.0 Pgenernl formula I or a salt thF'reof with a physiolcgicral-'y tolerable acid, in admixture ic-nj>'inction with a prnarmaouut- ically suiitable carrier. If desired, the preparation may

contain two or more compounds selected frnxu compounds of the reneral formula I and salts thereof with phjsiologically tolerable acids.

Tablets contain, for example, 0.1 to 0.5 gram of active

ingredient and 0.1 to 5 grams of a pharmacologically inert

auxiliary material. As auxiliary materials there may be used,

for example, for tablets, lactose, starches, talcum gelatines

and magnesium stearate.

The present invention further provides a system which

comprises a compound of the general formula I or a salt thereof

with a physiologically tolerable acid, together with instruct-

ions for its use for controlling or treating protozoa.

'1 For topical application the pharmaceutical preparations

may be in the form of powders, solutions, suspensions, aerosols

and vaginal tablets, and for parenteral administration they

may be in the form of aqueous and oily solutions or suspensions.

The preparation of the amidines or salts thereof used

as starting materials is carried out, for example, by (A)

reactinp known imino-esters of the general formula IV

6

N

NH 0 N 2 1 x

in which X has the meaning given above and R represents an

alkyl group containing 1 to 4 carbon atoms, with ammonia or

an ammonium salt. The following exemplifies an analogous procedure:

)I 0 a

9.9 grams (50 mmoles) of 5-nitro-l-methyl-2-imidazolyl-

imino-carboxylic acid ethyl ester and 2.7 grams (50 mmoles) of

powdered ammonium chloride were boiled in methanol for 72 hours.

After evaporating off the solvent, the residue was digested

while hot with 100 ml of ethyl acetate. There were obtained

6.1 grams (47% of the theoretical yield) of an equimolar mixture

of 5-nitro-l-methyl-2-imidazolyl-carboxamidinium chloride and

ammonium chloride. Melting point: 225 2270C.

0.52 (2 gram mmoles) of the latter mixture and 0.55 gram

(4 mmoles) of potassium carbonate were stirred in 10 ml of

acetone for 48 hours. After filtration, the filtrate was o

o" concentrated and the free amidine that remained behind was recrystallized from ethyl acetate. There was obtained 0.14

gram (40% of the theoretical yield) of the product melting at 14L4 1460C.

SExample 1 64,6-Dimethyl-2-(5'-nitro-l'-methyl-2'-imidazolyl)-pyrimidine.

0.52 Gram (2 mmoles) of an equimolar mixture of ;O.o l-methyl-2-imidazolyl-carboxamidinium chloride and ammonium

chloride, 0.21 gram (2.1 mmoles) of acetyl-acetone and 0.33 gram of anhydrous sodium acetate were boiled in L4 ml of acetic

acid for 2 hours. The whole was then concentrated to dryness,

and the residue was triturated with water and recrystallized

from isopropanol. There was obtained 0.32 gram (69% of the

theoretical yield) of the product melting at 148 1500C.

Example 2

2-(5'-Nitro-l'-methyl-2'-imidazolyl)-pyrimidine.

The compound was obtained in a manner analogous to that

described in Example 1 with r.alondialdehyde tetraethyl-acetal.

Meltinr point: 194 1960C.

Example 3

5-(2'-Acetoxy-ethoxy)-2-(5"-nitro-l"-methyl-2"-imidazolyl)-

pyrimidine. The compound was obtained in a manner analogous to that 09

"l described in Example 1 with 3-dimethylamino-2-(2'-hydroxy-

ethoxy)-acrolein, and acetic anhydride may be used instead of

acetic acid. After concentrating the reaction solution, water

was added to the residue, the product was extracted with ethyl

acetate, and the residue from the ethyl acetate extract was

.1 triturated with methanol.

S Melting point: 148 15000.

Example 4

5-(2'-Hydroxy-ethoxy)-2-(5"-nitro-l"-methyl-2"-imidazolyl)-

pyrimidine hydrochloride.

0.2 Gram of 5-(2'-acetoxy-ethoxy)-2-(5"-nitro-l"-methyl-

2"-imidazolyl)-pyrimidine was boiled in 5 ml of ethanol with

ml of concentrated hydrochloric acid. After concentrating

in vacuo, the residue was recrystallized from ethyl acetate.

Melting noint: 158 1600C.

