CS225804B2 - Process for preparing heterocyclic guanidine derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of 5-, 6- or 7-membered fully saturated 1-azacarbocyclo-2-ylidene derivatives of guanidine which have secretory and hypoglycemic activity. British Patent No. 1,409,768 describes certain heterocyclic derivatives of guanidine 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 present invention differ in that they are saturated monoazaheterocyclic derivatives of guanidine and in addition have a bulky substituent on the imine nitrogen of the guanidine moiety. Another state of the art, but more distant, can be presented by German publication No. 2,321,330 and No. 2,502,397. The subject of the invention is a process for the production of new heterocyclic guanidine derivatives of the general formula R3—π” /R4 CD n2—kN^=N-C-N I where n is an integer 1, 2 or 3, R1 is hydrogen, alkyl with 1 to 8 carbon atoms, cycloalkyl with 3 to 6 carbon atoms

Description

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

British Patent No. 1,409,768 describes certain heterocyclic derivatives of guanidine 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 present invention differ in that they are saturated monoazaheterocyclic derivatives of guanidine and in addition have a bulky substituent on the imine nitrogen of the guanidine residue. Further prior art, but more distant, can be represented by German Publication No. 2,321,330 and No. 2,502,397.

The subject of the invention is a method for producing new heterocyclic guanidine derivatives of the general formula ^R 3—π” / ^R 4 CD ⁿ 2—k _N ^=NCN

I where n is an integer 1, 2 or 3,

R ₁ is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms (preferably cyclopentyl and cyclohexyl), alken-2-yl of 3 to 5 carbon atoms, hydroxyalkyl of 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, íb, is hydrogen, alkyl of 1 to 6 carbon atoms and aryl of 6 to 10 carbon atoms (preferably phenyl),

R^ 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,

Rg 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

metal atoms, together represent a 3- to 7-membered saturated heterocyclic ring, which is optionally interrupted by an oxygen or sulfur atom or another nitrogen atom, which other nitrogen atom is optionally substituted by alkyl with 1 to 4 carbons, phenyl or benzyl or ,

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

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

1-adamantylmethyl, tricycloalkenyl with 9 to 10 carbon atoms such as 3-(2,3,5,6a-tetrahydro-1S-1,3a-ethanepentalenyl), 5-(3a,4,5,6,7,7a-hexahydro-4,7rmethanoindenyl and the like, arylalkyl in which aryl is a member selected from the group consisting of phenyl and naphthyl and the alkyl has 1 to 4 carbons such as benzyl, E- or 1-alpha-phenethyl, alpha,alpha-dimethylbenzyl, alpha,alpha-dimethyl-beta-phenethyl, d- or 1-(alpha-naphthyl)ethyl and the like, alpha,alpha-tetramethylphenethyl, diphenylalkyl in which the alkyl has 1 to 2 carbon atoms such as 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, in which the cycloalkyl has 5 to 7 carbon atoms, such as cis- or trans-2-phenylcycloheptyl and the like, cycloalkylcycloalkyl, in which each cycloalkyl has from 5 to 7 carbon atoms, such as cis- or trans-2-cyclohexylcyclopentyl, cis- or trans-2-oxycyclopentylcyclopentyl 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 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,

3-pyridyl and 3-pyridyl substituted with 1 to 2 substituents each selected from the group consisting of 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, the essence of which is that a compound of general formula III is reacted

Y (III) in which X is a methoxy group or an ethoxy group and Y" is a BF3 group or CH2OSO3 or OSC2F3 and R1, Rg, fj and n have the same meaning as in formula I, with a compound of formula IV

NR

II + H ₂ NC-NR ₄ R ₅ (IV) where R, R^ and Rj have the meaning as in general formula I, in an anhydrous organic solvent, the reaction being carried out in the range of 0° C to 100° C, preferably at room temperature, to form a compound of general formula V

Řs-HeWn D·

R ₂ —< _n >=N- ^c -N ^r 4R ₅ hy

I «1 (V) in which R, R, Rg, R- _|( R^, an have the meaning as in general formula I and Y has the meaning as Y' in formula III, which is converted into the corresponding compound of general formula I, e.g. by treatment with alkali and optionally a pharmaceutically acceptable acid addition salt or quaternary salt is prepared.

The produced compounds have interesting pharmacological properties.

Where in this description the prefix lower indicates the corresponding group with 1 to 4 carbon atoms and the term halogen represents halogens with an atomic weight less than

127, that is chlorine, bromine, fluorine, iodine. Preferably, when any of the above n is ₂ ^or 3 alkyl or aryl, the other is hydrogen and when n is the whole number 2 or 3, then H and Rj are hydrogen.

Due to the presence of tertiary nitrogen in the compounds of formula 1, their acid addition salts and quaternary salts are readily obtained and are included within the scope of the present invention as pharmaceutically acceptable salts. Said compounds 1 can be converted into their therapeutically active non-toxic acid addition salts by treatment with a suitable acid, such as an inorganic acid, such as a hydrohalic acid, for example hydrochloric, hydrobromic and the like, sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, p-aminosalicylic acid and the like. Conversely, the salt formed can be converted to the free base form by the action of alkali.

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 alkyl sulfates-dimethyl sulfate, diethyl sulfate; lower alkyl aryl sulfonates-methyl p-toluene sulfonate; methyl fluorosulfonate; and the like. The quaternary reaction can 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 under refrigeration, 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 present invention in terms of their extraordinary hypoglycemic efficacy can be represented by the following formula:

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

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

is methyl or ethyl;

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

-NS 2 Sg together is a member selected from the group consisting of pyrrolidino, piperidino, morpholino and thiamorpholino groups;

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

R ₁₀ is Sien selected from the group consisting of hydrogen and alkyl of 1 to 3 carbons;

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

The compounds of formula I are preferably prepared by reacting a lactam salt of formula III, wherein n, Rj, R ₂ and Rj are as defined above, X is either methoxy or ethoxy and X" is either BF^- or OSOgF", with a guanidine derivative of formula IV, wherein R, R^, Rg and NR^R^ have the meanings given above, preferably using stoichiometric amounts of the reactants.

Suitable non-aqueous organic solvents for carrying out the reaction are aliphatic alcohols such as methanol, ethanol, 2-propanol, 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 into the corresponding basic form I by conventional means, e.g. by treatment with suitable alkalis such as alkali metal or alkaline earth metal hydroxides, carbonates and the like.

The reaction can be represented as follows.

Lactamfluoroborates of formula III, where X" is BF^", are generally known and can be obtained by procedures described in the literature, e.g. see Canadian Patents S. 850 1,6 and 950 464; U.S. Patents S. 3,876,658; Ber. £2, 2,063 (1956); and Org. Synth. 46, 113, 120 (1966).

