CH635339A5 - Process for the preparation of 2-phenyl-5-(5-1H-tetrazolyl)pyrimidin-4(3H)one derivatives - Google Patents

Description

635339

2nd

mei

PATENT CLAIMS 1. Process for the production of compounds of the

(I)

wherein R1, R2 and Rs, which may be the same or different, each represent hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy, -O-lower alkenyl,

-0- (CH2) m-C ^^ H2) n, where m = 0 or a whole

Number from 1 to 6 and n = an integer from 2 to 7,

-OCH2 (CH2) xO (CH2) yCH3, where x = 0 or an integer from 1 to 6 and y = 0 or an integer from 1 to 6, CF3, -OCF3, -OCH2CF3, hydroxy, lower-alkylthio, / '—V

Amino, nitro, -NjCH2) r, where r = 4 or 5, -N_0, never-

cdrig-alkyl-amino, di-lower-alkylamino, carboxyl, -C02 - lower-alkyl, -0 (CH2) uC02Ra, where u = an integer from 1 to 6 and Ra = hydrogen or lower-alkyl, acyl, Acylamino, acyloxy,

O

l'I

-0-C-NHRb, where Rb = lower alkyl,

-0 (CH2) 1: 0H, where k = an integer from 2 to 6, -OCH2-CH-CH2OH, -0CH2-CH-CH20CH3 or

I I

OH OH

-OCH2CaH5, mean

as well as pharmaceutically acceptable salts thereof, it being possible for not all of the substituents R1, R2 and R3 to be the same, except for the case where they mean lower alkoxy, characterized in that a substituted benzamidine of the formula

The invention relates to the production of certain 2-phenyl-5- (5-lH-tetrazolyl) pyrimidine-4 (3H) -one derivatives which are effective as inhibitors of allergic reactions.

Various drugs have been used to treat allergic reactions such as bronchial asthma and allergic rhinitis, which are thought to result primarily from an antigen-antibody interaction. For bronchial asthma, one of the most severe of these diseases of allergic origin, bronchodilators, such as theophylline, isoproterenol, epinephrine and atropine, have mainly been used for symptomatic relief. However, these agents result in undesirable side effects, e.g. cardiac stimulation and gastrointestinal discomfort or pain.

15 With the recently launched by J.S.G. Cox et al. in Adv. in Drag Res., 5, 115-196 (1970) disodium cromoglycate, the medicinal product was made available to the medical practitioner which, when administered to asthmatic patients, prior to inhalation of special antigens, the release of mediators, e.g. Inhibits histamine and SRS-A (slow-reacting anaphylaxis substance), which are believed to be responsible for the asthmatic response. Although dinarium cromoglycate makes it possible to treat bronchial asthma prophylactically without cardio-25 vascular side effects, which represents a considerable advance, this substance has the disadvantage that it is not absorbed orally and must be administered by inhalation.

30th

R

NH,

The following literature describes compounds which are structurally related to the 2-phenyl-5- (5-1H-tetrazolyl) pyrimidine-4 (3H) -one derivatives prepared according to the invention.

1. The preparation of the unsubstituted acid and ester 35 of the formula

40

45

R

NH

(VII)

where R is hydrogen or ethyl is described by S. Ruhemann in Ber., 30, 821 (1897).

2. The p-methylphenyl and p-methoxyphenyl-substituted-5o th esters and acids of the formula and ethyl ethoxymethylene cyanoacetate are reacted with sodium azide and ammonium chloride in approximately equimolar amounts in an inert organic solvent and, if appropriate, the compound thus obtained is converted into a corresponding, pharmaceutically acceptable salt.

2. The method according to claim 1, characterized in that one selects the solvent from the group of dimethylformamide, dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoramide.

3. The method according to any one of claims 1 or 2, characterized in that one carries out the reaction at temperatures from 100 ° C to the reflux temperature of the solvent system.

55

60

where R is hydrogen or ethyl and X is methyl or methoxy are described by Mitter et al. in J. Chem. Soc., 123, 65 2179 (1923) and Quart. J. Indian Chem. Soc., 2, 61 (1925).

3. By Shen et al. U.S. Patents 3,660,403 and 3,745,161 disclose compounds of the general formula

3rd

635339

Ar-

N

4?

• described cox, in which R- [Ar] - can be substituted phenyl, Y can be hydrogen and X can mean various substituents including hydroxy, alkoxy or n-heterocyclo. These reference compounds are described as having anti-inflammatory or anti-inflammatory, anti-pyretic and analgesic activity; Nothing is said about a possible use as an anti-allergic agent.

4. In U.S. Patent 3,883,653, antiallergic compounds of the formula

HO

(CH0) -Ar 2 m described, wherein m is an integer of 0 or 1 and Ar is the meaning of pyridyl, thienyl, furyl, phenyl or phenyl substituted by hydroxy, methyl, methoxy, nitro, chlorine, fluorine, 3,4 -Dimethoxy, 3,4,5-trimethoxy or alkanoylamino.

5. In U.S. Patent 3,448,107 are lipid regulating agents of the formula

X2

<CVn

I.

NH

l

N

described in which X1 and X2 can be different substituents including hydroxy, phenyl, p-chlorophenyl, p-methylphenyl and p-aminophenyl and n can have the meaning from 0 to 4. The compounds according to the invention in which n in the above formula has the meaning of 0 and in which the pyridinyl ring system is substituted in the 4-position by hydroxyl and in the 2-position by substituted phenyl are not described.

The invention relates to a process for the preparation of new therapeutically valuable 2- (substituted) phenyl-5- (5-lH-tetrazolyl) pyrimidine-4 (3H) -one derivatives. The compounds created according to the invention are particularly valuable in the prophylactic treatment of allergic bronchial asthma by the oral route.

The antiallergic agents obtained according to the invention can by the general formula

10th

7 ^

RJ

are represented, in which R1, R2 and R3, which may be the same or different, each represent hydrogen, halogen, lower-alkyl, lower-alkenyl, lower-alkoxy, -O-lower-alkenyl,

-0- (CH2) m-CH ~ (CH2) n, where m = 0 or a whole

Number from 1 to 6 and n = an integer from 2 to 7.20 -OCH2 (CH2) xO (CH2) yCH3, where x = 0 or an integer from 1 to 6 and y = 0 or an integer from 1 to 6, CF3, -OCF3j -OCH2CF3, hydroxy, low-alkylthio,

S ^ / "\

Amino, nitro, -Nj (CH2) r, where r = 4 or 5, -N O, never-

25 cdrig-alkyl-amino, di-lower-alkylamino, carboxyl, -C02 - lower-alkyl, -0 (CH2) u'C02Ra, where u = an integer from 1 to 6 and Ra = hydrogen or lower-alkyl , Acyl, acylamino, acyloxy,

O

30 l '|

-0-C-NHRb, where Rb = lower alkyl,

-0 (CH2) k0H, where k = an integer from 2 to 6, -OCH2-CH-CH2OH, -OCH2CH-CH2OCH3j or

I I

35 OH OH

-OCH2C6H5, mean

and the pharmaceutically acceptable salts thereof, where R1, R2 and R3 may not all be the same except where they mean lower alkoxy. 40 The above-mentioned substituents R1, R2 and R3 can be in any possible position of the phenyl ring, i.e. are in the 2- to 6-positions. The substituents can be the same or different, but the only compounds according to the invention in which R1 = R2 45 = R3 are compounds in which R1, R2 and R3 are each lower alkoxy. The above substituent groups can be further defined as follows:

(a) Halogen includes chlorine, bromine, fluorine and iodine. Preferred halogen substituents are chlorine and fluorine, so (b) lower alkyl substituents include straight and branched chain saturated aliphatic hydrocarbon groups of 1 to 10 carbon atoms including e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-oc-55 tyl, n -Nonyl and n-decyl. The preferred substituents have 1 to 6 carbon atoms, and C 1 -C 4 -alkyl radicals are particularly preferred.

(c) Low alkenyl includes straight or branched chain unsaturated aliphatic hydrocarbon residues with one

60 double bonds and having 2 to 10 carbon atoms including, for example, vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl. Preferred groups are the C2 to C6 alkenyl radicals.

(d) Lower alkoxy includes Cr to C10 alkoxy, the alkyl part of which is 65 as defined above under (b). Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, etc. Preferred groups are the Cx to C6-

635339

Alkoxy groups, and the Cr to C4 alkoxy radicals are particularly preferred.

(e) -O-lower alkenyl groups include radicals in which the alkenyl part is as defined under (c) above, for example vinyloxy, allyloxy or isopropenyloxy. A particularly preferred group is the allyloxy group.

(f) -Q- (CH2) m-CH (CH2) n includes cyclo lower alkyl

oxy- and cyclo-lower alkyl ^ Cj-C ^ alkyloxy groups, wherein the cycloalkyl ring has 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Examples of such groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethylpropoxy and cyclohexylhexoxy.

