MXPA99005459A

MXPA99005459A - Espiro [piperidin-4,1'-pirrolo [3,4-c] pirr

Info

Publication number: MXPA99005459A
Application number: MXPA/A/1999/005459A
Authority: MX
Inventors: Rover Stephan; Wichmann Jurgen; Adam Geo; Kolczewski Sabine; Dautzenberg Frank
Original assignee: F Hoffmannla Roche Ag
Priority date: 1998-06-12
Filing date: 1999-06-11
Publication date: 2000-08-01

Abstract

The present invention relates to compounds of general formula (I), wherein the substituents are described in the application, and pharmaceutically acceptable addition salts thereof. The compounds of the invention are useful in the treatment of diseases related to the orphanin FQ receptor (QFQ), which include psychiatric, neurological and physiological disorders, such as anxiety and stress disorders, depression, traumas, loss of memory due to Alzheimer's disease or other dementias, deficits of cognition and learning, epilepsy and seizures, acute or chronic pain conditions, and withdrawal symptoms of drug addiction, water balance control, Na + excretion, disorders of the arterial blood pressure, and metabolic disorders such as obesity

Description

ESPIRO [PIPERIDIN-4, 1 '-PIRRÓLO [3, 4-c] PIRROL] Description of the Invention The present invention relates to compounds of general formula wherein R1 is cycloalkyl of 5 to 12 carbon atoms, optionally substituted with lower alkyl; decahydro-naphthalen-1-yl; decahydro-naphthalene-2-ylo; indan-1-yl or indan-2-yl, optionally substituted with lower alkyl; decahydro-azulen-2-yl; bicyclo [6.2.0] dec-9-yl; acenaphthen-1-yl; bicyclo [3.3.1] non-9-yl; 2, 3-dihydro-lH-phenalen-1-yl; 2,3, 3a, 4,5,6-hexahydro-lH-phenalen-1-yl; octahydro-inden-2-yl; 1,2,3, 4-tetrahydro-naphthalene-1-yl; 1,2,3, 4-tetrahydro-naphthalen-2-yl; Naphthalene-alkyl REF.:30305 lower-1-yl; naphthalene-lower alkyl-2-yl; acenaphthen-1-yl; and 5-isopropyl-2-methyl-bicyclo [3.1.0] hex-3-yl; R2, R3 are hydrogen; hydroxyl; lower alkyl; = 0; or phenyl, optionally substituted with lower alkyl, halogen or alkoxy; R4 is hydrogen; lower alkyl; - (CH2) nCH (OH) CF3; - (CH2) n-cycloalkyl of 3 to 6 carbon atoms; phenyl; benzyl; tetrahydrofuran-3-yl; - (CH2) n0CH2C6H5, - (CH2) nmorpholinyl; 3-methyl-oxetan-3-yl-methyl; - (CH2) pCH20H; -S (0) 2-lower alkyl; -C (0) -lower alkyl; -C (0) CF3; -C (0) (CH2) n0CH3; - (CH2) nC (0) N (lower alkyl) 2; -S (O) 2 -heteroaryl; -C (O) heteroaryl; -S (0) 2-phenyl; -S (0) 2-N (lower alkyl) 2; -C (0) -cycloalkyl of 3 to 6 carbon atoms; -C (0) O-phenyl; or -C (0) O-lower alkyl: R5 is hydrogen; halogen; lower alkyl; trifluoromethyl or lower alkoxy; n is 0-3; and pharmaceutically acceptable acid addition salts thereof. The compounds of formula I and their salts are characterized by their interesting therapeutic properties. It has surprisingly been found that the compounds of the present invention are agonists and / or antagonists of the FQ orphanin receptor (OFQ). Consequently, they are useful in the treatment of psychiatric, neurological and physiological disorders, and especially, although they are not limited to them, they are useful for the improvement of symptoms of anxiety and stress disorders, depression, traumas, loss of memory due to Alzheimer's disease or other dementias, deficits in cognition and learning, epilepsy and seizures, chronic and / or chronic pain conditions, withdrawal symptoms addictive to the drug, water balance control, Na + excretion, arterial blood pressure and metabolic disorders such as obesity.

These indications are described in the following references: - Nociceptin / Orphanin FQ and the ORL1 receptor of the opioid receptor type, Eur. J. Pharmacol., 340: 1-15, 1997; - The orphan opioid receptor and its endogenous ligand nociceptin / orphanin FQ, Trends Pharmacol. Sci., 18: 293-300, 1997; - Orphanin FQ is an antiopioid functional peptide, Neuroscience, 75: 333-337, 1996; - Absence of orphanin FQ / nociceptin, of antinociceptive, hyperalgesic or allodynic effects in acute thermal or mechanical tests, after intracerebral or intrathecal intra-muscular administration, in mice or rats, Eur, J. pain. 2: 267-280, 1998; - Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress, Proc, Nati, Acad, Sci., USA, 94: 14854-14858, 1997; - Orphanin FQ, an ORLl opioid receptor agonist in orphan, stimulates the feeding of rats, Neuroreport, 8: 369-371, 1996; - Facilitation of long-term potentiation and memory in mice devoid of nociceptin receptors, Nature, 394: 577-581, 1998; - Distribution of the nociceptin / orphanin FQ receptor transcript in the human central nervous system and immune cells, J. Neuroimmuno, 81: 184-192, 1998. - The OFQ, a heptadeca peptide, has been isolated from the brain of the rat and is a natural ligand to a receptor (OFQ-R), coupled to the G protein that is found at high levels in brain tissue. The OFQ presents an agonistic activity to OFQ-R both in vitro and in vivo.

Julius (Nature 377, 476, [1995]) describes the discovery of OFQ, indicating that this peptide shares the greatest sequence homology with dynorphin A, an endogenous ligand, established for opioid receptors. OFQ inhibits adenylate cyclase in CHO cells (LC 132+) in culture and induces hyperalgesia when administered intracerebroventricularly to the mouse. The results model indicates that this heptadecapeptide is an endogenous agonist of the LC 132 receptor and appears to have pronociceptive properties. It has been described that when injected intracerebroventricularly in mice, OFQ slows motor activity and induces hyperalgesia and it has been concluded that OFQ can act as a brain neurotransmitter to modulate nociceptive and locomotor behavior. The subject of the present invention are the compounds of formula I and the pharmaceutically acceptable addition salts thereof, the racemic mixtures and their corresponding enantiomers, the preparation of the compounds mentioned above, the medicaments containing them and their preparation, and also the use of the compounds mentioned above for the control or prevention of diseases, especially of diseases and disorders of the types described above, or in the preparation of the corresponding medicaments. The following definitions of the general terms used in the present description apply regardless of whether the terms in question appear alone or in combination, such as p. ex. lower alkyl and lower alkoxy- As used herein, the term "lower alkyl" represents a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. The term "cycloalkyl" represents a saturated carbocyclic group containing from 5 to 12 carbon atoms, preferably cyclohexyl, cyclooctyl, cyclononyl and cyclodecyl. The term "heteroaryl" includes a 5-6 membered aromatic ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl are furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, pyrrazolyl, pyridinyl and pyrimidinyl.

The term "halogen" represents chlorine, iodine, fluorine and bromine. The term "pharmaceutically acceptable acid addition salts" comprises the salts with inorganic and organic acids already known in the art for pharmaceutical purposes, such as for example hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acid fumaric, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulfonic acid, and the like. Preferred compounds of the present invention are those of formula I in which R1 is cycloalkyl of 5 to 12 carbon atoms, optionally substituted with lower alkyl, for example, the following compounds: (3'aRS, 6'aSR) -l -cyclononyl-5 'methyl-2' -phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole]; (3'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2'-phenyl-hexahi-dro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione; (3'aRS, 6'aSR) -l-cyclodecyl-5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrol; (3 'aRS, 6'aSR) 1- (cis-4-isopropyl-cyclohexyl) -5'-methi1-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) 1- (cis-4-isopropyl-cyclohexyl) -5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-butyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [ 3, 4-c] pyrrole]; (3 'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-cyclo-propylmethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) - pyrrolo [3, 4-c] pyrrole]; (3'aRS, 4'SR, 6'aRS) -1- (cis-4-isopro-yl-cyclohexyl) -4 ', 5'-dimethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] ] pyrrole]; (3 'aRS, 6'aSR) -l-cyclodecyl-5'-methi1-2' -phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole]; (3 'aRS, 6' aSR) -l-cyclononyl-5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, -c] pyrrole]; (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-methi1-2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c ] irol] - ', 6'-dione; (3'aRS, 6'aSR) -1- (cis-4-isopropy1-cyclohexyl) -5'-ben-cil-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -c] pyrrole] -4 ', 6'-dione; (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-benzyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3 , 4-c] pyrrole]; (3 'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-cyclohexyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) - pyrrolo [3, 4-c] pyrrole]; (3 'aS, 6'aR) 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole]; (3'aR, 6'aS) 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -5'- (2-hydroxy-ethyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) -2- [l- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole ] -5'-yl] -N, -dimethyl-acetamide; (3'aRS, 6'aRS) - [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] - 5'-yl] -pyridin-3-yl-methanone; (3'aRS, 6'aSR) -2 '- (3-fluoro-phenyl) -l- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4, 1'-pyrrole -lo [3, -c] pyrrole] -4 ', 6'-dione; (3 'aS, 6'aR) -l-cyclononyl-5'-methyl-2-phenyl-hexahydro spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole]; (3'aS, 6'aR) -l-cyclododecyl-2'- (2-fluoro-phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, -c] pyrrole]; (3 'aRS, 6' aSR) -l-cyclononyl-2 '- (4-fluoro-phenyl) -5' -methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole ]; (3'aRS, 6'aSR) -l-cyclononyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole]; (3'aRS, 6'aSR) - (1-cyclononyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrol] -5'-yl) -cyclopropyl- ethanone; and (3'aRS, 6'aSR) - (1-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrol] -5'-yl) -cyclopropyl -metanone; (3'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -5 'il] -thiophen-2-yl-methanone. Other preferred compounds of formula I are those in which R 1 is decahydronaphthalen-2-yl. Examples of said compounds are: Mixture of (3'aSR, ß'aRS) - and (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -5 '-methyl-2' -phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole]; Mixture of (3'aSR, 6'aRS) - y (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2'-phenyl-hexahydro- spiro [piperidin-4, 1 '-pyrrolo [3,4-c] pyrrole]; Mixture of (3'aSR, 6'aRS) - and (3 'aRS, 6'aSR) -5' -ethyl-l- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2 ' phenyl-hexahydrospiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -', 6'-dione; Mixture of (3 'aSR, 6'aRS) - and (3' aRS, 6'aSR) -5 '- ethyl-l- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2' phenyl-hexahydrospiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione; Mixture of (3'aSR, 6'aRS) - y (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-nattalen-2-yl] -2'-phenyl-hexahydro- spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione; and Mixture of (3'aSR, 6'aRS) - y (3'aRS, 6'aSR) -5'-ethyl-l- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole]. Other preferred compounds of formula I are for example: Mixture of (3 'aRS, 6'aSR) - and (3' aSR, 6'aRS) -5 '-methyl-l- [(RS) -4-methyl-indan -2-yl] -2'-phenyl-hexahydro-spiro (pipe-ridin-4,1 '-pyrrolo [3,4-c] pyrrole]; Mixture of (3'aRS, 6'aSR) - y (3 'aSR, 6'aRS) -1- [(RS) -4-me-tyl-indan-2-yl] -2' -phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4- c] pyrrole]; (3'aS, 6'aR) -5'-ethyl-2'-phenyl-1 - [(R) -l, 2,3,4-tetrahi-dro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole]; (3'aS, 6'aR) -5'-methyl-2'-phenyl-1 - [(R) - 1, 2, 3, 4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole]; (3'aSR, 6'aRS) -l- [(RS) -acenaften-1-yl] -5'-methyl-l '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3, 4-c] pyrrole ]; (3'aRS, 6'aSR) -1- [(1RS, 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl] -5 '-methyl-2' - phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole]; and Mixture of (3'aRS, 6'aSR) - and (3 'aSR, 6'aRS) -1- [(RS) -2, 3-dihydro-lH-phenalen-1-yl] -5'-methyl -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole]. The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the methods described below, which comprise: a) reductive amination of a compound of the formula: with a compound of formula: wherein R1 - R5 have the meanings given above, or b) reduction of a compound of formula: to give a compound of one of the formulas: 1-2 1-3 1-4 wherein R1, R4 and R5 have the meanings given above, or c) acylation or sulfonation of a compound of formula to give a compound of formula: wherein R1 - R3 and R5 have the meanings given above and Q is -S (0) 2-lower alkyl; -C (0) lower alkyl, -C (0) CF3; -C (0) (CH2) nOCH3; -C (O) N (lower alkyl) 2, -S (0) 2 -heteroaryl; -C (0) heteroaryl; - S (0) 2-phenyl; -C (0) -cycloalkyl of 3 to 6 carbon atoms; or -C (0) O-lower alkyl, and n is 0-3, or d) debenzylation of a compound of the formula: to give a compound of formula: wherein R1 - R3 and R5 have the meanings given above, except that R2 and R3 are not = 0 or hydroxyl, e) reaction of a ketone of formula: with the N-phenyl-glycine of formula: and capturing the formed azomethinolides, of formula: 0 = ¿r ° in a compound of formula: wherein the substituents have the meanings given above, or, if desired, converting a racemic mixture into its enantiomeric components, thereby obtaining optically pure compounds, and converting a compound obtained from formula I into a pharmaceutically acceptable acid addition salt. . According to variant a) of the process, the reductive amination of a ketonic compound of formula II with an amine of formula III is effected by stirring with a dehydrating agent in the presence of molecular sieve (4Á), in an inert solvent such as toluene or tetrahydrofuran (THF), at reflux temperature. An alternative method consists of dehydration in the presence of an acid catalyst with removal of water, for example with azeotropic removal of water, or with tetraisopropyl orthotitanate in THF. The intermediate enamine oi ina obtained is then reduced with a reducing agent, such as metal hydrides to hydrogen, in the presence of a hydrogenation catalyst, preferably with sodium cyanoborohydride in a protic solvent, for example in a mixture of THF and ethanol at acidic pH. Examples of the corresponding ketone compounds of formula II are the following: 2-indanone, bicyclo [6.2.0] dec-9-one or cycloalkanone of 5 to 12 carbon atoms, optionally substituted with lower alkyl. According to variant b) of the process, a compound of formula 1-1 is reduced to one of the compounds of formulas 1-2, 1-3 and 1-4. This process is carried out in a conventional manner with a reducing agent, preferably a metal hydride, such as lithium aluminum hydride or sodium borohydride, in an aprotic solvent, for example in diethyl ether, tetrahydrofuran or, dichloromethane. According to variant c) of the process, a compound of formula 1-5 is acylated or sulfonylated with a corresponding acid chloride, acid anhydride, sulfonyl chloride, carbamoyl chloride or carbonyl chloride, in the presence of triethylamine in a solvent such as dichloromethane. This reaction is carried out in a conventional manner. The process for the preparation of a compound of formula 1-5 according to process variant d) is carried out in conventional manner with catalytic amounts of 10% Pd / C with 1 atm hydrogen. in methanol and acetic acid, preferably in a 10: 1 ratio. The process according to variant e) is carried out by reacting a ketone with a slight excess of N-phenyl-glycine in an inert solvent such as toluene at elevated temperature in the presence of a base, such as triethylamine and capturing in situ the azomethine-ylides formed, with the desired dipolarifil compound of formula 1-1. Racemic mixtures can be converted into their enantiomeric components in a conventional manner, for example by preparative HPLC or by diastereomeric salts. The formation of the salt is carried out at room temperature, according to methods already known, and that are familiar to any person skilled in the specialty. They come into consideration not only the salts with inorganic acids, but also the salts with organic acids. Hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methanesulfonates, p-toluenesulfonates and the like are examples of such salts.

The compounds of formula II, III and IV which are used as starting materials are known compounds or can be prepared by methods known per se.

Scheme i In this scheme, R1, R4 and R5 have the meanings given above and E is a group that attracts electrons, for example E / E is -C (0) N (CH3) C (0) -. Cycloaddition with azomethinylides is described in Doepp et al., Chem. Ber. 121, 1988, 1651-1655. The process is carried out by treating an equimolar amount of (trimethylsilyl) methyl-trifluoromethane sulfonate and cesium fluoride in an inert solvent, preferably 1,2-dimethoxy ethane. The azomethine ylid is captured in situ with a dipoylurafil, for example with N-methyl maleimide, dimethyl maleate or dimethyl acetylenedicarboxylate. Another suitable method for preparing these compounds is described in Tsuge et al., Chem. Lett., 1986, p. 973 Scheme 2 This process is carried out by reacting a ketone of formula VI with a slight excess of N-phenyl-glycine in an inert solvent, such as toluene, at elevated temperatures in the presence of a base, such as triethylamine and capturing in situ. the illidas formed, with the desired dipo aclafilo.

