ZA200508486B - Guanidine derivatives and use thereof as neuropeptide FF receptor antagonists - Google Patents

Description

/ -

GUANIDINE DERIVATIVES AND THEIR USE AS NEUROPEPTIDE FF

RECEPTOR ANTAGONISTS

S

The present invention relates to guanidine derivatives of the general formula

HN

N a ® Sha

S

I in which

A represents a chain of 3-6 optionally substituted C atoms, one of which can be replaced by -N(R')- or -0-; and

R' represents hydrogen or a substituent; the ring skeleton containing only the two double bonds of the thiazole component ; pharmaceutically applicable acid addition salts of basic compounds of formula I, pharmaceutically applicable salts of acid group-containing compounds of formula I with bases,

C pharmaceutically applicable esters of hydroxy or carboxy group-containing compounds of formula I as well as hydrates or solvates thereof.

Guanidine derivatives of formula I which contain one or more asymmetric centres can be present as optically pure enantiomers, as mixtures of enantiomers, such as for example racemates, or optionally as optically pure diastereomers, as mixtures of diastereomers, as diastereomeric racemates or as mixtures of diastereomeric racemates.

® ®

The products defined at the outset are partly known and partly nowel, and they are characterized by valuable pharmacodynamic properties, acting as neuropeptide FE receptor antagonists.

In a first aspect the present invention relates to tle use of the compounds described at the outset of Formula I as well as tlhe salts, esters, hydrates and solvates likewise defined att the outset as neuropeptide FF receptor antagonist-s or for the preparation of corresponding medicinal products, in particular for the treatment of pain and hyperalgesia, withdrawal syndromes in the case of ( alcohol, psychotropic and nicotine dependences and for the improvemerat or elimination of these dependences, for the

I5 regulatiom of insulin secretion, food intake, memory functions, blood pressure, and of the electrolyte and energy bal ance and for the treatment of urinary incontinence or for the preparation of corresponding medicinal products.

The pains to be treated according to the invention can be chronic, a cute, long-lasting or temporary, these pain s being able to be of operative, traumatic, or patholog ical origin; an advantage achieved according to the invent ion consists im the prevention of opioid tolerance and/or [ opioid dep endence.

Back in 19 85 neuropeptide FF (NPFF; H-Phe-Leu-Phe-Gln -Pro-

Gln-Arg-Phe-NH, [99566-27-5]), an octapeptide, and neuropepticde AF (NPAF; H-Ala-Gly-Glu-Gly-Leu-Ser-Ser- _Pro-

Phe-Trp-Sex-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH, [99588-52-—0]), a related octadecapeptide, were discovered as neurotransrnitters of the central nervous system in cattle brains (Yarg et al., Proc. Natl. Acad. Sci. USA 1985, 82(22), 7757-61) and originally characterized as anti- opioid peptides. The carboxy-terminal amidated neuropepticles were, because of their reactivity with anti-

Phe-Met-Arg-Phe-NH, antiserum, included among the FMRF™-

® ® amide-like peptides. Both bept Edes have pain-modulating properties, the octapeptide hawing greater effectiveness.

Both peptides play an important. role both in opioid- dependent analgesia and in the development of tolerance to opioids (review article: Roumy and Zajac, Europ. J. Pharm. 1998, 345, 1-11; Panula et al., Prog. Neurobiol. 1996, 48, 461-87). Interestingly, in animal tests, NPFF shows, depending on the nature of the administration, both anti- opioid and pro-opioid actions. Thus NPFF can reverse the acute effects of opioids and ar increased concentration in the brain is possibly responsilble for the development of opicid tolerance and dependence. In rats, for example, the ( intracerebroventricular (i.c.v_.) administration of NPFF lowers the nociceptive threshold and reduces the analgesia induced by morphine. Administration of NPFF to morphine- tolerant rats causes symptoms of withdrawal phenomena. The analgesic effect of morphine ir morphine-tolerant rats was reproduced after i.c.v. injection of anti-NPFF IgG (Lake et al., Neurosci. Lett. 1991, 132, 29-32).

Immunoneutralization of NPFF bys intrathecally (i.t.) administered anti-NPFF antibodies increase the analgesia caused by endogenous and exogerious opioids. By direct injection of NPFF or NPFF-analogues into the spinal cord (i.t.) a pro-opioid effect with a long-lasting opioid-like analgesia and an increased pairi-relieving effect of ) morphine was obtained (Gouardérres et al., Eur. J.

Pharmacol. 1993, 237, 73-81; Kontinen and Kaso, Peptides 1995, 16, 973-977).

According to other reports NPFE also appears to play a role in physiological processes such as insulin secretion, regulation of food intake, memory functions, regulation of blood pressure and electrolyte balance (Panula et. al.,

Prog. Neurobiol. 1996, 48, 461-487).

In various types of mammal, such as humans, rats, mice and cattle, the discovery was reported of a gene, which codes

NPFF and NPAF as a common precursor protein, from which the

] two active peptides are finally split off (Perry et al.,

FEBS L.ett. 1997, 409, 426-30; Vilim et al. , Mol. Pharmacol. 1999, 55, 804-11). In humans the gene for this precursor is expressed both peripherally in various organs and in regiomms of the central nervous system, in particular in the cerebe=llum (Elshourbagy et al., J. Biol. Chem. 2000, 275 (34), 25965-71), while the expression in rats is restricted exclus-ively to specific regions of the central nervous systema such as the hypothalamus, medulla, and dorsal horn of thes spinal cord. On the basis of the demonstration of

NPFF in human blood plasma it is presumed, that the peptides are peripherally also responsible for hormone-like ® effect s (Sandblom et al., Peptides 1998, 19, 1165-70).

In tis sue samples from humans and rats two G-protein couple d receptors (GPCR), NPFF1l and NPFF2 were identified (Bonini et al., J. Biol. Chem. 2000, 275 (50), 39324-31;

Kotani et al., Br. J. Pharmacol. 2001, 133, 138-44), NPFF2 being identical to the receptor HLWAR77 or iginally described as an orphan (Elshourbagy et al. , J. Biol. Chem. 2000, 275 (34), 25965-71). NPFFl1l and NPFF2 were able to be charac terized as specific receptors with a ffinities in the nanomo lar and subnanomolar regions for the two neurop eptides FF and AF. NPFF binds to NPFFl with a binding constant Kd = 1.13 nM and to NPFF2 with Kd = 0.37 nM. The ® identi ty of NPFF1l and NPFF2 is around 50%. The comparison of the amino acid sequences with known GPCRs shows a 30-40% simila rity with human orexin-1, orexin-2, meuropeptide

Y (NPY) Y2, cholecystokinin A, NPY Y1, prolactin-releasing hormon-e receptor and NPY Y4. The distribut ion of NPFF1l and

NPFF2 din various tissue samples from humans and rats was determ ined by demonstrating the m-RNA using RT-PCR (reverse transcription-polymerase chain reaction). INPFF1 was demonstrated predominantly in the central mervous system (CNS) . By contrast, NPFF2 was found predomzDnantly in the spinal cord. These findings are supported by autoradiographic methods using selective NPFF1 and NPFF2 radiol jgands (Allard et al., Brain Res. 1989, 500, 169-176;

® ®

Neuroscience 1992, 49, 06-116, Gouardéres et al. ,

Neuroscience 2002 115:2 349-61).

The rmeuropeptides SF (NPSF, 37 amino acids) and neuropeptide VF (NPVF, octapeptide) described as NPFF- related peptides, both located on the so-called NIPVF-gene, bind with comparatively greater affinity and selesctivity to the INPFF1l receptor than NPFF and NPAV. The NPVF poeptides also block the morphine-induced analgesia in acut-e and inflammatory pain models more markedly than NPFF and emphasize the importance of the NPVF/FF1l system &as part of an emdogenous anti-opioid mechanism (Q. Liu et ak., J. o Biol . Chem. 2002,276 (40), 36961).

The incidence cof functional NPFF1l and NPFF2 receptors in adip ocytes and the effect of NPFF and NPAF on kew sites of sign al transmission in the adipose metabolism suggest that the two peptides, alongside their original pain-rnodulating effe cts, could also have an influence on the storage and use of body energy (I. Lefrére et al., J. Biol. «hem. 2002, 277 (42), 39169).

The desamino-Tyr-Phe-Leu-Phe-Gln-Pro-Gln-Arg-NH, peptide was described as the first NPFF-receptor antagon ist courateracting the NPFF effects. After i.c.v. inj ection this ® peptide reduced the withdrawal syndromes in the case of morphine dependence (Malin et al., Peptides 1991 , 12, 1011- 1014). However, this peptide showed no biocavaila bility whatever in the central nervous system. Optimiza_ tion of the tripeptide Pro-Gln-Arg-NH, in a combinative approach led to dansyl-Pro-Gln-Arg-NH,, or dansyl-Pro-Ser —Arg-NH,, bot with improved properties for passing through the blood-brain barrier, which, after systemic admiraistration in ats led to an improved antagonistic effect of the anti- opioid symptoms caused by NPFF (Prokai et al. J. Med. Chem. 20011, 44, 1623-1626).

A

® ® 6

The Arg-Tyr-amide peptoid BIBP3226 origin.ally described as an NPY Yl selective receptor antagonist s howed a 10-60 time=s higher affinity to the human and ra t-NPFFl receptor thara to the corresponding NPFF2 receptors (Bonini et al.,

J. Biol. Chem. 2000, 275 (50), 39324-31). From a series of compounds which originate from the NPY Y1 selective antagonist BIP3226, selective hNPFFl rece ptor antagonists were= obtained which showed affinities of 40-80 nM (Mol lereau et al., Europ. J. Pharmacol. 2 002, 45, 245-56).

The two neuropeptide FF analogues 1DME ([ D-

Tyr’, (Nme)Phe’]NPFF) and Nic-1DME (nicotin oyl-pro-1Dme) ( showed different pharmacological properti es in the mouse tail -flick test, although both compounds bind to NPFFl1 and

NPFF"2 with comparable affinity and select ivity. Both 1DME and Nic-1DME reinforce the morphine analg esia after i.t. and i.p. administration, but Nic-1DME can not suppress morprhine-induced analgesia after i.c.v. and i.p. admi nistration (Quelven et al., Europ. J. Pharmacol. 2002, 449, 91-98).

In WO 02/24192 Al synthetic NPFF ligands with a peptide structure, based on arginine as the centr al component, are desc ribed. ® The products defined at the outset are po tent and specific, low- molecular antagonists of neuropeptide FF1l receptors with non-peptide or non-peptoid structure s.

The current options for treatment of chromic pain are based on NSAIDs (non-steroidal anti-inflammator-y drugs), canadinoids and opioids. Thus, for example, morphine derivatives bind to the p-opiocid receptor and thereby have an amalgesic effect. Opioid binding to the p-opioid receptor involves the release of neuropeptide FF. Based on the animal experiments mentioned above it is presumed that the xeleased NPFF reduces the analgesic effect of the

® ® administered opioids and leads to tolerance to opioids. In order to obtain a constant analgesic effect with longer treatments, increasingly higher opioid doses must be administered as a result of this tolerance, which can finally lead to serious side effects. As already mentioned at the outset, as of today two neuropeptide FF receptors are known, the NPFF'1 receptor being located mainly in the central nervous sysstem and the NPFF2 receptor in the spinal cord in particular. Activation of the NPFF2 receptors shows an opioid-like analgesic effect. Blocking of the NPPF1 receptors by an antagonist prevents the development of tolerance to opioids and also increases their effect. ® As mentioned at thes outset, the products defined there are partly known and partly novel, and they are characterized by the valuable pharmacological property of blocking the interaction of neuropeptide FF with the neuropeptide FF1 receptor subtype.

If one or more of the C atoms in the chain A in formula I is/are substituted, then - one of the C atoms can carry one or two (i.e. geminal) identical or differ ent substituents; or - several of the C atoms can each carry one or two (i.e. geminal) identical «or different substituents. ® In Formula I, A together with the thiazole ring can form a cyclopentathiazole, benzothiazole, cycloheptathiazole, pyranothiazole, thiazolopyridine, thiazoloazepine or thiazolooxepane skeleton which contains only the two double bonds of the thiazole component, such as for example a 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H- cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole, 6,7- dihydro-4H-pyrano(4 ,3-d] thiazole, or 5,6,7,8-tetrahydro-4H- thiazolo[4,5-clazepine skeleton.

A subgroup of the compounds of Formula I can be represented by the general formula

® _

R, Rs HN

Ry N Pa

Ee

Ri Rs No ° n in which R,-R, mean hydrogen, alkyl, alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkanoyl, alkoxyal.kylcarbamoyl, alkoxya lkylthiocarbamoyl, alkoxycarbonyl, alkoxyc arbonylalkyl, alkoxycarbonylalkanoyl, alkylamido, alkylam inocarbonyl, alkylarylamino, alkylcarlamoyl, alkylth iocarbamoyl, alkylcarbonyl, alkylcarbonyloxy, alkylen edioxy, alkylsulphinyl, alkylsulphinyl alkyl, ® alkylsu lphonyl, alkylsulphonylalkyl, alkylthio, alkylsu lphonamido, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminoalkanoyl, aminoacyl, alkylamino, alkylam inocalkyl, alkylaminoalkanoyl, aminocar-bonyl, aminoca xbonylalkyl, aminocarbonylalkanoyl, alkylam inocarbonylamino, alkoxycarbonylamino, aryl, arylalkenyl, arylalkyloxy, arylalkyl, arylalkylamido, arylalkanoyl, arylamido, arylamino, aryl-amiraocarbonyl, arylcardPamoyl, arylthiocarbamoyl, aryloxy, aryloxyalkyl, aryloxyalkanoyl, aryloxyalkylamino, aryloxyal kylcarbamoyl, aryloxyalkylthiocarbamoyl, aryloxycarbonyl, aryloxye«<arbonylalkyl, aryloxycarbonylalkanoyl, aryloxye<arbonylalkylamino, aryloxycarbonylalkylcarbamoyl, ( aryloxyearbonylalkylthiocarbamoyl, arylsulphi.nyl, arylsulphinylalkyl, arylsulphonyl, arylsulphonylalkyl, arylsulphonylalkanoyl, arylsulphonamido, aryl thio, arylthieoalkyl, arylthiocalkanoyl, carboxy, carboxyl, carboxyalkyl, carboxyalkylamido, cyano, cyancalkyl, cyancalkylamido, cyancalkanoyl, cycloalkyl, cycloalkylamido, cyclcalkanoyl, cycloalkylami.no, cycloalkylaminocarbonyl, cycloalkyloxycarbony=l, cycloalkyloxycarbonylalkyl, cycloalkyloxy- carbonydalkylamido, cycloalkyloxycarbonylalka.noyl, dialkylaminocarbonyl, dialkylaminoalkyl, dialkylanmninoalkylamido, dialkylaminoalkanoyl, diarylamino, formyl, formylalkyl, halogen, halocalkoxy, hal ocalkyl,

_ haloal kylamido, haloalkanoyl, halo-alkylamirao, hetero arylamino, heterocarylamido, heterocycl.ylalkylamido, hetero arylaminocarbonyl, heteroaryloxycarboraylalkyl, hetero aryloxycarbonylalkylamido, hetero- aryloxycarbonylalkanoyl, heterocyclyl, hetexr-ocyclylamino, hetero cyclylamido, heterocyclylalkyl, heterocyclylalkanoyl, hetero cyclylalkylamino, heterocyclylalkylami do, hetero arylalkyl, heterocarylalkanoyl, heteroarylalkylamino, hetero arylalkylamido, heteroyclylalkylaminocarbonyl, hetero-cyclylalkoxycarbonylalkyl, heterocyclyslalkoxy- carbon ylalkanoyl, heterocyclylalkoxycarbonylalkylamino, heteroscyclylalkoxycarbonylalkylamido, hydroxy, o hydroxyalkyl, hydroxyalkanoyl, mercapto or nitro.

Prefer-red possible meanings for R, are methyl, ethyl, n- propyl , isopropyl, n-butyl, isobutyl, tert-loutyl, 1,1- dimeth.ylpropyl, or phenyl. If R,-R, are different from hydroagren, then they preferably mean methyl cr another low alkyl radical.