Lactam fluorosulfonates of formula III, where X" is OSOgF" are prepared similarly. Typically, the lactam of formula VI is reacted with the appropriate trialkyloxonium fluoroborate (VII) or methyl fluorosulfonate (VII) 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 chloroform, 1,2-dichloroethane, methylene dichloride (most preferred) and the like. Other inert non-aqueous organic solvents that can be used include ethers, e.g. 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 can be illustrated as follows:

dli-8)

(VI) (VII)

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

I «1 person ₂ f (lil —b)

Alternatively, the corresponding 2-lower alkylthiolactimethers of formula III-c can be prepared by reacting a lactam of formula VI with Ρ ₂ θ5 P° according to the procedure of R. Qompper and W. Elser, Org. Syn.,

Goll, Vol. V, p 780-783, thereby obtaining 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, gives the desired 2-lower alkylthiolactimethers as the corresponding salts.

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

'N

I I

(VI) ^R 3—|-< ^Cr Í2> _n ^R 2~

I ^R 1 (Via) lower alkylating agent

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

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

oso 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 for preparing compounds of formula I where R ₁ is hydrogen is by reacting the free base of formula III, rather than the fluoroborates or sulfonate salt, 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 affords the free base IX, which is then reacted with the desired guanidine derivative IV, preferably in an anhydrous lower alkanol solvent such as methanol, isopropanol, tert-butanol and the like, to afford the corresponding compounds of formula I, which may exist in the tautomeric form X.

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

H

NaOH.

ch ₂ ci ₂ i ₃ -p(CH ₂ ) _n 'r-Sr ¹ (iv) alkanol (III) (IX)

NR

II tautomer

-c-nr ₄ r ₅ ^=H

Ο-Γ-Κπψη fl ^R (X)

An alternative method for preparing compounds of formula X is to react lactam VI with dimethyl sulfate XI to give the corresponding methosulfate salt of formula 1X1 according 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, e.g. benzene, toluene, xylene and the like, an ether, e.g. tetrahydrofuran, dioxane and the like, or a halohydrocarbon, e.g. 1,2-dichloroethane, chloroform and the like. The methosulfate salt XII thus obtained is then reacted with the desired guanidine derivative IV as before, preferably at 25°C to 100°C, thereby obtaining the corresponding methylsulfate salts of formula I, which can in turn be converted into the corresponding free bases of formula I upon treatment with alkali.

The free bases of formula I can also be obtained from the methosulfate salt XII by reacting it with a lower alkali metal alkoxide, preferably sodium methoxide or ethoxide in an appropriate lower alkanol solvent according to the reaction conditions described in H. Bredereck, et al., Chem. Ber., 97, 3081-3087 (1964), to give the corresponding lactam acetal of formula XIIa.

with

The lactam acetal, on the other hand, can react with the corresponding guanidine of formula IV to give the free base of formula I. The resulting reaction schemes can be represented as follows: l3-r-(CH ₂ ) _n (MeO)-SO. i ₂ ~< _N >=o -z— ^R 1 (VI) —* (I) HOSOjMe ^R 3—r-(CH ₂ )„

Ro—JrO lower alkyl i O lower alkyl ^R 1 (Xlla) ⁿ 3-r< ^c H2 ^, n

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

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

1,2-dichloroethane and the like, and preferably an aromatic hydrocarbon, e.g., benzene, toluene, xylene and the like.

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

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

^R 1 (VI) ^R í (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 β Rj have the meanings given above. The above-mentioned 2-imino compounds XIV are mostly described in part 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, where R has the meanings previously described and preferably other than 9-fluorenyl, in an inert organic solvent, e.g. benzene, CHgClg, chloroform and the like at temperatures ranging from °C to room temperature for a period of 2 to 24 hours, in approximately equimolar amounts.

The thio group (=S) in the ureas XVI thus obtained, some of which are described in U.S. Patent No. 3,711,648, is then converted to an alkylthio group (-SR*) by reacting XVI with an alkylating agent of the formula R*X, where R* is ethyl or preferably methyl and X is iodide, preferably tosylate, methosulfate, mesylate, fluorosulfonate and the like. Typical solvents for these alkylations are preferably diethyl ether, tetrahydrofuran or dioxane, lower ketones, e.g. 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 up to a stoichiometric excess of the alkylating agent is used, depending on the reactivity of thiourea XVI or its solubility in the solvent used. The alkylation reaction can be carried out at ordinary temperatures or in suitably sealed vessels at elevated temperatures. Alkylthio compounds of formula XVII, upon addition of the acid salt (HX), then react at temperatures ranging from room temperature to the boiling point or in suitably sealed vessels at elevated temperatures. Alkylthio compounds of formula XVII in the addition salt of acid (HX) are then reacted with the appropriate amine of formula HNR^R^, where R^ and Rj are as defined above except that R^ is phenyl or substituted phenyl, preferably in a lower alkanol solvent such as isopropanol and tert-butanol and usually at reflux temperatures, to give guanidine derivatives of formula 1 in similar addition acid form, which are readily obtained as the corresponding base by conventional treatment with a suitable alkali. The foregoing reaction can be illustrated as follows.

R ₃ -r~ÍCH 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 Ry—< _n >=NC-NR . HZ

I ^R 1 ^R 3r-T-( ^c Hv)ny ^r 2—k _N J= ^N -C- ^NH R

I ^R 1 (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 _s

I ^R 1 (I)

The isothiocyanates of formula XV, most of which are known, can be prepared by extensive procedures given in the literature for the preparation of isothiocyanates. For example, they can be obtained according to the methodology given by M. Bogemann et al. in Methoden der Organische Chemie Houben-Weyl, Eugen Miiller (Ed.), Georg Thieme Verlag (Publ.) Stuttgart, NSR vol. 9, pp. 867 to 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, 1,549 ('970; U.S. Patents Nos. 2,395,455 and 3,304 '67; French Patent No. 1,528,249; New Synthesis of Aliphatic Isothiocyanates, Angew. Chem. Intern. Ed., 6, 174 (1967); Bull, Chem. Soc. Japan, 48, 2,981 (1975); Tetrahedron, 29, 691 (1973); Chem. Ber., 101, 1,746 (1968); and J. Indian Chem. Soc., 52, 148 (1975).

In the preceding reaction of XVII with the amine HNR^R^ it is advantageous to use a stoichiometric excess of the amine, e.g. in molar ratios of 1:1.05 and 1:2.0. If only a small excess of the amine HNR^R^ 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—HCHjIn ^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 resolution.

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

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

The two can then be easily separated by filtration and the latter can be converted back into the free base by conventional work-up with alkalis and reused. Typical preferred solvents are ethers, e.g. THF and the like, lower alkanones and esters, e.g. acetone, methyl ethyl ketone, ethyl acetate and the like, aromatic hydrocarbons, e.g. benzene, toluene, xylene and the like, acetonitrile and similar solvents.

Diethyl ether is usually preferred. The preceding reaction can be illustrated as follows.

