FI65243B - REFERENCE TO A FRAMEWORK OF HETEROCYCLIS DERIVATIVES OF GUANIDIN - Google Patents

Description

\ · Λ »Γ · \ rBl m) ANNOUNCEMENT

UTLÄCGNINGSSKRIFT 6 5243 C (4¾ Patent rry-inr.ettj '10 Cl 1904 \ ħ / Patent227 / 10, 401/12, (51) K ».fk.3 / lnt.ci.3 403/12, 413/12 , 417/12

// C 07 D 207/22, 211/72, 223/12 ENGLISH - FI N LAN D (21) P »t * nttlh« k * Tmi * -P «« nt «n * öknln * 77086U

(22) H »k # ml» pilvt - AnsSknlngtdag l8.03.77 (23) AlkupUvi — GlltlghMsdag 18.03-77 (41) Interpreters for Public - Bllvlt offmtllg 20.09-77

Patented relrfstcrlhallitin .............,. ,,,. .

_ '. (44) Date of issue of the publication *. -

Patent · och registratyrelMn '' AfttSkan utlagd och utl. * Krtft * n publkarad 30.12.83 (32) (33) (31) Claim claimed privilege —Begird prlorltet 19 · 03.76 20.12.76 United States Laboratories, Incorporated, Camp Hill Road, Fort Washington, Pennsylvania, USA (72) Chris Royce Rasmussen, Ambler, Pennsylvania, USA (7M Oy Kolster Ab (5I +) Method for the preparation of therapeutically useful guanidine heterocyclic derivatives - Förfarande för GB 1,409,768 discloses a number of heterocyclic derivatives of guanidine having a 5- or 6-membered saturated 1,3-diazacarbocyclic-2-ylidene in the heterocyclic moiety. In contrast, the compounds of this invention differ in that they are saturated monoaza-heterocyclic derivatives of guanidine and, in addition, have a subsubstituted substituent on the iminitrogen moiety of the guanidine moiety. substituent. The prior art is further represented by DE application publications 2,321,330 and 2,502,397.

The invention relates to a process for the preparation of therapeutically useful guanidine heterocyclic derivatives of the formula 2,6453

R3-NR R

• l | For the preparation of R 1 and their pharmaceutically acceptable acid addition salts and quaternary salts, wherein n is an integer of 1, 2 or 3; is hydrogen, C 1 -C 6 alkyl, C C 8 -C 8 cycloalkyl, C 8 -C 8 alken-2-yl, hydroxy-lower alkyl, aralkyl or aryl, R 6 is hydrogen, C 1 -C 6 alkyl or aryl;

R 9 is hydrogen, C 1 -C 6 alkyl or aryl; is hydrogen, methyl or ethyl;

Kg is C 1 -C 4 alkyl, C 6 -C 4 cycloalkyl, aralkyl or aryl; or group

-OF

denotes a 3-7 membered saturated heterocyclic ring in which, when -NR 2 R g, the 6-membered ring may be (i) in addition an oxygen or sulfur atom or another nitrogen atom which may have a lower alkyl, phenyl or benzyl substituent, or (ii ) the ring may have a lower alkyl substituent on a carbon atom other than the one immediately adjacent to the nitrogen atom attached to the carboximidamide group, for example pyrrolidinyl, piperidino, morpholino, thiomorpholino, 2,6-di-lower alkyl-morpholino (preferably 2,6-dimethyl-morpholino), 4-lower-alkyl-piperazinyl (preferably 4-methyl-piperazinyl), U-phenyl-piperazinyl, R is C 1 -C 4 alkyl, C 8 -C 8 cycloalkyl, C1-C10-bicycloalkenyl, C8-C8-tricycloalkyl, 1-adamantylmethyl, C8-C8-tricycloalkenyl, aryl-C1-C4-alkyl, the aryl group of which is phenyl or naphthyl, diphenyl-C - C 1 -C 7 alkyl, naphthyl; phenyl; methylenedioxyphenyl; phenyl having 1 to 3 substituents selected from halogen, lower alkyl and lower alkoxy; and phenyl substituted with amino, dimethylamino, methyl-3 65243 amino, diethylamino, lower alkanoylamino, thio-lower alkyl, sulfinyl-lower alkyl, trifluoromethyl, hydroxy, benzyloxy, lower-alkanoyloxy, lower-alkanoyl; or 3-pyridyl having 1 to 2 halogen, lower alkyl or lower alkoxy substituents on the ring carbon atoms.

As used herein, the prefix "lower" means that the group has 1 to 4 carbon atoms, and halogen means chlorine, bromine, fluorine or iodine. When one of the above or is alkyl or aryl, the other is most preferably hydrogen; and when n is an integer of 2 or 3, then R 2 and R 2 represent hydrogen.

Since the compounds of formula I contain a tertiary nitrogen, their acid addition and quaternary salts can be readily prepared and such pharmaceutically acceptable salts are also within the scope of this invention. The compounds of formula I may be converted into their therapeutically acceptable, non-toxic acid addition salt form by treatment with a suitable acid such as an inorganic acid such as hydrohalic acid, e.g. hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic. , propionic, glycol, embonic, fir grape, malonic, amber, maleic, fumaric, apple, wine, lemon, benzoic, cinnamon, almond, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, p-amino-salicylic acid. The salt form, on the other hand, can be converted into the free base form by alkali.

Therapeutically effective quaternary ammonium salts can be prepared by reacting a compound of formula I with alkylating agents, i. with alkyl, alkenyl or aralkyl halides, sulphates or sulphonate esters, for example: methyl iodide, ethyl bromide, propyl bromide; allyl chloride, benzyl chloride; or di-lower alkyl sulfates such as dimethyl sulfate, diethyl sulfate; lower alkyl aryl sulfonates such as methyl p-toluenesulfonate, methyl fluorosulfonate, etc. The quaternization reaction can be carried out either with or without a solvent depending on whether the quaternizing agent itself is suitable as a solvent, either at room temperature or under cooling, at room pressure or under closed pressure.

μ 65243

Suitable reaction-inert organic solvents for this purpose include 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 and butanol; or organic acid amides such as formamide or dimethylformamide. The anion function of the quaternary salt can be easily exchanged by conventional ion exchange techniques.

In view of their exceptionally potent hypoglycemic activity, the compounds of the invention which are preferred are those of the following formula I:

Rlin ~ <CVn J *! · R, rio— \ n / '= n-c-n \ (II) | R 8 R 6 and pharmaceutically acceptable acid addition and quaternary salts thereof, wherein n = 1 or 2;

Rg is lower alkyl, allyl, hydroxy-lower alkyl or benzyl;

Ry is methyl or ethyl;

Rg is lower alkyl, cyclopentyl or cyclohexyl; or -NRγRg is pyrrolidino, piperidino, morpholino or thiomorpholino;

R 9 is phenyl, substituted phenyl, 1-adamantyl and 1,1,3,3-tetramethylbutyl, cyclohexyl, diphenylmethyl, naphthyl or 9-fluorenyl as described above; R 1g is hydrogen or C 1 -C 6 alkyl; R 11 is C 1 -C 4 alkyl, provided that at least one of R 1 and R 2 is hydrogen.

The process according to the invention is characterized in that 65243 a) a compound of the formula _ © R3- | - (CH2> n * 2- ^ ϊΘ (III>

OF

u- h J

wherein X is methoxy or ethoxy and Y® is BF ^ ® or OSO ^ F Θ, is reacted with a compound of formula

NR

h2n-c-nr4r5 (IV) in a suitable anhydrous organic solvent to give a compound of formula

R3-r- (CH2) n NR

R2 - \ N ^ · = Ν-ί! - nR4Rs. HY (V) h and compound V are converted to base form I in a manner known per se, for example by treatment with alkali; or b) a compound of the formula R 1 - (CH 2) 3 2 n R 2 -L-S (lower alkyl) (III-e) ΙΘγ © R 1 wherein Υ ^ θ is an anion such as J®; OSC ^ F Θ, methyl sulfate; tosylate or mesylate, is reacted with a compound of formula (IV) as defined above in an anhydrous organic solvent, and the resulting salt of the compound of formula I is converted into base form (I) in a manner known per se, for example by treatment with alkali; or c) the free base form of a compound of formula (III) (wherein R 1 is hydrogen) of formula 6 65243 R 3 -I- <C? 2} n (IX) R? -L >> - x is reacted with a compound of formula (IV) in an anhydrous organic solvent, preferably at elevated temperature, to give a compound of formula

R3-— (CH2) n NR R3-— <CH) n NR

I II tautomers. f 11, v r 2 -L n> n-c-nv ^; - r2— \ n ^, L '[J' ^ rur5 (x)

B

or d) a compound of formula

-.O

R 1 -R- (CH 2) R 2 -SO 3 Me (XII) R 1 is reacted with a compound of formula (IV) in an anhydrous organic solvent, preferably at a temperature of 25-100 ° C, to give the methyl sulphate salt of the compound of formula I, which can be converted to the corresponding base of formula (I) by treatment with alkali; or e) a compound of formula

Rq --- (CH,) 3 2 n I _,. . (Xlla) R_I L-Ο lower alkyl K2 N / n.0 lower alkyl R! reacting with a compound of formula (IV) in an anhydrous organic solvent to give a free base of formula I; or 65243 f) a compound of formula R - (CH 2)

3 2 G

R 1 -L / i Cl C 1 W (XIII) I Θ R 1 is reacted with a compound of formula (IV) in an anhydrous aprotic solvent, preferably an aromatic hydrocarbon, to give a compound of formula I; or g) a compound of formula

Ro_ (CH0) SR * 3 | 2 n j R2 — L> -N “C- NR. H 2 (XVII) N 'k wherein R' is ethyl or methyl and H 2 is an acid is reacted with a compound of formula NHR 1 R 2 'wherein R 1' is the same as R 1 except phenyl and substituted phenyl, preferably in a lower alkanol solvent and at reflux temperature to give a compound of formula I in acid addition form which is converted to the base form by treatment with alkali; or h) two molar equivalents of a compound of formula r 3 (CH 2) n 2

R0-L '= NH

1 | (xiv) R 1 is reacted with a compound of formula

NR

ci-c-nr1 + r5, preferably in an aprotic solvent, to give a compound of formula (I) in base form; and if desired i) reducing the nitrothenyl group to an aminophenyl group, ii) converting the aminophenyl in the reaction with a lower alkanoic anhydride to a lower alkanoylaminophenyl group, iii) oxidizing the thio-lower alkylene group; is converted in the reaction with a lower alkanoic acid and a condensing agent to a lower alkanoyloxyphenyl group, and, if desired, the compound obtained is converted into a pharmaceutically acceptable acid addition salt or a quaternary ammonium salt.

