WO2008015538A2 - Use of diaza- and thiaza-cycloalkanediones for preventing and/or treating pain and /or migraine - Google Patents

Abstract

The present invention relates to the prevention and/or, treatment of pain and/or migraine in a subject in need of such prevention and/or treatment. These invention comprises administering to the subject a diaza- and thiaza- cycloalkanedione compound, an isomer of the compound, or a hydrate, solvate, or salt of the compound or isomer.

Description

METHODS FOR PREVENTING AND/OR TREATING PAIN AND/OR MIGRAINE

FIELD OF THE INVENTION

[0001] The present invention relates to methods for preventing and/or treating pain and/or migraine in a subject in need of such prevention and/or treatment. These methods comprise administering to the subject a diaza- and thiaza- cycloalkanedione compound, an isomer of the compound, or a hydrate, solvate, or salt of the compound or isomer.

SUMMARY OF THE INVENTION

[0002] The present invention is directed to a method for preventing and/or treating a condition selected from the group consisting of pain and migraine in a subject in need of such prevention and/or treatment. The method comprises administering to the subject a compound corresponding in structure to Formula I, a stereochemical isomer of the compound, or a hydrate, solvate, or pharmaceutically acceptable salt of the compound or isomer:

Generally, R₁, R₂, R₃, R₄, R₅, Z, m, and n are defined as follows: [0003] R₁ is H, -(CH₂)_S-, -(CH₂)₄-, -CH₂-S-CH₂-, or -S-CH₂-CH₂-. [0004] R₂ is N or S.

[0005] R₃ is H, Cj-Qo-alkyl, aryl, or arylalkyl. [0006] R₄ is -O- or -CH₂-. [0007] R₅ is

[0008] Z is C₂-Cio-alkylene, C₂-C₁o-alkenylene, or C₂-C₁₀-alkynylene.

[0009] n is zero or 1.

[0010] m is zero, 1, or 2.

[0011] Each R₆ is independently H, Ci-Cs-alkyl. Ci-Cs-alkoxy, OH, F₅ Cl₅ Br₅ or I.

[0012] X is -O-, -S-, -N(H)-, or -N(CH₃)-.

[0013] Y is -O- and -N(H)-.

[0014] W is -S- or -N(H)-.

[0015] Further benefits of Applicant's invention will be apparent to one skilled in the art from reading this patent application. DETAILED DESCRIPTION

[0016] This detailed description is intended to acquaint others skilled in the art with applicants' invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating embodiments of the present invention, are intended for purposes of illustration only. The present invention, therefore, is not limited to the embodiments described in this patent application, and may be variously modified.

[0017] In accordance with the present invention, applicants have found that certain diaza- and thiaza- cycloalkanedione compounds (including isomers of the compounds as well as salts, solvates, and hydrates of the compounds and isomers) tend to be useful to prevent and/or treat pain and/or migraine. In one aspect, Applicant has found that the compounds of the present disclosure reduce the so called "late phase" pain reaction in the formalin animal pain model, which is believed to be indicative of the alleviation of chronic pain symptoms, such as e.g. chronic inflammatory pain and chronic neuropathic pain syndromes.

[0018] Thus, the present invention is directed to a method for preventing and/or treating a condition selected from the group consisting of pain and migraine in a subject in need of such prevention and/or treatment. The method comprises administering to the subject a compound corresponding in structure to Formula I₅ a stereochemical isomer of the compound, or a hydrate, solvate, or pharmaceutically acceptable salt of the compound or isomer:

Generally, Ri, R₂, R₃, R₄, R₅, Z, m, and n are defined as follows:

[0019] R₁ is selected from the group consisting of H, -(CH₂)₃-, -(CH₂)₄-, -CH₂-S-CH₂-, and

-S-CH₂-CH₂-.

[0020] R₂ is selected from the group consisting of N and S.

[0021] n is zero or 1. [0022] Z is selected from the group consisting of C₂-C₁ o-alkylene, C2-C₁o-alkenylene, and

C₂-Cio-alkinylene.

[0023] R.₃ is selected from the group consisting of H, Q-Qo-alkyl, aryl, and arylalkyl.

[0024] m is zero, 1, or 2.

[0025] R₄ is selected from the group consisting of -O- and -CH₂-.

[0026] R₅ is selected from the group consisting of

[0027] Each R₆ is independently selected from the group consisting of H, CrCs-alkyl,

Ci-C₅-aJkoxy, OH, F, Cl, Br, and I.

[0028] X is selected from the group consisting of -O-, -S-, -N(H)-, and -N(CH₃)-.

[0029] Y is selected from the group consisting of -O- and -N(H)-.

[0030] W is selected from the group consisting of -S- and -N(H)-.

[0031] In some embodiments, the subject is a human.

[0032] In some embodiments, the condition being prevented and/or treated comprises pain.

[0033] In some embodiments, the pain being prevented and/or treated comprises chronic pain, particularly chronic inflammatory pain and/or chronic neuropathic pain.

[0034] In some embodiments, the condition being prevented and/or treated comprises migraine.

[0035] In some embodiments, a therapeutically effective (or an effective amount) is administered to the subject.

[0036] In some embodiments, the compound being administered corresponds in structure to

Formula I, wherein Z is C₂-C₁₀-alkylene, and R₅ is selected from the group consisting of:

[0037] In some embodiments, the compound being administered corresponds in structure to Formula I, wherein Z is butylene, and R₅ is selected from the group consisting of

[0038] In some embodiments, the compound being administered corresponds in structure to Formula I, wherein R₃ is H. [0039] In some embodiments, the compound being administered is selected from the group consisting of:

2- [4- [(Chroman-2-yl)methylamine]butyl] - 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2-[4-[(Chroman-2-yl)methylamine]butyl]- 1 ,3-dioxoperhydroimidazo[l ,5-b]thiazole;

2-[4-[(Chroman-2-yl)methylamine]butyl]-l,3-dioxoperhydroimidazo[l,5-c]-thiazole;

3-[4-[(Chroman-2-yl)methylamine]butyl]-2,4-dioxothiazolidin;

3-[5-[(Chroman-2-yl)methylamine]pentyl]-2,4-dioxothiazolidin;

3 - [6- [(Chroman-2-yl)methylamine]hexyl] -2,4-dioxothiazolidin;

2-[4-[(Naphth- 1 -yl)methylamine]butyl]- 1 ,3-dioxoperhydropyrrolo[ 1 ,2-c]imidazole;

2- [4- [(Naphth-2-yl)methylamine]butyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2-[4-[2-(Naphth-l-yl)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

3-[4-[2-(Naphth-l-yl)ethylamine]butyl]-2,4-dioxothiazolidin;

2-[4-[2-(Naphth-2-yl)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2-[4-[2-(Phenoxy)ethylamine]butyl]-l,3-dioxoperhydroρyrrolo[l,2-c]imidazole;

3-[4-[2-(Phenoxy)ethylamine]butyl]-2₅4-dioxothiazolidin;

2-[4-[2-(Naphth-l-oxy)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

3-[4-[2-(Naphth-l-oxy)ethylamine]butyl]-2,4-dioxothiazolidin;

2- [4- [(Benzimidazol-2-yl)methy laminejbutyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2-[4-[(o-Methoxyphenyl)methylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2-[4-[2-(o-Methoxyphenyl)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2- [4- [3 -(o-Methoxyphenyl)propy lamine]butyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2-[4-[4-(o-Methoxyphenyl)butylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole; and

2- [3 - [3 -(o-Methoxyphenyl)propylamine]propyl] - 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole.

[0040] In some embodiments, the compound being administered corresponds in structure to Formula I wherein m is zero; R₄ is CH₂; and R₅ is chromanyl.

[0041] In some embodiments, the compound being administered corresponds in structure to Formula I wherein m is 2; R₄ is O; and R₅ is phenyl or 1-naphthyl. [0042] In another aspect of the present invention the compounds being administered correspond in structure to Formula II:

their stereochemical^ isomer forms, hydrates, solvates and pharmaceutically acceptable salts thereof, wherein:

[0043] R₁ and R₂ are H or are methylene groups bound together forming with the heterocyclic ring a 5- or 6- membered ring;

then R₁ is H and R₂ is absent;

[0044] R₄ is selected from the group consisting of N and S;

[0045] n being an integer from 0 to 1 ;

[0046] X is selected from the group consisting of C₂-C₁o-alkyl, C₂-C₁₀-alkenyl and -CH₂-Y-

CH₂-; wherein Y is phenyl;

[0047] m being an integer from 1 to 2;

[0048] R₃ is selected from the group consisting of chroman-2-yl, 2-quinolyl and -O-phenyl, wherein the aromatic ring of the chromanyl moiety, the quinolyl or the phenyl residue is optionally substituted by one or more groups chosen from Q-C_ό-alkoxy, CrC₆-alkyl, halogen,

C₂-C₆-alkenyl, halo-(CrC₆)-alkyl, halo-(C₁-C₆)-alkoxy, phenyl, phenyl(Ci-C₆)-alkyl, phenoxy,

Ci-C₆-alkylcarbonyl, phenylcarbonyl, phenyl(C₁-C₆)alkylcarbonyl, Q-C_δ-alkoxycarbonyl, phenyl(Ci-C₆)alkoxycarbonyl, d-Q-alkylcarbonylamino, hydroxy, cyano, nitro, amino, N-(C₁-

C₆)-alkylamino, N₃N-(C ₁-C₆)-dialkylamino, carboxy, sulfo, sulfamoyl, sulfonylamino, (Q-

C₆)alkylaminosulfonyl or (Ci-C₆)alkylsulfonylamino; or wherein the phenyl ring is substituted by two neighbouring residues, which together with the phenyl ring to which they are attached form tetrahydronaphthyl; wherein each alkyl is optionally substituted with hydroxy or amino.

[0049] In one embodiment the compounds being administered have the general Formula II, wherein R₃ is preferably selected from the group consisting of chroman-2-yl, 2-quinolyl and -O- phenyl, wherein the phenyl residue is optionally substituted by a group chosen from C₁-C₆- alkoxy, CrC_ό-alkyl, or halogen. [0050] According to certain aspects of the present disclosure, the compounds being administered have the general Formula H₅ wherein

[0051] m is 1 and R₃ is optionally substituted chroman-2-yl;

[0052] m is 2 and R₃ is optionally substituted O-phenyl; or

[0053] m is 1 and R₃ is optionally substituted 2-quinolyl.

[0054] According to one aspect of the present invention, the compounds being administered have the general Formula II, wherein m is 1 and R₃ is chroman-2-yl, the phenyl ring of which is unsubstituted or substituted by one or more groups chosen from Ci-C₆-alkoxy, Ci-Cβ-alkyl, halogen, C₂-C₆-alkenyl, halo-(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkoxy, phenyl, phenyl(CrC₆)-alkyl, phenoxy, C_t-C_δ-alkylcarbonyl, phenylcarbonyl, pheny^Ci-C^alkylcarbonyl, C₁-C₆- alkoxycarbonyl, pheny^Q-C^alkoxycarbonyl, Ci-C_δ-alkylcarbonylarnino, hydroxy, cyano, nitro, amino, N-(C₁-C₆)-alkylamino, N₅N-(C₁ -C₆)-dialkylamino, carboxy, sulfo, sulfamoyl, sulfonylamino, (C₁-C₆)alkylaminosulfonylor (Ci-C₆)alkylsulfonylamino; wherein each alkyl is optionally substituted with hydroxy or amino. R₃ is preferably unsubstituted chroman-2-yl.

[0055] Unless specifically mentioned otherwise the term "chroman-2-yl" refers to an unsubstituted chroman-2-yl residue.

[0056] According to one embodiment of the present disclosure, the compounds being administered have the general Formula II, wherein R₁ and R₂ are methylene groups bound together forming with the heterocyclic ring a 5- or 6- membered ring and R₄ is N. Those compounds being administered wherein m is 1 and R₃ is chroman-2-yl, Ri and R₂ are methylene groups bound together forming with the heterocyclic ring a 5- or 6- membered ring; R₄ is N; and

X is selected from the group consisting of C₂-C₁o-alkyl, (.E)-2-butenyl, 3-methylbenzyl or 4- methylbenzyl are preferred.

[0057] In another embodiment the compounds being administered have the general Formula

II, wherein Ri is H; R₂ is absent; R₄ is S; m is 1; R₃ is chroman-2-yl; and X is selected from the group consisting of C₂-C₁ o-alkyl, C₂-Ci_O-alkenyl, or -CH₂-Y-CH₂-, wherein Y is phenyl. In one embodiment n is preferably 0.

[0058] In a more specific embodiment of the present invention, it provides compounds being administered which have the general Formula II, wherein Ri is H; R₂ is absent; R₄ is S; m is 1;

R₃ is chroman-2-yl; and X is C₂-C₁o~alkyl. In one embodiment n is preferably zero (0). [0059] Another embodiment of the invention relates to compounds being administered which have the general Formula II, wherein m is 2 and R₃ is -O-phenyl optionally substituted by one or more groups chosen from CrC₆-alkoxy, Q-Q-alkyl, halogen, C₂-C₆-alkenyl, halo-(C₁-C₆)-alkyl, halo-(Ci-C₆)-alkoxy, phenyl, phenyl(Ci-C₆)-alkyl, phenoxy, d-C_ό-alkylcarbonyl, phenylcarbonyl, phenyl(C₁-C₆)alkylcarbonyl, Cj-C₆-alkoxycarbonyl, phenyl(Ci- C₆)alkoxycarbonyl, Ci-C_ό-alkylcarbonylamino, hydroxy, cyano, nitro, amino, N-(C₁-C₆)- alkylamino, N,N-(C₁-C₆)-dialkylamino, carboxy, sulfo, sulfamoyl, sulfonylamino, (C₁- C₆)alkylaminosulfonyl or (C_t-C^alkylsulfonylamino; or wherein the phenyl ring is substituted by two neighbouring residues, which together with the phenyl ring to which they are attached form tetrahydronaphthyl; wherein each alkyl is optionally substituted with hydroxy or amino. [0060] According to a specific embodiment of the invention, the compounds being administered have the general Formula II, wherein: m=2 and R₃ is -O-phenyl, wherein the phenyl ring is substituted by one or more groups chosen from phenyl, CrCβ-alkoxycarbonyl, C₁- C₆-alkylcarbonylamino, CrC_ό-alkoxy, Ci-Cβ-alkyl, halo-(C₁-C₆)-alkyl, or halogen or wherein the phenyl group is substituted by two neighbouring residues, which together with the phenyl group to which they are attached form tetrahydronaphthyl.

[0061] Another embodiment relates to compounds being administered having the general Formula II, wherein m=2 and R₃ is -O-phenyl, wherein the phenyl ring is substituted by one or more groups chosen from Q-Q-alkoxy, Q-Ce-alkyl, or halogen.

[0062] Exemplary compounds of Formula II being administered are those wherein the phenyl residue is optionally substituted by one or more groups chosen from methoxy, ethoxy, propoxy, isopropoxy, ethyl, propyl, isopropyl, bromide, trifluoromethyl, methylamide or ethoxycarbonyl.

[0063] Particularly preferred compounds being administered are those compounds wherein the phenyl residue is substituted in ortho and/or meta position, particularly in ortho position. [0064] According to one embodiment of this disclosure, the compounds being administered have the general Formula II, wherein R₁ and R₂ are methylene groups bound together forming with the heterocyclic ring a 5- or 6- membered ring; and R₄ is N.

[0065] One aspect relates to compounds being administered that have the general Formula II, wherein R₁ and R₂ are methylene groups bound together forming with the heterocyclic ring a 5- membered ring; R₄ is N; n is 0; X is C₂-C₁₀-alkyl; m is 2; R₃ is -O-phenyl optionally substituted by one or more groups chosen from phenyl, Ci-Cβ-alkoxycarbonyl, C_t-C_ό-alkylcarbonylamino,

CrCβ-alkoxy, Ci-C₆-alkyl, halo-(C₁-C₆)-alkyl, or halogen or wherein the phenyl group is substituted by two neighbouring residues, which together with the phenyl group to which they are attached form tetrahydronaphthyl.

[0066] In a more specific embodiment, the compounds being administered have the general

Formula II, wherein R₃ is O-phenyl substituted by a group chosen from Q-Cβ-alkoxy, C₁-C₆- alkyl, or halogen.

[0067] In another embodiment, in the compounds of Formula II being administered, R₁ is H,

R₂ is absent and R₄ is S. Particularly those wherein X is C₂-C₁o-alkyl and n is 0.

[0068] According to another embodiment of the present disclosure, the compounds being administered have the general Formula II, wherein m is 1 and R₃ is 2-quinolyl, the aromatic ring of which is unsubstituted or substituted by one or more groups chosen from d-C₆-alkoxy, C₁-

C₆-alkyl, halogen, C₂-C₆-alkenyl, halo-(C₁-C₆)-alkyl, halo-(C₁-C₆)-alkoxy, phenyl, phenyl(d-

C₆)-alkyl, phenoxy, Cj-Cβ-alkylcarbonyl, phenylcarbonyl, phenyl(C₁-C₆)alkylcarbonyl, C₁-C₆- alkoxycarbonyl, phenyl^ -C₆)alkoxycarbonyl, d-C_δ-alkylcarbonylamino, hydroxy, cyano, nitro, amino, N-(C₁-C₆)-alkylamino,

carboxy, sulfo, sulfamoyl, sulfonylamino, (C]-C₆)alkylaminosulfonyl or (C₁-C₆)alkylsulfonylamino; wherein each alkyl is optionally substituted with hydroxy or amino. R₃ is preferably unsubstituted 2-quinolyl.