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

_Et2O

The preparation of various guanidine derivatives is extensively documented in the literature. Thus, guanidine precursors of formula IV are readily obtained by several convenient syntheses. For example, ureas of formula XX, where R is, as previously described, prepared according to the procedures described in IR. L

Frank and P. V. Smither, Org. Syn. Coll. vol. III, p. 735 (1955); A. Rasschaert et al.,

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

148 (1971); R. G. Neville and J. J. McGee, Org. Syn. 45, 69 (1965); C. P. Joshua and K. N. Rajasekharan, Chem. and Ind., p. 750 (1974); and in J. Chem. Soc. Transaotions, p. 1702 (1924), is converted to the alkylthio compound of formula XXI by alkylation of the thiourea with the previously described R*X alkylating agent.

The alkylthio compound XXI thus obtained is then reacted with the appropriate amine of the formula except where R^ 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 by conventional alkali treatment. To enhance the intensity of the reaction, a tertiary alkylamine, e.g. Et^N, may be advantageously used.

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

C. A., 82, 86 179t /1975/

R X 11 ’ RNH-C-NHg

R'X

->

SR' rn=c-nh ₂

HX

HNR ₄ R ₅ ->

NR.R, í 4 5

RN=C-NH ₂ . HX alkali

->

NR.R _C I ^{4 5}

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

The method for preparing guanidines of formula IV, where R is phenyl or substituted phenyl, R ₄ is hydrogen and R^ is phenyl or substituted phenyl, is starting from the corresponding N,N'-diarylthiourea of formula ArNHC(=S)NHAr*, where each of Ar and Ar* is phenyl or substituted phenyl, which is reacted with ammonia according to the method described in <J. Org. Chem. (SSSR) 2 (12),

144,(1966) (English translation).

Another method for preparing guanidines of formula IV, preferably when R is the previously described alkyl, cycloalkyl, aralkyl, diphenylalkyl, phenyl and phenyl substituted with lower alkyl, lower alkoxy, halogen and nitro groups, is the methodology described by E. Kuhl in Angew. Chem. Intern. Ed., 8, 24, 26 (1969) and references cited therein, which involves stepwise displacement 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. Intern. Ed., 6, 649 (1967) is reacted with an amine HNR^l-L, where R^ is other than phenyl or substituted phenyl, in the presence of a trialkylamine, e.g. triethylamine, in a suitable inert aprotic nonaqueous solvent, such as a halocarbon, an aromatic hydrocarbon, etc., to give the monohalide compound XXIV. Treatment of the reaction mixture with excess ammonia, followed by treatment with dilute alkalis, e.g. an alkali metal hydroxide or carbonate, gives the corresponding guanidine derivative IV.

Cl

AND

RN=C-C1 + NHR ₄ R ₅ + EtjN (XXIII)

NR.R„

I * ³ excess NH, RN=C-C1 -i-» nr ₄ r ₅

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

HC1 alkali

-?

(IV)

Another method for preparing guanidines of formula IV, where R is phenyl or substituted phenyl, is to react the corresponding aniline XXV with cyanamide of formula XXVI to give the guanidine salt XXII according to the procedure described by N. U. Golyshire et al. in British Patent No. 1,341,245 and 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.

HC1 alkali

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

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

^{4 5}

RN=C-C1 nh ₄ scn ·»*·'A

RN=C-NCS

H

-> (XXII) + COS

HOH (XXIV) (XXVII)

Yet another method for preparing a guanidine of formula IV, where R has the meaning originally described, is the method of H. G. Viehe and Z. Janousek, Angew. Chem. Intern. Ed., 12 (10), 806 (1973), by reacting the appropriate dichloromethyleneammonium salt of formula XXVIII, except where NR^Rjj 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 with alkalis as before to give the guanidine derivative IV.

Cl NR.R _r

I . I ⁵ excess NH,

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

--? (IV)

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

For example, compound I and its salts have antisecretory activity in the following acute gastric fistula test in rats. The antisecretory activity of the test compound is studied in female Sprague-Dawley rats after intraduodenal (i. d.) injection of the compound at doses ranging from 2.5-40 mg/kg body weight. The rats are fasted for 24 hours prior to the test and given water ad libitum and are housed in individual cages. On the day of the test, the rats are weighed and selected to weigh within 20 g for each test.

The procedure was performed under light ether anesthesia. Once the rat was anesthetized, it was removed with the teeth of small pincers. A midline abdominal incision about 1.5 centimeters long was made, exposing the stomach and duodenum. If the stomach was filled with grass or fecal matter at this point, the rat was euthanized. The basal portion of the stomach was sutured closed with 4-0 sutures, taking care not to puncture the blood vessels in this area. A small incision was made in the stomach in the center of the sutured portion, and a cannula consisting of a small vinyl tube with a flange at one end was inserted into the stomach and the sutured site was tightly closed around the flange. Immediately thereafter, 0.5 ml of I. D. was administered per 100 g of rat weight. Generally, three rats were used for each dose of the drug under test. Control rats received the test vehicle, usually a 0.5% aqueous solution of methylcellulose.

After administration of the test compound, the abdominal wall and skin are closed simultaneously with three to four 18 mm clips and a collection tube is placed on the cannula. Each rat is then placed in a box in which a slot has been created for the cannula to hang freely to allow the rat to move without restriction. The rat is then allowed to stabilize for 30 minutes, the collection tube on the cannula is discarded and replaced with a clean tube to obtain gastric juice. Collections are made over a period of one hour.

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

The collected sample of stomach contents is drained into a centrifuge tube and centrifuged, pressing the sediment down. The volumes are assessed and a 1 ml aliquot of the sludge water is placed in a beaker containing .0 ml distilled water and filtered to pH 7 0.01N NaOH.

Results are reported for volume, titratable acid, and total acid yield, where volume = total volume of gastric juice minus sediment; titratable acid (milliequivalents of 1) = amount of 0.01N NaOH required to titrate the acid to pH 7; and total acid yield = titratable acid x volume. Results are reported as % inhibition relative to control, and a minimum of 5% inhibition indicates antisecretory activity.

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, especially the compounds of formula II.

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

Male Sprague-Dawley rats (Charles River 184 to 250) are given water ad libitum and fasted for 24 hours prior to testing. Serial blood samples (0.1 ml) are collected from the tail without anesthesia at 0, 30, 60, 90, 120, 150 and 180 minutes after 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 ZnSO^ and glucose contents are determined by the glucoxidase assay described by L. P. Cawley et al. in Ultramicrohemical analysis of blood glucose by glucoxidase, Amer. J. Clin. Path., 32, 195 (1959).

Two to five rats are used for each test and control group. The 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, of 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's t-test against the mean values of the experimental group at each time point. If the compound reduces glucose content significantly at any time point with a 95% confidence limit, then the compound can be considered to have a hypoglycemic effect.

