CS225804B2 - The production of the heterocyclic derivates of the guanidine - Google Patents

Abstract

The present invention relates to a process for the preparation of 5-, 6- or 7-membered fully saturated 1-azacarbocyclo- -2-ylidene guanidine derivatives having secretory and hypoglycemic activity. British Patent No. 1,409,768 discloses certain heterocyclic guanidine derivatives, wherein the heterocyclic radical is a 5- or 6-membered saturated 1,3-diazacarbocyclo-2- -yliden. These derivatives are unsubstituted at the imine nitrogen of the guanidine moiety. In contrast, the compounds produced by the process of the invention differ in that they are saturated monoazaheterocycloid guanidine derivatives and moreover have a bulky substituent on the imine nitrogen of the guanidine residue. Another state of the art, but more distant, may be introduced German Patent Publication Nos. 2,321,330 and 2,502,397. The present invention provides a process for the preparation of novel heterocyclic guanidine derivatives formula R3 — π ”/ R4 CD n2-kN4 = N-C-N AND where n is an integer of 1, 2 or 3, R 1 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms

Description

The invention relates to a process for the preparation of 5-, 6- or 7-membered fully saturated 1-azacarbocyclo-2-ylidene guanidine derivatives having secretory and hypoglycemic activity.

British Patent No. 1,409,768 describes certain heterocyclic guanidine derivatives in which the heterocyclic moiety is a 5- or 6-membered saturated 1,3-diazacarbocyclo-2-ylidene. These derivatives are unsubstituted on the imine nitrogen of the guanidine moiety.

In contrast, the compounds produced by the process of the invention differ in that they are saturated monoazaheterocyclic derivatives of guanidine and moreover have a bulky substituent on the imine nitrogen of the guanidine residue. A further state of the art, but further away, can be presented by German Publication Nos. 2,321,330 and 2,502,397.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel heterocyclic guanidine derivatives of the general formula ^R 3-π "/ ^R 4 CD ⁿ 2 -k _N ^ = NCN

Where n is an integer of 1, 2 or 3,

R ₁ is hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl having 3 to 6 carbon atoms (preferably cyclopentyl and cyclohexyl), alkene-2-yl having 3-5 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms (preferably hydroxyethyl) , aralkyl of 7 to 14 carbon atoms (preferably benzyl) and aryl, (preferably phenyl) of 6 to 10 carbon atoms, b, is hydrogen, alkyl of 1 to 6 carbon atoms and aryl of 6 to 10 carbon atoms (preferably phenyl) )

R 6 is hydrogen, alkyl of 1 to 8 carbon atoms and aryl of 6 to 10 carbon atoms (preferably phenyl),

R4 is hydrogen, methyl and ethyl,

R 8 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms (preferably cyclopentyl and cyclohexyl), aralkyl of 7 to 14 carbon atoms (preferably benzyl) and aryl of 6 to 10 carbon atoms (preferably phenyl and substituted phenyl) or

together represent a 3- to 7-membered saturated heterocyclic ring optionally interrupted by oxygen or sulfur or another nitrogen atom, which additional nitrogen atom is optionally substituted by C1-4 alkyl or benzyl, or

R is butyl, alkyl of 4 to 10 carbon atoms (preferably branched) such as t-neopentyl, 1,1,3,3-tetramethylbutyl and the like;

cycloalkyl of up to 8 carbon atoms (preferably cyclopentyl and cyclohexyl), bicycloalkyl of 7 to 10 carbon atoms such as exo- and ento-2-norbonyl, 2-bicyclo (2,2,2] -octyl, ento-2 bicyclo [3.2.1] octyl and the like, bicycloalkenyl of 7 to 10 carbon atoms, such as anti-7-norboneyl and the like, tricycloalkyl of 9 to 10 carbon atoms, such as nor-adamantyl; - and 2-adamantyl, 1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoindanyl) and the like,

1-adamantylmethyl, tricycloalkenyl of 9 to 10 carbon atoms such as 3- (2,3,5,6a-tetrahydro-1S-1,3a-ethanopentalenyl), 5- (3a, 4,5,6,7, 7α-hexahydro-4,7-methanoindenyl and the like, arylalkyl wherein aryl is a member selected from the group consisting of phenyl and naphthyl and the alkyl has 1 to 4 carbons such as benzyl, β- or 1-alpha-phenethyl, alpha, alpha -dimethylbenzyl, alpha, alpha-dimethyl-beta-phenethyl, d- or 1- (alpha-naphthyl) ethyl and the like, alpha, alpha-triethylenephenethyl, diphenylalkyl in which the alkyl has 1 to 2 carbon atoms, such as e.g. diphenylmethyl,

2,2-diphenylethyl and the like, naphthyl, including alpha and beta-naphthyl, fused diarylcycloalkenyl such as 9-fluorenyl, 5-acenaphthyl and the like, fused arylcycloalkyl such as 4- (2,3-dihydro- 1H-indenyl), 1- (1,2,3,4-tetrahydronaphthyl), 7- (bicyclo 4,2,0 octa-1,3,5-trienyl) and the like, phenylcycloalkyl wherein the cycloalkyl has 5 to 7 carbon atoms, such as cis- or trans-2-phenylcycloheptyl and the like, cycloalkylcycloalkyl wherein each cycloalkyl has from 5 to 7 carbon atoms, such as, for example, cla- or trans-2-cyclohexylcyclopentyl, cis- or trans- 2-cyclopentylcyclopentyl and the like, phenyl, methylenedioxyphenyl, phenyl substituted with 1 to 3 substituents each selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms, and phenyl substituted with a member selected from amino, dimethylamino, methylethylamino, lamino diets, C 1 -C 4 alkanoylamino, C 1 -C 4 thioalkyl 4 carbon atoms, sulfinylalkyl having 1 to 4 carbon atoms, sulfonylalkyl having 1 to 4 carbon atoms, trifluoromethyl, hydroxyl, benzyloxy, alkanoyloxy having 1 to 4 carbon atoms, alkanoyl having 1 to 4 carbon atoms and nitro,

3-pyridyl and 3-pyridyl substituted with 1-2 substituents each selected from halogen, lower alkyl and lower alkoxy such as 6-methoxy-3-pyridyl, 6-chloro-3-pyridyl, 2, 6-dimethyl-3-pyridyl, 2,6-dichloro-3-pyridyl, 2,6-dimethoxy-3-pyridyl and the like, and

5-membered heterocycles, such as 2-furyl and 2-thienyl, which comprises reacting a compound of formula III

Y (III) wherein X is methoxy or ethoxy and Y "is either BF 3 or CH 3 OSO 4 or OSC 4 F" and R ", R 8, f 11 and n are as defined in formula I with a compound of formula IV

NR

II + H ₂ NC-NR ₄ R ₅ (IV) wherein R, R 4 and R 3 are as defined in formula I, in an anhydrous organic solvent, the reaction being carried out in the range of 0 ° C to 100 ° C, preferably at a temperature of of the compound of formula V

Řs-HeWn D ·

R ₂ - < _n > = N- ^c -N ^r 4 R ₅ hy

I - 1 (V) wherein R, R ', Rg, R' ₍ R ', n) are as defined in formula (I) and Y is as defined as Y' in formula (III) which is converted to the corresponding compound of formula (I) e.g. by treatment with alkali and optionally preparing a pharmaceutically acceptable acid addition salt or quaternary salt.

The compounds produced have interesting pharmacological properties.

In this specification, if the prefix is lower, it denotes the corresponding group having 1 to 4 carbon atoms and the term halogen represents halogens of atomic mass less than

127, that is chlorine, bronze, fluorine · iodine. Preferably, any of the above? ₂ ^{or B} 3 is alkyl or aryl, the other is hydrogen and when n is the whole of number 2 or 3, then H? and R 1 is hydrogen.

Due to the presence of tertiary nitrogen in the compounds of Formula 1, its acid addition salts and quaternary salts are readily obtainable and as pharmaceutically acceptable salts are included within the scope of this invention. Said compounds 1 may be converted to their therapeutically active non-toxic acid addition salts by treatment with a suitable acid, such as an inorganic acid such as a hydrohalic acid such as hydrochloric, hydrobromic and the like, sulfuric acid, nitric acid, phosphoric acid and the like or organic acid such as acetic, propionic, glycolic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamon, almond, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, p-toluenesulfamic, cyclohexansulfamic -aminosalicylic and similar acids. Conversely, the salt formed can be converted by treatment with alkali into the free base form.

Therapeutically active quaternary ammonium salts can be prepared by reacting a compound of Formula 1 with an alkylating agent, i.e., alkyl, alkenyl or aralkyl halides, sulfate or sulfonate esters such as methyl iodide, ethyl bromide, propyl bromide; allyl chloride; benzyl chloride; or di-lower-alkylsulfates-dimethylsulfate, diethylsulfan; lower-alkylarylsulfonate-methyl-p-toluenesulfonate; methylfluorosulfonate; etc. The quaternary reaction may be carried out in the presence or absence of a solvent, depending on whether the quaternizing agent itself is also capable of acting as a solvent at room temperature or with cooling, at atmospheric pressure or in a closed vessel under pressure.

Suitable inert organic solvents for this purpose are ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as benzene and heptane, ketones such as acetone and butanone, lower alkanols such as ethanol, propanol, butanol; or organic acid amides such as formamide or dimethylformamide. The anionic group of the quaternary salt is readily exchangeable by known ion exchange procedures.

The most preferred compounds of the invention for their extraordinary hypoglycemic activity may be represented by the following formula:

11-r- (CH ₂ ) _n- ^R 9 ^R 10 -k _N > = NCN, (H) i R a and their pharmaceutically acceptable acid addition salts and quaternary salts wherein n = 1 or 2

Sg is a member selected from the group consisting of lower alkyl, allyl, hydroxy-lower alkyl and benzyl;

is methyl or ethyl;

Sg is a member selected from the group consisting of loweralkyl, cyclopentyl and cyclohexyl;

-NS2Sg together is a member selected from the group consisting of pyrrolidino, piperidino, morpholino and thiamorpholino;

Kg is Sien selected from the group consisting of: phenyl, previously described substituted phenyls, other than sulfonyl-4-alkylphenyl, 1-adamantyl and 1,1,3,3-tetramethylbutyl, cyclohexyl, diphenylmethyl, naphthyl and 9-fluorenyl;

R, _of Siena is selected from the group consisting of hydrogen and alkyl of 1-3 carbons;

R ₁₁ is Si 2 selected from the group consisting of hydrogen and alkyl of 1 to 3 carbons, provided that at least one of R ₁₀ and R ₁₀ is hydrogen.

Compounds of formula I are preferably prepared by reacting a lactam salt of formula III wherein n, R 1, R ₂ and R 1 are as defined above, X is either 3 methoxy or ethoxy and X "is either BF 3 - or OSOgF", with a guanidine derivative of formula IV R, R ^, Rg and NR ^R R are as defined above, preferably stoichiometric amounts of reactants being used.