[0069] Unless specifically mentioned otherwise the term "2-quinolyl" refers to an unsubstituted quinolyl residue.

[0070] In one embodiment, the compounds being administered have the general Formula II, wherein R₁ and R₂ are methylene groups bound together forming with the heterocyclic ring a 5- or 6- membered ring; and R₄ is N. Those compounds wherein n is zero (0); and X is C₂-C₁₀-alkyl are particularly preferred.

[0071] In some embodiments, the compound of Formula I corresponds in structure to

Formula III:

Formula III wherein n is 2-7; and

A is selected from the group consisting of:

[0072] In some embodiments, the compound being administered corresponds in structure to Formula III, wherein A is

[0073] In some embodiments, the compound being administered corresponds in structure to Formula III, wherein n is 2, 3, 4, or 5.

[0074] In some embodiments, the compound being administered corresponds in structure to Formula III, wherein A is

[0075] In some embodiments, the compound being administered corresponds in structure to Formula III, wherein n is 3.

[0076] In some embodiments, the compound being administered, corresponding in structure to Formula III, is selected from the group consisting of:

(±)-2-[4-[(Chroman-2-yl)methylamino]butyl]-l,3-dioxoperhydropyrrolo[l₃2-c]imidazole;

(+)-2-[4-[(Chroman-2-yl)methylamino]butyl]-l,3-dioxoperhydroimidazo[l,5-ό]thiazole;

(+)-2-[4-[(Chroman-2-yl)methylamino]butyl]-l,3-dioxoperhydroimidazo[l,5-c]-thiazole;

(±)-3 - [4- [(Chroman-2-yl)methylamino]butyl] -2,4-dioxothiazolidine; (±)-3 - [5- [(Chroman-2-yl)methylamino]pentyl] -2,4-dioxothiazolidine;

(±)-3 - [6- [(Chroman-2-yl)methylamino]hexyl] -2,4-dioxothiazolidine;

2-[4-[(Chroman-2(i?)-yl)niethylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2- [5 - [(Chroman-2-yl)methylamino]pentyl] - 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2-[6-[(Chroman-2-yl)methylamino]hexyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2- [3 - [(Chroman-2-yl)methylamino]propyl] - 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole; and

2-[4-[(Chroman-2(.S)-yl)methylamino]butyl]- 1 ,3 -dioxoperhydropyrrolo [1 ,2-c]imidazole. [0077] In some embodiments, the compound of Formula I corresponds in structure to Formula IV:

Formula IV

wherein n is 2-7; and

A is selected from the group consisting of:

[0078] In some embodiments, the compound being administered corresponds in structure to Formula IV, wherein A is

[0079] In some embodiments, the compound being administered corresponds in structure to

Formula IV, wherein n is 3 or 7.

[0080] In some embodiments, the compound being administered corresponds in structure to

Formula IV, wherein R₆ is CrGj-alkoxy in ortho position of the phenyl ring.

[0081] In some embodiments, the compound being administered corresponds in structure to

Formula IV, wherein A is

[0082] In some embodiments, the compound being administered corresponds in structure to

Formula IV, wherein n is 3.

[0083] In some embodiments, the compound being administered corresponds in structure to

Formula IV, wherein R₆ is C]-C₄-alkoxy in ortho position of the phenyl ring.

[0084] In some embodiments, the compound being administered corresponds in structure to

Formula IV, wherein the compound is selected from the group consisting of:

2-[4-[2-(Phenoxy)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

3 - [4- [2-(Phenoxy)ethylamine]butyl] -2,4-dioxothiazolidin;

2- [4- [2-(ø~Methoxyphenoxy)ethylamino]butyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2-[4-[2-(σ-Ethoxyphenoxy)ethylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2-[4-[2-(c-Isopropoxyphenoxy)ethylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]

3-[4-[2-((?-Ethoxyphenoxy)ethylamino]butyl]-2,4-dioxothiazolidine;

3-[6-[2-(o-Ethoxyphenoxy)ethylamino]hexyl]-2,4-dioxothiazolidine;

3-[8-[2-(o-Ethoxyphenoxy)ethylamino]octyl]-2,4-dioxothiazolidine;

2-[4-[2-(σ-Ethoxyphenoxy)ethylamino]butyl]-l,3-dioxoρerhydroimidazo[l,5-α]pyridine; and 2-[6-[2-(o-Ethoxyphenoxy)ethylamino]hexyl]-l_?3-dioxoperhydroimidazo[l,5-α]pyridine. [0085] In some embodiments, the compound of Formula I corresponds in structure to Formula V:

Formula V wherein n is 2-7; and A is selected from the group consisting of:

[0086] In some embodiments, the compound being administered corresponds in structure to Formula V, wherein A is

[0087] In some embodiments, the compound being administered corresponds in structure to Formula V, wherein n is 3.

[0088] In some embodiments, the compound being administered corresponds in structure to Formula V₅ wherein the compound is

2-[4-[2-(Naphth-l -oxy)ethylamine]butyl]- 1 ,3-dioxoperhydropyrrolo[l ,2-c]imidazole or

3-[4-[2-(Naphth-l-oxy)ethylamine]butyl]-2,4-dioxothiazolidin. [0089] One aspect of the present invention is the use of a compound according to one of the

Formula I, II, III, IV or V or a specific compound as described herein in the production of a medicament for the treatment of pain and/or migraine, more specifically chronic pain such as, e.g. chronic inflammatory or chronic neuropathic pain. Preferably, the medicament is suitable for oral administration, and may comprise one or more pharmaceutically acceptable excipient, such as e.g. binders fillers, disintegrants, lubricants, and the like. Such excipients are well known to those skilled in the art.

[0090] Unless otherwise indicated, the term "alkyl" (alone or in combination with another term(s)) means a straight- or branch-chain saturated hydrocarbyl substituent.

[0091] Unless otherwise indicated, the term "alkenyl" (alone or in combination with another term(s)) means a straight- or branch-chain hydrocarbyl substituent containing one or more double bonds. Examples of such substituents include 1-propenyl and 2-butenyl).

[0092] Unless otherwise indicated, the term "alkynyl" (alone or in combination with another term(s)) means a straight- or branch-chain hydrocarbyl substituent containing one or more triple bonds. An example of such substituents is 2-butynyl.

[0093] The term "aryl" (alone or in combination with another term(s)) means a monocyclic aromatic hydrocarbyl containing between 5 and 12 carbon atoms, optionally interrupted by one or more heteroatoms independently selected from N₅ O, and S.

[0094] The term "aralkyl" (also known as "arylalkyl") means an alkyl (as defined above) substituted with an aryl. Examples of such substituents include benzyl and phenylethyl.

[0095] The compounds of Formula I can be used in the methods of this invention in the form of structural and/or stereoisomers. Structural isomers of the compounds of Formula I can include chain isomers {e.g., butyl and isobutyl) and position isomers {e.g., 1-chlorobutyl and

2-chlorobutyl; Δ -butylene and Δ²-butylene; o-methyl phenoxy and m-methyl phenoxy).

Stereoisomers of the compounds of Formula I can include E and Z isomers {i.e., isomers with regard to one or more double bonds); enantiomers {i.e., stereoisomers that have opposite configurations at all stereogenic centers); and diastereoisomers {i.e., stereoisomers that have the same configuration at one or more stereogenic centers, but differ at other stereogenic centers).

Thus, the compounds of Formula I can be used in the methods of this invention as mixtures of enantiomers, diastereomers, and/or isomers with regard to double bounds (including racemic mixtures), as well as as substantially optically pure and optically pure stereoisomers of the compounds of Formula I. Optically pure isomers may be prepared using chiral synthons or chiral reagents. Alternatively, optically pure isomers can be resolved using conventional techniques.

[0096] The compounds of Formula I can be used in the methods of this invention in the form of salts (including solvates and hydrates) of the compounds of Formula I (including their isomers). Depending on a particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.

[0097] The salts are preferably pharmaceutically acceptable and/or physiologically compatible. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.

[0098] Examples of suitable salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, o-toluene sulphonic acid, m-toluene sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid, o-naphthalene sulphonic acid, m-naphthalene sulphonic acid, p-naphthalene sulphonic acid, acetic acid, propionic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid.

[0099] Two alternative processes are provided to prepare the compounds of general Formula

I: by reaction of intermediate halogen derivatives VI (L=Cl, Br) with suitable amines VII in acetonitrile as reaction solvent (Scheme I below), or by reaction of intermediate amines VIII with appropriate halogen derivatives IX (L=Cl, Br) in acetonitrile as reaction solvent (Scheme II below).

O Scheme I

[00100] The compounds with R₃ different from H are produced by alkylation of the analogues wherein R₃ is hydrogen.

[00101] The definitions of Rj, R₂, n, Z, m, R₄ and R₅ in these schemes are identical to those made previously for the products of the invention.

[00102] The Formula VI intermediates are obtained by the reaction of hydantoin, diketopiperazine or cyclic imide with the appropriate halogen derivative in the presence of sodium hydride and N,N-dimethylformamide as a reaction solvent, as represented in Scheme III.

[00103] The Formula VIII intermediates are obtained by reaction of hydantoin, diketopiperazine or cyclic imide with the appropriate halonitrile in the presence of sodium hydride and N,N-dimethylformamide as reaction solvent, and subsequent catalytic hydrogenation, as represented in Scheme IV.

Scheme IV

[00104] Some of the intermediates VII and IX are commercial. It is also possible to obtain said intermediates following procedures disclosed in the literature or by conventional synthetic routes.

[00105] The final products have been structurally characterized by techniques of IR, NMR and quantitative elemental analysis. For easier handling, when the final product is not crystalline, it is transformed in a pharmaceutically acceptable salt, derived from an inorganic or organic acid.

[00106] The in vitro affinity of the compounds of general Formula I in the 5-HT_1A, 5-HT_2A,

5-HT₃, 5-HT₄, 5-HT₇, αj and D₂ cerebral receptors have been evaluated by radioligand displacement tests. The following specific ligands and tissues have been used:

(a) 5-HT_IA receptors: [³H]-8-OH-DPAT, rat cerebral cortex;

(b) 5-HT_2A receptors: [³H]ketanserin, rat cerebral cortex;

(c) 5-HT₃ receptors: [³H]LY278584, rat cerebral cortex;

(d) 5-HT₄ receptors: [³H]GRl 13808, rat striatum;

(e) 5-HT₇ receptors: [³H]-5-CT, rat hypothalamus;

(f) a_t receptors: [³H]prazosin, rat cerebral cortex;

(g) D₂ receptors: [³H] spiperone, rat striatum.

[00107] The functional character (agonist/antagonist) of the compounds of the present invention, has been studied in vitro by determining the inhibition of the stimulating effect of forskolin on adenylate cyclase in a cell line transfected with the 5-HT_1A receptor, occasionally comparing the effect obtained with the [³⁵S]GTPyS fixation test to coronal sections of rat brain as well as the hyperpolarizing effect in the hippocampal area CAl, and further studying, in vivo, the 5-HTI_A agonist character of the new compounds by analysis of the typical behavioural effects as well as of the hypothermia, and evaluating the prevention of these effects by the selective antagonist WAY-100635.

[00108] Furthermore, the neuroprotective activity of the compounds disclosed in the present invention has been studied, considering their capacity to prevent cell death, of a necrotic or apoptotic nature, in primary neuronal cultures and studying in vivo the prevention of neuronal death in the hippocampal area CAl of gerbils after transient global ischemia as well as the reduction in volume of cerebral infarction after permanent occlusion in the middle cerebral artery in rats. EXAMPLES

[00109] The following examples are merely illustrative, and not limited to this disclosure in any way.

Example 1

Synthesis of the Compounds of General Formula I

[00110] General Process: To 1.5 mmol of intermediate amine III or IV dissolved in 2 mL of acetonitrile, a solution of 1.0 mmol of halogen derivative II or V in 1.5 mL of acetonitrile is added dropwise. The reaction mixture is heated to 6O⁰C with stirring during 6-24 hours (t.l.c). After cooling, the solvent is removed at reduced pressure, the residue is dissolved in methylene chloride (20 mL) and is washed with an aqueous solution of 20% potassium carbonate. Next, the organic phase is dried over anhydrous Na₂SO₄ and the solvent is removed at reduced pressure. The resulting oil is purified by silica gel column chromatography, obtaining the final product in the form of a free base. The compound is isolated in the form of a hydrochloride and purified by recrystallization. The IR and NMR spectroscopic data correspond to the free base.

(±)-2-[4-[(Chroman-2-yl)methylamine]butyl]-l ,3-dioxoperhydropyrrolo[l ,2-c] imidazol, 1 [00111] Chromatography: toluene/methanol, 9:1. Yield: 35%. IR (CHCl₃, cm^"1): 1772, 1709, 1581, 1489, 1443. ¹H-NMR (CDCl₃, δ): 1.47-1.86 (m, 5H) , 1.91-2.12 (m, 4H) , 2.16-2.34 (m, IH), 2.64-2.92 (m, 6H), 3.16-3.28 (m, IH), 3.48 (t, 1=1.1 Hz, 2H), 3.66 (dt, J=I 1.2; 7.3 Hz, IH), 4.05 (dd, J=9.1; 7.3 Hz, IH), 4.11-4.18 (m, IH), 6.81(t, J=7.6 Hz, 2H), 7.00-7.10 (m, 2H). 1³C-NMR (CDCl₃, δ): 24.6; 25.6; 25.8; 26.9; 27.1; 27.5; 38.7; 45.4; 49.3; 54.1; 63.2; 75.0; 116.7; 120.1; 121.9; 127.1; 129.4; 154.5; 160.8; 173.9. Analysis calculated for C₂₁H₂₄N₂O₄S. HCl: C, 57.72; H, 5.77; N, 6.41, found: C, 57.64; H₅ 5.96; N, 6.19.

Example 2

(-fc)-2-[4-[(Chroman-2-yl)methylamine]butyl]-l,3-dioxoperhydro imidazo[l,5-b]thiazol [00112] Chromatography: toluene/ethanol, 9.5:0.5. Yield: 43%; m.p. 149-151⁰C (ethyl acetate). IR (CHCl₃, cm^"1): 3400, 1770, 1718, 1610, 1558, 1488. ¹H-NMR (CDCl₃, δ.): 1.48-1.86 (m, 5H), 2.01-2.10 (m, IH), 2.59-3.18 (m, 9H), 3.53 (t, J=7.0 Hz, 2H), 3.95-4.27 (m, IH), 4.49 (dd, IH, J=12.0; 6.0 Hz), 5.08 (s, IH), 6.56-6.92 (m, 2H), 7.03-7.13 (m, 2H) ¹³C-NMR (CDCl₃ δ): 23.9; 24.4; 25.5; 25.9; 32.7; 39.1; 48.4; 54.0; 58.3; 63.2; 74.8; 116.7; 120.0; 122.0; 127.1; 129.4; 154.6; 159.6; 171.6. Analysis calculated for Ci₉H₂₄N₃O₃S-HCl: C, 55.40; H, 6.36; N, 10.20, found: C, 55.38; H, 6.44; N, 9.87. Example 3

(±)-2-[4-[(Chroman-2-yl)methylamine]butyl]-l ₅3-dioxoperhydroimidazo[l ,5-c]-thiazol, 3 [00113] Chromatography: toluene/ethanol, 9.5:0.5. Yield: 38%; m.p. 142-144⁰C (ethyl acetate). IR (CHCl₃, cm^"1): 3400, 3500, 1770, 1716, 1582, 1540, 1508. ¹H-NMR (CDCl₃, δ): 1.49-1.74 (m, 5H), 1.98-2.05 (m, IH), 2.60-2.84 (m, 6H), 3.12 (dd, J=I 1.7; 5.8 Hz₅ IH), 3.33 (dd, J=13.5; 8.5 Hz, IH)₃ 3.52 (t, J=7.0 Hz, 2H), 4.12 (d, J=9.9 Hz, IH), 4.22-4.28 (m, IH), 4.33 (dd, J=8.5; 5.8 Hz, IH), 5.01 (d, J=9.9 Hz, IH), 6.77-6.88 (m, 2H), 7.04-7.13 (m, 2H). ¹³C-NMR (CDCl₃, δ): 23.8; 24.4; 25.6; 25.9; 32.7; 39.1; 49.2; 54.1; 58.2; 64.4; 74.2; 116.7; 120.3; 122.0; 127.1; 129.5; 154.5; 159.6; 171.9. Analysis calculated for C₁₉H₂₄N₃O₃S-HCl: C, 55.40; H, 6.36; N, 10.20, found: C, 55.02; H, 6.44; N, 9.85.

Example 4

(±)-3-[4-[(Chroman-2-yl)methylamine]butyl]-2,4-dioxothiazolidin, 4 [00114] Chromatography: toluene/ethanol, 9.5:0.5. Yield: 45%; m.p. 126-127⁰C (ethyl acetate). IR (CHCl₃, cm^"1): 3400, 1750, 1683, 1608, 1558, 1508. ¹H-NMR (CDCl₃, δ): 1.47-1.76 (m, 5H), 2.01-2.06 (m, IH), 2.57-3.01 (m, 6H), 3.62 (t, J=7.2 Hz, 2H), 3.92 (s, 2H), 4.10-4.25 (m, IH), 6.74-6.83 (m, 2H), 7.01-7.08 (m, 2H). ¹³C-NMR (CDCl₃, δ): 24.2; 24.5; 25.3; 25.9; 33.7; 41.8; 54.2; 58.4; 74.3; 116.7; 120.0; 122.0; 127.1; 129.5; 154.5; 171.4; 171.8. Analysis calculated for C₁₇H₂₁N₂O₃S-HCl: C, 55.05; H, 6.25; N, 7.55, found: C, 54.98; H, 6.33; N, 7.15.