Anothesr subgroup of the compounds of Formulas I can be represented by the general Formula

HN

N He ® —(_I >

S im in whi.ch R' means alkyl, alkanoyl, alkenyl, alkinyl, alkoxy carbonylalkyl, alkoxycarbonylaminocalka&noyl, alkylcarbamoyl, alkoxycarbonylalkylcarbamoyl, alkoxy carbonylalkylthiocarbamoyl, alkylthio«arbamoyl, mono- or disubstituted aminoalkanoyl, aryl, arylalkyl, arylal koxycarbonyl, arylalkanoyl, arylcarbammoyl, alkoxywalkanoyl, alkylsulphonyl, arylthiocaramoyl, aryloxycarbonylalkyl, aryloxycarbonylalkano—vl, aryloxycarbonylalkylcarbamoyl, aryloxycarbomylalkylthio- carbamoyl, arylsulphonyl, cycloalkyl, cycloalkanoyl,

‘ ® _ 10 cycloalkylcarbamoyl, cycloalkylthiocarbamoyl, cycloalkylcarbonyl, cycloalkyloxycarbonylalkyl, cycloalkyloxycarbonylalkanoyl, cycloalkyloxycarbonylalkylcarbamoyl, cycloalkyloxycarbonylalkyl-tthiocarbamoyl, heterocarylalkyl, heterocyclylalkyl, heterocycilylalkoxycarbonylalkyl, heterocyclylalkoxycarbonylaXkanoyl, heterocyclylalkoxycarbonylal kylcarbamoyl, heterocyclylalkoxycarbonylalkylthiocarbamoyl, heterocaryloxycarbonylalkyl, hetero- aryloxycarbonylalkylcarbamoyl or ® heteroaryloxycarbonylalkyltlhiiocarbamoyl.

R' preferably means methyl, ethyl, propyl, hexyl, 2,2- dimethylpropionyl, cyclopropylmethyl, 2-cyclohexylethyl, propinyl, ethyloxycarbonylethyl, benzyl, n- butyloxycarbonyl, tert-butyl oxycarbonyl, benzyloxy- carbonyl, 3-methyl-butyryl, pentanoyl, phenylacetyl, 2- propyl-pentanoyl, cyclopropanecarbonyl, isobutyryl, but-3- enoyl, 2-methoxy-acetyl, propane-2-sulphonyl, butane-1- sulphonyl, methanesulphonyl, tert-butyloxycarbonyl- aminopropionyl or 4-dimethyl amino-butyryl.

The use according to the invention of the following compounds of Formula III is preferred:

C7) 2-guanidino-6, 7-dihydro-4H-t hiazolo[5,4-clpyridine-5- carboxylic acid tert-butyl ester;

N- (5-hexyl-4,5,6,7-tetrahydro-thiazolo(5,4-clpyridine-2- vl) -guanidine;

N- [5- (2-cyclohexyl-ethyl)-4, 5,6, 7-tetrahydro-thiazolol[5, 4- clpyridine-2-yl] -guanidine;

N- (5-ethyl-4,5,6,7-tetrahydr o-thiazolo[5,4-c]pyridine-2- yl) -guanidine; 2-guanidino-6, 7-dihydro-4H-t hiazolo[5,4-c]pyridine-5- carboxylic acid butyl ester;

N- [5- (propane-2-sulphonyl)-4 ,5,6, 7-tetrahydro-thiazolo[5,4- clpyridine-2-yll] -guanidine;

_

N- (5-phenylacetyl-4,5,6,7-tetrahydro~thiazolo(5,4- clpyridine-2-yl) -guanidine; 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]lpyridine-5- carboxylic acid benzyl ester;

N- (5-pentanoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine- 2-yl) -guanidine; 2-guanidino-6, 7-dihydro-4H-thiazolo[ 5,4-c]pyridine-5- thiocarboxylic acid propyl amide;

N- [5- (2-propyl-pentanoyl)-4,5,6,7-te trahydro-thiazolol[5,4- clpyridine-2-yl] -guanidine;

N- (5-benzyl-4,5,6,7-tetrahydro-thiazolo[5,4-clpyridine-2- vl) -guanidine; ® N- (5-prop-2-ynyl-4,5,6,7-tetrahydro- thiazolo|[5,4- clpyridine-2-yl) -guanidine;

N- (5-cyclopropanecarbonyl-4,5,6,7-te trahydro-thiazolo([5,4- clpyridine-2-yl)} -guanidine;

N- [5- (butane-1-sulphonyl)-4,5,6,7-te trahydro-thiazolol[5, 4- clpyridine-2-yl] -guanidine;

N- (5-isobutyryl-4,5,6,7-tetrahydro-t hiazolo[5,4-c]pyridine- 2-yl) -guanidine;

N-[5-(2,2-dimethyl-propionyl)-4,5,6, 7-tetrahydro- thiazeolo[5,4-clpyridine-2-yl] -guanid ine; 2-guanidino-6,7-dihydro-4H-thiazolo[ 5,4-clpyridine-5- thiocarboxylic acid benzyl amide; 2-guanidino-6,7-dihydro-4H-thiazolo[ 5,4-c]pyridine-5- ® carboxylic acid tert-butyl amide;

N- (5-but-3-enoyl-4,5,6,7-tetrahydro- thiazolo([5,4- clpyridine-2-yl) -guanidine;

N- (5-benzyl-5,6,7,8-tetrahydro-4H-th iazolo[4,5-clazepine-2- yl) -guanidine; 3-(2-guanidino-6, 7-dihydro-4H-thiazolo [5,4-clpyridine-5- vl) -propionic acid ethyl ester; 2-guanidino-6,7-dihydro-4H-thiazolo [5,4-c]pyridine-5- carboxylic acid pentyl amide;

N-[5- (2-methoxy-acetyl)-4,5,6,7-tetrahydro-thiazolol[5,4- clpyridine-2-yl]-guanidine;

N- (5-cyclopropylmethyl-4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridine-2-yl) -guanidine;

® ® . PEE 23.86

N- (5-methanesulphonyl-4, 5, 6, 7- tet rahydro- thiazolo(5,4- clpyridine-2-yl) -guanidine;

N- [5- (3-methyl-butyryl)-4,5,6,7-tetrahydr o-thiazolo(5,4- clpyridine-2-yl] -guanidine; 2-guanidino-6, 7-dihydro-4H-thiazolo[5,4-c]pyridine-5- thiocarboxylic acid- (2-methoxy-1l-methyl-ethyl) -amide; 2-guanidino-6, 7-dihydro-4H-thiazolo[5,4-c]lpyridine-5- carboxylic acid phenyl amide; [3- (2-guanidino-6, 7-dihydro-4H-thiazolo [5 ,4-c]lpyridine-5- yl) -3-oxo-propyl] -carbamic acid tert-butyl ester;

N- [5- (4-dimethylamino-butyryl)-4,5,6, 7-tetrahydro- thiazolo[5,4-c]pyridine-2-yl] -guanidine; ® N- (5-propyl-4,5,6,7-tetrahydro-thiazolo[S,4-clpyridine-2- vl) -guanidine; and 2-guanidino-6, 7-dihydro-4H-thiazolo[5,4-c]pyridine-5- thiocarboxylic acid isopropyl amide.

Compounds of the Formula I defined at the outset in which A means a chain of 3-6 optionally substituted C atoms, one of which can be replaced by -0-, the ring skeleton containing only the two double bonds of the thiazole component; pharmaceutically applicable acid additiom salts of basic compounds, pharmaceutically applicable s alts of acid group- containing compounds with bases, pharmac eutically 2S applicable esters of hydroxy or carboxy group-containing ® compounds as well as hydrates or solvate s thereof; with the exception of - N-(4,5,6,7-tetrahydro-benzothiazole -2-yl)-guanidine; - (2-guanidino-4,5,6,7-tetrahydro-ben zothiazole-4-yl) - ethyl acetate ethyl ester; - N- (4-hydroxymethyl-4,5,6,7-tetrahydro-benzothiazole-2- yl) -guanidine; - N- (4-tosyloxymethyl-4,5,6,7-tetrahydro-benzothiazole- 2-y1l) -guanidine; - N- (4-azidomethyl-4,5,6,7-tetrahydro-benzothiazole-2- yl) -guanidine; - N- (4-aminomethyl-4,5,6,7-tetrahydro-benzothiazole-2- yl) -guanidine; and

® ® - N- (6~a.cetylaminomethyl-4 pM ,6,7-tetrahydro- benzothiazole-2-yl) -guanidine; are novel.

In a further aspect the present invention thus comprises these novell substances as such and as therapeut ic active ingredientss; methods for their preparation; medicinal products, containing one of the above novel sub stances; the preparatior of such medicinal products; and the use of these novell substances as neuropeptide FF recepstor antagonists or for the preparation of correspormding medicinal poroducts according to the first aspect described 9® above of the present invention.

In the novel compounds defined above of Formula I, in chain

A

- one of the C atoms can carry one or two (i.e. gemin al), identical or different substituents; or - sever al of the C atoms can each carry one or two (i.e. gemin al), identical or different substituents.

The substi tuent(s) can be selected from alkyl, alkenyl, cycloalkenyl, aryl, heteroaryl , aralkyl, alkoxycarbonyl, carboxamido, cyano or cyanolakwyl groups and/or from polymethyl groups linked with one and the same

C C atom.

In particular the substituent (s) can be select ed from - methyl, ethyl, n-propyl, isopropyl, n-but—wyl, isobutyl, sec-lIoutyl, tert-butyl, 1,1-dimethylpropyl , allyl and cyclohex-1-enyl groups; and/or - phenys/1, o-tolyl, m-tolyl, p-tolyl, 2-ethy lphenyl, 3- fluoxrophenyl, 4-fluorophenyl, 4-chlorophe nyl, 4- cyanophenyl, 4-benzyloxyphenyl, 3-methoxy phenyl, 4- methoxyphenyl, 3,4-dimethoxyphenyl, 3,4- methylenedioxyphenyl and bis-3,5-trifluor-omethylphenyl groupos; and/or - thiophene-2-yl1 and benzyl groups; and/or

® ® - ethoxycarbonyl groups; and/or - n-p ropylamino, benzylamino, N-methyl-N-phenethyslamino, 3-m ethylbutylamino, phenylamino, N-butyl-N-ethyslamino, di- n-propylamino, allylamino, piperidine-1 and mor-pholine-4-carbonyl groups; and/or - cyano and cyanoethyl groups; and/or - peratamethylene groups linked with one and the same C atom.

Novel compounds are preferred in which there is loc ated on one and the same C atom on the one hand a phenyl gr oup and

PS on the other hand an ethoxycarbonyl, cyano or phenyl group.

Quite particularly preferred novel substances are:

N-(5-ethyl-5-methyl-4,5,6,7-tetrahydro-benzothiazol e-2-yl)- guanidime and its formate;

N-(5,5-dimethyl-4,5,6,7-tetrahydro-benzothiazole-2—vyl)- guanidime and its formate;

N-(5,5~ dimethyl-6-phenyl-4,5,6,7-tetrahydro-benzothiiazole- 2-yl) -guanidine and its formate;

N- (4-tert-butyl-4,5,6,7-tetrahydro-benzothiazole-2—yl)- guanidi ne;

N- (6-ismopropyl-4,5,6,7-tetrahydro-benzothiazole-2-=1) - guanidi.ne;

N-(5,5, 7-trimethyl-4,5,6,7-tetrahydro-benzothiazole-2-yl)- @® guanidi ne;

N-(6,6—dimethyl-4,5,6,7-tetrahydro-benzothiazole-2 -yl1)- guanidine;

N- (5-butyl-5,6,7,8-tetrahydro-4H-cycloheptathiazol -2-yl)- guanidine;

N-(4-etthyl-4-methyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) - guaniddne;

N-[6- (3, 4-dimethoxyphenyl) -4,5,6,7-tetrahydro- benzothiazole-2-yl] -guanidine and its formate;

N-(5-bwutyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) — guanid ine;

N-(6-phenyl-4,5,6,7-tetrahydro-benzothiazole-2-ylw - guanid ine;

' ®

N-(5-methyl-4,5,6,7 ~tetrahydro-benzothiazole-2-yl) - guanidine;

N-(4-methyl-4-propyl-4,5,6,7-tetrahydro-benzothiazole-2 ~ v1) -guanidine;

N-(6-propyl-4,5,6,7 -tetrahydro-benzothiazole-2-yl) - guanidine;

N- (4-cyclohex-1-eny 1-4,5,6,7-tetrahydro-benzothiazole-2 - v1) -guanidine and i ts formate;

N-(4-sec-butyl-4,5, 6,7-tetrahydro-benzothiazole-2-yl) - guanidine and its Formate; and

N- (4-isobutyl-4-met-hyl-4,5,6,7-tetrahydro-benzothiazole-2-

PN yl) -guanidine.

Other particularly preferred novel substances are:

N-(6-tert-butyl-4,5,6,7-tetrahydro-benzothiazole-2-y1l) — guanidine; 2-guanidino-6-phenwyl-4,5,6,7-tetrahydro-benzothiazole-&- carboxylic acid ethyl ester and its formate;

N-[6-(1,1-dimethyl —propyl)-4,5,6,7-tetrahydro- benzothiazole-2-yl]-guanidine;

N-(7-methyl-4,5,6, 77-tetrahydro-benzothiazole-~-2-yl) - guanidine and its formate;

N-[6-(3-methoxy-ph enyl)-4,5,6,7-tetrahydro-benzothiazole-2- vl] -guanidine and its formate;

N-(6-thiophene-2-y1-4,5,6,7-tetrahydro-benzothiazole-2 -yl)-

C guanidine and its formate;

N-(5,5,7,7-tetrame=thyl-4,5,6,7~-tetrahydro-benzothiazol e-2- vl) ~guanidine;

N- [6-(4-fluoropherayl)-4,5,6,7-tetrahydro-benzothiazole-2- yl]l-guanidine and its hydrobromide; 2-guanidino-4,5,6, 7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester a&nd its hydrobromide;

N-(4,4-dimethyl-4 _.5,6,7-tetrahydro-benzothiazole-2-yl1J - guanidine;

N-(4-methyl-4,5,6 _7-tetrahydro-benzothiazole-2-yl)- guanidine and its formate;

N-(4,5,6,7-tetrahvydro-benzothiazole-2-yl-4-spiro- cyclohexane) -guanzidine and its formate;

N-(5,6,7,8-tetrahydro-4H-cycloheptathiazol-2-y1) —guanidine;

N- (4 -allyl-4,5,6,7-tetrahydro-benzothiazole-2-yl» guanidine and its formate;

N- (6& -methyl-4,5,6,7-tetrahydro-benzothiazole-2-y1) -

S guaraidine;

N- [&-(3-fluorophenyl)-4,5,6,7-tetrahydro-benzothdazole-2- yl] —guanidine and its formate;

N- (6-cyano-6-phenyl-4,5,6,7-tetrahydro-benzothia=ole-2-y1)- guanidine and its hydrcbromide;

N-(4a-phenyl-4,5,6,7-tetrahydro-benzothiazole-2-y1)- guanidine and its formate; and

N-(&,6-diphenyl-4,5,6,7-tetrahydro-benzothiazole -2-y1) -

C guanidine and its formate.

Nove=l substances which are also preferred are:

N-[«- (4-methoxy-phenyl) -4,5,6,7-tetrahydro-benzo-thiazole-2- v1] -guanidine and its hydrobromide;

N- ( 5-phenyl-5,6,7,8-tetrahydro-4H-cycloheptathia zol-2-yl) - guamidine and its hydrobromide;

N-( 6,7-dihydro-4H-pyrano[4,3-dlthiazol-2-yl) -guanidine;

N- ( 6-benzo[1,3]dioxol-5-y1-4,5,6,7-tetrahydro- ben zothiazole-2-yl) -guanidine and its formate; 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl amide and its formate;

N-[ 6- (4-cyanophenyl)-4,5,6,7-tetrahydro-benzothi_azole-2- o vl] -guanidine and its formate;

N-( 4-benzyl-4,5,6,7-tetrahydro-benzothiazole-2-ywl) - guanidine and its formate;

N- (5-methyl-5-phenyl-4,5,6,7-tetrahydro-benzothiazole-2- yl) -guanidine and its formate;

N-[6-(3,5-to-trifluoromethylphenyl)-4,5,6, 7-tetxahydro- berazothiazole-2-yl] -guanidine and its formate;

N- €6-0-tolyl-4,5,6,7-tetrahydro-benzothiazole-2 —yl) - guanidine and its formate;

N-«6-m-tolyl-4,5,6,7-tetrahydro-benzothiazole-2 —yl)- guanidine and its formate;

N- T6-(2-ethyl-phenyl)-4,5,6,7-tetrahydro-benzothiazole-2- v1}X -guanidine and its formate;

® ®

N- [6 —~ {4-chlorophenyl)-4,5,6, J tetrahydro-benzothiazole-2- yl] -guanidine and its formate; 2-guanidino-4,5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid benzyl amide and its formate;

N-(5,6-dihydro-4H-cyclopentathiazol-2-yl) -cguanidine;

N- [6 (4-benzyloxy-phenyl)-4,5,6, 7-tetrahyd-ro-benzothiazole- 2-y1l] -guanidine and its hydrobromide; 2-guanidino-4,5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid methyl phenethyl amide and its format e;

N-(6 ~phenyl-4,5,6,7-tetrahydro-benzothiazo le-2-yl-4-spiro- cyclohexane) -guanidine and its hydrobromid. e;

N- (6 -p-tolyl-4,5,6,7-tetrahydro-benzothiaz ole-2-yl) - ® guan idine and its formate 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid -(3-methyl-butyl)-amide and its format.e; and

N- (4 -tert-butyl-6-phenyl-4,5,6,7-tetrahydr-o-benzothiazole- 2-yl )-guanidine.