Suitable non-aqueous organic solvents for carrying out the reaction are aliphatic alcohols such as methanol, ethanol, 2-propenol, tert-butanol and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like, lower halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane and the like; and aromatic hydrocarbons such as benzene, toluene, xylene and the like. Ambient temperatures up to 0 ° C can generally be used. The product V in the form of the corresponding HX salt is converted to the corresponding base form I by conventional means, e.g. by treatment with suitable alkali such as alkali metal or alkaline earth metal hydroxides, carbonates and the like.

The reaction can be illustrated as follows.

Lactamfluoroborate of formula III, wherein X 'is BF', are generally known and can be obtained by procedures described in the literature, eg, see Canadian patents S. 850 1,6 and 950 464; US Patents S. 3,876,658; Ber. £ 2,063 (1956); and Org. Synth. 46, 113, 120 (1966).

The lactam fluorosulfonates of formula III wherein X 'is OSOgF' are similarly prepared. Usually, the lectam of formula VI is reacted with the appropriate trialkyloxonium fluoroborate (VII) or methyl fluorosulfonate (VIII) to give the corresponding lactam salt.

The reaction is preferably carried out from 0 ° C to room temperature in an inert dry atmosphere (e.g., nitrogen, argon) in an inert non-aqueous lower halogenated hydrocarbon solvent such as, e.g., chloroform, 1,2-dichloroethane, methylene, dichloride (most preferably) and the like. Other inert non-aqueous organic solvents that may be used include ethers such as diethyl ether, dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane and the like; and aromatic hydrocarbons such as benzene, toluene, xylene and the like. The foregoing reactions may be illustrated as follows:

dli-8)

(VI) (VII)

+ MeOSOjF ^R 1 (VI) (Vlil) ^R 3 ~ Γ ^{, ε} ^ 2 · η R ₂ ——OMe

I «1 axis ₂ f (lil —b)

Alternatively, correspondingly! 2-nižšíalkylthiolaktimétery Formula III-c may be prepared by reacting the lactam of formula VI with ₂ θ5 Ρ ° P STUP Qomppera by R. and W. Elser Org. Son.,

Goll, Vol. V, p 780-783, to give the thiolactam of formula VIa.

Treatment of this thiolactam with a lower alkylating agent such as methyl iodide, methyl fluorosulfonate, dimethyl sulfate, methyl tosylate, methyl mesylate, and the like, affords the desired 2-lower alkylthiolactimethers as the corresponding salts.

Reaction of the lower alkylthiolactometer salts thus obtained with the corresponding guanidine of formula IV gives the corresponding salts of formula 1.

'N

I i

(VI) ^R 3 - | - < ^Cl 2> _n ^R 2 -

I ^R 1 (VIa) lower alkylating agent

lower alkyl (IV) '(I) (salt)

It has been found that, under the above reaction conditions of the lactam fluorosulfonates of formula III-b with the guanidines of formula IV, a side reaction may occur resulting in the following by-products:

axis ₂ f which can be isolated by conventional methods. These salts are quaternary derivatives of compounds of formula 1 with antisecretory and hypoglycemic activity.

A preferred method of preparing compounds of formula I wherein R ₁ is hydrogen is by reacting the free base of formula III, rather than the fluoroborates or sulfonate salts, with the guanidine derivative IV described herein. Standard treatment of salts of formula III with alkali, preferably in a halogenated hydrocarbon solvent such as methylene dichloride, chloroform and the like, readily yields the free base IX, which then reacts with the desired guanidine derivative IV, preferably in an anhydrous lower alkanol solvent such as methanol, isopropanol, butanol and the like to give the corresponding compounds of formula I which may exist in tautomeral form X.

Elevated temperatures up to reflux can be advantageously used during the second step, as well as a stoichiometric excess of the free base IX.

H

NaOH.

ch ₂ or _{2 3} -p (CH ₂ ) _n 'r-Sr ¹ (iv) alkanol (III) (IX)

NR

II tautomerv

-c-nr ₄ r ₅ = H

Fl-Γ-flη fl ^R

An alternative method of preparing compounds of formula X is reacting lactam VI with dimethyl sulfate XI to give the corresponding metosulfate salt of formula 1X1 corresponding to the reaction conditions described in Bredereck et al., Chem. Ber. 96, 1350 (1963).

The reaction is preferably carried out in an anhydrous inert organic solvent such as an aromatic hydrocarbon such as benzene, toluene, xylene and the like, an ether such as tetrahydrofuran, dioxane and the like, or a halogenated hydrocarbon such as 1,2-dichloroethane, chloroform and the like. The metosulfate salt XII thus obtained is then reacted with the desired guanidine derivative IV as before, preferably at 25 ° C to 100 ° C, to give the corresponding methylsulfate salts of the formula I, which in turn can be converted to the corresponding free bases of the formula .

The free bases of formula (I) may also be obtained from the metosulfate salt XII by reacting it with a lower alkali metal alkoxide, preferably sodium methoxide or ethoxide in the corresponding lower alkanol solvent in accordance with the reaction conditions described by H. Bredereck, et al., Chem. Ber., 97, 3 081 to 3 087 (1964) to give the corresponding lactamacetal of formula XIIa.

se

Lactamacetal, on the other hand, can be reacted with the appropriate guanidine of formula IV to give the free base of formula I. The foregoing reaction schemes may be depicted as follows: 13-r- (CH ₂ ) _n (MeO) -SO. i ~ _{2 <n>} = 1 ^R a -Z- (VI) - * (I) HOSOjMe ^R 3 N- (CH ₂₎ "

Ro-JRO loweralkyl and ^R 1 O nižáíalkyl (XIIa) 3 ^{N-R <C H2} N

I ^R 1 (XII) (IV) (IV) alkali metal lower alkoxide (I) (free base)

Another method of preparing compounds of formula I is by reacting guanidine of precursor IV with a chloride salt of formula XIII in an anhydrous aprotic solvent such as an ether such as diethyl ether, dioxane, THF, and the like, a halogenated hydrocarbon such as chloroform, methylene dichloride,

1,2-dichloroethane and the like, and preferably an aromatic hydrocarbon such as benzene, toluene, xylene and the like. alike.

The chloride salts of XIII are readily obtained by activating lactam VI with phosgene (C1COC1) or thionyl chloride (SOClg) according to the instructions of W. Jentzsche and 11. Seefeldra, Chem. Ber., 98, 274 (1965) with release of COg or SOg. The foregoing reaction scheme may be illustrated as follows.

♦ ^R 3 ~ Γ ^{, ε} Η2) η + CICOCI ^R --kN> = ⁰ (or SOCI ₂ ) co ₂ Tso ₂ t) ^R 3 — Γ ^ ΗίΙη ⁿ 2—— ^Cl cr Go (I).

^R1 (VI) ^R1 (XIII)

Instead of the above-mentioned lactams VI as starting materials, many compounds of formula I can be prepared from 2-imino compounds of formula XIV, where η, Η, β Rj and β Rj are as defined above. Said 2-imino compounds XIV are mostly described in the literature. If not, they can be obtained according to the technology of Canadian Patent No. 950,464 (e.g., see Example 14). These 2-imino precursors can be reacted with an isothiocyanate of formula XV, wherein R is as previously described and preferably other than 9-fluorenyl, in an inert organic solvent such as benzene, CH 2 Cl 2, chloroform and the like at temperatures ranging from ° C to room temperature. for 2 to 24 hours, in approximately equimolar amounts.

The thio group (= S) in the ureas thus obtained XVI, some of which are described in U.S. Pat. No. 3,711,648, is then converted to an alkylthio group (-SR *) by reacting XVI with an alkylating agent of formula R * X, where R * is ethyl or preferably methyl and X is iodide, preferably tosylethyl, metosulfate, mesylate, fluorosulfonate and the like. Typical solvents for these alkylations are preferably diethyl ether, tetrahydrofuran or dioxane, lower ketones such as acetone, 2-butanone and the like; halohydrocarbons and lower alkanols, preferably methylene dichloride and methanol.

Methyl iodide as an alkylating agent in methanol is particularly suitable. Usually, an equimolar amount is used up to a stoichiometric excess of the alkylating agent depending on the reactivity of thiourea XVI or its solubility in the solvent used. The alkylation reaction can be carried out at conventional temperatures or in appropriately sealed containers at higher temperatures. The alkylthio compounds of formula XVII, upon addition of the acid salt (HX), are then reacted at temperatures ranging from room temperature to the boiling point or in suitable sealed containers at higher temperatures. The alkylthio compounds of formula XVII in the addition of the acid salt (HX) are then reacted with the corresponding amine of formula HNR 2 R 2, where R 2 and R 2 are as defined above except that R 2 is phenyl or substituted phenyl, preferably in a lower alkanol solvent such as isopropanol and tert-butanol, and usually at boiling points, to give guanidine derivatives of formula 1 in a similar acid addition form, being readily obtained as the corresponding base by conventional treatment with a suitable alkali. The foregoing reaction may be illustrated as follows.

R ₃ -r ~ CH ₂ L R-ncs H ₂ —k _N J = NH (XV)

I ^R 1 (xiv)

R'Z

R _{3 -} r - (CH ₂ ) _n S ^R y - < _n > = NC-NR. HZ

I ^R 1 ^R 3 R-T- ^(C Hv) NY-2 to ^r _N J ^{N NH} R -C-

I ^R1 (XVI)

HNR4R5 ^r 3 ~ T- Κ5Η _{2) η}

R ₂ - < _n > = NC-NR ₄ R _b · HX alkali _r

I ^R 1 (I) salt · ^R 3 -] - (CH) _n «2 _<n> = ⁿ -C-NR _{4 R}

I ^R 1

Isothiocyanates of formula XV, most of which are known, can be prepared by extensive procedures described in the literature for the preparation of isothiocyanates. For example, they can be obtained according to the methodology reported by M, Bogemann et al. In Methoden der Organische Chemie Houben-Weyl, Eugen Miiller (Ed.), Georg Thieme Verlag (Publ.) Stuttgart, Germany, Vol. 9, pp. 867-884 ('955); Preparation of Aromatic Isothiocyanates by A. Rasschaert et al., Ind. Chim., Belge, 32,

106 (1967); NSR Patent No. 1,300,559; J. Org. Chem., 36, 1549 ('970; US Patent Nos. 2,395,455 and 3,394,767; French Patent No. 1,528,249; New Synthesis of Aliphatic Isothiocyanates, Angew. Chem. Dorm. Ed., 6, 174 (1967) Bull, Chem. Soc., Japan, 48, 2,981 (1975), Tetrahedron, 29, 691 (1973), Chem. Ber., 101, 1746 (1968), and J. Indian Chem. Soc., 52 148 (1975).

In the preceding reaction of XVII with an amine HNR? Rg, it is preferable to use a stoichiometric excess of amine, e.g. in molar ratios of 1: 1.05 and 1: 2.0. If only a small excess of HNR? R? Amine is used, it may be advantageous to add a stoichiometric equivalent of a tertiary alkylamine, e.g. Et? N, to increase the intensity of the reaction. By - products such as

NR

II

H ₂ NC - NR ₄ R ₅ . HX and ^r 3 — HCH 3 In ^r 2 - < _n > = NR ₄ R ₅ . X may be formed during the course of the reaction. These by-products can be separated from the desired product of formula I by standard known methods, such as fractional dissolution.