In the reaction according to process variant a), stoichiometric amounts of reactants are most preferably used to prepare the compound of formula IV. Suitable anhydrous organic solvents include lower aliphatic alcohols such as methanol, ethanol, 2-propanol, tert-butanol and the like; ethers such as, for example, diethyl ether, tetrahydrofuran, dioxane; lower halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene, xylene. In general, temperatures ranging from ambient to 0 ° C can be used. The product V in the form of the corresponding HY salt is converted into the corresponding base I by conventional methods, e.g. by treatment with a suitable alkali such as an alkali metal or alkaline earth metal hydroxide or carbonate.

The lactam fluoroborates of the formula III used as starting materials, in which Y® is, are generally known and can be obtained by methods described in the literature, see, for example, CA patents 850,116 and 950 H6H, U.S. Pat. No. 3,867,658, Ber. 2063 (1956) and Org. Synth. M_6, 113, 120 (1966). Lactam fluorosulfonates of formula III in which Y® is OSC ^ F® are prepared in a similar manner. In general, the lactam 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 at a temperature between 0 ° C and ambient temperature in an inert dry shielding gas (e.g. nitrogen or argon), in an inert anhydrous lower halogenated hydrocarbon solvent such as chloroform, 1,2-dichloroethane, methylene chloride (most preferably preferred). Other optionally used anhydrous inert organic solvents include ethers such as diethyl ether, dioxane, terahydrofuran 9 65243 (THF), 1-2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene, etc. The above reactions can be represented as follows: - Θ κΜ 'Ύη * «« w - * R ^ CiV "θ <Vn" (Ill-a) η Θ R3 r3 - - (CH2) n I + MeOSO? F -> j / Γ)

R2 -Kn / ~ 0 ί? 2 \ OMe OS02FW

I i

Ri (viii) R ± .m- - (VI) (Ill-b)

The 2-lower alkylthiolactime ethers of formula III-c used in process variant b) can be prepared by reacting a lactam of formula VI with P2S4 according to the method of R. Gompper and W. Ellser, Org.Syn., Coll. Butter. V pages 780-783 to give a thiolactam of formula Via. Treatment of this thiolactam with a lower alkylating agent such as methyl iodide, methyl fluorosulfonate, dimethyl sulfate, methyl thiosylate, methyl mesylate gives the desired 2-lower alkyl thiolactim ethers as the corresponding salts. Reaction of the lower alkylthiolactime ether salts thus obtained with the appropriate guanidine of formula IV gives the corresponding salts of formula I 10 6 524 3 R3 I (CH2) nps R3 Γ "CCH2Jn R -k 1 --R - 1, L-lower loi- 2 2 misaine

I I

Rx Rx (VI) (Via) R, - (CH,) 3 * L Ώ n .i c,. . (IV) \ (I) (salt) R, - 'is - S lower alkyl - nq I V © R1 (III-c)

It has been found that under the above conditions, in which the lactam fluorosulphonates of the formula III-b react with the guanidines of the formula IV, the following types of by-products may be formed in the side reactions:: 10

R3-j— (CH2Jn NR

R2- ^ XhKJ = N-1-NRt + R5. CH3 OSO2F2 which can be isolated by conventional recovery methods. Such salts are quaternary derivatives of formula I which have an inhibitory and hypoglycemic effect on gastric acid secretion.

The free base form (Formula IX) corresponding to the compound of formula III used as starting material in process variant c) is prepared by treating the salt with an alkali, preferably a halogenated hydrocarbon such as methylene dichloride or chloroform. The compound of formula IX is reacted with a guanidine derivative IV, preferably in an anhydrous lower alkanol such as methanol, isopropanol or tert-butanol, to give the corresponding compounds of formula I which may exist in tautomeric form X. Higher temperatures always refrigeration up to temperatures it is preferred to use during the latter step, as well as a stoichiometric excess of free base IX.

- Θ R3_T "(CH2) n R3 I (CH2) n

; | Y © NaOH. _ I | Y (IVK

! R2 \ N '· ^ X CH Cl ^ 2 ^ N ^' alkanol I H 22 (III) (IX)

R ~ —— (CH0N R3 [<CH2} n NR

3 2 NR tl I .. U „tautomer v ^ L .1—., ^ R2“ "\ N ^ tN_C_NR * 4R5 - r2 \ n N-C-NRlfR5

B

(X)

The starting material (XII) used in process variant d), which can be prepared by reacting lactam (VI) with dimethyl sulfate (XI) according to Bredereck et al. under the reaction conditions described in 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 or xylene, an ether such as tetrahydrofuran or dioxane, or halogenated hydrocarbons such as 1,2-dichloroethane, chloroform or the like. The resulting methosulphate salt (XII) is then reacted with the desired guanidine derivative (IV), most preferably at a temperature of 25-100 ° C, to give the corresponding methyl sulphate salts of formula I, which in turn can be converted to the corresponding free derivatives of formula I. bases by treatment with alkali.

According to process variant e), the free bases of the formula I are obtained using as starting material from the methosulfate salt XII in the reaction with an alkali metal lower alkoxide under the reaction conditions described by H. Bredereck I2 6524 3 et al., Chem. Ber. 97, 3081-3087 (1964) of the formula Xlla. The lactam acetal is in turn reacted with the appropriate guanidine of formula IV to give the free base of formula I. The above reactions can be represented as follows: R3 i (aVn (Me0) QSO0 R3 (CH2 \ i _ (IV) HOSO-Me R2- \ n / "° (XI) μ ^ ΜΘ 0S ° 3Me

OF

I i * ι Ri (VI) (XII) early metal alkoxide i / R3 - (IV) (I) (free R _ L 0 lower allyl base) 2 | 0 lower alkyl h (Xlla)

The reaction according to process variant f) is carried out in an anhydrous aprotic solvent such as, for example, an ether such as diethyl ether, dioxane or THF, halogenated hydrocarbons such as chloroform, methylene dichloride or 1,2-dichloroethane, most preferably toluene, an aromatic hydrocarbon, Chloride salts of formula XIII are readily obtained by activation of lactam VI with phosgene (C1COCl) or thionyl chloride (SOCl2) according to the instructions of W. Jentzsch and M. Seefelder, Chem. Ber. 98, 274 (1965), producing either CO 2 or SO 2 ', respectively. The above reaction i 65243 13 can be represented by the following formula: ^ 2 ♦ C 1 CO 3 3 i Ο (IV) V-1 '-n R 2 -L y) -C 1 C 1-4 (i) 2 O (or SO 0) S0o *) 2 ^> i I ©

Ri 1— -1- —1 (VI) K 1 (XIII)

In addition to using the above-mentioned lactams VI as starting materials, the compounds of formula I which are the subject of the invention can also be prepared from 2-imino compounds of the formula XIV in which n, R 1 and R 2 have the same meanings as described above. Said 2-imino compounds XIV are most known in the literature. They can also be prepared by the method described in CA 950 464 (see, for example, Example 14). The 2-imino compound is reacted with an isothiocyanate of formula XV wherein R is as defined above, but most preferably not 9-fluorenyl, in a reaction inert organic solvent, e.g. benzene, Cl 2 Cl 2 or chloroform, at a temperature between 0 ° C from ambient temperature, for about 2-24 h, in approximately equimolar proportions. In the thiourea compounds XVI thus obtained, several of which are known from U.S. Pat. No. 3,717,648, the thio function (= S) is then converted to an alkylthio function (-SR1) by reaction of compound XVI with an alkylating agent of formula R'X, wherein R * is ethyl, or most preferably methyl, and X is iodide (most preferably), tosylate, methosulfate, mesylate, fluorosulfonate, etc. Suitable solvents for use in the alkylation reaction include ethers, preferably diethyl ether, tetrahydrofuran or dioxane, lower ketones, e.g. butanone and the like, halogenated hydrocarbons and lower alkanols, preferably methylene chloride and methanol. A particularly suitable alkylating agent is methyl iodide in methanol. In general, from an equimolar amount to a large stoichiometric excess, an alkylating agent is used, the amount depending on the reactivity of the thiourea XVI or its solubility in the solvent used. The alkylation reaction may be carried out at temperatures ranging from ambient temperature to reflux temperature or in suitable closed vessels at higher temperatures.

In process variant g), alkylthio compounds of formula XVII in the form of acid addition salts (HX) are reacted with an amine of formula NHR 1 R 2 at temperatures ranging from ambient temperature to reflux temperature or in suitable sealed vessels at higher temperatures. The reaction is preferably carried out in a lower alkanol solvent such as isopropanol and tert-butanol at reflux to give the corresponding acid addition salt of the guanidine derivative of formula I which can be converted to the corresponding base form by treatment with a suitable alkali. The above reactions can be described as follows: R3- «Ä,> n r3 (CH2) n

R I R_NCS s R I I

R2 \ M NH -K2 - ^ = N-C-NHR

N (XV), J, k (XIV) (XVI)

Ro- (CH 2) opi R'Z. R it -> 2— \ n ^ 1N-C- = NR. HZ -> (XVII) R3- (° Η?) Η NR p (ru)

I I! 1V -. · NR

R 2 is k> N-C-NR 1 R 5. HX R2.