Other representative examples of the novel substances are: 2-guanidino-4,5, 6, 7-tetrahydro-benzothiazole-6-carboxylic acid phenyl amide and its formate; 2-guianidino-4,5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid butyl ethyl amide and its formate;

N-[4-(2-cyano-ethyl)-4,5,6,7-tetrahydro-benzothiazole-2- yl] —guanidine and its formate; ® 2-guanidino-4,5,6, 7-tetrahydro-benzothiazele-4-carboxylic acid ethyl ester and its hydrobromide; 2-guanidino-4,5,6, 7-tetrahydro-benzothiaz-ole-4-carboxylic acid dipropyl amide and its formate; 2-gwuanidino-4,5,6,7-tetrahydro-benzothiaz ole-4-carboxylic acid phenyl amide and its formate; 2-guanidino-4,5, 6, 7-tetrahydro-benzothiaz ole-6-carboxylic acid allyl amide and its formate; 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid propyl amide and its formate;

N-[ 4-(piperidine-1l-carbonyl)-4,5,6,7-tetrrahydro- benzothiazole-2-yl] -guanidine and its formate;

° ® 2-guanidino-4,5, 6, 7-tetrahydro-benzotiniazole-4 -carboxylic acid allyl amide and its formate; 2-guanidino-4,5,6, 7-tetrahydro-benzotliiazole-6-carboxylic acid- (3-methyl-butyl)-amide and its formate;

N-[4-(morpholine-4-carbonyl)-4,5,6,7-t-etrahydro- benzothiazole-2-yl]-guanidine and its formate; and 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid diisopropyl amide and its formate.

The term "alkyl", alone or in combination, describes a linear ox branched hydrocarbon radical with 1-8 C atoms. @® Representative, but not limitative, examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n—butyl, tert-butyl, isobutyl (or 2-methylpropyl), n-pentyl ( or n-amyl), isopentyl (or isoamyl), n-hexyl n-heptcyl, n-octyl and the like. The alkyl radical can carry one or more substituents which are selected independently of each other from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alky-lsulphinyl, alkylsulphinylalkyl, alkylsulphonyl, &a&lkylsulphonylalkyl, alkylthio, alkylthiocalkyl, alkynyl, armnino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, ar-yl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, ary loxycarbonyl, @ aryloxycarbonylalkyl, arylsulphinyl, arylsulphinylalkyl, arylsulphonyl, arylsulphonylalkyl, arylthio, arylthioalkyl, carboxy, carboxyalkyl, cyano, cyanocalkyl, formyl, formylalkyl, halogen, haloalkoxy, hal-ocalkyl, heterocyclyl, hydroxy, hydroxyalkyl, mercapto, nitro and the like, and which can be linked with any C atom of the alkyl group.

The term "low alkyl", alone or in combination, describes alkyl groups with 1-4 C atoms. Repres entative, but not 1limitative, examples of low alkyl are methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl and the like.

®

The term "alkenyl", alone or in combination, describes a linear or branched hydrocarbon radical of 2-8 C atoms in which at least one carbon-carbon double bond (RR, C=CRR,) is present. R,-R, describe sul»stituents which are chosen hb] independently of each other from hydrogen, alkyl, alkoxy, alkoxyalkyl, and the like. Representative, but not limitative, examples of al.kenyl are ethenyl, 2-propenyl, 2- methyl-2-propenyl, 3-buterayl, 4-pentenyl, 5-hexenyl and the like.

The term "alkylenedioxy", alone or in combination, describes a -0(CH,) O group, in which n means 1 or 2, the O- @ atoms being bound to two meighbouring C atoms of the main molecule skeleton. Representative, but not limitative, examples of alkylenedioxy are methylenedioxy, ethylenedioxy and the like.

The term "alkynyl", alone or in combination, describes a linear or branched hydrocarbon radical with 2-8 C atoms, in which at least one carbon-carbon triple bond (R,-C=C-R,) is present. R, and R describe substituents which are chosen independently of each other from hydrogen, alkenyl, alkoxy, alkoxyalkyl, and the like . Representative, but not limitative, examples of alkynyl are acetylenyl, 1l-propynyl, 2-propynyl, 1l-butynyl, 3-butynyl, 2-pentynyl and the like. od The term "alkoxy", alone or in combination, describes an alkyl group which is linked via an oxygen bridge.

Representative, but not 1 imitative, examples of alkoxy are methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term "alkoxyalkyl", alone or in combination, describes an alkoxy group which is linked via an alkyl radical.

Representative, but not 1 imitative, examples of alkoxyalkyl are tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

.

The term "alkoxycarbonyl", alone or in combination, describes an alkoxy group which is linked via a carbonyl group. Representative, but not limitative, examples of alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, tert-

Dbutoxycarbonyl and the like.

The term "alkoxycarbony/lalkyl", alone or in combination, describes an alkoxycarbonyl group which is linked via an alkyl radical. Representative, but not limitative, examples of alkoxycarbonylalkyl are methoxycarbonylpropyl, ethoxycarbonylbutyl, 2—tert-butoxycarbonylethyl and the like. ® The term "alkylcarbonyl", alone or in combination, describes an alkyl group which is linked via a carbonyl group. Representative, but not limitative, examples of alkylcarbonyl are acetyl, 1l-oxopropyl, 2,2-dimethyl-1- oxopropyl, 1l-oxobutyl, 1l-oxopentyl and the like.

The term "alkylcarbonylalkyl", alone or in combination, describes an alkylcarbonyl group which is linked via an alkyl group. Representative, but not limitative, examples of alkylcarbonylalkyl are 2-oxopropyl, 3,3-dimethyl-2- oxopropyl, 3-oxobutyl, 3-oxopentyl and the like.

The term "alkylcarbonyRoxy", alone or in combination, ® describes an alkylcarbonyl group which is linked via an oxygen bridge. Represemtative, but not limitative, examples of alkylcarbonyloxy are acetyloxy, ethylcarbonyloxy, tert- butylcarbonyloxy and the like.

The term "alkylsulphiny1", alone or in combination, describes an alkyl group which is linked via a sulphinyl group. Representative, but not limitative, examples of alkylsulphinyl are methiylsulphinyl, ethylsulphinyl and the like.

The term "alkylsulphinyslalkyl", alone or in combination, describes an alkylsulphinyl group which is linked via an

® alkyl group. Representative, but not limitative , examples of alkylssulphinylalkyl are methylsulphinylmethy-1, ethylsulphinylmethyl and the like.

The term '"alkylsulphonyl", alone or in combinat-ion, describes an alkyl group which is linked via a sulphonyl group. Representative, but not limitative, examples of alkylsulphonyl are methylsulphonyl, ethylsulphconyl and the like.

The term "alkylsulphonylalkyl", alone or in combination, refers to an alkylsulphonyl group which is linkzed via an

C alkyl group. Representative, but not limitative, examples of alkylssulphonylalkyl are methylsulphonylmethyrl, ethylsulphonylmethyl and the like.

The term "alkylthio", alone or in combination, describes an alkyl group which is linked via a thio group.

Representative, but not limitative, examples off alkylthio are methylsulphanyl, ethylsulphanyl, tert-butyl sulphanyl, hexylsulphanyl and the like.

The term "alkylthioalkyl", alone or in combinat-ion, describes an alkylthio group which is linked va an alkyl group. Representative, but not limitative, exarmples of alkylthicalkyl are methylsulphanyl-methyl, 2- ® (ethylsullphanyl)ethyl and the like.

The term "amino", alone or in combination, describes a -NR,_R, group, in which R, and R, are chosen indepoendently from hydrogen, alkyl, aryl, arylalkyl, acyl, allkylcarbonyl, arylcarbeonyl, carbamoyl, ureido, formyl, alkylssulphonyl, arylsulphonyl and the like.

The term "aminoalkyl", alone or in combination. describes an amino group which is linked via an alkyl greup.

Representative, but not limitative, examples o=f aminocalkyl are aminomethyl, 2-aminocethyl, N-benzyl-N-meth-yl- aminomet hiyl, dimethylamino-methyl and the like .

®

The t erm "aminocarbonyl", alone or in combination, descr ibes an amino group which is linked vzda a carbonyl group . Representative, but not limitative, examples of amino<arbonyl are dimethylaminocarbonyl, benzy laminocarbonyl, ethylaminocarbonyl and the like.

The term "aminocarbonylalkyl", alone or in combination, descr ibes an aminocarbonyl group which is JAinked via an alkyl group. Representative, but not limitaative, examples of amidnocarbonylalkyl are 2-amino-2-oxoethyl, 2- (benz=ylamino) -2-oxoethyl, 2-(methylamino) -22-oxoethyl, 4- ® amino —-4-oxobutyl, 4-(dimethylamino)-4-oxobutyl and the like.

The term "aryl", alone or in combination, describes an aromatic carbocyclic group containing at least one aromatic ring, for example phenyl or biphenyl, or condensed ring systerns in which at least one ring is aromatic, for example 1,2,3_,4-tetrahydronaphthyl, naphthyl, anthrryl, phenanthryl, fluoreenyl and the like. The aryl group can carry one or more substituents which are chosen independently of each other from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkyl enedioxy, ® alkylsulphinyl, alkylsulphinylalkyl, alkylsulphonyl, alkylsulphonylalkyl, alkylthio, alkylthiocal kyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarl>onylalkyl, arylallkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, aryl sulphinyl, arylsuilphinylalkyl, arylsulphonyl, arylsulphonylalkyl, arylthio, arylthioalkyl, carboxy, carboxyal kyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkoxy, haloal kyl, heterocyclyl, hydroxy, hydroxyalkyl, mercapto, nitro and the like.

The term "arylalkenyl", alone or in combina tion, describes an ary’l group which is linked via an alkenyl group.

) @ @® 23

Representative, but not limitatixse, examples of arylalkenyl are 2-phenylethenyl, 3-phenylpropen-2-yl, 2-naphth-2- ylethenyl and the like.

The term "arylalkoxy", alone or in combination, describes an aryl group which is linked via an alkoxy group.

Representative, but not limitatiwe, examples of arylalkoxy are 2-phenylethoxy, 5-phenylpentyloxy, 3-naphth-2-ylpropoxy and the like.

The term "arylalkyl", alone or ira combination, describes an aryl group which is linked via ara alkyl group. The aryl ® group can be unsubstituted or sulbstituted. Representative, but not limitative, examples of arylalkyl are benzyl, 2- phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl and the like.

The term "aryloxy", alone or in c¢ ombination, describes an aryl group which is linked via arm oxygen bridge. The aryl group can be unsubstituted or sulmstituted. Representative, but not limitative, examples of a ryloxy are phenoxy, naphthyloxy, 3-bromophenoxy, 4-chxlorophenoxy, 4- methylphenoxy, 3,4-dimethoxyphenosxy and the like. The aryl group can be unsubstituted or subestituted as defined. ® The term "carbamoyl", alone or in combination, describes a -C(O)NR_R, group.

The term "thiocarbamoyl", alone ox in combination, describes a ~C(S}NRR, group.

The term "carbonyl", alone or in eombination, describes a -C (0) - group.

The term "carboxy", alone or in combination, describes a -CO,H group.

The term "carboxyalkyl", alone or in combination, describes a carboxy group which is linked v ia an alkyl group. 40 Representative, but not limitativee, examples of

® carboxyalkyl are carboxymethyl 2 -carboxyethyl, 3- carboxypropyl and the like.

The term "cyano", alone or in combination, describes a ~C=N- group.

The term "cyanoalkyl", alone or im combination, describes a cyano group which is linked via an alkyl group.

Representative, but not limitative, examples of cyanoalkyl are cyanomethyl, 2-cyanocethyl, 3- cyanopropyl and the like.

The term "cycloalkyl", alone or in combination, describes a ® saturated cyclic hydrocarbon radi cal with 3-15 C atoms which can carry one or more substituents. The substituents are independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl , alkylcarbonyloxy, alkylenedioxy, alkylsulphinyl, alkylsulphinylalkyl, alkylsulphonyl, alkylsulphonylalkyl, alkylthio, 200 alkylthiocalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarborayl, aryloxycarbonylalkyl, arylsulphinyl, arylsulphinylalkyl , arylsulphonyl, arylsulphonylalkyl, arylthio, arylthiocalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, ® halogen, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, mercapto, nitro and the like. Representative, but not limitative, examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. In polycyclic cycloalkyl radicals one of the fused rings can be aromatic, such as for example 1l-indanyl, 2-indanyl, tetrahydronaphthyl and the like.

The terms "cycloalkenyl" and "cycloalkinyl" describe cyclic hydrocarbon radicals which contain at least one carbon- carbon double or triple bond. Like the cycloalkyl radicals, these radicals can carry one or more substituents.

® ® 25

The term “formyl", alone or in combination, describes a -C(O)H group.

The term "formylalkyl'™, alone or in combination, describes a formyl group which #s linked via an alkyl group.

Representative, but not limitative, examples of formylalkyl are formylmethyl, 2-formylethyl, and the like.

The term "halo" or "halogen", alone or in combination, describes fluorine, bromine, chlorine, and iodine.

The term "haloalkyl", alone or in combination, describes an ® alkyl group in which at least one hydrogen atom is replaced by halogen. Representative, but not limitative, examples of

I5 haloalkyl are chlorome=thyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-clmloro-3-fluoropentyl and the like.

The term "haloalkoxy", alone or in combination, describes an alkoxy group in whi ch at least one hydrogen atom is replaced by halogen. Representative, but not limitative, examples of haloalkoxy are chloromethoxy, 2-fluorethoxy, trifluoromethoxy, pent afluorcethoxy and the like.

The term "heterocyclyl ", alone or in combination, describes a monocyclic, bicyclic or polycylic ring system with up to ® 15 ring atoms, contain ing at least one heteroatom independently chosen fom nitrogen, oxygen, or sulphur, the ring (s) being able to De saturated, partially unsaturated or unsaturated or aromatic. Representative, but not limitative, examples of heterocyclyl are furyl, imidazolyl, imidazolinyl, imidazolzddinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolwl, oxazolyl, oxazolinyl, oxazolidinyl, piperazimyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyximidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinwl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1- dioxothiomorpholinyl, lenzimidazolyl, benzothiazolyl,

® ® benzothienyl, benzoxazolyl, benzofuranyl, indolyl, indolinyl, isobenzofuranyl, isobenzothienyl, isocindolyl , isoindolinyl, isoqguinolinyl, quinolinyl and the like. The heterocylyl radicals can carry one or more substituents , these being indeperidently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl , alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylenedioxy, alkylsulphinyl, alkylsulphinylalkyl, alkylsulphonyl, alkylsulphonylalkyl, alkylthio, alkylthiocalkyl, alkynyl, amino, aminocalkyl, aminocarbon. yl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalk yl, ® arylsulphinyl, arylsulphinylalkyl, arylsulphonyl, arylsulphonylalkyl, arylthio, arylthicalkyl, carboxy, carboxyalkyl, cyano, cyanocalkyl, cycloalkyl, formyl, formylalkyl, halogen, halocalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro and the like.

The term "heteroaryl", alone or in combination, is a special case of heterocyclyl and describes a monocyclic , bicyclic or polycylic ring system, in which the or at 1 east one ring is heteroaromatic.

The term "heterocyclylalkenyl", alone or in combination , describes a heterocyclyl group which is linked via an ® alkenyl group. Representative, but not limitative, examples of heterocyclylalkenyl are 2-pyrido-3-ylethenyl, 3- quinoline-3-ylpropen-2-yl, S5-pyrido-4-ylpentylen-4-yl amd the like.