(g) -Ò-CH2 (CH2) xO (CH2) yCH3 includes residues such as -OCH2OCH3, -0CH2CH20CH3, -0'CH2CH20CH2CH3, -OCH2OCH2CH3 and -OCHaCHaC ^ OCHjCHg.

(h) Lower alkylthio includes Cj to C10 alkylthio, wherein the alkyl portion is as defined in (b) above. Examples of such groups are methylthio, ethylthio, propylthio and butylthio.

(i) Lower alkylamino comprises Cr to C10-alkylamino radicals, wherein alkyl is as defined under (b). Examples of these groups are methylamino, ethylamino, propylamino and butylamino.

(j) Di-lower alkylamino includes di-C ,, - to Di-C10-alkylamino residues, wherein alkyl is as defined under (b) above. Examples of these groups are dimethylamino and diethylamino.

(k) -C02-lower alkyl includes ester radicals in which the alkyl portion is as defined in (b) above, e.g. Carbo-methoxy, carboethoxy, carbopropoxy and carbobutoxy.

1) -0 (CH2) uC02Ra represents radicals in which Ra is as defined in (b) above, such as -0CH2C02H, -OCH2CH2-

co2h, -och2ch2ch2co2h, -och2co2ch3, -ochzco2-

C2H5, -0CH2CH2C02CH3 and -0CH20H2C02C2Hs.

(m) Acyl comprises residues of the type R ° -CO-, wherein R ° is an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residue or a heterocyclic or heterocyclic-aliphatic residue or a heterocyclically substituted aliphatic residue, e.g. CHsCO-, C2HäCO-,

c3h, co-, c6h5co-, c6h5ch2co-,

ch2

Fl / \

^> - CH2CO- and CH2 CH-CO-. Preferred acyl

groups are those in which R ° alkyl is as defined in (b).

(n) Acylamino comprises residues of the type R ° -CO-NH-, in which R ° is as defined above in connection with acyl and preferably represents C 1 -C 10 -alkyl. Examples of these groups are CHsCONH-, C2H-CONH- and CeH5-CONH-.

(o) Acyloxy comprises residues of the type R ° -COO-, in which R ° is as defined above in connection with acyl and is preferably Cr to C10-alkyl. Examples are CH3COO-, C2H5COO-, C3HvCOO-, CsH5CH2COO- and CjjHjCOO-.

(p) -N ^ ÇCHj) ,. includes pyrrolidino and piperidino; and O

H

(q) -0-C-NHRb includes low alkyl carbamoyloxy residues. wherein the lower alkyl portion is as defined in (b) above. Examples of such substituents include -OCONHCH3, -OCONHC2Hs and -OCONHC3H7.

A preferred embodiment of the invention comprises the compounds of the formula

N - H

HN

R

wherein R1 and R2, which may be the same or different, as defined above in connection with the compounds of the general formula I, with the proviso that R1 cannot represent hydrogen, and the pharmaceutically acceptable salts of these compounds of the formula I '.

Preferred compounds and salts of formula P are those wherein R1 is lower alkoxy, i.e. straight or branched chain Cr to C10 alkoxy, -O-low-

Alkenyl or -0- (CH2) m-CH (CH2) n, where m = 0 or an integer from 1 to 6 and n = an integer from .2 to 7. Within this group, preferred subgroups represent the compounds and Salts of formula I 'in which

(a) R1 = -0-C1-C6-alkyl, particularly preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or sec-butoxy;

(b) R1 = -0-C2-C6-alkenyl, particularly preferably allyloxy; and

(c) R1 = -Q- (CH2) m-CH (CH2) | "wherein m = 0 or an integer from 1 to 4 and n = an integer from 2 to 5, particularly preferably cyclopropylmethoxy.

The preferred substituents R2 for the compounds of the formula I 'are hydrogen, lower alkoxy, -O-lower-

Alkenyl, -0- (CH2) m -CH ^ (CH2) n, where m = 0 or an integer from 1 to 6 and n = an integer from 2 to 7, nitro, amino or di-lower alkylamino. Particularly preferred substituents R2 are hydrogen, lower alkoxy, nitro, amino or di-lower alkylamino.

A more preferred embodiment of the invention comprises the compounds of the formula

NH

wherein R1 and R2, which may be the same or different, as defined above in connection with the compounds of general formula I, with the proviso that R1 is not hydrogen, and the pharmaceutically acceptable salts of these compounds of formula I ".

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

635339

Preferred compounds and salts of the formula I "are those in which R1 = lower alkoxy, -O-lower alkenyl or in which m = 0 or an integer from 1 to 6 and n = an integer from 2 to 7. Within these Group are preferred subgroups of compounds and salts of the formula I "in which

(a) R1 = -O-Cj-Cj-alkyl, particularly preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or sec-butoxy;

(b) R1 = -0-C2-C6-alkenyl, particularly preferably allyl-oxy; and

(c) R1 = -Q- (CH2) m-CH (CH2) n, where m = 0 or an integer from 1 to 4 and n = an integer from 2 to 5, particularly preferably cyclopropylmethoxy.

The preferred substituents R2 for the compounds of the formula I "are hydrogen, lower alkoxy, -O-lower -

Alkenyl, -0- (CH2) m-CHJCH2) n, where m = 0 or an integer from 1 to 6 and n = an integer from 2 to 7, nitro, amino or di-lower alkylamino. Particularly preferred substituents R2 are hydrogen, lower alkoxy, nitro, amino or di-lower alkylamino.

Particularly preferred compounds and salts of the formula I "are those in which R1 = methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy or cyclopropylmethoxy and R2 = methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy, cyclopropylmethoxy, nitro, amino or dimethylamino.

A further preferred embodiment of the invention comprises the compounds of the formula in which R1 = halogen, lower alkyl, lower alkenyl, lower alkoxy, -O-lower alkenyl, -0- (CH2) m-CHJCH2) n,

where m = 0 or an integer from 1 to 6 and n =

an integer from 2 to 7, -OCH2 (CH2) xO (CH2) yCH3,

where x = 0 or an integer from 1 to 6 and Y = 0 or an integer from 1 to 6, CF3, -OCF3, -OCH2CF3,

Hydroxy, lower alkylthio, amino, -N (CH2) r, where r = 4 or 5, -NO, lower alkylamino, di-lower alkylamino, carboxyl, -C02-lower alkyl, -0-CH2) uC02Ra , where u = an integer from 1 to 6 and Ra = hydrogen or lower-alkyl, acyl (preferably Rc-CO-, where R ° = lower-alkyl), acylamino (preferably Rc-CO-NH-, where Rc = lower alkyl), acyloxy (preferably R ° -COO-, where O

II

Rc = lower alkyl), -0-C-NHRb, where R "= lower alkyl, -0 (CH2) k0H, where k = an integer from 2 to 6, -OCH2-CH-CH2OH, -0CH2CH- CH20CH3 or -OCH2C6H5,

I I

ÖH OH

and the pharmaceutically acceptable salts thereof.

A preferred group of compounds within the scope of the formula I '"includes compounds of the formula I'", in which R1 = lower alkoxy, -O-lower alkenyl,

5 -Q- (CH2) m-CH (CH2) n, where m = 0 or an integer from 1 to 6 and n = an integer from 2 to 7, -OCH2- (CH2) xO (CH2) yCH3, where x = 0 or an integer from 1 to 6 and y = 0 or an integer from 1 to 6, -OCF3, -OCH2CF3, hydroxy, lower-alkylthio, amino, lower-Al-lo kylamino, di-lower- alkylamino, -0 (CH2) uC02R% where u = an integer from 1 to 6 and Ra = hydrogen or lower alkyl, -0 (CH2) k0H, where k = an integer from 2 to 6, -OCH2-CH -CH2OH, -OCH2-CH-OH2OCH3 or -OCH2C6H5,

I I

15 OH OH

or a pharmaceutically acceptable salt thereof.

Within this group, the compounds are preferred in which R1 = lower alkoxy, -O-lower alkenyl,

20 Q- (CH2) m-OH (CH2) n, where m = 0 or an integer from 1 to 6 and n = an integer from 2 to 7, -OCH2- (CH2) xO (OH2) yCH3, wherein x = 0 or an integer from 1 to 6 and y = 0 or an integer from 1 to 6, -OCF3, -OCH2CF3, hydroxy, -0 (CH2) uC02Ra, where u = an integer from 1 to 6 and Ra = hydrogen or lower alkyl, -0 (CH2) k-0; H, where k = an integer from 2 to 6, -OCH2-CH-CH2OH, -OCH2-CH-CH2OCH3 or -OCH2C6H5,

I I

OH OH

30 or the pharmaceutically acceptable salts thereof.

Other preferred compounds and salts of formula I '"are those wherein R1 = lower alkoxy, -O-lower alkenyl or -0- (CH2) m-CH- (CH2) n, where m = 0 or one

35 integer from 1 to 6 and n = an integer from 2 to 7.