R1 R1 (!) * SU ° la (I) 15 65243

Isothiocyanates of formula XV, several of which are known, can be prepared by methods for preparing isothiocyanates known from the literature. They can be obtained, for example, by the methods described in the following references: M. Bogemann et al. "Methoden der Organischen Chemie Houben-Weyl", Eugen Mliller (Ed.), Georg Thieme (Ed.), Stuttgart, Germany, Vol. 9, pp. 867-884 (1955); "Preparation des Isothiocyanates Aromatics", A. Rasschaert et al., Ind. Chim., Belgium, 32, 106 (1967); DE Patent 1,300,559; J. Org. 36, 1549 (1971); U.S. Patent Nos. 2,395,455 and 3,304,167; FR Patent 1,528,249; "A New Synthesis of Aliphatic Isothiocyanates," Angew.Chem. internat. Ed., 6, 174 (1967); Bull. Chem.Soc.Japan, 48, 2981 (1975); Tetrahedron, 29, 691 (1973); Chem. Ber., 101, 1746 (1968); and J.Indian Chem.Soc. 52, 148 (1975).

In the above reaction of compound XVII with an amine, HNR 1 R 2, there is a stoichiometric excess of the latter, e.g. so that the molar ratios are 1: 1.05 to 1: 2.0. If only a small excess of the amine HNR 2 R 2 is used, it may be advantageous to add a stoichiometric equivalent of a tertiary alkyl amine, e.g. Et 2 N, to promote the reaction rate. By-products may be formed during the reaction, such as:

NR

Il Rq — T (CH2) n H „N _C_ NRaR,. HX and i R2- \ kt> NR4R5 · N Λ I Θ R1 Such by-products can be separated from the desired product of formula I by known methods, e.g. by fractional dissolution.

In process variant h), the 2-imino compound XIV is reacted in a molar equivalent ratio of about 2: 1 with a compound of formula XVIII. An equivalent salt XIX of the 2-imino compound XIV is also formed in the reaction. Therefore, the reaction is preferably allowed to proceed in an aprotic solvent which primarily dissolves the desired product of formula I in the form of a base and an acid addition salt XIX as a precipitate. The two can then be easily separated by a filter rod 65243, and the salt can be converted to the free base by conventional treatment and reused. Typical selective solvents include ethers, e.g., diethyl ether and THF, lower alkanols and esters, e.g., acetone, methyl ethyl ketone, ethyl acetate, and the like, aromatic hydrocarbons, e.g., benzene, toluene, xylene, and the like, and acetonitrile. Diethyl ether is generally preferred. The above reaction can be represented as follows:

R ~: (CH0) NR

3 f n II

2 r2 —J = .- nh + ci-c-nr4r5> R1 (XIV) (XVIII) R3 - (CH2) n NR R3 j (aVn | r2— ^ n ^ nc-nr4r5 'HCl ψ I 1 R1 * 1 (I) (XIX)

The preparation of various guanidine derivatives has been extensively described in the literature. Therefore, guanidine derivatives of formula IV are obtained by a number of synthetic methods. For example, a thiourea of formula XX wherein R is the same as the compound described above has been prepared according to the methods described by R.L.Frank & P.V.Smith, Org. Syn. Coll. Part III, page 735 (1955); A. Rasschaert et al. Ind.Chim. Belgium, 32, 106 (1967); G.Barnikow & J.Bodeker, J.fiir prakt. Chemie, 313, 1148 (1971); R.G. Neville & J.J.McGee, Org.Syn.45, 69 (1965); C.P.Joshua & K.N. Rajasekharan, Chem. & Ind. page 750 (1974); and J.Chem.Soc. Transactions, p. 1702 (1924) 7, is converted to an alkylthio compound of formula XXI by alkylation of the former with R'X of the alkylating agent described above. The alkylthio compound XXI thus obtained is then reacted with the appropriate amine of the formula HNR 1 R 4 (however, neither phenyl nor substituted phenyl) is obtained to give the guanidine derivative XXII in the form of an acid addition salt HX, which can then be converted into the corresponding base form. IV by conventional treatment with alkali. To accelerate the reaction rate, a tertiary alkylamine, e.g. Et 2 N, can be preferably used. The conditions of the above reaction are the same as in the previously described reaction in which thiourea XVI was converted to the alkylthio compound XVII and the final product I. E. kts, L.A. Kiselev et al., C.A., 82, 86179 t (1975) .7.

S SR '

Il I HNR R

RNH-C-NH2 R'X>. RN = C-NH2'HX ^ (tautomeric) (XX) (XXI), ΡΛ RN = C-NH, 'HX a-lKal! ^ RN = C-NH, i s 1 (tautomeric) (XXII) (IV)

In a process for the preparation of guanidines of formula IV wherein R is phenyl or substituted phenyl, R 1 is hydrogen and R 1 is phenyl or substituted phenyl, starting from the appropriate N'N-diarylthiourea of the formula ArNHC (= S) NHAr * wherein both Ar that Ar 'represents phenyl or substituted phenyl and is reacted with ammonia according to the method described in J.Org.Chem. (Soviet Union), 2 (1), 2144 (1966) (English translation).

Another process for the preparation of guanidines of formula IV, preferably those in which R is alkyl, cycloalkyl, aralkyl, diphenylalkyl, phenyl and phenyl substituted by lower alkyl, lower ie 65243 alkoxy, halogen or nitro as described above. , is described in Angew.Chem.internat. Ed.

8, 24, 26 (1969), E. Kiihle, and references cited therein; the process involves the intermittent transfer of chloride from a suitable isocyanine di-dihaloid XXIII. The latter, the preparation of which has been described by E. Kiihle et al. Angew, Chem. Internat .Ed. 6. 649 (1967), is reacted with an amine HNR 1 R 4 other than phenyl or substituted phenyl, in which case a trialkylamine, e.g. triethylamine, is present in the solution. The reaction is carried out in a reaction-inert aprotic anhydrous solvent such as diethyl ether, a halogenated hydrocarbon, an aromatic hydrocarbon and the like to give the monohaloid compound XXIV. Treatment of the reaction mixture with excess anhydrous ammonia and then with dilute alkali, for example alkali metal hydroxide or carbonate, gives the corresponding guanidine derivative IV.

Cl NR „R, I I μ 5 RN = C-C1 + HNR4R5 + EtgN -> RN = C-C1 + Et3N * HCl (XXIII) (XXIV)

NR R

I xs nh3 RN = C-C1 -> C1V '(XXIV)

Guanidides of formula IV wherein R is phenyl or substituted phenyl may also be prepared by a method of reacting the appropriate aniline XXV with a cyanamide of formula XXVI to give the guanidine salt XXII; this method has been described by N.M. Golyshin et al. British Patent No. 1,341,245 and Chem.Abs. 79, 66052 f (1973), 80, 95571 a (1974), 82, 86179 t and 68, 86760 g (1968).

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

19 65243 R-NH2 + NC-NR4 - HCl -> (XXII) -αj <a · 1-1- (IV) (XXV) (XXVI) In addition, guanidines of the formula IV in which R is phenyl can be prepared or substituted phenyl, according to the method of W. Abraham & G. Barnikow, Tetrahedron, 29, 691, 699 (1973), which describes the acid hydrolysis of a suitable 2-isothiocyanatotoamidine of formula XVII, and the compound is obtained the reaction of compound XXIV with ammonium cyanate.

NR4R5 nr4r5 RN = C-C1rn = C-NCS - (XXII) + cos

huh

(XXIV) (XXVII)

Another way to prepare guanidines of formula IV in which R is the same as originally described is the method of H.G. Vihehe A Z. Janousek, Angew. Chem. internat.Ed.12, (10), 806 (1973), which gives a suitable dichloromethylene ammonium salt of formula XVII, except when NR4R & is thiomorpholino-1-oxide, with the corresponding amine XVIII to give the corresponding monohaloid compound XVIII, which then treated with excess ammonia followed by alkali as above to give the desired guanidine derivative IV.

Cl NR. Rc I I 4 5 RNH0 + C1-C = NR. R ®C1 ^ - ^ RNC = C-C1 XS- NH3- ^ alkal1 · ~> - (IV) (XXV) (XXVIII) (XVIII)

The compounds of the formula I and their acid addition and quaternary salts have valuable pharmacological properties, in particular anti-secretory and hypoglycemic agents. The compounds have been shown to have anti-secretory activity in gastric rumen experiments performed on rats. The experiments were performed on female Sprague-Dawley rats by injecting the test compound intraduodenally (i.d.) at doses of 2.5 to 40 mg / kg body weight. Rats were fasted for 24 h before the test and received water ad libidum and housed in individual cages. On the day of the test, the rats were weighed and selected so that in each test the weights of the rats varied - 20 g.

The operation was performed under mild ether anesthesia. As soon as the rat was anesthetized, its teeth were removed using small forceps. An incision approximately 11/2 cm in length was made along the midline of the abdomen and the stomach and duodenum were exposed. If at this point the stomach was full of food or feces, the rat was rejected. A suture 4-0 was made in the bottom of the stomach with a wrinkle band loop, taking care not to pierce the blood vessels in the area. A small notch was made in the stomach in the center of the wrinkle tape and a cannula was placed in the stomach, i.e. a small vinyl tube with a flange at one end and a shirring wire loop tightly closed around the flange. Immediately thereafter, the test compound was administered i.d. 0.5 ml / 100 g per rat weight. Usually, three rats were used for each dose of drug tested. Control rats received vehicle, usually 0.5% aqueous methylcellulose.

After administration of the test compound, the abdominal coverings and skin were closed simultaneously with three four 18 mm wound hooks and a collection tube was placed in the cannula. Each rat was placed in a box with a longitudinal slot from which the cannula could hang freely and thus allowed the rat to move freely. After the rat was allowed to stabilize for 30 min, the cannula collection tube was removed and replaced with a clean tube for gastric fluid collection. Collection was continued for 1 h. At the end of the experiment, the cannula was removed and the rat was killed.