The term "heterocyclylalkoxy", alone or in combination, describes a heterocyclyl group which is linked via an alkoxy group. Repressentative, but not limitative, examples of heterocyclylalkoxy are 2-pyrido-3-ylethoxy, 3-quinol ine- 3-ylpropoxy, 5-pyrido-4-ylpentyloxy and the like.

The term "heterocyc lylalkyl", alone or in combination, describes a heterocyclyl group which is linked via an alkyl

S

® ® 27 group as defined. Representative, but not limitative, examples of kheterocyclylalkyl are 2-pyrido-3-ylmethyl, 2- pyrimidine-2—~ylpropyl and the like.

The term "het-erocyclyloxy", alone or in combination, describes a heterocyclyl group which is linked via an oxygen bridge. Representative, but not limitative, examples of heterocycllyloxy are pyrido-3-yloxy, quinoline-3-yloxy and the like _

The terms "hydroxy" or "hydroxyl", alone or in combination, ® describe a -OH group.

The term "hydroxyalkyl", alone or in combination, descri.bes an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group. Representative, but not limitative, examples of hydroxyalkyl are hydroxymethyl, 2- hydroxyethyl. 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl and the like.

The term "nitro", alone or in combination, describes a -NO,- group.

The term "oxo", alone or in combination, describes a =0-— group. ® The term "oxy", alone or in combination, describes a -0-— group.

The terms "mezrcapto" and "thiol" describe a -SH- group.

The terms "tlaio", "sulphinyl" and "sulphonyl" describe a -S(0),.- group with n= 0,1 and 2.

The compoundss defined at the outset of Formula I can be present in frree form, as pharmaceutically applicable aci.d addition salts, as pharmaceutically applicable salts of acid compounds of Formula I with bases, as pharmaceutically

. ® ® 28 applicable esters of hydroxy or carboxy group-containing compounds of Formula I and as hydrates or solvatess thereof.

The term " pharmaceutically applicable salts" referss to salts which do not reduce the biological effect ard properties of the free bases and which are not biologically or otherwi se undesirable.

The acid addition salts are formed from the free Ibases using inorganic acids, such as hydrochloric acid, hydrobromi ¢ acid, sulphuric acid, nitric acid, phosphoric acid and the like., preferably hydrochloric acid or hydrobromi ¢ acid, or using organic acids, such as acetic ® acid, prop ionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, tartaric acid, salicylic acid, citric acid, benzoic acid, mandelic acid, methanesulphonic acid, p-toluenesulphonic acid and the like.

Compounds of Formula I which contain acid gro ups can 200 form salts with inorganic bases or with organic ba ses.

Preferred salts with inorganic bases are, but not exclusively, sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Preferred salts with organic bases are, but not exclusively, salts with primary , secondary and tertiary, optionally substituted amimes ® including all naturally occurring substituted amin es, with cyclic amires and with basic ion-exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysines, arginine, N-ethylpiperidine, piperidine, polyamine resins and the like. Compounds of Formula I which contain an acid group can also be present as zwitterions.

Pharmaceuti cally applicable esters of hydroxy or carboxy group-conta ining compounds of Formula I are also mentioned at the outs et. "Pharmaceutically applicable esters'' means that in compounds of Formula I corresponding functional groups are derivated to ester groups in such a way that v

J they are transformed back to their active form again in vivo. On the one hand COOH groups can be esterified.

Examples of suitable estexs of this type are alkyl and aralkylesters. Preferred esters of this type are methyl, ethyl, propyl, butyl and benzylesters and (R/S)-1- [ (isopropoxycarbonyl)oxy] ethyl esters. Ethyl esters and the isomeric butylesters are particularly preferred. On the other hand OH-groups can be esterified. Examples of such compounds contain physiologically acceptable and metabolically labile estex groups, such as methoxymethyl esters, methylthiomethyl esters, pivaloyloxymethyl esters ® and similar ester groups.

Compounds of Formula I we xe examined in the following test for their affinity to the NPFF receptors:

Hamster cells suitable for neuropeptide FF receptor-binding studies (Chinese Hamster Ovary cells, CHOSP10) which in each case produce the NPF Fl or NPFF2 receptor, were multiplied in standard ce ll-culture conditions. The cell- culture medium was sucked. out and 5 ml of buffer A (5 mM

Tris pH=7.4, 1 mM MgCl,) added per 17cm Petri dish. The cells were scraped off the cell-culture plate and transferred into a 50 ml Falcon vessel. The cells were then centrifuged for 5 minutes at 450 g, resuspended in buffer A ® once again and mixed for 30 seconds on a Polytron vortex.

After centrifugation at 30,000 g for 20 minutes the supernatant was discarded and the membrane pellet taken up in 500 pl buffer C (75 mM Tris pH=7.4, 25 mM MgCl,, 250 mM sucrose, 0.1 mM PMSF, 0.1 mM phenanthroline). The membrane- buffer mixture was then divided into aliquots and deep- frozen. The protein content of an aliquot was determined by the Lowry method.

The binding test was carried out in a final volume of 250 pl. 100 pul membrane-buffer mixture corresponding to 35 ug protein content was mixed with 95 pl binding buffer (50 mM

® @®

Tris pH 7.4, 60 mM NaCl, 0.1 % protease-free BSA, 0.01%

NaN,). After addition of 5 ul each of a concentration of test substance per measurement point, 0.2 nM I-Tyrl-NPFF (NEN, NEX381) per measurement. point was added in 50 ul.

After 90 minutes’ incubation at room temperature the samples were sucked out through a GF/C filter (Millipore (MAHFC1H60)) and the filter was washed with ice cold binding buffer with 3 times 300 pl (Packard Filtermate) .

After addition of 55 pl Microscint 40 (Packard 6013641) scintillation fluid the measurement points were quantified in the gamma counter (Packard, Top Count NXT). ® Non-specific binding was ascertained in the presence of 1 uM unmarked neuropeptide FF. Specific binding is defined as the difference between total and non-specific binding. IC, values are defined as that c-oncentration of the antagonist which displaces 50% of the “ °I-marked neuropeptide FF. This concentration is ascertained by linear regression analysis after logit/log-transformati on of the binding values.

Preferred compounds according to the invention show, in the receptor binding study descr-ibed above, IC, values below 1000 nM, particularly preferred compounds show IC, values below 100 nM, quite particul arly preferred ones, below 50 () 25 nM.

The results of the representative compounds of Formula I measured in the biological test described above are summarized in Table 1 below.

Table 1: NPFF1l receptor binding

Binding

Compound NPFF-1 1C50 [pM]

N- (5-ethyl-5-methyl-4,5,6,7 -tetrahydro- 0.0002 benzothiazole-2-yl)-guanidime

N- (5,5-dimethyl-4,5,6,7-tetrahydxo- 0.002 benzothiazole-2-yl) -guanidine

N- (4-tert-butyl-4,5,6,7-tetrahydxo- 0.002 benzothiazole-2-yl)-guanidine }

N-(5,5-dimethyl-6-phenyl-4,5,6,7- 0.002 tetrahydro-benzothiazole-2-yl) -guanidine )

N- (6-isopropyl-4,5,6,7-tetrahydro- 0.004 benzothiazole-2-yl)-guanidine )

N-(6,6-dimethyl-4,5,6,7-tetrahydxo- 0.004 ( benzothiazole-2-yl)-guanidine

N-(5,5,7-trimethyl-4,5,6,7-tetrahydro- 0.004 benzothiazole-2-yl)-guanidine ]

N-(5-butyl-5,6,7,8-tetrahydro-4H— 0.008 cycloheptathiazol-2-yl)-guanidine

N-(5-butyl-4,5,6,7-tetrahydro- 0.005 benzothiazole-2-yl)-guanidine )

N-(4-ethyl-4-methyl-4,5,6,7-tetrahydro- 0.005 benzothiazole-2-yl) -guanidine )

N-[6-(3,4-dimethoxyphenyl)-4,5,6, 7- 0.005 o tetrahydro-benzothiazole-2-yl] -guanidine )

N- (5-Methyl-4,5,6,7-tetrahydro- 0.006 benzothiazole-2-yl)-guanidine )

N- (6-phenyl-4,5,6,7-tetrahydro- 0.006 benzothiazole-2-yl)-guanidine )

N- (6-propyl-4,5,6,7-tetrahydro- 0.007 benzothiazole-2-yl)-guanidine )

N- (4-methyl-4-propyl-4,5,6,7-tetr ahydro- 0.007 benzothiazole-2-yl) -guanidine )

. ® ® 32

N-— (4-cyclohex-1-enyl-4,5,6,7-tetrahydro- 0.008 benzothiazole-2-yl) -guanidine

N— (4-sec-butyl-4,5,6,7-tetrahydro- 0.009 benzothiazole-2-yl) -guanidine

N- (4-isocbutyl-4-methyl-4,5,6,7- 0.005 tetrahydro-benzothiazole-2-yl) -guanidine

N— (6-tert-butyl-4,5,6,7-tetrahydro- 5.010 benzothiazole-2-yl) -guanidine [ Ass mentioned at the outset, the substances defined there, because of their capacity to block the neuropeptide FF receptors, are valuable in the treatment of pain, hypersensitivity to pain (hyperalgesia) and chronic, acute, long-lasting or temporary pain, which pain be of operative, txaumatic, or pathological origin. Above al l they supplement the current treatment methods for chronic pain with the advantage of preventing undesirabl e opioid 100 tolerance and/or opioid dependence. The compounds can also be used for the regulation of insulin secretion, food intake, memory functions, blood pressure, and electrolyte ard energy balance and for the treatment off urinary incontinence. ® The substances defined at the outset can be transformed into suitable galenic dosage forms using methods which are generally known and familiar to every person skilled in the axt. Such dosage forms are for example tabl ets, coated tablets, dragées, capsules, injection solut-ions etc.

Switable excipients and adjuvants are also generally known amid familiar to every person skilled in the art for the pxeparation of such galenic dosage forms. In addition to ore or more of the substances defined at the outset these dosage forms can also contain further pharmnacologically a<tive compounds.

® ® 33

The dosage of the substances defined at the outset or of t-he dosage forms containing them is to be matched by the

Aoctor in attendance to the respective needs of the

Patient. In general a daily dose of 0.1 -20 mg, preferably

Q.5-5 mg of one of the substances defined at the outset per kg body weight of the patient should be appropriate.

The guanidine derivatives of general Formula I, and the corresponding starting and intermediate products, can be produced using methods known in organic synthesis and isolated and purified using known techn. iques such as

Precipitation, chromatography, crystall ization, preparative ® reversed-phase HPLC, etc.. Stereoisomer mixtures which may

Ibe obtained, such as racemates, can be separated by generally customary methods, preferably by chiral-phase chromatography.

The preparation of the guanidine der ivatives of general

Formula I takes place according to Diag ram 1 below:

Diagram 1 5 NH, a HN * Or On = Oe -_ A Hn

Hal Ss 1 2 1

A. compound of Formula 1, in which the n itrogen atom which may be present in A is protected, is ha logenated in o- pcsition to form the carbonyl group, wh-ereupon the obtained c compound of Formula 2, is subjected to -a cyclocondensation with a thiourea derivate such as 2-imineo-4-thiobiuret of

Formula 3, optionally the protective greup located on the nitrogen atom which may be present is split off from the c ompound obtained, optionally this nitregen atom is c orrespondingly substituted with an agemt releasing a

® @® radical R' and optionally an obtained basic compound is converted into a pharmaceutically applicable acid addition salt, or an obtained compound, containing an acid group, into a pharmaceutically applicable salt with a base, or an obtained hydroxy or carboxy group-corataining compound into a pharmaceutically applicable ester and optionally the obtained product is converted into a hydrate or solvate.

Because, in the novel compounds of Formula I, the chain A cannot contain a nitrogen atom, the &\bove remarks concerning a N-protective group, its splitting-off and optional N-substitution of the end-product are irrelevant ® for the preparation of these novel compounds. Accordingly the novel products according to the #Hnvention can be produced by simply halogenating a cormpound of the above

Formula 1 in a-position to form the «—arbonyl group, subjecting the obtained compound of the above Formula 2 to a cyclocondensation with 2-imino-4-thiobiuret of the above

Formula 3 and optionally converting &n obtained basic compound into a pharmaceutically applicable acid addition salt, or an obtained compound, containing an acid group, into a pharmaceutically applicable salt with a base, or an obtained hydroxy or carboxy group-cortaining compound into a pharmaceutically applicable ester and optionally the obtained product into a hydrate or solvate. ® Typically the synthesis both of the «guanidine derivatives of Formula I and of the corresponding intermediate products is carried out in solution using an corganic solvent. The introduction and removal of protecti=e groups takes place with typical methods known to a person skilled in the art (T.W. Greene & P.G.M. Wuts in Protective Groups in Organic

Synthesis, Third Edition, John Wiley & Sons, 1999).

Generally cycloalkanones (1) can be halogenated with known methods in position a to form the carbonyl group. The following cyclocondensation of a-hal«w-oxo compounds (2) with a thiourea derivate, such as e.«g. 2-imino-4-thiobiuret

® (3) takes place in known manner and leads to the desired guanidine derivatives of Formula I (J. Med . Chem. 1991, 34(3) , 914-918; J. Med. Chem. 1994, 37(8), 1189-1199).

Generally, heterocyclic oxo compounds (1) <<an be converted analogously to the corresponding target cornpounds of

Formula I. It is to be borne in mind that an -NH-group presemt in A of the starting product (see Formula 4 below) is to be provided with a common protective group (PG), see

Diagram 2 below:

Diagram 2

HN

9 _0 _0 3 _0 N Hn «I — ro J _— oI — ra J Dama

Hal S 4 5 6 7

HN HN

N Hn N po — Le ep . S S 1

The required cyclic azaketones of Formula 4 are partly knowri1 from the literature (Yokoo et al., Bull. Chem. Soc.

Japarn 1959, 29, 631; Griss et al., DE 2206385, published 10th February 1972) or can be produced analogously to the precursor stage for Example N-07. ® The halogenation of 5 and cyclocondensation of 6 with 2- imino-4-thiobiuret (3) to the correspondimgly N-protected bicyclic guanidinothiazole 7 takes place -~under known cond itions. After splitting-off of the protective group, which leads to 8, the R’-radicals defined at the ocutset are converted under known conditions by means of the 40 corresponding R'-releasing reagents in each case, such as e.g. alkylhalides, carboxylic acid halides or anhydrides, or also carboxylic acids in the presence of coupling reagents and with bases as auxiliary reagent, chloroformates, sulphonyl halides, isocyanates,

i ® ® 36 isothiocyanates and the like to the corresponding compound of Formula III.

Suitable organic solvents are tho se which behave inertly under the chosen reaction conditieons. These are preferably ethers, such as diethyl ether, dieoxan, tetrahydrofuran or glycoldimethylether; or alcohols, such as for example methanol, ethanol, propanol, isopropanol, butancl, isobutanol or tert-butanol; or hyedrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions; or halogenated hydrocazrbons, such as dichloromethane, trichloromethane , tetrachloromethane, @® dichloroethylene, trichloroethyleme or chlorobenzene; or also ethyl acetate, triethylamine , pyridine, dimethylsulphoxide, dimethylformamnide, hexamethylphosphoramide, acetonitrile, acetone or nitromethane. Mixtures of the sol-vents mentioned can also be used.

Bases which can be used for the desscribed processes, are generally inorganic or organic basses. Preferred are alkali hydroxides, for example sodium or potassium hydroxide, alkaline-earth metal hydroxides, for example barium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate, alkaline-ear®th metal carbonates, such ® as calcium carbonate, or alkali ox alkaline-earth metal j alkoxides such as sodium or potasssium methoxide, sodium or potassium methoxide or potassium- tert-butoxide, or organic amines, e.g. trialkyl-(C,-C,)-amine=s, such as triethylamine, or heterocyclic amines, such as 1_4- diazabicyclo[2.2.2]octane (DABCO) , 1,8- diazabicyclo[5.4.0]lundec-7-ene (DEBU)}, pyridine, 4- dimethylaminopyridine, N-methyl-pDperidine or N- methylmorpholine. It is also posszble to use alkali metals, such as sodium, or its hydrides, such as sodium hydride.

The bases mentioned can, where expedient, be used as an acid-binding auxiliary.