Example 5

(±)-3-[5-[(Chroman-2-yl)methylamine]pentyl]-2,4-dioxothiazolidin, 5 [00115] Chromatography: toluene/ethanol, 20:1 → 8:2. Yield: 38%; m.p. 172-174°C (chloroform/ethyl acetate). IR (CHCl₃, cm^"1): 1751, 1682, 1683, 1608, 1581, 1488, 1456. 1H-NMR (CDCl₃, δ): 1.25-2.04 (m, 8H) , 2.67 (t, J=7.0 Hz, 2H) , 2.75-2.94 (m, 4H), 3.63 (t, J=7.3 Hz, 2H), 3.92 (s, 2H), 4.08-4.17 (m, IH), 6.78-6.85 (m, 2H)₅ 7.01-7.11 (m, 2H). ¹³C-NMR (CDCl₃. δ): 24.4; 24.6; 25.7; 27.4; 29.4; 33.7; 42.0; 49.6; 54.2; 75.0; 116.7; 120.2; 122.0; 127.2; 129.5; 154.6; 171.4; 171.7. Analysis calculated for C₁₈H₂₄N₂O₃S₁HCl: C₅ 56.17; H₅ 6.55; N₅ 7.28, found: C, 55.49; H₅ 6.49; N₅ 7.10.

Example 6 (±)-3-[6-[(Chroman-2-yl)methylamine]hexyl]-2,4-dioxothiazolidin₅ 6 [00116] Chromatography: toluene/ethanol, 20:1. Yield: 30%; m.p. 175-177⁰C (chloroform/ethyl acetate). IR (CHCl₃, cm^"1): 3416, 3321, 1751, 1670, 1608, 1581, 1489, 1456. ¹H-NMR (CDCl₃, δ): 1.25-2.01 (m, 10H) , 2.66 (t, J=7.1 Hz, 2H), 2.76-2.95 (m, 4H), 3.62 (t, J=7.3 Hz, 2H), 3.93 (s, 2H), 4.09-4.19 (m, IH)₅ 6.78-6.85 (m, 2H), 7.01-7.11 (m, 2H). ¹³C-NMR (CDCl₃, δ): 24.6; 25.7; 26.6; 26.8; 27.5; 29.8; 33.7; 42.0; 49.8; 54.2; 75.1; 116.7; 120.2; 122.0; 127.2; 129.5; 154.6; 171.4; 171.7. Analysis calculated for C₁₉H₂₆N₂O₃S-HCl: C, 57.18; H, 6.82; N, 7.02, found: C, 56.78; H, 6.72; N, 6.94.

Example 7

2- [4- [(Naphth- 1 -yl)methylamine]butyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazol, 7 [00117] Chromatography: ethyl acetate. Yield. 42%; m.p. 150-153°C (chloroform/hexane). IR (CHCl₃, cm^'1): 3300-3500, 1770, 1708, 1696, 1510, 1442, 1416. ¹H-NMR (CDCl₃, δ): 1.48-1.71 (m, 5H), 1.99-2.08 (m, 2H), 2.16-2.24 (m, IH), 2.74 (t, J=6.9 Hz, 2H), 3.16-3.24 (m, IH), 3.47 (t, J=6.9 Hz, 2H), 3.64 (dt, J=I 1.1; 7.8 Hz, IH), 4.02 (dd, J=9.3; 7.8 Hz, IH), 4.20 (s, 2H), 7.37-7.54 (m, 4H), 7.74 (d, J=7.2 Hz, IH) , 7.82-7.85 (m, IH) , 8.08 (d, J=8.4 Hz, IH). .SUp¹³C-NMR (CDCl₃, δ): 25.9; 27.0; 27.2; 27.5; 38.8; 45.5; 49.3; 51.6; 63.3; 123.6; 125.4; 125.6; 125.9; 126.1; 127.7; 128.7; 131.8; 133.9; 136.0; 160.9; 173.9. Analysis calculated for C₂₁H₂₅N₃O₂-HCl: C, 65.02; H, 6.76; N, 10.83, found: C, 64.53; H, 6.71; N₅ 10.44.

Example 8

2- [4- [(Naphth-2-yl)methylamine]butyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazol, 8 [00118] Chromatography: chloroform/methanol, 9:1. Yield: 25%; m.p. 125-127°C (ethyl acetate). IR (CHCl₃, cm^"1) : 3417, 1769, 1707. ¹H-NMR (CDCl₃, δ): 1.52-1.80, 1.92-2.23 (m, 3H) , 2.80 (t, J=7.1 Hz, 2H), 3.13-3.25 (m, IH), 3.42 (t, J=6.6 Hz, 2H), 3.56-3.74 (m, IH), 4.06-4.13 (m, 3H), 5.19 (sa, IH), 7.45-7.50 (m, 2H), 7.61 (d, J=8.8 Hz, IH), 7.78-7.92 (m, 4H) . ¹³C-NMR (CDCl₃, δ): 25.2; 26.8; 27.3; 29.5; 37.8; 45.3; 46.2; 51.5; 63.2; 126.3; 126.4; 126.7; 127.5; 127.8; 128.6; 129.0; 130.0; 132.9; 133.0; 160.5; 173.8. Analysis calculated for C₂₁H₂₅N₃O₂-HCLH₂O: C, 62.14; H₃ 6.95; N, 10.35. found: C, 62.54; H, 7.06; N, 9.95.

Example 9

2-[4-[2-(Naphth-l-yl)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazol, 9 [00119] Chromatography: ethyl acetate/ethanol, 1 :1. Yield: 48%; m.p. 95-97°C (ethyl acetate). IR (CHCl₃₅ cm^"1): 3400 (NHR, 1770, 1710. ¹H-NMR (CDCl₃₅ δ): 1.56-1.78 (m, 5H) , 2.00-2.28 (m, 3H)₅ 2.72 (t, 3=6.8 Hz₅ 2H), 3.02 (t, J=7.1 Hz, 2H)₅ 3.11-3.38 (m, 3H)₅ 3.48 (t, J=7.2 Hz₅ 2H)₅ 3.63-3.74 (m₅ IH)₅ 4.01-4.10 (m, IH)₅ 7.37-7.54 (m, 4H)₅ 7.71-7.76 (m, IH)₅ 7.82-7.86 (m, IH), 7.08-7.13 (m, IH). ¹³C-NMR (CDCl₅ δ): 27.9; 27.0; 27.1; 27.6; 33.4; 37.8; 45.5; 49.3; 50.4; 63.3; 123.7; 125.5; 125.9; 126.6; 127.0; 128.8; 132.0; 134.0; 136.0; 160.8; 174.0. Analysis calculated for C₂₂H₂₇N₃O₂₁HCLH₂O: C₅ 62.92; H₅ 7.20; N₅ 10.01, found: C₅ 63.40; H₅ 7.09; N₅ 9.61.

Example 10

3-[4-[2-(Naphth-l-yl)ethylamine]butyl]-2,4-dioxothiazolidin, 10

[00120] Chromatography: ethyl acetate. Yield: 37%; m.p. 128-129°C (ethyl acetate). IR (CHCl₃₅ cm⁴): 175I₅ 1682, 1682, 1510. ¹H-NMR (CDCl₃, δ): 1.52-1.63 (m₅ 4H)₅ 2.70 (t₅ J=6.8 Hz, 2H)₅ 2.94 (s, IH), 3.03 (t, J=7.3 Hz, 2H), 3.32 (t, J=7.6 Hz, 2H) 3.62 (t, J=6.8 Hz, 2H), 3.93 (s, 2H), 7.33-7.55 (m, 4H), 7.71-7.75 (m, IH)₅ 7.83-7.88 (m, IH), 8.04-8.08 (m, IH). ¹³C-NMR (CDCl₃, δ): 25.4; 26.3; 32.7; 33.8; 41.7; 48.7; 49.9; 123.7; 125.7; 125.8; 126.1; 126.8; 127.3; 128.9; 131.0; 134.0; 135.4; 171.0; 171.5. Analysts calculated for C₁₉H₂₂N₂O₂S-HCl: C, 60.82; H, 6.85; N, 7.09, found: C, 62.87; H, 6.45; N, 6.90.

Example 11

2-[4-[2-(Naphth-2-yl)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazol, 11 [00121] Chromatography: ethyl acetate/ethanol, 9:1. Yield: 25%; m.p. 130-132°C (ethyl acetate). IR (CHCl₃, cm-¹): 3421, 1769, 1705. ¹H-NMR (CDCl₃, δ): 1.59-1.89 (m, 5H), 2.03-2.27 (m, 3H), 2.98 (t, J=7.8 Hz, 2H)₅ 3.01-3.32 (m₅ 5H)₅ 3.47 (t₅ J=6.6 Hz, 2H), 3.57-3.77 (m, IH)₅ 4.05 (dd, J=9.3; 7.3 Hz, IH), 6.29 (sa, IH), 7.32-7.48 (m, 3H)₅ 7.68-7.80 (m, 4H). ¹³C-NMR (CDCl₃, δ): 25.4; 27.1; 27.5; 31.2; 33.1; 37.9; 45.5; 47.1; 49.1; 63.4; 125.5; 125.8; 126.2; 126.9; 127.4; 127.6; 128.6; 131.8; 133.5; 139.5; 160.7; 174.1. Analysis calculated for C₂₂H₂₇N₃O₂-HCLH₂O: C, 62.92; H₅ 7.20; N, 10.01, found: C₅ 63.34; H, 7.46; N, 9.65.

Example 12

2- [4- [2-(Phenoxy)ethylamine] butyl] - 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazol, 12 [00122] Chromatography: toluene/ethanol, 9.5:0.5. Yield: 54%. m.p. 145-147⁰C (ethyl acetate). IR (CHCl₃, cm^"1): 3315, 1770, 1709, 1599, 1587, 1497. ¹H-NMR (CDC₃, δ): 1.47-1.77 (m, 6H), 1.98-2.29 (m, 3H), 2.70 (t, J=6.8 Hz, 2H), 2.99 (t, J=4.9 Hz, 2H), 3.23 (ddd, J=I 1.2; 7.6; 5.2 Hz, IH)₅ 3.49 (t, J=7.3 Hz, 2H)₅ 3.67 (dt, J=I 1.2; 7.6 Hz, IH)₅ 4.02-4.10 (m, 3H)₅ 6.87-6.98 (m, 3H)₅ 7.23-7.32 (m, 2H). ¹³C-NMR (CDC₃, δ): 26.0; 27.1; 27.3; 27.7; 38.9; 45.7; 48.9; 49.4; 63.4; 67.3; 114.7; 121.0; 129.6; 158.3; 160.7; 174.0. Analysis calculated for Ci₈H₂₅N₃O₃-HCl: C, 58.77; H, 7.12; N, 11.42, found: C, 58.79; H, 7.04; N, 11.16.

Example 13

3-[4-[2-(Phenoxy)ethylamine]butyl]-2,4-dioxothiazolidin, 13

[00123] Chromatography: ethyl acetate.fwdarw.ethyl acetate/ethanol, 9:1. Yield: 37%; m.p. 173-174⁰C. (ethyl acetate). IR (CHCl₃, cm^"1): 3413, 3327, 1751, 1685, 1599, 1587, 1497. 1H-NMR (CDCl₃, δ): 1.48-1.72 (m, 4H), 2.70 (t, J=7.1 Hz, 2H), 2.99 (t, J=7.9 Hz, 2H), 3.65 (t, J=7.1 Hz, 2H), 3.93 (s, 2H), 4.06 (t, J=5.1 Hz, 2H), 6.88-6.98 (m, 3H), 7.23-7.32 (m, 2H). 1³C-NMR (CDC₃, δ): 25.4; 27.1; 33.7; 41.8; 48.8; 49.1; 67.1; 114.5; 120.8; 129.4; 158.8; 171.4; 171.5. Analysis calculated for C₁₅H₂₀N₂O₃S-HCl: C, 52.17; H, 6.14; N, 8.12, found: C, 51.77; H, 6.04; N, 8.10.

Example 14

2-[4-[2-(Naphth-l -oxy)ethylamine]butyl]-l ,3-dioxoperhydropyrrolo[ 1 ,2-c]imidazol, 14 [00124] Chromatography: ethyl acetate → ethyl acetate/ethanol, 9:1. Yield: 43%; m.p. 163-164⁰C (ethyl acetate). IR (CHCl₃, cm^"1): 3354, 1771, 1707, 1582, 1508. ¹H-NMR (CDCl₃, δ): 1.58-1.77 (m, 5H), 1.93-2.30 (m, 3H), 2.86 (t, J=7.1 Hz, 2H), 3.15-3.27 (m, 3H), 3.49 (t, J=6.8 Hz, 2H), 3.60-3.73 (m, IH), 4.05 (dd, J=9.0; 7.3 Hz, IH), 4.30 (t, J=4.9 Hz, 2H), 6.80 (dd, J=8.5; 1.2 Hz, IH), 7.31-7.53 (m, 4H), 7.75-7.83 (m, IH), 8.22-8.28 (m, IH). ¹³C-NMR (CDCl₃, δ): 25.7; 26.3; 27.0; 27.5; 38.5; 45.5; 48.3; 48.8; 63.3; 66.7; 104.9; 120.6; 121.9; 125.3; 125.8; 126.4; 127.5; 125.5; 134.5; 154.3; 160.8; 174.0. Analysis calculated for C₂₂H₂₇N₃O₃-HCLH₂O: C, 60.61; H, 6.94; N, 9.64, found: C, 61.00; H, 6.57; N, 9.46.

Example 15

3-[4-[2-(Naphth-l -oxy)ethylamine]butyl]-2,4-dioxothiazolidin, 15 [00125] Chromatography: ethyl acetate → ethyl acetate/ethanol, 9:1. Yield: 46%; m.p. 149-151°C (ethyl acetate). IR (CHCl₃, cm^"1): 3332, 1684, 1582, 1508. ¹H-NMR (CDCl₃, δ): 1.58-1.70 (m, 4H), 2.81 (t, J=6.8 Hz, 2H), 3.17 (t, J=5.4 Hz, 2H), 3.65 (t, J=6.8 Hz, 2H), 3.92 (s, 2H), 4.27 (t, J=5.1 Hz₅ 2H)₅ 6.81 (dd, J=7.1; 1.5 Hz₅ IH), 7.30-7.56 (m, 4H)₅ 7.75-7.83 (m, IH)₅ 8.22-8.38 (m, IH). ¹³C-NMR (CDCl₃, δ): 25.3; 26.7; 33.7; 41.7; 48.5; 48.9; 67.1; 104.9; 120.5; 121.9; 125.2; 125.8; 126.4; 127.5; 125.6; 134.5; 154.4; 171.4; 171.5. Analysis calculated for C₁₉H₂₂N₂O₃S₁HCl: C, 57.79; H, 5.87; N₅ 7.09, found: C₅ 57.75; H₅ 5.79; N, 6.59.

Example 16

2-[4-[(Benzimidazol-2-yl)methylamine]butyl]-l,3-dioxoperhydropyrrolo[l₅2-c ]imidazol, 16 [00126] Chromatography: toluene/ethanol, 9.5:0.5. Yield: 50%; m.p. 208-210°C (ethyl acetate). IR (CHCl₃, cm^"1): 340O₅ 1775, 1714. ¹H-NMR (CDCl₃₅ δ): 1.42-1.70 (m, 5H) , 1.92-2.28 (m, 3H)₅ 2.63 (t, J=6.5 Hz, 2H)₅ 3.13-3.25 (m, IH), 3.43 (t, J=6.5 Hz₅ 2H), 3.55-3.64 (m, IH), 4.00 (m, 2H)₅ 7.10-7.18 (m, 2H)₅ 7.47-7.53 (m, 2H). ¹³C-NMR (CDCl₃₅ δ): 25.4; 26.2; 27.0; 27.5; 38.4; 45.4; 47.6; 48.5; 63.3; 115.0; 122.0; 139.0; 154.0; 160.8; 174.0.

Example 17

2-[4-[(o-Methoxyphenyl)methylamine]butyl]- 1 ,3-dioxoperhydropyrrolo[l ₅2-c]imidazol, 17 [00127] Chromatography: ethyl acetate/hexane. Yield: 42%; oil. IR (CHCl₃, cm-¹): 3016-2837, 177O₅ 1706, 160O₅ 1492, 1442, 1415, 1242. ¹H-NMR (CDCl₃, δ): 1.47-1.72 (m, 3H) , 1.95-2.09 (m, 2H)₅ 2.17-2.28 (m, IH), 2.59 (t, J=7.1 Hz₅ 2H)₅ 3.18-3.26 (m, IH)₅ 3.45 (t₅ J=7.1 Hz₅ 2H)₅ 3.65 (dt, J=I 1.1; 7.9 Hz₅ IH), 3.76 (s, 2H)₅ 3.82 (s, 3H), 4.04 (dd, J=9.3; 7.9 Hz₅ IH) , 6.83-6.91 (m, 2H) , 7.20-7.25 (m, 2H) . ¹³C-NMR (CDCl₃, δ): 24.4; 26.0; 27.0; 27.5; 38.9; 45.5; 47.1; 53.3; 63.3; 110.1; 120.3; 127.1; 130.3; 157.5; 160.9; 174.0. Analysis calculated for C_]8H₂₄N₃O₃.HC1.3/2H₂O: C, 54.88; H, 7.16; N, 10.67, found: C, 54.52; H, 7.09; N, 10.52.