The collected gastric fluid sample was poured into a centrifuge tube and centrifuged to allow the sediment to settle down. Volume readings were taken and 1 ml of the supernatant was placed in a beaker containing 10 ml of distilled H 2 O and titrated to pH 7 using 0.01 M NaOH. The following values were determined: volume, titratable acid, and total acid consumption; volume - total amount of gastric fluid in ml minus sediment; titratable acid (milli- 21 6524 3 equivalents / l) = the amount of 0.01-m NaOH required to titrate the acid to pH 7; total acid consumption = acid to be converted x volume. The results are expressed as percent inhibition compared to control experiments and a minimum inhibition of 5% proves the inhibitory effect of secretion.

The following table shows the test results obtained with the reference compounds A, B, C and D (the four most preferred compounds of U.S. Patent 3,566H 010) and with the compounds of the invention in the experiment described above.

Compound pre- Dose, mg / kg p.o. Maximum% block from mark no.

I / D, XIV 100 41 VI-4 100 61 VI-17 100 28 VI-23 10 (sc)> 25 VI-19 100 16 XV-15 100 53 XV- 21 10> 25 XVI- 1 100 52 VI-1 100> 25 VI-13 100 59 XV-22 10> 25 XV-23 10> 25 XV-24 100 20 XV-25 10 12 XV- 29 100 28 XXXI 100 (sC) 48 XVI- 9 100> 25 XVI-10 100> 25 XVI-13 100 48 XVI-15 100 54 VI-18 10 49 VI-7 100 25 VI-20 100 (sc) 52 VI-15 100 36 VI-3 10 21 VI-16 100 41 VI-10 100 40 VI-21 50 (sc) 40 22 6 5 24 3

Compound pre- Dose, mg / kg p.o. Maximum% block from mark no.

VI-11 10 (sc) 26 XVI-3 100 15 XV-3 100 14 XV-7 100 59 VI-22 100 (sc) 41 XVIII / A 100 66 XV-9 5 27 XV-10 5 11 XV-14 100 13 XV-2 0 10 19 XV-28 100 (sc) 45 XV-26 10 10 XV-31 10 8 VI-8 100 (sc) 38 XV-2 7 100 (sc) 25 XVI-11 100 (sc) 35 XVI-14 100 (sc) 32 XXX 100 (sc) 20 Λ

Reference compound A 309 20 B 401 37 C 353 21 D 165 17 A = 2-thioureido-3,3, -diienyl-5H-pyrroline Ί B = 2- (N * -n-butyl) thioureido-3,3 -diphenyl-5-methyl-Δ-pyrroline C = 2- (N'-methoxymethyl) thioureido-3,3-diphenyl-5-methyl-A-pyrroline D = 2-guanido-3,3-diphenyl-5-methyl - ^ - pyrroline

In addition, the compounds of formula I and their salts have been found to lower blood sugar (i.e., have hypoglycemic properties), as demonstrated in a sugar stress test in rats; in particular the compounds of formula II are hypoglycemic.

The rat glucose stress test is a standard test and a very sensitive method used to diagnose diabetes and hypoglycemic conditions.

23 65243

Male Sprague-Dawley rats (Charles River 184-250 g) are given water ad libidum and fasted for 24 h before the experiment. Take several blood samples (0.1 ml) from the tail without anesthesia at 0, 30, 60, 90, 120, 150 and 180 min. after oral administration of 1 g glucose / kg body weight to rats in 1 ml water. Blood samples are immediately deproteinized with aqueous solutions of Ba (OH) 2 and ZnSO 4 and Glu values are determined by glucose oxidase analysis as described by LPCawley et al., "Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase", Amer.J. . Clin. Path. 32, 195 (1959).

2-5 rats are used for each experiment and control group. Test compounds (1-200 mg / kg s.c. or i.p.) are administered suspended in 0.5 or 1.0 ml, most preferably 0.5 ml, of 0.5-1.0% methylcellulose. Control animals are administered the same amount of vehicle subcutaneously. Blood glucose values at each time point are expressed as mg percent (mg glucose / 100 ml blood). The mean glucose values of the control animals are compared statistically according to the "Student's t-test" with the mean values of the experimental group at each corresponding time. If a compound clearly lowers blood glucose at any time with 95% confidence, the compound is considered to have a hypoglycemic effect.

Example I

A. N- (1-Methyl-2-pyrrolidinylidene) -N'-phenylthiourea: to 6.75 g (0.05 mol) of 2-imino-1-methyl-pyrrolidine hydrochloride as a stirred suspension in benzene , 5 ml of 50% aqueous NaOH solution are added. Stirring is continued for about 2 minutes. and the organic layer is then decanted onto CO 2 (anhydrous) and the extraction is repeated twice with fresh benzene. After drying, the combined extracts are suction filtered rapidly (through a pad of diatomaceous earth), air contact is avoided as closely as possible to prevent carbonate salt formation and 6.76 g (0.05 mol) of phenyl isothiocyanate are added in one portion. Stir for three hours and recover the solid obtained.

The second catch is obtained from the mother liquor. Recrystallization from ethyl acetate gives the pure product, N- (1-methyl-2-pyrrolidinylidene) -N'-phenylthiourea, m.p. 142 to 143.5 ° C.

2 »f 6 5 2 4 3 B. Methyl N- (1-methyl-2-pyrrolidinylidene) -N'-phenylcarbamidothioate hydroiodide:

To a solution of 34.86 g (0.15 moles) of N- (1-methyl-2-pyrrolidinylidene) -N'-phenylthiourea in 500 ml of acetone is added 21.3 g (0.15 moles) of iodomethane in acetone. The mixture is heated with a vertical condenser for 1/2 h and allowed to stand at room temperature for another 1 h. Upon cooling, a solid crystallizes (ice bath). Recrystallization from methanol-isopropanol gives pure methyl N- (1-methyl-2-pyrrolidinylidene) -N'-phenylureathiothioate hydroiodide, m.p. 145-147 ° C.

C. Treatment of the compound of Example IA in either lower alkanol solvents, acetone or lower halogenated hydrocarbons using either methyl p-toluenesulfonate, dimethyl sulfate, methyl fluorosulfonate, trimethyloxonium fluoroborate or methyl methanesulfonate as an example of methyl methanesulfonate affords 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 h. Upon cooling, a solid crystallizes (on ice). The crystals are collected by filtration and the mother liquor is set aside (see Example XXVI).

After recrystallization from isopropanol and methanol-ether, the crystals give pure N- (1-methyl-2-pyrrolidinylidene) -N * -phenyl-1-pyrrolidinecarboximidamide hydroiodide, m.p. 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, m.p. 128-31 ° C; b. 2-imino-1-methyl-pyrrolidine fluoroborate, m.p. 109-11 ° C; c. 2-imino-1-ethyl-pyrrolidine hydrochloride, m.p. 181-8 5 ° C; d. 2-Imino-1-n-butyl-pyrrolidine-cyclohexanesulfamate, m.p. 110-114.5 ° C 25 6524 3 e. 2 * imino-1-benzyl pyrrolidine fluoroborate, m.p. IM-112 ° C; f. 2-imino-1,5-dimethylpyrrolidine fluoroborate, m.p. 100-102 ° C; g. 2-imino-l-methyl-piperidine hydrochloride; and h. hexahydro-2-imino-1-methyl-ΙΗ-azepine-cyclohexane sulfamate, m.p. 143-45 ° C; i. 1-hydroxyethyl 2-iminopyrrolidine-cyclohexanesulfamate, m.p. 105-108 ° C.

Each of these salts is converted to the free base form with 50% NaOH as shown in Example I-A.

Example III

Following the isothiocyanate preparation instructions described by J.C. Jochims & A.Seeliger, Angew.Chem. internat. Ed. 6 (2), 17U (1967), the following are obtained: a. 1- and 2- (2,3,3a, * +, 5,6,7,7a-octahydro- * 4,7-methanoindanyl) - isocyanates; b. 1,1-dimethylphenethyl isothiocyanate; c. 1-phenethyl isothiocyanate; d. d-phenethyl isothiocyanate; e. 1-benzyl cyclopentyl isothiocyanate ·, f. 7- (bicyclo [4.2.0] octa-1,3,5-trienyl) isothiocyanate; g. 1-adamantylmethyl isothiocyanate; h. 2-adamantyl isothiocyanate; i. trans-2-phenylcyclopentyl isothiocyanate; j. cis-2-phenylcyclopentyl isothiocyanate; k. trans-2-cyclohexyl cyclopentyl isothiocyanate; l. cis-2-cyclohexyl cyclopentyl isothiocyanate, and m. cis-2-phenylcycloheptyl isothiocyanate.

Example IV

Following the procedure for the preparation of Example IA, except that an equivalent amount of the appropriate 2-imino compound obtained in Example II is used as the starting material in reaction with an equivalent amount of the appropriate isothiocyanate, the following thioureas of formula XVI are obtained, respectively: a. N- (2 -hexahydro-1H-1-methyl-azapinylidene) -N'-phenyl-thiourea, m.p. 157-59 ° C; 26 65243 b. N- (1-methyl-2-pyrrolidinylidene) -N'-diphenylmethyl-thiourea, m.p. 112-114 ° C (polymorph), 119-120 ° C; c. N- (1-methyl-2-pyrrolidinylidene) -N1-p-nitrophenylthiourea, m.p. 179-180 ° C (dec.); d. N- (1-methyl-5-phenyl-2-pyrrolidinylidene) -N'-phenylthiourea, m.p. 135-140 ° C; e. N- (1-methyl-2-pyrrolidinylidene) -N'-fluorophenylthiourea, m.p. 152-154 ° C; f. N- (1-methyl-2-pyrrolidinylidene) -N'-benzylurea, m.p. (71) 74-81 ° C; g. N- (1-methyl-2-pyrrolidinylene) -N'-2-naphthylurea, m.p. 159-162 ° C (dec.); h. N- (1-methyl-2-pyrrolidinylene) -N'-cyclohexylthiourea, m.p. 88-93 ° C; i. N- (1-methyl-2-pyrrolidinylene) -N * -p-methoxyphenylthiourea, m.p. (149) 150-152 ° C (dec.); j. N- (1-methyl-2-pyrrolidinylene) -N, β-chlorophenylthiourea, m.p. 154-156 ° C (dec.); k. N- (1-methyl-2-pyrrolidinylene) -N'-2,6-dimethylphenylthiourea, m.p. (164) 165-168 ° C; 1. N- (1-methyl-2-pyrrolidinylene) -N'-1,1,3,3-tetramethyl-butylthiourea, m.p. 115 to 116.5 ° C; m. N- (1-methyl-2-pyrrolidinylene) -N'-1-adamantylthiourea, m.p. 150-152 ° C; n. N- (1-ethyl-2-pyrrolidinylene) -N'-phenylthiourea; mp.

