ZA200603338B

ZA200603338B - Method for producing (3-oxo-2,3-dihydro-1H-isoindol-1yl) acetylguanidine derivatives

Info

Publication number: ZA200603338B
Application number: ZA200603338A
Authority: ZA
Inventors: Schubert Gerrit; Rieke-Zapp Joerg; Keil Johannes; Kleemann Heinz-Werner; Hanna Reda; Huang Bao-Guo; Wu Xiao-Dong; Gouraud Yves
Original assignee: Sanofi Aventis Pharma Deutschl
Priority date: 2003-12-02
Filing date: 2006-04-26
Publication date: 2007-06-27
Also published as: EP1692105B1; TWI334348B; ECSP066597A; HK1097525A1; DE10356717A1; DE502004007177D1; ES2304634T3; CA2548020C; OA13293A; EG25498A; JP2007516243A; CN100526297C; PL1692105T3; CY1108187T1; RS50571B; WO2005054195A1; CR8376A; NO20063058L; MY136467A; PA8618701A1

Description

Method for producing (3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetylguanidine derivatives ® The present invention relates to processes for preparing (3-oxo-2,3-dihydro-1H- isoindol-1-yl)acetylguanidine derivatives via 3-hydroxy-2,3-dihydro-1H-isoindol-1-one derivatives or 3-(2-carbamoylphenyl)acrylic ester derivatives as intermediates, to a process for optical resolution, and also to intermediates of the process according to the invention. (3-Oxo-2,3-dihydro-1H-isoindol-1-yl)acetylguanidine derivatives of the formula

O NH,

Po,

R1 N—R3

R2 0 are NHE1 inhibitors and are described in PCT/EP03/05279. However, the syntheses described there lead to racemic regioisomer mixtures, which entails costly and inconvenient separation processes and reduces the yield of the desired compound.

Hitherto, it has only been possible to obtain the isomers by a costly and inconvenient chromatographic separation on chiral supports. However, the substance throughput is restricted in chromatographic separations.

There is therefore a great interest in finding regioselective preparation processes for (3-ox0-2,3-dihydro-1H-isoindol-1-yl)acetylguanidine derivatives and processes for recovering the enantiomers. The improved, regioselective preparation of the racemic (3-ox0-2,3-dihydro-1H-isoindol-1-yl)acetylguanidine derivatives succeeds by two independent routes which are shown in scheme 1 and scheme 3. The resolution of the racemates succeeds by crystallization as the salts of 2,3-O-acylated D- or

L-tartaric acids, as shown in scheme 5. Gentle base-catalyzed racemization of the in each case undesired enantiomer makes possible substantial conversion of the racemate to the desired enantiomer. The processes mentioned enable the simple preparation of enantiomerically enriched or enantiomerically pure (3-ox0-2,3-dihydro- 1H-isoindol-1-yl)acetylguanidine derivatives. The novel processes now make possible the simple preparation of large amounts of substance of the compounds of the formula | on the industrial scale. ® The present invention thus relates to a process for preparing compounds of the formula

LAC

Nd NH,

I

R1 N—R3

R2 o where

R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2, 2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyi or alkyl having 1, 2, 3 or 4 carbon atoms;

R3 is Alk-R4 or trifluoromethyl;

Alk is alkyl having 1, 2, 3 or 4 carbon atoms;

R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; which comprises, as shown in scheme 1,

OH

H nf — eT pe

R2 O 0] \Y Ry 0 O NH,

R5 i — » Rt N-R3 — RI N—R3

R2 o) R2 O

Vil

Scheme 1 a) formylating the amide of the formula IV and then cyclizing to the compound of the formula Vi, ® b) reacting the compound of the formula VI with an alkoxycarbonylmethylene- triphenylphosphorane, with a 1-alkoxy-1-trimethylsiloxyethylene or with a trialkyl phosphonoacetate to give the compound of the formula VII, and c) reacting the compound of the formula VII with guanidine to give the compound of the formula |, where, in the compounds of the formulae IV, Vl and VII,