Particularly preferred compounds and salts of the formula I '"are those in which R1 = -0-CrC6-alkyl, particularly preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or sec-butoxy; -O- ^ -Cg alkenyl, especially

40 ^

preferred allyloxy; or -0- (CH2m-CHJCH2) n, where m = 0 or an integer from 1 to 4 and n = an integer from 2 to 5, particularly preferably cyclopropylmethoxy.

Particularly preferred compounds and salts of For-45 mei I '"are those in which R1 = methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy or cyclopropylmethoxy.

Since the compounds prepared according to the invention are amphoteric in nature, they can be dissolved in 5o * salts either by acids or bases by treatment with an essentially equimolar amount of the chosen acid or base in an aqueous solution or in a suitable organic solvent such as methanol or ethanol , being transformed. If such salts are to be used for human consumption, the acids or bases used to prepare the pharmaceutically acceptable salts should of course be those which do not form toxic salts. Examples of suitable acids include hydrochloric acid, hydrobromic acid, iodine-60 hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, succinic acid, maleic acid, gluconic acid, ascorbic acid and p-toluenesulfonic acid. Pharmaceutically acceptable salts can be made from bases such as ammonia, organic amines and metal salts, e.g. Metal salts containing sodium, potassium, calcium, magnesium, barium and aluminum cations. Examples of such bases are ammonia, primary amines, such as n-propylamine,

635 359

n-butylamine, ethanolamine, ethylenediamine, cyclohexylamine, benzylamine, ethylamine, octylamine or tris (hydroxmethyl) aminomethane, secondary amines such as diethanolamine, tertiary amines such as triethanolamine, N-methylpyrrolidine, N-methylmorpholine or 1,5 -Diazabicyclo- [4.3.0] -5-nonen, and metal compounds such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydroxide or aluminum hydroxide.

It will be apparent to those skilled in the art that the compounds represented by Formula I contain two tautomeric hydrogen atoms and the compounds can thus exist in the forms 1-6 shown below. All of these forms can be present to a greater or lesser extent and are in a dynamic state of equilibrium with one another. The present invention encompasses all such forms, but for the sake of simplicity in the present Belo specification, structure 1 was chosen arbitrarily in order to describe the compounds according to the invention.

7

635339

The process according to the invention for the preparation of the compounds of the formula I comprises the reaction of a substituted benzamidine of the formula

^ NH

VII

(wherein R1, R2 and R3 are as defined above with respect to Formula I) and an ethyl ethoxymethylene cyanoacetate of the formula

C2H5 ° 2C \ / CN c II

CHO / H 2 5

in an inert organic solvent with sodium azide and ammonium chloride. Approximately equimolar amounts of the four reagents are used in an organic solvent which is inert to the reaction 5 and which should have good solubility for the sodium azide. Suitable solvents include dimethyl formamide, dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoramide. The most preferred solvent is dimethylformamide. To achieve the best results, the reaction is carried out with heating, preferably at temperatures from about 100 ° C. to the reflux temperature of the solvent system. When the reaction is complete, the desired product can be obtained by adding sufficient water, followed by acidification to precipitate compound I from the reaction mixture.

The above process enables compound I to be prepared directly from the basic benzamidine and ethyl ethoxymethylene cyanoacetate starting materials in one step without the need to first prepare and isolate the 20 or more intermediates required for the methods described above. The advantages that result from the overall yield and the simple procedure are evident from the examples below. 25 The starting materials of formula VII are either known or are prepared by known methods. A preferred method for the preparation of substituted benzamidines can be represented by the following reaction sequence (illustrated for the case R1 = -OC2H5):

(c2h5) 3 ° + bf;

0C2H5

1. NH, in CjH CK

2. HaOH

In this procedure, described in US Pat. No. 3,819,631 and in J. Org. Chem., 55 33, 1679 (1968), the above-mentioned triethyloxonium fluoroborate reagent can be replaced by alkyl fluorosulfonates (eg methyl fluorosulfonate), dimethyl sulfate or by other alkyloxonium fluoroborates will. A particularly preferred procedure involves the use of the relatively inexpensive dimethyl sulfate [(CH30) 2S02] as an alkylating agent instead of the more expensive alkyl fluorosulfonates and the triethyloxonium fluoroborate. This procedure, which is cited below, leads to the formation of a benzamidine methyl sulfate salt.

635339

8th

^ COHHj uu c2h5

(ch3o) 2so2.

C1CH2CH2C1 reflux

och3 ..

00®

^ oc2H5

- B0S03CF3

nh3, c2h5oh

- hoso-ch,

An alternative procedure for the preparation of the benzamidine compounds of the formula VII comprises the following 20 reactions (illustrated for the case R1 = -OC2H5):

0c2H5

NELOH 'KCl 2

Base catalytic hydrogenation e.g. H0 / Raney kickel

In the preparation of the compounds of the formula I in which R1, R2 or R3 contain free hydroxyl, amino or carboxyl groups, it is understood that such groups are protected by suitable known protective groups during the reaction steps which are carried out with the benz -amido starting materials and lead to the formation of the final tetrazoles.

The protective group or groups can then be removed by methods known per se to form the desired products which have the unprotected substituent groups. In the preparation of the compounds of the formula I in which R1, R2 or R3 are lower-alkylamino or di-lower-alkylamino, the corresponding amino-substituted compound can first be prepared and then alkylated by methods known per se. Alternatively, the dialkylamino substituted compounds can be prepared directly from the corresponding benzamidine starting material.

As mentioned above, it has been found that the compounds of the formula I prevent the release of toxic products, i.e. Mediators that inhibit the combination of certain types of antibodies and specific ones

Antigen result. They are particularly valuable in preventing the symptoms of allergic bronchial asthma in mammals by administering a mediator-inhibiting dose of a compound of formula I. The compounds may also be useful in relieving and preventing other allergic reactions such as allergic rhinitis.

The compounds prepared according to the invention can be administered either as individual therapeutic agents or as mixtures with other therapeutic agents, but are generally given in the form of pharmaceutical compositions, i.e. as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents. Examples 60 of such compositions include tablets, troches, capsules, powders, aerosol sprays, aqueous or oily suspensions, syrups, elixirs and aqueous solutions for injection. Preferably the compounds are administered in oral dosage forms.

65 The nature of the pharmaceutical composition and the pharmaceutical carrier or diluent will of course depend on the desired route of administration, i.e. orally, parenterally or by inhalation.

9

635339

Oral compositions can be in the form of tablets or capsules and can be conventional excipients such as binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide), breaking agents (e.g. starch) or wetting agents (e.g. sodium lauryl sulfate). Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc. or can be presented as a dry product for reprocessing in water or other suitable vehicles before use. Such liquid preparations can contain conventional additives such as suspending agents, flavoring agents, diluents or emulsifiers. For parenteral administration or inhalation, solutions or suspensions of a compound of formula I with conventional pharmaceutical vehicles can be used, e.g. as an aerosol spray for inhalation or as an aqueous solution for intravenous injection or as an oily suspension for intramuscular injection. The compounds can also be administered by inhalers or other devices which allow the active compounds to be brought into direct contact with the lungs in the form of dry powders.

The compounds or pharmaceutical compositions or pharmaceutical compositions thereof obtained according to the invention can be administered to human asthamatic patients in individual oral doses of about 1-500 mg of the active ingredient and in several oral doses with a total of up to about 1000 mg / day of the active ingredient. When administered by inhalation, lower doses are generally given, i.e. on the order of about 0.1 of the normal oral dosage for the particular compound in question. These values are given by way of example only and ultimately the doctor can determine the appropriate dosage for a particular patient based on factors such as age, weight, severity of symptoms and the particular agent to be administered.

In vivo animal model studies, which are described below, have shown that the compounds of the formula I are highly effective antiallergic agents.

Biological activity data

The rat reactive cutaneous anaphylaxis (PCA) screening test, used to evaluate the present compounds, is generally considered to be one of the best animal models useful in predicting the anti-allergic activity of test compounds in humans. In short, the method consists of passively sensitizing skin parts of the test animals with antibodies containing reagin, after which the agent to be examined is administered after 24 hours and the antigen is tested. The allergic reaction is measured using the Evans' blue dye and assessed by the diameter of the spots at the injection site. The details of the investigation are listed below.

materials

Ovalbumin (5 times crystalline)

Dinitrobenzenesulfonic acid, Na + salt Bordetella pertussis vaccine - phase I

10-20 X 109 killed organisms / ml aluminum hydroxide gel -10 mg / ml potassium carbonate

Male Sprague-Dawley (S / D) rats - 200 g

Female Sprague-Dawley rats -100 g tris-buffered saline (TBS) - 0.02 m 2-amino-2-hy-

droxymethyl-l, 3-propanediol (Tris), 0.15 M NaCl, pH = 8.2.