Scheme 3 Scheme 3 describes a process for the preparation of a compound of formula 1-9, wherein a compound of formula 1-1 is treated with a Grignard reagent (R ^ MgCl or R ^ MgBr) in an inert solvent, such as diethyl ether or tetrahydrofuran. The resulting compound of formula VII is then reduced with sodium cyanoborohydride in a solution of methanol and trifluoroacetic acid. As mentioned above, the compounds of formula I and their pharmaceutically acceptable addition salts possess pharmacodynamic properties of interest. It has been found that the compounds of the present invention are agonists and / or antagonists of the OFQ receptor and have effects in animal models of psychiatric, neurological and physiological disorders, such as anxiety, stress disorders, depression, trauma, memory loss. due to Alzheimer's disease or other dementias, deficits of knowledge and learning, epilepsy and seizures, acute and / or chronic conditions of pain, withdrawal symptoms in drug addicts, control of water balance, Na + excretion, blood pressure disorders arterial and metabolic disorders such as obesity. The compounds were tested for their pharmacological activity according to the methods described below: Test methods of the OFQ-R union Cell culture HEK-293 cells adapted to growth in suspension (293s) were grown in HL medium plus 2% FBS. The cells were transfected with the OFQ receptor of the rat cDNA (LC132), FEBS Lett. 347, 284-288, 1994, were cloned into the expression vector pCEP4 / Invitrogen, San Diego, CA, USA) using lipofectin (Life Technologies, Bethesda, MD, USA). The transfected cells were selected in the presence of hygromycin (1000 U / ml) (Calbiochem, San Diego, CA, USA). A set of resistant cells was tested for the expression of OFQ-R by the binding of [αH] -OFQ (Amersham PLC, Buckinghamshire, England). These cells (293s-OFQ-R) were expanded for large-scale culture and for membrane preparation.

Preparation of the membrane The 293s-OFQ-R cells were collected by centrifugation, washed 3 times with phosphate buffered saline (PBS) before being resuspended in buffer A (50 mM Tris-HCl, pH 7.8, 5 mM MgCl2, 1 M EGTA) and disruption with a tissue homogenizer (30 seconds, fit 4, Pt 20, Kinematica, Kriens-Lucern, Switzerland). A fraction of the total membrane was obtained by centrifugation at 49,000 x g at 4 ° C. This procedure was repeated twice and the pellet from the centrifugation was resuspended in buffer A. Aliquots were stored at -70 ° C and protein concentrations were determined using the BCA ™ protein assay reagent (Pierce, Rockford, IL). following the manufacturer's instructions.

Binding assays Comparison studies of [3H] -OFQ were performed with 77 μg of membrane protein in a final assay volume of 0.5 ml of buffer. At plus 0.1% BSA and 0.01% bacitracin (Boehringer-Mannhei, Mannheim, Germany) for one hour at room temperature. 50 nM of unlabeled OFQ were used to define the non-specific binding. The tests were terminated by filtration through Whatman GF / C filters (Unifilter-96, Canberra Packard SA, Zurich, Switzerland), pretreated with 0.3% polyethyleneimine (Sigma, St. Louis, MO, USA) and 0, 1% BSA (Sigma) for 1 hour. The filters were washed 6 times with 1 ml of 50 mM Tris-HCl, pH 7.5, cooled with ice. The retained radioactivity was determined with a Packard Top-Count microplate scintillation counter, after adding 40 μl of Microscint 40 (Canberra Packard). The effects of the compounds were determined using at least 6 concentrations in triplicate and were determined twice. The IC50 values were determined by fitting the curve, and these values were converted to K ^ values by the method of Cheng and Prusoff, Biochem. Pharmacol., 22, 3099, 1973.

The affinity for the OFQ receptor, given as pK ±, ranges from 7.5 to 10.0.

The preparation of the following compounds is described in Examples 1-166; The compounds of formula I as well as their pharmaceutically acceptable acid addition salts can be used as medicaments, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of an injectable solution. The compounds of formula I and their pharmaceutically acceptable acid addition salts can be prepared with pharmaceutically inert, inorganic or organic excipients for the preparation of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. excipients such as for tablets, dragees and hard gelatine capsules can be used as such.

Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for injectable solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, sequestering agents or antioxidants. They may also contain other therapeutically valuable substances. The dosage can vary within wide limits and must of course be adjusted to the individual needs of each particular case. In general, the dosage for oral or parenteral administration is 0.01-20 mg / kg / day, preferably a dosage of 0.1-10 mg / kg / day for all the indications described. The daily dosage for an adult of 70 kg of weight is therefore between 0.7-1400 mg / day, preferably 7-700 mg / day, although the above-mentioned upper limit can also be exceeded when necessary. The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius. EXAMPLE 1 Hydrochloride mixture of (3'aRS, 6'aSR) -5'-methyl-l - [(RS) - and - [(SR) -4-methyl-indan-2-yl] -2'-phenyl -hexahydro-spiro [piperi-din-4, 1 '-pyrrolo [3, 4-c] pyrrole] -4'6' -dione (1: 1) A mixture of (3'aRS, 6'aSR) -5'-methyl-l '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3, 4-c] ] pyrrole] -4 ', 6'-dione (0.51 g, 1.7 mmol), 1,3-dihydro-4-methyl-2H-inden-2-one (1.7 mmol) and molecular sieves ( 4 A, 5.0 g) in toluene (120 ml), boiled for 16 hours. The mixture was filtered hot, the molecular sieves washed thoroughly with hot toluene, and the filtrate was evaporated. The residue was dissolved in a mixture of THF (45 mL) and ethanol, (50 mL), sodium cyanoborohydride (1.7 mmol) was added, and the pH was adjusted to 4. The reaction mixture was stirred for 16 hours at room temperature. Water / ice (30 ml) and potassium carbonate solution (50%, 10 ml) were added. The mixture was extracted with dichloromethane (3x60 ml), the organic phases were combined, washed with brine (40 ml), dried with Na 2 SO 4, and the solvents were evaporated. Chromatography on silica gel (dichloromethane / methanol 2%) gave the desired product (0.65 g, 83%), which crystallized in the form of its hydrochloride salt, with ethyl acetate, obtaining a colorless solid with m.p. 250 ° C and MS: m / e = 430.5 (M + H +). EXAMPLE 2 Mixture of fumarate of (3'aRS, 6'aSR) -1- [(RS) - and - [(SR) -4-methyl-indan-2-yl] -2'-phenyl-hexahydro-spiro [ piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4'6' -dione (1: 1) The title compound, mp > 230 ° C desc. and E / M: m / e = 416.3 (M + H +), was prepared according to the general method of Example 1 from 1,3-dihydro-4-methyl-2H-inden-2-one and (3 'aRS, 6'aSR) -2' -phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4'6' -dione. EXAMPLE 3 Hydrochloride mixture of (3 'aRS,' aSR) -1- [(RS) - and - [(SR) -indan-1-yl] -5 '-methyl-2'-phenyl-hexahydro-spiro [pipe ridin-4, 1 '-pyrrolo [3, 4-c] pyrrole] -A' 6 '-dione (1: 1) A mixture of (3' aRS, 6 'aSR) -5' -methyl-1 '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole] -4'6'-dione (0.5 g, 1.7 mmol), 1 Indanone (1.7 mmol) and tetraisopropyl orthotitanate (2.1 mmol) in THF (30 mL) was stirred at room temperature for 16 hours. The solvent was removed in vacuo, the residue was dissolved in ethanol (10 ml), sodium cyanoborohydride was added and the mixture was stirred for 16 hours at room temperature.

Water was added, the suspension was filtered and the filtrate was evaporated. Chromatography on silica gel (dichloromethane / 2% methanol) gave the desired product (0.35 g, 50%) which crystallized in the form of its HCl salt from ethyl acetate to give a colorless solid of m.p. > 171 ° C desc. and MS: m / e = 416.2 (M + H +) Example 4 Mixture of fumarate of (3'aRS, 6 'aSR) -1- [(RS) - and - [(SR) -indan-1-il ] -2'-phenyl-hexahydro-spiro [piperidin-4,1'-pyrrolo [3,4-c] pyrrole] -4 '' -dione (1: 2) The title compound, mp > 148 ° C desc. and MS: m / e = 402.5 (M + H +) was prepared according to the general method of Example 3 from 1-indanone and (3 'aRS, 6'aSR) -2'-phenyl-hexahydro -spiro [piperidin-4, 1 '(2?) -pyrrolo [3, 4-c] pyrrole] -4'6' -dione. Example 5 (3 'to S, 6' to R) -5 '-ethyl-1- [(R) -1, 2, 3, 4-tetrahydro-naphtha-len-l-yl] -2'-phenyl- hexahydro-spiro [piperidin-4,1 'pyrrolo [3, 4-c] pyrrole] -4'6' -dione. A mixture of (R) -1- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -piperidin-4-one (0.75 g, 3.2 mmol), aniline (3.2 mmol) ) and p-toluenesulfonic acid (10 mg) in toluene (30 ml) was boiled with water separation for 20 hours. The solvent was removed in vacuo and the residue was dissolved in dimethoxyethane (25 ml) and cooled to 0 ° C. To the cold solution was added (trimethylsilyl) -methyl-trifluoromethanesulfonate (3.2 mmol, the mixture was allowed to warm and stirred for 2 hours at room temperature) Cesium fluoride (3.2 mmol) and N-ethyl maleimide were added. (9 mmol), and the mixture was stirred for 20 hours at room temperature, the solvent was removed in vacuo and the residue partitioned between sodium bicarbonate and dichloromethane.The organic phases were combined, dried with Na 2 SO 4 and evaporated. chromatography on silica gel (ethyl acetate / hexane 1: 2) provided the desired product (0, 64 g, 45%) in the form of a yellow foam with MS: m / e = 444.4 (M + H +). Example 6 Fumarate of (3'aR, 6'aS) -5'-ethyl-2'-phenyl-1- [(R) -1,2,3,4-tetrahydro-naphthalen-1-yl] -hexahydro- spiro [piperidin-4,1'-pyrrolo [3, 4-c] irrol] -4 '6' -dione (1: 1) The title compound, mp 222-224 ° C and MS: m / e 444.4 (M + H +) was prepared according to the general method of Example 5 from (R) -1- (1, 2, 3, 4-tetrahydro- naph- • talen-1-yl) -piperidin-4-one, aniline, (trimethylsilyl) -methyl-trifluoromethanesulfonate and N-ethyl maleimide and separated from their diastereomers (example 5) by chromatography on silica gel with ethyl acetate / hexane (1: 2) Example 7 (3'aS, 6'aR) -5 '-methyl-2'-phenyl-1- [(R) -1,2,3,4-tetrahi-dronaphthalen-1-yl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4'6'-dione The title compound, MS: m / e = 430.5 (M + H +), was prepared according to the general method of Example 5 from (R) -1- (1,2,3,4-tetrahydro-naphthalen-1-yl) -piperidin-4-one, aniline, (trimethylsilyl) -methyl-trifluoromethanesulfonate and N -methyl maleimide. Example 8 (3'aR, 6'aS) -5 '-methyl-2'-phenyl-1- [(R) -1,2,4,4-tetrahydro-naphthalen-1-yl] -hexahydro- Spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4'6'-dione The title compound, MS: m / e = 430.5 (M + H +) was prepared according to the general method of Example 5 from (R) -1- (1,2,4,4-tetrahydro-naphthalen-1-yl) -piperidin-4-one, aniline, (trimethylsilyl) -methyl-trifluoromethanesulfonate and N -methyl maleimide and separated from its diastereomer (example 7) by chromatography on silica gel with ethyl acetate / hexane (1: 2). Example 9 (3 'aS, 6'aR) -2' -phenyl-1- [(R) -1,2,3,4-tetrahydro-naphthalen-l-yl] -hexahydro-spiro [piperidin-4] , 1 '-pyrrolo [3, 4-c] pyrrole] -4'6'-dione The title compound, MS: m / e 416.2 (M + H +) was prepared according to the general method of Example 5 from (R) -1- (1,2,3,4-tetrahydro-naphthalen-1-yl) -piperidin-4-one, aniline, (trimethylsilyl) -methyl-trifluoromethanesulfonate and maleimide. Example 10 (3 'aR, 6'aS) -2' -phenyl-1- [(R) -1,2,3,4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4,1] pyrrolo [3, 4-c] irrol] -4 '6"-dione The title compound, MS: m / e = 416.2 (M + H +) was prepared according to the general method of example 5 to from (R) -1- (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -piperidin-4-one, aniline, (trimethylsilyl) -methyl-trifluoromethanesulfonate and maleimide and separated from its diastereomer ( example 9) by chromatography on silica gel with ethyl acetate / hexane (1: 2).

EXAMPLE 11 Mixture of fumarate of (3'aSR, 6'aRS) - and (3 'aRS, 6' aSR) -5 '-ethyl-1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalene-2-yl ] -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4'6'-dione (1: 1) The title compound, mp 177 - 180 ° C and MS: m / e = 450. 4 (M + H +) was prepared according to the general method of Example 5 from (2RS, 4aSR, 8aRS) -1 - (decahydro-naphthalen-2-yl) -piperidin-4-one, aniline, (trimethylsilyl ) -methyl-trifluoromethanesulfonate and N-ethyl maleimide. Example 12 Hydrochloride mixture of (3 'aSR, 6'aRS) - and (3'aRS, 6' aSR) -5'-methyl-l- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl ] -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4'6'-dione (1: 1) The title compound, mp 168 - 171 ° C and MS: m / e = 436. 5 (M + H +), was prepared according to the general method of Example 5 from (2RS, 4aSR, 8aRS) -1 - (decahydro-naphthalen-2-yl) -piperidin-4-one, aniline, ( trimethylsilyl) -methyl-trifluoromethanesulfonate and N-methylmaleimide.

EXAMPLE 13 Mixture of fumarate of (3'aSR, 6'aRS) - y (3'aRS, 6 'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2' - phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4'6'-di none (1: 1) The title compound, mp 247 - 250 ° C desc. and MS: m / e = 422.5 (M + H +), was prepared according to the general method of Example 5 from (2RS, 4aSR, 8aRS) -1 - (decahydro-naphthalen-2-yl) - piperidin-4-one, aniline, (trimethylsilyl) -methyl-trifluoromethanesulfonate and maleimide. Example 14 Mixture of fumarate of (3'aRS, 6'aSR) - and (3 'aSR, 6' aRS) -5 '-ethyl-1- [(RS) -4-methyl-indan-2-yl] - 2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 2) The title compound, mp. > 165 ° C desc. and MS: m / e = 416.3 (M + H +), was prepared according to the general method of Example 1 from 1,3-dihydro-4-methyl-2H-inden-2-one and (3) 'aRS, 6' aSR) -5 '-ethyl-2' -phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] Example 15 Mixture of fumarate of (3' aRS, 6'aSR) - and (3 'aSR, 6' aRS) -5 '-methyl-1- [(RS) -4-methyl-indan-2-yl] -2' -phenyl-hexahydro-spiro [piperidin- 4,1 '-pyrrolo [3, 4-c] pyrrole] (1: 2) A mixture of (3'aRS, 6'aSR) -5'-methyl-l- [(RS) - and - [(SR ) -4-methyl-indan-2-yl] -2'-phenyl-hexahydro-spiro [pipe-ridin-4, l'-pyrrolo [3,4-clpyrrole] -4 ', 6'-dione (0, 49 g, 1.1 mol) and lithium aluminum hydride (3.4 mmol) in diethyl ether (12 mL) and THF (10 mL) was stirred for 0.5 hour at room temperature and boiled for 1 hour. ,5 hours. The reaction mixture was quenched with water (40 μl), sodium hydroxide solution (15%, 40 μl) and water (120 μl), stirred for 1 hour, filtered and the filtrate was evaporated. Chromatography on silica gel deactivated with triethylamine (dichloromethane / methanol 5%) provided the desired product (0.37 g, 81%), which crystallized as its fumarate salt with ethyl acetate to obtain a colorless solid with p. F. > 146 ° C desc. and MS: m / e = 402.5 (M + H +). Example 16 Mixture of fumarate of (3 'aRS, 6'aSR) - and (3'aSR, 6'aRS) -1- [(RS) -4-methyl-indan-2-yl] -2'-phenyl- hexahydro-spiro [pipe-ridin-4, 1 '-pyrrolo [3, 4-c] pyrrole] (1: 2.1) The title compound, mp > 181 ° C desc. and MS: m / e = 388.4 (M + H +), was prepared according to the general method of Example 15 from (3 'aRS, 6' aSR) -1- [(RS) - and - [ (SR) -4-methyl-índan-2-yl] -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione.