R1 to R3 are each as defined in formula | and

Rb5is alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

The invention also provides a process for preparing compounds of the formula where

R1and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2 2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms;

R3 is Alk-R4 or trifluoromethyl;

Ak is alkyl having 1, 2, 3 or 4 carbon atoms;

R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; wherein, as shown in scheme 2,

. H

EE N- ny + HN< rs wl R3 ® R2 o R2 o

I 1] ny,

CHO OH

H

— mfr Le — Tp

R2 © RZ o)

Y VI

0 O NH,

PN

R5 N” TNH, -— _ Pe

R2 0 R2 0} vil !

Scheme 2 a) the compound of the formula Hl is reacted with the amine of the formula ill to give the amide of the formula IV, b) the amide of the formula IV is formylated at the ortho-position to the amide function to give the formyl amide of the formula V, c) the formyl amide of the formula V is cyclized to the compound of the formula VI, d) the compound of the formula VI is reacted with an alkoxycarbonylmethylenetriphenylphosphorane, with a 1-alkoxy-1-trimethylsiloxy- ethylene or with a trialkyl phosphonoacetate to give the compound of the formula Vii and e) the compound of the formula VII is reacted with guanidine to give the compound of the formula I, where, in the compounds of the formulae ll, lll, IV, V, VI and VII,

R1 to R3 are each as defined in formula |,

RS5 is alkoxy having 1, 2, 3 or 4 carbon atoms and

X is Cl, Br, OH or alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

The compound of the formula il is typically reacted, in an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, for example dichloromethane, at a ® temperature between -30°C and the boiling point of the solvent, preferably at RT, with an amine of the formula lll, if appropriate in the presence of an activating agent, to give the amide of the formula IV.

The ortho-formylation may, for example, be carried out by initially charging an alkyl- metal compound, for example an alkyllithium compound, preferably t-BuLi, with a complex ligand, preferably TMEDA, in an inert solvent such as an ether or hydrocarbon, for example THF, at a temperature between -100°C and 0°C, preferably between —80°C and -50°C. Then, the amide of the formula IV is added and deprotonation is effected over a period between 10 minutes and 10 hours, preferably between 10 minutes and 60 minutes, at a temperature between -100°C and 0°C, preferably between —80°C and —50°C. Subsequently, a formylating agent, preferably DMF, is added and reaction with the anion is effected at a temperature between -100°C and 40°C, preferably between -80°C and room temperature.

Preference is given to leaving the solution to come to RT after addition of the DMF over a period of from 10 minutes to 3 hours, for example within 30 minutes. Amide of the formula V formed as an intermediate generally cyclizes directly to the isoindolone of the formula VI.

The isoindolone of the formula VI is reacted with a (C1-C4)-alkoxycarbonyl- methylenetriphenylphosphorane in an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, for example toluene, at a temperature between 0°C and the boiling point of the solvent, preferably between 20°C and the boiling point of the solvent, or with a tri(C4-C4)-alkyl phosphonoacetate in the presence of a base, for example sodium hydride, in an inert solvent such as an ether , hydrocarbon or halogenated hydrocarbon, for example 1,2-dimethoxyethane, at a temperature between 0°C and the boiling point of the solvent, preferably between 20°C and the boiling point of the solvent. Alternatively, the isoindolone of the formula V1 is reacted with a 1-(C4-Ca)-alkyloxy-1-trimethylsiloxyethylene in the presence of a Lewis acid, for example titanium(IV) chloride or trimethylsilyl triflate, in an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, for example dichloromethane, at a temperature between -80°C and the boiling point of the solvent, preferably at a ® temperature between -80°C and 20°C (Synth. Commun. 1987, 17, 1).