158 ° C; o. N- (1-ethyl-2-pyrrolidinylene) -N'-p-methoxyphenylthiourea, m.p. 128-130 ° C; and p. N- (1-methyl-2-piperidinylidene) -N'-phenylthiourea, m.p. 132-134 ° C.

Example V

Following the S-methylation method of Example I-B using the indicated solvent with the thiourea precursor of Example IV as the methylating starting material, the following methylthiohydroiodide salts of formula XVII are obtained: 6 5 2 4 3 27

Example precursor Solvent S-Me * HJ (m.p.)

and CH 2 Cl 2 157-59 ° C

b acetone 122-23 ° C

c MeOH ---

d MeOH 150-52 ° C

e MeOH / acetone 104-1C5 ° C

mp acetone 123-25 ° C

g CH2C12 glassy h CH2Cl2 (oil)

in CH 2 Cl 2 124-25 ° C

j ch2c12 16 5-68 ° C

k CH 2 Cl 2 189-92 ° C (decomposed) 1 MeOH (oil)

m. MeOH 14 5-4 8 ° C

n CH 2 Cl 2 117-19 ° C

0 acetone (oil)

p acetone 164-6 5 ° C

28 65243

Example VI

The procedure of Example ID for the preparation of guanidine derivatives of formula I in the form of a free base or an acid addition salt is followed, except that a suitable methylthiohydroiodide precursor obtained from Examples IB and V and a suitable amine of formula HNR 1 R 4 are used as starting materials. in a molar ratio of 1: 1.5 to 1: 3, respectively, using a vertical condenser in isopropanol or preferably in tert-butanol to give the corresponding product of formula I as the corresponding hydroiodide salt, which is then isolated as such or converted to the corresponding base by conventional aqueous alkali solution. by treatment, or reconverted to another acid addition salt by reacting the base form with the indicated acid. In addition, the guanidines of the formula IV can be formed as by-products and can be isolated from the reaction mixture, for example by selective dissolution or fractional crystallization, in the form of either the free base or the acid addition salt.

S-Me * HJ Formula (I) Precursor -NR ^ R ^ Product Form Sp. C ° C)

Example IB -N 2) HJ 193-200 "" -NH-Q 111 186-183.5 "" -N 2 N-Ph eTnäs 131-33 N_ / "" -N 2 -H ° (163-4) 171-73 " "no. 8 2-84" "-N (Me) CH2Ph HJ 180-82" "-1 / ^ N-Me hj 161-161.5

Nle "" -Ι · Γό HJ (193) 197-199 (decomposed) 2HJ 269-27 0 <ha3osl) '^' ie HJ (= hydroiodide) 65243 29 ς-Nfc HT Formula (I) -NR4R5 Product worm Sp. (C)

Preface v_a _, Q HJ 192-93 Vb "" 218-20 Vd "" 201-03 Ve "" 190-92 "Vf" "(165) 167-71" vg "" 187-89 "Vh" "203- 04 "Vi" "142-44" Vj "" 183-85 "Vl" HC104 154-55 "Vm" HJ 171-73 "Vn" "142-43 * Vo" "164-66" Vp "" 151-53

Example VII

A. This example illustrates the preparation of N-benzoyl thioureas according to the methods of R.L.Frank & P.V.Smith *, Org.Synth. Coll. Vol III, page 735 (1955) / Cf. see also G.Barnikw & J.B.Bodeker, J.Prakt. Chemie, 313, 1148 (1971). Thus, the following benzoylthioureas are prepared: a. N-benzoyl-N'-3,4-dimethoxyphenylthiourea, m.p. 133-34 ° C; b. N-benzoyl-N'-p-benzyloxyphenylthiourea, m.p. (120) 132-37 ° C.

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

30 5 5 4 3 B. Substitution of carbethoxy isothiocyanate instead of benzoyl isothiocyanate gives N-carbethoxy-N '- (3,4-methylenedioxyphenyl) thiourea, m.p. (137) 146-148 ° C.

Example VIII

This example illustrates the hydrolysis of suitable benzoylthioureas and carbethoxythioureas to thioureoes of formula XX according to the method described by R.L. Frank & P.V. Smith, Org. Syn.Coll., Vol III, page 735 (1955).

A. 3,4-Dimethoxyphenylthiourea. To a one liter beaker containing 95.85 (0.302 moles) of N-benzoyl-N1-3,4-dimethoxyphenylthiourea is added 230 ml of 10-12% NaOH solution and 60 ml of H2O. The mixture is heated to about 60-80 ° for 5-10 min. until complete hydrolysis has taken place. Filter while hot, wash the solid with water until the filtrate is neutral, wash with MeOH and dry to give the product, 3,4-dimethoxyphenylthiourea, m.p. 234-242 ° C (dec.).

B. p-Benzyloxyphenylthiourea: The procedure of Example VIII-A above is repeated except that an equivalent amount of N-benzoyl-N'-p-benzyloxyphenylthiourea is used as the hydrolyzable material to give p-benzyloxyphenylthiourea, m.p. 193-95 ° C.

C. 4-methylthiophenylthiourea, m.p. (187) 190-191 ° C, is obtained in the same manner.

D. 3,4'-methylenedioxyphenylthiourea, m.p. 207-209 ° C, alkaline hydrolysis of N-carboxyethoxy-N '- (3,4-methylenedioxyphenyl) thiourea under the above conditions, followed by neutralization with mineral acid (Warning: strong evolution of CQ) gives 3, 4-methylenedioxyphenylthiourea, m.p. 207-209 ° C.

Example IX

This example illustrates the preparation of thioureas of formula XX according to C.P.Joshuan & K.N.Rajasekharan, Chem. & Ind. page 750 (1974).

A. 4-n-Butylphenylthiourea: To 100 mL of hot HCl (18%) is added 90.2 g (0.605 moles) of pn-butylaniline (97%) followed by 46.1 g (0.605 moles) of NH 4 SCN. . The resulting mixture is heated with a reflux condenser for about 1 h and then poured onto 31,624 3 crushed ice to give crystals which are recrystallized from ethyl acetate to give the pure product, 4-n-butylphenylthiourea, m.p. 123-25 ° C.

B. 3,4-methylenedioxyphenylthiourea, m.p. 208-210 ° C (decomposed) C. 4-methoxyphenylthiourea, m.p. 207-210 ° C.

Example X

This example further illustrates another process for the preparation of thioureas of formula XX which comprises the action of excess ammonia on a suitable isocyanate, usually in an ether type solvent.

A. 1- (Exo-2-norbornyl) thiourea: Exo-2-norbornyl isothiocyanate prepared by Diveley et al. according to the method of J.Org.Chem. 34, 616 (19 6 9 (27.17 g, 0.178 mol) in 200 ml of dry monoglyme, treated with ammonia gas for 5 h. The mixture is allowed to stand overnight. The product is filtered off and washed with ether to give a solid, 1- (exo). -2-norbornyl) thiourea, mp 181-183 ° C.

B. N- (9-fluorenyl) thiourea: To 16.52 g (0.074 moles) of 9-fluorenyl isothiocyanate in ether is added excess anhydrous NH 4 under cooling. The reaction mixture is covered and allowed to stand overnight at 0 ° C. Filtration gives the product N- (9-fluorenyl) thiourea, m.p. (158) 182-129 ° C.

C. Following the above examples of this example except that an equivalent amount of the appropriate isothiocyanate is reacted with an excess of ammonia, the following products are obtained: 2- (bicyclo [2.2.2] octyl) thiourea endo-2- (bicyclo (17-octyl) -thiourea; Anti-7-norbornenyylitiourea; 1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoindanyl) thioureas; 3- (2,3,6,6a-tetrahydro-1H-1,3a-ethanopentalenyl) thiourea; 5- (3a, 4,5,6,7,7a-hexahydro-4,7-methanoindenyl) thiourea; 1, l-dimetyylifenetyylitiourea; 32 65243 d-o-phenethylthiourea; l-phenethyl liturea; 1-bentsyylisyklopentyylitiourea; 1-bicyclo [4.2.0] octa-1,3,5-trienylthiourea; 1-adamantylmethylthiourea; 2-adamantylthiourea; cis-2-fenyylisyklopentyylitiourea; cis-2-phenylcycloheptylthiourea and cis-2-cyclohexylcyclopentylthiourea.

Example XI

A. Methyl N- (9-fluorenyl) urea thiolate hydroiodide: To 7.85 g (0.033 moles) of N- (9-fluorenyl) thiourea in 200 ml of acetone is added 4.68 g (0.033 moles) of methyl iodide. . The mixture is allowed to stand at room temperature for about 4 hours. Ether (400 mL) is added and the mixture is allowed to stand overnight to give a crystalline product, methyl N- (9-fluorenyl) urea thiolate hydroiodide, which is filtered off; mp. (208) 212-14 ° C.