Example I

A. N-(1-ethyl-2-pyrrolidinylidene)-N-phenylthiourea:

To 6.73 g (0.05 mol) of 2-imino-1-methylpyrrolidine hydrochloride, while stirring the suspension in benzene, was added 5 ml of 50% aqueous NaOH solution. After stirring for about 2 minutes, the organic layer was decanted onto KgCO^ (anhydrous) and the extraction was repeated twice with fresh benzene. After drying, the combined extracts were rapidly filtered (kieselguhr pad) under suction, contact with air being minimized to prevent the formation of carbonate salts, and 6.76 g (0.05 mol) of phenylisothiocyanate was added in one portion. After stirring for three hours, the resulting solids were collected. A second crop was recovered from the mother liquor. Recrystallization from ethyl acetate gave the pure product; N-(1-methyl-2-pyrrolidinylidene)-N'-phenylthiourea, m.p. 142 to 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 was added 21.3 g (0.15 mol) of methyl iodide in acetone. The mixture was heated under reflux for 0.5 hour and allowed to stand at room temperature for another hour. The solid crystallized upon 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 either a lower alkanol solvent, acetone or a lower halocarbon with methyl p-toluenesulfonate, dimethyl sulfate, methyl fluorosulfonate, trimethyloxonium fluoroborate or methyl methanesulfonate provides the methylthio compound of Example I-B as the 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 is heated under reflux for 24 hours. Solids crystallize out upon cooling (ice). The crystals are filtered off and the mother liquor is set aside (see Example XXVI).

After recrystallization of the crystals from isopropanol and methanolic ether, pure N-(1-methyl-2-pyrrolidinylidene)-N ^, -phenyl-1-pyrrolidinecarboximidamide hydroiodide is obtained; 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-phenylpyrrolidinefluoroborate, m.p. 128-131°C;

b) 2-imino-1-methyl-pyrrolidinefluoroborate, m.p. 109-111°C;

c) 2-imino-1-ethyl-pyrrolidine hydrochloride, m.p. 181-185°C;

d) 2-imino-1-n-butyl-pyrrolidinecyclohexanesulfameth, m.p. 110-114.5°C;

e) 2-imino-1-benzylpyrrolidinefluoroborate, m.p. 112-114°C;

f) 2-imino-1,5-dimethylpyrrolidinefluoroborate, m.p. 100-102°C;

g) 2-imino-1-methylpiperidine hydrochloride a

h) hexahydro-2-imino-1-methyl-1H-azepinecyclohexanesulfame, m.p. 143 to 145 °Cj

i) 1-hydroxyethyl-2-iminopyrrolidine-cyclohexanesulfameth, m.p. 105-108°C.

Each of the above salts is converted to the free base by treatment with 50% NaOH as described in Example I-A.

Example III

By following the procedure described by J. C. Jochime and A. Seeliger, Angw. Chem. Intern. 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-methanoindanyl)isothiocyanates}

b) 1,1-dimethylphenethyl isothiocyanate;

c) 1-alpha-phenethylisothiocyanate;

d) d-alpha-phenethyl isothiocyanate;

·) 1-benzyl cyclopentyl isothiocyanate;

f) 7-(bicyclo[4,2,0]octa-1,3,5-trienylisothiokyenate;

g) . 1-adamantyl methyl isothiocyanate;

h) 2-adamantyl isothiocyanate;

i) trans-2-phenylcyclopentyl isothiocyanate

j) Cis-2-phenylcyclopentyl isothiocyanate;

k) trans-2-cyclohexylcyclopentyl isothiocyanate;

l) cis-2-cyclohexylcyclopentyl isothiocyanate;,and

m) cis-2-phenylcycloheptylisothiokyemeth.

Example IV

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

a) N-2-(hexahydro-1H-1-methyl-azapinylidene-N'-phenylthiourea, m.p. 157 to 159 °3;

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

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

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

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

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

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

h) N-1-methyl-2-pyrrolidinylidene-N*-cyclohexylthionioate, m.p. 88-93°C;

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

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

k) N-1-methyl-2-pyrrolidinylidene-N*-2,6-dimethylphenylthiourea, m.p. (164) 165 to

168°C;

l) N-1-methyl-2-pyrrolidinylidene-N*-1,1,3,3-tetramethylbutylthiourea, m.p. 115 to

116.5°C;

m) N-1-methyl-2-pyrrolidinylidene-N'-1-adamantylthiourea, m.p. 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 to 130°C; and

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

Example V

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

Precursor from Example IV Solvent S-Me*HI (t. . t.) and ch ₂ ci ₂ 157 to 159 °C b acetone 122 to 123 °C c MeOH - d MeOH 150 to 152 °c e MeOH/acetone 104 to 105 °c f acetone 123 to 125 o.-, in with _{CH2C12 ​} glass h ch ₂ ci ₂ (oil) and ch ₂ ci ₂ 124 to 125 °c j ch ₂ ci ₂ 165 to 168 °c to ch ₂ ci ₂ 189 to 192 (decomposition) °c 1 MeOH (oil) m MeOH 145 to 148 °c n ch ₂ ci ₂ 117 to 119 O-, in 0 acetone (oil) P acetone 164 to 165 °c

Example VI

The procedure of Example I-D is followed in the preparation of guanidine derivatives of formula I as free base or acid addition salt, except that the appropriate hydroiodide precursor obtained from Examples I-B and V and the appropriate amine of formula HNR^R^ are used as starting materials in molar ratios of 1:1.5 to 1:3, under reflux of isopropanol or preferably tert-butanol, thereby obtaining the product of the corresponding formula I as the corresponding hydroiodide salt, which is then isolated as such or converted to the corresponding base by conventional workup.

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

Sl£e'HI -NR.Rn precursor ⁴ ·*

Form of the product of formula I

Melting point (<°C) example I-b example I-b

body

HI example I-E

-N N-Ph \—/ base example I-E

-N O

HI example I-E

base

196 to

186 to

131 to (163 to 164) to

200

188.5

133

171 to 173 example IE -N(ke)CH ₂ Ph

HI

180 to 182 example I-b —N N-Me

HI

161 to 161.5

Example I-b

HI (193) 197 to 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 table continued

S-Jke*Hl precursor -NR.R. 4 5 Formula I product form 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 to 171 example V-g -a HI 187 to 189 example V-h Ό HI 203 to 204 example V-i HI 142 to 144 example V-j -a HI 183 to 185 example V-l -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 1 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 and P. V. Smith, Org. Synth. Goll. Vol. III, p. 735 (1955) (see also G. Barnikow and J. B. Bodeker, J. prakt. Chemie, 313, 1 148 /1971/).

Accordingly, the following benzoylthioureas were prepared:

a) N-benzoyl-N*-3,4-dimethoxyphenylthiourea, m.p. 133 to 134 °C;

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

c) N-benzoyl-N*-(4-methylthiophenyl)thiourea, m.p. 160-161 °C.

B. Substitution of carbethoxyisothiocyanate for benzoylisothiocyanate gives N-carbethoxy-N*-(3,4-methylenedioxyphenyl)urea, m.p. (137) .46-.48°C.