Another method for preparing compounds of formula I from 2-imino precursors of formula XIV is by reacting two molar equivalents of free base XXV with a compound of formula XVIII, wherein R 1, and R 2 are as previously described.

During the reaction, the equivalent of the 2-iminoprecursor is formed as the salt of XIX. For this reason, the reaction is preferably carried out in an aprotic solvent, which preferably dissolves the product of the desired formula I in basic form allowing the precipitation of the acid addition salt XIX.

The two can then be easily separated by filtration and the other can be re-converted to the free base by conventional alkali treatment and reused. Typical preferred solvents are ethers such as THF and the like, lower alkanones and esters such as acetone, methyl ethyl ketone, ethyl acetate and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, acetonitrile and the like.

Diethyl ether is usually preferred. The foregoing reaction may be illustrated as follows.

^R 3 -T ^(C ^ 2) n ^r 2-^ n> -NH ⁺ CI-C-NR ₄ R _with ^R 1 (xiv) (xviii)

Et ₂ O

The preparation of various guanidine derivatives is extensively documented in the literature. Thus, guanidine precursors of formula IV are readily obtained by several suitable syntheses. E.g. urea of formula XX, wherein R is as previously described according to the procedures described by IR. L

Frank and P.V. Smitherm, Org. Son. Coll. St. III, 735 (1955); A. Rasschaert et al.,

Indian. Chim. Belge, 32, 106 (1967); G. Barnikow and J. Bodeker, J. fiir prakt. Chemistry, 3'3,

148 (1971); Neville, R.G., and J. J. McGee, Org. Son. 45, 69 (1965); C.P. Joshua and K.N. Rajasekharan Chem. and Ind. 750 (1974); and in J. Chem. Soc. Transaotions, page 1 702 (1924), is converted to an alkylthio compound of formula XXI by alkyl thiourea as previously described by the R * X alkylating agent.

The thus obtained alkylthio compound XXI is then reacted with the corresponding amine of the formula except where R 6 is phenyl or substituted phenyl to give the guanidine derivative in the form of an acid addition salt (HX), which can then be converted to the corresponding base form IV, conventional treatment with alkali. To increase the intensity of the reaction, a tertiary alkylamine such as Et 2 N can be advantageously used.

The reaction conditions for the foregoing are the same as those for the conversion of thiourea XVI to the alkylthio compound XVII to the final product I. (See L. A. Kiseley et al.,

C.A., 82, 86179t (1975)

R X 11 RN RNH-C-NHg

R'X

->

SR 'rn = c-nh ₂

HX

HNR ₄ R ₅ ->

NR.R, 14.5

RN = C-NH ₂ . HX alkali

->

NR.R _C I ^{4 5}

RN = C-NH '(tautomerism) (tautomerism) (XX) (XXI) (XXII) (IV)

A process for the preparation of guanidines of formula IV wherein R is phenyl or substituted phenyl, R ₄ is hydrogen and R 6 is phenyl or substituted phenyl, when starting from the corresponding N, N'-diarylthiourea of formula ArNHC (= S) NHAr *, wherein each z Ar and Ar * is phenyl or substituted phenyl which is reacted with ammonia according to the method described in <J. Org. Chem. (USSR) 2 (12)

144, (1966) (English translation).

Another method for preparing guanidines of formula IV, preferably when R is as previously described alkyl, cycloalkyl, aralkyl, diphenylalkyl, phenyl and phenyl substituted with lower alkyl, lower alkoxy, halogen and ni tro, is the methodology described by E. Kuhl in Angew. Chem. boarding house. Ed., 8, 24, 26 (1969) and references cited therein which contain a sequential substitution of the chloride from the appropriate isocyanide dihalide (XXIII). This compound, the preparation of which is described by E. Kuhl et al. In Angew. Chem. boarding house. Ed., 6, 649 (1967) is reacted with an amine HNR 1 L 1, where R 1 is other than phenyl or substituted phenyl, in the presence of a trialkylamine such as triethylamine in a suitable inert aprotic non-aqueous solvent such as halogenated hydrocarbon, aromatic hydrocarbon and the like to give the monohalide compound XXIV. Treatment of the reaction mixture with excess ammonia followed by treatment with dilute alkali such as an alkali metal hydroxide or carbonate gives the corresponding guanidine IV derivative.

Cl

AND

RN = C-C1 + NHR ₄ R ₅ + Et ₃ N (XXIII)

NR.R '

I * ³ excess NH, RN = C-C1-1 → nr ₄ r ₅

-> RN = C-C1 + EtN (XXIV)

HCl alkali

-?

(IV)

Another method for preparing guanidines of formula IV wherein R is phenyl or substituted phenyl is by reacting the corresponding aniline XXV with a cyanamide of formula XXVI to give a guanidine XXII salt according to the procedure described by N. U, Golyshir et al. In British Patent No. 1,341,245; Chem. Abs. 79, 66052f (1973), 80, 95571a (1974), 82, 86179t (1975) and 68, 86760g (1968).

See also J. Diamond et al., U.S. Patent No. 3,976,643, September 24, 1976.

HCl alkali

R-NH ₂ + NC-NR ₄ R ₅ -t (XXII) - (IV) (XXV)

Another method for preparing guanidines of formula IV wherein R is phenyl or substituted phenyl is by W. Abraham and G. Barnikow, Tetrahedron, 29, 691, 699 (1973), which describes the acid hydrolysis of the corresponding 2-isothiocyanatoamidine of formula XXVII, is obtained from the interaction of the monohalide compound XXIV with ammonium thiocyanate.

í ^{4 5}

RN = C-C1 nh ₄ scn

RN = C-NCS

H

(XXII) + COS

HOH (XXIV)

Yet another method of preparing guanidine of formula IV wherein R is as previously described is the method of H. G. Viehe and Z. Janoušek, Angew. Chem. boarding house. Ed., 12 (10), 806 (1973), by reacting the corresponding dichloromethylene ammonium salt of formula XXVIII, except when NR 1 R 3 is thiamorpholino-1-oxide with the appropriate amine XXV to give the corresponding monohalide compound of formula XVIII, which is then treated with excess ammonia and then alkali as before to give the guanidine IV derivative.

Cl NR.R _r

I. ¹⁵ excess NH,

RNH., + C1-C = NR ₄ R ₅ Cl-> RN = C-C1 - (XXVIII) (XVIII) Alkali

-? (IV)

The compounds of the invention of formula I and their acid addition salts and quaternary salts have pharmacological properties, in particular as antisecretory and hypoglycemic agents.

For example, compound I and its salts have an antisecretory effect in the following acute gastric fistula test in rats. The antisecretory effect of the test compound was studied in female Sprague-Dawley rats following intraduodenal (i. D.) Injection of the compound at doses ranging from 2.5-40 mg / kg body weight. Rats are affected 24 hours prior to challenge and are given water ad libitum, keeping them in individual cages. On the day of the test, the rats were weighed and selected so that they weighed up to 20 g in each test.

The procedure was performed under slight anesthesia with ether. As soon as the rat is anesthetized, it is removed with small tongs. A middle incision is made on the abdomen about 1.5 centimeters long and the stomach and duodenum are exposed. If, at this point, the stomach is filled with grass or faeces, the rat is discarded. Using 4-0 stitching, the stomach is sutured, taking care not to pierce the blood vessels in this area. A small incision is made into the stomach at the center of the withdrawn portion and a cannula consisting of a small vinyl tube with a flange at one end is inserted into the stomach and the suture is tightly closed around the flange. Immediately thereafter, I.D. is administered in a volume of 0.5 ml per 100 g of rat weight. Generally, three rats are used for each dose of drug tested. Control rats received a test vehicle, usually a 0.5% aqueous methylcellulose solution.

After administration of the test compound, the abdominal wall and skin are closed simultaneously with three to four 18mm clips and the collecting tube is placed on the cannula. Each rat is then placed in a box in which a slot for loosely hanging the cannula has been formed to allow the rat to move unhindered. The rat is then allowed to stabilize for 30 minutes, the cannula collection tube is discarded and replaced with a clean tube to obtain gastric juice. The collections were performed for one hour.

At the end of the test, the cannula is removed and the rat is sacrificed.

The collected sample of the stomach contents is discharged into a centrifuge tube and centrifuged to compress the sediment downwards. Evaluate the volumes and place a 1 ml aliquot of the sludge water in a beaker containing 0 ml distilled water and filter to pH 7 with 0.01 N NaOH.

Results are reported for volume, titratable acid and total acid yield, where volume = total volume of gastric juice minus sediment; titratable acid (milliequivalents 1) = amount of 0.01N NaOH required to titrate the acid to pH 7; and total acid yield = titratable acid x volume. The results are given in% inhibition versus control and at least 5% inhibition shows an antisecretory effect.

Further, the compounds of formula I and their salts have a blood sugar lowering effect (i.e., hypoglycemic properties), as demonstrated in the following tolerance test, in particular of the compounds of formula II.

The rat glucose tolerance test is a standard and particularly sensitive procedure used in the diagnosis of diabetes and hypoglycaemic disease states.

Male Sprague-Dawley rats (Charles River 184-250) are given water ad libitum and fasted 24 hours before the test. A series of blood samples (0.1 ml) are taken from the tail without anesthesia 0, 30, 60, 90, 120, 150 and 180 minutes after the oral administration of 1 g glucose / kg body weight in 1 ml water. Blood samples are immediately deproteinized with aqueous solutions of Ba (OH) g and ZnSO4 and the glucose contents are determined by the glucoxidase assay described by L. P. Cawley et al. In Ultramicroohemic Analysis of Blood Glucose Glucooxidase, Amer. J. Clin. Path., 32, 195 (1959).

Two to five rats were used for each test and control group. Test compounds (1-200 mg / kg s.c. or i.p.) are administered suspended in 0.5 or 1.0 ml, but preferably 0.5 ml, 0.5 to 1.0% methylcellulose.

The control group receives the same amount of vehicle. Blood glucose values at each time interval are expressed in mg% (mg glucose / 100 ml blood).

The mean glucose values of the control group are statistically compared using the student t-test against the mean values of the experimental group at each time point. If the compound decreases the glucose content significantly at any time with a 95% confidence limit, then the compound is believed to have a hypoglycemic effect.

Example I

A. N- (1-Ethyl-2-pyrrolidinylidene) -N-phenylghiourea:

To 6.73 g (0.05 mol) of 2-imino-1-methylpyrrolidine hydrochloride, while stirring the suspension in benzene, was added 5 ml of a 50% aqueous NaOH solution. After stirring for about 2 minutes, the organic layer was decanted to KgCO3 (anhydrous) and the extraction was repeated twice with fresh benzene. After drying, the combined extracts are quickly filtered (diatomaceous earth) with suction, minimizing air contact to prevent carbonate salt formation, and 6.76 g (0.05 mol) of phenyl isothiocyanate added in one portion. After stirring for three hours, the resulting solids were collected. A second crop is obtained from the mother liquor. Recrystallization from ethyl acetate gave pure product; N- (1-methyl-2-pyrrolidinylidene) -N'-phenylghiourea, mp 142-143.5 ° C. F

B. Methyl N- (1-methyl-2-pyrrolidinylidene) -N ^z -phenylcarbamimidothioate hydroiodide:

To a solution of 34.86 g (0.15 mol) of N- (1-methyl-2-pyrrolidinylidene) -N'-phenylthiourea in 500 ml of acetone is added 21.3 g (0.15 mol) of methyl iodide in acetone. The solution was heated under reflux for 0.5 hour and allowed to stand at room temperature for an additional hour. The solid crystallized under cooling (ice bath). Subsequent recrystallization from a mixture of methanol and isopropanol gave pure methyl N- (1-methyl-2-pyrrolidinylidene) -N'-phenylcarbamimidothioate hydroiodide, m.p. 145-147 ° C.