The ester of the formula VII may be reacted by commonly known processes with guanidine to give the acylguanidine of the formula |. The reaction is preferably effected in the manner known to those skilled in the art in a protic or aprotic, polar but inert organic solvent. For example, in the reaction of the methyl ester (formula

VII; R5=0CH3) with guanidine, useful solvents have been found to be methanol, isopropanol or THF at temperatures of from 20°C up to the boiling temperature of these solvents. In most reactions of compounds of the formula VII with salt-free guanidine, operation is effected, for example, in aprotic, inert solvents, for example ethers such as THF, dimethoxyethane or dioxane. However, water may also be used when use is made of a base, for example NaOH, as a solvent in the reaction of compounds of the formula VII with guanidine. In the reaction of compounds of the formula VII with salts of guanidine, for example guanidine hydrochloride, the reaction is typically effected in the presence of a base, for example potassium tert-butoxide, sodium methoxide or sodium ethoxide, in an inert solvent such as dimethylformamide, NMP, 2-propanol, at a temperature between 20°C and the boiling point of the solvent.

In addition to the carboxylic esters of the formula VII, it is also possible to use further activated acid derivatives in the reaction with guanidine, for example carbonyl chlorides, carboxylic thioesters or carboxylic anhydrides. An activation of the carboxylic acid with, for example DCC can also be effected. The activated acid derivatives can be prepared in the manner known to those skilled in the art directly from the parent carboxylic esters of the formula Vil or from the corresponding carboxylic acids which can be obtained from the esters by customary hydrolysis methods. A series of suitable methods for preparing activated carboxylic acid derivatives are specified with citation of source literature in J. March, Advanced

Organic Chemistry, Third Edition (John Wiley & Sons, 1985, p. 350).

The process steps described in scheme 1 and 2 may each independently be effected continuously or batchwise. A workup of the reaction mixture may be effected at any of the process steps. The workup and, if desired, the purification of the products is effected by the customary methods such as extraction, pH separation, ® chromatography or crystallization and the customary dryings.

The starting compounds of the formulae Il and lll are commercially available or can be prepared according to or in a similar manner to the processes described in the literature and familiar to those skilled in the art.

Also claimed is a process for preparing compounds of the formula

NT NH,

RA N—R3

R2 o where

R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-triflucroethyl or alkyl having 1, 2, 3 or 4 carbon atoms;

R3 is Alk-R4 or trifluoromethyl;

Alk is alkyl having 1, 2, 3 or 4 carbon atoms;

R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; which comprises, as shown in scheme 3, 0

P NH

RE H.NR3 2

NH 2 = a 2 in = —_— 2 © R1 o — RI N—R3

Ra oH R2 OH R2 lo}

IX Xl l

Scheme 3

2 8 a) reacting the amine of the formula 1X via a diazonium salt with an alkyl acrylate to ® give the cinnamic acid derivative of the formula XI, b) reacting the compound of the formula XI with the amine of the formula III and with guanidine to give the acylguanidine of the formula l, where, in the compounds of the formulae Ill, IX and XI,

R1 to R3 are each as defined in formula | and

R6 is alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

The present invention also relates to a process for preparing the compounds of the formula

O NH,

Pon

R1 N—R3 !

R2 o where

R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2, 2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms;

R3 is Alk-R4 or trifluoromethyl;

Alk is alkyl having 1, 2, 3 or 4 carbon atoms;

R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; wherein, as shown in scheme 4,

0

Im.

Nso NH,

R1 - ° Le

R2 vin R2 1x OH 0 «.N

N~ | R6

R1 o

R2 x OH

R2 x1 OH 0 0

H,NR3 | R6 ll AB OH

R1 o R1 N—R3

R2 R2 0

Xit HN, Xt . > | B x CNL 0] ? NH 2 R7 = B,C

Sa -— Rf N—R3

R1 N—R3

R2 lo]

R2 0)