Example 17 (3'aR, 6'aS) -5-ethyl-2'-phenyl-1- [(R) -1,2,3,4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin] -4, 1 '-pyrrolo [3, 4-c] pyrrole] The title compound, MS: m / e = 416.3 (M + H +) was prepared according to the general method of example 15 from ( 3 'aS, 6' aR) -5 '-ethyl-1- ((R) -1, 2, 3, 4-tetrahydronaf-talen-1-yl] -2'-phenyl-hexahydro-spiro [piperidin-4] pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione Example 18 (3' aS, 6 'aR) -5' -ethyl-2 '-phenyl-1- [(R) -1, 2, 3, 4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4], 1 '-pyrrolo [3, 4-c] pyrrole] The title compound, MS. m / e = 416.3 (M + H +) was prepared according to the general method of Example 15 from (3 'aR, 6'aS) -5' -ethyl-1- [(R) -1, 2,3,4-tetrahydronaphthalen-1-yl] -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione, Example 19 (3'aR, 6 'aS) -5' -methyl-2'-phenyl-1 - [(R) -1,2,3,4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [ piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] The title compound, MS: m / e = 402.5 (M + H +) was prepared according to the general method of Example 15 from (3 ', aS, 6'aR) -5' -methyl-2 '-phenyl-1- [(R) -1,2, 3, 4-te-trahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4, 1 '-pi-rrolo [3,4-c] pyrrole] -4', 6'-dione. Example 20 (3 'aS, 6' aR) -5 '-methyl-2'-phenyl-1- [(R) -1, 2, 3, 4-tetrahi-dro-naphthalen-1-yl] -hexahydro- spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] The title compound, MS: m / e = 402.5 (M + H +) was prepared according to the general method of example 15 to starting from (3'aR, 6'aS) -5 '-methyl-2'-phenyl-1- [(R) -1, 2, 3, 4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [ piperidin-4, 1'-pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione. Example 21 (3'aS, 6'aR) -2'-phenyl-l- [(R) -1,2,3,4-tetrahydro-naphthalen-l-yl] -hexahydro-spiro [piperidin-4] , 1 '-pyrrolo [3, 4-c] pyrrole] The title compound, MS: m / e = 388.3 (M + H +) was prepared according to the general method of Example 15 from (3') aR, 6'aS) -2'-phenyl-l- [(R) -1,2,3,4-tetrahydronaphthalen-1-yl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -c] pyrrole] -4 ', 6'-dione.

Example 22 (3 'aR, 6' aS) -2 '-phenyl-1- [(R) -1,2,4,4-tetrahydronaphthalen-l-yl] -hexahydro-spiro [piperidin-4,1] pyrrolo [3, 4-c] pyrrole] The title compound, MS: m / e = 388.3 (M + H +) was prepared according to the general method of example 15 from (3'aS, 6 'aR) -2' -phenyl-1- [(R) -1,2,4,4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -cjpirrol] -4 ', 6' -dione.

Example 23 (3 'aR, 6' aS) -2 '-phenyl-1- [(R) -1, 2, 3, 4-tetrahydronaphthalen-l-yl] -5'- [(S) -4 , 4, 4-trifluoro-3-hydroxy-butyl-hexa-hydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] A mixture of (3'aR, 6'aS) -2 '-phenyl-l- [(R) -1,2,3,4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole] ( 45 mg, 0.12 mmol), 4,4,4-trifluoro-3-hydroxy-butyl ester of (S) -toluene-4-sulfonic acid (0.13 mmol) and potassium carbonate (0.23 mmol) in 2-butanone (2 ml), boiled for 16 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2x10 mL). The organic phases were combined, dried with Na 2 SO 4 and the solvents were evaporated. Chromatography on silica gel (dichloromethane / (2% methanol) gave the desired product (32 mg, 54%) as a beige foam with MS: m / e = 514.4 (M + H +) Example 24 Mixture of fumarate (3'aRS, 6 'aSR) - y (3'aSR, 6' aRS) -5 '-ethyl-1- [(RS) -indan-1-yl] -2'-phenyl-hexahydro- spiro [pi-peridin-4, 1 '-pyrrolo [3,4-c] pyrrole] (1: 1.75) The title compound, mp> 132 ° C dec. and MS: m / e: 402, 5 (M + H +), was prepared according to the general method of Example 3 from 1-indanone and (3 'aRS, 6' aSR) -5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin -4, 1 '-pyrrolo- [3, 4-c] pyrrole] Example 25 Fumarate of (3' aRS, 6 'aSR) -1- [(RS) - or - [(SR-) -indan-1 -yl] -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] (1: 3) The mixture of (3'aRS, 6 ' aSR) -1- [(RS) - and - [(SR) -indan-1-yl] -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4 -c] pyrrole] -4'-6'-dione, separated by chromatography on whether licagel with dichloromethane / methanol 2% in its diastereomers and reduced following the general procedure of example 15, obtaining the title compound, m.p. > 128 ° C desc. and MS: m / e = 388.3 (M + H +).

Example 26 (3'aRS, 6'aSR) -l- [(SR) - or - [(RS) -indan-1-yl-] -5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin- 4, 1 '-pyrrolo [3, 4-c] pi-rrol] The mixture of (3'aRS, 6'aSR) -1- [(RS) - and - [(SR) -indan-1-yl] -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin- 4,1 '-pyron [3, 4-c] pyrrole] -4'-6'-dione was separated by chromatography on silica gel with 2% dichloromethane / methanol in its diastereomers and reduced following the general procedure of example 15, obtaining the title compound, MS: m / e = 388.3 (M + H +). Example 27 Mixture of fumarate of (3'aSR, 6'aRS) - y (3 'aRS, 6' aSR) -5 '-ethyl-1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl ] -2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] (1: 2.3) The title compound, mp > 130 ° C desc. and MS: m / e = 422.5 (M + H +), was prepared according to the general method of Example 15 from the mixture of (3 'aSR, 6' aRS) - and (3 'aRS, 6 'aSR) -5' -ethyl-1- [(2RS, 4aSR, 8aRS) -decahydro-naphtha-len-2-yl] -2'-phenyl-hexahydro-spiro (piperidin-4,1 '-pyrrolo [3 , 4-c] pyrrole] -4'6' -dione.

Example 28 Mixture of fumarate of (3'aSR, 6'aRS) - y (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -5 '- methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 2.4) The title compound, mp > 152 ° C desc. and MS: m / e = 408.5 (M + H +), was prepared according to the general method of Example 15 from the mixture of (3'aSR, 6'aRS) - and 3'aRS, 6 ' aSR-5'-methyl-l- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2'-phenyl-hexahydro-spiro (piperidin-4,1 '-pyrrolo- [3, 4-c] pyrrole] -4'-6'-dione Example 29 Mixture of (3'aSR, 6'aRS) - and (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalene -2-yl] -2 '-phenyl-hexahi-dro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] The title compound, MS: m / e = 394.4 (M + H +), was prepared according to the general method of Example 15 from the mixture of (3'aSR, 6'aRS) - and (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo (3,4-c] pyrrole] -4'6'-dione.

EXAMPLE 30 Hydrochloride of (3'aRS, 6'aSR) -1- (2-naphthalenylmethyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4 '6' -dione A mixture of 2-bromomethylnaphthalene (1 mmol), (3'aRS, 6'aSR) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3 , 4-c] pyrrole] -4'6'-dione (1 mmol) and sodium bicarbonate (2 mmoles) in 2-butanone (10 mL), was boiled with stirring overnight. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (ethyl acetate) to obtain the desired product (0.29 g, 97%) which was crystallized in the form of its HCl salt with ethyl acetate to give a solid. colorless with pf > 234 ° C desc. and MS: m / e = 426.4 (M + H +). Example 31 Fumarate of (3 'aR, 6'aS) -l-cyclononyl-5' -methyl-2'-phenyl) -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 3,2) The title compound, light red solid, m.p. 178 ° C (dec.); [a] D20 = + 76.4 ° > 2 = 0, 0772 in MeOH), and MS: m / e = 396.6 (M + H +) was prepared by reduction of (3'aR, 6'aS) -l-cyclononyl-5'-methyl-2 ' phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione, and subsequent fumarate formation, according to the general method of Example 89. (3 'aR, 6' aS) -l-cyclononyl-5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2 'H) -pyrrolo [3 , 4-c] pyrrole] -4 ', 6'-dione, from (3'aR, 6'aS) -5' -methyl-1 '-phenyl-hexahydro-spiro [piperidin-4, 1' (2 H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione and cyclononanone, according to the general method of example 3. EXAMPLE 32 Fumarate of (3'aSR, 6' aRS) - 1- (2-naphthalenylmethyl) -2'-phenyl-hexahydro-spiro (piperidin-4,1 '-pyrrolo [3,4-c] pyrrole (1: 2) Lithium aluminum hydride (3.8 mmol) was added ) to a stirred solution of (3 'aRS, 6' aSR) -1- (2-naphthalenyl-methyl) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] ? irol] -4 ', 6' -dione (0.5 m) moles) in THF (10 ml). The mixture was stirred at room temperature for half an hour and then boiled with stirring overnight. The cooled mixture was hydrolyzed by the addition of water (0.14 ml), sodium hydroxide solution (0.28 ml, 15%) and water (0.42 ml) and dried with the addition of Na 2 SO 4. After filtering and removing the solvent in vacuo, a residue was obtained which was purified by chromatography on silica gel (dichloromethane / methanol 5%), obtaining the desired product (0.11 g, 59%) as a colorless solid that crystallized as its fumarate salt with ethyl acetate / ethanol to provide a colorless solid with mp > 161 ° C desc. and MS: m / e = 398.5 (M + H +). EXAMPLE 33 Fumarate of (3 'aSR, 6' aRS) -1- (1-naphthalenylmethyl) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] (1 : 1,5) The title compound, mp 192-194 ° C (dec.) And MS: m / e = 398.5 (M + H +) was prepared according to the general method of example 32 from (3 'aRS, 6' aSR) -1 - (1-naphthalenylmethyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione. EXAMPLE 34 Fumarate of (3 'aSR,' aRS) -1- [(RS) -acenaften-1-yl] -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin-4,1 '(2' H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione (1: 3) The title compound, white solid, mp 199 ° C (dec.) And MS: m / e = 452.4 (M + H +) was prepared according to the general method of example 5 from (RS) -l-acenaphthen-1-yl-piperidine. -4-one, aniline and N-methyl-maleimide and subsequent fumarate formation. EXAMPLE 35 Fumarate of [(3 'aRS, 6' aSR) -1- [(RS) -acenaften-1-yl] -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin-4, 1 '( 2'H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione (1: 0.72) The title compound, white solid, mp 234 ° C (dec.) And MS: m / e = 452.4 (M + H +) was prepared according to the general method of Example 5 from the (RS) -l-acenaphthen-l-yl-piperidin-4-one, aniline and N-methyl-maleimide and subsequent fumarate formation. Example 36 Fumarate of (3 'aRS, 6'aSR) -1- [(RS) -acenaften-1-yl] -5'-methyl-1'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] pyrrole] (1: 2.5) The title compound, white solid, mp 180 ° C (dec.) And EM. m / e = 424.4 (M + H +) was prepared by reduction of (3'aSR, 6'aRS) -1- [(RS) -acenaften-1-yl] -5 '-methyl-1' - phenyl-hexahydro-spiro [piperidin-4,1 '(2' H) -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione and fumarate formation according to the general method of example 15. EXAMPLE 37 Fumarate of (3 'aSR, 6' aRS) -1- [(RS) -acenaften-1-yl] -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin-4,1 '(2 'H) -pyrrolo [3, 4-c] pyrrole] (1: 2) The title compound, light red solid, mp 180 ° C (dec.) And EM. m / e = 424.5 (M + H +) was prepared by reduction of (3'aRS, 6'aSR) -1- [(RS) -acenaften-1-yl] -5 '-methyl-1' - phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and fumarate formation according to the general method of example 15. EXAMPLE 38 Fumarate of (3'aRS, 6 'aSR) -1- [(1RS, 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl] -5'-methyl -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4'6' -dione (1: 2) The title compound, solid white, mp 181 ° C and EM. m / e = 470.3 (M + H +) was prepared according to the general method of Example 5 from (1RS, 3aRS) -1- (2,3, 3a, 4,5,6-hexahydro-1H) phenylene-1-yl) -piperidin-4-one, aniline and N-methyl-maleimide and subsequent fumarate formation. Example 39 Fumarate of (3'aSR, 6'aRS) -1- [(1RS, 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl] -5'-methyl -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] irrol] -4', 6'-dione (1: 4) The title compound, solid white, mp 219 ° C and MS: m / e = 470.3 (M + H +), was prepared according to the general method of example 5 from (1RS, 3aRS) -1- (2, 3, 3a, 4, 5,6-hexahydro-lH-phenalen-1-yl) -piperidin-4-one, aniline and N-methyl-1-maleimide and subsequent fumarate formation. Example 40 Fumarate of (3'aSR, 6'aRS) -1- [(1RS, 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl] -5'-methyl -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] (1: 2,35) The title compound, light yellow solid, m.p. 158 ° C (dec.) And MS: m / e = 442.4 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -1- [(1RS, 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-l-yl] -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3 , 4-c] pyrrole] -4 ', 6'-dione and subsequent fumarate formation, according to the general method of example 15. Example 41 Fumarate of (3'aRS, 6'aSR) -1- [(1RS , 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl] -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2? ) -pyrrolo [3, 4-c] pyrrole] (1: 2.2) The title compound, off-white solid, mp 184 ° C and MS: m / e = 442.5 (M + H +), was prepared by reduction of (3 'aSR, 6'aRS) -1- [(1RS, 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl] -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c ] pyrrole] -4 ', 6'-dione and subsequent fumarate formation, according to the general method of example 15.

Example 42 Fumarate of (3 'aRS, 6'aSR) -l-cyclooctyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3, 4- c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, light yellow solid, mp 213 ° C (dec.) And MS: m / e = 410.5 (M + H +), was prepared from (3 'aRS, 6'aSR) -5' -methyl-1 '-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cyclooctanone, and subsequent fumarate formation, according to the general method of the example 3.

Example 43 Fumarate of (3 'aRS, 6'aSR) -l-cycloheptyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4- c] pyrrole] -4 ', 6'-dione (1: 1.17) The title compound, white solid, mp 211 ° C (dec.) And MS: m / e = 396.3 (M + H +), was prepared from (3'aRS, 6 'aSR) -5' -methyl-1 '-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cycloheptanone, and subsequent fumarate formation, according to the general method of the example 3.

Example 44 Fumarate of (3'aRS, 6'aSR) -l-cyclooctyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4- c] pyrrole] (1: 2.27) The title compound, pale pink solid, mp 235 ° C and MS: m / e = 382.4 (M + H +), prepared by reduction of (3 'aRS, 6'aSR) -l-cyclooctyl-5' -methyl-2'-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and fumarate formation, according to the general method of example 15. Example 45 Fumarate of (3 'aRS, 6'aSR) -l-cyclononyl-5' -methyl-2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, white solid, mp 238 ° C (dec.) And MS: m / e = 424.5 (M + H +), was prepared from the (3'aRS, 6'aSR) -5 '-methyl- 1' -phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cyclononanone, and subsequent fumarate formation, according to the general method of the example 3. EXAMPLE 46 Fumarate of (3 'aRS, 6'aSR) -l-cyclononyl-5' -methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] pyrrole] (1: 2.25) The title compound, white solid, mp 242 ° C (dec.) And MS: m / e = 396.4 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -l-cyclononyl-5' -methyl-2 ' phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate, according to the general method of Example 15. Example 47 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3 , 4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, white solid, mp 234 ° C and MS: m / e = 438.5 (M + H +), was prepared from (3 'aRS, 6' aSR) -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin -4, 1 '(2?) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cyclodecanone and subsequent fumarate formation, according to the general method of example 3. Example 48 the mixture of (3'aRS, 6'aSR) - y (3'aSR, 6'aRS) -1- [(RS) -2, 3-dihydro-lH-phenalen-l-yl] -5 '-methyl-2'-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] (1: 3) The title compound, pale brown solid, mp 173 ° C and MS: m / e = 438.5 (M + H +), was prepared by reduction of a mixture of (3'aRS, 6'aSR) - and (3'aSR, 6'aRS) -l- [(RS) -2, 3-dihydro-lH-phenalen-l-ip-5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3, 4] -c] pyrrole] -4 ', 6'-dione and subsequent fumarate formation, according to the general method of example 15. Example 49 Fumarate of (3' aRS, 6'aSR) -l-cyclodecyl-5 '- methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] (1: 2.2) The title compound, pale pink solid, pf 240 ° C and MS: m / e = 410.5 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2'-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and subsequent fumarate formation, according to the general method of example 15. Example 50 Fumarate of (3'aRS, 6'aSR) -l-cycloundecyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] ] pyrrole] -4 ', 6'-dione (1: 1.1) The title compound, white solid, mp 209 ° C and MS: m / e = 452.5 (M + H +), was prepared from (3'aRS, 6'aSR) -5 '-methyl-1'-phenyl-hexahydro-spiro [piperidin -4,1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cyclooundecanone and subsequent fumarate formation, according to the general method of example 3.