5

Production of the antigen - DNP-d EA

A substituted ovalbumin antigen is used both as an immunogen and as a stimulus antigen. The antigen is prepared as follows: 500 mg ovalbumin (EA) io and 500 mg K2C03 are dissolved in 25 ml distilled water and stirred at room temperature for 5 minutes. 500 mg of dinitrobenzenesulfonic acid, Na + salt (previously recrystallized from hot absolute ethanol) are then slowly added with continuous stirring. The reaction mixture is then introduced immediately into the dark and stirring is continued for 2 hours. After 2 hours, the mixture is placed in a suitable dialysis tube and dialyzed against 5 changes (41 each) of distilled water at 5 ° C. After dialysis, the product is lyophilized and stored in a brown or amber-colored container at room temperature. The antigen obtained appears as a light yellow amorphous solid, which is very readily soluble in water or saline. It is called DNP, denatured ovalbumin (DNP-d EA).

25th

Immunization method for IgE generation

Adult male Sprague-Dawley rats are used as a source of reagin-rich antisera for the PCA model. The immunization is carried out by a combination of>> 30 nations of DNP-d EA on Al (OH) 3 gel and B. pertussis vaccine. The DNP-d EA gel immunogen is prepared as follows: The Dnp-d EA is dissolved in TBS so that a concentration of 10 mg / ml is obtained. Slowly add 1 ml of this solution to 10 ml of 35 Al (OH) 3-gel (10 mg solid / ml) with constant stirring at room temperature. The mixture is then stirred for a further 30 minutes in order to achieve a uniform adsorption of the antigen on the gel.

The resulting preparation is then combined 40 with the B. pertussis vaccine, phase I, for the immunization of male S / D rats in the following manner: 0.1 ml of DNP-d EA gel suspension is intramuscularly in each rat Rear leg administered (200 DNP-d EA and 2 mg gel total dose). Following these 45 injections, 1.0 ml of B. pertussis vaccine (10-20 X 109 organisms) are administered intraperitoneally. A mild ether anesthesia is recommended for this procedure to enable clean intramuscular and intraperitoneal injections. 9 days after immunization (but not longer than 10), the animals are bled through cardiac puncture or abdominal aorta cannula under ether or pentobarbital anesthesia. All of the collected blood is allowed to clot, the serum is separated off by centrifugation and the individual serum samples are stored in a frozen manner up to 55 for the evaluation of the IgE content.

Selection of serum samples with high titer for pool formation

Individual serum samples are selected to concentrate the 60 reagin antibodies before pooling with other sera, as not all rats respond to immunization with reagin production. A 1:50 salt dilution of serum for each immunized rat is used for this purpose. Intradermal injections of 0.05 ml 65 of the diluted serum are administered into the shaved backs of two small female recipient rats of 100-120 g. Different serum samples can be examined simultaneously on the recipient animals. After a load

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Period of 24 to 48 hours is an antigen stimulus by intravenous administration of 1 mg DNP-d EA in

0.5.ml 0.5% Evans' blue dye in saline achieved on each rat. Sera that give positive PCA reactions in the 1:50 dilution, measured 20 to 30 minutes after irritation, are combined, divided into small equal parts and stored at - 70 ° C or below until use. Negative sera can be discarded.

The IgE content of the combined anti-sera is then determined. Two-fold serial dilutions (1: 5 to 1: 160) of unheated sera and sera heated at 56 ° C for 1 hour are made in saline, and 0.05 ml of each of these dilutions are intradermally in the back injected from female recipient rats. At least four animals should be used for both the warmed and the non-warmed serum titrations. After a 24 hour latency period, each group is challenged with 1 mg DNP-d EA in 0.5 ml 0.5% Evans' blue dye. Responses are assessed by reflecting the skin 20 to 30 minutes after irritation. The intensity (blue color) and the spot diameter are measured and recorded. The titer of the pool is defined as the reciprocal of the greatest dilution of the unheated serum, which produces a measurable PCA reaction (> 6 mm diameter) in at least half of the recipient animals. Antisera pools with a titer of 50 or above are suitable for PCA assessment. These pools should be sterile filtered and stored at -70 ° C or below until use. Alternatively, small aliquots can also be lyophilized.

PCA assessment or screening method

1. Animals

Young Sprague-Dawley female rats (90-110 g) are used. The rats should be conditioned (or acclimatized) at least 5 days before the examination, with free feeding and water.

2. Passive awareness

The test animals are prepared for passive sensitization by carefully shaving areas on each side of the back with a fine-toothed clipper. Intradermal injections of salt water dilutions of the antiserum pool are performed using a 27 gauge 5/8 "needle on a 1 ml tuberculin syringe. Four dilutions (two on each side) of the aniserum are used. The exact dilutions depend on the titer of the pool.For example, if the anti-serum pool has a titer of 50, dilutions of 1:10, 1:20, 1:30 and 1:40 are used; the pool has a titer of 100 , the dilutions are 1:20, 1:40, 1:60 and 1:80. The administration of each dilution should be either clockwise or counter-clockwise to facilitate evaluation. The latency period should be at least 24, but not longer than 48 hours.

3. Administration of drugs - standard and unknown

4 animals are used for each test compound. Disodium cromoglycate (DSCG) dissolved in saline is administered intravenously (IV) at the time of antigen challenge. The tetrazole test compounds are solubilized in aqueous sodium bicarbonate. The compounds to be examined are i.v. or administered orally (p.o.) either 1-5 or 10 minutes before antigen challenge.

4. Antigen irritation and evaluation of the reaction

The PCA reaction is visualized by intravenous administration of 1 mg DNP-d EA in 0.5 ml 0.5% Evans' blue dye in saline to each rat. The 5 PCA rections occur a maximum of 20 or 30 minutes after the irritation. The reactions should be assessed visually for the color intensity and the average diameter of the spots, measured at each antiserum thinning site. Both operations are carried out with reflection on the skin. For comparison purposes, the control group (not treated) uses at least 5% and usually 10% of the total animals examined on a particular day.

The observed inhibition of the agents is reported as a percentage reduction in the effective antiserum titer in treated animals in comparison with control groups.

Results

20 Results for certain preferred compounds of the present invention when administered i.v. and p.o. are given in Table I below along with the data for DSCG. The results are given as ID50 values, i.e. than the dose of the compound that inhibits 50% of the response.

TABLE I

Rat PCA screening data for 2-phenyl-5- (5-lH-tetrazolyl) pyrimidin-4 (3H) -one

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E.g. ID50 in mg./kg.

No. R1 R2 iv. p.o.

45

6 och, h - ~ 0.1

1 oc2h5 h 0.02 0.09

50 2 och2ch2ch3 h - 0.04

3 och (oh3) 2 h - ~ 0.04

4 och2ch2ch2ch3 h - ~ 0.07 j5 5 och (ch3) ch2ch3 h - 0.05

7 och2ch (ch3) 2 h - ~ 0.1

8 0ch2-ch = ch2 h - 0.24

9 och, h - 0.07 60. ^

10 och2ch2ch3 och3 - 0.03

14 och2ch2ch3 n02 - 5

15 och2ch2ch3 nh2 - - 0.1 65 16 och2ch2ch3 n (ch3) 2 - ~ 0.4

0.3> 30

11

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The following examples serve to illustrate the preparation of the starting materials and the compounds according to the invention; however, they are not intended to be a limitation. All temperatures are given in ° C. “Skellysolve B” is a petroleum ether fraction with a boiling point of 60-68 ° C., consisting essentially of n-hexane (commercial product from Skelly Oil Co.).

Production of raw materials

The substituted benzamidines or benzamidine salts used as starting materials can be prepared in the following way.

Preparation 1: 2-ethoxybenzamidine hydrochloride

A suspension of 87 g (0.53 mol) of 2-ethoxy-benzamidine in 915 ml of methylene chloride was added all at once to an ice-cooled solution of 100 g (0.53 mol) of triethyloxonium fluoroborate in 226 ml of methylene chloride. The resulting solution was stirred at room temperature for 36 hours. The solution was concentrated to y3 of its volume and diluted with about 600 ml of diethyl ether, whereby 130 g of crude ethyl 2-ethoxybenzimidate fluoroborate of F = 116 to 113 ° were precipitated.

The above salt was dissolved in 500 ml of cold 10% ethanol. Ammonia suspended and the solution was stirred at room temperature for 36 hours. The solution was drawn off to dryness and the residue was partitioned between ethyl acetate and 5N NaOH. The ethyl acetate layer was dried to give a viscous oil. About 200 ml of acetonitrile was added to the oil, whereupon a solid separated, which was obtained to give 36 g of a material of F = 180 to 183 °. The solid was dissolved in about 60 ml of methanol and acidified with hydrogen chloride. By adding about 11 dry ether, 31.2 g of the desired hydrochloride salt from F = 198 to 199 ° precipitated.