Examle

-Hydroxy-ethoxy)-2-(5"-nitro-l"-methyl-2"-imidazolyl)-

pyrimidine hydrochloride.

To 5 ml of a iN-solution of sodium methylate in methanol

were added 0.78 gram (5 mmoles) of 3-dimethylamino-2-(2'-hydroxy-

ethoxy)-acrolein and 1.3 grams (5 mmoles) of an equimolar mixture

of 5-nitro-l-methyl-2-imidazolyl-carboxamidinium chloride and

ammonium chloride. After boiling the whole for 20 hours, the methanol was distilled off, the residue was maintained at 800C

for 50 minutes, and water was added. The product was extracted

with ethyl acetate, the ethyl acetate was evaporated, and the I residue was digested with isopropanol. The free base so obtained

.10 wns converted with methanolic hydrochloric acid into the hydro- 0

chloride melting at 158 160 0.

The same product was obtained by heating equimolar auantities of 5-nitro-l-methyl-2-imidazolyl-carboxamidine and 5-dimethylamino-2-(2'-hydroxy-ethoxy)-acrolein in dimethylformam-

a. *5 ide or without a solvent, and converting the mixture so obtained,

optionally after evaporating off the solvent, into the hydro- chloride.

Example 6

-Acetoxy-ethoxy)-2-(5"-nitro-l1"-methyl-2"-imidazolyl)-

2 pyrimidine.

0.29 Gram (1 mmole) of 5-(2'-hydroxy-ethoxy)-2-(5"-nitro-

l"-methyl-2"-imidazolyl)-pyrimidine hydrochloride was heated

ir 3 ml of acetic anhydride for 1 hour at 100 0 C. After being

cooled, the whole was introduced into water and the product

was filtered off.

Melting point: 148 150°C.

Example

pyrimidine. 0.34 Gram (2 mmoles) of 5-nitro-1-methyl-2-imidazolyl- 0.26 gram (2.1 mmoles) of 3-acetyl--2-pentanone and 0.33 gram (4 mmoles) of anhydrous sodium acetate were boiled in 4 ml of glacial acetic acid. for 4 hours. After concentrat- ing the mixture, the residue was digested with water and purif- ied by preparative layer- chromat ography. Melting point: 110 00

(from ethyl acetate).

Example 8 4, 6-Dimethyl-5- (2 '-ac etyl ethyl) 5"-nitro-l -methyl-2- imidazolyl)-pyrimidine. The compound was obtained in a manner analogous to that

described in Example 7 with 3-acetyl-2,6-heptandione. 0 Melting point: 14200 (from ethyl acetate).

Example 9 ?-(5'-Nitro-l'-methyl-2'-imidazolyl)-4-methyl-5,6-dihydrobenzo-

C h]-nuinazoline. The compound was obtained in a manner analogous to that

described in Example 7 with 2-acetyl-l-tetralone. Melting point: 14700 (from isopropanol).

Example J.0 4-Trfluromtby-('-nitro-l '-methyl-2 '-imidazolyl)-6-(2"-

thienyl)-pyrimridine. The compound was obtained in a manner analogous to that

described in Example 7 with 1-thenoYl-3,3,3-trifluoracetone.

Purification was carried out by recrystallization from ethyl

acetate. Melting point: 1880C.

Example 11

4-Methyl-6-ph nyl-2-(5'-nitro-l'-methyl-2'-imidazolyl)- pyrimidine.

The compound was obtained in a manner analogous to that

described in Example 7 with 2-acetyl-acetophenone. Purificat- ion was carried out by recrystallization from ethyl acetate.

Melting point: 1500C. The invention also includes within its ambit the hitherto

*unknown compound of the formula II and a process for the manufacture thereof.

o e

o

C

*O 0

Claims

The claims defining the invention are as follows:

1. A compound of the general formula I

R1

02N N N S X R2

or a salt thereof with a physiologically tolerable acid,

in which X represents an alkyl group containing 1 to 4 carbon atoms,

R1 and R 2 each represents a hydrogen atom, an alkyl group

containing 1 to 4 carbon atoms, a phenyl group, a

trifluoromethyl group or a monocyclic heterocyclic group,

and

R represents a hydrogen atom, rn alkyl group containing 1

to 4 carbon atoms, a free or esterified hydroxyalkoxy

group containing 2 to 4 carbon atoms in the alkoxy group,

the ester group being derived from an alkane-carboxylic

ac4 d containing 1 to 4 carbon atoms, an oxo-alkyl group

,cortaining a total of 3 to 6 carbon atoms or, when R1 or R 2 represents a phenyl group, an alkylene group which

is connected to the 2-position of the phenyl ring.