® ®

Dehydrating reagents, for example carbodiimides, such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3- dimethylaminopropyl) —N'-ethylcarbodiimide-hydrochloride, ox carbonyl compounds, such as carbonyldiimidazole, or 1,2- oxazolium compounds, such as 2-ethyl-5-phenyl-isoxazolium- 3-sulphonate, or also propane phosphonic acid anhydride or isobutyl chloroformate or benzotriazolyloxy-tris- (dimethylamino)phosphionium-hexafluorophosphate (BOP) or diphenylphosphoramidate or methanesulphonyl chloride, if expedient in the presence of bases, such as triethylamine or N-ethylmorpholine or N-methylpiperidine or ® diisopropylethylamine, can serve as coupling reagents.

The examples below serve to explain the present invention, but in no way limit it. The products obtained are given in

Tables 3 and 4 below.

Example C-01 rac. N-(6-isopropyl-4.,5,6,7-tetrahydro-benzothiazole-2-yl) — guanidine 2-imino-4-thicbiuret (5 mmol) is added accompanied by stirring to a solution of 2-bromo-4-isopropyl-cyclohexanone (5 mmol) in ethanol (10 ml) and the reaction mixture is then refluxed for 16 hours. After evaporating-off of the solvent ethyl acetate is added to the residue and the o precipitated-out product is isolated by filtering off: t, 2.75 min (LC-1, one peak); ESI-MS (+/-): m/z 239.25 [M+H]~ / 237.24 [M-H] . 2-bromo-4-isopropyl-cyclohexanone (starting product for

Example C-01)

Bromine (5 mmcl) is added dropwise at room temperature to = solution of 4-isopropyl-cyclohexanone (5 mmol) in diethyl ether (10 ml). When the addition is complete the reaction mixture is stirred for another 30 min. After the addition of saturated aqueous sodium sulphite solution (5 ml) extraction is carried out with diethyl ether, the combined organic phases are concentrated by evaporation after drying

® over sodium sulphate. The bromoketone obtained as crude product is reacted directly in the next step with 2-imino- 4-thiobiuret without further purification.

Analogously to the preparation of Example C-01, the compounds accordirig to Examples C-02 to C-73 in Table 3 are prepared starting from the corresponding a-bromo- or a- chloroketones.

The bromination of the ketones used in Examples C-02 to C- 17 takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. ® The a-bromoketoness are generally reacted as crude products without further characterization. 3-butylcyclohexanone (precursor-product for Example C-05)

A solution of copper iodide (6.3 mmol) in dimethyl sulphide (12 ml) is cooled to 50°C. A solution of butyl lithium (6.2 mmol) is added dropwise accompanied by stirring and stirred for a further 5 to 15 mins. The reaction mixture is cooled to -78°C and then a solution precooled to -78°C of cyclohex-2-enone £6 mmol), dissolved in dimethyl sulphide (1 ml), is slowly added dropwise. After stirring for one hour at -78°C the mixture is quenched with saturated aqueous ammonium chloride solution. The reaction mixture @ 25 which has been heated to room temperature is extracted with diethyl ether. The combined ether phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulphate. After evaporating-off of the solvent the residue obtained i.s taken up in hexane, the solution is filtered and concesntrated by evaporation. After chromatography of the residue on silica gel with ethyl acetate/ hexane 1: 4 pure 3-butylcyclohexanone is obtained (Tetrahedron 1989, 45 (2), 425-434). 2-bromo-5-butyl-cyclohexanone (starting product for Example

C-05)

[} _

The bromination of 3-butylcyclohexanone takes place in a manner simillar to that described above for the preparation of 2-bromo-a-isopropyl-cyclohexanone. The title «compound is reacted as a crude product without further characterization. 2-tert-buty’l-6-chlorocyclohexanone (starting product for

Example C-077)

N-butyl lithium is added dropwise to a solution, cooled to 0°C, of diisopropylamine (5.5 mmol) in dry tetralaydrofuran.

After the addition is complete the mixture is cooled to - ® 78°C, and a solution of 2-tert-butylcyclohexanone (5 mmol) in dry tetrahydrofuran (50 ml) is introduced, followed by the additior of p-toluenesulphonyl chloride (5 mruwol), also dissolved ir dry tetrahydrofuran (50 ml). The reaction mixture is heated to room temperature and after stirring for 30 mins over silica gel filtered with ether as eluant.

After concentration by evaporation in a vacuum 2-—tert- butyl-6-chlorcyclchexanone (760 mg) is obtained An a yield of 81% (Tet. Lett. 1999, 40(12), 2231-2234). 4,4-dimethyl cyclohexanone (precursor-product for Example C- 11)

A solution of 4,4-dimethyl-cyclohex-2-enone (3 mrmol) in ethyl acetate is hydrogenated overnight at room tcemperature ® using P4d/C (0.05 mmol) with hydrogen under normal pressure.

Filtration over celite and then concentration by evaporation produces 4,4-dimethyl-cyclohexanone «355 mg) in a yield of 94% (J. Org. Chem. 2001, 66 (3), 733-7738). 2-bromo-4,4- dimethylcyclohexanone (starting produact for

Example C-11)

The brominat. ion of 4,4-dimethylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characteriza tion.

{ ® ® 40 2-sec-butyl-6-chloro-cyclohexanone (starting product for

Example (C-18)

The chlorination of 2-sec-butylcyclohexanone takes place in a manner similar to that described above for the preparatzion of 2-tert-butyl-6-chloro-cyclohexano-ne. The title compound is reacted as a crude product wit hout further characterization. 3-chloro-bicyclohexyl-1'-en-2-one (starting product for

Example (C-19)

The chlorination of 2- (l-cyclohexenyl) cyclohexanone takes o place im a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanosne. The title compound is reacted as a crude product wit hout further characterization. 2-benzyl -6-chloro-cyclohexanone (starting product for

Example C-20)

The chlorination of 2-benzylcyclohexanone takes place in a manner similar to that described above for the psreparation of 2-temt-butyl-6-chloro~-cyclohexanone. The titl e compound is reacted as a crude product without further characterization. ® 2-allyl —6-chloro-cyclohexanone (starting product. for

Example C-21)

The chlorination of 2-allylcyclohexanone takes place in a manner similar to that described above for the p»reparation of 2-temxt-butyl-6-chloro-cyclohexanone. The titl e compound is reacted as a crude product without further characterization. 2-chloro-6-phenyl-cyclohexanone (starting produc=t for

Example C-22)

The chlorination of 2-phenylcyclohexanone takes place in a manner similar to that described above for the reparation of 2-temt-butyl-6-chloro-cyclohexanone. The title compound

L

® ® 41 is reacted as a crude product without further characterization.

Ethyl (3-chloro-2-oxo-cyclohexyl) -aceatate (starting product for Example C-23)

The chlorination of ethyl (2-oxo-cycl chexyl)-acetate takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro—cyclchexanone. The title compound is reacted as a crude product without further characterization. 3-(3-chloro-2-oxo-cyclohexyl) -propiomitrile (starting ® product for Example C-24)

The chlorination of 2-oxo-l-cyclohexanepropionitrile takes

Is place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro—cyclohexanone. The title compound is reacted as a crude product without further characterization. 2-chlorxo-6-methyl-cyclohexanone (starting product for

Example C-25)

The chlorination of 2-methylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanome. The title compound is reacted as a crude product withou t further ® characterization. 2,2-dimethyl-cyclohexanone (precurso r-product for Example

Cc-26)

A suspension of potassium hydride (5 .5 mmol) and 2- methylcyclohexanone (5 mmol) in dry tetrahydrofuran (10 ml) is stirred for 30 mins at room tempe:-rature. Triethylborane (6.25 mmol) is slowly added dropwise- and the mixture is stirred for 16 hours at room tempera_ture. After addition of methyl iodide stirring is continued for another 8 hours, the reaction is then quenched with ssaturated aqueous ammonium chloride solution and twices extracted with diethyl ether. The combined organic phases are dried over sodium

® ® 42 sulphate and concentrated to dryness in a vacuum and produce the title compound, which can be reacted without [without] purification (JAC.S 1985, 107, 19, 5391-5396). 6-bromo-2,2-dimethyl-cyclohexanone (starting product for

Example C-26)

The bromination of 2,2-dimethyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization. 9D 2-ethyl-2-methyl -cyclohexanone (precursor-product for

Example C-27)

The alkylation of 2-methylcyclohexanone with ethyl iodide takes place in a manner similar to that described above for the preparation of 2,2-dimetthyl-cyclchexanocne. 6-bromo-2-ethyl-2-methyl-cyclohexanone (starting product for Example C-27)

The bromination of 2-ethyl-2-methyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further @ characterization. 2-isobutyl-2-methyl-cyclohexanone (precursor-product for

Example C-28)

The alkylation of 2-methylcyclohexanone with 1-iodo-2- methyl-propane takes place in a manner similar to that described above for the preparation of 2,2-dimethyl- cyclohexanone. 6-bromo-2-isobutyl-2-methyl- cyclohexanone (starting product for Example C-28)

The bromination of 2-isobuty l-2-methyl-cyclohexanone takes place in a manner similar to that described above for the

’ preparation of 2-bromo-4-isopropyl-cyclohexanone. The titl e compound is retracted as a crude product without further characterization. 2-methyl-2-propyl-cyclohexanone (precursor-product for

Example C-29)

The alkylatiom of 2-methylcyclohexanone with 1-iodopropane takes place ira a manner similar to that described above for the preparation of 2,2-dimethyl-cyclohexanone. 6-bromo-2-metlayl-2-propyl-cyclohexanone (starting product ® for Example C—29)

The bromination of 2-methyl-2-propyl-cyclohexanone takes place in a marmaner similar to that described above for the preparation off 2-bromo-4-isopropyl-cyclohexanone. The titl e compound 1s reacted as a crude product without further characterization.

Example C-30 2-guanidino-4, 5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester

Analogously to the preparation of Example C-01, 3-bromo-2- oxo-cyclohexarae carboxylic acid ethyl ester is reacted wit h 2-imino-4-thiocbiuret to produce the title compound. ® 3-bromo-2-oxo—cyclohexane carboxylic acid ethyl ester (starting product for Example C-30)

The bromination of 2-oxo-cyclohexane carboxylic acid ethyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl- cyclohexanone. The title compound is reacted as a crude product withowt further characterization.

Guanidino-4,5, 6,7-tetrahydro-benzothiazole-4-carboxylic acid

A suspension of 2-guanidino-4,5,6,7-tetrahydro- benzothiazole—4-carboxylic acid ethyl ester (5 mmol) and

® ® sodium hydroxide (20 mmol) in methanol/ water (4:1, 10 ml) is stirred overnight at room temperature. The pH is set at by adding 25% hydrochloric acid and the precipitated product is filtered off. In this way the title compound is 5 obtained (671 mg) in a yield of 56%: t, 0.64 min (LC-1);

ESI-MS (+/-): m/= 241.49 [M+H) / 239.37 [M-H]) .

Example C-31 2-quanidino-4,5, 6,7-tetrahydro-benzothiazole-4-carboxylic acid benzylamide and its formate 2-guanidino-4,5, 6, 7-tetrahydro-benzothiazole-4-carboxyli.c acid (0.1 mmol), diisopropylethylamine (0.2 mmol), O- ® (benzotriazol-1-y1)-N,N,N’ ,N’-tetramethyluronium- hexafluorophosphate (0.1 mmol) and benzylamine (0.2 mmol) are dissolved in dimethylformamide (0.5 ml) and stirred overnight at room temperature. After removal of the solwent in a vacuum the residue is dispersed in ethyl acetate (1 ml) and 1M aqueous caustic soda solution (0.5 ml). The phases are separated, the organic phase is dried over sodium sulphate, the solvent is evaporated off and the pure title compound is obtained using preparative HPLC (Waters

Prep LC equipped with a Waters 600 Controller, Waters 2767

Sample Manager, Waters 996 mass spectrometer and photodiode-array detector). o Analogously to Example C-31 the compounds of Examples C—32 to C-41 listed im Table 3 are produced by reaction of 2— guanidino-4,5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid with the corresponding amines in the presence of a coupling reagent such as O- (benzotriazol-1-yl)-N,N,N’,N” - tetramethyluronium-hexafluorophosphate.

Example C-42 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-6-carboxyli c acid ethyl ester

Analogously to the preparation of Example C-01, 3-bromo—4- oxo-cyclohexane carboxylic acid ethyl ester is reacted with 2-imino-4-thiobiuret to form the title compound.

® ® 45 3-bromo-4-oxo-cyclohexane carboxylic acid ethyl ester (Starting product for Example C-42)

The bromination of 4-oxo-c yclohexane carboxylic acid ethyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl- cyclohexanone. The title compound is reacted as a crude product without further characterization. 2-guanidino-4,5,6,7-tetralhydro-benzothiazole-6-carboxylic acid

Analogously to the preparation of 2-~-guanidino-4,5,6,7- ® tetrahydro-benzothiazole-4-carboxylic acid, 2-guanidino- 4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester is saponified to foxm the title compound: t, 2.49 min (LC~1); ESI-MS (+/-): m/z 241.04 [M+H] / 238.39 [M-2H] .

In a similar way to Example C-31 the compounds of Examples

C-43 to C-46 listed in Tale 3 are produced by reaction of 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid with the correspondi ng amines in the presence of a coupling reagent such as O- (benzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium-hexafl uorophosphate.

Example C-47 ® N- (tetrahydro-benzothiazole~2-yl-4-gpiro-cyclohexane) - guanidine and its formate

Analogously to the prepar-ation of Example C-01, 2-bromo- spiro{5.5]lundecan-1-one i.s reacted with 2-imino-4- thiobiuret to form the ti tle compound. 2-bromo-spiro(5.5]undecar-1-one (Starting product for

Example C-47)

The bromination of spiro [5.5]undecan-1-one takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-csclohexanone. The title compound is reacted as a crude product without further characterization.

® . ® 46

Spiro {5.5]undecan-1-one (precursor-product for Example C- 47)

Dibromopentane (5 mmol) is added to a solution of cyclohexanone (5 mmol) and potassium-tert-butanolate (10 mmol) in toluene (7.5 ml) and the reaction mixture is refluxed for 48 hours. After cooling to room temperature 25% hydrochloric acid is added amd extraction is carried out with diethyl ether. The comb ined organic phases produce, after drying over sodium sulphate, removal of the solvent in a vacuum and chromatography of the residue using silica gel (ethyl acetate/ heptane, 1:5) pure ® spiro (5.5]Jundecan-1-one (Tetrahedron 1964, 20, 2553-2573): t, 1.90 min. (LC-2); ESI-MS (+): an/z 167.27 [M+H] .

Example C-48

N- (6-phenyl-4,5,6,7-tetrahydro-loenzothiazole-2-yl-4-spiro- cyclohexane) -guanidine and its hydrobromide salt

The title compound is produced starting from 4-phenyl- spiro[5.5]Jundecan-1-one instead of spiro(5.5]undecan-1-one in a similar way to N-(tetrahydxo-benzothiazole-2-yl-4- spiro-cyclohexane) -guanidine. 4-phenyl-spiro[5.5]undecan-l-one (precursor-product for

Example C-48) @® The preparation of the title compound takes place in a manner similar to that describe d above for the preparation of spiro[5.5Jundecan-l-one: t, 1.92 min (LC-2); ESI-MS(+): m/z 243.36 (M+H] .'H NMR (ppm,CDC1): 7.3(5H); 3.25(1H); 2.8(1H); 2.35(1H); 2.2(2H); 1.95(3H); 1.75(2H); 1.65(2H); 1.4(4H); 1.15(1H). 4,4-diphenylcyclohexanone (precursor-product for Example C- 49)

The preparation of 4,4-diphenylcyclohexanone takes place in a manner similar to that described above for the preparation of 4,4-dimethylcycdohexanone: t, 3.68 min (LC- 1); ESI-MS(-): m/z 249.00 [(M-HJ] .

A

® _ 47 2-bromo-4,4-diphenyl cyclohexanone (starting product for

Example C-49)

The bromination of 4 ,4-diphenylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization. 3-bromo-4-oxo-1-phenwyl-cyclohexane carboxylic acid ethyl ester (starting product for Example C-50)

The bromination of 4 -oxo-1l-phenyl-cyclohexane carboxylic o acid ethyl ester tak-es place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl- cyclohexanone. The t itle compound is reacted as a crude product without further characterization. 3-bromo-4-oxo-1-phenwvl -cyclohexanecarbonitrile (starting product for Example «-51)

The bromination of 4 -oxo-1-phenyl-cyclohexanecarbonitrile takes place in a manmer similar to that described above for the preparation of 2 -bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.

C 3-bromo-4-arylcycloheexanone (Starting product(s] for

Examples C-52 to C-66&)

The bromination of the 4-arylcyclohexanone derivatives (precursor stages fox Examples C-52 to C-66) takes place in a manner similar to that described above for the preparation of 2-brormo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.