Example 51 Fumarate of (3'aRS, 6'aSR) -l-cycloheptyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] ] pyrrole] (1: 2.4) The title compound, orange solid, mp 172 ° C and MS: m / e = 368.4 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -l-cycloheptyl-5'-methyl-2'-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and subsequent fumarate formation, according to the general method of example 15. Example 52 Fumarate of (3'aRS, 6 'aSR) -l-cycloundecyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3, 4-c] ] pyrrole] (1: 2) The title compound, white solid, mp 237 ° C (dec.) And MS: m / e = 424.5 (M + H +), was prepared by reduction of (3'aRS, 6 'aSR) -l-cycloundecyl-5'-methyl-2' phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent fumarate formation, according to the general method of example 15 Example 53 Fumarate of (3 'aRS, 6'aSR) -l-cyclododecyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3, 4- c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, white solid, mp 206 ° C and MS: m / e = 466.4 (M + H +), was prepared from (3 'aRS, 6'aSR) -5' -methyl-1 '-phenyl-hexahydro-spiro [piperidin -4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and cyclododecanone and subsequent fumarate formation, according to the general method of Example 3. Example 54 Fumarate of (3 'aRS, 6'aSR) -l-cyclododecyl-5' -methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole ] (1: 2) The title compound, white solid, mp 220 ° C and MS: m / e = 438.5 (M + H +), prepared by reduction of (3'aRS, 6'aSR) -l-cyclododecyl-5'-methyl-2'-phenyl hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent fumarate formation, according to the general method of example 15 Example 55 Fumarate of (3'aRS, 6'aSR) -1- (cis-octahydro-inden-2-yl) -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4, 1' ( 2?) -pyrrolo [3, 4-c] pyrrole] -4 ',' -dione (1: 1) The title compound, white solid, mp 204 ° C (dec.) And MS: m / e = 422.4 (M + H +), was prepared from (3'aRS, 6'aSR) -5 '-methyl-1' -phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cis-octahydro-inden-2-one and subsequent fumarate formation, according to the general method of example 3. Example 56 Fumarate of (3'aRS, 'aSR) -1- (cis-octahydro-inden-2-yl) -5' -methyl-2'-phenyl-hexahydro-spiro [ piperidin-4, 1 '(2?) -pyrrolo [3,4-c] pyrrole] (1: 2.2) The title compound, orange solid, mp 150 ° C (dec.) And MS: m / e = 394.4 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -1- (cis-octahydro-inden-2- il) -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2 'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate, according to the general method of example 15. Example 57 Fumarate of (3'aRS, 6'aSR) -1- (decahydro-azulen-2-yl) -5 '-methyl-2'-phenyl-hexahydro -spiro [piperidin-4, 1 '(2?) -pyrrolo [3, 4-c] pyrrole] -4 6'-dione (1: 1) (config. del, cis and trans azuleno group) The title compound , solid white, mp 225 ° C (dec.) And MS: m / e = 436.4 (M + K "), was prepared from (3'aRS, 6'aSR) -5 '-methyl-1'-phenyl- hexahydro-spiro [piperidin-4, 1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and decahydro-azulen-2-one cis / trans mixture) and subsequent formation of the fumarate, according to the general method of example 3. Example 58 Fumarate of (3'aRS, 6'aSR) -1- (decahydro-azulen-2-yl) -5'-methyl-2'-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] (1: 2) (config of the cis and trans azuleno group) The title compound, white solid, mp 170 ° C (dec.) and MS: m / e = 408.5 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -1- (decahydro-azulen-2-yl) ) -5 '-methyl-2' -phenyl-hexahydro-spiro [piperidin-4], 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione (config of the cis and trans azuleno group) and subsequent fumarate formation, according to the general method of Example 15. Example 59 Fumarate of (3'aRS, 6'aSR) -1-bicyclo [3.3.1] non-9-yl-5'-cyclohexyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione (1: 1.2) The title compound, light brown solid, mp 241 ° C and MS: m / e = 422.4 (M + H +), was prepared according to the general method of Example 5 from 1-bicyclo [3.3.1] non-9-yl-piperidin- 4-one, aniline and N-methyl-maleimide and subsequent fumarate formation.

Example 60 Fumarate of (3'aRS, 6'aSR) -1-bicyclo [3.3. l] non-9-yl-5'-cyclohexyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] (1: 2.2 ) The title compound, light brown solid, mp 229 ° C (dec.) And MS: m / e = 394.4 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -1-bicyclo [3.3. l] non-9-yl-5'-cyclohexyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] -4', 6 '- dione) and subsequent formation of the fumarate, according to the general method of example 15. Example 61 Fumarate of (3'aRS, 6'aSR) -1- (octahydro-inden-2-yl) -5'-methyl-2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione (1: 1.7) (mixture of diastereoisomers; of the indene group in C3a and C7a cis) The title compound, light yellow solid, mp 160 ° C (dec.) And MS: m / e = 422.4 (M + H +), was prepared from (3'aRS, 6 'aSR) -5' -methyl-1 '-phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cis-octahydro-inden-2-one and subsequent fumarate formation, according to the general method of example 3.

EXAMPLE 62 Fumarate of (3 'aRS, 6'aSR) -1- (octahydro-inden-2-yl) -5' -methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] pyrrole] (1: 1.9) (mixture of diastereoisomers; config of the indene group in C3a and C7a cis) The title compound, light orange solid, mp 190 ° C (dec.) And MS: m / e = 394.4 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -1- (octahydro-inden-2-yl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione (mixture of diastereomers; config of the indene group in C3a and C7a cis) and subsequent formation of the fumarate, according to the general method of example 15. Example 63 Fumarate of (3 'aRS, 6'aSR) -1-bicyclo [6.2.0] dec -9-yl-5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] (1: 2.52) (mixture of diastereoisomers; config of the bicyclodecane group in Cl and cis C8) The title compound, light brown solid, mp 177 ° C (dec.) And MS: m / e = 339.4 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -1-bicyclo [6.2.0] dec-9 -yl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4- c] pyrrole] -4', 6'-dione) (mixture of diastereoisomers; config of the bicyclodecane group in Cl and C8 cis) and subsequent fumarate formation, according to the general method of example 15. The (3'aRS, ß'aSR) -l-bicyclo [6.2.0] dec -9-yl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione) ( mixture of diastereomers; config of the bicyclodecane group in Cl and C8 cis), was prepared from (3'aRS, 6'aSR) -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione) and the cis-bicyclo (6.2.0) dec-9-one, according to the general method of Example 3. Example 64 Mixture of fumarate of (3'aRS, 6'aSR) - and (3'aSR, 6'aRS) -5 '-methyl-2'-phenyl-l- [(RS) -1, 2 , 3, 4-tetrahydro-naphthalen-2-yl] -hexahydro-esp iro [piperidin-4, 1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, white solid, m.p. 206 ° C and MS: m / e = 430.5 (M + H +), was prepared from (3'aRS, 6'aSR) -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin -4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and 1,2,3,4-tetrahydro-naphthalen-2-one and subsequent fumarate formation according to the general method of example 3.

Example 65 Mixture of fumarate of (3'aRS, 6'aSR) - and (3 'aRS, 6' aSR) -5 '-methyl-2'-phenyl-1- [(RS) -1, 2, 3, 4-tetrahydro-naphthalen-2-yl] -hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] (1: 2.2) The title compound, solid of white color, mp 16 ° C (dec.) And MS: m / e = 402.5 (M + H +), was prepared by reduction of a mixture of (3'aRS, 6'aSR) - and (3'aSR, 6'aRS ) -5'-methyl-2'-phenyl-1- [(RS) -1,2,4,4-tetrahydro-naphthalen-2-yl] -hexahydro-spiro [piperidin-4,1 '(2'H ) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione and subsequent fumarate formation according to the general method of example 15.

Example 66 Fumarate of (3 'aRS, 6' aSR) -1- (5-isopropyl-2-methyl-bicyclo [3.1.0] hex-3-yl) -5 '-methyl-2'-phenyl-hexahydro- spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione (1: 3) (mixture of diastereoisomers) The title compound, yellow solid clear, mp 197 ° C (dec.) And MS: m / e = 436.5 (M + H +), was prepared from (3'aRS, 6'aSR) -5 '-methyl-1' -phenyl-hexahydro -spiro [piperidin-4, 1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and 5-isopropyl-2-methyl-bicyclo [3.1.0] hex- 3-one (mixture of diastereoisomers) and subsequent formation of the fumarate according to the general method of example 3. Example 67 Fumarate of (3'aRS, 'aSR) -1- (5-isopro-yl-2-methyl-bicyclo [3.1.0] hex-3-yl) -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole] (1 : 2,2) (mixture of diastereoisomers) The title compound, orange solid, m.p. 182 ° C (dec.) And MS: m / e = 408.5 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -1- (5-isopropyl-2-methyl- bicyclo [3.1.0] hex-3-yl) -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole] - 4 ', 6'-dione (mixture of diastereoisomers) and subsequent formation of the fumarate according to the general method of example 15. Example 68 Fumarate of (3' aRS, 6'aSR) -l-cyclodecyl-5'-ethyl- 2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, solid white, mp 235 ° C and MS: m / e = 452.5 (M + H +), was prepared from (3 'aRS, 6' aSR) -5 '-ethyl-1' -phenyl-hexahydro-spiro [piperidine] -4, 1 '(2?) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and cyclsdecanone and subsequent fumarate formation according to the general method of example 3. Example 69 Fumarate of ( 3'aRS, 6'aSR) -l-cyclodecyl-5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] (1 : 2,2) The title compound, orange solid, mp 232 ° C (dec.) And MS: m / e = 424.5 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -l-cyclodecyl-5'-ethyl-2 ' phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] irrol] -4', 6'-dione and subsequent fumarate formation according to the general method of the example fifteen.

EXAMPLE 70 Fumarate of (3 'aRS, 6' aSR) -l-cyclononyl-5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] ] pyrrole] -4 ', 6'-dione (1: 1.2) The title compound, white solid, mp 238 ° C (dec.) And MS: m / e = 438.5 (M + H +), was prepared from (3'aRS, 6 'aSR) -5'-ethyl-1' -phenyl-hexahydro -spiro [piperidin-4, 1 '(2?) -pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cyclononanone and subsequent formation of the fumarate according to the general method of example 3.

EXAMPLE 71 Fumarate of (3 'aRS, 6'aSR) -l-cyclononyl-5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-] c] pyrrole] (1: 2) The title compound, orange solid, mp 229 ° C (dec.) And MS: m / e = 410.5 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -l-cyclononyl-5'-ethyl-2 ' phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate according to the general method of example 15 Example 72 Fumarate of (3'aRS, 6'aSR) -5'-cyclohexyl-1-cyclononyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4 -c] pyrrole] (1: 2.2) The title compound, white solid, mp 164 ° C (dec.) And MS: m / e = 378.5 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -5'-cyclohexyl-1-cyclononyl-2 ' phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate according to the general method of the example 15. La (3 'aRS, 6'aSR) -5' -cyclohexyl-1-cyclononyl-2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3, 4-c] ] pyrrol] -4 ', 6'-dione, was prepared according to the general method of Example 5 from N-cyclononyl-piperidin-4-one, aniline and N-cyclohexyl-maleimide and subsequent fumarate formation. Example 73 Fumarate of (3'aS, 6'aR) -1- [(R) -acenaften-1-yl] -2'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2 'H) -pyrrolo [3, 4-c] pyrrole] (1) The title compound, light red solid, mp 180 ° C (dec.); [a] D20 = -48.5 ° (c = 0.1030 in MeOH) and MS: m / e = 424.4 (M + H +), was prepared by reduction of (3 'aS, 6' aR) -l - [(R) -acenaften-l-il] -5'-methyl-1'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole ] -4 ', 6'-dione and fumarate formation according to the general method of example 15. The (3'aS, 6'aR) -1- [(R) -acenaften-1-il] -5' -methyl-1 '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione was prepared according to the general method of Example 5 from (R) -acenaphthen-1-yl-piperidin-4-one, aniline and N-methyl-maleimide. Example 74 Fumarate of (3'aR, 6'aS) -1- [(R) -acenaften-1-yl] -2'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2 ?) -pyrrolo [3, 4-c]? irrol] (1: 2.6) The title compound, light red solid, mp 150 ° C (dec.); [a] D20 = + 41.3 ° (c = 0.1091 in MeOH) and MS: m / e = 424.4 (M + H +), was prepared by reduction of (3'aR, 6'aS) -l- [(R) -acenaften-1-yl] -5'-methyl-1'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole ] -4 ', 6'-dione and fumarate formation according to the general method of example 15. The (3'aR, 6'aS) -l- [(R) -acenaften-1-il] -5' -methyl-1'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] irol] -4', 6'-dione was prepared according to the general method of Example 5 from (R) -1-acenaphthen-1-yl-piperidin-4-one, aniline and N-methyl-maleimide.

EXAMPLE 75 Fumarate of (3 'aRS, 6'aSR) -5'-benzyl-l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] - 4-dione (1: 1) The title compound, light yellow solid, mp 174 ° C and MS: m / e = 514.4 (M + H +), was prepared according to the general method of example 5 from l-cyclodecyl-piperidin-4-one, aniline and N-benzyl- maleimide and subsequent fumarate formation. Example 76 Fumarate of (3'aRS, 6'aSR) -5'-benzyl-l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] ( 1: 1) The title compound, white solid, mp 215 ° C (dec.) And MS: m / e = 486.5 (M + H +), was prepared by reduction of (3'RS, SR) -5'-benzyl-l-cyclodecyl-2'-phenyl- hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent fumarate formation, according to the general method of example 15. Example 77 Hydrochloride of ( 3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] irrol] -4 '6' -dione (1: 1.6) Cis- [1- (4-isopropyl-cyclohexyl) -piperidin-4-ylidene] phenylamine (2.00 g, 6.70 mmol) was dissolved in 1,2-im-imethoxy ethane (35 ml) and treated at 0 ° C with (trimethylsilyl) methyl trifluoromethane sulfonate (1.90 g, 8.04 mmol). After stirring at room temperature for 2 hours N-ethyl maleimide (2.10 g, 18.0 mmol) was added followed by cesium fluoride (1.2 g, 8.04 mmol) and the reaction mixture was stirred at room temperature. room temperature for 40 hours. The desired product (960 mg, 34%) precipitated from the reaction mixture, m.p. 184 ° C (basic compound) and MS: m / e = 424.5 (M + H +). The HCl salt was obtained by treating an ethereal solution of the free base with an excess of HCl in diethyl ether.

Example 78 Fumarate of (3'aRS, 6'aSR) -l- (cis-4-isopropyl-cyclohexyl) -2 ', 5'-diphenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4 -c] pyrrole] -4 ', 6'-dione (1: 0.9) The title compound, mp. 155 ° C and MS: m / e = 468.4 (M + H +) was prepared according to the general method of example 77 from cis- [1- (4-isopropyl-cyclohexyl) -piperidin-4-ylidene ] phenyl amine and N-phenyl maleimide. Example 79 Fumarate of (3'aRS, 6'aSR) -l- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione (1: 0.9) The title compound, dec. > 200 ° C and MS: m / e = 410.5 (M + H +) was prepared according to the general method of Example 77 from cis- [1- (4-isopropyl-cyclohexyl) -piperidin-4-ylidene ] phenylamine and maleimide. Example 80 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1'-pyrrolo [3 , 4-c] pyrrole] -4 ', 6'-dione (1: 1.15) The title compound, mp 214 ° C and MS: m / e = 438.4 (M + H +) was prepared according to the general method of Example 77 from cis- [1- (4-isopropyl-cyclohexyl) -piperidin-4-ylidene ] phenyl-amine and N-ethyl maleimide.