Example VIII

This example shows the hydrolysis of the corresponding benzoylthioureas and carbethoxythioureas to ureas of formula (XX) according to the methodology described by R. L. Frank and P. V. Smith, Org. Syn. 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-dimethoxyphenylthiourea was added 230 mL of a 10-12% NaOH solution and 60 mL of HgO. The mixture was heated to 60-80°C for 5-10 minutes until hydrolysis was complete. The hot solids were filtered off, washed with water until the filtrate was neutral, then washed with MeOH and dried to give 3,4-dimethoxyphenylthiourea, mp 234-242°C (decomposition).

B. , p-Benzyloxyphenylthiourea

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

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

D. 3,4-Methylenedioxyphenylthiourea, m.p. 207 to 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 evolution) provides 3,4-methylenedioxyphenylthiourea, mp 207-209 °C.

Example IX

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

A. 4-n-Butylphenylthiourea:

To 100 ml of hot HCl (18%) was added 90.2 g (0.605 mol) of NH4SCN. The resulting mixture was heated under reflux for about one hour and then poured onto crushed ice, giving crystals which were recrystallized from ethyl acetate to give the pure product 4-n-butylphenylthiourea, m.p. 123-125 °C.

B. 3,4-Methylenedioxyphenylthiourea, m.p. 208 to 210 °C, decomposition

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

Example X

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

A. 1-(exo-2-Morbornyl)urea: Exo-2-Norbornyl isothiocyanate (prepared by the method of Diveley, J. Org. Chem. 34, 616 (1969) (27.17 g, 0.178 mol) in 200 ml of dry monoglyme was treated with ammonia gas for 5 hours. The mixture was allowed to stand overnight. The product was filtered and washed with ether to give 1-(exo-2-norbornyl)urea as a solid, m.p. 181-183°C.

B. N-(9-Fluorenyl)thiourea:

To 16.52 g (0.074 mol) of 9-fluorenyl isothiocyanate in ether was added an excess of anhydrous NH3 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 excess ammonia to give the following products:

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

anti-7-norbomeyl thi omo substance;

1- and 2-(2,3,3α,4,5,6,7,7α-octahydro-4,7-methanoindanyl)thioureas;

3-(2,3,6,6α-tetrahydro-1H-1,3α-ethanepentalenyl)urea;

5-(3α,4,5,6,7,7α-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-cyclohexyloylpentylthiourea. .

Example XI

A, Methyl-N-(9-fluorenyl)carbemimidothioether hydroiodide:

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 preceding 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 indicated molar ratios and the indicated reaction medium is used to provide the following product of Formula XXI as the hydroiodide salt:

C. By repeating the previous 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, the corresponding carbamimidothioate hydroiodides of formula XXI are obtained.

SM

AND

RN='C-NH ₂ . HI (XXI)

R Solvent Ratio of the reactive components 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 _CH2Cl2 - _MeOII (4:1) 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 to 202 3,4-CH„ 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 spread out 4-OMePh acetone 1:1.1 161 to 164 4-SMePh acetone 1:1 158 to 160

225604 table continuation

with Solvent Ratio of the reactive components 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 of acetone was heated under reflux for 3 h 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 h. The reaction mixture was cooled, diluted with ether and the resulting solids were collected. Recrystallization from acetone-ether gave N-(4-tolyl)-1-pyrrolidinecarboximidamide hydroiodide, mp 166-168 °C. The usual treatment in CH2Cl2 with aqueous solution (10 to 20%) of NaOH will give the corresponding free base.

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

A mixture of 14.52 g (0.04 mol) of methyl-N-2,6-dichlorophenylcarbamimidothioethhydroiodide and 5.69 g (0.08 mol) of dry pyrrolidine in 30 ml of tBuOH was heated under reflux for 3 days. The solvent was removed in vacuo and the resulting non-crystalline hydroiodide salt was converted to the free base in CH2Cl2 with cold 20% NaOH, then dried (KgCO^), the solvent was removed, the base was converted to the HCl salt in isopropanol with anhydrous HCl.

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

C. The preceding procedures of Examples XII-A and B are followed except that an equivalent amount of methylthiohydroiodide of formula (XXX) is reacted with the appropriate amine (HNR^R^) in the indicated molar ratio, bu3 with or without an additional equivalent of EtjN, as indicated under reflux of tert-buteinol, to give the following guanidines isolated bu3 as the free base or as the indicated acid addition salt.

NR.R _K I ^{4 5}

RN=C-NH ₀

HX

R -nr ₄ r ₅ HX Mol. ratio Added policy Melting point (OC) Ph -N^S \__y HBr 1:1.1 EtjN 203 and 205 3,4- _CH2Ph -O HI 1:2 - 171 and 172.5 ''''Cl p-n-C^Hg-Ph -NEtg fumarate 1:2 - 96 and 98 p-OH-Ph -a HI .1:2 - 216 and 218 m-lie,Ph -N(Mb)-^ 1 to deceive 1:1.06 Et-jN 170 and 172 p-Me-Ph -G HI 1:2 - 166 to 168 m-CI-Ph —N O base 1:2 - 143.5 to 145.5 2,6-diCl-Ph -G HC1 1:2 - 292 to 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 to 142 decomposition (Ph) ₂ CH -N^O <_/ base 1:2 - 122 to 242

table continuation

R-NR ₄ R ₅

HX Mol. Added Melting point ratio base (°C)

Ph p-Me-Ph (Ph) ₂ CH exo-2-norbornyl

HI 1:1,3 Etymology

HI 1:2

HI 1:2

HI 1:2 exo-2-norbornyl

HI 1:2

Ph

3,4-diMeO-Ph m-CFj-Ph

1-naphthyl

HC1 1:2

HI 1:2 fumarate 1:1,3 EtjN 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 1 63

198 to 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 continued

H -nr ₄ h ₅ HX Mol. ratio Added policy Melting point (°C) 4-PhC ₂ O-Ph -O tosylate 1:2.1 - 187 to 190 3-0lie-Ph -o fumaret 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 _Et3N (1) 174 to 175.5 4-NMe ₂ Ph -Ό base 1 :2 - (111) 117 to 119 4-Niue ₂ Ph -O HC1 - - 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- _CH2 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 _Et3N (1) 1.9 to 120

table continuation

R -NH.R _K 4 5 HX Mol. ratio Added policy Melting point (°C) -O 4-Me-Ph HOAc - - 119 to 123 polymorphic (133) 134 to 137 3-Me-Ph -O base 1 :1 Et ₃ N(1 ) 105 3-OMe-Ph —N(Me)—| base 1:2.6 _Et3N (2,6) 93 to 95 3-Me-Ph —IV O HI 1 :2 - (160) 168 to 191 3-OMe-Ph -N S HI 1:1.2 Et ₃ N(1 ) (188) 189 to 192

D. Each of the foregoing acid addition salts obtained in Example XII-C is converted to the corresponding free base by conventional treatment with alkalies.