C. Treatment of the compound of Example I-A in a cell with a lower alkanol solvent, acetone or lower halogenated hydrocarbon with either methyl p-toluenesulfonate, dimethylsulfate, methylfluorosulfonate, trimethyloxonium fluoroboronate or methyl methanesulfonate affords the methylthio compound of Example I-B as the corresponding corresponding salt.

D. N- (1-Methyl-2-pyrrolidinylidene) -N * -phenyl-1-pyrrolidinecarboximidamide hydroiodide:

A solution of 15.02 g (0.04 mol) of the compound of Example I-B and 4.31 g (0.06 mol) of 99% pyrrolidine in 100 ml of isopropanol was refluxed for 24 hours. Upon cooling (ice), solids crystallize. The crystals are filtered off and the mother liquor is left aside (see Example XXVI).

Recrystallization of the crystals from isopropanol and methanol ether gives pure N- (1-methyl-2-pyrrolidinylidene) -N ^, -phenyl-1-pyrrolidinecarboximidamide hydroiodide; mp 206-208 ° C.

Example II

According to Canadian Patent No. 950,464, the following acid addition salts of 2-imino compounds of formula (XIV) are obtained:

a) 2-Imino-1-methyl-5-phenylpyrrolidine fluoroborate, mp 128-131 ° C;

b) 2-Imino-1-methyl-pyrrolidine fluoroborate, mp 109-111 ° C;

c) 2-imino-1-ethyl-pyrrolidine hydrochloride, mp 181-185 ° C;

d) 2-imino-1-n-butyl-pyrrolidinecyclohexanesulfamet, mp 110-114.5 ° C;

e) 2-Imino-1-benzylpyrrolidine fluoroborate, mp 112-114 ° C;

f) 2-imino-1,5-dimethylpyrrolidine fluoroborate, mp 100-102 ° C;

(g) 2-Imino-1-methylpiperidine hydrochloride a

h) hexahydro-2-imino-1-methyl-1H-azepine-cyclohexanesulfamet, m.p. 143-145 ° C;

i) 1-hydroxyethyl-2-iminopyrrolidinoyclohexane sulfamet, m.p. 105-108 ° C.

Each of the preceding salts was converted to a large base by treatment with 50% NaOH as shown in Example I-A.

Example III

Following the procedure described by JC Jochime and A. Seeliger, Angw. Chem. boarding house. Ed., 6 (2), 174 (1967) for the preparation of isothiocyanates, the following compounds were obtained:

a) 1- and 2- (2,3,3a, _{4,5,6,7,7a-octahydro-4>} 7-metanoindanyl) isothiocyanates}

b) 1,1-dimethylphenethylisothiocyanate;

c) 1-alpha-phenethylisothiocyanate;

d) d-alpha-phenethylisothiocyanate;

1-benzylcyclopentylisothiocyanate;

f) 7- (bicyclo [4.2.0] octa-1,3,5-trienylisothiocyanate;

g). 1-adamantylmethylisothiocyanate;

h) 2-adamantylisothiocyanate;

i) tran-2-phenylcyclopentylsothiocyanate

j) Cis-2-phenylcyclopentylisothiocyanate;

k) trans-2-cyclohexylcyclopentyl isothiocyanate;

l) cis-2-cyclohexylcyclopentylisothiocyanate;

m) cis-2-phenylcycloheptylisothiomethyl.

Example IV

By repeating the procedure of Example I-A, except that the equivalent amounts of the 2-imino compound obtained from Example 11 were used as starting material in reaction with an equivalent amount of the appropriate isothiocyanate, the following thioureas of formula (XVI) were obtained as appropriate products:

a) N-2- (hexahydro-1H-1-methyl-azapinylidene-N'-phenylthiourea, mp 157-159 ° 3);

b) N-1-methyl-2-pyrrolidinylidene-N'-diphenylmethylthiourea, mp 112-114 ° C (polymorphic), 119-120 ° C;

c) N-1-methyl-2-pyrrolidinylidene-N'-p-nitrophenylthio-urea, m.p. 179-180.5 ° C (dec.)}

d) N-1-methyl-5-phenyl-2-pyrrolidinylidene-N * -phenylthiourea, mp 135-140 ° C;

e) N-1-methyl-2-pyrrolidinylidene-N'-p-fluorophenylthiourea, mp 152-154 ° C;

f) N-1-methyl-2-pyrrolidinylidene-N'-benzylthiourea, mp (71) 74-81 ° C;

g) N-1-methyl-2-pyrrolidinylidene-N'-2-naphthylthiourea, mp, 159-162 ° C (dec.);

h) N-1-methyl-2-pyrrolidinylidene-N * -cyclohexylthionic acid, mp 88-93 ° C;

i) N-1-methyl-2-pyrrolidinylidene-N * -p-methoxyphenylthiourea, mp (149) 150-152 ° C (dec.);

j) N-1-methyl-2-pyrrolidinylidene-N'-p-chlorophenylthiourea, mp 154-156.5 ° C (dec.);

k) N-1-methyl-2-pyrrolidinylidene-N * -2,6-dimethylphenylthiourea, m.p.

168 [deg.] C .;

l) N-1-methyl-2-pyrrolidinylidene-N * -1,1,3,3-tetramethylbutylthiourea, m.p.

116.5 ° C;

m) N-1-methyl-2-pyrrolidinylidene-N'-1-adamantylthiourea, mp 150-152 ° C;

n) N-1-ethyl-2-pyrrolidinylidene-N'-phenylthiourea, mp 158 ° C;

o) N-1-ethyl-2-pyrrolidinylidene-N * -p-methoxyphenylthiourea, mp 128-130 ° C; and

p) N-1-methyl-2-piperidinylidene-N * -phenylthiourea, mp 132-134 ° C.

Example V

The S-methylation procedure of Example I-B was carried out using the labeled urea precursor solvent of Example IV as the starting material to be methylated to give the following methylthiohydroiodide salts of formula (XVII):

The precursor of Example IV Solvent S-Me * HI (i.e. . t.) and ch ₂ or ₂ 157 to 159 Noc: 2 ° C b acetone 122 to 123 Noc: 2 ° C C MeOH - d MeOH 150 to 152 ° c E MeOH / acetone 104 to 105 ° c F acetone 123 to 125 O.-, in with CH ₂ Cl ₂ glass h ch ₂ or ₂ (oil) and ch ₂ or ₂ 124 to 125 ° c j ch ₂ or ₂ 165 to 168 ° c to ch ₂ or ₂ 189 to 192 (decomposition) ° c 1 MeOH (oil) m MeOH 145 to 148 ° c n ch ₂ or ₂ 117 to 119 O-, in 0 acetone (oil) P acetone 164 to 165 ° c

Example VI

The procedure of Example ID is carried out in the preparation of guanidine derivatives of formula I as the free base or acid addition salt, except that the corresponding hydroiodide precursor obtained from Examples IB and V and the corresponding amine of formula HNR ^R ^ are used as starting materials in molar ratios of 1: 1.5 to 1: 3, at reflux of isopropanol or preferably tert-butanol, to give the product of the formula I as the corresponding hydroiodide salt, which is then isolated as such or converted to the corresponding base by conventional processing

225604 with an aqueous alkali solution or converted to another acid addition salt by reaction of the base ε labeled with an acid. In addition, guanidines of formula IV can be formed as by-products and can be isolated from the reaction mixture, e.g., by selective solution or fractional crystallization, either as the free base or an acid addition salt.

Sl £ e'HI -NR.Rn precursor ⁴ · *

Product form of formula I

Melting point <° C) Example I-b Example I-b

tíl

HI Example I-E

-N-N-Ph - / base Example I-E

-N O

HI Example I-E

base

196 až

186 až

131 to (163 to 164) to

200

188.5

133

171-173 Example IE -N (ke) CH ₂ Ph

HI

180-182 Example I-b - N N-Me

HI

161 to 161.5

Me example I-b

HI (193) 197-199 decomposition Example I-b Example V-a Example V-b

Me

Me / - (—N NH

HI

HI

HI

269 to 270 decomposition

192 to 193

218 to 220 continued table

S-Jke * Hl precursor -NR.R. 4 5 Product form of formula I Melting point (° C) Example V-d -Q HI 201 to 203 Example V-e HI 190 to 192 Example V-f  -C HI (165) 167-171 Example V-g -and HI 187 to 189 Example V-h Ό HI 203 to 204 Example V-i HI 142 to 144 Example V-j -and HI 183 to 185 Example V-1 -C HC1O ₄ 154 to 155 Example V-m -C HI 171 to 173 Example V-n -G HI 142 to 143 Example V-o -G HI 164 to 66 Example V-p -Q HI 151 to 153

»

Example VII

A. This example illustrates the preparation of N-benzoylthioureas according to the methods of R. L. Frank et. V. Smith, Org. Synth. Goll. Vol. III, p. 735 (1955) (see also G. Barnikow and J. B. Bodeker, J. Prakt. Chemie, 313, 1148 (1971)).

Accordingly, the following benzoylthioureas were prepared:

a) N-benzoyl-N * -3,4-dimethoxyphenylthiourea, mp 133-134 ° C;

b) N-benzoyl-N * -p-benzyloxyphenylthiourea, m.p. (120) 132-138 ° C;

c) N-benzoyl-N- (4-methylthiophenyl) thiourea, mp 160-161 ° C.

B. Substitution of the carbetoxyisothiocyanate with the benzoyl isothiocyanate affords N-carbetoxy-N + - (3,4-methylenedioxyphenyl) urea, mp (137), 46-48 ° C.

Example VIII

This example illustrates the hydrolysis of the corresponding benzoylthioureas and kerbetoxythioureas to the ureas of formula (XX) according to the methodology described by R. L. Frank et. V. Smith, Org. Son. Coll., Vol. III, p. 735 (1955).

A. 3,4-Dimethoxyphenylthiourea

To a 1 liter beaker containing 95.85 g (0.302 mol) of N-benzoyl-N * -3,4-dimethoxyphepylthiourea was added 230 mL of a 10-12% NaOH solution and 60 mL of HgO. The mixture is heated to a temperature of 60 to 80 ° C for 5 to 10 minutes until hydrolysis is complete. The hot solids are filtered off, washed with water until the filtrate remains neutral, then washed with MeOH and dried to give 3,4-dimethoxyphenylthiourea, mp 234-242 ° C (dec.).