EXAMPLE 81 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-cyclopropylmethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] pyrrole] -4 ',' -dione (1: 1) 1.0 g (2.44 mmoles) of (3'aRS, 6'aSR) -1- (cis) were dissolved -4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro (piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione in 15 ml of anhydrous tetrahydrofuran. Next, triphenylphosphine (640 mg, 2.44 mmol), hydroxymethylcyclopropane (176 mg, 2.44 mmol) and diethyl azodicarboxylate (425 mg, 2.44 mmol) in 5 ml of tetrahydrofuran were added, and the mixture at room temperature for 24 hours The tetrahydrofuran was evaporated and the residue was purified by column chromatography (hexane / ethyl acetate / triethylamine 40: 10: 1) The desired product was obtained as a yellow solid ( 725 mg, 64%) which precipitated in the form of its fumarate salt with diethyl ether, mp 184 ° C (salt) and MS: m / e = 464.4 (M + H +).

EXAMPLE 82 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-cyclohexyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3 , 4-c] pyrrole] -4 ', 6'-dione (1: 1.1) The title compound, desc. > 195 ° C and MS: m / e = 492.4 (M + H +), was prepared according to the general method of Example 81, from (3 'aRS, 6'aSR) -1- (cis-4) -isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro (piperidin-4, 1-pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione and cyclohexanol Example 83 (3') fumarate aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-benzyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, mp 103 ° C and MS: m / e = 492.4 (M + H), was prepared according to the general method of example 81, from (3 'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -2' -phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole ] -4 ', 6'-dione and benzyl alcohol Example 84 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-butyl-2'-phenyl-hexahydro -spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, mp 184 ° C and MS: m / e = 466 , 4 (M + H +), was prepared from a according to the general method of example 81 from (3 'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -2' -phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione and n-butanol. Example 85 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-5- (tetrahydro-furan-3-yl) -hexahydro-spiro [piperidin-4] , 1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, m.p. 188-190 ° C and MS: m / e = 480.5 (M + H +), was prepared according to the general method of Example 81, from (3'aRS, 6'aSR) -1- (cis -4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and rac-3-hydroxy-tetrahydrof rano Example 86 Fumarate of (3'aRS, 6'aSR) -5 '(2-benzyloxy-ethyl) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, mp. 155 ° C and MS: m / e = 544.3 (M + H +), was prepared according to the general method of Example 81, from (3'aRS, 6'eSR) -1- (cis-4) -isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and 2-benzyloxy ethanol.

Example 87 Fumarate of (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'- (3-methyl-oxetan-3-ylmethyl) -2'-phenyl-hexahydro-spiro [ piperidin-4, 1 '(2?) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, mp 171 ° C and MS: m / e = 494.4 (M + H +), was prepared according to the general method of Example 81, from (3'aRS, 6'aSR) -1- (cis-4) -isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and 3-hydroxy-methyl-3-methyl -oxetan. Example 88 Fumarate of (3'aRS, 6'aSR) -l- (cis-4-iso-ro-pyl-cyclohexyl) -5 '- (2-morpholin-4-yl-ethyl) -2'-phenyl-hexahydro- spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione (1: 2.2) The title compound, m.p. 170 - 175 ° C and MS: m / e = 523.3 (M + H +), was prepared according to the general method of Example 81, from (3 'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -2'phenyl- hexahydro-spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and N- (2-hydroxyethyl) -morpholine.

EXAMPLE 89 Fumarate of (3'aRS, 6'aSR) -l- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3 , 4-c] pyrrole] (1: 1.5) (3 'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5' -methyl-2'-phenyl-hexahydro was dissolved. I respir [piperidin-4, pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione (212 mg, 0.5 mmol) in methylene chloride (4 mL) and diethyl ether ( 5 ml) and lithium aluminum hydride (55 mg, 1.45 mmol) The reaction mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction mixture was treated consecutively with 0.05 ml of water, 0.05 ml of 15% sodium hydroxide solution, and 0.15 ml of water. The solid material was separated by filtration and the filtrate was evaporated. Column chromatography (hexane / ethyl acetate / triethylamine 10: 10: 1) of the residue gave the desired product (140 mg, 70%) which was precipitated as its fumarate salt with a mixture of methanol and diethyl ether, . >; 165 ° C, MS: m / e = 396.4 (M + H +). Example 90 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4, 1-pyrrolo [3 , 4-c] pyrrole] (1: 1.5) The title compound, dec. > 200 ° C and MS: m / e 410.5 (M + H +), was prepared according to the general method of example 89, from (3'aRS, 6'aSR) -1- (cis-4) -isopropyl-cyclohexyl) -5'-ethyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3,4- c] pyrrole] -4', 6'-dione. EXAMPLE 91 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -2 ', 5'-diphenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4 -c] pyrrole] (1: 1.5) The title compound, dec. > 255 ° C and MS: m / e = 410.5 (M + H +), was prepared according to the general method of example 89, starting with (3'aRS, 6'aSR) -1- (cis- 4-isopropyl-cyclohexyl) -2 ', 5'-diphenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione.

EXAMPLE 92 Fumarate of (3'aRS, 6'aSR) -l- (cis-4-isopropyl-cyclohexyl) -5'- (3-methyl-oxetan-3-ylmethyl) -2'-benzylhexylidene -spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] (1: 1) The title compound, mp. 213-215 ° C and MS: m / e = 466.4 (M + H +), was prepared according to the general method of example 89, starting with (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5 '- (3-methyl-oxetan-3-ylmethyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione. Example 93 Fumarate of (3'aRS, 6'aRS) -5'- (2-benzyloxy-ethyl) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro - [piperidin-4 , 1 '-pyrrolo [3, 4-c] pyrrole] (1: 2, 05) The title compound, mp. 168-170 ° C and MS: m / e = 516.4 (M + H +), was prepared according to the general method of example 89, starting with (3'aRS, 6'aSR) -5'- (2-benzyl-oxy-ethyl) -1- (cis-4-isopropyl-cyclohexyl) -2 'phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] -4 ' , 6 '-diona. Example 94 Hydrochloride of (3'aRS, 6'aRS) -4- (cis-4-isopropyl-cyclohexyl) -5'-benzyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H ) -pyrrolo [3, 4-c] pyrrole] (1: 2.3) The title compound, dec. > 190 ° C and MS: m / e = 427.4 (M + H +), was prepared according to the general method of Example 89, from (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5 '- benzyl-2'-phenyl-hexahydro-spiro - [picidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione. EXAMPLE 95 Fumarate of (3'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-5 '- (tetrahydro-furan-3-yl) -hexahydro-spiro [piperidin- 4,1 '-pyrrolo [3, 4-c] pyrrole] (1: 2) The title compound, dec. > 205 ° C and MS: m / e = 452.6 (M + H +), was prepared according to the general method of example 89, from (3'aRS, 6'aSR) -1- (cis- 4-isopropyl-cyclohexyl) -2'-phenyl-5 '- (tetrahydrofuran-3-yl) -hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] -4 ', 6' -Diona. Example 96 Fumarate of (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-cyclohexyl-2 'phenyl-hexahydro-spiro [piperi -din-4,1' (2? ) -pyrrolo [3, 4-c] pyrrole] (1: 2.18) The title compound, dec. > 190 ° C and MS: m / e = 464.5 (M + H +), was prepared according to the general method of example 89, from (3'aRS, 6'aSR) -1- (cis- 4-isopropyl-cyclohexyl) -5'-cyclohexyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione. Example 97 Fumarate of (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-butyl-2 'phenyl-hexahydro-spiro [piperidin-4, -1' (2'H ) -pyrrolo [3,4-c] pyrrole] (1: 2.2) The title compound, dec. > 220 ° C and MS: m / e = 438.5 (M + H +), was prepared according to the general method of example 89, from (3'aRS, 6'aSR) -1- (cis- 4-isopropyl-cyclohexyl) -5'-butyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione.

Example 98 Fumarate of; 3'aRS, 6'aSR) -4- (cis-4-isopro-yl-cyclohexyl) -5'-cyclopro? Ilmethyl-2'-phenyl-hexahydro-spiro - [piperidin-4,1 '(2?) -pyrrolo [3, 4-c] pyrrole] (1: 1.8) The title compound, dec. > 215 ° C and MS: m / e = 436.5 (M + H +), was prepared according to the general method of example 89, from (3'aRS, 6'aSR) -1- (cis- 4-isopropyl-cyclohexyl) -5'-cyclopropylmethyl-2'-phenyl-hexahi-dro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione. Example 99 Fumarate of (3 'aS, 6'aR) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4, 1-pyrrolo [3 , 4-c] pyrrole] (1: 2.1) 3.04 g (7.68 mmole) of the racemic mixture of (3 'aSR, 6'aRS) -1- (cis-4-isopropyl-) was dissolved. cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo- [3,4-c] pyrrole], in 70 ml of methanol and water (95: 5), and 1.65 g (4.61 mmol) of (-) -0,0-dibenzoyl-L-tartaric acid was added. The mixture was heated to reflux until complete dissolution and the solvent was partially removed by distillation until the precipitate formed. Cooling slowly took place the precipitation of 1.3 g (22%) of crystals. The enantiomeric excess was determined by chiral HPLC resulting to be 98.6%, [a] 20 589 +101.08, [to 20 = +124.22 (fumarate salt, c = 0.9982, methanol). EXAMPLE 100 Fumarate of (3 'aR, 6'aS) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3 , 4-c] pyrrole] (1: 1.85) The title compound was prepared according to the method of example 99 from the racemic mixture (3'aSR, 6'aRS) -1- (cis-4 -isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] and (+) -0,0-dibenzoyl-L acid -tartaric. The enantiomeric excess was determined by chiral HPLC to be 98.4%, [a] 58920 = -112.49, [ajs; 20 = -137.91, (fumarate salt, c = 0.7947, methanol). Example 101 Mixture of the diastereomers, hydrochloride of (3'aRS, 4'RS, 6'aSR) - and (3 'aRS, 4' SR, 6'aSR) -4 'hydroxy-1- (cis-4-isopropyl -cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -6'one (1: 1) (3' was dissolved aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4, l-pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione (846 mg, 2.0 mmol) in isopropanol (12 mL) and water (2 mL) and boron sodium hydride (515 mg, 13.6 mmol) was added. stirred at room temperature for 16 hours. The solid material was separated by filtration and the filtrate was evaporated. Column chromatography (methylene chloride / methanol / ammonium hydroxide 250: 10: 1) of the residue afforded the desired product (450 mg, 53%) as a colorless oil, which was precipitated as its HCl salt from a mixture of methanol and diethyl ether, dec. > 115 ° C, MS: m / e = 426.5 (M + H +). Example 102 (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-methi1-2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4 -c] pyrrol] -6'-one The (3'aRS, 4 'RS, 6'aSR) - and the (3'aRS, 4' SR, 6'aSR) -4 'hydroxy-1- ( cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -6' -one (mixture of diastereomer, 3.02 g, 7.10 mmol) in 30 ml of dichloromethane and then 8.25 g (71.0 mmoles) of triethylsilane and 40.5 g (355 mmoles) of trifluoroacetic acid were added. After stirring at room temperature for 3 days, the reaction mixture was poured into 100 ml of 2N sodium carbonate solution and extracted with dichloromethane. The organic phase was dried with MgSO and concentrated. Chromatography on silica gel (hexane / ethyl acetate / triethylamine 10: 10: 1) gave 2.6 g (89%) of the desired product as a white solid, m.p. 153 ° C, MS: m / e = 410.6 (M + H +). Example 103 (3'aRS, 4 'RS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -4', 5'-dimethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -6'-one and (3'aRS, 4' SR, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -4 ', 5' - dimethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrol] -6'-one The (3'aRS, 6'aSR) -1- (cis -4-isopropyl-cyclohexyl) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo (3,4-c] pyrrol] -4 ', 6'-dione (1.00 g, 2, 36 mmoles), in 25 ml of tetrahydrofuran and treated at room temperature with methylmagnesium chloride solution (1.73 ml, 3M in tetrahydrofuran) After stirring for 16 hours at room temperature, 10 ml of 1N HCl and 20 ml were added. NaOH IN, and then extracted with dichloromethane The organic phase was dried with MgSO 4 and concentrated The crude product was dissolved in 25 ml of methanol, and sodium cyanoborohydride (148 mg, 2.36 mmol) was added and 3 drops of methylene red (indi Trifluoroacetic acid was added dropwise until, the reaction mixture turned reddish and stirring was continued for 2 hours "while a further addition of trifluoroacetic acid was necessary (the mixture had to be red in color). A 1N NaOH solution was added until the pH was 8-9 and the methanol was evaporated. The residue was dissolved in dichloromethane and extracted with water. The organic phase was dried with MgSO and concentrated. Chromatography on silica gel (hexane / ethyl acetate / triethylamine 50: 10: 1) yielded 36 mg (3.6%) of (3'aRS, 4 'RS, 6'aSR) -1- (cis-4-isopropyl -cyclohexyl) -4 ', 5'-dimethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo (3,4-c] pyrrol] -6'-one, pure, dec. >; 180 ° C, MS: m / e = 424.5 (M + H +) and 207 mg (21%) of (3'aRS, 4 'SR, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) ) -4 ', 5'-dimethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo (3,4-c] pyrrol] -6'-one, pure, mp 135 ° C, MS : m / e = 424.5 (M + H +) Example 104 Fumarate of (3 'aRS, 4' RS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2 ', 4' -diphenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -6'one (1: 1) The title compound, dec.> 203 ° C and MS: m / e = 486.6 (M + H +), was prepared according to the general method of Example 103 from (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) ) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and phenyl magnesium chloride.

EXAMPLE 105 Fumarate of (3'aRS, 4 'SR, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -4', 5'-dimethyl-2'-phenyl-hexahydro-spiro [piperidin-4] , 1 '-pyrrolo [3, 4-c] pyrrole] (1: 4) The title compound, dec. > 132 ° C and MS: m / e = 410.5 (M + H +), was prepared according to the general method of Example 89 from (3 'aRS, 4' SR, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -4 ', 5'-dimethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] -6'-one. Example 106 (3'aRS, 6'aSR) -4- (cis-4-isopropyI-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4 -c] pyrrole] Hydrogenated (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-benzyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -? irrolo [3, 4-c] pyrrole] (5.5 g, 11.6 mmol) and Pd / C 10.% (0.67 g) in 67 ml of methanol and 6.7 ml of glacial acetic acid , with hydrogen at 1 atm. for 20 hours. The Pd / C was removed by filtration and the methanol and acetic acid were coevaporated with toluene. Chromatography of the residue (dichloromethane / methanol / ammonium hydroxide 140: 10: 1) gave 3.77 g (85%) of the desired product, m.p. 127 ° C and MS: m / e = 382.4 (M + H +).

Example 107 Fumarate of, 3 'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -5' - (2-hydroxy-ethyl) -2'-phenyl-hexahydro-spiro [piperidin-4, 1 '(2'H) -pyrrolo [3,4-c] pyrrole] (1: 1) The (3'aRS, 6'aRS) -5'- (2-benzyloxy-ethyl) -1- ( cis-4-isopropyl-cyclohexyl) -2 '-phenyl-hexahydro-spiro [pi -peridin-4,1' -pyrrolo [3,4-c] pyrrole] (430 mg, 0.833 mmol) and Pd / C 10% (50 mg) in 10 ml of methanol and 5 ml of 2.7 N HCl / MeOH, with hydrogen at 1 atm. for 20 hours. The Pd / C was removed by filtration and the methanol was evaporated. The residue was dissolved in ethyl acetate and extracted with 2N NaOH solution. The organic phase was dried with MgSO4 and concentrated. Column chromatography (dichloromethane / methanol / ammonium hydroxide 140: 10: 1 afforded 170 mg (48%) of the desired product, which precipitated in the form of its fumarate salt with methanol and diethyl ether, mp 194 ° C and MS : m / e = 426.6 (M + H +) Example 108 Fumarate of (3'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -5'-methylsulfonyl-2'-phenyl-hexahydro -spiro [pi -peridin-4, 1 '-pyrrolo [3, 4-c] pyrrole] (1: 1) (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) was dissolved ) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3,4-c] pyrrole] (500 mg, 1.31 mmol) in 10 ml of dichloromethane and treated ° C with triethylamine (166 mg, 1.64 mmol) and methanesulfonyl chloride (158 mg, 1.38 mmol) After stirring at room temperature for 1 hour the reaction mixture was diluted with 50 ml of dichloromethane and extracted The organic phase was dried with MgSO.sub.4 and concentrated and chromatographed on silica gel (hexane / ethyl acetate / triethylamine 70: 30: 4). it gave 440 mg (73%) of the desired compound, which precipitated in the form of its fumarate salt with a mixture of diethyl ether and methanol, dec. > 243 ° C, MS: m / e = 460.5 (M + H +). Example 109 Fumarate of (3'aRS, 6'aRS) -1- [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrol [3] 4-c] pyrrol] 15 '-yl] -ethanone (1: 1) The title compound was prepared, dec. > 218 ° C and MS: m / e = 424.5 (M + H +) according to the general method of example 108 from (3 'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and acetic anhydride.