Preparation cof the 4 —arylcyclohexanone derivatives (precursor-products For Examples C-54 to C-66): \

® ® 1,4-dioxaspirof[4.5]dec~-7-en—8-yl-trifluormethane-sulphonic acid ester 1,4-dioxaspiro[4.5]decan-8-one (1 mmol), dissolved in . tetrahydrofuran (2 ml), is added to a solution, cooled to -78°C, of lithium-bis- (trimethylsilyl) -amide (1M in tetrahydrofuran, 1.1 mmol) An dry tetrahydrofuran. The mixture is stirred for another 1.5 hours at -78°C and then a solution of N-phenyl-trifluormethanesulphonimide (1.07 mmol) in tetrahydrofuran (2 ml) is added. Then the mixture is stirred overnight at room temperature and the solvent is then removed in a vacuum. After drying of the residue in a vacuum 1,4-dioxaspiro(4.5)dec-7-en-8-yl-trifluormethane- @ sulphonic acid ester is obtained, which is immediately reacted again without additional purification (Tetrahedron 1999, 55, 14479-14490): 'H NMR (ppm, CDCl,): 5.65 (1H); 4 (4H); 2.55(2H); 2.4 (2H); 1.9(2H). 4-(4-fluorophenyl) -cyclohexanone (precursor-product for

Example C-54) a) 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene:

In an argon-charged flask, 2M sodium carbonate (4.8 mmol), 1,2-dimethoxyethane (8 ml), 4-fluorophenylboric acid (2.8 mmol), lithium chloride (6 twmol), 1,4-dioxaspiro(4.5]dec-7- en-8-yl-trifluormethane-sulphonic acid ester (2 mmol) and tetrakis(triphenyl-phosphine)palladium (0.1 mmol) are

Qo combined and stirred overnight at 80°C. The reaction mixture is concentrated in a vacuum and the residue is dispersed in dichloromethane/ 2M aqueous sodium carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are then dried over sodium sulphate and the solvent is evaporated off in a vacuum. From the residue, after column chromatography using silica gel (ethyl acetate/ heptane 1:4), pure 8- (4- fluorophenyl) -1,4-dioxaspiro[4.5]dec-7-ene is isolated (Synthesis 1993, 735-762): t, 3.61 min (LC-1); ESI-MS (+): m/z 235.34 [M+H]'. 'H NMR (ppm, CDCl): 7.35(2H); 6.95 (2H); 5.9(1H); 4.05(4H); 2.65(2H) ; 2.45(2H); 1.9(2H).

i ® 'y 49 b) 8- (4 -fluorophenyl)-1,4-dioxaspiro(4.5]decane: 8- (4-fluorophenyl)-1,4-dioxaspiro(4.5]dec-7-ene is hydrogenated using Pd/C with hydrogen. After filte ring-off of the catalyst over celite and evaporating-off of the solventz, 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec ane is obtained in a quantitative yield: t, 3.65 min (LC-21); ESI-

MS(+): m/z 237.26 [M+H]'. c) 4-(«<a-fluorophenyl) -cyclohexanone: 8-(4-f luor-phenyl)-1,4-dioxaspiro(4.5]decane (2 mmol) is dissolved in dioxane (6.5 ml) and treated with 3 ml 50% agueou s sulphuric acid accompanied by stirring at room ® temper ature for 5 hours. After dilution with water (12 ml) extrac tion is carried out twice with dichloromethane. The raw title compound is obtained from the combined organic phases after drying over sodium sulphate and evaporating- off of the solvent in a vacuum (Tetrahedron 1998, 54, 15509-15524): t, 3.44 min (LC-1); ESI-MS(+): m/z 1.93.29 [M+H]" .

The preparation of the precursor-products for Examples C-55 to C~&6 takes place in a manner similar to that described above for the preparation of 4-(4-fluorophenyl) - cyclohexanone. [ 4-o-tolyl-cyclohexanone (precursor-product for Example C- 55) 'H NMR (ppm,CDCl,)): 7.3 (2H); 7.1 (2H); 3.15 (1H); 2.45 (4H); 2.35 (3H); 2.1 (2H); 1.85 (2H); 1.65(2H); 1..4 (4H); 1.15( 1H). 4- (2- ethyl-phenyl) -cyclohexanone (precursor-produict for

Examp-le C-56) t, 3.62 min (LC-1); ESI-MS (+): m/z 203.29 [M+H]" . 4-(3, 4-dimethoxyphenyl) -cyclohexanone (precursor —product for Example C-57) t, 3.43 min (LC-1); ESI-MS (+): m/z 235.28 [M+H]" .

® 4- (4-cyanophenyl) -cyclohexanone (precursor-product. for

Example C-5 8) t, 1.92 min (LC-2); ESI-MS (+): m/z 200.33 [M+H]" .

S

4-(3,5-bis- trifluormethylphenyl)-cyclohexanone ({(prrecursor- product for Example C-59) t, 2.46 min (LC-2); ESI-MS (+): m/z 311.29 [M+H]' . 4-p-tolyl-c yclohexanone (precursor-product for Example C- 60) t, 2.11 min (LC-2); ESI-MS (+): m/z 189.32 [M+H]". 4-m-tolyl-cyclohexanone (precursor-product for Example C- 61) t, 2.12 min (LC-2); ESI-MS (+): m/z 189.32 [M+H]'. 4- (3-methoxy-phenyl) -cyclohexanone (precursor-prociuct for

Example C-6&2) t, 2.08 min (LC-2); ESI-MS (+): m/z 205.35 [M+H]". 4-(4-chloro-phenyl) -cyclohexanone (precursor-prod-uct for

Example C-6&3) t, 2.26 min (LC-2); ESI-MS (+): m/z 209.23 [M+H]". ® 4- (3-fluorcophenyl) -cyclohexanone (precursor-product for

Example C-64) t, 2.11 min. (LC-2); ESI-MS (+): m/z 193.26 [M+H]" . 4-thiophene-2-vl-cyclohexanone (precursor-product. for

Example C-&5) t, 2.05 mim (LC-2); ESI-MS (+): m/z 219.29 [M+H] . 4-benzo[1l, 3]dioxol-5-yl-cyclohexanone (precursor —product for Example C-66) t, 2.05 mim (LC-2); ESI-MS (+): m/z 181.23 [M+H]".

® 2-bromo-5 s-dimethyl-cyclohexanone (starting product for

Example C-67); 2-bromo-5 -ethyl-5-methyl-cyclohexanone (starting peroduct for Example C-68) and 2-bromo-5-methyl-5-phenyl-cyclohexanone (starting product for Example C-69)

The bromination of 3,3-dimethyl-cyclohexanone, 3-ethyl-3- methyl -cy?clochexanone, and 3-methyl-3-phenyl-cyclolhexanone respectively (precursor stages of Examples C-67 to C-69) takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexancne. The title compounds are reacted as crude products witliout @® further characterization. 2-bromo-5,5-dimethyl -4-phenyl-cyclohexanone (starting product f£or Example C-70)

The bromination of 3,3-dimethyl-4-phenyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization. 3,3-dimetthyl-4-phenyl-cyclohexanone (precursor stage of

Example C-70)

Lithium chloride (0.6 mmol) and copper iodide (0.3 mmol) ® are introduced first under argon in dry tetrahydrofuran (18 ml). At O°C 3-methyl-4-phenylcyclohex-2-enone (3 tmnmol) is added and stirring continues for another 10 min at this temperature. Then a solution of methylmagnesium bromide (3.6 mmol) is slowly added dropwise and the react don mixture Dis maintained at 0°C for 3 hours accompan ied by stirring . The reaction is stopped by adding saturated aqueous ammonium chloride solution. The mixture is extracted with diethyl ether. The title compound is obtained from the combined organic phases after drying over sodium sulphate and evaporating-off of the solvent in a vacuum («J. Organom. Chem. 1995, 502, C5-C7): t, 2.36 min (LC-2); ESI-MS (+): m/z 203.35 [M+H] .

K _ 2-bromo-3-methyl-cyclohexanone (st-arting product for

Example C-71)

A solution of N-bromosuccinimide €0.48 mmol) and sodium acetate (0.04 mmol) in THF/ water (1:1, 5.2 ml) is cooled to 0°C and trimethyl- (3-methyl-cyclohex-1-enyloxy)-silane (0.4 mmol, 80% pure) is added dropowise. The reaction mixture is heated to room temperat-ure and stirring is continued overnight. After addition of water extraction is carried out with ethyl acetate. Tlie title compound is obtained from the combined organic phases after drying over sodium sulphate and evaporating-offf of the solvent in a

C vacuum (JOC 1997, 62, 19, 6692-6636) .

Trimethyl-(3-methyl-cyclohex-1-eny-loxy)-silane (precursor- product for Example C-71)

Lithium chloride (2 mmol) and coppeer iodide (1 mmol) are introduced first under argon in tetrahydrofuran (5.6 ml) and cooled to -78°C. Cyclohex-2-enone (1 mmol) and trimethylsilyl chloride (1.1 mmol) are added and the solution is stirred for another 10 min. Then a solution of methylmagnesium bromide (1.2 mmol) is slowly added dropwise. After stirring for 3 hou rs at -78°C saturated aqueous ammonium chloride solution is added and extraction 1s carried out with ether. The combined organic phases are @ dried over sodium sulphate and the solvent is removed in a vacuum. The crude product obtained contains according to

LC-MS 80% trimethyl- (3-methyl-cycl.ohex-1l-enyloxy)-silane and 20% of the starting compound amd is used in the subsequent reaction without further purification (J.

Organom. Chem. 1995, 502, C5-C7): ~H NMR (ppm, CDCl): 4.75(1H); 2.25(1H); 1.95(2H); 1.75 (2H); 1.05(1H); 0.95 (3H); 0.2 (9H). 2-bromo-6-phenyl-cycloheptanone (starting product for

Example C-72)

The bromination of 3-phenylcyclohepotanone takes place in a manner similar to that described aloove for the preparation

'@® _ of 2-bromo-4-isopropyl-cycl ochexanone. The title compound is reacted as a crude product without further characterization. 5S 2-tert-butyl-6-chloro-4-phenyl-cyclohexanone (starting product for Example C-73)

The chlorination of 2-tert-Dutyl-4-phenyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization. <9 2-tert-butyl-4-phenyl-cyclohexanone (precursor stage for

Example C-73) a) Trimethyl- (4-phenyl-cyclohex-1l-enyloxy)-silane: sodium iodide (12.4 mmol) dissolved in acetonitrile (12.4 ml), is added dropwise at room temperature to a solution of 4 -phenylcyclohexanone (10 mmmol) in hexane (10 ml), followed by triethylamine (12.4 mmol ) and trimethylchlorosilane (12.4 mmol). After stirring for two hours cold pentane and ice water are added. The agueous phase is extracted with hexane. The combined organi< phases are washed with ice water, dried over sodium sulphate and the solvent is removed in a vacuum. Trimethyl- (4-phenyl-cyclohex-1- enyloxy)-silane (1.8 g) is obtained in pure form in a yield ( of 73% (Tetrahedron 1987, 43, 9, 2075-2088): t, 2.29 min (LC-2); ESI-MS (+): m/z 247 .27 [M+H] . b) 2-tert-butyl-4-phenyl-cy<lohexanone:

Trimethyl- (4-phenyl-cyclohex-1-enyloxy)-silane (7.27 mmol) and tert-butyl chloride (7.85 mmol) are introduced first in dichloromethane under nitrogen and cooled to -45°C. A solution, also cooled to -45°C, of titanium tetrachloride (7.63 mmol) in dichloromethane (3.6 ml) is added, and stirring is continued for 3 hours at this temperature. The reaction mixture is diluted with dichloromethane and washed with ice water. The organic phase is dried over sodium sulphate and the solvent is removed in a vacuum. Column chromatography (ethyl acetatce/ heptane 1:4) of the residue i _ produces the title compound (250 mg) in a yield of 15% (Angew Chem Int Ed Engl 1978, 17, 1, 48-49). 'H NMR (ppm,

CDCl,): 7.35(5H); 3.15 (1H); 2.55(1H); 2.4 (3H); 2.25(1H); 2(1H); 1.8(1H); 1.05 (SH).

Example N-Q01 2-quanidino-6,7-dihydxo-4H-thiazolo[5,4-clpyridine-5- carboxylic acid tert-kutyl ester

Analogously to the preparation of Example C-01, 3-bromo-4- oxo-piperidine-l-carboxylic acid tert-butyl ester is reacted with 2-imino-4-thiobiuret to form the title ® compound. t, 2.55 min (LC-1); ESI-MS (+): m/z 298.25 ([M+H]" . 3-bromo-4-oxo-piperiddne-1-carboxylic acid tert-butyl ester (starting product for Example N-01)

The bromination of 4-oxo-piperidine-1l-carboxylic acid tert- butyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl- cyclohexanone. The title compound is reacted as a crude product without further characterization.

N-(4,5,6,7-tetrahydro—thiazolo[5,4-clpyridine-2-vyl)- guanidine (splitting-off of the protective group from the product according to Example N-01, 2-guanidino-6,7-dihydro- 4H-thiazolo([5,4-clpyridine-S-carboxylic acid tert-butyl [ ester) 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-clpyridine-5- carboxylic acid tert-loutyl ester (9.6 mmol) is suspended in a solution of ethanol (10 ml) and concentrated hydrochloric acid (3.8 ml) and stirred for 3 hours at room temperature.

After filtration, the product is precipitated by adding ethyl acetate to the «lear solution. The white precipitate is filtered off, washesd with ethyl acetate and then dried in a vacuum. The title compound is obtained in pure form (1.63 g) as dihydrochloride salt in a yield of 62%: t, 0.83 min (LC-1); ESI-MS (-) : m/z 232.23 [M-H] .

Example N-02

@ ®

N-(5-hexyl-4,5,6, )-tetrahydro. thiazolo 5.4-clpyridine-2- yl) -quanidine l-bromohexane (0.11 mmol) is added to a suspension of N- (4,5,6,7-tetrahydro-thiazolo[5,4-c] pyridine-2-yl)-guanidine

Ss (0.1 mmol) and caesium carbonate (0 .22 mmol) in dimethylformamide (0.3 ml) and the @xeaction mixture is stirred overnight at room temperatuzxe. After adding 2M caustic soda solution (1 ml) the mixture is extracted with ethyl acetate, the combined organic phases are dried over sodium sulphate and then concentrated by evaporation, the title compound being obtained in pu xe form. ® Analogously to Example N-02 the compounds of Examples N-03 to N-10 listed in Table 4 are produced by reaction of N- 1s (4,5,6,7-tetrahydro-thiazolo[5,4-c] pyridine-2-yl)-guanidine with the corresponding alkylhalides ("R'-reagents').

Example N-07

N- (5-benzyl-5,6,7,8-tetrahydro-4H-t hiazolo[4,5-¢clazepine-2- yl) -guanidine

Using an alternative method, analogously to the preparation of Example 1, 1-benzyl-4-bromo-azepan-3-one is reacted with 2-imino-4-thiobiuret to form the ti tle compound. 1-benzvl-azepan-3-one (precursor-pr-oduct of Example N-07) ® a) 5-(benzyl-ethoxycarbonylmethyl-amino)-pentanoic acid:

N-benzylglycine ethyl ester (1.87 ml) and 5-bromovaleric acid ethyl ester (1.92 ml) are disssolved in dimethylformamide (100 ml) and stirred in the presence of potassium carbonate (1.66 g) for 2 days at room temperature. The reaction is quenched with saturated aqueous ammonium chloride solution, and extraction is carried out with ethyl acetate. Aftter drying over sodium sulphate the combined organic phases are concentrated by evaporation. From the obtained reszdidue, 5- (benzyl- ethoxycarbonylmethyl-amino) -pentanomic acid is isolated in a yield of 30% by chromatography usimg silica gel (ethyl acetate/heptane 1:5).

'@® b) 1-benzyl-azepan-3 -one:

A suspension of pota ssium tert-butylate (336 mg) in toluene (2.5 ml) is refluxed for 10 min. Then S- (benzyl- ethoxycarbonylmethyl -amino) -pentanoic acid (695 mg) in toluene (1 ml) is slowly added to the suspension and when the addition is comp lete the mixture is refluxed for another 1.5 hours. After cooling to room temperature 25% hydrochloric acid (1 ml) is added. The organic phase is separated off and washed with 25% hydrochloric acid (4x 1 100 ml). The combined hydrochloric-acid aqueous phases are then refluxed for 5 hours . After cooling to room temperature the solution is made alkaline (pH 11) with 2N caustic soda ® solution and extract don is carried out with ethyl acetate.