Example XIII

N-Phenyl-1-pyrrolidinecarboximidamide hydrochloride:

To 1.74 g (0.01 mol) of phenylisocyanide 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 EtjN.HCl was filtered off. The filtrate was added to a saturated solution of anhydrous NHj in isopropanol. The NH^Cl formed was filtered off, the filtrate was concentrated in vacuo to remove excess ammonia, and dry HCl was added to give the crystalline product N-phenyl-1-pyrrolidinecarboximidamide hydrochloride, m.p. 181-184 °C after crystallization from methanolisopropanol.

Example XIV

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

To 1.64 g (0.013 mol) of trifluoride etherate in Et2O (anhydrous) under N2 was added 1.02 g (0.011 mol) of epichlorohydrin with rapid stirring over 3 h. The resulting crystalline triethyloxonium fluoroborate was washed with fresh anhydrous ether by decantation under N2. The crystals were dissolved in dry CH2Cl2. To the solution was added 1.09 g (0.011 mol) of 1-methyl-2-pyrrolidinone and the mixture was stirred for 2 h. To the resulting solution was added 0.01 mol of N-phenyl-1-pyrrolidinecarboximidamide while cooling with 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 crystals of the HBF salt of N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide.

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

The resulting solution is concentrated by addition of isopropanol until substantially all of the MeOH has evaporated, yielding the tartrate salt upon cooling. Recrystallization from isopropanol with a sufficient amount of MeOH affords the pure product, N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide L-(+)tartrate, m.p. 153.5-156 °C.

Example XV

By proceeding as in Example XIV except that the appropriate lactanfluoroborate of formula IIIa is reacted with the appropriate guanidine of formula IIIa with the appropriate guanidine of formula IV in the indicated molar ratio, the following compounds of formula I are obtained and isolated either as the free base or as the indicated acid addition salts.

O"

-< _N >=NC-NR ₄ R ₅

I I

Compound number n R «I r ₂ ^phi 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 1 Ph _-CH2CH = _CH2 H H 16 Ph Me H n-CgH,γ

table continuation

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 1 m-CF^Ph Me H H ’ 20 2 -CHPh ₂ Me H H 21 1 Ph Me II H 22 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 3,4-(0Me) ₂ Ph Me H H 27 1 4-PhCH ₂ O-Ph Me H H 28 1 3-OMePh Me H H 29 1 4-OMePh Me H H 30 1 4-OMePh Me To H 31 1 4-SMePh Me H ii 32 1 4-NMe ₂ Ph Me H H 33 1 Ph Me H H 34 1 3-pyridyl (inverse Addn) Me H H 35 1 Ph n-CgH,γ H H 36 1 3-C(O)CH ₃ Ph Me H H

Compound number NB.IL· 4 5 Mole ratio (III):(IV) Product form 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

table continuation

Compound number Ntí,H _K 4 5 Mole ratio (III):(IV) Product form Melting point (°C) 5 1.2:1 HI 185 to 187 6 -a 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 to 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 HC1 204 to 207 12 -<Tb 1.08:1 fumarate (220) 224 to 226 13 -say ₂ 1.05:1 fumarate 187 to 189 14 -Í1 1.1:1 HI 230 to 232

decomposition

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

table continuation

Compound number NR.iL· 4 5 Mole ratio (III):(IV) Product form Heat^heating 18 -NET ₂ 1.08:1 fumarate 163 to 165 19 1.08:1 fumarate (135 to 137) 139 to 141 20 -N 0 \_y 1 :1 L-(+)-Tartrate 146 to 148.5 2, -N(Me)^ | 1.08:1 HI (120) 128.5'to 130 22 -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 Ό ' 2.5:1 son ₄ (151) 152 to 154 28 -o 1.1:1 HN0 ₃ 104 to 109 29 2:1 fumarate 179 to 180.5 30 - _N (H) _CH2-0 2:1 0.5 fumarate 208 to 209 decomposition

decomposition of the continuation table

Compound number no. ₄ year ₅ Mole ratio (III):(IV) Product form 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 NH ^Me 1 :1 2HI 269 to 270 decomposition ³⁴ Λ“\ —N O / 1:1.1 1.5 fumarate 138 to 139.5 35 --Q 1:1.1 tartrate oil 36 About 1:1.1 pamoate 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 _CH2Cl2 under _{dry N2} was added 3.99 g (0.035 mol) of methylfluorosulfonate. After 2 h, a solution of 6.52 g (0.03 mol) of N-(2,6-dimethylphenyl)-1-pyrrolidinecarboximidamide, free base, in dry CH2Cl2 was added at room temperature with stirring all 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 CH2Cl2.

The combined organic extracts are dried over anhydrous KgCO^, filtered and the solvent is removed in vacuo. The residual oil is dissolved in ether and the solution is filtered through diatomaceous earth. Treatment of the filtrate with a hot solution of fumaric acid in isopropanol until neutral gives the product as the fumaric salt. Recrystallization from isopropanol (hot filtration) gives the pure product, N-(2,6-dimethylphenyl)-N'-(1-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide fumarate, m.p. 182-184 °C (slight decomposition).

Example XVII

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

^(CH ,2>n |ϊ” _n >=NC-NR4R ₅

I «1

Compound number 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 v_y 2 Me 14 3-0MePh —N S 1 that v_y 15 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 to 141.5 6 1 :1 L-(+)-Tartrate 153 to 155 7 1:1 fumarate 180 to 182 8 1.2:1 fumarate (161 to 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 to 144) 148 to 151 14 1.2:1 HI 185 to 186 15 1.2:1 fumarate 161 to 164 decomposition

fj

Example XVIII

This example provides methods for preparing quaternary salts of compounds of formula I.

A. N-(2,6-Dichlorophenyl)-N'-(1-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidaπlidinemethofluorosulfonate:

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) of methyl fluorosulfonate with stirring under N 2 .

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 the pure product, N-(2,6-dichlorophenyl)-N(1-methyl-2-pyrrolicinylidene)-1-pyrrolidinecarboximidamide methfluorosulfonate, mp 148-150°C.

B. N-(1-Methyl-2-pyrrolidinylidene)-N'-phenyl1-1-pyrrolidinecarboximidimidinemethiodide:

A solution (0.05 mol) of N-(1-methyl-2-pyrrolidinylidene)-N*-phenyl-1-pyrrolidinecarboximidamide (Example ID) 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-pyrrolidinecarboximidamide methiodide, mp (156) 162-164 °C.

Analysis: calculated for C,

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

C. Similarly, treatment of the product of Example ID as the free base (0.05 mol) in ether (dry) with methyl fluorosulfonate (0.05 mol) rapidly gave an oily precipitate which crystallized. Recrystallization from t-BuOH gave the product of Example XVIIIB as the corresponding meth fluorosulfonate salt, m.p. 135.5-137°C.