I XIV

Scheme 4 a) the nitro compounds of the formula VIII is converted to the amine of the formula 1X, b) the amine of the formula IX is converted to the diazonium salt of the formula X, c) the diazonium salt of the formula X is reacted with an alkyl acrylate to give the cinnamic acid derivative of the formula XI, d) the compound of the formula Xl is converted to the amide of the formula Xl and e) the compound of the formula Xll is converted to the acylguanidine of the formula |, either by converting the compound of the formula XII in the presence of a base to the isoindolone derivative of the formula XIII and subsequently by reaction with guanidine with activation to give the acylguanidine of the formula | (alternative A), or, after formation of the isoindolone derivative of the formula XII, in the presence of g base, from the compound of the formula Xl, by converting the compound of the formula Xl to the ester of the formula XIV and subsequently by reacting with ® guanidine to give the acylguanidine of the formula | (alternative B), or by converting the compound of the formula XII in the presence of a strong base to the ester of the formula XIV and subsequently by reacting with guanidine to the acylguanidine of the formula | (alternative C), or by directly reacting the compound of the formula XII with guanidine in the presence of a base with simultaneously proceeding guanylation and cyclization to give the isoindolone of the formula | (alternative D), where, in the compounds of the formulae VIII, IX, X, XI, Xil, Xlll and XIV,

R1 to R3 are each as defined in formula | and

R6 and R7 are each independently alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

The nitro compounds of the formula Vill may be reduced by known methods (for example described in “Houben-Weyl, Methoden der organischen Chemie“, Volume

Xi/1, Nitrogen compounds Il, Georg Thieme Verlag Stuttgart, 1957, p. 360ff) to the aniline of the formula IX. Preference is given to catalytic hydrogenation, for example using Pd/C, for example using 5% Pd/C or 10% Pd/C, in a solvent, for example an alcohol, preferably ethanol, under a hydrogen atmosphere of from 1 bar to 200 bar pressure, preferably from 1 bar to 10 bar of pressure.

The subsequent diazotization of the aniline of the formula IX is effected in an inert solvent, preferably ethanol, in the presence of an acid whose anion does not substitute the diazonium ion itself, for example HBF4 or HPFg, preferably HBF4, or, for example, H.SO,4 and in the presence of a nitrite, preferably NaNO», at a temperature between -30°C and the boiling point of the solvent, preferably between 0°C and 30°C.

The diazonium salt of the formula X is preferably reacted directly with a (C1-C4)-alkyt acrylate, preferably ethyl acrylate, in the presence of a palladium catalyst, preferably

Pd(OAc)2, at a temperature between 0°C and the boiling point of the solvent, preferably between 45°C to 55°C, to give the cinnamic acid derivative of the formula XI. : fa IN ® The benzoic acid function of the compound of the formula XI may be converted to the amide of the formula XII by methods known to those skilled in the art, preferably via the acid chloride or with the aid of DCC. This reaction may also be conducted in such a way that the amide of the formula Xll is cyclized in the reaction mixture directly to the ester of the formula XIV, i.e. the reaction of the compound of the formula XI to give the ester of the formula XIV is carried out in one step. This may be done either under the basic reaction conditions of amide formation or the cyclization may be brought about by adding a base, for example triethylamine, Hinig's base or potassium tert-butoxide. A further alternative consists in converting the compound of the formula XI directly to the compound of the formuia | by successively carrying out amide formation, cyclization and guanidation in the same reaction vessel, in which case the reaction may be effected without isolating intermediates.

For the further conversion of the compound of the formula XII to the acylguanidine of the formula | there are 4 alternatives:

Alternative A: The conversion of the amide of the formula XII is preferably effected using aqueous alkali solution, preferably aqueous NaOH solution, in a solvent such as an alcohol, preferably methanol or ethanol, at a temperature between -30°C and the boiling point of the solvent, preferably at RT. Both the hydrolysis of the ester function and the cyclization to the isoindolone derivative of the formula XlI| take place. The compound of the formula XIII is activated for acylation by commonly known processes (and as described for scheme 1), for example using the acid chloride or with DCC, and the acylguanidine of the formula | is obtained.