The combined organic phases are concentrated by evaporation after drying over sodium sulphate. The obtained residue produces, after chrornatography using silica gel (ethyl acetate/ heptane 1:5) the desired title compound (197 mg) in a yield of 45 % (Bull. Chem. Soc. Jpn. 1956, 29, 631- 632; DE2206385). l-benzyl-4-bromo-azepan-3-one (starting product for Example

N-07)

The bromination of 1-—benzyl-azepan-3-one takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropywyl-cyclohexanone. The title compound is

C reacted as a crude pwxoduct without further characterization.

Example N-11

N-(pentanoyl-4,5,6,7—tetrahydro-thiazolo[5,4-clpyridine-2- yl) -quanidine

Diisopropylethylamine (0.22 mmol) and then pentanoyl chloride (0.11 mmol) are added to a stirred suspension of

N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]lpyridine-2-yl) - guanidine-dihydrochloride (0.1 mmol) in dimethylformamide (0.7 ml) and the reaction mixture is stirred for another 16 hours at room temperature. After the addition of 2M caustic soda solution (1 ml) extraction is carried out with ethyl

K

@ acetate. The <ombined organic phases produce the pure title compound aftexr drying over sodium sulphate and concentrating to dryness.

Analogously to Example N-11, the compounds of Exarunples N-13 to N-33 listed in Table 4 are produced by reactiorh of N- (4,5,6,7-tetrahydro-thiazolo([5,4-¢c]pyridine-2-yl) —guanidine with the corresponding acid chlorides ("R’-reagentms").

Example N-12

N-(5-but-3-encyl-4,5,6,7-tetrahydro-thiazolo[5,4- clpyridine-2-=/1) -quanidine ® Diisopropylethylamine (0.22 mmol), vinyl acetic acid (0.11 mmol) and ben=otriazolyloxy-tris- (dimethylamino)phosphonium-hexafluorophosphate (0 .11 mmol) are added successively to a stirred suspension of N- (4,5,6,7-tetrahydro-thiazolo([5,4-clpyridine-2-yl) — guanidine-dihsydrochloride (0.1 mmol) in dimethylformamide (0.7 mL), and the reaction mixture is stirred for 16 hours at room tempexature. After the addition of 2M caustic soda solution (1 ml) there is extraction with ethyl acetate. The combined orgamic phases produce the pure title cormpound after drying over sodium sulphate and concentratirmg to dryness.

C Analogously to Example N-12 the compounds of Examples N-19 to N-21 listed in Table 4 are realized by reactiorh of N- (4,5,6,7-tetrahydro-thiazolo[5,4-c]lpyridine-2-yl) —quanidine with the corresponding carboxylic acids ("R’-reagents") in the presence of benzotriazolyloxy-tris- (dimethylamino)phosphonium-hexafluorophosphate as coupling reagent.

Example N-22 2-guanidino-6, 7-dihydro-4H-thiazolo[5,4-clpyridine-5- carboxylic acid benzyl ester

Benzyl chloroformate is added to a stirred suspension of N- (4,5,6,7-tetrahydro-thiazolo[5,4-clpyridine-2-yl) —guanidine

@ ® (0-1 mmol) and diisopropylethylamine (0.22 mmc1l) in dimethylformamide (0.7 ml) and the mixture is stirred for another 3 hours at room temperature. After the addition of satturated aqueous sodium carbonate solution e>xtraction is carried out with ethyl acetate; the combined organic phases produce the pure title compound after drying over sodium sulphate and complete evaporation of the solveant.

Analogously to Example N-22 the compound of Example N-23 listed in Table 4 is produced by reaction of NI-(4, 5, 6, 7- tettrahydro-thiazolo[5,4-clpyridine-2-yl) -guani dine with ® butyl chloroformate ("R’-reagent").

Example N-24

N-[5-(propane-2-sulphonyl)-4,5,6,7-tetrahydro- thiazolo[5,4- clpyridine-2-vl)]-guanidine

Propane-2-sulphonyl chloride is added to a stirred suspension of N-(4,5,6,7-tetrahydro-thiazolo(5 ,4- clpyridine-2-yl)-guanidine (0.1 mmol) and dii sopropylethylamine (0.22 mmol) in dimethylf ormamide (0.7 ml) and the mixture is stirred for another 16 hours at room temperature. After the addition of 2M caustic soda solution (1 ml) extraction is carried out with ethyl ac etate; the combined organic phases produce [from] the pur-e title compound after drying over sodium sulphate and. complete ® eva.poration of the solvent.

Ana logously to Example N-24 the compounds of E xamples N-25 and N-26 listed in Table 4 are produced by rea ction of N- (4, 5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2- yl) -guanidine wit h the corresponding sulphonyl chlorides ("R ’'-reagents").

Example N-27 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-clpyri dine-5- cardoxylic acid phenyl amide

Dii sopropylethylamine (0.2 mmol) and, after 5 min, phenyl iso cyanate (0.11 mmol) are added to a suspension of N- (4, 5,6,7-tetrahydro-thiazolo[5,4-clpyridine-2--yl) -guanidine

@ ® s dihydrochloride (0.1 mmol) in timethyl formamide (0.5 ml).

The reaction mixture is stirred for another 3 hours at room temperature. Then saturated aqueous sodium carbonate solution is added and extraction is carried out with ethyl acetate. The pure title compound is obtained after drying of the combined organic phases over sodium sulphate and removal of the solvent in a vacuum.

Analogously to Example N-27 the compounds of Examples N-28 and N-29 listed in Table 4 are produced by reaction of N- (4,5,6,7-tetrahydro-thiazolo[5,4-clpyridine-2-yl) -guanidine dihydrochloride with the "R’-xeagents" tert-butyl ® isocyanate, and pentyl isocyarate respectively.

Example N-30 2-guanidino-6,7-dihydro-4H-thdazolo[S5,4-clpyridine-5- thiocarboxylic acid benzyl amide

Benzylamine (0.1 mmol), dissolved in dimethylformamide (0.3 ml), is added under argon to a solution of 1'-thiocarbonyldiimidazole (0-1 mmol) in dimethylformamide (0.5 ml). After stirring for 2.5 hours at room temperature a solution of N-(4,5,6,7-tetrahydro-thiazolo[5,4- clpyridine-2-yl)-guanidine dihydrochloride (0.1 mmol) and diisopropylethylamine (0.2 mmol) in dimethylformamide are added successively to the reaction mixture. This is stirred ® for another 16 hours at room temperature and then quenched with saturated aqueous sodium carbonate solution. There is extraction with ethyl acetate and the combined organic phases are dried over sodium sulphate. After removal of the solvent in a vacuum the pure title compound is obtained (Bioog. Med. Chem. Lett. 2002, 12, 337-340).

Analogously to Example N-30 tlhe compounds of Examples N-31 to N-33 listed in Table 4 are produced by reaction of N- (4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl) -guanidine dihydrochloride with the corressponding amines in the presence of 1l'-thiocarbonyldiimidazole.

. _ ® &0

Preparative LC-MS

Preparative separations of mixtures of substances are carried out on a preparative LC-MS apparatus (Waters Prep

LC-MS equipped with a Waters €00 Controller, Waters 2767

Sample Manager, Waters 996 mass spectrometer and photodiode-array detector). Am Xterra Prep MS C18 column (5 pm particle size, length 50 men, diameter 19 mm) is used, with a linear gradient of water/0.06% formic acid (A) and acetonitrile/0.06% formic acid (B) and a flow rate of 20 ml/min.

Analytical methods ® The 'H-NMR-spectra are measurexd on a Varian Oxford 300 spectrometer at 300 K; the chemical shift J is given in ppm deep field shifted from the tetramethylsilane signal as reference, with the residual signals of deuterated dimethyl sulphoxide (J (H) 2.49 ppm), deuterated chloroform (J(H) 7.24 ppm) and deuterium oxide serving as internal standard. ®

Table 2 1H-NMR data of selected compounds of Formula I. le coz | (4H); 2.65 (3H); 2.15 (1H); 1.85 (2H); 1.4 (1H); 1 (3H) 08 |e (4H); 2.5 (4H); 2.05 (1H); 1.85 DMSO-cig (1H); 1.65 (1H); 1.3 (6H), 0.95 (3H)

EEE ( 4H); 2.75 (lH); 2.45 (4H); 1.8 (2H); 1.45 (2H); 1.2 (6H), 0.95 (3H)

EEE (4H); 7.3 (4H); 7.2 (1H); 2.95 (2H); 2.75 (3H): 2 (3H)

C-12 [7 (4H); 2.75 (lH); 2.45 (1H); 2.25 DMSO-3¢ ® (1H); 1.55 (1H); 1.15 (1H); 1.1 (3H); 1 (3H); 0.85 (3H)

C-24 [8.3 (4H); 7.4 (5H); 4.35 (2H); 4.25 DMSO-d, (2H) ; 3.55 (2H); 2.9 (2H); 2.1 (2H) (1H); 3.3 (1H); 1.95-1.5 (10H); 1.15 (5H) (2d); 2.1 (1H); 1.85 (1H); 1.15 (3H)

BE ( 4H); 7.3 (51); 4.05 (2H); 3.45 DMSO-d (1H); 3.1 (1H); 2.65 (lH); 2.4 (3H); 1.05 (3H) 2.7 (3H); 2 (2H) (3H); 2.95 (2H); 2.7 (3H); 2 (2H)

ERE (1H); 2.5 (2H); 1.85 (2H); 1.6 (1H); 1.3 (1H); 1.15 (3H) ® (2H); 3.55 (2H); 2.9 (2H); 2.05 (2H)

EEE (4H); 3.05 (2H); 3 (2H); 2.7 (3H); DMSO-d 2.5 (22H)

N-13 [6.8 (<4H); 4.5 (2H); 3.75 (2H); 2.95 DMSO-d (1H); 2.6 (lH); 2.5 (lH); 1 (6H)

N-22 [7.3 (®H); 6.8 (4H); 5.1 (2H); 4.45 DMSO-d 4 (2H); 3.7 (2H); 2.55 (2H)

N-26 |7 (4H); 4.2 (2H); 3.45 (2H); 2.9 (3H): DMSO-d 2.65 (2H)

N-29 [6.8 (4H); 6.55 (1H); 4.3 (2H); 3.6 DMSO-d (2H); 3 (2H); 2.5 (2H); 1.4 (2H); 1.25 (4H); 0.85 (3H) (2H); 4.8 (2H); 4.1 (2H); 2.6 (2H)

@ @ NN 9 1

The compounds produced are analyzed by means of reversed- bhase HPLC, on a Waters Alliance LC, equipped with a UWV- detector and a MassLynx-NT mass spectrometer.

S

LC-1: GROM-SIL 120 ODS-4 HE HPLC column (particle size 3um, column length 30 mrm, diameter 2mm), with a linear graddent with water/0.06% formic acid (A) and acetonitrile/0.06% formic acid (B) of 5% to 95% B in 3 min. with a flow rate of 0.75 ml/min. ) LC-2: XTerra MS C18 HPLC column (particle size Sum, column length 50 mm, diameter 2.1 mm), with a linear gradient with water/0.06% formic acid (A) and acetonitrile/0.06% formic acid (B) of 5% to 95% B in 2.5 min. with a flow rate of 0.75 ml/min. _

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Claims (21)

‘* ® Claims

1. Use of guanidine derivatives of general formula HN oss S I o in which A represents a chain of 3-6 optionally substituted C atoms, one of which can be replaced by -N(R')- or -0-; and R' repxesents hydrogen or a substitute; the rimg skeleton containing only the two double bonds of the th iazole component; of pha rmaceutically applicable acid addition salts of basic compounds of formula I, pharmaceutically agoplicable salts of acid group-containing compounds of formala I with bases, pharma ceutically applicable esters of hydroxy or carboxy group- containing compounds cof formula I and hydrates or solvat.es thereof; as neuropeptide FF receptor antagonists or for the [) preparation of corresponding medicinal products.

2. Use according to claim 1 for the treatment of pain and hyperalgesia, withdrawal syndromes in the case of alcohol, psychotropic and nicotine dependences and for the improvement or elimination of these dependences, for the regulation of insulin secretion, food intake, memory funct ions, blood pressure, and of the electrolyte and energy balance and for the treatment of urinary incontinence or for the preparation of corresponding medicinal products.

® CE EL8E ®

3. Use according to claim 1 or 2 of compounds of the gener al formula HN N Hs — s 11 in wh ich R' means alkyl, alkanoyl, alkenyl, alkinyl, alkox ycarbonylalkyl, alkoxycarbonylaminoalkanoyl, alkyl carbamoyl, alkoxycarbonylalkylcarbamoyl, alkox-ycarbonylalkylthiocarbamoyl, alkylthiocarbamoyl, mono- [ or di substituted aminoalkanoyl, aryl, arylalkyl, aryla lkoxycarbonyl, arylalkanoyl, arylcarbamoyl, alkox-yalkanoyl, alkylsulphonyl, arylthiocarbamoyl, aryloxycarbonylalkyl, aryloxycarbonylalkanoyl, aryloxycarbonylalkylcarbamoyl, aryloxycarbonylalkyXEthio- carbammoyl, arylsulphonyl, cycloalkyl, cycloalkanoyl, cycloalkylcarbamoyl, cycloalkylthiocarbamoyl, cycloalkylcarbonyl, cycloalkyloxycarbonylalkyl, cycloalkyloxycarbonylalkanoyl, cycloalkyloxycarbonylalkylcarbamoyl, cycloalkyloxycarbonylalkyl-thiocarbamoyl, heteroaryrlalkyl, heterocyclylalkyl, heterocyclylalkoxycarbonylalkyl, heterocyclylalkoxycarbonylalkanoyl, ® heterocyclylalkoxycarbonylalkylcarbamoyl, heterocyclylalkoxycarbonylalkylthiocarbamoyl, heteroaryloxycarbonylalkyl, hetero- aryloxycarbonylalkylcarbamoyl or heteroaryloxycarbonylalkylthiocarbamoyl.

4. Use according to claim 3, in which the ring skeleton contains a thiazolopyridine, thiazolocazepine or thiazolooxepane skeleton, which contains only the t.wo double bonds of the thiazole component.

@ ®

5. Use according to claim 4 > in which the ring skeleton is a 5,6-dihydro-4H-cyclopentathiazole, 6,7-dihydro-4H- pyrano[4, 3-d]lthiazole, or 5,6,7,8-tetrahydro-4H- thiazolo[4,5~-c]lazepine skeleton.

6. Use according to one of claims 3-5, in which R' means methyl, ethyl, propyl, hexyl, 2,2-dimethylpropionyl, cyclopropylmethyl, 2-cyclohexylethyl, propinyl, ethyloxycarbonylethyl, benzyl, n-butyloxycarbonyl, tert- butyloxycarbonyl, benzyloxy-carbonyl, 3-methyl-butyryl, pentanoyl, phenylacetyl, 2-propyl-pentanoyl, [ cyclopropanecarbonyl, iscbutyryl, but-3-enoyl, 2-methoxy- acetyl, propane-2-sulphonyl, butane-1-sulphonyl, methanesulphonyl, tert-butyloxycarbonyl-aminopropionyl or 4-dimethylamino-butyryl.