Preparation 2: 2-ethoxybenzamidine hydrochloride (alternative procedure)

14.5 g (0.127 mol) of methyl fluorosulfonate was added to a solution of 20.0 g (0.121 mol) of 2-ethoxybenzamidine in 324 ml of methylene chloride. After 3 hours the solvent was removed under reduced pressure. The residue was triturated with diethyl ether and the mixture was filtered. The collected crude ethyl 2-ethoxybenz imidate fluorosulfonate (28.5 g) of F = 83 to 110 ° was added to 120 ml of saturated ammoniacal ethanol. The mixture was stirred at room temperature for 4 days. The mixture was filtered and the filtrate concentrated. The residue was triturated with 2N sodium hydroxide and the resulting mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated. A solution of the residual oil in 50 ml of acetonitrile was treated with hydrogen chloride. By adding 700 ml of diethyl ether, 11.0 g of 2-ethoxybenzamidine hydrochloride fell from F = 193 to 196 °

out.

Preparation 3: 2-ethoxybenzamidine

To a solution of 13.0 g (0.0785 mol) of 2-ethoxybenzamidine in 34 ml of dry methylene chloride was added all at once a suspension of 15.0 g (0.07885 mol) of triethyloxonium fluoroborate in 137 ml of methylene chloride . The solution that formed immediately upon addition of the fluoroborate was stirred at room temperature for 19 hours. The solution was concentrated to about% of its volume and diluted with about 100 ml of diethyl ether, precipitating the ethyl 2-ethoxybenzimidate fluoroborate which, when dried, gave 19.2 g of F = 113 to 166 °.

The above imidate fluoroborate was then added to 100 ml of ethanol, which contained 1.4 g of NH3. The resulting solution was stirred at room temperature for 78 hours while keeping the flask tightly closed. The solvent was removed under reduced pressure to give a colorless solid, which was dissolved in a small volume of water and made basic with 6N NaOH. After extracting with ethyl acetate, the solvent extract was dried, whereby 7.4 g of the title compound of F = 78 to 84 ° were obtained.

Replacing the 2-ethoxybenzamide used above with an equimolar amount of 2-isopropoxybenzamide or 2n-propoxybenzamide gives 2-isopropoxybenzamidine or 2n-propoxybenzamidine.

Preparation 4: 2-ethoxybenzamidine fluorosulfonate (method A)

256 ml (3.17 mol) of methyl fluorosulfonate were added to a suspension of 500 g (3.03 mol) of 2-ethoxybenzamide in 81 dry methylene chloride. The resulting solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was triturated with diethyl ether and the mixture was filtered. The solid obtained was washed with ether and then added to a cooled (ice-water) solution of 500 g of ammonia in 3 l of ethanol. The mixture was stirred in the cold for 0.5 hours and then at room temperature for 16 hours. The solution was concentrated and the residue was crystallized from 1,2-dichloroethane, 517 g (65%) of 2-ethoxybenzamidine fluorosulfonate having a melting point of 98 to 99 ° being obtained.

Analysis: C9H12N20. HFSOä

Calculated: C 40.90 H 4.96 N 10.60% Found: C 40.95 H 4.83 N 10.73%

Preparation 5: 2-ethoxybenzamidine fluorosulfonate (method B)

538 ml (6.66 mol) of methyl fluorosulfonate were added to a suspension of 1 kg (6.05 mol) of 2-ethoxybenzamide in 12.5 l of methylene chloride. The mixture was stirred at room temperature for 18.5 hours. Ammonia gas was then blown into the mixture for 8 hours, the temperature of the mixture being kept below 26 °. The mixture was stirred for a further 16 hours at room temperature. The solvent was removed in vacuo to give 1.7 kg of crude 2-ethoxybenzamidine fluorosulfonate.

Preparation 6: 2-ethoxybenzamidine methyl sulfate

A solution of 16.5 g (0.1 mol) of 2-ethoxybenzamide and 19.0 ml (0.2 mmol) of dimethyl sulfate in 60 ml of 1,2-dichloroethane was heated for 17 hours with stirring and under reflux. The solvent was removed under reduced pressure and the remaining oil was stirred with 200 ml of diethyl ether for 0.5 hours. The methyl 2-ethoxy benzimidate methyl sulfate was collected by filtration, dried and then added to 150 ml of stirred saturated ethanolic ammonia. The solution was left at room temperature for 18 hours and then filtered, after which the filtrate was concentrated. The residue was triturated with diethyl ether, after which 19.9 g (72%, based on 2-ethoxybenzamide) of 2-ethoxybenzamidine methyl sulfate was collected by filtration.

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Preparation 7: 2-n-propoxybenzamidine hydrochloride

A. Ethyl 2-n-propoxybenzimidate fluoborate

A solution of 33.0 g (0.175 mol) of triethyloxonium fluoborate in 75 ml of methylene chloride was added over 10 minutes to a stirred solution of 31.3 g (0.175 mol) of 2-n-propoxybenzamide in 150 ml of methylene chloride. The solution was stirred for a further 18 hours at room temperature. The solution was concentrated to about V5 of its volume and diluted with ethyl ether to precipitate 44.0 g (85% yield) of ethyl 2-n-propoxybenzimidate fIuoborate from F = 108 to 112 °.

B. 2-n-propoxybenzamidine hydrochloride

100 ml of ethanol containing 6.5 g of ammonia were added to a stirred suspension of 44.0 g of ethyl 2-n-propoxybenzimidate fluoborate in 25 ml of ethanol over 5 minutes. The resulting solution was stirred at 25 ° for 20 hours. The solution was drawn off to dryness and partitioned between diethyl ether and 5N sodium hydroxide. The ethereal layer was washed with brine, dried over sodium sulfate and concentrated. A solution of the residue in 500 ml of ether and 50 ml of ethanol was treated with hydrogen chloride to precipitate 28.8 g (76.6% yield) of 2-n-propoxybenzamidine hydrochloride of F = 184 to 186.5 °.

Preparation 8: 2-n-propoxybenzamidine methyl sulfate

950 ml (10.0 mol) of dimethyl sulfate were added to a warm, stirred solution of 896 g (5.0 mol) of 2-n-propoxybenzamide in 5 liters of 1,2-dichloroethane over a period of about 0.5 hours. The mixture was stirred and heated under reflux for 17 hours after which the solvent was removed. The remaining oily solid was collected by filtration, washed with ethyl acetate and dried, yielding 430 g of methyl 2-n-propoxybenzimidate-methylsulfate of F = 79 to 82 °. The filtrate combined with the washing solutions was left at 0 ° for 18 hours and gave a second connection of 503 g of the benzimidate from F = 81 to 83 °. A slurry of 906 g of the methyl 2-n-propoxybenzimidate methyl sulfate in 11 ethanol was added to 4 liters of ethanol which had previously been saturated with gaseous ammonia. The mixture was left at room temperature for 17 hours and filtered. The filtrate was evaporated to dryness, giving 872 g (60%) of 2-n-propoxybenzamidine methyl sulfate with a melting point of 86 ° to 88 °.

Preparation 9: 2-isopropoxybenzamidine hydrochloride

A solution of 38.4 g (0.202 mol) of triethyloxonium fluoborate in 75 ml of methylene chloride was added over 15 minutes to a stirred solution of 36.2 g (0.202 mol) of 2-isopropoxybenzamide in 100 ml of methylene chloride. The mixture was stirred at room temperature for 18 hours. The solution was concentrated to about V5 in volume and diluted with diethyl ether to precipitate 60 g of the crude ethyl 2-isopropoxybenzimidate fluoborate in the form of colorless crystals of F = 90 to 110 °. By recrystallizing this material from methylene chloride-diethyl ether, 55 g of a colorless material of F = 114 to 120 ° were obtained.

150 ml of 8% ethanolic NHS was added to a stirred suspension of 55 g of the above fluoroborate in 50 ml of ethanol. The mixture was stirred at 25 ° for 64 hours. The solution was drawn off to dryness and the residue was made basic with 100 ml of 5N NaOH. The basic mixture was extracted with ether and the ethereal extract was dried. A solution of the residue in 500 ml of ether and 50 ml of ethanol was treated with hydrogen chloride to precipitate 24.1 g of the colorless 2-iso-propoxybenzamidine hydrochloride of F = 162 to 164 °.

Preparation 10: 2-n-butoxybenzamidine hydrochloride

A solution of 32.4 g (0.171 mol) of triethyloxonium fluoborate in 75 ml of methylene chloride was converted into a stirred solution of 33.0 g (0.171 mol) of 2-n-butoxybenzamide [J. Pharm. Pharmacol., 4, 872 (1952)] added in 200 ml of methylene chloride at 25 °. The mixture was stirred at 25 ° for 20 hours and the solution was concentrated to about 1/5 of the original volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether, giving 28.7 g of ethyl 2-n-butoxybenzimidate fluoborate of F = 82 to 88 °. 150 ml of 8% ethanol ammonia were added to a stirred, cooled (ice-water) suspension of 28.7 g of the fluoborate in 75 ml of ethanol. The mixture was stirred at 25 ° for 20 hours. The ethanol was removed and the residue was partitioned between ether and 5N sodium hydroxide (100 ml). The ethereal layer was washed with brine, dried over sodium sulfate and then concentrated. A solution of the remaining oil in ether was treated with hydrogen chloride to precipitate 16.8 g of the title compound of F = 150 to 155 °.