B. The S-methylation procedure of Example XI-A above is followed except that an equivalent amount of the appropriate thiourea is reacted with methyl iodide at the indicated molar ratios and using the indicated solvent as the reaction medium to give the following products of formula XXI as hydroiodide salts: r 33 65243 SMe

RN = C-NH2-HI

Reagents R Solvent ratio Sp. (° C)

H 2 -O-2-norbonyl acetone 1: 1: 1 (oil) pn-Bu-Ph acetone 1: 1 77-79 9-fluorenyl acetone 1: 1 (201) 212-14 1-naphthyl CH 2 Cl 2 -MeOH (4: 1) 1: 1 191-192 m-CF 2 -PH acetone 1: 1 120-22 m-MePh acetone 1: 1.5 145-50 3.4-diOMe-Ph MeOH 1: 4 186-193 p-PhCH 2 O-Ph acetone 1: 2.2 (195) 198-202 3.4-CH 9 Cl 2 MeOH 1: 1 138-138.5 3-OMePh acetone 1: 1.5 119-123 3- Cl-Ph MeOH 1: 1.1 (120) 125-129 4-NO 2 -Fh MeOH 1: 2 190-197 dec.

4-QMePH acetone 1: 1.1 161-164 4-SMePh acetone 1: 1 158-160 4-NMe2-Fh MeOH 1: 1 166-168 3-pyridyl acetone 1: 1 98-100 (free base) 4-MePh MeOH 1: 1 129-130.5 C. The S-methylation procedure of Example XI-X above is repeated, but using an equivalent amount of each thiourea obtained in Example XC and using methanol as the reaction solvent and a small stoichiometric excess of methyl iodide to give the corresponding urea thiolate of formula XXI. -hydrojodideja.

34 6524 3

Example XII

A. N- (4-Tolyl) -1-pyrrolidinecarboximidamide hydroiodide: 4-Tolylthiourea (33.2 g, 0.2 mol) in 200 mL of acetone is heated with reflux for 3 h with methyl iodide (31.4 g, 0.221). mole). The solvent is removed in vacuo and the resulting 2-methyl-1- (4-tolyl) -2-thiopseudourea hydroiodide is dissolved in 200 ml of tert-butanol. Pyrrolidine (28.4 g, 0.4 mol) is added and the mixture is heated with a condenser for 18 h. The reaction mixture is cooled, diluted with ether and the resulting solid is isolated. Recrystallize from acetone-ether to give N- (4-tolyl) -1-pyrrolidinecarboximidamide hydroiodide, mp 166-168 ° C. When the salt is treated conventionally in CH 2 Cl 2 with 10-20% aqueous NaOH, the corresponding free base is obtained.

3. N-2,6-dichlorophenyl-1-pyrrolidinecarboximidamide hydrochloride:

A mixture of 14.52 g (0.04 mol) of methyl N-2,6-dichlorophenylurea thiolate hydroiodide and 5.69 g (0.08 mol) of dry pyrrolidine in 30 ml of t-BuOH, heated with a condenser for 3 d. The solvent is removed in vacuo and the resulting non-crystalline hydroiodide salt is converted to the free base in CH 2 Cl 2 using cold 20% NaOH followed by drying (K 2 CO 4), removal of the solvent and conversion of the base to the HCl salt in isopropanol. using anhydrous HCl. Recrystallize from isopropanol, using sufficient MeOH to improve dissolution, to give the pure product, N-2,6-dichlorophenyl-1-pyrrolidinecarboximidamide hydrochloride, m.p. 292-295 ° C.

C. Follow the procedures of Examples XII-A and B above, except that an equivalent amount of the appropriate methylthiohydroiodide (Formula XXI) is reacted with the appropriate amine (HNR 2 R 2) in the indicated molar ratio, either using an additional equivalent amount of Et 2 N as indicated. , with or without a vertical condenser in tert-butanol, to give the following guanidines, which are isolated either as the free base or as the indicated acid addition salts: i 65243 35 nr4r5

RN = C KH2'HX

Mole- Added r -NR ^ R ^ HX ratio of base to Sp. (° C)

Ph -a '' HBr 1: 1.1 Et, N 7.03-205 Ο χ 3.4- CH Ph -tT) HJ 1: 2 - 171-172.5 2 "θ '^ £ -2-c4H9-Ph -NEt2 furrarate 1: 2 ~ 9δ ~ 98 o-OH-Ph -Nj] HJ 1: 2 - 216-218 m-Me-Ph -N (Me) * Cj cyclamate 1: 1.06 Et3N 170-172 £ -Me-Ph -iQ HJ 1 : 2 - 166-168 m-Cl-Ph "-O0 base 1: 2 - 143.5-145.5 2.6-äiCl-Ph -N ^ HCl 1: 2 - 292-295

Ph -NjJo ^ 1: 2 - 175-177

Ph -N 2) HNO 3 1: 2 - 139-141 £ -NO 2 -PH-Cl HJ 1: 2 - 240-24 2 (dec.) (Ph) 2CH

Ph -N (Me) C | HJ 1: 1.3 Et ^ N 149-152 £ -Me-Ph -iQ HJ 1: 2 - 166-168 (Ph) 2CH - * Q HJ 1: 2 - 205-206

Exo-2-norhornyy - N ^ j HJ 1: 2 - 160-163 li r— \

Hi 1: 2 - 198-199.5

Ph -tT] HCl 1: 2 - 181-134 3.4- diMeO-Ph -Nj HJ 1: 2 - 221-222 m-CF3-Ph -N (Me) -Q 'fungarate 1: 1-3 St3N 150-153 1-naphthyl -N (Me). base 1: 2 to 132-133 -NEt2 fungarate 1: 4 to 208-210 (decomposed) 9-fluorenyl -nj HJ 1: 2 to 247-249 (decomposed) 1-naphthyl -nJ HJ 1: 2 - 209- 211 2.6-diMe-Ph -ijl HJ 1: 2 - 191-192 65243 36

Msoli- Added Q

p. -NR, R_ HX ratio base Sp. (C) - i 5 - - - - 4-PhCH20-Ph-iQ tosylate 1: 2-1 - 187-190 3-OMe-Ph fumarate 1: 2 - 187-189 4-OMe-Pn N (Me) - (1 base 2: 120 to 120-122 4-OMe-Ph N (H) -CH 2 - (^) base 1: 2 to 134-135 4-SMe-Ph-H 2 H 2 H 1: 1.1 Et N (1) 174 -175.5 4-NMe2Ph -1 (3 en ^ s 1: 2 - (111) 117-119 4-NMe Ph -N ~ ') HCl - - 206-207 Chaj.) Δ —__ m e ph -iT ^ NH 2 HJ 1: 2.4 - 266 (dec.) - (- Me - 3 - pyridyl - (?) - 1: 2.1 - 188-190 S'® \ / - y 3,4-CH_ Ph -N (Me) - <) base 1: 2 - 121.5-123 4- Me-Ph -N 2 YO ^ 1: 2 (197-204 4-Me-? H -tT> base 1: 1.2 Et Nil) 119-120 4-Me-Ph HOAc ~ - 119-123polymor- (133) 134-137 fi 3-Me-Ph -iQs enfis 1: 1 Et3N (1) 105 3-OMe-Ph -N (Me) - ^ J enfis 1: 2.6 Et N (2.6) 93-95 3-Me-Ph-N 2 JD HJ 1: 2 - (160) 168-191 3-OMe-Ph HJ 1: 1.2 Et N (1) (188) 189-192 65243 37 D. Each of the above the acid addition salts obtained in Example XII-C are 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 are added 0.71 g (0.01 mol) of pyrrolidine and 1.01 g (0.01 mol) triethylamine under N 2 in dry ether with stirring and cooling. The resulting mixture is allowed to stir for 1/2 h and the resulting EtgN.HCl is filtered. The filtrate is added to a saturated solution of anhydrous NH 4 in isopropanol. The resulting NH 4 Cl is filtered off and the filtrate is concentrated in vacuo to remove excess ammonia, followed by the addition of dry HCl followed by the formation of a crystalline product, N-phenyl-1-pyrrolidinecarboximidamide hydrochloride, m.p. 181-184 ° C crystallized from methanol-isopropanol.

Example XIV

N- (1-methyl-2-pyrrolidinylidene) -N * -phenyl-1-pyrrolidinecarboximidamide L - (+) - tartrate: to 1.84 g (0.013 mol) of boron trifluoride etherate in Et 2 O (anhydrous) under a nitrogen atmosphere, 1.02 g (0.011 mol) of epichlorohydrin are added with rapid stirring for 3 h. The resulting crystalline triethyloxonium fluoroborate is washed with fresh anhydrous ether by decantation under N 2. The crystals are dissolved in dry Cl 2 Cl 2. 1.09 g (0.011 mol) of 1-methyl-2-pyrrolidinone are added to the solution and the mixture is stirred for 2 h. 0.01 mol of N-phenyl-1-pyrrolidinecarboximidamide is added to the resulting solution under cooling in an ice-water bath. The reaction mixture is stirred overnight (ca. 16 h). The mixture is dried in vacuo and then dissolved in ether to give coarse crystals, N- (1-methyl-2-pyrrolidinylidene) -N1-phenyl-1-pyrrolidinecarboximidamide HBF2 salt. The crystals are recrystallized from acetone to give the pure fluoroborate salt; mp. 164-166 ° C. The fluoroborate salt is converted to the free base in CH 2 Cl 2 with NaOH (20%) on ice. The organic layer is dried over anhydrous CH 2 Cl 2, filtered and dried in vacuo to give the free base. To the free base in MeOH is added an equimolar amount of 38 65243 L - (+) - tartaric acid. The resulting solution is concentrated while adding isopropanol until all of the MeOH has evaporated, and upon cooling, the tartrate salt is obtained. Recrystallization of the isopropanol list with a small amount of MeOH gives the pure product, N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximamide L- (+) -tartrate, m.p. . 153.5 to 156 ° C.