Example 110 Fumarate of (3'aRS, 6'aRS) -1- [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -c] pyrrole] 15'-yl] -2,2,2-trifluoro-ethanone (1: 1) The title compound was prepared, dec. > 190 ° C and MS: m / e = 478.5 (M + H +) according to the general method of example 108 from (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and trifluoroacetic anhydride. Example 111 Fumarate of (3'aRS, 6'aRS) -1- [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -c] pyrrol] 5'-yl] -2-methoxy-ethanone (1: 1, 05) The title compound was prepared, dec. >; 238 ° C and MS: m / e = 454.6 (M + H +) according to the general method of example 108 from (3 'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and methoxy acetic acid chloride. EXAMPLE 112 Fumarate of the acid diethylamide (3'aRS, 6'aRS) -l- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro- [piperidin-4,1'-pyrrolo [3 , 4-c] pyrrole] -5'-carboxylic acid (1: 1) The title compound was prepared, dec. > 224 ° C and MS: m / e = 481.5 (M + H +) according to the general method of example 108 from (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and dimethylcarbamoyl chloride. Example 113 Fumarate of (3 'aRS, 6'a3R) -2- [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrol] 5 '-yl] -N, N-dimethyl acetamide (1: 1.6) The title compound was prepared, dec. > 228 ° C and MS: m / e = 467.4 (M + H +) according to the general method of Example 108 from (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and dimethylcarbamoyl chloride. EXAMPLE 114 Fumarate of (3'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-5 '- (thiophene-2-sulfonyl) -hexahydro-spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] (1: 1) The title compound was prepared, dec. > 254 ° C and MS: m / e = 528.3 (M + H +) according to the general method of Example 108 from (3 'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] and 2-thiophene sulfinyl chloride.

Example 115 Fumarate of (3'aRS, 6'aRS) - [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c ] pyrrol] -5'-yl] -pyridin-3-yl-methanone (1: 1) The title compound was prepared, dec. > 248 ° C and MS: m / e = 487.4 (M + H +) according to the general method of example 108 from (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and nicotinic acid chloride. Example 116 Fumarate of (3'aRS, 6'aRS) -5-benzenesulfonyl-l- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4, l-pyrrolo [3, 4-c] pyrrole] (1: 1) The title compound was prepared, dec. > 243 ° C and MS: m / e = 522.3 (M + H +) according to the general method of example 108 from (3 'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and benzenesulfonyl chloride.

Example 117 Fumarate of (3'aRS, 6'aRS) -cyclopropyl- [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -c] pyrrol] -5'-yl] -methanone (1: 1.1) The title compound was prepared, dec. > 247 ° C and MS: m / e = 476.3 (M + H +) according to the general method of example 108 from (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] and cyclopropylcarbonyl chloride. EXAMPLE 118 Fumarate of (3'aRS, 6'aSR) -furan-2-yl- [1- (cis-4-isopropyl-cyclohexyl) -5'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrol] -5'-yl] -methanone (1: 1.5) The title compound was prepared, dec. > 250 ° C and MS: m / e = 476.3 (M + H +) according to the general method of example 108 from (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) ) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2?) -pyrrolo [3,4-c] pyrrole] and furan-2-carboxylic acid chloride. Example 119 Tere ester fumarate. acid butyl (3 'aRS,' aRS) -1- (cis-4-isopropyl-cyclohexyl) -2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] -5 ' -carboxylic (1: 1), 05 The (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrol- was dissolved. [3, 4-c] pyrrole] (1.40 g, 3.67 mmol, in 40 ml of 1,4-dioxane and 20 ml of water, and treated at room temperature with sodium carbonate (620 mg, 7.34 mmol) and di-tert-butyl dicarbonate (960 mg, 4.40 mmol) After stirring at room temperature for 16 hours, the reaction mixture was diluted with 100 ml of ethyl acetate and extracted The organic phase was dried with MgSO 4 and concentrated, chromatography on silica gel. (hexane / ethyl acetate / triethylamine 40: 10: 1) provided 1.15 g (65%) of the desired compound, which precipitated as its fumarate salt with a mixture of diethyl ether and methanol, dec. > 244 ° C, MS: m / e = 482.5 (M + H +). EXAMPLE 120 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 2) compound of the title, white solid, mp 200 ° C and MS: m / e = 396.4 (M + H +), was prepared by hydrogenation of (3 'aRS, 6' aSR) -5'-benzyl-l-cyclodecyl-2'-phenyl-hexahydro- Spiro [piperidin-4, 1 '(2'H) -pyrrolo [3,4-c] -pyrrole] and subsequent fumarate formation, according to the general method of Example 106. Example 121 Fumarate of (3' aRS, 6'a'SR) -l-cyclodecyl-2 '- (4-fluoro-phenyl) -5'-methyl-hexahydro-spiro [piperidin-4, 1-pyrrolo- [3,4-c] pyrrole] - 4 ', 6'-dione (1: 1) The title compound, white solid, mp 244 ° C and MS: m / e = 456.5 (M + H +), was prepared according to the general method of Example 5 from 1-cyclo-decyl-piperidin-4-one, p-fluoro- aniline and N-methyl-maleimide and subsequent fumarate formation. Example 122 Fumarate of (3'aRS, 6'aSR) -2 '- (4-fluoro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, white solid, mp 220 ° C and MS: m / e = 442.5 (M + H +), was prepared according to the general method of example 5 from cis-1- (4-isopropyl-cyclohexyl) -piperidine-4- ona, p-fluoro-aniline and N-methyl-maleimide and subsequent fumarate formation. Example 123 Fumarate of (3'aRS, 6'aSR) -2 '- (4-fluoro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] (1: 1) The title compound, light red solid, mp 200 ° C and MS: m / e = 414.5 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -2' - (4-fluoro-phenyl) -1- (cis-4-isopropylcyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4, 1 '-pirr [3, 4-c] -pyrrole] -4', 6'-dione, and subsequent formation of the fumarate according to the general method of example 15.

Example 124 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-2 '- (3-fluoro-phenyl-5'-methyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4- c] pyrrole] (1: 2) The title compound, light orange solid, mp 234 ° C (dec.) and MS: m / e = 428.6 (M + H +), was prepared by reducing the (3'aRS, 6'aSR) -l-cyclodecyl-2 '- (3-fluoro-phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1'-pyrrolo [3, 4-c] - pyrrole] -4 ', 6'-dione, and subsequent formation of the fumarate, according to the general method of example 15. The (3'aRS, 6'aSR) -l-cyclodecyl-2' - (3-fluoro- phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] -pyrrol] -4', 6'-dione, was prepared according to the general method of example 5 from 1-cyclodecyl-piperidin-4-one, m-fluoro-aniline and N-methyl-maleimide Example 125 Fumarate of (3'aRS, 6 'aSR) -l-cyclodecyl-2' - (4- fluoro-phenyl-5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] (1: 2) The title compound, colloidal solid or light yellow, m.p. 236 ° C (dec.) And MS: m / e = 428.6 (M + H +), was prepared by reduction of (3 'aRS, 6'aSR) -l-cyclodecyl-2' - (4-fluoro) phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1'-pyrrolo [3, 4-c] -pyrrole] -4 ', 6'-dione, and subsequent fumarate formation according to general method of example 89. Example 126 Fumarate of (3 'aRS, 6'aSR) -2' - (3-fluoro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro- spiro [piperidin-4, 1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, white solid, mp 242 ° C (dec.) And MS: m / e = 442.4 (M + H +), was prepared according to the general method of Example 5, from cis-1- (4-isopropyl-cyclohexyl) -piperidin-4-one, m-fluoro-aniline and N-methyl-maleimide, and subsequent fumarate formation. Example 127 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2 '- (4-methyl-phenyl) -hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4 -c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, white solid, mp 243 ° C (dec.) And MS: m / e = 452.5 (M + H +), was prepared according to the general method of Example 5, from the 1-cyclodecyl-piperidin-4-one, p -methyl-aniline and n-methyl-maleimide, and subsequent formation of the fumarate.

Example 128 Fumarate of (3'aRS, 6'aSR) -2 '- (3-fluoro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperi-din- 4,1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione (1: 2) The title compound, white solid, mp 210 ° C (dec.) And MS: m / e = 414.5 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -2 '- (3-fluoro-phenyl) - 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione, and subsequent formation of the fumarate, according to the general method of example 89. Example 129 Fumarate of (3 'aS, 6'aR) -l-cyclononyl-5' -methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] -pi-rrol] (1: 2.3) The title compound, light orange solid, mp 132 ° C (dec.); [a] D20 = -78.6 ° (c = 0.1044 in MeOH) and MS: m / e = 396.4 (M + H +), was prepared by reduction of (3 'aS, 6'aR) -l-cyclononyl-5'-methyl-2'-phenylhexahydro- Spiro [piperidin-4, 1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4', 6'-dione, and subsequent fumarate formation, according to the general method of example 89. The (3'aS, 6'aR) -l-cyclononyl-5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione, was prepared from (3' aS, 6'aR) -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione and cyclononanone, according to the general method of example 3. Example 130 Fumarate of (3'aS, 6'aR) -l-cyclodecyl- 2 '- (2-fluoro-phenyl) -5' -methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo- [3,4-c] -pyrrole] (1: 2.1) The title compound , light orange solid, mp 223 ° C (dec.) And MS: m / e = 428.6 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -l-cyclodecyl-2 '- (2-fluoro) phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione, and subsequent fumarate formation, according to the method Example 89. (3'aRS, 6'aSR) -l-cyclodecyl-2 '- (2-fluoro-phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3 , 4-c] -pyrrole] -4 ', 6'-dione, was prepared according to the general method of Example 5, from 1-cyclodecyl-piperidin-4-one, o-fluoro-aniline and N -methyl-maleimide. Example 131 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2 '- (4-methyl-phenyl) -hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4 -c] -pyrrole] (1: 2.2) The title compound, light pink solid, mp 249 ° C (dec.) And MS: m / e = 424.5 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -l-cyclodecyl-2 '- (4-methyl) ) -phenyl) -5'-methyl-hexahydro-spiro [pi? eridin-4,1 '-pyrrolo [3, 4, c] pyrrole] -4', 6'-dione, and subsequent fumarate formation, in accordance with the general method of example 89. Example 132 Fumarate of (3'aRS, 6'aSR) -l-cyclononyl-2 '- (4-fluoro-phenyl) -5'-methyl-hexahydro-spiro [piperidin-4, 1 '-pyrrolo- [3,4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, white solid, mp 247 ° C (dec.) And MS: m / e = 442.4 (M + H +), was prepared according to the general method of Example 5 from the 1-cyclononyl-piperidin-4-one, p- fluoro-aniline and N-methyl-maleimide, and subsequent formation of the fumarate. EXAMPLE 133 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2 '- (3-methyl-phenyl) -hexahydro-spiro [piperidin-4,1' -pyrrolo- [3, 4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, whitish solide, mp 249 ° C (dec.) And MS: m / e = 452.5 (M + H +), was prepared according to the general method of Example 5 from l-cyclodecyl-piperidin-4-one, m-methyl-aniline and N-methyl-maleimide, and subsequent fumarate formation. (3'aRS, 6'aSR) -2'- (4-chloro-phenyl) -1-cyclodecyl-5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo- [3, 4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, light yellow solid, mp 241 ° C (dec.) and MS: m / e = 472.34 (M + H +), was prepared according to the general method of Example 5 from l-cyclodecyl-piperidin-4-one, p-chloroaniline and N-methyl-maleimide, and subsequent fumarate formation.

EXAMPLE 135 Fumarate of (3'aRS, 6'aSR) -2'- (4-chloro-phenyl) -1-cyclodecyl-5'-methyl-hexahydro-spiro [piperidin-4,1'-pyrrolo- [3, 4-c] pyrrole] (1: 2) The title compound, light pink solid, mp 243 ° C (dec.) And MS: m / e = 444.4 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -l-cyclodecyl-2'- (4-chlorophenyl) ) -5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent formation of fumarate according to the general method of example 89 .

Example 136 Fumarate of (3'aRS, 6'aSR) -l- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2 '- (4-methyl-phenyl) -hexahydro-spiro- [piperidin-4] , 1 '-pyrrolo [3, 4-c] pyrrole] (1: 2.3) The title compound, light red solid, mp 256 ° C (dec.) And MS: m / e = 410.6 (M + H +), was prepared by. reduction of (3 'aRS, 6' aSR) -2 '- (4-methyl-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5' -methyl-hexahydro-spiro- [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] -A', 6 '-dione and subsequent fumarate formation according to the general method of example 89. (3'aRS, 6'aSR) -2' - (4-methyl-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione, was prepared according to the general method of Example 5, from cis-1- (4-isopropyl-cyclohexyl) -piperidin-4-one, p-methyl-aniline and N-methyl-maleimide . Example 137 Fumarate of (3'aRS, 6'aSR) -2 '- (2-fluoro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro- [piperi-din -4, 1 '-pyrrolo [3, 4-c] irrol] (1: 2,3) The title compound, light orange solid, mp 160 ° C (dec.) And MS: m / e = 414.4 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -2 '- (2-fluoro-phenyl) - 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate according to the general method of example 89. The (3'aRS, 6'aSR) -2 '- (2-fluoro-phenyl) -l- (cis-4-isopropyl-cyclohexyl) -5'-methyl hexahydro-spiro [piperidin-4,1 '-α-fluoro [3,4-c] pyrrole] -4', 6'-dione was prepared according to the general method of example 5, from the cis- 1- (4-isopropyl-cyclohexyl) -piperidin-4-one, o-fluoro-aniline and N-methyl-maleimide. EXAMPLE 138 Fumarate of (3 'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2' - (3-methyl-phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3, 4 -cjpyrrole] (1: 2) The title compound, light pink solid, mp 219 ° C (dec.) and MS: m / e = 424.5 (M + H +), was prepared by reducing the ( 3 'aRS, 6' aSR) -l-cyclodecyl-2 '- (3-methyl-phenyl) -5'-methyl-hexahydro-spiro- [piperidin-4,1' -pyrrolo- [3, 4-c] pyrrole] -4 ', 6'-Dione and subsequent fumarate formation according to the general method of example 89. Example 139 (3' aRS, 6'aSR) -l-cyclononyl-2 '- (4-fluoro) fumarate phenyl) -5 '-methyl-hexahydro-spiro- [piperidin-4,1' -pyrrolo- [3,4-c] pyrrole] (1: 2) The title compound, light pink solid, mp 225 ° C and MS: m / e = 414.4 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -l-cyclononyl-2 '- (4-fluoro-phenyl) -5 '-methyl-hexahydro-spiro- [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione and subsequent formation of the fumarate according to the metho General example of example 89. Example 140 Fumarate of (3 'aRS, 6'aSR) -5' -benzyl-1-cyclononyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -c] pyrrole] (1: 2) The title compound, off-white solid, mp 210 ° C (dec.) And MS: m / e = 472.4 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -5 '-benzyl-1-cyclononyl-2' phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and subsequent fumarate formation according to the general method of example 89. The ( 3'aRS, 6'aSR) -5'-benzyl-1-cyclononyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6 ' -dione, was prepared according to the general method of example 5, starting from l-cyclononyl-piperidin-4-one, aniline and N-benzyl-maleimide.

Example 141 Fumarate of (3'aRS, 6'aSR) -l-cyclononyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 3.5 ) The title compound, off-white solid, mp 173 ° C and MS: m / e = 382.4 (M + H +), was prepared by hydrogenation of the (3 'aRS, 6' aSR) -5'-benzyl-1-cyclononyl-2'-phenyl-hexahydro -spiro- [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] and subsequent formation of the fumarate according to the general method of example 106. Example 142 Fumarate of (3'aRS, 6'aSR) - l-cyclodecyl-2 '- (4-fluoro-phenyl) -hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] -pyrrole] -4 ', 6'-dione (1: 1) The title compound, light yellow solid, mp 246 ° C (dec.) And MS: m / e = 442.4 (M + H +), was prepared according to the general method of Example 5 from the 1-cyclodecyl-piperidin-4-one, p- fluoro-aniline and maleimide and subsequent fumarate formation.