Example 18

2-[4-[2-(o-Methoxyphenyl)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]-imidazol, 18 [00128] Chromatography: ethyl acetate/hexane. Yield. 25%; m.p. 160-162°C (chloroform/hexane). IR (CHCl₃, cm^"1): 3018-2899, 1770, 1709, 1495, 1443, 1418, 1244. 1H-NMR (CDCl₃, δ): 1.60-1.77 (m, 5H), 1.96-2.27 (m, 3H)₅ 2.75 (t₅ J=6.8 Hz₅ 2H), 2.92 (s, 4H)₅ 3.15-3.27 (m, IH)₅ 3.45 (t, J=6.6 Hz, 2H)₅ 3.65 (dt, J=ILO; 7.6 Hz, IH)₅ 3.79 (s, 3H)₅ 4.05 (dd, J=9.0; 7.3 Hz, IH)₅ 4.62 (sa₅ IH)₅ 6.80-6.89 (m, 2H), 7.13-7.22 (m, 2H). ¹³C-NMR (CDCl₃, δ): 25.6; 27.0; 27.5; 27.5; 29.7; 38.4; 45.5; 48.3; 48.7; 55.2; 63.3; 110.3; 120.5; 127.2; 127.7; 130.4; 157.5; 160.7; 173.9. Analysis calculated for C₁₉H₂₆N₃O₃-HCLH₂O: C₅ 57.20; H, 7.33; N, 10.53, found: C, 57.43; H₅ 7.03; N₅ 10.41. Example 19

2- [4- [3 -(o-Methoxyphenyl)propylamine]butyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c]imidazol, 19 [00129] Chromatography: toluene/methanol. Yield: 52%; oil. IR (CHCl₃, cm^"1): 3018-2700, 1772, 1709, 1492, 1442, 1418, 1244. ¹H-NMR (CDCl₃, δ): 1.60-1.81 (m, 5H), 1.93-2.34 (m, 5H), 2.67 (t, J=6.8 Hz, 2H), 2.77 (m, 4H), 3.16-3.28 (m, IH), 3.46 (t, J=6.6 Hz), 3.67 (dt, J=I 1.1; 7.6 Hz, IH), 3.75 (s, 3H), 4.07 (dd, J=9.3; 7.3 Hz, IH), 6.81-6.90 (m, 2H), 7.10-7.21 (m, 2H) . 1³C-NMR (CDCl₃, δ): 24.9; 25.6; 27.1; 27.5; 27.6; 27.9; 38.3; 45.6; 48.1; 48.4; 55.4; 63.4; 110.4; 120.6; 127.4; 129.3; 130.0; 157.4; 160.8; 174.0. Analysis calculated for C₂oH₂₈N₃0₃.HC1.3/2H₂0: C, 56.93; H, 7.64; N, 9.93, found: C, 57.23; H, 7.21; N, 9.40.

Example 20

2- [4- [4-(o-Methoxyphenyl)butylamine]butyl] - 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazol, 20 [00130] Chromatography: chloroform/methanol, 9.5:0.5. Yield: 27% (oil). IR (CHC₃, cm^"1): 3700, 1770, 1709, 1601, 1443, 1495, 1585, 1215. ¹H-NMR (CDCl₃, δ): 1.58-1.74 (m, 9H), 2.01-2.11 (m, 2H), 2.17-2.27 (m, IH), 2.60 (t, J=7.3 Hz, 2H), 2.65-2.570 (m, 4H), 3.18-3.26 (m, IH), 3.46 (t, J=6.8 Hz, 2H), 3.66.(dt, J=I 1.2; 7.6 Hz, IH), 3.79 (s, 3H), 4.05 (dd, J=9.0; 7.6 Hz, IH), 6.80-6.87 (m, 2H), 7.09-7.17 (m, 2H). .sup.l3C-NMR (CDCl.sub.3, .delta.): 23.4; 25.2; 26.3; 27.0; 27.4; 29.6; 37.8; 45.4; 47.1; 47.8; 55.1; 63.4; 110.1; 120.3; 127.1; 129.7; 129.9; 157.2; 160.6; 173.9. Analysis calculated for C₂₁H₃N₃O₃.HC1.3/2H₂O: C, 60.31; H, 7.95; N, 10.05, found: C, 60.70; H, 7.56; N, 9.77.

Example 21

2-[3-[3-(o-Methoxyphenyl)propylamine]propyl]- 1 ,3 -dioxoperhydropyrrolo [1 ,2-c]imidazol, 21 [00131] Chromatography: chloroform/methanol, 9.5:0.5. Yield: 27% (oil). IR (CHCl₃, cm^"1): 3700, 1770, 1707, 1601, 1587, 1493, 1445, 1215. ¹H-NMR (CDCl₃, δ): 1.62-1.86 (m, 5H), 2.02- 2.32 (m, 3H), 2.56-2.67 (m, 6H), 3.24 (m, IH), 3.54 (t, J=6.8 Hz, 2H), 3.67 (dt, J=I 1.2; 7.6 Hz, IH), 3.81 (s, 3H), 4.06 (dd, J=9.0; 7.3 Hz, IH), 6.81-6.91 (m, 2H), 7.10-7.22 (m, 2H). .sup¹³C- NMR (CDCl₃, δ): 26.9; 27.5; 27.8; 28.4; 30.0; 36.9; 45.5; 46.7; 49.5; 55.2; 63.3; 110.2; 120.3; 127.0; 129.8; 130.5; 157.4; 160.9; 174.0. Analysis calculated for C₁₈H₂₅N₃O₃.HC1.3H₂O: C, 51.24; H, 7.64; N₃ 9.96, found: C, 51.26; H, 7.25; N, 9.57.

Example 22.

2-[4-[(Chroman-2(R)-yl)methylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole,

(diastereoisomers) (a).

[00132] Chromatography: ethyl acetate. Yield: 35%.1H-NMR (CDCl₃, δ): 1.47-1.86 (m, 5H₅ - (CH₂)₂-, H₇), 1.91-2.12 (m, 4H, 2H₃., 2H₆), 2.16-2.34 (m, IH, H₇), 2.64-2.92 (m, 6H, 2CH₂NH, 2H₄.), 3.16-3.28 (m, IH, H₅), 3.48 (t, J= 7.1 Hz, 2H, NCH₂), 3.66 (dt, J= 11.2, 7.3 Hz, IH, H₅), 4.05 (dd, J= 9.1, 7.3 Hz, IH, H_7a), 4.11-4.18 (m, IH, H_2'), 6.81 (t, J= 7.6 Hz, 2H, H₆-, H₈ ), 7.00-7.10 (m, 2H, H₅-, H₇ ).¹³C-NMR (CDCl₃, δ): 24.6 (C₃), 25.6 (C₄), 25.8 (CH₂), 26.9 (CH₂), 27.1 (C₆), 27.5 (C₇), 38.7 (NCH₂), 45.4 (C₅), 49.3 (CH₂CH₂NH), 54.1 (HNCH₂CH), 63.2 (C_7a), 75.0 (C₂), 116.7 (C₈-), 120.1 (C₆-), 121.9 (C₄._a), 127.1 (C₇-), 129.4 (C₅-), 154.5 (C₈._a), 160.8 (C₃), 173.9 (d).Analysis calculated for C₂₀H₂₇N₃O₃.HCl:C, 60.98; H, 7.16; N, 10.67, Found: C, 60.15; H, 7.14; N, 10.45

Example 23.

2-[4-[(Chroman-2-yl)methylamino]butyl]-l,3-dioxoperhydroimidazo[l,5-a]pyridine, (b).

[00133] Chromatography: ethyl acetate. Yield: 30%. H-NMR (CDCl₃, δ): 1.06-1.40 (m, 3H, H_6ax, H_7ax, H_8ax), 1.60-1.62 (m, 7H, H_6ec, -(CH₂)₂-, 2H₃0, 1-88-2.09 (m, IH, H_7ec), 2.11-2.18 (m, IH, Hs_eo), 2.71-2.74 (m, 4H, 2NHCH₂), 2.85-2.87 (m, 3H, H_5ax, 2H₄'), 3.47 (t, 2H, J= 6.6 Hz, NCH₂), 3.67 (dd, IH, J= 11.9, 4.3 Hz, H_8a), 4.03-4.14 (m, 2H, H₅₆₀, H₂-), 6.76 (t, 2H, J= 7.6 Hz, H₆-, H₈.), 6.98 (t, 2H, J= 6.3 Hz, H₅., H_7').Analysis calculated for C₂₁H₂₉N₃O₃-HCl-H₂O: C, 59.21; H, 7.57; N, 9.87, Found:C, 58.76; H, 7.01; N, 9.89 Example 24. 2-[4-[(Chroman-2-yl)methylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2-a]pyrazine, (c).

[00134] Chromatography: ethyl acetate. Yield: 35%. H-NMR (CDCl₃, δ): 1.14-2.09 (m, 9H, - (CHt)₂-, 2H₇, H₈, 2H₃O, 2.28-2.34 (m, IH, H₈), 2.65-2.93 (m, 6H, 2NHCH₂, 2H₄-), 3.29-3.56 (m, 4H₅ NCH₂, 2H₆), 3.71 (d, IH, J= 11.9 Hz, H₃), 4.04-4.14 (m, 3H, H₃, H_8a, H₂-), 6.67-6.80 (m,

2H₃ H₆., H₈.), 6.95-7.22 (m, 2H, H₅-, H₇-). '³C-NMR (CDCl₃, δ): 22.8 (C₇), 24.7, 25.0, 25.7, 26.7, 29.0 (-(CHs)₂-, C₈, C₃', C₄.), 45.4 (NCH₂), 46.0 (C₆), 49.4 (NHCH₂), 51.9 (C₃), 54.0 (NHCH₂), 59.2 (C₈₃), 74.7 (C₂.), 116.9 (C₈.), 120.4 (C₆.), 122.1 (C_4a0, 127.4 (C₇=), 129.7 (C₅.), 154.6 (C_8a.), 163.4 (C₄), 167.4 (d).Analysis calculated for C₂₁H₂₉N₃O₃.HC1-2H₂O: C, 56.81; H, 7.72; N, 9.46, Found: C, 56.73; H, 7.09; N, 9.55

[00135] Example 25. 2-[5-[(Chroman-2-yl)methylamino]pentyl]-l, 3- dioxoperhydropyrrolofl, 2-c] imidazole, (d).

Chromatography: ethyl acetate.

Yield: 32%-

¹H-NMR (CDCk δ): 1.34-1.39 (m, 2H, -(CH₂)-), 1.61-1.76 (m, 6H, -(CH₂)₂-, 2H₃.), 2.01-2.10

(m, 3H, 2H₆, H₇), 2.17-2.33 (m, IH, H₇), 2.75-2.78 (m, 4H, CH₂CH₂NH, HNCH₂CH), 2.81-2.94

(m, 2H, 2H₄.), 2.93-2.98 (m, IH, H₅), 3.45 (t, J= 7.1 Hz, 2H, NCH₂), 3.58-3.78 (m, IH, H₅), 4.06

(dd, J= 9.1, 7.3 Hz, IH, H_7a), 4.29-4.39 (m, IH, H₂-), 6.82-6.89 (m, 2H, H₆., H₈.), 7.02-7.11 (m,

2H₅ H₅., H₇-).

¹³C-NMR (CDCk δ): 23.6 (CH₂), 24.9 (C₃.), 25.1 (C₄.), 26.9 ((CH₂)₂), 27.2 (C₆), 27.4 (C₇), 38.0

(NCH₂), 38.5 (C₅), 45.3 (CH₂CH₂NH), 47.9 (HNCH₂CH), 63.3 (C_7a), 70.9 (C₂), 117.1 (C₈.), 121.0 (C₆.), 121.2 (C₄-O, 127.4 (C₅-), 129.3 (C₇-), 153.0 (C₈-0, 160.7 (C₃), 173.9 (C₁).

C, 59.21; H, 7.57; N, 9.87 Found: C, 59.19; H₅ 7.17; N, 9.64

[00136] Example 26. 2-[6-[(Chroman-2-yl)methylamino]hexyl]-l,3- dioxoperhydropyrrolo[l, 2-c] imidazole, (e).

Chromatography: chloroform/methanol, 9.5:0.5. Yield: 35%-

¹H-NMR CCDCk S): 1.28-1.35 (m, 4H, -(CH₂)₂-)₅ 1.60-1.80 (m, 6H, -(CH₂)₂-, 2H₃-), 1.96-2.14 (m, 3H₅ 2H₆, H₇), 2.17-2.33 (m, IH, H₇), 2.77-3.03 (m, 6H₅ CH₂CH₂NH, HNCH₂CH, 2H₄-), 3.17-3.30 (m, IH, H₅), 3.45 (t, J= 7.1 Hz, 2H, NCH₂), 3.58-3.78 (m, IH, H₅), 4.06 (dd, J= 9.1, 7.3 Hz, IH, H_7a), 4.29-4.39 (m, IH, H₂-), 6.80-6.93 (m, 2H, H₆-, H₈-), 7.00-7.08 (m, 2H₅ H₅-, H₇-). ¹³C-NMR (CDCk δ): 24.1 (CH₂), 24.3 (C₃-), 25.5 (C₄.), 26.3, 26.5, 27.0 ((CH₂)₃), 27.5 (C₆), 27.8 (C₇), 38.7 (NCH₂), 45.5 (C₅), 49.2 (CH₂CH₂NH), 53.1 (HNCH₂CH)₅ 63.3 (C_7a), 72.7 (C₂'), 116.9 (C₈.), 120.4 (C₆-), 121.7 (C₄-0, 127.3 (C₅.), 129.5 (C₇-), 154.1 (C₈-O, 160.9 (C₃), 174.0 (C₁). Analysis calculated for CTjHrIN₁ ⁽XHCLH₂O:

C, 60.06; H, 7.79; N, 9.55 Found: C₅ 60.46; H, 7.41; N, 9.54

[00137] Example 27. 2-[3-[(Chroman-2-yl)methylamino]proρyl]-l, 3- dioxoperhydropyrroϊofl, 2-c] imidazole, (f).

Chromatography: ethyl acetate. Yield: 40%. ¹H-NMR (ODCK δ): 1.64-2.32 (m, 8H, -(CH₂)-, 2H₆, 2H₇, 2H_3'), 2.68-2.88 (m, 6H, 2CH₂NH,

2H₄.), 3.18-3.30 (m, IH, H₅), 3.58 (t, 2H, J = 6.8 Hz, NCH₂), 3.65-3.70 (m, IH, H₅), 4.03-4.17

(m, 2H, H_7a, H₂>), 6.79-6.86 (m, 2H, H₆-, H₈.), 7.02-7.11 (m, 2H₅ H₅-, H₇O-

¹³C-NMR (CDCl₃, δ): 24.6 (C₃-), 25.6 (C₄-), 26.9 (CH₂), 27.5 (C₆), 28.1 (C₇), 36.9 (NCH₂), 45.5

(C₅), 46.9 (CH₂CH₂NH), 54.0 (HNCH₂CH), 63.3 (C₇₈), 74.9 (C₂), 116.8 (C₈.), 120.2 (C₆O, 122.0

(C₄-B), 127.2 (C₇-), 129.5 (C₅O, 154.6 (C_ffa), 160.9 (C₃), 174.0 (C₁).

C, 60.07; H, 6.90; N, 11.06 Found: C, 59.65; H, 6.91; N, 10.55

[00138] Example 28. 3-[8-[(Chroman-2-yl)methylamino]octyl]-2,4~dioxothiazolidine, (g).

Chromatography: ethyl acetate.

Yield: 35%; m.p. 108-111 ⁰C.

¹H-NMR (CDCl₃, δ): 1.29-1.31 (m, 8H, -(CH₂)₄-), 1.55-1.66 (m, 4H, CH₂, 2H₃-), 1.71-1.86 (m,

2H, CH₂), 2.70-2.93 (m, 6H, 2NHCH₂, 2H₄-), 3.60 (t, J= 7.6 Hz, 2H, NCH₂), 3.94 (s, 2H, 2H₅),

4.19-4.25 (m, 2H₅ H_2', NH), 6.80-6.86 (m, 2H₅ H₆>, H₈.), 7.01-7.11 (m, 2H, H₅-, H₇-).

¹³C-NMR (CDCl₃, δ): 24.3, 25.4, 26.4, 26.9, 27.3, 28.8, 28.9, 29.0 (-(CHa)₆-, C₃-, C₄-), 33.5 (C₅),

41.9 (NCH₂), 49.3, 53.3 (2CH₂NH), 74.0 (C₂'), 116.6 (C₈'), 120.2 (C₆-), 121.7 (C₄₁-), 127.1 (C₇-),

129.3 (C_5'), 154.2 (C_8a-), 171.3, 171.7 (C₂, C₄).