Production 11: (■ ±.) - 2-sec-butoxybenzamidine hydrochloride In the same manner as described for the production of 2-n-butoxy-benzamidine hydrochloride in production process 10 (±) -2-sec-butoxybenzamidine hydrochloride from F = 142 to 144 ° from (±) -2-sec-butoxybenzamide, which in turn is described in J. Pharm. Pharmacol., 9, 855 (1957).

Preparation 12: 2-isobutoxybenzamidine

A cold (ice-water) solution of 70.1 g (0.363 mol) of 2-isobutoxybenzamide1) in 800 ml of methylene chloride was added to a cooled solution of 69.0 g (0.363 mol) of triethyl oxonium fluoborate in 175 ml of methylene chloride. The resulting solution was stirred at room temperature for 16 hours. Approximately% of the solvent was removed and the residue was diluted with 500 ml of diethyl ether. The mixture was filtered and 76.5 g of ethyl 2-isobutoxybenzimidate fluoborate 1 'of F = 110 to 112 ° were obtained, which was added to 350 ml of ethanol saturated with gaseous ammonia. After 67 hours at room temperature the solution was evaporated to dryness. The residue was treated with 160 ml of 5N sodium hydroxide and the mixture was extracted with methylene chloride (3 X200 ml) and the combined extracts were washed with water, dried over sodium sulfate and concentrated. The residue was recrystallized from cyclohexane, giving 42.9 g (total 61.5%) of 2-isobutoxybenzamidine (F = 49 to 51 °).

Analysis: CuH16N20

Calculated: C 68.72 H 8.39 N 14.57% Found: C 68.60 H 8.42 N 14.28%

Preparation 13: 2-isobutoxybenzamidine fluorosulfonate

5.65 g (0.0495 mol) of methyl fluorosulfonate was added to a stirred solution of 8.6 g (0.0445 mol) of 2-isobutoxybenz-

1> B.J. Broughton, B.J. Large, S.M. Marshall, D.L. Pain and K.R.H. Wooldridge, U.S. Patent 3,819,631 (1974).

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amid1) added in 100 ml of methylene chloride under nitrogen. The solution was stirred at room temperature for 18 hours. Ammonia gas was then bubbled through the solution with stirring for 3 hours. The solution was concentrated and the residue was recrystallized from 1,2-dichloroethane to give 1.1 g (8.5% yield) of the title compound.

Preparation 14: 2-ethoxy-5-methoxybenzamidine hydrochloride

A. 2-Ethoxy-5-methoxybenzamide

41.8 g (0.250 mol) of 5-methoxysalicylamide were dissolved in a solution of 6.37 g (0.277 gram atom) of sodium in 250 ml of ethanol. The resulting cooled (ice-water) solution was mixed with 38.9 g (0.250 mol) of iodoethane over 20 minutes. The reaction mixture was allowed to warm to room temperature over 0.75 hours and was then heated under reflux for 19 hours. The mixture was concentrated and the residue was triturated with water. The mixture was filtered and the solid obtained was recrystallized from acetonitrile,

whereby 34.5 g (70.7%) of 2-ethoxy-5-methoxybenzamide were obtained from F = 128 to 130 °.

Analysis: C10H13NO3

Calculated: C 61.52 H 6.71 N 7.18%

Found: C 61.45 H 6.51 N 6.93%

B. 2-ethoxy-5-methoxybenzamidine hydrochloride

28.4 g (0.248 mol) of methyl fluorosulfonate was added to a cooled (ice-water) solution of 33.5 g (0.172 mol) of 2-ethoxy-5-methoxybenzamide in 450 ml of methylene chloride for 20 minutes. The mixture was stirred at room temperature for 4 hours. % of the solvent was removed and the residue was diluted with diethyl ether. The precipitated crude methyl 2-ethoxy-5-methoxy-benzimidate fluorosulfonate (50.0 g) from F = 144 to 152 °

was dissolved in 300 ml of cold ethanol which had been saturated with ammonia. The mixture was stirred under cooling (ice-water) for 2 hours and then at room temperature for 17 hours. The ethanol was removed under reduced pressure to give a semi-solid material which was treated with 200 ml of 5N sodium hydroxide. The mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated. A solution of the residue in acetonitrile / acetone (2/5) was mixed with hydrogen chloride gas, as a result of which 10.5 g (26.5%) of 2-ethoxy-5-methoxybenzamidine hydrochloride with a melting point of 166-167 ° precipitated.

Preparation 15: S-carbomethoxy-2-ethoxybenzamidine

4. 5-carbomethoxy-2-ethoxybenzamide

5-Carbomethoxy-2-ethoxybenzamide from F = 159 to 161 ° was prepared from 5-carbomethoxysalicylamide, iodoethane and sodium methoxide in methanol in an analogous manner to that described for the preparation of 2-ethoxy-5-methoxybenzamide under preparation 14A.

B. 5-carbomethoxy-2-ethoxybenzamidine

5-Carbomethoxy-2-ethoxybenzamidine of F = 133 to 135 ° was prepared from 5-carbomethoxy-2-ethoxybenzamide in a manner similar to that described above in Preparation 12 for the preparation of 2-isobutoxybeczamidine.

11 B.J. Broughton, B.J. Large, S.M. Marshall, D.L. Pain and K.R.H. Wooldridge, U.S. Patent 3,819,631 (1974).

13 635339

Preparation 16: 5-chloro-2-ethoxybenzamidine hydrochloride

A. 5-chloro-2-ethoxybenzamide

A mixture of 16.0 g (0.093 mol) of 5-chlorosalicyl-amide, 31.8 g (0.204 mol) of iodoethane and 13.1 g (0.095 mol) of potassium carbonate in 225 ml of ethanol was heated under reflux for 20 hours. The hot mixture was filtered. The filtrate was evaporated to dryness and the residue was triturated with water. The mixture was filtered, and the solid obtained was recrystallized from acetonitrile, giving 6.8 g (36.6%) of 5-chloro-2-ethoxy-benzamide with a melting point of 136 ° to 139 °.

Analysis: C9H10ClNO2

Calculated: C 54.14 H 5.05 Cl 17.76 N 7.02% 15 Found: C 54.25 H 4.85 Cl 17.42 N 6.89%

B. 5-Chloro-2-'àthoxybenzamidine hydrochloride

If the production method 10 is repeated, replacing the 2-n-butoxybenzamide used there with an equi-20 molar amount of 5-chloro-2-ethoxybenzamide, the title compound is obtained from F = 227 ° (dec.).

Analysis: C9HnClN20. HCl

Calculated: C 45.97 H 5.15 N 11.91% Found: C 46.23 H 5.20 N 11.87%

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Preparation 17: 2,5-dimethoxybenzamidine hydrochloride

Repeating the production method 10 with replacement of the 2-n-butoxybenzamide used there by an equimolar amount of 2,5-dimethoxybenzamide gives the 30 title compound of F = 170 to 172 °.

Preparation 18: 2-cyclopropylmethoxybenzamidine hydrochloride

35 A. 2-Cyclopropylmethoxybenzamide

A stirred mixture of 10.02 g (0.074 mol) of salicylic amide, 10.24 g (0.074 mol) of potassium carbonate and 10.0 g (0.074 mol) of bromomethylcyclopropane in 15 ml of ethanol was heated under reflux for 19 hours. The mixture was concentrated and the residue was treated with water. The mixture was filtered and the solid obtained was recrystallized from benzene-Skellysolve B, giving 10.0 g (71.6%) of 2-cyclopropylmethoxybenzamide with an F = 102 to 105 °.

45

B. 2-Cyclopropylmethoxybenzamidine hydrochloride

A solution of 99.1 g (0.522 mol) of triethyloxonium fluoborate in 225 ml of methylene chloride was added to a stirred solution of 99.2 g (0.518 mol) of 2-cyclopropylmeth-50 oxybenzamide in 450 ml of methylene chloride. The mixture was stirred at 22 ° for 18 hours. The solution was concentrated to about V5 of its volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether, where 104.7 g (65.7%) of ethyl 2-cyclopropylmethoxybenzimidate fluoborate were obtained from F = 120 to 121 °. 400 ml of 6% ethanolic ammonia were added to a stirred, cooled (ice-water) mixture of 104.7 g of the fluoborate in 100 ml of ethanol. The mixture was stirred for 18 hours-60 den at 20 °. The mixture was concentrated and the residue was partitioned between diethyl ether and 3N sodium hydroxide. The ethereal layer was washed with brine and dried over sodium sulfate. The dried solution was treated with hydrogen chloride. 65 The precipitate was recrystallized from methylene chloride-diethyl ether, giving 71.5 g (92.5%, based on the fluoborate) of 2-cyclopropylmethoxybenzamidine hydrochloride of F = 166 to 171 °.