Example XV

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Example XVI

N- (2,6-dimethylphenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide fumarate:

To a solution of 3.47 g (0.035 moles) of dry 1-methyl-2-pyrrolidinone in dry CH 2 Cl 2 in a dry atmosphere is added 3.99 g (0.035 moles) of methyl fluorosulfonate. After 2 h, a solution of 6.52 g (0.03 mol) of the free base of N- (2,6-dimethylphenyl) -1-pyrrolidinecarboximidamide in dry CH 2 Cl 2 is added at room temperature with stirring in one portion. Stir overnight at ambient temperature and then basify the reaction mixture with excess cold NaOH (20%). The organic layer is separated and the aqueous layer is extracted with 2 x 50 mL of fresh CH 2 Cl 2. The combined organic extracts are dried over anhydrous K 2 CO 3, filtered and the solvent removed in vacuo. The residual oil is dissolved in ether and the solution is filtered through diatomaceous earth. The solution is treated with a hot solution of fumaric acid in isopropanol until neutral to give the product as a fumarate salt. Recrystallize from isopropanol (hot filtration) to give the pure product, N- (2,6-dimethylphenyl) -N1- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide fumarate, 3p. 182-184 ° C (decomposes slightly).

Example XVII

The procedure of Example XVI is repeated, except that the appropriate guanidine of formula IV is reacted with the appropriate compound of formula IIIb in the indicated molar ratio instead of N- (2,6-dimethylphenyl) -1-pyrrolidinecarboximidamide to give the following products of formula I which are taken recovered 'and isolated either in the form of the free base or as the indicated acid addition salt: - (CH2) n NR,

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Example XVIII

This example illustrates methods for preparing quaternary salts of compounds of formula X.

A. N- (2,6-Dichlorophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamidinium metofluorosulfonate: to 6.83 g (0.02 moles) of N- (2,6- dichlorophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide in dry CH 2 Cl 2 is added 2.70 g (0.023 mol) of methyl fluorosulphonate with stirring in gas. The mixture is stirred overnight and evaporated to dryness in vacuo to leave an oily residue which is triturated with ether to give crystals. Recrystallize from acetone followed by ethyl acetate to give the pure product, N- (2,6-dichlorophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamidinium methofluorosulfonate, m.p. m8-150 ° C.

B. N- (1-Methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximididinium methyl iodide:

A solution of 0.05 moles of N- (1-methyl-2-pyrrolidinylidene-N1-phenyl-1-pyrrolidinecarboximidamide (Example ID), free base in 30 ml of acetone is treated with 0.05 moles of methyl iodide. the crystals are collected and recrystallized from acetone to give pure N- (1-methyl-2-pyrrolidinylidene-N * -phenyl-1-pyrrolidinecarboximidamidinium methyl iodide, mp (156) 162-164 ° C.

C H N

Anal. Calculated 49.52 6, 11 13.59

Found: 49.58 6.11 13.59.

C. Similarly, treatment of the product of Example ID D as the free base (0.05 moles) in ether (dry) with methyl fluorosulfonate (0.05 moles) rapidly yields an oily precipitate which crystallizes. Recrystallization from t-BuOH gives Example XVIII B as the corresponding metofluorosulfonate salt, m.p. 135.5-137 ° C.

44 6 5 2 4 3

Example XIX

N-phenyl-N '- (2-pyrrolidinylidene) -1-pyrrolidiinikarboksimidami-dihydroiodide:

A solution of 0.07 mol of triethyloxonium fluoroborate in dry CH 2 Cl 2 is prepared in the usual manner. To this solution is added 6.08 g (0.070 mol) of 2-pyrrolidinone. After stirring for 2 1/2 h, the mixture is basified with NaOH (50%) while cooling in an ice-water bath. The organic layer is separated and dried over K 2 CO 2, filtered and treated with 12.28 g (0.065 moles) of N-phenyl-1-pyrrolidinecarboximidamide. The C Recrystallize from tert-butanol to give the pure salt, N-phenyl-N '- (2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide, m.p. 223-225 ° C, dec.

Example XX

N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide L - (+) - tartrate: to 1.74 g (0.01 mol) of phenyl isocyanide dichloride in dry Et 2 O 0.71 g (0.01 mol) of pyrrolidine are added under cooling in Nj gas, followed by 1.01 g (0.01 mol) of Et2N with stirring. The mixture is stirred for 1 1/2 h and then filtered to remove precipitated EtgN.HCl. To the filtrate is added 1.96 g (0.02 mol) of 1-methyl-2-iminopyrrolidine in an ice-water bath. The resulting mixture is stirred overnight in N 2 gas and then filtered to remove N-methyl-2-iminopyrrolidine hydrochloride, m.p. 182-188 ° C. The filtrate is evaporated to dryness in vacuo to give an oil which is dissolved in MeOH (10 ml) and treated with an equimolar amount of L (+) - tartaric acid. The resulting solution is concentrated by adding i-PROH to form crystals. Recrystallization from isopropanol-acetonitrile gives pure, N- (1-methyl-2-pyrrolidinylidene) -N * -phenyl-1-pyrrolidinecarboximidamide L - (+) - tartrate salt, m.p. 153-56 ° C.

65243 45

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, 1.26 g (0.01 mol) of dimethyl sulfate are slowly added with stirring at room temperature. The reaction mixture is stirred for 5 h. 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide are slowly added to the mixture. The resulting mixture is stirred overnight at room temperature. The mixture is evaporated to dryness in vacuo and then dissolved in CH 2 Cl 2, followed by conversion to the free base with NaOH (50%) at the wedding. The organic layer is dried (CH 2 Cl 2), filtered and evaporated to dryness in vacuo to give 2.7 g of an oil, the oil is dissolved in MeOH and 1.5 g (0.01 mol) of L (+) - tartaric acid are added. Recrystallization from methanol-isopropanol gives the product, N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide L - (+) - tartrate, m.p. 153-156 ° C.

Example XXII

N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide L - (+) - tartrate: To a cooled solution of 1.98 g (0.02 mol) of 1-methyl- 2-pyrrolidone in dry toluene, 3.95 g (0.04 mol) of phosgene are added. The resulting solution is allowed to stir in N 2 gas at room temperature for 45 min. to give white crystals. Excess COCl 2 and solvent are removed with the aid of a filter tube (in N 2 gas). Fresh toluene is added and removed in vacuo to remove residual phosgene. The crystals are washed in this way with fresh toluene twice more and then dissolved in dry CH 2 Cl 2, after which 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide and 1.01 g (0 mol) of .01 moles) of triethylamine. The resulting mixture is stirred overnight under N 2 gas. The mixture is evaporated to dryness in vacuo, the residue is dissolved in CH 2 Cl 2 3a, the latter solution is treated with NaOH (50%) on ice. The organic layer containing the product in the form of the free base is separated, dried over anhydrous CH 2 Cl 2, filtered and evaporated to dryness in vacuo to leave an oily residue.

The oil is dissolved in isopropanol, after which L - (+) - tartaric acid is added so that the pH is about 6-7. The resulting crystals are recrystallized from isopropanol to give the pure product, N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide-1 - (+) - 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-pyrrolinium iodide in t-butanol 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidinecarboximidamide are added. The resulting mixture is allowed to boil under a condenser overnight. The evolving MeSH is recovered in concentrated NaOH solution. Cool and triturate to give 3.65 g (92%) of crude product which is recrystallized from t-butanol to give pure N- (1-methyl-2-pyrrolidinylidene-N'-phenyl-1-pyrrolidinecarboximidamide dihydroiodide, 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 moles) of 2,2-diethoxy-1- methylpyrrolidine in dry benzene 1.42 g (0.0075 mol) of N-phenyl-1-pyrrolidinecarboximidamide are added, the mixture is heated with a condenser overnight, then evaporated to dryness in vacuo and the residue is treated with dilute hydrochloric acid (10%). with cold NaOH (20%) and the free product is extracted with ether, the dry (K 2 CO 3) extracts are evaporated to dryness in vacuo and the residual oil is dissolved in i-PrQH and treated with one molar equivalent of L - (+) - tartaric acid. from i-PROH, and pure N1-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 using the indicated acid in each case: i 65243 47 fumarate m.p. 156-157 ° C; phosphate, m.p. 200-201 ° C (dec.); hydrobromides, m.p. (206) 207-209 ° C; oxalate, m.p. 129-131 ° C; pamoate, m.p. 253-256 ° C (dec.); nitrate, m.p. 170-171 ° C (decomposed slightly); maleate, m.p. 115-117 ° C; and p-hydroxybenzoate, m.p. 179-180 ° C.

Example XXVI

A. N-Phenyl-1-pyrrolidinecarboximidamide hydrochloride and B. 1- (1-Methyl-2-pyrrolidinylidene) pyrrolidinium iodide hydrate A. The mother liquor set aside in Example ID D is evaporated to dryness in vacuo and the residue is dissolved in methylene chloride.

and basified with cold dilute NaOH. Extract with CH 2 Cl 2 (200 mL) three times. The combined organic extracts are dried over anhydrous K 2 CO 3, filtered and evaporated to dryness in vacuo to leave a brown thick syrup. Extract the syrup by trituration with hexane (2 x 200 mL) and ether (3 x 20 mL) to give a dark residue (set aside). The organic layers are combined and treated with charcoal, filtered and dried in vacuo to give a brown syrup which is converted to the HCl salt and recrystallized from isopropanol-ether to give N-phenyl-1-pyrrolidinecarboximidamide hydrochloride, m.p. 181-184 ° C. C H

Analysis calculated. HCl:% 8.53 7, 15% found: 58.59 7.08%.

B. The dark residue set aside above is dissolved in isopropanol and treated with a large amount of carbon. Filter and remove the solvent in vacuo to give a dark brown glassy substance which is triturated with acetone and carbon simultaneously to give white crystalline 1- (1-methyl-2-pyrrolidinylidene) -pyrrolidinium iodide which forms a hydrate of about 1/4 mole. with H 2 O, m.p. (98) 108-110 ° C. On a wet day, the crystals absorb excess water and melt, but they recrystallize as the humidity drops.

65243 48

C H J

Analysis: Calculated for C 18 H 17 N 2 +. β>. 1/4 H 2 O: 37, 98 6.02 44.58 H 2 O 1.58%

Found: 38.15 6.11 45.25 H 2 O 1.13%.