B., p-Benzyloxyphenylthiourea

The procedure of Example VIII-A is repeated except that an equivalent amount of N-benzoyl-N &apos; -p-benzyloxyphenylthiourea is used as the hydrolyzed material to give p-benzyloxyphenylthiourea as a product, m.p. 93-195 ° C.

C. 4-Methylthiophenylthiourea, m.p. (187), 90-19 ° C, was obtained similarly.

D. 3,4-Methylenedioxyphenylthiourea, m.p. 207-209 ° C,

Alkaline hydrolysis of N-carbethoxy-N '- (3,4-methylenedioxyphenyl) thiourea under the conditions described above, followed by neutralization with mineral acid (caution: violent CO ₂ development) affords 3,4-methylenedioxyphenylthiourea, mp 207-209 ° C.

Example IX

This example illustrates the preparation of thioureas of formula XX according to the method of C. F. Joshua and K. N. Rajaeekharana, Chem. and Ind., 750 (1974).

A. 4-n-Butylphenylthiourea:

To 100 mL of hot HCl (18%) was added 90.2 g (0.605 mol) of NH 4 SCN. The resulting mixture was heated to reflux for about one hour and then poured onto crushed ice to give crystals which were recrystallized from ethyl acetate to give pure 4-n-butylphenylthiourea, mp 123-125 ° C.

B. 3,4-Methylenedioxyphenylthiourea, mp 208-210 ° C, decomposition

C. 4-Methoxyphenylthiourea, mp 207-210 ° C.

Example X

This example, which mentions another method of preparing thioureas of formula XX, involves reacting excess ammonia with the appropriate isothiocyanate, usually in an ether type solvent.

A. 1- (exo-2-Morbornyl) urea: exo-2-Norbornylisothiocyanate (prepared according to the method of Diveley, J. Org. Chem. 34, 616 (1969) (27.17 g, 0.178 mol) in 200 ml dry monoglyme) The mixture was allowed to stand overnight and the product was filtered off and washed with ether to give 1- (exo-2-norbornyl) urea solid, mp 181-183 ° C.

B. N- (9-Fluorenyl) thiourea:

To 16.52 g (0.074 mol) of 9-fluorenylisothiocyanate in ether was added excess anhydrous NH 3 with cooling. The reaction mixture was sealed and allowed to stand overnight at 0 ° C. Filtration gave the product, N- (9-fluorenyl) thiourea, mp (158 ° C) 182-189 ° C.

C. As in the previous procedures of this example, except that an equivalent amount of the appropriate isothiocyanate is reacted with an excess of ammonia to give the following products:

2- (bicyclo [2.2.2.] Octyl) thiourea endo-2- (bicyclo [3.2.1.] Octyl) urea;

anti-7-norbomeyl thiourea;

1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoindanyl) thiourea;

3- (2,3,6,6a-tetrahydro-1H-1,3a-ethanopentalenyl) urea;

5- (3a, 4,5,6,7,7a-hexahydro-4,7-methanoindenyl) urea;

1,1-dimethylphenethylthiourea;

d-alpha-phenethylthiourea;

1-alpha-phenethylthiourea;

1-benzylcyclopentylthiourea;

1-bicyclo [4.2.0.] Octa-1,3,5-trienylthiourea;

1- adamantylmethylthiourea;

2-adamantylthiourea;

cis-2-phenylcyclopentylthiourea;

225804 20 cis-2-phenylcycloheptylthiourea and cis-2-cyclohexyloyclopentylthiourea. .

Example XI

A, Methyl-N- (9-fluorenyl) kerbemimidothioethydrojodide:

To 7.85 g (0.033 mol) of N- (9-fluorenyl) thiourea in 200 ml of acetone was added 4.68 g (0.033 mol) of methyl iodide. The mixture was allowed to stand at room temperature for about 4 hours. Ether (400 mL) was added and the mixture was allowed to stand overnight to give the crystalline product methyl H- (9-fluorenyl) carbamimidothioate hydroiodide which was filtered off, m.p. (208) 212-214 ° C.

B. The previous S-methylation procedure of Example XI-A is repeated except that an equivalent amount of the appropriate urea is reacted with methyl iodide in the stated molar ratios and the reaction medium is used to give the following product of formula XXI as the hydroiodide salt:

C. Repeating the preceding S-methylation procedure of Example XI-A but using an equivalent amount of each thiourea obtained from Example X-C in methanol as the reaction solvent and with a slight excess of methyl iodide gave the corresponding carbamimidothioate hydroiodides of formula XXI

SMe

AND

RN = 'C-NH _second HI (XXI)

R Solvent Ratio reaction ingredients Melting point <° C) exo-2-norbornyl acetone 1: 1.1 (oil) p-n-Bu-Ph acetone -1: 1 77 to 79 9-fluorenyl acetone 1 - 1 (201) 212 to 2.14 1-Naphthyl CH ₂ Cl ₂ -MeOII (1: 1) 191 to 192 m-CK ₃ -Ph acetone 1 - 1 120 to 122 m-MePh acetone 1: 1.5 145 to 150 3,4-diOMe-Ph MeOH 1J4 186 to 193 p-PhCH ₂ O-Ph acetone 1 .2,2 (195) 198-202 3,4-CH 2 Ph MeOH 1 - 1 138 to 138.5 3-OMePh acetone 1: 1.5 119 to 123 3-Cl-Ph MeOH 1: 1.1 (120) 125 to 129 4-NO ₂ -PR MeOH 1: 2 190 to 197 4-OMePh acetone 1: 1.1 161 to 164 4-SMePh acetone 1 - 1 158 to 160

225604 continued table

with Solvent Ratio reaction ingredients Melting point (° C) 4-KMe ₂ -Ph MeOH 1 - 1 166 to 168 3-pyridyl acetone 1 - 1 98 to 100 (free base) 4-MePh MeOH 1 - 1 129 to 130.5

Example XIX

A. N- (4-Tolyl) -1-pyrrolidinecarboximidamide hydroiodide:

4-Tolylthiourea (33.2 g, 0.2 mol) in 200 ml acetone was heated at reflux for 3 hours with methyl iodide (31.4 g, 0.221 mol). The solvent was removed in vacuo and the resulting 2-methyl-1- (4-tolyl) -2-thiopseudourea hydroiodide was dissolved in 200 ml of tert-butanol. Pyrrolidine (28.4 g, 0.4 mol) was added and the mixture was heated under reflux for 18 hours. The reaction mixture was cooled, diluted with ether and the resulting solids collected. Recrystallization from acetone-ether gave N- (4-tolyl) -1-pyrrolidinecarboximidamide hydroiodide, m.p. 166-168 ° C. Conventional treatment with CH 2 Cl 2 with an aqueous solution (10-20%) of NaOH provided the corresponding free base.

Β. N-2,6-Dichlorophenyl-1-pyrrolidinecarboximidamide hydrochloride:

A mixture of 14.52 g (0.04 mole) of methyl N-2,6-dichlorophenylcarbamimidothioethioiodide and 5.69 g (0.08 mole) of dry pyrrolidine in 30 ml of tBuOH was heated at reflux for 3 days. The solvent was removed in vacuo and the resulting non-crystalline hydroiodide salt was converted to the free base in CH 2 Cl 2 with cold 20% NaOH, dried (KgCO 4), the solvent removed, the base converted to the HCl salt in isopropanol with anhydrous HCl.

Recrystallization from isopropanol using sufficient MeOH to form a solution gives pure product K-2,6-diohlorophenyl-1-pyrrolidinecarboximidamide hydrochloride, m.p. 292-295 ° C.

C. The foregoing procedures of Examples XII-A and B were carried out except that an equivalent amount of methylthiohydroiodide of formula (XXX) was reacted with the appropriate amine (HNR? R?) At the stated molar ratio, either with or without another equivalent of Et 3 N. is disclosed at reflux of tert-butinol to give the following guanidines isolated either as the free base or as said acid addition salt.

NR.R _K I ^{4 5}

RN = C-NH ₀

HX

R -nr ₄ y ₅ HX Mol. ratio Added principle Melting temperature (OC) Ph -N ^ S \ __ y HBr 1: 1.1 EtjN 203 and 205 3,4-CH ₂ -Ph -O HI 1: 2 - 171 and 172.5 '' Cl '' p-n-C ^Hg-Ph -NEtg fumarate 1: 2 - 96 and 98 p-OH-Ph -and HI .1: 2 - 216 and 218 m-lie, Ph -N (Mb) - oyklamét 1: 1.06 Et-jN 170 and 172 p-Me-Ph -G HI 1: 2 - 166 to 168 m-Cl-Ph —N O base 1: 2 - 143.5 to 145.5 2,6-diCl-Ph -G HCl 1: 2 - 292-295 Ph -O HI 1: 2 - 175 to 177 Ph -O HNOj 1: 2 - 139 to 141 p-NOg-Ph - ⁿ G HI 1: 2 - 240-142 decomposition (Ph) ₂ CH -N ^ O <_ / base 1: 2 - 122 to 242

continued table

R-NR ₄ R ₅

HX Mol. Added melting point alkali ratio (° C)

Ph p-Me-Ph (Ph) ₂ CH exo-2-norbornyl

HI 1: 1.3

HI 1: 2

HI 1: 2

HI 1: 2 exo-2-norbornyl

HI 1: 2

Ph

3,4-diMeO-Ph m-CF 3 -Ph

1-Naphthyl

HCl 1: 2

HI 1: 2 fumarate 1: 1.3 Et 1 N base 1: 2

1-Naphthyl

-NEt ₂ fumarate 1: 4

9-fluorenyl

1-Naphthyl

2,6-diMe-Ph

-O

-Ό

- <]

HI 1: 2

HI 1: 2

HI 1: 2

149 to 152

66 to 1 68

205 to 206

160 to 1663

198-199.5

181 to 184

221 to 222

150 to 153

132 to 133

208 to 210 decomposition

247 to 249 decomposition

209 to 211

191 to 192 table continuation

H -nr ₄ h ₅ HX Mol. ratio Added principle Melting point (° C) 4-PhC ₂ O-Ph -O tosylate 1: 2.1 - 187 to 190 3-0ie-Ph -O fumarét 1: 2 - 187 to 189 4-OMe-Ph N (Me) - base 1: 2 - 120 to 122 4-OKe-Ph N (H | —CH ₂ - base 1: 2 - 134 to 135 4-SMe-Ph -O HI 1: 1.1 Et ₃ N (2) 174-175.5 4-NMe ₂ Ph -Ό base 1: 2 - (111) 117-119 4-Niue ₂ Ph -O HCl - - 206 to 207 decomposition Ph _χ Μβ —N NH 2HI 1: 2.4 - 266 decomposition 3-pyridyl -O base 1: 2.1 - 188 to 190 3,4-CH ₂ Ph -N (Me) - (\ base 1: 2 - 121.5 to 23 4-Me-Ph -O HI 1: 2 - 197 to 204 4-Me-Ph - ^ s \ _y base 1: 1,2 Et ₃ N (2) 1.9 to 120

continued table

R -NH.R _K 4 5 HX Mol. ratio Added principle Melting point (° C) -O 4-Me-Ph HOAc - - 119 to 123 polymorphic (133) 134-137 3-Me-Ph -O base 1 - 1 Et ₃ N (2) 105 3-OMe-Ph —N (Me) - | base 1: 2.6 Et ₃ N (2.6) 93 to 95 3-Me-Ph —IV O HI 1: 2 - (160) 168-191 3-OMe-Ph -N S HI 1: 1,2 Et ₃ N (2) (188) 189-192

D. Each of the preceding acid addition salts obtained in Example XII-C was converted to the corresponding free base by conventional alkali treatment.