7. Use according to claim 1 or 2 of 2-guanidino-6, 7-dihydro-4H-thiazolo[5,4-¢c]pyridine-5- carboxylic acid tert-butyl ester; N-(5-hexyl-4,5,6,7-tetrahydro-thiazolo(5,4-clpyridine-2- v1) -guanidine; N-[5- (2-cyclochexyl-ethyl)-4,5,6,7-tetrahydro-thiazolol[5, 4- clpyridine-2-yl] -guanidine; N- (5-ethyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2- yl) -guanidine; ® 2-guanidino-6,7-dihydro-4H-thiazolo [5,4-c]pyridine-5- carboxylic acid butyl ester; N- [5- (propane-2-sulphonyl) -4,5,6, 7-tetrahydro-thiazolo [5,4 - clpyridine-2-yll-guanidine; N-(5-phenylacetyl-4,5,6,7-tetrahydro-thiazolo(5, 4- clpyridine-2-yl)-guanidine; 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester; N- (5-pentanoyl-4,5,6, 7-tetrahydro-thiazolo[5,4-c]pyridine- 2-yl)-guanidine; 2-guanidino-6,7-dihydro-4H-thiazolo[5,4-clpyridine-5- thiocarboxylic acid propyl amide;

'@ N- [5- (2-propyl-pentaroyl) -4, oe , 7-tetrahydro-thiazole(5,4- clpyridine-2-yl] -guariidine; N- (5-benzyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2- vl) -guanidine; N-(5-prop-2-ynyl-4,5, 6,7-tetrahydro-thiazolo([5,4- clpyridine-2-yl) -guaraidine; N- (5-cyclopropanecarloonyl-4,5,6,7-tetrahydro-thiazolo[5,4- clpyridine-2-yl) -guaraidine; N- [5- (butane-1-sulphenyl)-4,5,6,7-tetrahydro-thiazolo[5, 4-

clpyridine-2-yl]-guamidine;

N- (5-isobutyryl-4,5,6 ,7-tetrahydro-thiazolo[5,4-c]lpyridine- 2-yl) -guanidine;

o N- [5-(2,2-dimethyl-propionyl)-4,5,6,7-tetrahydro- thiazolo([5,4-c]pyridi ne-2-yl] ~guanidine;

2-guanidino-6,7-dihydro-4H-thiazolo([5,4-¢clpyridine-5- thiocarboxylic acid benzyl amide; 2-guanidino-6,7-dihyd ro-4H-thiazolo[5,4-clpyridine-5- carboxylic acid tert- butyl amide;

N-(5-but-3-enoyl-4,5, 6,7-tetrahydro-thiazolo[5,4-

clpyridine-2-yl)-guan idine;

N- (5-benzyl-5,6,7,8-t etrahydro-4H-thiazolo[4,5-clazepine-2- yl) -guanidine; 3-(2-guanidino-6,7-dithydro-4H-thiazolo[5,4-c]pyridine-5- yl) -propionic acid ethyl ester;

2-guanidino-6,7-dihydzo-4H-thiazolo[5,4-c]lpyridine-5-

® carboxylic acid pentyl amide; N- [5- (2-methoxy-acetyl}-4,5,6,7-tetrahydro-thiazolol[5,4- clpyridine-2-yl] -guanzidine; N- (5-cyclopropylmethy1-4,5,6,7-tetrahydro-thiazolo([5,4-

clpyridine-2-yl) -guanzidine;

N- (5-methanesulphonyl—4,5,6,7-tetrahydro-thiazolo[5, 4- clpyridine-2-yl)-guanzidine;

N- [5- (3-methyl-butyryl)-4,5,6,7-tetrahydro-thiazolo[5, 4- clpyridine-2-yl] -guanidine;

2-guanidino-6,7-dihydro-4H-thiazolo[5,4-c]lpyridine-5- thiocarboxylic acid- (2-methoxy-1-methyl-ethyl) -amide; 2-guanidino-6, 7-dihydro-4H-thiazolo[5,4-¢clpyridine-5- carboxylic acid phenyl. amide;

@ ® [3- (2-guanidino-6, 7-dihydro-4n. thiazole [5,4-clpyridine-5- yl) -3-oxo-propyl] -carbamic acid tert-butyl ester; N- [5- (4-dimethylamino-butyryl) -4,5, 6, 7—tetrahydro- thiazolo([5,4-clpyridine-2-yl] -guanidine; N-(5-propyl-4,5,6,7-tetrahydro-thiazolo[5,4-clpyridine-2- vl) -guanidine; and 2-guanidino-6,7-dihydro-4H-thiazolo[5, 4-clpyridine-5- thiocarboxylic acid isopropyl amide.

8. Compounds of Formula I defined in claim 1, in which A means a chain of 3-6 optionally substittuted C atoms, one of which can be replaced by -0-, the ring skeleton containing ® only the two double bonds of the thiazole component; pharmaceutically applicable acid addition salts of basic compounds, pharmaceutically applicable salts of acid group- containing compounds with bases, pharmaceutically applicable esters of hydroxy or carboxy group-containing compounds as well as hydrates or solvates thereof; with the exception of - N-(4,5,6,7-tetrahydro-benzothiazole-2-yl) -guanidine; - (2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-yl) - ethyl acetate ethyl ester; - N- (4-hydroxymethyl-4,5,6,7-tetrahydro-benzothiazole-2- yl) -guanidine; - N- (4-tosyloxymethyl-4,5,6,7-tetralaydro-benzothiazole- ® 2-yl) -guanidine; - N- (4-azidomethyl-4,5,6,7-tetrahydro-benzothiazole-2- yl) -guanidine; - N- (4-aminomethyl-4,5,6,7-tetrahydro-benzothiazole-2- yl) -guanidine; and - N- (6-acetylaminomethyl-4,5,6,7-tetrahydro- benzothiazole-2-yl) -guanidine.

9. Compounds according to claim 8, ima which, in chain A - one of the C atoms carries one or two identical or different substituents; or - several of the C atoms each carry one or two identical or different substituents.

@

10. Compounds according to claim 9, in which the substituent (s) are selected from alkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, aralkyl, alkoxycarbonyl, carboxamido , cyano or cyanclakyl groups and/or from polymethyl groups linked with one and the same C atom.

11. Compoumds according to claim 10, in which the substituent (s) is/are selected from - methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, allyl and cycloheax-1-enyl groups; and/or ® - phenyl , o-tolyl, m-tolyl, p-tolyl, 2-ethylphenyl, 3- fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- cyanopkenyl, 4-benzyloxyphenyl, 3-methoxyphenyl, 4- methoxsphenyl, 3,4-dimethoxyphenyl, 3,4- methylenedioxyphenyl and to-3,5-trifluoromethylphenyl groups ; and/or - thiophene-2-yl and benzyl groups; and/or - ethoxycarbonyl groups; and/or - n-propywlamino, benzylamino, N-methyl-N-phenethylarnino, 3-methylbutylamino, phenylamino, N-butyl-N-ethylarnino, di-n-prropylamino, allylamino, piperidine-1- and morphol ine-4-carbonyl groups; and/or - cyano and cyanoethyl groups; and/or ® - pentamethylene groups linked with one and the same C atom.

12. Compourads according to claim 11, in which there is located on one and the same C atom on the one hand a phenyl group and ora the other hand an ethoxycarbonyl, cyano ox phenyl group.

13. N-(5-et.hyl-5-methyl-4,5,6,7-tetrahydro-benzothiazole- 2-yl)-guanidline and its formate; N-(5,5-dimet -hyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) — guanidine ard its formate;

@ ® N-(5,5-dimethyl-6-phenyl-4,5,6,7-tetrahydro-benzothiazol e- 2-yl) -guanidine and its formate; N-(4-tert-butyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) - guanidine; N-(e6-isopropyl-4,5, 6,7-tetrahydro-benzothiazole-2-yl) - guanidine; N-(5,5,7-trimethyl—4,5,6,7-tetrahydro-benzothiazole-2-y1.)- guanidine; N-(6,6-dimethyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) - guanidine; N- (5-butyl-5,6,7,8—tetrahydro-4H-cycloheptathiazol-2-yl)» - guanidine; ® N-(4-ethyl-4-methyl-4,5,6,7-tetrahydro-benzothiazole-2-wl) - guanidine; N-[6-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro- benzothiazole-2-yl1] -guanidine and its formate; N-(5-butyl-4,5,6,7—tetrahydro-benzothiazole-2-y1)- guanidine; N-(6-phenyl-4,5,6, 7-tetrahydro-benzothiazole-2-yl) - guanidine; N-(5-methyl-4,5,6, 7-tetrahydro-benzothiazole-2-y1l) - guanidine; N-(4-methyl-4-propwl-4,5,6,7-tetrahydro-benzothiazole-2 — yl) -guanidine; N-(6-propyl-4,5,6, 7-tetrahydro-benzothiazole-2-yl) - ® guanidine; N- (4-cyclohex-1-enwyl-4,5,6,7-tetrahydro-benzothiazole-2 — yl) -guanidine and dts formate; N- (4-sec-butyl-4,5 ,6,7-tetrahydro-benzothiazole-2-yl) - guanidine and its formate; and N- (4-isobutyl-4-methyl-4,5,6,7-tetrahydro-benzothiazole -2- yl) -guanidine.

14. N-(6-tert-butwl-4,5,6,7-tetrahydro-benzothiazole-2 - yl) -guanidine; 2-guanidino-6-phenvyl-4,5,6,7-tetrahydro-benzothiazole-6 - carboxylic acid ethyl ester and its formate;

@ N-[6-(1,1-dimethyl-propyl)-4, 5,6, 7-tetrahydro- benzothiazole-2-yl)] -guanidine; N- (7-methyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) - guanidine and its formate; N-[6-(3-methoxy-phenyl)-4,5,6,7-tetrahydro-benzothiazole-2- vl] -guanidine and its formate; N- (6-thiophene-2-yl-4,5,6,7-ttetrahydro-benzothiazole-2-yl) - guanidine and its formate; N-(5,5,7,7-tetramethyl-4,5,6, 7-tetrahydro-benzothiazole-2- yl) -guanidine; N- [6-(4-fluorophenyl) -4,5,6, 7-tetrahydro-benzothiazole-2- yl] -guanidine and its hydrobxomide; ® 2-guanidino-4,5,6, 7-tetrahydxo-benzothiazole-6-carboxylic acid ethyl ester and its hydmobromide; N-(4,4-dimethyl-4,5,6,7-tetrahydro-benzothiazole-2-yl)- guanidine; N- (4-methyl-4,5,6,7-tetrahydwo-benzothiazole-2-yl) - guanidine and its formate; N-(4,5,6,7-tetrahydro-benzothiazole-2-yl-4-spiro- cyclohexane) -guanidine and its formate; N-(5,6,7,8-tetrahydro-4H-cycdoheptathiazol-2-yl) -guanidine; N-(4-allyl-4,5,6,7-~tetrahydro-benzothiazole-2-yl) -guanidine and its formate; N- (6-methyl-4,5,6,7-tetrahydxo-benzothiazole-2-yl) - guanidine; C N-[6-(3-fluorophenyl) -4,5,6, 7-tetrahydro-benzothiazole-2- yl] -guanidine and its formate; N- (6-cyano-6-phenyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) - guanidine and its hydrobromide; N-(4-phenyl-4,5,6,7-tetrahydwro-benzothiazole-2-yl)- guanidine and its formate; amd N-(6,6-diphenyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) - guanidine and its formate.

15. N-[6-(4-methoxy-phenyl) -4,5,6,7-tetrahydro- benzothiazole-2-yl] -guanidin<e and its hydrobromide; N- (5-phenyl-5,6,7,8-tetrahydzro-4H-cycloheptathiazol-2-yl) - guanidine and its hydrobromide;

i . ® 99

N-(6,7-dihydro-4H-pyrano[4,3-d]thiaz o0l-2-yl) -guanidine; N- (6-benzo[1,3]dioxol-5-yl-4,5,6,7-t etrahydro- benzothiazole-2-yl)-guanidine and it-s formate; 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid propyl amide and its formate;

N-[6- (4-cyanophenyl)-4,5,6,7-tetrahy-dro-benzothiazole-2- yl] -guanidine and its formate;

N- (4-benzyl-4,5,6,7-tetrahydro-benzothiazole-2-yl) - guanidine and its formate;

N-(5-methyl-5-phenyl-4,5,6,7-tetrahy>dro-benzothiazole-2- yl) -guanidine and its formate; N-[6-(3,5-to-trifluoromethylphenyl) —4,5,6,7-tetrahydro-

® benzothiazole-2-yl] -guanidine and it=s formate; N-(6-0-tolyl-4,5,6,7-tetrahydro-ben=othiazole-2-yl) -

guanidine and its formate; N-(6-m-tolyl-4,5,6,7-tetrahydro-ben=othiazole-2-yl) - guanidine and its formate;

N-[6- (2~-ethyl-phenyl)-4,5,6,7-tetralhydro-benzothiazole-2- yl] -guanidine and its formate;

N-[6-(4-chlorophenyl)-4,5,6,7-tetralhydro-benzothiazole-2- yl] -guanidine and its formate; 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid benzyl amide and its formate; N-(5,6-dihydro-4H-cyclopentathiazol —2-yl) -guanidine;

N-[6-(4-benzyloxy-phenyl)-4,5,6,7-tetrahydro-benzothiazole-

C 2-yl] -guanidine and its hydrobromidez; 2-guanidino-4,5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid methyl phenethyl amide and its formate; N- (6-phenyl-4,5,6,7-tetrahydro-benzcothiazole-2-yl-4-spiro-

cyclohexane) -guanidine and its hydrcobromide; N-(6-p-tolyl-4,5,6,7-tetrahydro-ben=othiazole-2-yl) - guanidine and its formate 2-guanidino-4,5,6, 7-tetrahydro-benzothiazole-4-carboxylic acid- (3-methyl-butyl) -amide and its formate; and

N-(4-tert-butyl-6-phenyl-4,5,6,7-tekrahydro-benzothiazole- 2-yl) -guanidine.

’ ® Ce 100

16. 2-guanidino-4,5,6,7-tetrahydro-benzothia zole-6- carboxylic acid phenyl amide and its formate; 2 —guanidino-4,5,6, 7-tetrahydro-benzothiazole—4-carboxylic accid butyl ethyl amide and its formate; N-—{4-(2-cyano-ethyl)-4,5,6,7-tetrahydro-benzothiazole-2- yl] -guanidine and its formate; 2 -guanidino-4,5,6, 7-tetrahydro-benzothiazole —4-carboxylic a<cid ethyl ester and its hydrobromide; 2 -guanidino-4,5,6,7-tetrahydro-benzothiazole—4-carboxylic a cid dipropyl amide and its formate; 2 -guanidino-4,5, 6, 7-tetrahydro-benzothiazole—4-carboxylic a cid phenyl amide and its formate; ® 2 -guanidino-4,5, 6, 7-tetrahydro-benzothiazole—6-carboxylic a cid allyl amide and its formate; 2 -guanidino-4,5,6,7-tetrahydro-benzothiazole —4-carboxylic a cid propyl amide and its formate; MN¥-[4- (piperidine-1-carbonyl)-4,5,6,7-tetrahyciro- I»enzothiazole-2-yl]-guanidine and its formate; 2 -guanidino-4,5,6, 7-tetrahydro-benzothiazole -4-carboxylic a.cid allyl amide and its formate; 2 -guanidino-4,5,6,7-tetrahydro-benzothiazole -6-carboxylic a.cid- (3-methyl-butyl)-amide and its formate; NJ-[4- (morpholine-4-carbonyl)-4,5,6,7-tetrahy dro- I>enzothiazole-2-y1] -guanidine and its format e; and 2 -guanidino-4,5,6,7-tetrahydro-benzothiazole -4-carboxylic ® acid diisopropyl amide and its formate.

1.7. Compounds according to one of claims 8- 16 for use as therapeutic active ingredients.

1.8. A medicinal product, containing a compo und according to one of claims 8-16 and an inert carrier.

R92. Use of compounds according to one of cl aims 8-16, &ccording to claim 1 or 2.

20. Use of —~ N-(4,5,6,7-tetrahydro-benzothiazole-2-y~1) -guanidine;

L 3 ® Ce 101 - (2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-yl) - ethyl acetate ethyl ester; - N - (4-hydroxymethyl-4,5,6,7-tetrahydro-benzothiazole-2- vl) -guanidine; - N - (4-tosyloxymethyl-4,5,6,7-tetrahydro—benzothiazole- 2-yl) -guanidine; - N - (4-azidomethyl-4,5,6,7-tetrahydro-berzothiazole-2- yl) -gu anidine; - N ~(4-aminomethyl-4,5,6,7-tetrahydro-bemzothiazole-2- yl) -guanidine; and - N -(6-acetylaminomethyl-4,5,6,7-tetrahycdro- benzot hiazole-2-yl)-guanidine C accord ing to claim 1 or 2.

21. Method for the preparation of compounds according to one of claims 8-16, characterized in that a compound of the following Formula 1 S NH any Sn HN 0 _=0 3 N Hn, J = (Z, —— {+ @® Hal S 1 2 I is hal ogenated in a-position to form the ca. rbonyl group, the ob»tained compound of the above Formula 2 is subjected to a cyclocondensation with 2-imino-4-thiol»iuret of the above Formula 3 and optionally an obtained basic compound is comxverted into a pharmaceutically applictable acid addition salt or an obtained compound, cont.aining an acid group, into a pharmaceutically applicable salt with a base or an obtained, hydroxy- or carboxy group-ceontaining, compound into a pharmaceutically applicable= ester and optiomally the obtained product into a hydr-ate or solvate.