EXAMPLE 143 Fumarate of (3 'aRS, 6' aSR) -2 '- (4-chloro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5' -methyl-hexahydro-spiro [piperidin-4, 1'-pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, white solid, mp 219 ° C and MS: m / e = 458.4 (M + H +), was prepared according to the general method of example 5 from cis-l- (4-isopropyl-cycloexyl) -piperidin-4- ona, m-chloro-aniline and N-methyl-maleimide and subsequent fumarate formation. Example 144 Fumarate of (3'aRS, 6'aSR) -2 '- (4-chloro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole] (1: 2.1) The title compound, light red solid, mp 241 ° C (dec.) And MS: m / e = 430.5 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -2 '- (4-chloro-phenyl) - 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate according to the general method of example 89. Example 145 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -2 '- (4-methoxy-phenyl) -5 '-methyl-hexahydro-spiro- [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole] -A ', 6'-dione (1: 1) The title compound, white solid, mp 205 ° C and MS: m / e = 454.5 (M + H +), was prepared according to the general method of Example 5 from cis-l- (4-isopropyl-cycloexyl) -piperidin-4- ona, p-methoxy-aniline and N-methyl-maleimide and subsequent fumarate formation. EXAMPLE 146 Fumarate of (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -2 '- (4-methoxy-phenyl) -5'-methyl-hexahydro-spiro- [piperidin-4 , 1 '-pyrrolo [3, 4-c] pyrrole] (1: 2) The title compound, light orange solid, mp 245 ° C (dec.) And MS: m / e = 426.6 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -2 '- (4-methoxy-phenyl) - 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro (piperidin-4,1 '-pyrrolo [3, 4, c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate according to the general method of example 89. Example 147 Fumarate of (3 'aRS, 6' aSR) -l-cyclodecyl-5'-cyclopropyl-methyl-2 '- (4-fluoro-phenyl) -hexahydro-spiro - [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione (1: 1) The title compound, light yellow solid, mp 247 ° C (dec. ) and MS: m / e = 496.3 (M + H +), was prepared by the Mitsunobu reaction of (3 'aRS, 6' aSR) -l-cyclodecyl-2 '- (4-fluoro-phenyl) hexahydro-spiro (piperidin-4,1'-pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione and cyclopropyl-methanol and subsequent fumarate formation according to the general method of example 81.

EXAMPLE 148 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-cyclobutyl-methyl-2 '- (4-fluoro-phenyl) -hexahydro-spiro- [piperidin-4,1' -pyrrolo [ 3, 4-c] pyrrole] -4 ', 6'-dione (1: 1) The title compound, light yellow solid, mp 245 ° C (dec.) And MS: m / e = 510.5 (M + H +), was prepared by the Mitsunobu reaction of (3'aRS, 6'aSR) -l-cyclodecyl-2 '- ( 4-fluoro-phenyl) -hexahydro-spiro (piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and cyclobutyl-methanol and subsequent fumarate formation according to the method Example 81. Example 149 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-cyclobutyl-methyl-2 '- (4-fluoro-phenyl) -hexahydro-spiro- [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] (1: 2,3) The title compound, light pink solid, mp 249 ° C (dec.) And MS: m / e = 482.5 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -l-cyclodecyl-5'-cyclobutyl-methyl- 2 '- (4-fluoro-phenyl) -hexahydro-spiro [pipe-ridin-4,1' -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione and subsequent fumarate formation in accordance with the general method of example 89.EXAMPLE 150 Fumarate of (3'aRS, 'aSR) -l-cyclodecyl-5'-cyclopropyl-methyl-2' - (4-fluoro-phenyl) -hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3 , 4-c] pyrrole] (1: 2) The title compound, light pink solid, mp 242 ° C (dec.) And MS: m / e = 468.4 (M + H +), was prepared by reduction of (3'aRS, 6'aSR) -l-cyclodecyl-5'-cyclopropylmethyl- 2 '- (4-fluoro-phenyl) -hexahydro-spiro [pi-peridin-4,1' -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione and subsequent fumarate formation in accordance with the general method of example 89. Example 151 Fumarate of (3'aRS, 6'aSR) -5'-tert-butyl-1-cyclononyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1 '- pyrrolo [3, 4-c] pyrrole] (1: 2.5) The title compound, light red solid, mp 220 ° C (dec.) And MS: m / e = 438.5 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -5 '-tert-butyl-1-cyclononyl- 2'-phenyl-hexahydro-spiro [piperidin-4,1 'pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate according to the general method of example 89. (3 'aRS, 6' aSR) -5 '-tert-butyl-1-cyclononyl-2'-phenyl) -hexahydro-spiro [piperidin-4, 1-pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione was prepared according to the general method of Example 5 from l-cyclononyl'piperidin-4-one, aniline and N-tert-butyl-maleimide. Example 152 * Fumarate of (3'aRS, 6'aSR) - (1-cyclononyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -5' -yl) -cyclopropyl-methanone (1: 1) The title compound, light red solid, mp 236 ° C (dec.) And MS: m / e = 450.4 (M + H +), was prepared by reaction of (3 'aRS, 6' aSR) -l-cyclononyl-2'-phenyl-hexahydro- Spiro [piperidin-4, pyrrolo [3, 4-c] pyrrole] with the cyclopropanecarbonyl chloride and subsequent fumarate formation according to the general method of example 108. Example 153 Fumarate of (3'aRS, 6'aSR ) -l-cyclononyl-5-methylsulfonyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 1) The title compound, red solid clear, mp 179 ° C (dec.) And MS: m / e = 460.4 (M + H +), was prepared by reaction of the (3 'RS, 6' aSR) -l-cyclononyl-2'-phenyl-hexahydro- spiro [piperidin-4, pyrrolo [3, 4-c] pyrrole] with methanesulfonyl chloride and subsequent formation of the fumarate according to the general method of example 108.

EXAMPLE 154 Fumarate of (3'aRS, 6'aSR) -5'-cyclopropylmethyl-2 '- (4-fluoro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -hexahydro-spiro- [piperidin-4] , 1 '-pyrrolo [3, 4-c] pyrrole] (1: 2) The title compound, white solid, mp 209 ° C and MS: m / e = 454.6 (M + H +), was prepared by reduction of (3'aRS, 6 'aSR) -5'-cyclopropylmethyl-2'- (4-fluoro-phenyl) - (l-cis-4-isopro-yl-cyclohexyl) -hexahydro-spiro [pi-peridin-4, pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione and subsequent formation of the fumarate according to the general method of example 89. Example 155 Fumarate of (3'aRS, 6'aSR) -5 '-cyclobutylmethyl'-2'- (3-fluoro-phenyl) -1- (cis-4-) isopropyl-cyclohexyl) -hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 2) The title compound, light red solid, mp 235 ° C (dec.) And MS: m / e = 454.6 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -5 '-cyclopropylmethyl-2' - (3- fluoro-phenyl) -1- (cis-4-isopropyl-cyclohexyl) -hexahydro-spiro [piperidin-4, pyrrolo [3, 4-c] -4 ', 6'-dione and subsequent formation of the fumarate according to with the general method of example 89.

Example 156 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-cyclopropylmethyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4 ', 6' -dione (1: 1) The title compound, light yellow solid, mp 236 ° C (dec.) And MS: m / e = 478.5 (M + H +), was prepared by the Mitsunobu reaction of (3'aRS, 6'aSR) -l-cyclodecyl-2'-phenyl hexahydro-spiro [pipe-ridin-4, pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione and cyclopropyl-methanol, and subsequent formation of the fumarate according to the general method of the example 81. EXAMPLE 157 Fumarate of (3'aRS, 6 'aSR) - (1-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole] -5 ' -yl) -phenyl-methanone (1: 1) The title compound, light pink solid, mp 203 ° C (dec.) And MS: m / e = 500.4 (M + H +), was prepared by the reaction of (3 'aRS, 6' aSR) -l-cyclodecyl-2'-phenyl-hexahydro- spiro [piperidin-4, 1 '-pyrrolo [3, -c] pyrrole] with benzoyl chloride and subsequent fumarate formation according to the general method of example 108.

EXAMPLE 158 Fumarate of (3'aRS, 6'aSR) - (1-cyclodecyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -5' - il) -cyclopropyl-methanone (1: 1) The title compound, white solid, mp 225 ° C (dec.) And MS: m / e = 464.4 (M + H +), was prepared by the reaction of (3'aRS, 6'aSR) -l-cyclodecyl-2'-phenyl-hexahydro- spiro [piperidin-4,1'-pyrrolo [3, 4-c] pyrrole] with cyclopropanecarbonyl chloride and subsequent fumarate formation according to the general method of example 108. Example 159 Fumarate of (3'aRS, 6'aSR ) -1- (1-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrol] -5'-yl) -ethanone (1: 1) The compound of the title, light yellow solid, mp 200 ° C (dec.) And MS: m / e = 438.5 (M + H +), was prepared by the reaction of (3 'aRS, 6'aSR) -l-cyclodecyl-2'-phenyl-hexahydro- spiro [piperidin-4, 1 '-pyrrolo [3, 4-c] pyrrole], with acetyl chloride and subsequent fumarate formation according to the general method of example 108.

Example 160 Fumarate of (3 'aRS, 6' aSR) -l-cyclodecyl-5'-cyclopropylmethyl-2'-phenyl) -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 2.1) The title compound, light red solid, mp 219 ° C (dec.) And MS: m / e = 450.5 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -l-cyclodecyl-5'-cyclopropylmethyl-2 ' phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] -4', 6'-dione and subsequent formation of the fumarate according to the general method of the example 89, Example 161 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-5'-methylsulfonyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole ] (1: 1) The title compound, white solid, mp 252 ° C (dec.) And MS: m / e = 474.4 (M + H +), was prepared by reaction of (3'aRS, 6 'aSR) -5' -l-cyclodecyl-2'-phenyl- hexahydro-spiro [piperidin-4,1'-pyrrolo [3, 4-c] pyrrole] with methanesulfonyl chloride and subsequent fumarate formation according to the general method of example 108.

EXAMPLE 162 Fumarate of the acid phenylamide (3 'aRS, 6'aSR) -1-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] -5 '-carboxylic (1: 0.8) The title compound, white solid, mp 202 ° C (dec.) And MS: m / e = 515.3 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] with phenyl isocyanate and subsequent formation of the fumarate according to the general method of example 108. Example 163 Fumarate of the (3'aRS, 6'aSR ) -1- (1-Cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrol] -5'-yl) -2,2-dimethyl-propan-1 -one (1: 0.9) The title compound, white solid, mp 232 ° C (dec.) And MS: m / e = 480.5 (M + H +), was prepared by reaction of (3'aRS, 6 'aSR) -l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] with pivaloyl chloride and subsequent fumarate formation according to the general method of example 108. EXAMPLE 164 Fumarate of the ethyl ester of the acid (3'aRS, 6'aSR) -1-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -5'-carboxylic acid (1: 1) The title compound, solid white, mp 260 ° C (dec.) And MS: m / e = 468.4 (M + H +), was prepared by reaction of (3'aRS, 6 'aSR) -l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] with ethyl chloroformate and subsequent fumarate formation according to the general method of example 108. EXAMPLE 165 Fumarate of acid dimethylamide (3') aRS, 6'aSR) -1-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -5'-sulfonic acid (1: 1) The compound of title, solid white, mp 253 ° C (dec.) And MS: m / e = 503.4 (M + H +), was prepared by reduction of (3 'aRS, 6' aSR) -l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] with N, N-dimethylsulphamoyl chloride and subsequent fumarate formation according to the general method of example 108. EXAMPLE 166 Fumarate of (3'aRS, 6'aSR) -l-cyclodecyl-2'-phenyl-5'-benzenesulfonyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] (1: 1) The title compound , solid white, mp 235 ° C (dec.) And MS: m / e = 536.4 (M + H +), was prepared by reaction of (3 'aRS, 6' aSR) -l-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole] with phenylsulfonyl chloride and subsequent fumarate formation according to the general method of example 108. Example 167 Fumarate of (3'aRS,' aSR) - [1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrol] -5' -yl] -pyridin-2 -yl-methanone (1: 1, 12) The title compound, desc. > 240 ° C and MS: m / e = 487.5 (M + H +), was prepared according to the general method of example 108, from (3'aRS, 6 'aSR) -4- (cis-4) -isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] and 2-picolinic acid chloride. Example 168 Fumarate of (3 'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c ] pyrrol] -5'-yl] -thiophen-2-yl-methanone (1: 1.1) The title compound, dec. > '243 ° C and MS: m / e = 492.4 (M + H +), was prepared according to the general method of example 108, from (3' aRS, 6 'aSR) -4- (cis- 4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4- c] pyrrole] and 2-thiophenecarbonyl chloride.

EXAMPLE 169 Fumarate of (3'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c ] pyrrol] -5'-yl] -morpholin-4-yl-methanone (1: 1) The title compound, dec. > 253 ° C and MS: m / e = 495.5 (M + H +), was prepared according to the general method of example 108, from (3'aRS, 6'aSR) -4- (cis-4) -isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] and morpholine-N-carbonyl chloride. EXAMPLE 170 Fumarate of (3 'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c ] pyrrol] -5'-yl] -pyridin-4-yl-methanone (1: 1) The title compound, dec. > 250 ° C and MS: m / e = 487.5 (M + H +), was prepared according to the general method of example 108, from (3 'aRS, 6' aSR) -4- (cis-4 -isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] and isonicotinoyl chloride. EXAMPLE 171 Phenyl ester fumarate of the acid (3 'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [pipe ridin-4,1' -pyrrolo [3 , 4-c] pyrrole] -5'-carboxylic acid (1: 1) The title compound, dec. > 225 ° C and MS: m / e = 502.4 (M + H +), was prepared according to the general method of example 108, from (3 'aRS, 6' aSR) -4- (cis-4) -isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] and phenyl chloroformate.

Example 172 Fumarate of (3 'aRS, 6'aSR) - [1- (cis-4-isopropyl-cyclohexyl) -2' - (4-fluoro-phenyl) phenyl-hexahydro-spiro [piperidin-4,1 ' -pyrrolo [3, 4-c] pyrrol] -5'-yl) -pyridin-3-yl-methanone (1: 1) The title compound, dec. > 230 ° C and MS: m / e = 505.4 (M + H +), was prepared according to the general method of example 108, from (3'aRS, 6'aSR) -1- (cis-4) -isopropyl-cyclohexyl) -2 '- (4-fluoro-phenyl) -hexahydro-spiro- [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] and nicotinic acid chloride. Synthesis of intermediates Example AA Cis- [1- (4-isopropyl-cyclohexyl) -piperidin-4-ylidene] phe nyl-amine The cis-1- [4-isopropyl-cyclohexyl) -piperidin-4-one was stirred ( 5.0 g, 23.4 mmol), aniline (3.3 g, 35.3 mmol) and molecular sieves (20 g, 4 A), in 100 pentane at room temperature for 6 days. The molecular sieves were separated by filtration and the solvent was evaporated. The crude product was used without further purification for the next step. Example AB (3 'aRS, 6' aSR) -l-benzyl-5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione The title compound, light yellow foam, MS: m / e = 390.3 (M + H +), was separated according to the general method of Example 5 from 1-benzyl-piperidin-4-one, aniline and N-methyl-maleimide.

Example AC (3 'aRS, 6' aSR) -5 '-methyl-1' -phenyl-hexahydro-spiro [pipe-ridin-4, 1 '(2' H) -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione The title compound, light brown foam, MS: m / e = 300.3 (M + H +), was prepared by hydrogenation of the (3' aRS, 6 'aSR) - 5 '-methyl-2' -phenyl-1- [(R) -1-phenyl-ethyl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6 '-diona, according to the general method of example 106.