Analysis calculated for C₂IH₃JJN₂OIS-HCI-SH₂O:

C₅ 52.43; H, 7.75; N, 5.82 Found: C, 52.33; H₅ 6.78; N₅ 5.79

[00139] Example 29. 2-[4-[(Chroman-2(S)-yl)methylamino]butyl]-l ,3- dioxoperhydroρyrrolo[l,2-c]imidazole, (diastereoisomers) (h).

Chromatography: ethyl acetate.

Yield: 38%.

[D]²⁵D = +65 (c = 0.5, CHCl₃).

Analysis calculated for C_nHjnN?OjS.HCl-3H_?O:

C₅ 53.62; H, 7.65; N₅ 9.38 Found: C₅ 53.45; H, 7.34; N₅ 9.45

[00140] Example 30. 2-[8-[(Chroman-2-yl)methylamino]octyl]-l₅3- dioxoperhydropyrrolo[l ,2-c]imidazole₅ (i).

Chromatography: ethyl acetate.

Yield: 35%.

¹H-RMN (CDCIj, δ): 1.29-1.31 (m, 8H₅ -(CH₂)₄-)₅ 1.55-1.88 (m, 7H₅ -(CH₂V, 2H₃.₅ H₇), 1.94-

2.34 (m, 3H₅ 2H₆, H₇), 2.54 (br S₅ IH₅ NH)₅ 2.66-2.97 (m, 6H₅ 2CH₂NH₅ 2H₄.)₅ 3.18-3.29 (m, IH₅

H₅), 3.44 (t, 2H₅ J= 7.3 Hz₅ NCH₂), 3.62-3.74 (m, IH₅ H₅), 4.06 (dd₅ IH₅ J= 7.8, 7.6 Hz₅ H_7a),

4.14-4.21 (m, IH, H₂'), 6.80-6.86 (m, 2H₅ H₆', H₈.), 7.01-7.11 (m, 2H, H₅., H₇').

¹³C-RMN (CDCk δ): 24.6, 25.7, 26.6, 27.0, 27.1, 27.6, 27.9, 29.0 (-(CH₂)₆-, C₃., C₄.), 29.3 (C₆),

29.6 (C₇), 39.0 (NCH₂), 45.5 (C₅), 49.8 (CH₂CH₂NH)₅ 54.0 (HNCH₂CH), 63.3 (C_7a), 74.7 (C₂.),

116.8 (C₈.), 121.2 (C₆.), 121.9 (C₄._a), 127.2 (C₅-), 129.5 (C₇0, 154.5 (C₈._a), 160.9 (C₃), 174.0 (C₁).

[00141] Example 31. (E)-2-[4-[(Chroman-2-yl)methylamino]but-2-enyl]-l ,3- dioxoperhydropyrrolo[l ₅2-c]imidazole₅ (1).

Chromatography: ethyl acetate. Yield: 43%. ¹H-RMN (CDCk δ): 1.63-2.31 (m, 6H, 2H₆, 2H₇, 2H₃.), 2.65-2.93 (m, 4H, CH₂NH, 2H₄.), 3.17- 3.31 (m, 3H, CH₂NH, H₅), 3.67 (dt, IH, J = 11.2, 7.6 Hz, H₅), 4.03-4.14 (m, 4H, NCH₂, H_7a, H₂'), 5.54-5.85 (m, 2H, CH=CH), 6.77-6.85 (m, 2H, H₆-, H_8'), 7.00-7.10 (m, 2H, H₅-, H₇-). 1³C-RMN (CDCl₃, δ): 24.7 (C₃-), 25.7 (C_4'), 27.1 (C₆), 27.6 (C₇), 40.2 (NCH₂), 45.6 (C₅), 50.9, 53.6 (2CH₂NH), 63.5 (C_7a), 75.1 (C₂), 116.8 (C₈-), 120.3 (C₆-), 122.1 (C₄._a), 124.8 (CH), 127.3 (C₇'), 129.6 (C₅-), 132.3 (CH), 154.6 (C₈._a), 160.4 (C₃), 173.6 (C₁). Analysis calculated for C_2nH₂SN₁OrHCHH₂O:

C, 51.78; H, 7.39; N, 9.06 Found: C, 52.16; H, 7.00; N, 9.16

[00142] Example 32. 2-[4-[2-(o-Methoxyphenoxy)ethylamino]butyl]-l,3- dioxoperhydropyrrolofl ,2-c] imidazole (m).

Chromatography: ethyl acetate.

Yield: 38%.

¹H-RMN (CDCl₃, S): 1.63-1.71 (m, 5H, -(CH₂)₂-, H₇), 1.99-2.29 (m, 3H, 2H₆, H₇), 2.78 (t, 2H, J

= 6.8 Hz, CH₂NH), 3.01-3.10 (m, 2H, CH₂NH), 3.21 (ddd, IH, J= 11.2, 6.1, 5.6 Hz, H₅), 3.57-

3.80 (m, 3H, NCH₂, H₅), 3.83 (s, 3H, OCH₃), 4.00-4.18 (m, 3H, OCH₂, H_7a), 6.87-6.90 (m, 4H,

ArH).

¹³C-RMN (CDCl₃, δ): 25.5, 25.6 (-(CH₂)₂-), 26.5, 27.4 (C₆, C₇), 38.4 (NCH₂), 45.4 (C₅), 48.1,

48.6 (2CH₂NH), 63.2 (C_7a), 67.7 (OCH₃), 71.0 (OCH₂), 111.8 (C₆.), 120.9 (C₄'), 125.9, 129.7

(C₃-, C₅.), 130.5 (C₂.), 147,8 (C₁.), 160.6 (C₃), 173.9 (C₁).

Analysis calculated for C₁QHT₂N₁O₄-HCUH₂O:

C, 48.56; H, 7.72; N, 8.94 Found: C, 48.16; H, 7.32; N, 8.48

[00143] Example 33. 2-[4-[2-(m-Methoxyphenoxy)ethylamino]butyl]-l,3- dioxoperhydropyrrolo[l ,2-c] imidazole, (n).

Chromatography: ethyl acetate.

Yield: 38%.

¹H-RMN (CDCl₃. S): 1.42-1.70 (m, 4H, -(CH₂)₂-), 1.95-2.06 (m, 3H, 2H₆, H₇), 2.10-2.19 (m, IH₅

H₇), 2.64 (t, 2H, J= 6.8 Hz, CH₂NH), 2.92 (t, 2H, J= 5.4 Hz, CH₂NH), 3.16 (ddd, IH, J- 11.2,

7.3, 5.4 Hz, H₅), 3.39 (t, 2H, J= 6.3 Hz, NCH₂), 3.59 (dt, IH, J= 11.3, 7.6 Hz, H₅), 3.71 (s, 3H,

OCH₃), 3.97-4.07 (m, 3H, OCH₂, H_7a), 6.41-6.47 (m, 3H, H₂-, H₄-, H₆O, 7.10 (t, IH, J= 7.8 Hz₃

H₅-).

¹³C-RMN TCDCl₃, δ): 25.8 (-(CH_j)₂-), 27.0, 27.5 (C₆, C₇), 38.7 (NCH₂), 45.6 (C₅), 48.3, 49.0

(2CH₂NH), 63.2 (C₇₈), 67.2, 68.6 (OCH₃, OCH₂), 101.0 (C₂-), 106.4, 106.6 (C₄-, C₆-), 129.8 (C₅O,

138.9 (CiO, 160.0 (C₃O, 160.8 (C₃0, 173,9 (C₁).

Analysis calculated for CiQH₂₂N₃O₄-HCl-SH₂O:

C, 50.49; H, 7.58; N, 9.30 Found: C, 50.71; H, 7.18; N, 8.90

[00144] Example 34. 2-[4-[2-(o-Bromophenoxy)ethylamino]butyl]-l,3- dioxoperhydropyrrolo[l ,2-c]imidazole, (o).

Chromatography: ethyl acetate.

Yield: 48%; m.p. 98-99 ⁰C.

¹H-RMN TCDCl₃. δ): 1.46-1.69 (m, 4H, -(CHb)₂-), 1.98-2.20 (m, 4H, 2H₆, 2H₇), 2.70 (t, 2H, J =

6.8 Hz, CH₂NH), 3.00 (t, 2H, J = 5.1 Hz, CH₂NH), 3.19 (ddd, IH, J = 11.2, 7.3, 5.4 Hz, H₅),

3.46 (t, 2H, J = 7.1 Hz, NCH₂), 3.64 (dt, IH, J = 11.2, 7.6 Hz, H₅), 3.99-4.12 (m, 3H, OCH₂, H_7a), 6.80 (dt, 2H₅ J= 8.1, 8.0 Hz₅ H₄-, H₆.), 7.21 (td, IH, J= 5.9, 1.2 Hz, H_5'), 7.49 (dd, IH, J=

7.8, 1.4 Hz₅ H₃.).

¹³C-RMN (CDCl₃, δ): 25.6, 26.8 (-(CH₂)₂-)₅ 26.9, 27.4 (C₆, C₇), 38.6 (NCH₂), 45.4 (C₅), 48.2,

48.9 (2CH₂NH)₅ 63.1 (C_7a), 68.4 (OCH₂), 112.2 (C₂-), 113.4 (C₆.), 121.9 (C₄-), 128.3 (C₅.), 133.1

(C₃.), 155.0 (Cr), 160.6 (C₃), 173.8 (C₁).

Analysis calculated for C2RH24BrN3O3.HCl.2H9O:

C, 44.78; H, 6.05; N, 8.70 Found: C, 44.38; H₅ 5.65; N₅ 9.05

[00145] Example 35. 2-[4-[2-(m-Bromophenoxy)emylamino]butyl]-l,3- dioxoperhydropyrrolo[l ,2-c]imidazole, (p).

Chromatography: ethyl acetate.

Yield: 42%; m.p. 140-143 ⁰C.

¹H-RMN TCDCl₃, S): 1.42-1.74 (m, 4H₃ -(CH₂)₂-), 1.94-2.22 (m, 4H₅ 2H₆, 2H₇), 2.68 (t, 2H, J=

7.1 Hz₅ CH₂NH), 2.96 (t, 2H, J = 5.1 Hz₅ CH₂NH)₅ 3.19 (ddd, IH₅ J = 11.2, 7.3, 5.1 Hz₅ H₅),

3.45 (t₅ 2H, J = 7.8 Hz₅ NCH₂), 3.64 (dt₅ IH₅ J = 11.2, 7.6 Hz, H₅), 3.99-4.14 (m, 3H, OCH₂,

H_7a), 6.78-6.83 (m, IH₅ H₄-), 7.02-7.10 (m, 3H, H₂-, H₅., H₆-).

¹³C-RMN (CDCl₃, δV 25.6, 26.9, 27.4 (-(CH₂)₂-, C₆, C₇), 38.6 (NCH₂), 45.4 (C₅), 48.4, 49,0

(2CH₂NH)₅ 63.2 (C_7a), 67.3 (OCH₂), 113.4 (C₆O, 117.7 (C₂-), 122.6 (C₃'), 123.8 (C₄-), 130.4

(C₅-), 159.5 (C₁.), 160.7 (C₃), 173.8 (C₁).

C₅ 44.78; H₅ 6.05; N, 8.70 Found: C, 44.47; H₅ 5.65; N, 9.30

[00146] Example 36. 2-[4-[2-(o-Emylphenoxy)emylamino]butyl]-l,3- dioxoperhydropyrrolo[l ,2-c] imidazole, (q).

Chromatography: chloroform/methanol, 9.5:0.5.

Yield: 28%; m.p. 115-118 ⁰C (hexane).

¹H-RMN TCDCl₃, δ): 1.19 (t, 3H, J = 7.4 Hz₅ CH₃), 1.59-1.74 (m, 5H₅ -(CH₂)₂-₅ H₇), 1.97-2.09

(m, 2H, 2H₆), 2.17-2.28 (m, IH, H₇), 2.63 (q, 2H₅ J= 7.6 Hz, CH₂CH₃), 2.80 (t, 2H₅ J= 7.1 Hz₅

CH₂NH)₅ 3.08 (t, 2H, J = 5.1 Hz₅ CH₂NH)₅ 3.17-3.29 (m₅ IH, H₅), 3.50 (t, 2H, J = 6.8 Hz, NCH₂), 3.61-3.75 (m, IH, H₅), 4.02-4.15 (m, 3H, OCH₂, H_7a), 6.82-6.94 (m, 2H₅ H₄>, H₆-), 7.11-

7.17 (m, 2H₉ H₃', H₅O-

¹³C-RMN TCDCl₃, δ); 12.2 (CH₃), 23.2, 25.7, 26.6 (CH₂CH₃, -(CH_j)₂-), 27.0, 27.5 (C₆, C₇), 38.6

(CH₂NCO), 45.5 (C₅), 48.5, 48.9 (2CH₂NH), 63.3 (OCH₂, C_7a), 111.3 (C₆-), 120.8 (C₄-), 126.8,

129.0 (C₃-, C₅.), 132.7 (C₂-), 156.3 (C_r), 160.8 (C₃), 167.4 (C₁).

Analysis calculated for C₂PH₂QN₃O₁-HCUH₉O:

C, 55.61; H₅ 7.93; N₅ 9.73 Found: C₅ 55.89; H₅ 7.53; N, 9.81

[00147] Example 37. 2-[4-[2-(m-Ethylphenoxy)ethylamino]butyl]-l,3- dioxoperhydropyrrolo[l ,2-c]imidazole₅ (r).

Chromatography: ethyl acetate. Yield: 43%.

¹H-RMN (CDCl₃, δ): 1.24 (t, 3H, J= 7.6 Hz, CH₃), 1.59-1.74 (m, 5H₅ -(CH₂)₂-₅ H₇), 1.97-2.09 (m, 2H₅ 2H₆), 2.17-2.28 (m, IH, H₇), 2.63-2.74 (m, 4H₅ CH₂CH₃, CH₂NH)₅ 3.12 (t, 2H, J= 5.1 Hz, CH₂NH), 3.17-3.29 (m, IH, H₅), 3.50 (t, 2H₅ J = 7.1 Hz₅ NCH₂), 3.61-3.75 (m, IH, H₅), 4.02-4.15 (m, 3H, OCH₂, H_7a)₅ 6.72-6.86 (m, 3H, Hy, H₄., H₆-), 7.21 (t, IH₅ J= 7.8 Hz₅ H₅.). ¹³C-RMN (CDCl₃. δ): 15.5 (CH₃), 25.5, 25.8, 27.0 (CH₂CH₃, -(CH_j)₂-), 27.3, 27.6 (C₆, C₇), 38.8 (NCH₂), 45.6 (C₅), 48.7, 49.0 (2CH₂NH)₅ 63.4 (C_7a)₅ 66.9 (OCH₂), 111.5 (C₂.), 114.4 (C₆-), 120.6 (C₄-), 129.3 (C₅0, 146.0 (C₃.), 158.9 (C,.), 160.9 (C₃), 174.0 (C₁).

C, 58.03; H, 7.79; N₅ 10.15 Found: C, 57.92; H, 7.91; N₅ 10.12 [00148] Example 38. 2-[4-[2-(o-Isopropylphenoxy)ethylamino]butyl]-l,3- dioxoperhydropyrrolo [ 1 ,2-c] imidazole, (s) .

Chromatography: ethyl acetate.

Yield: 23%.

¹H-RMN (ODCl₃, δ): 1.21 (d, 6H, J= 7.9 Hz, 2CH₃), 1.44-1.76 (m, 5H, -(CH₂)₂-, H₇), 1.95-2.32

(m, 3H, 2H₆, H₇), 2.71 (t, 2H, J= 6.8 Hz, CH₂NH), 3.02 (t, 2H, J= 5.1 Hz, CH₂NH), 3.17-3.37

(m, 2H, CH, H₅), 3.49 (t, 2H, J= 7.1 Hz, NCH₂), 3.67 (dt, IH₅ J= 7.6, 3.9 Hz, H₅), 4.00-4.09 (m,

3H, OCH₂, H₇₈), 6.82-6.96 (m, 2H, H₄., H₆-), 7.09-7.22 (m, 2H, H₃-, H₅-).

¹³C-RMN (CDCl₃, δ): 22.7 (CH₃), 25.9, 26.9, 27.0, 27.3, 27.6 (-(CH₂)₂-, CH, C₆, C₇), 38.8

(NCH₂), 45.6 (C₅), 49.0, 49.2 (2CH₂NH), 63.4 (C_7a), 67.5 (OCH₂), 111.5 (C₆.), 120.8 (C₄-),

126.1, 126.6 (C₃', C₅-), 135.3 (C₂0, 157.5 (Cr), 160.8 (C₃), 173.9 (C₁).

[00149] Example 39. 2-[4-[(2-Quinolyl)methylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2- c] imidazole, (t).

Chromatography: ethyl acetate.

Yield: 33%; m.p. 125-126 ⁰C

IR CCHCk cm^'1): 1770, 1708 (CONCON), 1601, 1504, 1442, 1416 (Ar).