Alternative B: As in alternative A, the carboxylic acid of the formula XIII is synthesized. Subsequently, standard processes for ester preparation, preferably using SOCI> in an alcohol such as methanol or ethanol, are used to prepare, for example, the methyl or ethyl ester of the formula XIV. The ester of the formula XIV is subsequently converted to the acylguanidine of the formula | as described for scheme 1.

Alternative C: The conversion of the amide of the formula XII is effected in a solution ® of a strong base, preferably methoxide or t-butoxide in an alcoho! such as methanol or ethanol, and the methyl or ethyl ester of the formula XIV is obtained. The conversion of the ester of the formula XIV to the acylguanidine of the formula | is effected as described for scheme 1.

Alternative D: The amide of the formula Xl is converted under customary conditions for the acylation of guanidine. The solvent used is an inert solvent such as an ether, hydrocarbon or halogenated hydrocarbon, preferably DMF. Typically, a guanidinium salt is initially reacted with a strong base, preferably KOtBu, which releases the free guanidine. The mixture is added to the solution of the compound of the formula XII in a solvent such as an alcohol, ether, hydrocarbon or halogenated hydrocarbon, for example DMF, NMP or 2-propanol. In the course of the addition, the guanylation and the cyclization to the isoindolone of the formula | occurs simultaneously. In one variant, the compound of the formula Xl is cyclized to the compound of the formula

XIV and then converted in situ to the compound of the formula | successively in time using a catalytic amount of a strong base, for example potassium tert-butoxide or sodium methoxide or sodium ethoxide, in a solvent, for example DMF, NMP or 2-propanol.

Preference is given to alternative D in which the conversion of the benzoic acid derivative of the formula Xl is carried out in a one-pot process to give acylguanidine of the formula |.

The process steps described in scheme 2 may be effected continuously or batchwise. A workup of the reaction mixture may be effected after any of the process steps. The workup and, if desired, the purification of the products is effected by the customary methods such as extraction, pH separation, chromatography or crystallization and the customary dryings.

The starting compounds of the formulae Ill and Viil are commercially available or can be prepared according to or in a similar manner to the processes described in the literature and known to those skilled in the art.

The invention also provides compounds of the formula XII _ 0

R6

R1 0

R2 x HN where

R1andR2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms;

R3 is Alk-R4 or trifluoromethyl;

Alk is alkyl having 1, 2, 3 or 4 carbon atoms;

R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;

R6 is alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

Also claimed is the use of the compounds of the formula Xl as a synthetic intermediate.

Compounds of the formula 1 in enantiomerically enriched or in enantiomerically pure form may advantageously be prepared by a novel optical resolution process which likewise forms part of the subject matter of the present invention. To this end, the racemates of the compounds of the formula | are crystallized as salts of 2,3-O- acylated D- or L-tartaric acid, in the course of which the enantiomers are enriched in the crystal or in the mother liquor. Subsequently, the free bases are released again from the salts.

The present invention thus relates to a process for isolating compounds of the formula la and Ib

O NH, O NH, = =

PS i A Pon

R1 N—R3 la R1 Lp Ib

R2 O R2 O where

R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms; :

R3 is Alk-R4 or trifluoromethyl;

Alk is alky! having 1, 2, 3 or 4 carbon atoms;

R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; which comprises, as shown in scheme 5,

O NH, 0 NH, 0 NH, - i Lo om NZ nk, A 2 R* ; _ — N—R3 + N~R3 ol R3 R1 R*/2 a x R¥2

RO 0 R2 o R2 ©

XVa XVb } { 0 NH 0 NH, 2

Pn A on ~~

R1 N—R3 R1 go. N—R3

Scheme 5 a) converting the compound of the formula | to salts of a 2,3-O-acylated D- or

Claims

What is claimed is:

1. A process for preparing compounds of the formula | © Zo «J. Udo 8 Nd NH, R1 N—R3 R2 0 where R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms; R3 is Alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 carbon atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; which comprises OH H a SN a Lp R2 o R2 0 Vv VI 0 O NH, A R5 N” “NH, R2 0) R2 o vil a) formylating the amide of the formula IV and then cyclizing to the compound of the formula VI,

b) reacting the compound of the formula VI with an alkoxycarbonylmethylene- triphenylphosphorane, with a 1-alkoxy-1-trimethylsiloxyethylene or with a trialkyl ® phosphonoacetate to give the compound of the formula VII, and c) reacting the compound of the formula VII with guanidine to give the compound of the formulal, where, in the compounds of the formulae IV, VI and VII, R1 to R3 are each as defined in formula | and RS is alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

2. The process for preparing compounds of the formula | as claimed in claim 1 where R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2 2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms; R3 is Alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 carbon atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; wherein

H —_— N— ng + HN os fl R3 ® R2 o R2 o fl 1] (\V; CHO OH H —_— ofr Lf — wT ge R2 0 R2 lo) \Y \Z 0 O NH, PN R5 N” TNH, R2 0 R2 0 vii a) the compound of the formula Il is reacted with the amine of the formula Ill to give the amide of the formula IV, b) the amide of the formula IV is formylated at the ortho-position to the amide function to give the formyl amide of the formula V, c) the formyl amide of the formula V is cyclized to the compound of the formula VI, d) the compound of the formula VI is reacted with an alkoxycarbonylmethylenetriphenylphosphorane, with a 1-alkoxy- 1-trimethylsiloxyethylene or with a trialkyl phosphonoacetate to give the compound of the formula VII and e) the compound of the formula VII is reacted with guanidine to give the compound of the formula |, where, in the compounds of the formulae Il, Ill, IV, V, VI and VII, R1 to R3 are each as defined in formula I, R5 is alkoxy having 1, 2, 3 or 4 carbon atoms and X is Cl, Br, OH or alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

3. The process as claimed in claim 1 and/or 2, in which the process steps are i 55 each independently conducted continuously or batchwise.

® 4. The process as claimed in one or more of claims 1, 2 or 3, wherein the compound of the formula | is defined as N-{2-[3-ox0-2-(2,2,2-trifluoroethyl)- 6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)acetyl}guanidine, and pharmaceutically acceptable salts thereof.

S. A process for preparing compounds of the formula NT NH, R1 N—R3 R2 0 where R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2, 2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms; R3 is Alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 carbon atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; which comprises 0 ? NH R6 H NR3 2 NH 2 = 2 if v= R1 NH, 0 — Ri 0 — RT N—R3 Re OH R2 OH R2 lo) IX XI I a) reacting the amine of the formula IX via a diazonium salt with an alkyl acrylate to give the cinnamic acid derivative of the formula XI, C b) reacting the compound of the formula XI with the amine of the formula Ill and with guanidine to give the acylguanidine of the formula |, where, in the compounds of the formulae lll, IX and XI, 2 0 i 2 ’ 3 “ < 7 er R1 to R3 are each as defined in formula | and R6 is alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

6. The process for preparing compounds of the formula | as claimed in claim 5 where R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifiucroethyi or alkyl having 1, 2, 3 or 4 carbon atoms; : R3 is Alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 carbon atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof, wherein

. 0

I. Neo NH, R1 —_— ® 0 le R2 vig oH R2 x OH 0 NN | R6 R1 o R2 x OH RZ XI OH 0 0 H,NR3 | R6 mn AB OH R1 o R1 N—R3 R2 R2 0] XH HNS 4 Xi 3% k A C Nl o ? NH 2 R7 = B,C A ~—— RI N—R3 R1 N—R3 R2 lo) R2 lo] XIV a) the nitro compounds of the formula Vil is converted to the amine of the formula IX, Db) the amine of the formula IX is converted to the diazonium salt of the formula X, c) the diazonium salt of the formula X is reacted with an alkyl acrylate to give the cinnamic acid derivative of the formula XI, d) the compound of the formula XI is converted to the amide of the formula XII and e) the compound of the formula XII is converted to the acylguanidine of the formula |, either by converting the compound of the formula XII in the presence of a base to the isoindolone derivative of the formula Xl and subsequently by reaction with guanidine with activation to give the acylguanidine of the formula | (alternative A), or, after formation of the isoindolone derivative of the formula Xlll, in the presence of g