Example XIII

N-Phenyl-1-pyrrolidinecarboximidamide hydrochloride:

To 1.74 g (0.01 mol) of phenyl isocyanide dichloride was added 0.71 g (0.01 mol) of pyrrolidine and 1.01 g (0.01 mol) of triethylamine under Ng in dry ether with stirring and cooling. The resulting mixture was allowed to stir for 1/2 hour and the resulting Et 3 N · HCl was filtered off. The filtrate was added to a saturated solution of anhydrous NH 3 in isopropanol. The resulting NH 4 Cl was filtered off, the filtrate was concentrated in vacuo to remove excess ammonia, then dry HCl was added to give a crystalline product of N-phenyl-1-pyrrolidinecarboximidamine hydrochloride, m.p. 181-184 ° C after crystallization from methanol-propanol.

Example XIV

N- (1-Methyl-2-pyrrolidinylidene) -N * -phenyl-1-pyrrolidinecarboximidaraid L - (+) - tartrate:

To 1.64 g (0.013 mol) of trifluoride etherate in EtgO (anhydrous) under Ng was added 1.02 g (0.011 mol) of epichlorohydrin with rapid stirring for 3 hours. The resulting crystalline triethyloxonium fluoroborate was washed with fresh anhydrous ether to decanter under Ng. The crystals were dissolved in dry CH 2 Cl 2. 1.09 g (0.011 mol) of 1-methyl-2-pyrrolidinone was added to the obtained solution, and they were stirred for 2 hours. To the resulting solution was added 0.01 mol of N-phenyl-1-pyrrolidinecarboximidamide while cooling in an ice water bath.

22580 * 26

The reaction mixture was allowed to stir overnight (about 16 hours). The mixture was dried under vacuum and then diluted with ether to give the crystals of the HBF 4 salt of N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide.

The crystals were recrystallized from acetone to give the pure fluoroborate salt 164-166 ° C. The fluoroborate salt was converted to the free base in CH ₂ Cl ₂ NaOH (20 µL) on ice. The organic layer was dried over anhydrous KgCO3, then filtered and dried under vacuum to give the free base. To the aqueous base in MeOH was added an aquimolemic amount of L - (+) tartaric acid.

The resulting solution was concentrated by adding isopropanol until substantially all of the MeOH was evaporated to give the tartrate salt upon cooling. Recrystallization from isopropanol with MeOH yields pure product, N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidomide L - (+) tartrate, mp 153.5-156 ° C.

Example XV

In the procedure of Example XIV, except that the corresponding lactan fluoroborate of formula IIIa is reacted with the appropriate guanidine of formula IIIa with the appropriate guanidine of formula IV in said molar ratio to obtain the following compounds of formula I and isolated either by free base or by addition salts with acids.

O"

- _<N> = NC-NR ₄ R ₅

I i

Compound number n R "AND r ₂ ^fí 3 1 1 -CHPh ₂ Me H H 2 1 Ph Me H H 3 Ph Me Me H 4 1 Ph Me H * Ph 5 1 1-naphthyl Me H H 6 Ph Ph H H 7 1 Ph Ue H H 8 1 Ph Ό H H 9 Ph -CHgPh H H 10 Ph -ch ₂ ch ₂ oh H H 11 p-CIPh Me Ph H 12 1 Ph Me Ph H 13 1 1-Naphthyl Me H H , 4 1 9-fluorenyl Me H H 15 Dec 1 Ph -CH ₂ CH = CH ₂ H H 16 Ph Me H n-CgH, γ

continued table

Compound number n R ^R 1 ^R 2 ^R 3 17 1 Ph Me ⁿ ^ 4 ^ 9 H 18 1 p-nC ₄ H ₉ Ph Me H H; 19 Dec 1 m-CF 3 Ph Me H H ’ 20 May 2 -CHPh ₂ Me H H 21 1 Ph Me II H 22nd 1 p-MePh Me H H 23 1 3.4CH, Ph Me H H 24. 1 m-CIPh Me H H 25 1 m-MePh Me H H 26 1,4- (0Me) ₂ Ph Me H H 27 Mar: 14-PhCH ₂ O-Ph Me H H 28 3-OMePh Me H H 29 4-OMePh Me H H 30 4-OMePh Me TO H 31 4-SMePh Me H ii 32 1 4-NMe ₂ Ph Me H H 33 1 Ph Me H H 34 13-Pyridyl (Inverse Addn) Me H H 35 1 Ph n-CgH, γ H H 36 13 3-C (O) CH ₃ Ph Me H H

Compound number NB.IL · 4 5 Mol. ratio (III) :( IV) Form product Melting point (° C) 1 1.1: 1 HI 218 to 220 2 NHPh 1.2: 1 base 180 to 183 3 - »□ 1 - 1 HI 158 to 160 4 -C 1 - 1 HI 215 to 217

continued table

Compound number Ni, H _K 4 5 Mol. ratio (III) :( IV) Form product Melting point (° C) 5 1.2: 1 HI 185 to 187 6 -and 1.1: 1 HI 193.5 to 194.5 7 -NEtg 1.2: 1 HI . 155 to 157 8 -Q 1.1: 1 saccharinate 165-166.6 9 -O 1.2: 1 fumarate 208 to 210 10 -O 1.2: 1 base 128 to 130 11 -Nllřh 1.1: 1 HCl 204 to 207 12 - <Tb 1.08: 1 fumarate (220) 224-226 13 -rcet ₂ 1.05: 1 fumarate 187 to 189 14 -I1 1.1: 1 HI 230 to 232

decomposition

-O 1.2: 1 hcio ₄ 105.5 to 107 6 -O 1 - 1 tosylate (130) 133-135 7 -O 1 - 1 HI 130 to 131

continued table

Compound number NR.iL · 4 5 Mol. ratio (III) :( IV) Form product Heat 18 -NEt ₂ 1.08: 1 fumarate 163 to 165 19 Dec 1.08: 1 fumarate (135 to 137) 139 to 141 20 May -N 0 \ _y 1 - 1 L - (+) - Tartrate 146-148.5 2, -N (Me) 2; 1.08: 1 HI (120) 128.5 to 130 22nd -C 1.2: 1 fumarate 176 to 178 23 -O 1.17: 1 HI 144 to 146 24 —N 0 \ _y 2 - 1 fumarate 177.5 to 179.5 25 -NfMel ^ J 1.2: 1 fumarate 133 to 136 26 -C 1.1: 1 phosphate 201 to 204 decomposition 27 Mar: Ό ' 2.5: 1 hcio ₄ (151) 152-154 28 -O 1.1: 1 HN0 ₃ 104 to 109 29 2 - 1 fumarate 179 to 180.5 30 - _N (H) CH ₂ -O 2 - 1 0.5 fumarate 208 to 209 decomposition

decomposition continuation table

Compound number nr ₄ r ₅ Mol. ratio (III) :( IV) Form product Melting point <° C) 31 -O Ť ' 1.08: 1 HI 142 to 144 32 -O 1.08: 1 HI 171 to 172 33 .Me / \ —N NH4 Me 1 - 1 2HI 269 to 270 decomposition ³⁴ Λ "\ —N O / 1: 1.1 1,5 fumerate 138-139.5 35 --Q 1: 1.1 tartrate oil 36 O 1: 1.1 pamoát 158 to 164 decomposition

Example XVI

N- (2,6-Dimethylphenyl) -N * - (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide fumarate:

To a solution of 3.47 g (0.036 mol) of dry 1-methyl-2-pyrrolidinone in dry CH ₂ Cl ₂ under dry N ₂ was added 3.99 g (0.035 mol) of methyl fluorosulfonate. After 2 hours, a solution of 6.52 g (0.03 mol) of N- (2,6-dimethylphenyl) -1-pyrrolidinecarboximidamide, free base in dry CH 2 Cl 2 was added at room temperature with stirring at once. After stirring overnight at room temperature, the reaction mixture was basified with excess cold NaOH (20%). The organic layer was separated and the aqueous phase was extracted with 2 x 50 mL of fresh CH 2 Cl 2.

The combined organic extracts were dried over anhydrous K 2 CO 4 and filtered and the solvent was removed in vacuo. The residual oil was dissolved in ether and filtered through celite. Treatment of the filtrate with a hot solution of fumaric acid in isopropanol to neutrality gives the product as a fumarate salt. Recrystallization from isopropanol (hot filtration) gave the pure product, N- (2,6-dimethylphenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide fumarate, mp 182-184 ° C (slight decomposition) .

Example XVII

The procedure of Example XVI is repeated except that the corresponding guanidine of formula IV is substituted for the N- (2,6-dimethylphenyl) -1-pyrrolidinecarboximidamide used for the reaction with the corresponding compound of formula IIIb at the indicated molar ratio to give the corresponding product of formula I, which is obtained and isolated either as the free base or said acid addition salt.

^(CH , 2> n | ϊ ” _n > = NC-NR ₄ R ₅

I «1

Compound No. nR ₄ to ₅

Ph v_y

Me

Ph

NHCHgPh

Me

1-naphthyl p-NOg-Ph

2,6-diCl-Ph

O

-a c

Me

Me

Me

Ph

Me exo-2-norbornyl

3.4CH ₂ Ph

4-MePh

4-MePh

3-MePh

3-OMePh

-N O \ _y

N (Me) i - ~ A, —N O

-O / ~ Λ

-N S

-N (Me)

Me

Me

Me

Me

-ch ₂ ch = ch ₂

-ch ₂ ch = ch ₂ table continuation

Compound number R «He knows n ^R 1 13 3-MePh —N 0 you 2 Me 14 3-0MePh —N S 1 tóe you 15 Dec 3-MePh —N 0 1 Me

\ _y

Compound number Molar ratio (Illb): (IV) Product form Melting point (° C) 1 1.09: 1 HI 188 to 190 2 1.2: 1 fumarate 130 to 132 3 1.2: 1 HI 225 to 226 4 1 - 1 base 113 to 114.5 5 1, 14: 1 base 139-141.5 6 1 - 1 L - (+) - tartrate 153 to 155 7 1 - 1 fumarate 180 to 182 8 1.2: 1 fumarate (161-164) 174 decomposition 9 1.2: 1 HI 190 to 191 decomposition. 10 1.2: 1 HI 166 to 168 decomposition 11 1.17: 1 HI 158 to 160 decomposition 12 1.17: 1 fumarate. 1/8 HgO 120 to 122 13 1.2: 1 fumarate (142-144) 148-151 14 1.2: 1 HI 185 to 186 15 Dec 1.2: 1 fumarate 161 to 164 decomposition

fj

Example XVIII

This example illustrates methods for preparing quaternary salts of compounds of Formula I.