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Preparation 19: 5-methoxy-2-n-propoxybenzamidine hydrochloride

A. 5-methoxy-2-n-propoxybenzamide

56.0 g (0.335 mol) of 5-methoxysalicylamide was added to a cooled, stirred solution of 8.55 g (0.372 gram atom) of sodium in 335 ml of ethanol. The resulting suspension was added dropwise with 41.3 g (0.335 mol) of 1-bromopropane over 20 minutes. The mixture was stirred at room temperature for 1 hour and then heated under reflux for 19 hours. The solvent was removed under reduced pressure and the residue was treated with 500 ml of cold water. The solid was collected by filtration and recrystallized from acetonitrile, giving 29.0 g (41.4%) of 5-methoxy-2-n-propoxy-benzamide with a melting point of 83 ° to 87 °.

Analysis: CnH15N03

Calculated: C 63.14 H 7.23 N 6.69%

Found: € 63.28 H 7.43 N 6.47%

B. 5-methoxy-2-n-propoxybenzamidine hydrochloride

15.8 g (0.139 mol) of methyl fluorosulfonate were added to a solution of 29.0 g (0.139 mol) of 5-methoxy-2-n-propoxybenzamide in 200 ml of methylene chloride at 5 °. The solution was stirred at room temperature for 5 hours. Most of the solvent was removed and the remaining solution was diluted with 500 ml of diethyl ether. The precipitated methyl 5-methoxy-2-n-propoxybenzimidate - fluorosulfonate (35.4 g) of F = 117 to 126 ° was obtained and added to 220 ml of cold, saturated ethanolic ammonia. The mixture was stirred at room temperature for 19 hours. The solution was concentrated and the remaining oil was dissolved in a mixture of acetonitrile and ether. The resulting solution was treated with hydrogen chloride to precipitate 31.5 g of 5-methoxy-2-n-propoxybenzamidine hydrochloride in the form of an oil, which was separated by decanting the solvents.

Preparation 20-1: 2-methoxybenzcimidine hydrochloride

In the same way as described above for the preparation of 2-n-propoxybenzamidine hydrochloride under preparation 7, 2-methoxybenzamidine hydrochloride of F = 150 to 152 ° was obtained from 2-methoxybenzamide.

Preparation 20-2: 2-ethylthiobenzamidine hydrochloride

A. 2-ethylthiobenzamide oxime

A solution of 29.0 g (0.178 mol) of 2-ethylthiobenzo-nitrile [described by K. Brand et al. in J. Prakt. Chem., 108, 19 (1924)] in 284 ml of ethanol became a solution of 4.47 g (0.64 mol) of hydroxylamine hydrochloride and 31.2 g (0.29 mol) of sodium carbonate in 474 for 30 minutes ml of water added. The mixture was heated under reflux for 1.75 hours. The cooled mixture was reduced to y5 in volume. The residue was partitioned between diethyl ether and hydrochloric acid. The ethereal and aqueous layers were separated. The ethereal layer was extracted twice with fresh hydrogen chloride. The combined aqueous layers were adjusted to pH 5.5 with sodium bicarbonate. The mixture was extracted with ether (3X200 ml) and the combined ethereal extracts were dried over sodium sulfate and concentrated to give 12.5 g (36%) of 2-ethylthiobenzamide oxime, F = 72-78 °. Recrystallization from 2-propanol ether gave an analytical material with an F = 79 to 83 °.

Analysis: C9H12N2OS

Calculated: C 55.09 H 6.17 N 14.28%

Found: C 54.92 H 6.27 N 14.08%

B. 2-ethylthiobenzamidine hydrochloride

Raney nickel was added to a solution of 6.0 g (30.6 mmol) of 2-ethylthiobenzamide oxime in 200 ml of ethanol, and the mixture was shaken in an atmosphere of hydrogen at an initial pressure of 3.5 kg / cm 2 for 3 hours. The mixture was filtered and the filtrate was concentrated. The remaining oil was dissolved in a mixture of 30 ml of ethanol and 400 ml of diethyl ether. The solution was treated with hydrogen chloride and the precipitated 2-ethylthiobenzamidine hydrochloride (2.4 g, 36.2%) of F = 290 to 291 ° was made from 2-phopanol ether to form an analytical material of F = 296 to 297 ° recrystallized.

example 1

2- (2-n-propoxyphenyl) -5- (5-lH-tetrazolyl) pyrimidine -

-4 (3H) -on

To a chilled (ice bath) solution of 1.00 g (5.61 mmol) of 2-n-propoxybenzamidine in 4 ml of dry N, N-dimethylformamide was added 0.94 g (5.61 mmol) of ethyl ether-oxymethylene cyanoacetate. 20 minutes later 0.447 g (6.88 mmol) sodium azide and 0.368 g (6.88 mmol) ammonium chloride were added. The ice bath was removed and the mixture was heated by means of an oil bath kept at 127 ° for 30 hours. The cooled mixture was poured into 400 ml of ice-water and acidified with 6N hydrochloric acid. The solid obtained (0.93 g) with a F = 245 to 248 ° (dec.) Was recrystallized from 2-methoxyethanol, 0.69 g (41%) of the title compound having a F = 256 to 257 ° (dec.) received.

Example 2

2- (2-isopropoxyphenyl) -5- (5-lH-tetrazolyl) pyrimidine

-4 (3H) -on

By replacing the 2-n-propoxybenzamidine in Example 1 with 2-isopropoxybenzamidine, the title compound was obtained in the same way; recrystallized product (38%): F = 282 to 283 ° (dec.).

Example 3

2- (5-nitro-2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3 H) -one

1.03 g (3.46 mmol) of 2- (2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidine-1 (3H) -one was added to a one cooled to 5 ° over 20 minutes Mixture of 1.7 ml (26.9 mmol) of 70% nitric acid and 2 ml of concentrated sulfuric acid added. The mixture was left at room temperature for 2 hours and poured into 200 ml of ice-water. The precipitate was recrystallized from 2-methoxyethanol to give 0.73 g (61.3%) of the title compound of F = 251 to 252 ° (dec.).

Analysis: C14H13N, 04

Calculated: C 48.98 H 3.82 N 28.56%

Found: C 48.76 H 3.71 N 28.47%

Example 4

2- (5-Amino-2-n-propoxyphenyl) -5- (5-lH-tetrazolyl) pyrimidin-4 (3 H) -one

A mixture of 5.0 g of 2- (5-nitro-2-n-propoxyphenyl) -5 (5-1H-tetrazolyl) pyrimidin-4 (3H) -one and 4.0 g of palladium

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

15

635 339

on carbon (10%) in 900 ml of 2-methoxyethanol was shaken in a hydrogen atmosphere at an initial pressure of 3.5 kg / cm219 hours. The mixture was filtered and the filtrate evaporated to dryness to give 3.6 g (79%) of the title compound of F = 250 to 253 ° (dec.). Recrystallization from 2-methoxyethanol gave an analytical material with an F = 261 to 262 °.

Analysis: C14H15N702

Calculated: C 53.66 H 4.83%

Found: C 53.92 H 5.04%

Example 5

2- (5-Dimethylamino-2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one

To a suspension of 0.50 g (1.6 mmol) of 2- (5-amino-2-n-propoxyphenyl) -5- (5-lH-tetrazolyl) -pyrimidin-4 (3H) -one in 40 ml Acetonitrile was added to 1.32 ml (16.0 mmol) of 37% formaldehyde in water. 0.302 g (4.8 mmol) of sodium cyanoborohydride was added, and finally 1.67 ml of glacial acetic acid were added. The suspension was stirred at room temperature for 15 minutes and then heated under reflux for 3 hours. The mixture was cooled in an ice bath. The precipitate was recrystallized from acetonitrile and gave 0.19 g (35%) of the title compound of F = 258 to 259 °.

Analysis: C16H10N, O2

Calculated: Found:

C 56.29 C 55.92

H 5.61 H 5.42

N 28.73% N 28.63%

R1

R2

R3

2-OH

H

H

5 2-CH3

H

H

2-C2H5

H

H

2-C3H7

H

H

10 2-CH2CH = CH2

H

H

2-CH = CH2

H

H

2-cyclopropyloxy

H

H

15 2-OCH2OCH3

H

H

2-OCH2CH2OCH3

H

H

2-CF3

H

H

20 2-OCF3

H

H

2-OCH2CF3

H

H

2-SCH3

H

H

25 2-SC2H5

H

H

\

-N Y)

H

H

Example 6

Following the general procedure of Examples 1 to 5, the following compounds can be prepared using the appropriate nitrile starting materials.