Example AD 1-cyclodecyl-piperidin-4-one To a solution of cyclodecylamine (6.78 g, 44 mmol) in ethanol (80 ml) was added a solution of potassium carbonate (0.60 g, 3.9 mmol) and iodide of 1-ethyl-1-methyl-4-oxo-piperidino (16.2 g, 60 mmol) in water (40 ml) and the mixture was heated to reflux for 100 minutes The reaction mixture was poured into a solution of NaHCO2 (120 mL / ice (400 mL) and extracted with ethyl acetate (2x 300 mL) The combined layers of the organics were dried (MgSO) and evaporated. Column chromatography on silica gel (toluene / ethyl acetate 2: 1) gave the title compound (8.8 g, 85%) as a light brown oil, MS: m / e = 238.4 ( M +). Example AE l-cyclononyl-piperidin-4-one The title compound, yellow oil, MS: m / e = 223 (M +), was prepared by reaction of cyclononylamine and l-ethyl-iodide -methyl-4-oxo-piperidinium, according to the general method of the example AD. Example AF (R) -1- (1-phenyl-ethyl) -piperidin-4-one The title compound, light brown oil, [a] D20 = + 13.3 ° (c = 0.4286 in CHC13) and MS: m / e = 203 (M + H +), was prepared by reaction of cyclononylamine and l-ethyl-l-methyl-4-oxo-piperidinium iodide, according to the general method of Example AD. Example A6 (3'aS, 6'aR) -5 '-methyl-2'-phenyl-1- [(R) -1-phenyl-ethyl] -hexahydro-spiro [piperidin-4,1' -pyrrolo [3 , 4-c] pyrrole] -A ', 6"-dione The title compound, white foam, [a] D20 = -143.3 ° (c = 0.2855 in CHC13) and MS: m / e = 404 , 4 (M + H +), was prepared according to the general method of example 5. from (R) -l- (l-phenyl-ethyl) -piperidin-4-one, aniline and N-methyl-maleimide Example AH (3 'aR, 6' aS) -5 '-methyl-2'-phenyl-1- [(R) -1-phenyl-ethyl] -hexahydro-spiro [piperidin-4,1' -pyrrolo [ 3, 4-c] pyrrole] -4 ', 6'-dione The title compound, white foam, [a] D20 = + 104.7 ° (c = 0.2751 in CHC13) and MS: m / e = 404.5 (M + H +), was prepared according to the general method of Example 5, from (R) -1- (1-phenyl-ethyl) -piperidin-4-one, aniline and N-methyl-maleimide.

Example AI. (3 'aS, 6' aR) -5 '-methyl-2' -phenyl-hexahydro-spiro [piperi -din-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6 '- diona The title compound, white solid, mp 159 ° C; [a] D20 = -124.0 ° (c = 0.2862 in CHC13) and MS: m / e = 300.3 (M + H +), was prepared by hydrogenation of (3 'aS, 6'aR) -5 '-methyl-2' -phenyl-l- [(R) -1-phenyl-ethyl) -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -A', 6 '-dione according to the general method of example 106. Example AJ (3' aR, 6 'aS) -5' -methyl-2 '-phenyl-hexahydro-spiro [pipe-ridin-4, 1' -pyrrolo [3, Ac] pyrrole] -A ', 6'-dione The title compound, white solid, mp 160 ° C; [a] D20 = + 117.0 ° (c = 0.2862 in CHC13) and MS: m / e = 300.3 (M + H +), was prepared by hydrogenation of the (3 'aR, 6' aS) -5 '-methyl-2' -phenyl-1- [(R) -1-phenyl-ethyl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6 ' -dione according to the general method of example 106. EXAMPLE AK Fumarate of (3'aRS, 6 'aSR) -5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3 , 4-c] pyrrole] (1: 1.4) The title compound pf > 190 ° C desc. and MS: m / e = 286.2 (M + H +), was prepared according to the general method of Example 15 from (3'aRS, 6'aSR) -5'-ethyl-2'-phenyl - exahydro-spiro [piperidin-4, 1 '(2' H) -pyrrolo [3, 4-c] -pyrrol] -4 ', 6'-dione. Example AL (4-fluoro-phenyl) - [1- (cis-4-isopropyl-cyclohexyl) -pipe-ridin-4-ylidene] -amine The cis-1- (4-isopropyl-cyclohexyl) -piperidine- was stirred 4-one (5.0 g, 23.4 mmol), 4-fluoroaniline (3.3 g, 35.3 mmol) and molecular sieves (20 g, 4A), in 100 ml of pentane at room temperature during 6 days. The molecular sieves were separated by filtration and the solvent was evaporated. The crude product was used without further purification for the next step. EXAMPLE A Tablets of the following composition were prepared in the usual manner: mg / tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystalline cellulose 34 Magnesium stearate 1 Tablet weight 100 Example B Capsules of the following composition were prepared: mg / capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Weight of the filled capsule 200 First, the active substance, the lactose and the corn starch were mixed in a mixer and then in a crushing machine. The mixture was reintroduced into the mixer, the talc was added thereto and mixed thoroughly. The mixture was machine-laced in hard gelatin capsules.

Example C Suppositories of the following composition were made: mg / suppository Active substance 15 Suppository mass 1285 Total 1300 The suppository mass was melted in a glass or steel vessel, mixed thoroughly and cooled to 45 ° C. The finely divided active substance was then added and stirred until it had completely dispersed. The mixture was poured into suppository molds of the appropriate size and individually packed in wax paper or metal foil.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

R E I V I N D I C A C I O N S

1. Formula compounds characterized in that R1 is cycloalkyl of 5 to 12 carbon atoms, optionally substituted with lower alkyl; decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl; indan-1-yl or indan-2-yl, optionally substituted with lower alkyl; decahydro-azulen-2-yl; bicyclo [6.2.0] dec-9-yl; acenaphthen-1-yl; bicyclo [3.3.1] non-9-yl; 2, 3-dihydro-lH-phenalen-1-yl; 2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl; octahydro-inden-2-yl; 1,2,3, 4-tetrahydro-naphthalene-1-yl; 1,2,3, 4-tetrahydro-naphthalen-2-yl; naphthalene-lower alkyl-1-yl; naphthalene-lower alkyl-2-yl; acenaphthen-1-yl; and 5-isopropyl-2-methyl-bicyclo [3.1.0] hex-3-yl; R2, R3 are hydrogen; hydroxyl; lower alkyl; = 0; or phenyl, optionally substituted with lower alkyl, halogen or alkoxy; R4 is hydrogen; lower alkyl; - (CH2) nCH (OH) CF3; - (CH2) n-cycloalkyl of 3 to 6 carbon atoms; phenyl; benzyl; tetrahydrofuran-3-yl; - (CH2) nOCH2C6H5, - (CH2) pmorpholinyl; 3-methyl-oxetan-3-yl-methyl; - (CH2) nCH20H; -S (0) 2-lower alkyl; -C (0) -lower alkyl; -C (0) CF3; -C (0) (CH2) n0CH3; - (CH2) nC (0) N (lower alkyl) 2; -S (O) 2 -heteroaryl; -C (O) heteroaryl; -S (0) 2-phenyl; -S (0) 2-N (lower alkyl) 2; -C (0) -cycloalkyl of 3 to 6 carbon atoms; -C (0) O-phenyl; or -C (0) O-lower alkyl: R5 is hydrogen; halogen; lower alkyl; trifluoromethyl or lower alkoxy; n is 0-3; racemic mixtures and their corresponding enantiomers and pharmaceutically acceptable acid addition salts, thereof.

2. A compound according to claim 1, characterized in that R1 is cycloalkyl of 5 to 12 carbon atoms, optionally substituted with lower alkyl.

3. A compound according to claim 2, characterized in that: (3 'aRS, 6'aSR) -l-cyclononyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pirr [3, 4-c] pyrrole]; (3'aRS, 6'aSR) -l-cyclodecyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole] -4 ', 6'-dione; (3'aRS, 6'aSR) -l-cyclodecyl-5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole]; (3 'aRS, 6'aSR) 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) 1- (cis-4-isopropyl-cyclohexyl) -5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pi-rrol]; (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-butyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [ 3, 4-c] pyrrole]; (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-cyclo-propylmethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) - pyrrolo [3, 4-c] pyrrole]; (3'aRS, 4 'SR, 6'aRS) -l- (cis-4-isopropyl-cyclohexyl) -4', 5'-dimethyl-2'-pheny1-hexahydro-spiro [piperidin-4,1 '- pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3, 4-c] ] pyrrole]; (3'aRS, 6 'aSR) -l-cyclodecyl-5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole]; (3 'aRS, 6'aSR) -l-cyclononyl-5'-ethyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole]; (3'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c ] pyrrole] -4 ', 6'-dione; (3 'aRS, 6'aSR) -1- (cis-4-isopropyl-cyclohexyl) -5'-ben-cil-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4 -c] pyrrole] -4 ', 6'-dione; (3'aRS, 6'aSR) -A- (cis-4-isopropyl-cyclohexyl) -5'-benzyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '(2?) -pyrrolo [3 , 4-c] pyrrole]; (3 'aRS, 6'aSR) -4- (cis-4-isopropyl-cyclohexyl) -5'-cyclohexyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) - pyrrolo [3, 4-c] pyrrole]; (3 'aS, 6'aR) 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole]; (3'aR, 6'aS) 1- (cis-4-isopropyl-cyclohexyl) -5'-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -5'- (2-hydroxy-ethyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pi -rolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) -2- [l- (cis-4-iso? Ropil-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] ] pyrrolid] -5'-yl] -N, N-dimethyl-acetamide; (3'aRS, 6'aRS) - [1- (cis-4-isopropyl-cyclohexyl) -2'-phe nyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrole ] -5'-yl] -pyridin-3-yl-methanone; (3'aRS, 6'aSR) -2 '- (3-fluoro-phenyl) -l- (cis-4-isopropyl-cyclohexyl) -5'-methyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] pyrrole] -4 ', 6'-dione; (3 'aS, 6'aR) -l-cyclononyl-5'-methyl-2-phenyl-hexahydro spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole]; (3'aS, 6'aR) -l-cyclododecyl-2 '- (2-fluoro-phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] ] pyrrole]; (3'aRS, 6'aSR) -l-cyclononyl-2 '- (4-fluoro-phenyl) -5'-methyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3, 4-c] ] pyrrole]; (3 'aRS, 6'aSR) -l-cyclononyl-2'-phenyl-hexahydro-spiro- [piperidin-4,1' -pyrrolo [3,4-c] pyrrole]; (3'aRS, 6'aSR) - (1-cyclononyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrol] -5'-yl) -cyclopropyl- methanone; and (3'aRS, 6'aSR) - (1-cyclodecyl-2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4-c] pyrrol] -5' -yl) -cyclopropyl -metanone; or (3 'aRS, 6'aRS) -1- (cis-4-isopropyl-cyclohexyl) -2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole] - 5'yl] -thiophen-2-yl-methanone.

4. A compound according to claim 1, characterized in that R1 is decahydro-naphthalen-2-yl.

5. A compound according to claim 4, characterized in that: mixture of (3 'aSR, 6'aRS) - and (3' aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalene- 2-yl] -5 '-methyl-2'-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole]; mixture of (3'aSR, 6'aRS) - and (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2'-phenyl-hexahydro- spiro [piperidin-4, 1 '-pyrrolo [3,4-c] pyrrole]; mixture of (3'aSR, 6'aRS) - and (3'aRS, 6'aSR) -5'-ethyl-1 [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2 '- phenyl-hexahydrospiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione; mixture of (3'aSR, 6'aRS) - and (3 'aRS, 6'aSR) -5' -methyl-1 [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2 '- phenyl-hexahydrospiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione; mixture of (3'aSR, 6'aRS) - and (3'aRS, 6'aSR) -1- [(2RS, 4aSR, 8aRS) -decahydro-nattalen-2-yl] -2'-phenyl-hexahydro- spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole] -4', 6'-dione; and mixture of (3 'aSR, 6'aRS) - and (3' aRS, 6'aSR) -5'-ethyl-l- [(2RS, 4aSR, 8aRS) -decahydro-naphthalen-2-yl] -2 '-phenyl-hexahydro-spiro [piperidin-4,1' -pyrrolo [3,4-c] pyrrole].

6. A compound according to claim 1, characterized in that: mixture of (3'aRS, 6'aSR) - and (3'aSR, 6'aRS) -5'-methyl-1 [(RS) -4- methyl-indan-2-yl] -2'-phenyl-hexahydro-spiro (piperidin-4,1 '-pyrrolo [3,4-c] pyrrole]; mixture of (3' aRS, 6'aSR) - y ( 3'aSR, 6'aRS) -1- [(RS) -4-me-tyl-indan-2-yl] -2'-phenyl-hexahydro-spiro [piperidin-4,1 '-pyrrolo [3, 4 -c] pyrrole]; (3'aS, 6'aR) -5'-ethyl-2'-phenyl-1- [(R) -1,2,3,4-tetrahydro-naphthalen-1-yl ] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole]; (3'aS, 6'aR) -5'-methyl-2'-phenyl-1 - (R) -1, 2, 3, 4-tetrahydro-naphthalen-1-yl] -hexahydro-spiro [piperidin-4,1 '-pyrrolo [3,4-c] pyrrole]; (3 'aSR, 6' aRS) -1- [(RS) -acenaften-l-il] -5 '-methyl-1' -phenyl-hexahydro-spiro [piperidin-4, 1 '(2'H) - pyrrolo [3, 4-c] pyrrole]; (3'aRS, 6'aSR) -1- [(1RS, 3aRS) -2, 3, 3a, 4, 5, 6-hexahydro-lH-phenalen-1-yl] -5 '-methyl-2' - phenyl-hexahydro-spiro [piperidin-4,1 '(2'H) -pyrrolo [3,4-c] pyrrole]; or mixture of (3'aRS, 6'aSR) - and (3'aSR, 6'aRS) -1- [(RS) -2, 3-dihydro-lH-phenalen-1-yl] -5'-methyl -2 '-phenyl-hexahydro-spiro [piperidin-4,1' (2'H) -pyrrolo [3,4-c] pyrrole].

7. A medicament containing one or more compounds as claimed in any one of claims 1 to 6, and pharmaceutically acceptable excipients.

8. A medicament according to claim 7 for the treatment of diseases related to the orphanin FQ receptor (OFQ), which comprise psychiatric, neurological and physiological disorders, such as anxiety and stress disorders, depression, traumas, loss of memory due to Alzheimer's disease or other dementias, deficits of cognition and learning, epilepsy and seizures, acute or chronic pain conditions, and withdrawal symptoms of drug addiction, water balance control, Na + excretions, arterial blood pressure, and metabolic disorders such as obesity.

9. A process for the preparation of a compound of formula I as defined in claim 1, characterized in that it comprises: a) reductive amination of a compound of formula: T ° with a compound of formula: wherein R1-R5 have the meanings given in claim 1, or b) reduction of a compound of formula to give a compound of one of the formulas: wherein R1, R4 and R5 have the meanings given in claim 1, or c) acylation or suphonation of a compound of the formula: to give a compound of formula: wherein R1 - R3 and R5 have the meanings given above and Q is -S (0) 2-lower alkyl; -C (0) lower alkyl, -C (0) CF3; -C (0) (CH2) n0CH3; -C (O) N (lower alkyl) 2, -S (0) 2 -heteroaryl; -C (0) heteroaryl; - S (0) 2-phenyl; -C (0) -cycloalkyl of 3 to 6 carbon atoms; or -C (0) O-lower alkyl, and n is 0-3, or d) debenzylation of a compound of the formula: to give a compound of the formula: wherein R1 - R3 and R5 have the meanings given above, except that R2 and R3 are not = 0 or hydroxyl, e) reaction of a ketone of formula: VI with the N-phenyl-glycine of formula: and capturing the formed azomethinides, of formula: 'Xr < in a compound of formula: wherein the substituents have the meanings given in claim 1, or, if desired, converting a racemic mixture into its enantiomeric components, thereby obtaining optically pure compounds, and converting the compound of formula I obtained, a pharmaceutically acidic addition salt acceptable.

10. A compound according to any one of claims 1 to 6, provided that it is prepared by the process as claimed in claim 9, or by a method equivalent thereto.

11. The use of a compound claimed in any one of claims 1 to 6 for the treatment of diseases related to the orphanin FQ receptor (OFQ), which include psychiatric, neurological and physiological disorders, such as anxiety and disorders of stress, depression, traumas, memory loss due to Alzheimer's disease or other dementias, cognitive and learning deficits, epilepsy and seizures, acute or chronic pain conditions, and withdrawal symptoms of drug addiction, balance control water, Na + excretions, disorders of arterial blood pressure, and metabolic disorders such as obesity, or for the preparation of a medicine useful in the treatment of diseases. SUMMARY OF THE INVENTION The present invention relates to compounds of the general formula: wherein the substituents are described in the application, and pharmaceutically acceptable acid addition salts thereof. The compounds of the invention are useful in the treatment of diseases related to the orphanin FQ receptor (QFQ), which include psychiatric, neurological and physiological disorders, such as anxiety and stress disorders, depression, traumas, loss of memory due to Alzheimer's disease or other dementias, deficits of cognition and learning, epilepsy and seizures, acute or chronic pain conditions, and withdrawal symptoms of drug addiction, control of water balance, Na + excretion, disorders of the arterial blood pressure, and metabolic disorders such as obesity.