A. N- (2,6-Dichlorophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximide-dinimidomethyl fluoride sulfonate:

To 6.83 g (0.02 mol) of N- (2,6-dichlorophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide in dry CH 2 Cl 2 was added 2.70 g (0.023 mol) methylfluorosulfonate with stirring under Ng.

The mixture was stirred overnight and then dried in vacuo and the oily residue was covered with ether to give crystals. Recrystallization from acetone and then from ethyl acetate gave pure product, N- (2,6-dichlorophenyl) -N (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamidinomethyl fluorosulfonate, mp 148-150 ° C.

Β. N- (1-Methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamidine methiodide:

A solution (0.05 mol) of N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide (Example ID) of the free base in 30 ml of acetone was treated with 0.05 mol of methyl iodide. After two days, the crystals were collected and recrystallized from acetone to give pure N- (1-methyl-2-pyrrolidinylidene-N'-phenyl-1-pyrrolidinecarboximidamidine methiodide, mp (156) 162-164 ° C.

Analysis: calculated for C,

I: 49.52% C; 6.11% H; N, 13.59. Found: C, 49.58; 6.11% H; 13.59% N.

C. Similarly, treatment of the product of Example 1D as the free base (0.05 mol) in ether (dry) with methyl fluorosulfonate (0.05 mol) rapidly yields an oily precipitate which crystallizes. Recrystallization from t-BuOH afforded the product of Example XVIIIB as the corresponding methofluorosulfonate salt, mp 135.5-137 ° C.

Example XIX

N-Phenyl-N '- (2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide:

A solution of 0.07 mole of triethyloxonium fluoroborate in dry CH 2 Cl 2 was prepared in a conventional manner. To this solution was added 6.08 g (0.070 mol) of 2-pyrrolidinone. After stirring for 2.5 hours, the mixture was basified with NaOH (50%) with cooling (ice water bath).

The organic layer was separated and dried, then filtered and treated with 12.28 g (0.065 mol) of N-phenyl-1-pyrrolidinecarboximidamide. The CH 2 Cl 2 solvent was evaporated, then replaced by the target with butanol, and the resulting solution was heated under reflux for 22 hours. The reaction mixture was allowed to cool to room temperature and then neutralized with HI (47%) to give crude HI salt crystals. Recrystallization from t-butanol gives the pure salt of N-phenyl-N- (2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide, mp 223-225 ° C, with decomposition.

225804 34

Example XX

N- (1-Methyl-2-pyrrolidinylidene) - N'-phenyl-1-pyrrolidinecarboximidamide L - (+) - tartrate:

To 1.74 g (0.01 mole) of phenyl isocyanide dichloride in dry EtgO while cooling under Ng was added 0.71 g (0.01 mole) of pyrrolidine, then 1.01 g (0.01 mole) of Et2O with stirring. May; is allowed to stir for 1.5 hours and then filtered to remove precipitated Et 2 N. HCl.

To the filtrate was added 1.96 g (0.02 mol) of 1-methyl-2-iminopyrrolidine in an ice water bath. The resulting mixture was allowed to stir overnight under Ng and then filtered to give N-methyl-2-iminopyrrolidine hydrochloride, m.p. 182-188 ° C. The filtrate was evaporated to dryness in vacuo to give an oil which was dissolved in MeOH (10 mL) and treated with an equimolar amount of L - (+) - tartaric acid. The resulting solution was concentrated with the addition of isopropyl alcohol to give crystals. Recrystallization from isopropanol acetonitrile gives pure L - (+) - tartrate, N- (1-methyl-2-pyrrolidinylidene) - N -phenyl-1-pyrrolidinecarboximidamide, mp 153-156 ° C.

Example XXI

N- (1-Methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide L- (+) - tartrate:

To 0.99 g (0.01 mol) of 1-methyl-2-pyrrolidone in dry benzene was added slowly under stirring at reflux temperature, 1.26 g (0.01 mol) of dimethyl sulfate.

The reaction mixture was stirred for 5 hours. 1.6 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide was slowly added to the mixture. The resulting mixture was allowed to stir overnight at room temperature. The mixture was dried in vacuo and then dissolved in CH 2 Cl 2 before being converted to the free base of NaOH (50%) on ice. The organic layer was dried (K2CO4), filtered and evaporated to dryness in vacuo to give 2.7 g of an oil.

Dissolve the oil in MeOH and add L - (+) - tartaric acid (1.5 g, 0.01 mol) by crystallization from methanol-isopropanol to give N- (1-methyl-2-pyrrolidinylidene) -N phenyl-1-pyrrolidinkarboximidamid L - (+) - guilty, mp 153-1 5O ^r 0th

Example XXII

N- (1-Methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide L - (+) - tartrate:

To a cold solution of 1.98 g (0.02 mol) of 1-methyl-2-pyrrolidone in dry toluene was added 3.95 g (0.04 mol) of phosgene. The resulting mixture was allowed to stir under N ₂ at room temperature for 45 minutes to give bare crystals. The excess COC1 ₂ and the solvents removed by a filter rod (Ng below).

Fresh toluene is added, then removed under vacuum to remove residual phosgene. The crystals were washed in this way with fresh toluene twice and then dissolved in dry CH 2 Cl 2, then 1.89 g (0.01 mol) of fenyl-phenyl -, - pyrrolidinecarboximidamide and 1.01 g (0.01 mol) of triethylamine were added.

The resulting mixture was stirred under nitrogen overnight. The mixture was dried in vacuo, the residue was dissolved in CH 2 Cl 2 and this solution was treated with NaOH (50%) on ice.

The organic layer, which contains the free base of the product, is separated, dried over anhydrous ^K 2 ^CO 3, filtered ^and dried under vacuum to give an oily residue. The oil is dissolved in isopropanol, followed by addition of L - (+) - tartaric acid to about 6-7. The resulting crystals are recrystallized from isopropanol to give pure N- (1-methyl-2-pyrrolidinylidene) -N '. -phenyl-1-pyrrolidinecarboximidamide-L - (+) - tartrate, mp 155-156 ° C.

Example XXIII

N- (1-Methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide hydroiodide:

To 2.57 g (0.01 mol) of 1-methyl-2-methylthio-1-pyrrolidinium iodide in tBuOH was added 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide.

The resulting mixture was allowed to reflux overnight. The MeSH release is collected in a concentrated NaOH solution. Cooling and scraping gave 3.65 g of crude product which, upon recrystallization from t.BuOH, gave pure N- (1-methyl-2-pyrrolidineylidene-N'-phenyl-1-pyrrolidinecarboximidamide hydroiodide, m.p. in all respects with the example ID product.

Example XXIV

N- (1-Methyl * 2-pyrrolidinylidene-N'-phenyl-1-pyrrolidinecarboximidamide-L (+) - tartrate:

To 1.29 g (0.0075 mol) of 2,2-diethoxy-1-methylpyrrolidine in dry benzene was added 1.42 g (0.0075 mol) of N-phenyl-1-pyrrolidinecarboximidamide. The mixture was refluxed overnight and dried in vacuo. The residue was treated with dilute hydrochloric acid (10%), then basified with cold NaOH (20%) and the free product was extracted with ether, dried (K ₂ CO ₃ ) extracts were dried in vacuo and the residual oil was removed with isopropyl alcohol and treated with 1 molar. L - (+) - tartaric acid equivalent.

Recrystallization from MeOH-isoPrOH gave pure N-1-methyl-2-pyrrolidinylidene-N'-phenyl-1-pyrrolidinecarboximidamide-L - (+) - tartrate, mp 153-156 ° C.

Example XXV

N- (1-Methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide is converted to the following organic and inorganic pharmaceutically acceptable acid addition salts by conventional treatment with the appropriate acid:

fumarate, mp 156-157 ° C;

phosphate, m.p. 200 DEG-201 DEG C. (decomposition);

hydrobromide, m.p. (206) 207-209 ° C;

oxalate, mp 129-131 ° C;

pamoate, mp 253-256 ° C (dec.);

nitrate, m.p. 170-171 ° C (slight decomposition);

maleate, mp 115-117 ° C and p-hydroxybenzoate, mp 179-180 ° C.

Example XXVI

A. N-Phenyl-, - pyrrolidinecarboximidamide hydrochloride a

B. 1- (1-Methyl-2-pyrrolidinylidene) pyrrolidinium iodide hydrate

The mother liquor set aside in Example 1D was dried under vacuum and the residue was taken up in methylene chloride and basified with cold dilute NaOH. The extraction of CH ₂ Cl ₂ (200 mL) was repeated three times. The combined organic extracts were dried over anhydrous KgCO ^ filtered and dried under vacuum to give a brown, heavy syrup. Extraction of the syrup by covering with hexane (2 x 200 mL) and ether (3 x 200 mL) leaves a dark residue (left aside). The organic layers were combined and treated with charcoal, filtered and dried under vacuum to give a brown syrup which was converted to HCl and recrystallized from isopropanol-ether to give N-phenyl-1-pyrrolidinecarboximidamide hydrochloride, mp 181-184 ° C.

Analysis:

Calcd for C 10 H 11 N 4 · HCl: 58.53% C; H, 7.15. Found: C, 58.59; 7.08% H.

B. The dark residue left aside is taken up with isopropanol and treated with a large amount of activated carbon. Filtration and removal of the solvent in vacuo yielded a dark brown glassy material which, when overlaid with acetone with concomitant charcoal purification, yields white crystals of 1-O-methyl-2-pyrrolidinylidene) pyrrolidinium iodide which forms a hydrate with about 1/4 mole HgO; mp (98) 108-110 ° C.

On a wet day, the crystals will gain excess water and melt, but will solidify again when the moisture drops.

Analysis:

Calcd. for C14H18N3O4.1 / 4HgO: 37.98% C; 6.02% H; 44.58% I; 1.58% HgO found: 38.195% C, 6.11% H; 45.25% I; 1.13% H ₂ O.

AND

Example XXVII

N- (4-Aminophenyl) -N (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydrobromide:

N- (1-Methyl-2-pyrrolidinylidene) -N '- (4-nitrophenyl) -1-pyrrolidinecarboximidamide (product of Example XVII), 2.46 g (0.0078 mol) in 50 ml of absolute ethanol are hydrogenated (ca. 3 atmospheres) in a Parr shaker through Raney nickel as a catalyst. The hydrogenation is complete after about 0.5 hours. The catalyst was removed by filtration and washed with ethanol. The combined filtrates were evaporated in vacuo. The residue was dissolved in ethanol and neutralized with one equivalent of aqueous HBr solution (48%).

The resulting solid was recrystallized from ethanol-ether to give pure N- (4-aminophenyl) -N'- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydrobromide, mp 241-241.5 ° C.

Analysis:

calculated for C ₁₆ H ₂₃ N ₅ HBr: C 52.46; 6.60% H; 19.12 96 N found: 52.44% C; 6.60% H; 19.09% N.