°8 = 2008/6730 base, from the compound of the formula XI, by converting the compound of the formula XIII to the ester of the formula XIV and subsequently by reacting with o guanidine to give the acylguanidine of the formula | (alternative B), or by converting the compound of the formula XII in the presence of a strong base to the ester of the formula XIV and subsequently by reacting with guanidine to the acylguanidine of the formula | (alternative C), or by directly reacting the compound of the formula XII with guanidine in the presence of a base with simultaneously proceeding guanylation and cyclization to give the isoindolone of the formula | (alternative D), where, in the compounds of the formulae VII, 1X, X, XI, XII, XII and XIV, R1 to R3 are each as defined in formula | and R6 and R7 are each independently alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

7. The process as claimed in claim 6, wherein, in process step e), alternative D is used.

8. The process as claimed in claim 6 and/or 7, in which process steps d) and e) are carried out in a one-pot process.

9. The process as claimed in claim § and/or 6, in which the process steps are each independently conducted continuously or batchwise.

10. The process as claimed in one or more of claims 5 to 9, wherein the compound of the formula | is defined as N-{2-[3-ox0-2-(2,2,2-trifluoroethyl)-6-trifluoromethyl- 2,3-dihydro-1H-isoindol-1-ylJacetyi}guanidine, and pharmaceutically acceptable salts thereof.

11. A compound of the formula XI

ES VPP I ® ror R1 0] R2 HN. XII R3 where R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms; R3 is Alk-R4 or trifluoromethyi; Alk is alkyl having 1, 2, 3 or 4 carbon atoms; R4 is hydrogen, trifluoromethyl! or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; R6 is alkoxy having 1, 2, 3 or 4 carbon atoms; and salts thereof.

12. A compound of the formula Xll as claimed in claim 11 for use as a synthetic intermediate.

13. A process for isolating compounds of the formula la and Ib 7 PS ~ N” TNH, <~ TN” TNH, R1 N—R3 la of poe Ib R2 O R2 0 where R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2, 2-trifluoroethyl or alkyl having 1, 2, 3 ® or 4 carbon atoms; R3 is Alk-R4 or trifluoromethyl; Alk is alkyl having 1, 2, 3 or 4 carbon atoms; R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; and salts thereof; which comprises

O NH O NH, O NH, Pn Pn, AP, : 5 : R* > : R1 N-R3 —= RI N-Re x + nL, x R2 0] R2 0 . R2 0 ob O NH, i Ho AA R1 N—R3 R1 HL RZ ) R2 © la Ib a) converting the compound of the formula | to salts of a 2,3-O-acylated D- or L-tartaric acid and obtaining the two salts of the formulae XVa and XVb separately by crystallization, and b) releasing the free bases of the formulae la and Ib from the two salts of the formulae XVa and XVb respectively, where, in the compounds of the formulae |, XVa and XVb, R1 to R3 are each as defined in the formulae la and Ib R* is

J xX ® ore 0 R8 HO,C HO,C._ _~ 2 eos or 2 7 coH O° O° R8 R8 R8 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents from the group of F, Cl, Br, |, alkyl having 1, 2, 3 or4 carbon atoms or alkoxy having 1, 2, 3 or 4 carbon atoms.

14. The process as claimed in claim 13, wherein the undesired enantiomer of the formulae la or Ib is racemized again.

15. The process as claimed in claim 13 and/or 14, wherein the compounds of the formulae la and Ib are (R)-N-{2-[3-o0x0-2-(2,2,2-trifluoroethyl)-6-trifluoromethyl-2,3- dihydro-1H-isoindol-1-ylJacetyl}guanidine and (S)-N-{2-[3-0x0-2-(2,2,2-trifluoroethyl)- 6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl]acetyl}guanidine.