Example XIX

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

A solution of 0.07 mol of triethyloxonium fluoroborate in dry CH 2 Cl 2 was prepared in the usual 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%) under 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 CH2Cl2 solvent was evaporated, replaced with tert-butanol, and the resulting solution was refluxed for 22 hours. The reaction mixture was allowed to cool to room temperature and then neutralized with HI (47%), giving crystals of the crude HI salt. Recrystallization from tert-butanol gave the pure salt N-phenyl-N*-(2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide hydroiodide, m.p. 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 mol) of phenylisocyanide dichloride in dry Et2O while cooling under N2 is added 0.71 g (0.01 mol) of pyrrolidine, then 1.01 g (0.01 mol) of Et2N with stirring. The mixture is allowed to stir for 1.5 hours and then filtered to remove precipitated Et2N. 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 stirred overnight under Ng and then filtered to give N-methyl-2-iminopyrrolidine hydrochloride, mp 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 by addition of isopropyl alcohol to give crystals. Recrystallization from isopropanolacetonitrile gave 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 with stirring at reflux temperature 1.26 g (0.01 mol) of dimethyl sulfate.

The reaction mixture was stirred for 5 hours. 1.65 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 CH2Cl2, then converted to the free base with NaOH (50%) on ice. The organic layer was dried (Kg2CO3), filtered and evaporated to dryness in vacuo to give 2.7 g of an oil.

The oil is dissolved in MeOH, after which 1.5 g (0.01 mol) of L-(+)-tartaric acid is added, and recrystallization from a methanol-isopropanol mixture yields the product N-(1-methyl-2-pyrrolidinylidene)-N-phenyl-1-pyrrolidinecarboximidamide L-(+)-tartaric acid, mp 153-156 ^°C .

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 min to give bare crystals. Excess COCl ₂ and solvent were removed using a filter rod (under N 2 ).

Fresh toluene is added, then removed under vacuum to remove residual phosgene. The crystals are washed in this manner with fresh toluene twice and then dissolved in dry CH2Cl2, after which 1.89 g (0.01 mol) of N-phenyl-,-pyrrolidinecarboximidamide and 1.01 g (0.01 mol) of triethylamine are added.

The resulting mixture was stirred overnight under nitrogen. 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 ^K2CO3 , filtered ^and dried in vacuo to give an oily residue. The oil is dissolved in isopropanol and L-(+)-tartaric acid is added to approximately 6-7 parts per million. The resulting crystals are recrystallized from isopropanol to give the pure product 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 t.BuOH was added 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide.

The resulting mixture was allowed to reflux overnight. The liberated MeSH was collected in concentrated NaOH solution. Cooling and scraping gave 3.65 g of crude product which, on recrystallization from t.BuOH, gave pure N-(1-methyl-2-pyrrolidineylidene-N'-phenyl-1-pyrrolidinecarboximidamide hydroiodide, mp 206-207 °C, identical in all respects to the product of Example ID.

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. The dried (K ₂ CO ₃ ) extracts were dried in vacuo and the residual oil was taken up in isopropyl alcohol and treated with one molar equivalent of L-(+)-tartaric acid.

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

Example XXV

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

fumarate, mp 156 to 157 °C;

phosphate, mp 200 to 201 °C (decomposition);

hydrobromide, mp (206) 207-209 °C;

oxalate, mp 129-131°C;

pamoate, mp 253-256°C (decomposition);

nitrate, mp 170 to 171°C (slight decomposition);

maleate, mp 115 to 117°C and p-hydroxybenzoate, mp 179 to 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 ID was dried in vacuo and the residue was taken up in methylene chloride and basified with cold dilute NaOH. The _CH2Cl2 extraction (200 mL) was repeated three times. The combined organic extracts were dried over anhydrous _KgCO3 , filtered, and dried in vacuo to give a brown, heavy syrup. Extraction of the syrup by overlaying with hexane (2 x 200 mL) and ether (3 x 200 mL) left a dark residue (set aside). The organic layers were combined and treated with charcoal, filtered, and dried in vacuo to give a brown syrup which was converted to HCl salt and recrystallized from isopropanol-ether to give N-phenyl-1-pyrrolidinecarboximidamide hydrochloride, mp 181-184 °C.

Analysis:

calculated for C,,Η,^N^.HCl: 58.53% C; 7.15% H found: 58.59% C; 7.08% H.

B. The dark residue set aside is taken up in isopropanol and treated with a large amount of activated charcoal. Filtration and removal of the solvent under vacuum gives a dark brown glass which, when covered with acetone with subsequent purification with activated charcoal, gives white crystals of 1-(O-methyl-2-pyrrolidinylidene)pyrrolidinium iodide, which forms a hydrate with about 1/4 mole of HgO; m.p. (98) 108-110°C.

On a humid day, the crystals will absorb excess water and melt, but will solidify again when the humidity drops.

Analysis:

calculated for C^H^Ng.I".1/4 HgO: 37.98% C; 6.02% H; 44.58% I; 1.58% HgO found: 38.1 5 96 Cj 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 was hydrogenated (about 3 atmospheres) in a Parr shaker over Raney nickel as a catalyst. Hydrogenation was complete after about 0.5 hour. The catalyst was filtered off 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 is 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, ₆ H ₂₃ N ₅ HBr: 52.46% C; 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 steam bath with 25 ml of anhydrides for about 1 hour. After this time, the reaction mixture was diluted with ethanol and heated for another hour. The volatiles were removed in vacuo and the residue was treated with dilute aqueous NaOH and extracted into methylene chloride.

After drying _{with K2CO3} , filtration and removal of the solvent, a residual oil is obtained, which is converted into the corresponding HBr acid addition salt in an ether-ethanol mixture. Recrystallization

225804 from an ethanol-ether mixture gives the pure product N-(4-acetylaminophenyl)-N*-(1-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide, m.p. 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 from Example XV) as free base was dried with methylene chloride, cooled to 0 °C, and 3.6 g (0.018 mol) of m-chloroperoxybenzoic acid was added with stirring so that the temperature did not rise above 5 °C.

The mixture was allowed to stir at these temperatures for 0.5 h, then washed with saturated NaHCO3 (3 x 40 mL) and NaCl (3 x 35 mL) solutions, respectively. The organic layer was dried (KgCO3) then filtered (filter media) and evaporated in vacuo to near dryness. Dilution with MeOH gave insoluble material which was filtered off and discarded. The filtrate was evaporated to near dryness on a steam bath. Dilution with ether gave crystals, m.p. 160-166 °C.

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

* Analysis:

calculated for 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 mol) of N-(4-methylthiophenyl)-N'-(1-methyl-2-pyrrolidinylidene)-4-morpholinecarboximidamide (compound 31 from Example XV) as the free base in CH ₂ Cl ₂ at 5° was added 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 saturated NaHCO 3 solution (3 x 30 mL) and saturated NaCl solution (2 x 30 mL), respectively, then dried over K 2 CO 3 (anhydrous).