2. A compound selected from:

4,6-Dimethyl-2-(5'-nitro-l'-methyl-2'-imidazolyl)-

pyrimidine,

2-(5'-Nitro-l'-methyl-2'-imidazolyl)-pyrimidine, imni liazely! )-py'inidine, irni~ Iwo~y1?)pyrimidrine hy-Iron~h~oriede, thl n Ul I- ne,

(7hey-vrImie p t0 or ir-1-eh7-2 mdazoll

OA nroce or manufsicture of a compound of the t-onerql. I'Ormu: I

x

x r-Pfrf'-'fPn*; in ,ilkvl c-rotun containing 1. to 4 cairbon atoms, "ad ici r 'i hydro -n 'itcm, n alky]. )qroup

r~nn-inln t *1 c n-bon riloms;, a phonyl frroup, a

''rompthvy r'ro'ir or li monocyclic heterocyclic gop

R represents a hydrogen atom, an alkyl group containing

1 to 4 carbon atoms, a free or esterified hydroxyalkoxy

containing 2 to 4 carbon atoms in the alkoxy group, the

ester Froup being derived from an alkane-carboxylic acid

containing 1 to 4 carbon atoms, an oxo-alkyi group

containing a total of 3 to 6 carbon atoms or, when R 1

or R 2 represents a phenyl group, an alkylene group which

is connected to the 2-position of the phenyl ring,

or a salt thereof with a physiologically tolerable acid, wherein

X N

.L (I r 0 N N N NH2

I

in which X has the meaning Riven above, or a salt thereof,

is reacted with a (-dicarbonyl compound of the general formula

IIl

R R1 0 O C.

H R (III)

O =C

2 in which R1, R 2 and R 3 have the meanings given above, or a derivative thereof, and, if desired, in the resulting compound any acylo7-y group is hydrolysed to form a free hydroxyl group and/or any free hydroxyl group is esterified to form an acyloxy group derived from an alkane-carboxylic acid contain- ing 1 to 4 carbon atoms and/or, if desired, any resulting free compound is converted into a salt thereof with a physiologically tolerable inorganic or organic acid and/or any resulting salt is converted into the corresponding free compound.

4. A process as claimed in claim 3, wherein the derivative of the P-dicarbonyl compound is an acetal or, when R and R **2 each represents a hydrogen atom, an enamine. A process as claimed in claim 3 or 4, wherein the amidine

S: of the general formula II or the salt thereof has been obtained by the reaction of an imino-ester of the general formula IV e.

c (IV) 02 N N OR S0 N 2 X

in which X has the meaning given in claim 3 and R represents an alkyl group containing 1 to 4 carbon atoms, with ammonia or

with an ammonium salt. 6. A process as claimed in claim 5, wherein the ammonium salt is ammonium chloride.

7. A process as claimed in claim 3, conducted substantially

as described in any one of the foregoing Examples 1 to 6 or

7 to 11.

8. A pharmaceutical preparation which comprises at least

one compound as claimed in claim 1 or claim 2, in admixture

or conjunction with a pharmaceutically suitable carrier.

9. A pharmaceutical preparation as claimed in claim 8, which

is in the form of a pill, dragee, capsule, vaginal tablet or

syrup.

*n p 10. A pharmaceutical preparation as claimed in claims 8 or 9, 0 p

which is in the form of a tablet containing 0.1 to 0.5 gram of 0

*0 the active ingredient. *0 11. A pharmaceutical preparation as claimed in claim 8, which

is in the form of a powder, solution, suspension or aerosol

suitable for topical application.

12. A pharmaceutical preparation as claimed in claim 8, which *p is in the form of an aqueous or oily solution or suspension

suitable for parenteral administration. o P p. 13. A system which comprises a compound as claimed in claim 0n

1 or claim 2, together with instructions for its use for

controlling or treating protozoa.

1L. A compound of the general formula II.

A process for the manufacture of a compound as claimed

in claim 14, such process being substantially as herein

described.

DATED this 15th day of February, 1973.

SCHERING AKTIENGESELLSCHAFT By its Patent Attorneys ARTHUR S. CAVE CO.