16. A compound of the formula XVa and/or XVb O NH, 0 NH, A MAA N~ TNH, "NT UNH, R1 N—R3 R1 N—R3 x R¥/2 x R¥/2 R2 Oo R2 O XVa XVb where R1 and R2 are each independently hydrogen, F, Cl, trifluoromethoxy, 2,2,2-trifluoroethoxy, trifluoromethyl, 2,2,2-trifluoroethyl or alkyl having 1, 2, 3 or 4 carbon atoms; R3 is Alk-R4 or trifluoromethyl;

EL CE Alk . is alkyl having 1, 2, 3 or 4 carbon atoms; ) I R4 is hydrogen, trifluoromethyl or cycloalkyl having 3, 4, 5, 6 or Qo 7 carbon atoms; R* is i x ore 0” "R8 HO,C HO,C._ _~ 2 aos or 2"coH O° oN ° R8 R8 R8 is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 substituents from the group of F, Ci, Br, |, alkyl having 1, 2, 3 or 4 carbon atoms or alkoxy having 1, 2, 3 or 4 carbon atoms.

17. (S)-N-{2-[3-0x0-2-(2,2,2-trifluoroethyl)-6-trifluoromethyl-2,3-dihydro-1H- isoindol-1-yl]acetyl}guanidine hydrogenfumarate hydrate of the formula XVi FF A N" NH, 0) : = OH “Cry Fx er X H,0 © O F

18. A compound of the formulae XVa or XVb as claimed in claim 16 or of the formula XVI as claimed in claim 17 for use as a medicament.

19. 19. The use of a compound of the formulae XVa and/or XVb as claimed in claim 16 or of the formula XVI as claimed in claim 17, alone or in combination with other medicaments or active ingredients, for producing a medicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic or by reperfusion events, for the treatment or prophylaxis of arrhythmias, of life-threatening cardiac ventricular fibrillation, of myocardial infarction, of angina pectoris, for the treatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and tissues, for the treatment or prophylaxis of states of shock, of diseases in which cellular proliferation represents a [ primary or secondary cause, of cancer, of metastasis, of prostate hypertrophy and of prostate hyperplasia, of atherosclerosis or of disturbances of lipid metabolism, of high blood pressure, of essential hypertension, of disorders of the central nervous system, of disorders resulting from overexcitability of the CNS, epilepsy or centrally induced convulsions, of disorders of the central nervous system, especially of anxiety states, depressions or psychoses, for the treatment or prophylaxis of non- insulin-dependent diabetes mellitus (NIDDM) or late damage from diabetes, of thromboses, of disorders resulting from endothelial dysfunction, of intermittent claudicating, for the treatment or prophylaxis of fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels and fibrotic disorders of the heart, for the treatment or prophylaxis of heart failure or of congestive heart failure, of acute or chronic inflammatory disorders, of disorders caused by protozoa, of malaria or of coccidiosis in poultry, and for use for surgical operations and organ transplantations, for preserving and storing transplants for surgical procedures, for use in bypass operations, for use in resuscitation after cardiac arrest, for preventing age-related tissue change, for producing a medicament directed against aging or for prolonging life, for the treatment and reduction of cardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.

20. A medicine for human, veterinary and/or phytoprotective use, comprising an effective amount of a compound of the formulae XVa or XVb as claimed in claim 16 together with pharmaceutically acceptable excipients and additives.

21. A medicine for human, veterinary or phytoprotective use, comprising an effective amount of a compound of the formulae XVa or XVb as claimed in claim 16 together with pharmaceutically acceptable excipients and additives in combination with other pharmacological active ingredients or medicaments.

22. A medicine for human, veterinary and/or phytoprotective use, comprising an effective amount of a compound of the formula XVI as claimed in claim 17 together with pharmaceutically acceptable excipients and additives.

23. A medicine for human, veterinary or phytoprotective use, comprising an effective amount of the compound of the formula XVI as claimed in claim 17 together ® with pharmaceutically acceptable excipients and additives in combination with other pharmacological active ingredients or medicaments.