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

*

Analysis:

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

Example XXXI

N-(4-Hydroxyphenyl)-N'-(1-methyl-2-pyrrolidinylidene)-'-pyrrolidinecarboximidamide (product 27 from Example XV) as its corresponding free base in 50 mL of acetic acid was placed in a Parr shaker and hydrogenated at about 3 atmospheres over 10% Pd/C for about 2 hours or until hydrogenation was 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 methanol-acetone-ether to give pure N-(4-hydroxyphenyl)-N'-(1-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide hydroiodide, m.p. 174-178 °C.

Analysis:

calculated for C, ₆ H ₂₂ N ₄ O . HI: 46.39% C; 5.60% H; 13.52% N found: 46.62% C; 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 was 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 Example XXXI) and 41.2 g (0.20 mol) of N,N'-dicyclohexylcarbodiimide in 400 ml of acetone. The reaction mixture was stirred at room temperature under nitrogen for 3 days.

The Ν,Ν'-Dicyclohexylurea was removed by filtration and the filtrate was concentrated to dryness in vacuo to give an amber oil. Several layers of 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, ₈ H ₂₄ N ₄ 0 ₂ . HI: 47.38% C; 5.52% Hj 12.28% N found: 47.31% C; 5.57% H; 12.26% N.

Claims (7)

SUBJECT OF THE INVENTION 1. A process for the preparation of heterocyclic guanidine derivatives of the general formula I ar-ICHA ^R _{4 2} A _n >=ncn (I) and its pharmaceutically acceptable acid addition salts and quaternary salts, wherein n is an integer 1, 2 or 3, R, 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^ is hydrogen, alkyl of 1 to 8 carbon atoms, and aryl of 6 to 10 carbon atoms, R ₄ is hydrogen, methyl and ethyl, Rj is alkyl with 1 to 4 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, aralkyl with 7 to 14 carbon atoms and aryl with 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, which is optionally substituted by alkyl with 1 to 4 carbon atoms, phenyl or benzyl, 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 in which the aryl group is from the group consisting of phenyl and naphthyl and the alkyl group has 1 to 4 carbon atoms, alpha,alpha-tetramethylenephenethyl, diphenylalkyl in which the alkyl group has 1 to 2 carbon atoms, naphthyl, fused diarylcycloalkenyl selected from the group consisting of fluorenyl and 5-acenaphthyl, fused arylcycloalkyl selected from the group consisting of 4-(2,3-dihydro-1H-indenyl), 1-0,2,3,4-tetrahydronaphthyl), 7-(bicyclo [4.2.0. ij octa-1,3,5-trienyl), phenylcycloalkyl in which the cycloalkyl group has 5 to 7 carbon atoms, cycloalkylcycloalkyl in which each cycloalkyl group has 5 to 7 carbon atoms, phenyl, methylenedioxyphenyl, phenyl substituted with 1 to 3 substituents each selected from the group consisting of halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, and phenyl substituted with a member selected from the group consisting of amino, dimethylamino, methylethylamino, diethylamino, alkanoylamino with 1 to 4 carbon atoms, thioalkyl with 1 to 4 carbon atoms, sulfinylalkyl with 1 to 4 carbon atoms, sulfonylalkyl with 1 to 4 carbon atoms, trifluoromethyl, hydroxyl, benzyloxy, alkanoyloxy with 1 to 4 carbon atoms, alkanoyl with 1 to 4 carbon atoms and a nitro group and six-membered heteroaryls, where the heteroatoms are 1 to 3 nitrogen atoms and said heteroaryls substituted on the ring carbons by 1 to 2 members selected from the group consisting of halogen, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms and methylmercapto, characterized in that a compound of general formula III (III) is reacted in which X is a methoxy group or an ethoxy group and Y" is either a BF^ or CH^OSO^ or OSOjF group and R,, Rj, B. and n have the meaning as in general formula I, with a compound of general formula IV (IV) NR +h ₂ nc-nr ₄ r ₅ where R, R ₄ and R^ have the meaning as in general formula I, in an anhydrous organic solvent, the reaction being carried out in the range of 0 to 100 °C, preferably at room temperature, to form a compound of general formula V «3—r< ^Cí l2>n íl” R ₂ —k _N >=NC-NR ₄ R ₅ . HY I ^R 1 in which R, R,, R ₂ , R^, R^, R^ and an have the same meaning as in general formula I and Y has the same meaning as Y in formula III, which is converted into the corresponding compound of general formula I by treatment with alkali and optionally a pharmaceutically acceptable acid addition salt or quaternary salt is prepared. 2. A process according to item 1 for the production of N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide and its pharmaceutically acceptable acid salts and quaternary salts, characterized in that methyl-N-(1-methyl-2-pyrrolidinylidene)-N'-phenylcarbamimidothioate hydroiodide is reacted with pyrrolidine and optionally the product is converted to the free base. 3. A process according to item 1 for the preparation of N-(1-methyl-2-pyrrolidinylidene)-N*-phenyl-4-morpholinecarboximidamide and pharmaceutically acceptable acid addition salts and quaternary salts, characterized in that N-(1-methyl-2-pyrrolidinylidene)-N'-phenylcarbamimidothioethhydroiodide is reacted with morpholine and optionally the product is converted to the free base. 4. A process according to item 1 for the production of N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-4-thiamorpholinecarboximidamide and pharmaceutically acceptable acid addition salts and quaternary salts, characterized in that 1-methyl-2-pyrrolidinone is reacted with methylfluorosulfone and then the product is reacted with N-phenyl-4-triamorpholinecarboximidamide and optionally the product is converted to the free base. 5. A process according to item 1 for the production of N-(4-fluorophenyl)-N'-(1-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide and its pharmaceutically acceptable acid addition salts and quaternary salts, characterized in that N-1-methyl-2-pyrrolidinylidene-N'-p-fluorophenyl-thiourea is reacted with pyrrolidine and optionally the product is converted to the free base. 6. A process according to item 1 for the production of N-(4-methylphenyl)-N*-(1-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide and its pharmaceutically acceptable acid salts and quaternary salts, characterized in that triethyloxonium fluoborate is reacted with 1-methyl-2-pyrrolidone and the product is reacted with N-(4-methylphenyl)-1-pyrrolidinecarboximidamide and optionally _the product is converted to the free base. * 7. The process according to item 1 for the production of N-(3-chlorophenyl)-1,2-(1-methyl-2-pyrrolidinylidene)-4-yl -morpholinecarboximidamide and its pharmaceutically acceptable acid addition salts and quaternary salts, characterized in that triethyloxonium fluoborate is reacted with β 1-methyl-2-pyrrolidinone and the product is reacted with N-(3-chlorophenyl)-4-morpholinecarboximidamide and optionally the product is converted to the free base.