Example XXVII

N- (4-aminophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydrobromide: N- (1-methyl-2-pyrrolidinylidene) -N' - (4-nitrothenyl) - 1-Pyrrolidinecarboximidamide (product of Example XVII 4), 2.46 g (0.0078 mol) in 50 ml of abs. Ethanol is hydrogenated (about 3 atmospheres) in a Parr stirrer using a Raney nickel catalyst.

Hydrogen uptake is complete after about 0.5 h. The catalyst is filtered off and washed with ethanol. The combined filtrates are evaporated to dryness in vacuo. The residue is dissolved in ethanol and neutralized with one equivalent of aqueous HBr (48%). The solid obtained is recrystallized from ethanol-ether to give pure N- (4-aminophenyl) -N '- (1-methyl-2-pyrro-1-ylylidene) -1-pyrrolidinecarboximidamide hydrobromide, m.p. 241 to 241.5 ° C.

C H N

Analysis calculated for C & H2.HBr: 52.46 6.60 19.12

Found: 52.44 6.60 19.09.

Example XXVIII

N- (4-acetylaminophenyl) -N '- (1-methyl-2-pyrrolidinylidene-1-pyrrolidinecarboximidamide hydrobromide: N- (4-aminophenyl-N' - (1-methyl-2-pyrrolidinylidene-1-pyrrolidinecarboximidamide) (product of Example XXVII) as the free base, 3.4 g (0.0119 moles) are heated in a steam bath with 25 ml of acetic anhydride for about 1 h. The reaction mixture is then diluted with ethanol and heated for a further 1 h. The volatiles are removed in vacuo and the residue is taken up in dilute aqueous NaOH and extracted with methylene chloride, the extracts are dried over K2CO2, filtered and the solvent is removed to give an oil which is converted into the corresponding HBr acid addition salt in ether-ethanol. N- (4-acetylaminophenyl) -N '- (1-methyl-2-pyrrolidinylidene-1-pyrrolidinecarboximidamide, mp 2 H 6-2 4 7 ° C.

Example XXIX

N- (1-methyl-2-pyrrolidinylidene) -N '- (4-methylsulfinyl-phenyl) -4-morfoliinikarboksiimidamidi :.

To a stirred solution of 1.98 g (0.006 moles) of N- (4-methylthiophenyl) -N '- (1-methyl-2-pyrrolidinylidene) -4-morpholinecarboximidamide (Example XV Compound 31) as the free base CP At 5 ° C, 1.22 g (0.006 mol) of m-chloroperoxybenzoic acid are added so that the temperature is maintained at 5 ° C. The reaction mixture is then allowed to warm to room temperature and stirred for 2 h. The organic layer is washed with saturated NaHCO 3 solution (3 x 30 mL) and saturated NaCl solution (2 x 30 mL), then dried over K 2 CO 3 (anhydrous). After filtration, removal of the solvent in vacuo and treatment of the residue with ether-hexane, a crude product is obtained which is recrystallized from ether-hexane to give pure N- (1-methyl-2-pyrrolidinylidene) -N '- (4-methylsulfinylphenyl) -. 4-morpholinecarboximidamide, m.p. (115) 117-120 ° C: ^

C H

Analysis calculated for C 17 H 24 N 4 O 2 • 58.60 6.94

Found: 58.58 6.91.

Example XXX

N- (4-hydroxyphenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide: /

A solution of 26.6 g (0.071 mol) of N- (N-methyl-2-pyrrolidinylene) -N * - (4-benzyloxyphenyl) -1-pyrpolidinecarboximidamide (Example XV product 27) as the corresponding free as a base in 50 ml of acetic acid, is placed in a Parr stirrer and hydrogenated at about 3 atmospheres with 10% Pd / C for about 2 h until complete absorption of hydrogen has taken place, at room temperature. The reaction mixture is filtered and the solvent is removed in vacuo to give a viscous oil which is dissolved in acetone and treated with one equivalent of HJ (concentrated aqueous solution). The crude crystals are recrystallized from methanol-acetone / ether to give pure N- (4-hydroxyphenyl) -N '- (1-methyl-2-pyrrolidin-656524idene) -1-pyrrolidinecarboximidamide hydroiodide, m.p. 174-178 ° C.

C H N

Analysis calculated for C 18 H 18 N 2 O 3: 46.39 5.60 13.52

Found: 46.62 5.59 13.63.

Example XXXI

N- (4-acetoxyphenyl) -N '- (1-mepyl-2-pyrrolidinylidene-1-pyrrolidinecarboximidamide hydroiodide: 12 g (0.20 mol) of glacial acetic acid are slowly added to a solution of 5.15 g (0.012 mol) of N - (4-hydroxyphenyl) -N'-1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide (Example XXX compound) and 41.2 g (0.20 mol) of N, N'-dicyclohexylcarbode -imide in 400 ml of acetone. The reaction mixture is stirred at room temperature under N 2 for 3 d. The N, N'-dicyclohexylurea is removed by filtration and the filtrate is concentrated to dryness in vacuo to give an amber oil. Triturate several times with ether to give a yellow solid. Recrystallization from acetone-ether gives white crystals with a melting point of (188) 195-197 ° C. Further crystallization from methanol-acetone-ether gives pure N- (4-acetoxy-phenyl) -N '- (1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximidamide hydroiodide, a white crystalline solid, mp. 196-199 ° C.

C H N

Analysis calculated .HJ: 47.38 5.52 12.28

Found: 47.31 5.57 12.26.

I,

Claims (3)

A process for the preparation of therapeutically useful heterocyclic derivatives of guanidine of the formula Ro_ (CH9) I2NNR which formula n is the integer 1, 2 or 3; R ^ is hydrogen, C ^-Cg alkyl, Cg-Cg cycloalkyl, Cg-Cg alken-2-yl, hydroxy-lower-alkyl, aralkyl or aryl; R 2 is hydrogen, C 1 -C 6 alkyl or aryl; R 8 is hydrogen, C 1 -C 6 alkyl or aryl; R 2 is hydrogen, methyl or ethyl; R 6 is C 1 -C 4 alkyl, C 8 -C 4 cycloalkyl, aralkyl or aryl; or the group Λ -N ^R5 represents a 3- to 7-membered saturated heterocyclic ring, wherein -NR ^Rg represents a 6-membered ring, (i) may additionally contain an oxygen or sulfur atom or an additional nitrogen atom, which may be substituted by lower alkyl, phenyl or benzyl, or (ii) said ring may be substituted by lower alkyl at a carbon atom other than a carbon atom immediately adjacent to the nitrogen atom attached to the carboxymidamide group, e.g. pyrrolidinyl, piperidino, morpholino, thiomorpholino, 2,6-dimethyl-alkyl-morpholino (preferably 2,6-dimethyl-morpholino), 4-lower-alkyl-piperazinyl (preferably 4-methyl-piperazinyl), 4-phenyl-piperazinyl; R is C ^-C ^ g alkyl, Cg-Cg cycloalkyl, C ^-C ^ g bicycloalkyl, C ^-C ^ g bicycloalkenyl, Cg-C1Q tricycloalkyl, 1-adamantylmethyl, Cg -C ^ g-tricycloalkenyl, aryl-C - ^-C ^ alkyl, wherein the aryl group is phenyl or naphthyl; diphenyl-C₁-C₄ alkyl; naphthyl; phenyl; methylenedioxyphenyl; phenyl substituted with 1-3 substituents of the following: halogen, lower alkyl and lower alkoxy; and phenyl substituted with amino, dimethylamino, methylethylamino, diethylamino, lower-alkanoylamino, thio-lower-alkyl, sulfinyl-lower-alkyl, trifluoromethyl, hydroxy, benzyloxy, lower-alkanoyloxy, lower-alkanoyl or nitro; 57 6 5 2 4 3 or 3-pyridyl, which in its ring carbon atoms is substituted with 1-2 halogenated, lower alkyl or lower alkoxy substituents, characterized in that a) reacting a compound of formula r - © Ro_l, cUi. »X YÖ (III) Ni- R! where X is methoxy or ethoxy and Y 2 is BF 2 or OSC> 2 with a compound of formula NR h 2n-c-nr 4r5 (IV) in a suitable anhydrous organic solvent, to prepare a compound of formula R3 (CH2 n NR · HY (V) in R 1 and convert compound V to the corresponding base form (I) in a manner known per se, such as by treatment with a suitable alkali; or b) reacting a compound of formula R Z n Ro-s (lower-alkyl) is an anion such as io; OSO 3A methyl sulfate; tosylate or mesylate, with a compound similar to that defined above (IV), in an anhydrous organic solvent, and convert the poured salt of the compound of formula (I) into the corresponding base form (I) in a manner known per se, such as by bone dilution with alkali; or c) reacting the free base form of the compound of formula (III) (which is hydrogen) having the formula * 3 | <CH2> n i <IX) —v. Λ— x 2 KY with the compound of formula (IV) in an anhydrous organic solvent, preferably at elevated temperature, to prepare a compound of formula R3 (CH2) nNR R3 -j- CH2, n NR r2 -Ln-C-NR. Rj tautoj ^ r ^^ (X) I ----------- HX or d) reacting a compound of the formula -ιΘ R [, 'Luu OMe ΟΞΟ, Μθ U (XII) 2 3 | L 59 6 5 2 4 3 with a compound of formula (IV) in an anhydrous organic solvent, preferably at 25 ° -100 ° C to prepare the corresponding methyl sulfate salt of the compound of formula (I), which can be converted to free base of formula (I) by treatment with alkali; or e) reacting a compound of formula R 3 -R- (CH 2> n + 1, (XIIa) R 2'1 y 0 lower-alkyl 0 lower-alkyl R 1 with a compound of formula (IV) in an anhydrous organic solvent to prepare the free base form of formula (I); or f) reacting a compound of formula With a compound of formula (IV) in an anhydrous aprotic solvent, preferably in an aromatic hydrocarbon, to prepare a compound of formula (I), or g) reacting a compound of formula R3 Τ '(CH2) n SR1 r2 -J ^ n / J = nc = No. HZ (XVII) R1