30th

35

40

45

50

R1

R2

R3

2-C1

H

H

3-OCH3

H

H

3-CF3

H

H

4-OCH3

H

H

4-C1

H

H

4-CF3

H

H

2-F

H

H

2-OCH2C6H5

H

H

2-NH2 2-NHOH3 2-NHC2H5 2-N (CH3) z 2-COOH 2-C02CH3 2-C02C2H5 2-0CH2C02H 2-0CH2C02CH3

O

2-0-C-NHCH3

O

\\

60 2-OCH3

O

II

2-C-Gft

65 O

II

2-NH-C-CH,

55

H

H

H H H H H H H H H

H H H H

H

H

H H H H H H H H ■ H

H H H

635339

16

R1

R2

R3

R1

R2

R3

O

il

2-NH-C-C6H5 O

l \

2-0-C-CH3

O

11

2-0-C-CH2C6Hs O

2-0-C-C6H5 2-OCH, CH, OH

2-0-n-C, H7

H H

H

H H

2-OCH2-CH-CH2OH

H

1

OH

2-OCH2-'CH-CH2OCH3

H

i

OH

2-OCH2CHzCH2OH

H

2-OCH

3rd

4-OCH3

3-CH3

4-CH3

2-C1

5-C1

2-F

5-F

3-OCH3

4-OCH3

2-0-n-C3H7

5-CÎ

5-F

5-CH3

5-C2H5

5-CH2CH = CH2

5-CH = CH2

5-OC2H5

5-0-n-C3H,

5-OCH (CH3) 2

5-OCH2CH = CH2

5-OCH2CH2OCH3

5-CF3

5-OCF3

5-OCH2CF3

5-OH

5-SCHj

5-NHCH3

«

H

e

5-N

H

e

10th

15

H • H

H 20

25th

30th

35

/ - \ 5-N 0

v_y

H H H H H H

H 40

H

H

H 45 H H H H H H H H H H H

H 65

50

55

2-0-CH (CH3) 2

60

\

5-NHGjHg 5-COOH 5-C02CH3 5-COjCJHJ

5-0CH2C02H 5-0CH2C02CH3 O

11

5-0-C-NHCH3

o II

5-C-CH3

O

II

5-C-C2H5 O

II

5-NH-C-CH3 O

II

5-NH-C-C6H5 O

II

5-0-C-CH3 O

II

5-0-C-CH2C6H5 O

5-0-C-C6H5

5-OCH2CH2OH

5-OCH »-CH-CH, OH

OH

5-OCH2-CH-CH2OCH3

OH

5-OCH3

5-OC2H5

5-0-n-C3H7

5-OCH ('CH3) 2

5-OCH2CH = CH2

5- € R

H

H

H H H H H H

H

H

H

H

H

H

H

H

H H

H

H H H H H H

17th

635339

R1

R2

R3

2-OC2H5

5-OCH3

H

2-OCjH5

5-OC2H5

H

2-OC2H5

5-0-n-C3H7

H

2-OC2H5

5-OCH (CH3) 2

H

2-0-n-C4H9

5-OC2H5

H

2-0-n-C4H9

5-0-n-C3H,

H

2-0-n-C4H9

5-OCH (CH3) 2

H

3-OOH3

4-OCH3

5-OCH3

Example 9

Ethylene diamine dihydrate salt of 2- (2-n-propoxyphenyl) -5 - (5-lH-tetrazolyl) pyrimidin-4 (3 H) -one

5 0.625 g (0.0104 mol) of ethylenediamine were added to a stirred suspension of 2.98 g (0.010 mol) of 2- (2-n-prop-oxyphenyl) -5- (5-lH-tetrazolyl) pyrimidine-4 ( 3H) -one added in 30 ml of water. A complete dissolution was achieved by gentle heating. The solution was lyophilized to give the title compound in quantitative yield from F = 177 to 180 °, which was kept in equilibrium with atmospheric moisture for one month. Analysis: 'C14H14N602. C2H8N2. 2HaO

Calculated: C 48.72 H 6.64 N 28.41 HzO 9.13% 15 Found: C 48.98 H 6.21 N 29.25 8.75%

Example 7

2- (2-n-propoxyphenyl) -5- (5-lH-tetrazolyl) pyrimidine - 4 (3H) -one, sodium salt

A slurry of 298 mg (1 mmol) of 2- (2-n-prop-oxyphenyl) -5- (5 "1H-teirazolyv-pyrimidin-4 (3H) -one in 10 ml of water was mixed with 1 ml of 1N-sodium hydroxide The resulting solution was filtered, the volume of the filtrate was reduced, the filtrate was added with acetone, the slurry was stirred for 20 minutes, the sodium acid was collected by filtration, washed with acetone, dried and left in the air for 1 week.

Analysis: C14H13N6Na02. 2HaO

Calculated: C 47.19 H 4.81 N 23.59 HjO 10.11% Found: C 47.37 H 4.55 N 24.54 11.70%

By replacing the 2- (2-n-propoxyphenyl) -5- (5-lH-tetrazolyl) pyrimidin-4 (3H) -one in the above procedure with an equimolar amount by weight of the other 5- (5--1H -Tetrazolyi) pyrimidine-4 (3'H) -one compounds, prepared in Examples 2 to 6, the corresponding sodium salts are obtained for each of the compounds mentioned.

By replacing the sodium hydroxide in the above procedure with other bases, e.g. KOH, Ca (OH) 2, Mg (OH) 2 or NH4OH, the corresponding base addition salts are obtained.

The 5- (5-lH-tetrazolyl) pyrimidine-4 (3H) -one compounds of Examples 1 to 6 can be added to their acid addition salts by adding a stoichiometric equivalent of a suitable acid, e.g. HCl, HBr, HI, CH3COOH or HsP04, can be converted into a methanolic solution of the desired pyrimidine - 4 (3H) -one compound.

Example 8

Ethanolamine monohydrate salt of 2 ~ (2-n-propoxypheny!) - 5 - (5-lH-tetrazolyl) pyrimidin-4 (3H) -one

141.6 g (2.32 mol) of freshly distilled ethanolamine were added to a stirred suspension of 671.4 g (2.25 mol) of micropulverized 2- (2-n-propoxyphenyl) -5- (5-lH-tetra-zoIyI ) -pyrimidin-4 (3H) -one added in 7 liters of distilled water. Stirring was continued at 40 ° to effect almost complete dissolution. The mixture was filtered and the filtrate lyophilized to give 831.4 g (98%) of the title compound of F = 145 to 148 °.

Analysis: C14H14NG02. C2H7NO. H20

Calculated: C 50 92 H 6.14 N 25.98 H20 4.77%

Found: C 50.71 H 6.09 N 26.18 5.64%

Example 10

Following the general procedure of Example 8, but replacing the ethanolamine with diethanolamine, tri-20 ethanolamine and tris (hydroxymethyl) aminomethane, the following water-soluble salts of 2- (2-n-prcpoxy-phenyl) -5- ( 5-lH-tetrazolyl) -pyrimidin-4 (3H) -one prepared:

Diethanolamine salt, C14H14N602. C4HnN02,

25 F = 138 to 143 °

Triethanolamine salt, C14H14Ne02. C6H1SN03,

F = 146 to 199 °

tris (hydroxymethyl) amino methane salt, C14H14N602. C4HuN03,

30 F = 180 to 195 °

By replacing the 2- (2-n-propoxyphenyl) -5-1H-tetrazolyl) pyrimidin-4 (3'H) -one in the procedures of Examples 8 to 10 with an equimolar amount by weight of the other 35 5- (5- 1H-Tetrazolyl) pyrimidine-4 (3H) -one compounds, prepared in Examples 2 to 6, give the corresponding salts of each of the listed compounds.

40

Example 11

2- (2-n-pentyloxyphenyl) -5- (5-lH-tetrazolyl) pyrimidine - 4 (3H) -3H) -one

A solution of 24.6 g of ethyl ethoxymethylene cyanoacetate (0.145 mol) in 50 ml of N, N-dimethylformamide (DMF) 45 was stirred into a solution of 30.0 g of 2 n-Pentyloxybenz-amidine (0.145 mol) was dropped into 70 ml of DMF. Stirring in the cold was continued for 20 minutes and then 11.5 g sodium azide (0.178 mol) and 9.5 g animosonium chloride (0.178 mol) were added. The mixture was kept in an oil bath at 123-127 ° C for 24 h, then poured into cold water and concentrated with 50 ml of hydrochloric acid. acidified. The solid material formed was separated and recrystallized from 2-methoxyethanol to give 18.1 g of the title compound in 18% yield. Recrystallization from 2-methoxyethanol and then from 2-propanol resulted in colorless needles of F = 236-238 ° C (dec.).

Analysis: C16H18Ne02 60 Calculated: C 58.88 H 5.56 N 25.75% Found: C 58.77 H 5.69 N 25.55%

The title compound obtained when administered orally in the rat PCA test gave ID50 ~ 0.4 mg / kg. The compound was solubilized with aqueous sodium bicarbonate and administered 10 minutes prior to test assessment.