Example XXVIII

N- (4-Aoethylaminophenyl) -N'- (1-methyl-2-pyrrolidinylidene-1-pyrrolidinecarboximidamide hydrobromide:

N- (4-Aminophenyl) -N (1-methyl-2-pyrrolidinylidene-1-pyrrolidinecarboximidamide (product of Example XXVII) as its free base, 3.4 g (0.0119 mol) was heated on a 25 ml steam bath After this time, the reaction mixture was diluted with ethanol and heated for an additional hour, the volatiles removed in vacuo and the residue treated with dilute aqueous NaOH and extracted into methylene chloride.

After drying of K ₂ CO ₃ , filtration and removal of the solvent, a residual oil is obtained which is converted to the corresponding HBr acid addition salt in ether-ethanol mixture · Recrystallization

225804 from ethanol-ether gives the pure product N- (4-acetylaminophenyl) -N * - (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide, mp 246-247 ° C.

Example XXIX

N- (1-Methyl-2-pyrrolidinylidene) -N (4-methylsulfonylphenyl) -4-morpholinecarboximidamide:

To 1.98 g (0.0006 mol) of N- (4-methylthiophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -4-morpholinecarboximidamide (compound 31 of Example XV) as the free base was dried with methylene chloride, cooled 3.6 g (0.018 mol) of m-chloroperoxybenzoic acid are added while stirring so that the temperature does not rise above 5 ° C.

The mixture was allowed to stir at these temperatures for 0.5 hours, then washed appropriately with saturated NaHCO 3 (3 x 40 mL) and NaCl (3 x 35 mL). The organic layer was dried (KgCO ^), then filtered (filtering agent) and evaporated to near dryness in vacuo. Dilution with MeOH gives an insoluble material which is filtered off and discarded. The filtrate was evaporated to near dryness on a steam bath. Dilution with ether gives crystals of m.p. 160-166 ° C.

Recrystallization from ether gave pure N- (1-methyl-2-pyrrolidinylidene) -N '- (4-methylsulfonylphenyl) -4-morpholinecarboximidamide, m.p. (165) 167-170 ° C.

* Analysis:

calculated for C C ^Hg ^N ^O ^S: 56.03% C; 6.64% H found; 56.05% C; 6.69% H.

Example XXX

N- (1-Methyl-2-pyrrolidinylidene) -N '- (4-methylsulfinylphenyl) -4-morpholinecarboximidamide:

To a stirred solution of 1.98 g (0.006 mole) of N- (4-Methylthiophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -4-morfolinkarboximidamidu (Compound 31 from Example XV) as the free base in CH ₂ C1 ₂ at 5 °, add 1.22 g (0.006 mol) of m-chloroperoxybenzoic acid, maintaining the temperature at 5 ° C. The reaction mixture was then allowed to warm to room temperature and stirred for 2 hours.

The organic layer was washed with an appropriately saturated NaHCO 3 solution (3 x 30 mL) and a saturated NaCl solution (2 x 30 mL), then dried over KgCO 3 (anhydrous).

Filtration, removal of the solvent in vacuo and treatment of the residue with ether / hexane gave the crude product which was recrystallized from ether-hexane to give N- (1-methyl-2-pyrrolidinylidene) -N '- (4-methylsulfinylphenyl) -4-morpholinecarboximidamide, mp (115) 117-120 ° C.

*

Analysis:

calculated for C C ^Hg ^N ^OgS: 58.60% C; H, 6.94. Found: C, 58.58; 6.91% H.

Example XXXI

N- (4-Hydroxyphenyl) -N '- (1-methyl-2-pyrrolidinylidene) -'-pyrrolidinecarboximidamide (product 27 of Example XV) as its corresponding free base in 50 mL acetic acid was stored in a Parr shaker and hydrogenated at about 3 atmospheres at 10% Pd / C for about 2 hours, or until residence is complete, at room temperature. The reaction mixture was filtered and the solvent was removed in vacuo to give a viscous oil which was taken up in acetone and treated with one equivalent of HI (concentrated aqueous). The crude crystals were recrystallized from a methanol-acetone-ether mixture to give pure N- (4-hydroxyphenyl) -N * - (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide, m.p. 174-178 ° C.

Analysis:

calculated for C ₁₆ H ₂₂ N ₄ O. HI: 46.39% C; 5.60% H; N, 13.52. Found: C, 46.62; 5.59% H; 13.63% N.

Example XXXII

N- (4-Acetoxyphenyl) -N (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximide hydroiodide:

g (0.20 mol) of glacial acetic acid is slowly added to a solution of 5.15 g (0.0124 mol) of N- (4-hydroxyphenyl) -N1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide (compound of of Example XXXI) and 41.2 g (0.20 mole of Ν, Ν'-dicyclohexylcarbodiimide in 400 mL acetone). The reaction mixture was stirred at room temperature under nitrogen for 3 days.

Ν, Ν'-Dicyclohexylurea was removed by filtration and the filtrate was concentrated to dryness under vacuum to give an amber oil. Covering several times with ether gave a yellow solid. Recrystallization from acetone-ether gave a white solid, mp (188) 195-197 ° C. Further recrystallization from methanol-acetone ether gave pure N- (4-acetoxyphenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide as a white solid, mp 196-199 ° C. ·

Analysis:

calculated for C ₁₈ H ₂₄ N ₄ O ₂ . HI: 47.38% C; 5.52% H, 12.28% N found: 47.31% C; 5.57% H; 12.26% N.

Claims (7)

SUBJECT OF THE INVENTION A process for the preparation of heterocyclic guanidine derivatives of the general formula I and -CH 2 R _{4 2} A _n = nc (I) and pharmaceutically acceptable acid addition salts and quaternary salts thereof, wherein n is an integer of 1, 2 or 3, R 1 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alken-2-yl of 3 to 5 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, aralkyl of 7 to 14 carbon atoms, and aryl of 6 to 10 carbon atoms, Hj is hydrogen, alkyl of 1 to 6 carbon atoms and aryl of 6 to 10 carbon atoms, R 6 is hydrogen, alkyl of 1 to 8 carbon atoms and aryl of 6 to 10 carbon atoms, R ₄ is hydrogen, methyl and ethyl, R 1 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aralkyl of 7 to 14 carbon atoms and aryl of 6 to 10 carbon atoms, or the group -N 'represents a 3- to 7-membered saturated heterocyclic ring which is optionally interrupted by an oxygen or sulfur atom or another nitrogen atom optionally substituted by a (C 1 -C 4) alkyl, phenyl or benzyl atom, R is alkyl of 4 to 10 carbon atoms, cycloalkyl of 5 to 8 carbon atoms, bicycloalkyl of 7 to 10 carbon atoms, bicycloalkenyl of 7 to 10 carbon atoms, tricycloalkyl of 9 to 10 carbon atoms, 1-adamantylmethyl, tricycloalkenyl of 9 to 10 carbon atoms Arylalkyl wherein the aryl group is selected from the group consisting of phenyl and naphthyl and the alkyl group has 1 to 4 carbon atoms, alpha, alpha-tetramethylenephenethyl, diphenylalkyl wherein the alkyl group has 1 to 2 carbon atoms, naphthyl, fused diarylcycloalkenyl selected from fluorenyl and 5-acenaphthyl; fused arylcycloalkyl selected from 4- (2,3-dihydro-1H-indenyl), 1-0,2,3,4-tetrahydronaphthyl), 7- (bicyclo [4.2. Oi (octa-1,3,5-trienyl), phenylcycloalkyl wherein the cycloalkyl group has 5 to 7 carbon atoms, cycloalkylcycloalkyl wherein each cycloalkyl group has 5 to 7 carbon atoms, phenyl, methylenedioxyphenyl, phenyl subs substituted with 1 to 3 substituents each selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and phenyl substituted with a member selected from the group consisting of amino, dimethylamino, methylethylamino, diethylamino, alkanoylamino of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, sulfinylalkyl of 1 to 4 carbon atoms, sulfonylalkyl of 1 to 4 carbon atoms, trifluoromethyl, hydroxyl, benzyloxy, alkanoyloxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbon atoms and nitro and six membered heteroaryls wherein the heteroatoms are 1 to 3 nitrogen atoms and said heteroaryls substituted on 1 to 2 ring carbons selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms, and methylmercapto, the compound of formula III (III) is reacted therein X is methoxy or ethoxy and Y "is either a group CH or BF ^ ^ ^ OSO OSOjF or R ,, and R, B and n are as defined in formula I, with a compound of formula IV (IV) NR + h ₂ nc-nr ₄ r ₅ wherein R, R ₄ and R 6 are as defined in formula I, in an anhydrous organic solvent, wherein the reaction is carried out in the range of 0 to 100 ° C, preferably at room temperature, to form compounds of general formula V '3 — r < ^C12 > nil ” R ₂ —k _N > = NC-NR ₄ R ₅ . HY ^R 1, wherein R, R 1, R ₂ , R ₂ , R 2, R 2 and n are as in formula (I) and Y is as in Y (III), which is converted to the corresponding compound of formula (I) by treatment with alkali and optionally a pharmaceutically acceptable acid addition salt or quaternary salt is prepared. 2. A process according to claim 1 for the preparation of N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide and a pharmaceutically acceptable acid and quaternary salt thereof, characterized in that methyl-N- ( 1-methyl-2-pyrrolidinylidene) -N'-phenylcarbamimidothioate hydroiodide with pyrrolidine and optionally converting the product to the free base. 3. A process according to claim 1 for the preparation of N- (1-methyl-2-pyrrolidinylidene) -N ' -phenyl-4-morpholinecarboximidamide and a pharmaceutically acceptable acid addition salt and a quaternary salt, characterized in that N- (1) is reacted. (methyl-2-pyrrolidinylidene) -N'-phenylcarbamimidothioethydiododide with morpholine and optionally converting the product to the free base. 4. A process according to claim 1 for the preparation of N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-4-thiamorpholinecarboximidamide and a pharmaceutically acceptable acid addition salt and a quaternary salt, characterized in that 1-methyl- 2-pyrrolidinone with methylfluorosulfonate and then reacting the product with N-phenyl-4-triamorpholinecarboximidamide and optionally converting the product to the free base. 5. A process according to claim 1 for the preparation of N- (4-fluorophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide and its pharmaceutically acceptable acid addition salts and quaternary salts, characterized in that with N-1-methyl-2-pyrrolidinylidene-N'-p-fluorophenylthiourea and pyrrolidine and optionally converting the product to the free base. 6. A process according to claim 1 for the preparation of N- (4-methylphenyl) -N * - (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide and a pharmaceutically acceptable acid and quaternary salt thereof, characterized in that it is reacted. trietyloxoniumfluoboritan with 1-methyl-2-pyrrolidone, and the product is reacted with N- (4-methylphenyl) -1-pyrrolidinkarboximidamidem and optionally converting the product _to the free base. * 7. The process of item 1 for the preparation of N- (3-chlorophenyl) -1- (1-methyl-2-pyrrolidinylidene) -4-. morpholinecarboximidamide and pharmaceutically acceptable acid addition salts and quaternary salts thereof, characterized in that it is reacted with triethyloxonium fluoroborate β 1-methyl-2-pyrrolidinone and the product is reacted with N- (3-chlorophenyl) -4-morpholinecarboximidamide and optionally converted free base product.