¹H-RMN (CDCk δ): 1.52-1.67 (m, 5H, -(CHa)₂-, H₇), 1.90-2.27 (m, 3H, 2H₆, H₇), 2.50 (t, 2H, J

= 6.3 Hz, CH₂NH), 3.01-3.24 (m, IH, H₅), 3.42 (t, 2H, J = 6.8 Hz, NCH₂), 3.53-3.69 (m, IH,

H₅), 3.91-4.00 (m, 3H, CH₂Ar, H_7a), 7.47 (t, J = 7.1 Hz, IH, H₆-), 7.62-7.77 (m, 3H, H₃-, H₅',

H₇.), 8.02 (d, J= 8.3 Hz, IH, H₄.), 8.11 (d, J= 8.5 Hz, IH, H₈.). ¹³C-RMN (CDCk δ): 24.4, 25.8, 26.8, 27.4 (2CH₂, C₆, C₇), 38.7 (NCH₂), 45.4 (C₅), 53.8, 54.1 (CH₂Ar₅ CH₂NH), 63.1 (C₇₈), 120.9 (C₃.), 126.0 (C₆.), 127.2, 127.4 (C₅-, C₈.), 128.9, 129.2 (C₄-, C₇.), 130.7 (C₄-0, 155.9 (C₂-), 160.5 (C₈-0, 160.7 (C₃), 173.8 (C₁).

[00150] Example 40. 2-[4-[2-(o-Ethoxyphenoxy)ethylamino]butyl]-l ,3- dioxoperhydropyrrolo[l,2-c]imidazole, (u).

Chromatography: ethyl acetate.

Yield: 30%.

¹H-RMN (CDCl₃, δ): 1.43 (t, 3H, J = 6.8 Hz, CH₃), 1.62-1.72 (m, 5H, -(CHz)₂-, H₇), 1.94-2.27

(m, 3H, 2H₆, H₇), 2.78 (t, 2H, J= 6.6 Hz, CH₂NH), 3.06 (t, 2H, J= 5.1 Hz, CH₂NH), 3.22 (ddd,

IH, J = 12.4, 7.3, 5.1 Hz, H₅), 3.44-3.72 (m, 3H, NCH₂, H₅), 4.01-4.17 (m, 4H, OCH₂, H_7a,

CH₂CH₃), 6.87-6.92 (m, 4H, ArH).

¹³C-RMN (CDCl₃, δ): 14.8 (CH₃), 25.6, 26.4, 26.8, 27.4 (-(CEL_j)₂-, C₆, C₇), 38.5 (NCH₂), 45.4

(C₅), 48.3, 48.7 (2CH₂NH), 63.2 (C₇O, 64.3 (CH₂CH₃), 68.3 (OCH₂), 113.6, 115.1, 120.9, 121.8

(C₆., C₄., C₃., C₅-), 148.3 (C₂.), 149.1 (C_r), 160.7 (C₃), 173.8 (C₁).

[00151] Example 41; 2-[4-[2-(o-Isopropoxyphenoxy)ethylamino]butyl]-l,3- dioxoperhydropyrrolo[l,2-c]imidazole, (v).

Chromatography: ethyl acetate. Yield: 23%. H-RMN rCDCL. δ): 1.33 (d, 6H, J= 6.1 Hz, 2CH₃), 1.55-1.71 (m, 4H, -(CEb)₂-). 2.04-2.26 (m, 4H, 2H₆, 2H₇), 2.72 (q, 2H, J = 6.2 Hz, CH₂NH), 3.02 (q, 2H, J= 5.1 Hz, CH₂NH), 3.23 (ddd, IH, J= 12.5, 7.3, 5.1 Hz, H₅), 3.48 (t, 2H, J= 6.8 Hz, NCH₂), 3,67 (dt, IH, J= 11.0, 7.8 Hz, H₅), 4.02-4.13 (m, 3H, OCH₂, H_7a), 4.45 (sept, IH, J= 6.1 Hz, CH), 6.89-6.92 (m, 4H, ArH). 1³C-RMN TCDCl₃. δ): 22.1, 22.2 (CH₃), 25.8, 27.0, 27.5 (-(CEy₂-, C₆, C₇), 38.7 (NCH₂), 45.5 (C₅), 48.7, 49.0 (2CH₂NH), 63.3 (C₇O, 68.7 (OCH₂), 72.1 (OCH), 115.5, 116.7, 117.6, 121.8 (C₆-, C₄-, C₃., C₅.), 145.5 (C₂.), 151.2 (C₁-), 160.3 (C₃), 173.9 (C₁).

C, 58.03; H, 7.79; N, 10.15 Found: C, 57.92; H, 7.91; N, 10.12

[00152] Example 42. 2-[4-[2-[m-(Trifluoromethyl)phenoxy]ethylamino]butyl]-l,3- dioxoperhydropyrrolo[l, 2-c] imidazole, (w).

Chromatography: ethyl acetate/ethanol, 9:1.

Yield: 30%.

¹H-RMN (CDCl₃, S): 1.50-1.72 (m, 5H, -(CEk)₂-, H₇), 1.91-2.21 (m, 3H, 2H₆, H₇), 2.72 (t, 2H, J

= 6.8 Hz, CH₂NH), 3.01 (t, 2H, J= 5.2 Hz, CH₂NH), 3.11-3.22 (m, IH, H₅), 3.42 (t, 2H, J= 6.8

Hz, NCH₂), 3.58-3.67 (m, IH, H₅), 3.96-4.29 (m, 3H, OCH₂, H₇O, 7.05-7.17 (m, 3H, H₂., H₄-,

H₆.), 7.32 (t, IH, J= 7.9 Hz, H₅-).

Analysis calculated for C₁QHT₄FaN₁O₁-HCLH₇Q:

C, 50.28; H, 6.00; N, 9.26 Found: C, 50.62; H, 6.10; N, 8.75 [00153] Example 43. 2-[4-[2-(J, 1 '-Biphenyl-2-yloxy)ethylamino]butyl]-l, 3- dioxoperhydropyrrolo[l, 2-c] imidazole, (x).

Chromatography: ethyl acetate/ethanol, 9:1.

Yield: 35%. ^•

¹H-RMN (CDCl₃, δ): 1.22-1.77 (m, 4H, -(CH_JO₂-)). 1.93-2.08 (m, 3H₅ 2H₆, H₇), 2.16-2.30 (m,

IH, H₇), 2.57 (t, 2H, J = 7.0 Hz, CH₂NH), 2.95 (t, 2H, J= 5.1 Hz, CH₂NH), 3.12-3.21 (m, IH₃

H₅), 3.37 (t, 2H, J= 7.0 Hz, NCH₂), 3.53-3.62 (m, IH, H₅), 3.96-4.05 (m, 3H, OCH₂, H_7a), 6.79-

7.00 (m, 2H, ArH), 7.18-7.47 (m, 7H, ArH).

¹³C-RMN TCDCl₃. δV 25.7, 26.9, 27.0, 27.5 (-(CH₂)₂-, C₆, C₇), 38.7 (NCH₂), 45.5 (C₅), 48.5,

48.9 (2CH₂NH), 63.3 (C₇₃), 68.1 (OCH₂), 113.3 (C₆-), 121.3 (C₄'), 126.9, 128.6 (C₃-, C₅.), 127.9,

129.5, 130.8 (5CH-Ph)₅ 131.4 (C₂-), 138.5 (C-Ph), 155.7 (CiO, 160.8 (C₃), 173.9 (C₁).

Analysis calculated for C₂₄H₂QN₁Oi-HCLoH₂O:

C, 52.21; H, 7.67; N, 7.61 Found: C, 52.61; H, 7.27; N, 8.01

[00154]

Example 44. 2-[4-[2-[o-(Acetylamino)phenoxy]ethylamino]butyl]-l, 3- dioxoper hydropyrrolo[l, 2 -c] 'imidazole, (y).

Chromatography: ethyl acetate/ethanol, 9:1. Yield: 24%- H-RMN (CDCl₃, δ): 1.60-1.71 (m, 5H₅ -(CH₂)I-, H₇), 1.96-2.17 (m, 3H, 2H₆, H₇), 2.21 (s, 3H, CH₃), 2.78 (t, 2H, J= 6.9 Hz, CH₂NH), 3.09 (t, 2H, J = 4.9 Hz, CH₂NH), 3.14-3.26 (m, IH, H₅), 3.43 (t, 2H, J = 7.1 Hz, NCH₂), 3.62 (dt, IH, J = 11.2, 7.8 Hz, H₅), 3.93-4.19 (m, 3H, OCH₂, H_7a), 6.82-6.99 (m, 3H, ArH), 8.14 (dd, IH₃ J= 7.3, 1.7 Hz, ArH), 8.68 (br s, IH, NH). 1³C-RMN TCDCl₃. δ): 24.6 (CH₃), 25.2, 25.3, 26.9, 27.4 (-(CH₂)₂-, C₆, C₇), 38.0 (NCH₂), 45.3 (C₅), 47.7, 48.2 (2CH₂NH)₅ 63.2 (C_7a), 66.8 (OCH₂), 112.2 (C_6'), 121.5, 121.7 (C₃-, C₄-), 124.0 (C₅0, 128.1 (C₂.), 147.4 (C₁-), 160.6 (C₃), 169.0 (CONH), 173.9 (Ci). Analysis calculated for CTnHTgN₄O₄-HClJH₂O:

C, 50.15; H, 7.37; N, 11.70 Found: C, 50.55; H, 7.75; N, 11.98

[00155] Example 45. 2-[4-[2-[m-(Acetylamino)phenoxy]ethylamino]butyl]-l,3- dioxoperhydropyrrolo[l, 2-c] imidazole, (z).

Chromatography: ethyl acetate/methanol, 9:1. Yield: 31%-

¹H-RMN (CDCl₃, δ): 1.60-1.72 (m, 5H, -(CH₂)₂-₅ H₇), 1.96-2.15 (m, 3H, 2H₆, H₇), 2.21 (s, 3H, CH₃), 2.82 (t, 2H, J = 6.1 Hz, CH₂NH), 3.08 (t, 2H, J = 5.8 Hz, CH₂NH), 3.19 (ddd, IH, J = 11.2, 7.6, 5.1 Hz, H₅), 3.44 (t, 2H, J = 6.9 Hz, NCH₂), 3.62 (dt, IH, J= 11.2, 7.8 Hz, H₅), 4.00- 4.10 (m, 3H, OCH₂, H_7a), 4.54 (br s, IH, NH), 6.54-6.57 (m, IH, ArH), 6.97-7.19 (m, 3H, ArH). ¹³C-RMN (CDCl₃, δ): 24.7 (CH₃), 25.4, 25.9, 27.2, 27.6 (-(CH₂)₂-, C₆, C₇), 38.5 (NCH₂), 45.6 (C₅), 48.6, 48.8 (2CH₂NH), 63.5 (C_7a), 65.6 (OCH₂), 106.8 (C₂-), 110.2 (C₆O, 113.1 (C₄O, 129.9 (C₅O, 138.6 (C₃O, 158.7 (Cr), 160.9 (C₃), 169.4 (CONH), 174.2 (Ci). Analysis calculated for C₂OH₂RN₄O₄-HCLSH₂O:

C, 50.15; H₅ 7.37; N, 11.70 Found: C₅ 50.65; H, 7.65; N, 12.03 [00156] Example 46. 2-[4-[2-[o-(Ethoxycarbonyl)phenoxy]ethylamino]butyl]-l,3- dioxoperhydropyrrolo[l, 2-c] imidazole, (aa).

Chromatography: ethyl acetate/ethanol, 9:1.

Yield: 25%-

¹H-RMN TCDCl₃, δV 1.39 (t, J= 7.2 Hz, CH₃CH₂), 1.66-1.83 (m, 5H₅ -(CH₂)₂-, H₇), 1.94-2.45

(m, 5H₃ 2H₆, H₇, CH₂NH), 3.15-3.27 (m, 3H, CH₂NH, H₅), 3.44-3.54 (m, 2H, NCH₂), 3.66 (dt,

IH, J= 11.2, 7.6 Hz, H₅), 4.07 (dd, IH, J= 9.0, 7.3 Hz, H_7a), 4.33 (q, 2H, J= 7.1 Hz, CH₃CH₂),

4.54 (t, 2H₅ J= 4.6 Hz, OCH₂), 7.01-7.11 (m, 2H₅ ArH), 7.50 (td, IH₅ J= 7.8, 1.7 Hz₅ ArH), 7.84

(dd, IH₅ J= 7.8, 1.5 Hz₅ ArH).

¹³C-RMN TCDCl₃, δ): 14.0 (CH₃CH₂), 22.9, 24.8, 26.9, 27.4 (-(CH₂)₂-, C₆, C₇), 37.5 (NCH₂),

45.3 (C₅), 47.3, 47.4 (2CH₂NH), 61.5 (CH₃CH₂), 63.2 (C₇O, 65.7 (OCH₂), 116.2 (C₆'), 120.2

(C₂.), 122.3 (C₄0, 131.6 (C₃.), 134.4 (C₅0, 158.0 (C_r), 160.4 (C₃), 166.6 (COO), 173.8 (C₁).

Analysis calculated for C₂_iH?jShOs.HC1.3H_zO:

C₅ 51.06; H, 7.35; N, 8.51 Found: C₅ 51.36; H₅ 7.42; N₅ 8.68

[00157] Example 47. 2-[4-[2-(5, 6, 7, 8-Tetrahydronaphth-l-yloxy)ethylamino]butyl]-l, 3- dioxoperhydropyrrolofl, 2 -cj imidazole, (bb).

Chromatography: ethyl acetate/ethanol, 9:1. Yield: 32%-

¹H-RMN TCDCl₃, δ): 1.52-1.77 (m, 9H, -(CH₂)₄-, H₇), 1.98-2.15 (m, 2H, 2H₆), 2.17-2.29 (m, IH, H₇), 2.64-2.78 (m, 6H, CH₂NH, 2CH₂Ar), 3.01 (t, J = 5.1 Hz, CH₂NH), 3.17-3.29 (m, IH, H₅), 3.49 (t, 2H, J = 7.1 Hz, NCH₂), 3.65 (dt, IH, J = 11.2, 7.6 Hz, H₅), 4.02-4.10 (m, 3H, OCH₂, H_7a), 6.57 (d, IH, J= 8.1 Hz, ArH), 6.62 (d, IH, J= 7.6 Hz, ArH), 7.03 (t, IH, J= 7.8 Hz, ArH). ¹³C-RMN CCDCl₃, δ): 22.8, 23.1, 25.8, 27.0, 27.2, 27.6 (-(CH₂)₂-, -(CH₂)₄-, C₆, C₇), 38.8 (NCH₂), 45.5 (C₅), 48.8, 49.1 (2CH₂NH), 63.3 (C_7a), 67.1 (OCH₂), 107.9 (C₂'), 121.6 (C₄.), 125.6 (C₃.), 126.1 (C₈._a), 138.6 (C_4'a), 156.5 (C₁-), 160.8 (C₃), 173.9 (C₁).

C, 55.51; H, 8.05; N, 8.83 Found: C, 55.18; H, 7.77; N, 8.90

[00158] Example 48. 2-[4-[2-(2, 3-Dimethylphenoxy)ethylamino]butyl]-l, 3- dioxoperhydropyrrolo[l, 2-cJ imidazole, (cc).

Chromatography: ethyl acetate/methanol, 9:1. Yield: 30%- H-RMN TCDCl₃, S): 1.53-1.73 (m, 5H, -(CH₂)₂-, H₇), 1.98-2.23 (m, 3H₅ 2H₆, H₇), 2.14 (s, 3H, CH₃), 2.27 (s, 3H₅ CH₃), 2.72 (t, 2H₅ J = 6.8 Hz, CH₂NH)₅ 3.02 (t, 2H₅ J = 4.9 Hz₅ CH₂NH)₅ 3.17-3.29 (m, IH₅ H₅), 3.49 (t, 2H₅ J= 6.8 Hz₅ NCH₂), 3.67 (dt, IH₅ J= 11.2, 7.6 Hz₅ H₅), 4.02- 4.10 (m, 3H, OCH₂, H_7a), 6.70 (d, IH, J= 8.3 Hz, ArH)₅ 6.77 (d, IH₅ J= 7.6 Hz, ArH)₅ 7.03 (t, IH₅ J= 7.8 Hz, ArH).

'³C-RMN (CDCl₃, δ): 11.7, 20.1 (2CH₃), 25.9, 27.0, 27.2, 27.6 (-(CH_j)₂-, C₆, C₇), 38.8 (NCH₂), 45.6 (C₅), 49.0, 49.2 (2CH₂NH)₅ 63.4 (C_7a), 67.7 (OCH₂), 109.2 (C₆'), 122.4 (C₄-), 125.8 (C₅.), 137.9, 138.1 (C₂-, C₃-), 155.9 (C_r), 160.5 (C₃), 173.9 (C₁).

C₅ 53.38; H₅ 8.06; N, 9.34 Found: C₅ 52.99; H, 8.15; N, 9.74

[00159] Example 49. 2-[4-[(Chroman-2-yl)methylamino]butyl]-l,4-dioxoρerhydropyrido[l₅2- ajpyrazine, (dd).

Chromatography: ethyl acetate.

Yield: 35%.

¹H-RMN fCDCk S): 1.40-1.68 (m, 8H, -(CHz)₂-, 2H₇, H_8ax, H_9ax), 1.96-2.07 (m, 3H, H_8eC5 2H₃.)₅

2.33-2.58 (m, 2H, H_9ec, H_63x), 2.70-2.96 (m, 6H, 2NHCH₂, 2H₄-), 3.41 (t, 2H₅ J= 6.6 Hz₅ NCH₂),

3.82 (d, 2H, J= 11.7 Hz, H_9a), 3.96 (s, 2H, 2H₃), 4.14-4.19 (m, IH, H₂-), 4.67 (d, IH, J = 12.9

Hz, H_6ec), 6.83 (t, 2H, J= 1.6 Hz, H₆., H₈-), 7.02-7.11 (m, 2H₅ H₅-, H₇-).

¹³C-RMN CCDCl₁. δ): 24.2, 24.4, 24.6, 25.6, 26.9 (-(CH₂)₂-, C₇, C₈, C₃-, C₄-), 31.3 (C₉), 42.4

(C₆), 45.7 (NCH₂), 49.2, 49.3 (NHCH₂, C₃), 54.0 (NHCH₂), 59.2 (C_9a), 74.8 (C₂-), 116.8 (C₈.),

120.2 (C₆.), 122.0 (C₄₈-), 127.2 (C₇-), 129.5 (C₅-), 154.4 (C₈₆-). 161.3 (C₄), 164.9 (C₁).

Analysis calculated for C₂₂HnN₃O₁-HCl-H₂O:

C₅ 60.06; H, 7.79; N, 9.55 Found: C₅ 60.23; H₅ 7.43; N₅ 9.22 [00160] Example 50. (Z)-2-[4-[(Chroman-2-yl)methylamino]but-2-enyl]-l₅4- dioxoperhydropyrrolo[l ₅2-c]imidazole, (ee).

Chromatography: ethyl acetate.

Yield: 38%.

¹H-RMN (CDCk S): 1.59-2.32 (m, 6H₅ 2H₆, 2H₇, 2H₃.), 2.70-2.86 (m, 4H₅ CH₂NH₅ 2H₄.), 3.24

(ddd, IH, J= 11.2, 7.6, 5.4 Hz₅ H₅), 3.50 (d, 2H₅ J= 6.6 Hz₅ CH₂NH)₅ 3.68 (dt, IH₅ J= 11.2, 7.8

Hz, H₅), 4.03-4.19 (m, 4H₅ NCH₂, H_7a, H₂-), 5.47-5.57 (m₅ IH₅ CH), 5.70-5.82 (m₅ IH₅ CH)₅

6.79-6.86 (m, 2H, H_6', H₈-), 7.02-7.07 (m₅ 2H, H₅-, H₇-).

¹³C-RMN (CDCk δ): 24.5, 25.4, 26.8, 27.3 (C₃., C₄', C₆, C₇), 35.7 (NCH₂), 45.3, 45.9 (C₅,

CH₂NH), 53.6 (CH₂NH)₅ 63.2 (C_7a), 75.0 (C₂), 116.6 (C₈-), 119.9 (C₆-), 121.8 (C₄-_a), 124.3 (CH),

127.0 (C₇.), 129.3 (C₅.), 132.7 (CH), 155.8 (C₈._a), 156.2 (C₃), 172.4 (C₁).

Analysis calculated for C₂OH₂SN₁Or HCHH₂O:

C, 51.78; H, 7.39; N, 9.06 Found: C₅ 51.42; H, 7.02; N₅ 8.75

[00161] Example 51. 3-[4-[2-(o-Ethoxyphenoxy)ethylamino]butyl]-2,4-dioxothiazolidine, (ff).

Chromatography: ethyl acetate/ethanol, 9:1.

Yield: 55%; m.p. 70-74 ⁰C.

¹H-RMN (CDCl₃, δ): 1.44 (t, 3H, J= 7.0 Hz₅ CH₃), 1.57-1.74 (m, 4H, -(CH₂)₂-)₅ 2.83 (t, 2H₅ J=

7.0 Hz₅ CH₂NH), 3.13 (t, 2H, J= 5.0 Hz, CH₂NH)₅ 3.29 (t, 2H₅ J= 7.5 Hz₅ NCH₂), 3.96 (s, 2H,

2H₅), 4.08 (q, 2H, J= 7.0 Hz, CH₂CH₃), 4.19 (t, 2H₅ J= 5.0 Hz₅ OCH₂), 6.86-6.97 (m, 4H₅ ArH). ¹³C-RMN TCDCl₃, δ): 14.9 (CH₃), 24.0, 25.2 (-(CH_j)₂-), 33.8 (C₅), 41.6 (NCH₂), 48.2, 48.5

(2CH₂NH), 64.4 (CH₂CH₃), 68.3 (OCH₂), 113.6, 115.1, 121.0, 121.8 (C₆-, C₄-, C₃-, C₅-), 148.3,

149.1 (Cr₅ Cr)₅ IyLS (C₂₅ C₄).

Analysis calculated for C₁₇H₂₄N₂O₄S₁HCH^H₂O:

C₅ 51.31; H, 6.59; N₅ 7.04 Found: C₅ 51.36; H₅ 7.04; N₅ 6.66

[00162] Example 52. 3~[6-[2-(o-Ethoxyphenoxy)ethylamino]hexyl]-2,4-dioxothiazolidine, (gg).

Chromatography: ethyl acetate/ethanol, 9:1. Yield: 48%; m.p. 92-94 ⁰C.

¹H-RMN TCDCl₃, δ): 1.18-1.66 (m, HH₅ -(CH₂)₄-₅ CH₃), 2.73 (t, 2H, J= 7.1 Hz, CH₂NH)₅ 3.06 (t, 2H₅ J = 5.3 Hz, CH₂NH), 3.46 (br s, IH₅ NH)₅ 3.60 (t, 2H₅ J = 7.4 Hz, NCH₂), 3.92 (s, 2H, 2H₅), 4.06 (q, 2H₅ J= 7.0 Hz₅ CH₂CH₃), 4.15 (t, 2H₅ J= 5.0 Hz₅ OCH₂), 6.81-6.97 (m, 4H, ArH). ¹³C-RMN CCDCl₃, δ): 14.8 (CH₃), 26.3, 26.6, 27.3, 29.1 (-(CH_j)₄-), 33.6 (C₅), 41.9 (NCH₂), 48.4, 49.2 (2CH₂NH)₅ 64.4 (CH₂CH₃), 68.3 (OCH₂), 113.6, 115.I₅ 121.O₅ 121.8 (C₆-, C₄-, C₃-, C₅.), 148.3, 149.1 (C₁-, C₂-), 171.3 (C₂, C₄). Analysis calculated for CiQH₂SN₂O₄S-HCl-H₂O:

C, 52.46; H₅ 7.18; N₅ 6.44 Found: C, 52.64; H₅ 6.99; N, 6.45

[00163]

Example 53. 3-[8-[2-(o-Ethoxyphenoxy)ethylamino]octyl]-2,4-dioxothiazolidine, (hh).

Chromatography: ethyl acetate/ethanol, 9:1. Yield: 48%; m.p. 105-108 ⁰C.

¹H-RMN CCDCl₃, δ): 1.07-1.54 (m, 15H₃ -(CH₂V, CH₃), 2.73 (t, 2H, J= 7.4 Hz, CH₂NH), 3.04 (t, 2H, J = 5.2 Hz, CH₂NH), 3.44 (br s, IH₅ NH), 3.54 (t, 2H, J = 7.4 Hz, NCH₂), 3.87 (s, 2H, 2H₅), 4.01 (q, 2H, J= 7.0 Hz, CH₂CH₃), 4.13 (t, 2H, J- 5.2 Hz, OCH₂), 6.76-6.92 (m, 4H, ArH). '³C-RMN CCDCl₃, δ): 14.7 (CH₃), 26.4, 26.8, 27.3, 28.7, 28.8, 29.0 (-(CH₂)₆-), 33.5 (C₅), 41.9 (NCH₂), 48.1, 49.1 (2CH₂NH), 64.3 (CH₂CH₃), 68.0 (OCH₂), 113.5, 115.1, 120.9, 121.9 (C₆-, C₄-, C₃-, C₅.), 148.3, 149.2 (C₁-, C₂-), 171.3 (C₂, C₄). Analysis calculated for C₂₁H₃₂N₂O₄S₁HCH^H₂O:

C, 55.55; H, 7.55; N, 6.17 Found: C, 55.78; H, 7.34; N, 6.04

[00164] Example 54. 2-[4-[2-(o-Ethoxyphenoxy)ethylamino]butyl]-l,3- dioxoperhydroimidazo[l,5-a]pyridine, (ii).

Chromatography: ethyl acetate/ethanol, 7:3.

Yield: 31%.

¹H-RMN CCDCl₃, δ): 1.28-1.74 (m, HH₅ -(CH₂),-, CH₃, H_6ax, H_7ax, H_8ax, H_6ec), 1.94-2.03 (m, IH₅

H₇₆₀), 2.14-2.21 Cm₅ IH, H_8ec), 2.73-2.87 (m, 3H₅ H_5aX5 CH₂NH)₅ 3.11 (t, 2H₅ J = 5.2 Hz, CH₂NH), 3.51 (t, 2H, J = 6.5 Hz, NCH₂), 3.69-3.79 (m, IH, H_8a), 4.00-4.12 (m, 3H, CH₂CH₃,

H_5ec), 4.18 (t, 2H₅ J= 5.1 Hz, OCH₂), 6.77-6.87 (m, 4H₃ ArH).

¹³C-RMN TCDCl₃, δ): 15.1 (CH₃), 22.9, 25.1, 26.0, 27.9, 29.8 (-(CH₂)₂-, C₆, C₇, C₈), 38.3

(NCH₂), 39.4 (C₅), 48.3, 48.8 (2CH₂NH), 57.5 (C₈O, 64.6, 68.1 (CH₂CH₃, OCH₂), 113.7, 115.4,

121.2, 122.2 (C₆., C₄-, C₃-, C₅-), 148.3, 149.3 (C₁-, C₂-), 154.1 (C₃), 173.4 (C₁).

Analysis calculated for C₂₁H₁₁N₁O₄-HCl-H₂O:

C, 56.81; H, 7.72; N, 9.46 Found: C, 57.38; H, 8.00; N, 9.02

[00165] Example 54. 2-[6-[2-(o-Ethoxyphenoxy)ethylamino]hexyl]-l,3- dioxoperhydwimidazofl, 5-aJpyridine, (jj).

Chromatography: ethyl acetate/ethanol, 8:2.

Yield: 49%.

¹H-RMN (CDCl₃, δ): 1.23-1.63 (m, 14H, -(CH₂)₄-, CH₃, H_6ax, H_7ax, H_8ax), 1.71-1.75 (m, IH,

H₆ec), 1.96-2.01 (m, IH, H_7ec), 2.18-2.22 (m, IH, H_8ec), 2.70 (t, 2H, J = 7.3 Hz, CH₂NH), 2.77-

2.87 (m, IH, H_5ax), 3.03 (t, 2H, J = 5.3 Hz, CH₂NH), 3.48 (t, 2H, J= 7.3 Hz, NCH₂), 3.73 (dd,

IH, J = 11.9, 4.1 Hz, H₈O, 4.07 (q, 2H₅ J= 7.0 Hz, CH₂CH₃), 4.14 (t, 2H, J = 5.3 Hz, OCH₂),

4.18-4.19 (m, IH₅ H_5ec)₅ 6.86-7.26 (m, 4H₅ ArH).

¹³C-RMN (CDCl₃. δ): 14.7 (CH₃), 22.6, 24.8, 26.3, 26.6, 27.6, 27.0, 29.3 (-(CBL_j)₄-, C₆, C₇, C₈),

38.3 (NCH₂), 39.1 (C₅), 48.4, 49.3 (2CH₂NH)₅ 57.1 (C_8a)₅ 64.3, 68.4 (CH₂CH₃, OCH₂), 113.5,

114.9, 120.9, 121.6 (C₆-, C₄', C₃', C₅'), 148.3, 148.7 (C₁-_, C₂-), 154.4 (C₃), 173.1 (C₁).

C, 53.43; H, 8.38; N, 8.13 Found: C, 53.18; H, 7.82; N, 7.60 [00166] Example 55. 2-[4-[(2-Quinolyl)methylamino]butyl]-l,S-dioxoperhydroimidazo[l,5- ajpyridine, (kk).

Chromatography: ethyl acetate/ethanol, 7:3.

Yield: 45%; m.p. 206-208 ⁰C.

¹H-RMN (CDCL, δ): 1.21-1.77 (m, 8H, -(CH₂)₂-, H_6ax, H_7ax, H_8aXj H_6ec)₃ 1.95-1.99 (m, IH, H_7ec),

2.16-2.22 (m, IH, H_8ec), 2.76-2.86 (m, 3H, H_5ax, CH₂NH), 3.24 (br s, IH, NH), 3.53 (t, 2H, J =

6.9 Hz, NCH₂), 3.73 (dd, IH₅ J= 12.1, 4.4 Hz, H_8a), 4.12-4.18 (m, 3H, CH₂Ar, H_5ec), 7.46 (d,

IH, J = 8.4 Hz, H₃-), 7.44-7.54 (m, IH, H₆O, 7.67-7.73 (m, IH, H₇-), 7.81 (dd, IH, J= 8.2, 1.1

Hz, H₅'), 8.06 (d, J= 8.5 Hz, IH, H₄-), 8.13 (d, IH, J= 8.5 Hz, H₈-).

¹³C-RMN rCDCL. δ): 22.7, 24.9, 25.9, 26.3, 27.8 (-(CH₂)₂-, C₆, C₇, C₈), 38.2 (NCH₂), 39.3 (C₅),

48.7 (CH₂NH), 54.6 (CH₂Ar), 57.3 (C_8a), 120.4 (C₃O, 126.3 (C₆O, 127.3, 127.5 (C₅-, C₈O, 128.9.

129.6 (C₄-, C₇0, 136.7 (C₄._a), 147.5 (C₈._a), 154.5 (C₂0, 158.0 (C₃), 173.2 (C₁).

C, 56.25; H, 6.52; N, 12.50 Found: C, 56.66; H, 6.53; N, 11.94

[00167] Example 56. 2-[6-[(2_:Quinolyl)methylamino]hexyl]-l, 3-dioxoperhydroimidazo[l, 5- a] pyridine (U).

Chromatography: ethyl acetate/methanol, 7:3. Yield: 30%; m.p. 176-188 ⁰C. H-RMN (CDCl₃, δ): 1.19-1.74 (m, 12H, -(CH₂)₄-, H_6ax, H_7aX5 H_83x, H_6ec), 1.95-2.00 (m, IH₅ H_7eo), 2.17-2.22 (m, IH, H_8ec), 2.76 (t, 2H, J= 7.1 Hz, CH₂NH), 2.81-2.86 (m, IH, H_53x), 3.06 (br s, IH, NH), 3.48 (t, 2H, J = 7.3 Hz, NCH₂), 3.72 (dd, IH, J= 11.9, 4.3 Hz, H_8a), 4.14-4.19 (m, 3H, CH₂Ar, H_5ec), 7.46 (d, IH, J= 8.5 Hz, H_3'), 7.49-7.55 (m, IH, H₆>), 7.68-7.74 (m, IH, H_7'), 7.81 (dd, IH, J= 8.2, 1.1 Hz, H₅O, 8.06 (d, J= 8.5 Hz, IH, U₄-), 8.13 (d, IH₅ J= 8.4 Hz, H₈-). ¹³C-RMN (CDCl₃, S): 22.7, 24.9, 26.3, 26.6, 27.8, 28.0, 29.0 (-(CH₂)₄-₅ C₆, C₇, C₈), 38.4 (NCH₂), 39.2 (C₅), 49.2 (CH₂NH), 54.6 (CH₂Ar), 57.2 (C_8a), 120.3 (C₃-), 126.2 (C₆-), 127.3, 127.5 (C₅-, C₈O, 128.9, 129.6 (C₄-, C₇-), 136.7 (C₄-O, 147.5 (C₈0, 154.5 (C₂-), 158.2 (C₃), 173.2 (C₁).

C, 55.87; H, 7.13; N, 11.33 Found: C, 55.77; H, 7.09; N, 10.77

[00168] Example 57. 2-[3-[[(Chroman-2-yl)methylamino]methyl]benzyl]- 1 ,3- dioxoperhydropyrrolo[l ,2-c] imidazole, Q).

Chromatography: ethyl acetate.

Yield: 40%.

¹H-RMN (CDCk δ): 1.58-2.26 (m, 6H, 2H₆, 2H₇, 2H₃.), 2.69-2.96 (m, 4H, CH₂NH, 2H₄.), 3.23

(ddd, IH₅ J = 12.5, 7.6, 5.4 Hz, H₅), 3.69 (dt, IH, J= 11.2, 7.6 Hz, H₅), 3.85 (s, 2H, CH₂Ar),

4.04-4.22 (m, 2H₅ H_7a, H₂.), 4.62 (s, 2H, NCH₂), 6.82 (t, 2H₅ J= 6.8 Hz, H₆', H₈'), 7.02-7.11 (m,

2H₅ H₅., H₇-), 7.26-7.34 (m, 4H₅ ArH).

¹³C-RMN (CDCk S): 24.7 (C₃.), 25.6 (C₄.), 27.0 (C₆), 27.5 (C₇), 42.5 (NCH₂), 45.5 (C₅), 53.5,

53.6 (2CH₂NH)₅ 63.4 (C_7a), 75.2 (C₂), 116.8 (C₈.), 120.2 (C₆-), 122.0 (C₄._a), 127.0, 127.2, 127.7,

128.2, 128.8 (C₇., phenyl), 129.5 (C₅-), 136.1, 140.7 (phenyl), 154.7 (C₈-O, 160.5 (C₃), 173.6

(C₁).

Analysis calculated for CT₄H₂₇N₃O₁-HCI-SH₂O:

C, 58.12; H₅ 6.91; N₅ 8.47 Found: C, 58.19; H₅ 6.51; N, 8.07 [00169] Example 58. 2-[4-[[(Chroman-2-yl)methylamino]methyl]benzyl]-l₅3- dioxoperhydropyrrolo[l,2-c]iniidazole, (k).

Chromatography: ethyl acetate.

Yield: 44%.

¹H-RMN TCDCl₂, δ): 1.57-2.29 (m, 6H, 2H₆, 2H₇, 2H₃.), 2.75-2.95 (m, 4H, CH₂NH, 2H₄.), 3.24

(ddd, IH, J = 12.4, 7.3, 5.4 Hz, H₅), 3.69 (dt, IH, J = 11.2, 7.6 Hz, H₅), 3.84 (s, 2H, CH₂Ar),

4.04-4.22 (m, 2H, H_7a, H₂.), 4.61 (s, 2H, NCH₂), 6.82 (t, 2H, J= 8.1 Hz, H₆-, H₈-), 7.01-7.11 (m,

2H, H₅., Hy)₅ 7.28-7.38 (m, 4H, ArH).

Analysis calculated for C₂₄H₁₇N₃OrHO^H₂O:

C, 60.31 ; H, 6.75; N, 8.79 Found: C₃ 60.71; H, 6.40; N, 8.52

Example 59

Determination of the Receptor Affinity

[00170] Biochemical studies to determine the affinity of synthesized compounds have been carried out by radioligand displacement experiments, experiments being carried out to determine the receptor affinity for the 5-HTi A, 5-HT₂A, 5-HT₃, 5-HT₄, 5-HT₇, αi and D₂ receptors. [00171] The conditions for each receptor studied is summarized in Table 1 below, while the receptor affinity data is summarized in Table 2 below.

Incubation medium:

1. MgSO₄ 5 raM and EDTA 0.5 mM in Tris-HCl 50 mM, pH 7.4

2. MgSO₄ 10 mM, EDTA 0.5 mM, ascorbic acid 0.1% and pargyline 10 μM in Tris-HCl 50 mM, pH 7.4

3. Pargyline 10 μM, ascorbic acid 0.6 mM and CaCl₂ 5 mM in Tris-HCl 50 mM, pH 7.4

4. HEPES 50 mM, pH 7.4

5. CaCl₂4 mM, ascorbic acid 1 mg/mL, pargyline 0.01 mM and (-)pindolol 3 μM in Tris- HCl 50 mM, pH 7.4

6. MgCl₂ 2.5 mM in Tris-HCl 50 mM, pH 7.4

7. NaCl 120 mM, KCl 5 mM, CaCl₂ 1 mM and ascorbic acid 5.7 mM in Tris-HCl 50 mM, pH 7.4 Table 2. Receptor affinity data obtained.

Example 60

In Vitro Functional Characterization

[00172] The functional character of the new compounds was initially determined by studying their effect on adenylate cyclase in He-La cells transfected with the 5-human HT_1A receptor, measuring their inhibiting effect on the stimulation of the enzyme induced by forskolin (Table 3 below). The compounds included in this table behaved in all cases as pure agonists, so as to reach values close to 100% of inhibition of the activation induced by forskolin. The 50 effective concentration (CE₅₀), a concentration that produces 50% of the inhibition of the increase in enzymatic activity by forskolin, was in the nanomolar range. The action of the new compounds in this test was mediated in by the 5-HT_1A receptor as can be deduced from the blocking of the effect of all compounds studied by the selective 5-HT_1A antagonist WAY-100635 (10^"8 M).

Table 3. Test on adenylate cyclase m He-La cells.

Compound CE₅₀ (nM) % Maximum Inhibition

1 16.3 94.6

2 18.9 94.5

3 31.5 89.3

4 11.6 89.6

12 76.2 87.4

[00173] The in vitro agonist character of the new compounds was also evaluated in some cases by the fixation test of [³⁵S]-GTPyS to coronal sections of rat brain. In this test, the results obtained with compounds no. 1 and no. 3, at a concentration of 10 μM, were especially similar to those obtained with the 5-HT_1A, 8-OH-DPAT agonist prototype. In the autoradiograms, an increase in intensity of the signal in the hippocampus (CAl, CA2, CA3 and dentate gyrus), thalamic nuclei, amygdaloid complex, cortex and in the mediobasal hypothalamus nuclei was observed. The increase in intensity of the marking in these cerebral areas was reduced until reaching control levels when the incubation was carried out in the presence of both the molecule under study and the selective 5-HT_1A antagonist WAY-100635 (1 μM). [00174] The five compounds included in Table 3 likewise produced hyperpolarization of the potential of the neurons of the hippocampal area CAl. By carrying out dose-effect curves, it was observed that the action of compounds no. 1 and no. 2 in this test was indistinguishable in potency to that of the 5-HT_1A, 8-OH-DPAT type agonist.

Example 61

In Vivo Functional Characterization

[00175] All compounds previously characterized in vitro as 5-HT_1A agonists (Table 3) were delivered by subcutaneous injection to mice in order to quantify the hypothermia associated to stimulation of this serotonergic receptor subtype. In all cases, a reduction in the rectal temperature of the mouse was observed of a variable duration ranging from between 30 and 120 minutes. In Table 4 below, the minimum effective doses for each compound studied and the degree of hypothermia reached at this dose are shown. The maximum hypothermic effect was reached wish doses 4-8 times higher than those indicated in this Table 4, in some cases reaching temperature decreases of 4°C.

Table 4. Mouse hypothermia test

Example 62

Determination of the In Vitro Neuroprotective Action

[00176] The neuroprotective effect of the compounds considered was studied in experimental models in vitro, using primary cultures of rat hippocampus exposed to serum deprivation, to a toxic concentration of glutamate, or incubated in conditions of hypoxia and absence of glucose. [00177] In the model of apoptotic neuronal death induced by incubation of mixed cultures of neurons and glial cells for 24 hours in a medium without serum, the neuroprotective effect of compound no. 1 is to be highlighted, with which a concentration-dependent effect was observed which was even higher (more than 40% protection) than that obtained with the 8-OH-DPAT agonist. Other compounds were also shown to be effective such as no. 4 and no. 12, although in both cases the degree of protection was somewhat below at the various concentrations used in the tests.

[00178] In the model of excitotoxic neuronal death due to exposure of the neuronal cultures to 1 mM glutamate, compound 1 was that which most effectively prevented (37%) the associated damage. Likewise, this compound showed a neuroprotective effect (>20%) in the model of neuronal death due to exposure of the cultures to a transient hypoxia situation in the absence of glucose and subsequent incubation in a 5% CO₂ atmosphere.

Example 63

Determination of the In Vivo Neuroprotective Action

[00179] The in vivo neuroprotective action was evaluated both in the transient global ischemia model in gerbils and in the permanent focal ischemia model in rats.

[00180] In the transient ischemia model in gerbils induced by temporary occlusion of both carotid arteries, the delivery of compounds no. 1 and no. 12, 30 minutes before the induction of the ischemia, and 24 and 48 hours afterwards, significantly prevented the injury induced by the ischemic process in the hippocampal area CAl, which was evaluated by Nissl stain. The neuroprotective effect was dose-dependent, between 1-5 mg/kg by subcutaneous injection, reaching, with compound no. 1, a degree of total protection of the injury in approximately half the animals at a dose of 5 mg/kg. This protection was accompanied by a hypothermic effect, likewise dependent on the dose delivered.

[00181] In the focal ischemia model due to permanent occlusion of the middle cerebral artery in the rat, the delivery of compound no. 1 by intravenous injection, 45 minutes before and 45 minutes after the occlusion, significantly reduced the volume of the infarcted area. Specifically, at a dose of 2 mg/kg, the infarction volume was reduced by more than 25%.

Example 64 Formalin Pain Assay

[00182] Groups of 10 CD-I (CrI.) derived male mice weighing 24 ± 2g were used. Test substances and vehicle (0.2% HPMC/0.9% NaCl) were administered by intraperitoneal injection 15 minutes before subplantar injection of formalin (0.02 ml, 2% solution). Reduction of the formalin-induced hind paw licking time recorded at 5-minute intervals during the following 0- to 35-minute period after formalin injection. Reduction in licking time by 50 percent or more (>50%) indicates significant analgesic activity. Statistical analysis was performed by using Oneway ANOVA followed by Dunnett's test to compare the test compound-treated groups and vehicle control. Significance is considered at P < 0.05 level. Acute toxic symptoms and autonomic effects were observed before and after formalin injection. Hunskaar, S., Fasmer O.B. and Hole, K. Formalin test in mice, a useful technique for evaluating mild analgesics. J. Neuroscience Meth. 14: 69-76, 1985. [00183] Results of formalin pain assay are displayed below:

A means pain reduction of >75%

B means pain reduction of about 40-75%

C means pain reduction of about 10-40%

deduction of pain summarized in the period of 10 to 35 minutes following formalin injection

[00184] Further results are displayed below:

about 40-75%; C means pain

10%; - means not determined. * * * * * * * * * *

[00185] The words "comprise", "comprises", and "comprising" are to be interpreted inclusively rather than exclusively.

[00186] Ail references cited above {e.g., patents, patent application publications, scientific articles) are incorporated by reference in their entirety into this patent application. Any discussion of those references is intended merely to summarize statements made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art. Applicants reserve the right to challenge the accuracy and pertinence of the cited references.

Claims

WE CLAIM:

1. A method for preventing and/or treating a condition selected from the group consisting of pain and migraine in a subject in need of such prevention and/or treatment, wherein: the method comprises administering to the subject a compound, a stereochemical isomer of the compound, or a hydrate, solvate, or pharmaceutically acceptable salt of the compound or isomer, wherein: the compound corresponds in structure to Formula I:

R₁ is selected from the group consisting of H, -(CHa)₃-, -(CHa)₄-, -CH₂-S-CH₂-, and -S-CH₂-CH₂-;

R₂ is selected from the group consisting of N and S; n is zero or 1 ;

Z is selected from the group consisting of C₂-C₁₀-alkylene, C₂-C₁₀-alkenylene, and C₂-C₁ o-alkynylene;

R₃ is selected from the group consisting of H, Ci-Cio-alkyl, aryl, and arylalkyl; m is zero, 1, or 2;

R₄ is selected from the group consisting of -O- and -CH₂-;

R₅ is selected from the group consisting of

each R₆ is independently selected from the group consisting of H, Cj-Cs-alkyl, Ci-Cs-alkoxy, OH, F₅ Cl₅ Br₅ and I;

X is selected from the group consisting of -0-, -S-, -N(H)-, and -N(CH₃)-; Y is selected from the group consisting of -O- and -N(H)-; and W is selected from the group consisting of -S- and -N(H)-.

2. The method according to Claim 1₅ wherein the subject is a human.

3. The method according to Claim 1 , wherein the condition comprises pain.

4. The method according to Claim 1, wherein the condition comprises migraine.

5. The method according to Claim 1, wherein an effective amount of the compound, isomer, hydrate, solvate, or salt is administered to the subject.

6. The method according to Claim 1, wherein: Z is QrQo-alkylene; and

R₅ is selected from the group consisting of

7. The method according to Claim 1, wherein:

Z is butylene; and

R.₅ is selected from the group consisting of

8. The method according to Claim 1, wherein R₃ is H.

9. The method according to Claim 1, wherein the compound is selected from the group consisting of:

2-[4-[(Chroman-2-yl)methylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole; 2-[4- [(Chroman-2-yl)methylamine]butyl] - 1 ,3 -dioxoperhydroimidazo [ 1 ,5-b]thiazole; 2-[4-[(Chroman-2-yl)methylamine]butyl]- 1 ,3-dioxoperhydroimidazo[l ,5-c]-thiazole; 3 - [4- [(Chroman-2-yl)methylamine]butyl] -2,4-dioxothiazolidin; 3-[5-[(Chroman-2-yl)methylamine]pentyl]-2₅4-dioxothiazolidin; 3 - [6- [(Chroman-2-yl)methylamine]hexyl] -2,4-dioxothiazolidin; 2-[4-[(Naphth-l-yl)methylamine]butyl]-l,3-dioxoperhydroρyrrolo[l,2-c]imidazole; 2-[4-[2-(Naphth-l-yl)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l₅2-c]imidazole;

3-[4-[2-(Naphth-l-yl)ethylamine]butyl]-2,4-dioxothiazolidin;

2-[4-[2-(Phenoxy)ethylamine]butyl]- 1 ,3-dioxoperhydropyrrolo[l ,2-c]imidazole;

3-[4-[2-(Phenoxy)ethylamine]butyi]-2,4-dioxothiazolidin;

2-[4-[2-(Naphth-l-oxy)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole; and

3-[4-[2-(Naphth-l-oxy)ethylamine]butyl]-2,4-dioxothiazolidin.

10. The method according to Claim 1, wherein m is zero; R₄ is CH₂; and R₅ is chromanyl.

11. The method according to Claim 1 , wherein m is 2; R₄ is O; and R₅ is phenyl or 1- naphthyl.

12. The method according to Claim 1, wherein the compound corresponds in structure to Formula III:

wherein n is 2-7; and

A is selected from the group consisting of:

13. The method according to Claim 12, wherein A is

14. The method according to Claim 13, wherein n is 2, 3, 4, or 5.

15. The method according to Claim 12, wherein A is

16. The method according to Claim 15, wherein n is 3.

17. The method according to Claim 12, wherein the compound is selected from the group consisting of:

(±)-2- [4- [(Chroman-2-yl)methylamino]butyl]- 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c]imidazole;

(±)-2-[4-[(Chroman-2-yl)methylamino]butyl]-l,3-dioxoperhydroimidazo[l,5-&]thiazole;

(+)-2-[4-[(Chroman-2-yl)methylamino]butyl]-l,3-dioxoperhydroimidazo[l,5-c]-thiazole;

(+)-3-[4-[(Chroman-2-yl)methylamino]butyl]-2,4-dioxothiazolidine;

(±)-3-[5-[(Chroman-2-yl)methylamino]ρentyl]-2,4-dioxothiazolidine;

(±)-3-[6-[(Chroman-2-yl)methylamino]hexyl]-2,4-dioxothiazolidine;

2-[4-[(Chroman-2(i?)-yl)methylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2-[5-[(Chroman-2-yl)methylamino]pentyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

2- [6- [(Chroman-2-yl)methylamino]hexyl] - 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2- [3 - [(Chroman-2-yl)methylamino]propyl]- 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole; and

2-[4-[(Chroman-2(5)-yl)methylamino]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole.

18. The method according to Claim 1, wherein the compound corresponds in structure to Formula IV:

Formula IV wherein n is 2-7; and A is selected from the group consisting of:

19. The method according to Claim 18, wherein A is

20. The method according to Claim 19, wherein n is 3 or 7.

21. The method according to Claim 20, wherein R₆ is Ci-C₄-alkoxy in ortho position of the phenyl ring.

22. The method according to Claim 18, wherein A is

23. The method according to Claim 22, wherein n is 3.

24. The method according to Claim 22, wherein R₆ is Cj-C₄-alkoxy in ortho position of the phenyl ring.

25. The method according to Claim 18, wherein the compound is selected from the group consisting of:

2-[4-[2-(Phenoxy)ethylamine]butyl]-l,3-dioxoperhydropyrrolo[l,2-c]imidazole;

3-[4-[2-(Phenoxy)ethylamine]butyl]-2,4-dioxothiazolidin;

2- [4- [2-(o-Methoxyphenoxy)ethylamino]butyl]- 1 ,3 -dioxoperhydropyrrolo [ 1 ,2-c] imidazole;

2-[4-[2-(o-Ethoxyphenoxy)ethylamino]butyl]-l,3-dioxoperhydropyrrolo[l₃2-c]imidazole;

2-[A- [2-(o-Isopropoxyphenoxy)ethylamino] butyl] -1,3 -dioxoperhydropyrrolo [ 1 ,2-c]

3-[4-[2-(o-Ethoxyphenoxy)ethylamino]butyl]-2,4-dioxothiazolidine;

3-[6-[2-(o-Ethoxyphenoxy)ethylamino]hexyl]-2,4-dioxothiazolidine;

3-[8-[2-(o-Ethoxyphenoxy)ethylamino]octyl]-2,4-dioxothiazolidine;

2-[4-[2-(o-Ethoxyphenoxy)ethylamino]butyl]-l_J3-dioxoperhydroimidazo[l,5-α]pyridine; and

2-[6-[2-(o-Ethoxyphenoxy)ethylamino]hexyl]-l,3-dioxoperhydroimidazo[l,5-α]pyridine.

26. The method according to Claim 1 , wherein the compound corresponds in structure to Formula V:

Formula V wherein n is 2-7; and A is selected from the group consisting of:

27. The method according to Claim 26, wherein A is

28. The method according to Claim 26, wherein n is 3.

29. The method according to Claim 26, wherein the compound is 2-[4-[2-(Naphth~ I -oxy)ethylamine]butyl] - 1 ,3 -dioxoperhydropyrrolo [1 ,2-c]imidazole or 3-[4-[2-(Naphth-l-oxy)ethylamine]butyl]-2₅4-dioxothiazolidin.

30. The method according to Claim 1, wherein the pain is chronic pain.

31. The method according to Claim 30, wherein the pain is chronic inflammatory and/or chronic neuropathic pain.