PERHYDROQUINOXALINE DERIVATIVES

The present invention relates to perhydroquinoxaline derivatives and medicaments containing perhydroquinoxaline derivatives.

Treatment of pain is of great importance in medicine. Analgesic agents as a rule act by activating opioid receptors. Conventional opioids, such as morphine, are thus opioid analgesics which are often employed in clinical pain therapy because of their potent analgesic action. These activate the μ receptor. However, undesirable side effects of such pain therapy are sometimes considerable centrally mediated side effects, such as respiratory depression, vomiting and bradycardia. Possible psycho-dependencies are furthermore a disadvantage.

In view of the great importance of opioids in treating different types of pain and diseases associated with pain, there is a great need for new active compounds suitable to treat side effects of opioid adminstration (commonly also called "(analgesic) opioid induced side effects").

WO2009/080745 relates to perhydroquinoxaline derivatives useful as analgesic agents. The invention was based on the object to provide novel compounds which can be used as pharmaceutical active compounds, in particular for treating and/or preventing analgesic opioid induced side effects.

This object is achieved by the provision of perhydroquinoxaline compounds according to the general formula (I) as shown below or a solvate or hydrate thereof or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ is chosen from the group comprising H; Ci-Cio-alkyl; C ₃ -Cio-cycloalkyl; (COO(Ci-Cio-alkyl);

phenylalkyl with Ci-C ₆ -alkyl, wherein the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C ₆ - alkyloxy, NH ₂ , NH(C C ₅ -alkyl), N(C C ₅ -alkyl) ₂ , OH, S0 ₂ (CrC ₅ -alkyl), SO(C C ₅ -alkyl), CF ₃ , CN, N0 ₂ , S0 ₂ N(Ci-C ₅ -alkyl) ₂ , S0 ₂ NH ₂ , S0 ₂ NH(Ci-C ₅ -alkyl), S0 ₂ NH(aryl), S0 ₂ NH(phenyl) and/or S0 ₂ NH(heteroaryl);

Ci-Cio-acyl; heterocyclylacyl containing one, two, three or four hetero atoms chosen from the group comprising NH, O and/or S; phenylacyl, wherein the acyl radical is a Ci-C ₆ -acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C ₆ -alkyloxy, COO(Ci-C ₆ - alkyl), NH ₂ , NH(Ci-C ₅ -alkyl), N(Ci-C ₅ -alkyl) ₂ , CONH ₂ , CONH(Ci-C ₆ -alkyl), CON(Ci-C ₆ - alkyl) ₂ , OH, S0 ₂ (Ci-C ₅ -alkyl), SO(Ci-C ₅ -alkyl), CF ₃ , CN, N0 ₂ , S0 ₂ N(Ci-C ₅ -alkyl) ₂ , S0 ₂ NH ₂ , S0 ₂ NH(C C ₅ -alkyl), S0 ₂ NH(aryl), S0 ₂ NH(phenyl) and/or S0 ₂ NH(heteroaryl);

mono-, bi- or tricyclic heteroaryl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S;

mono-, bi- or tricyclic heteroarylalkyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the alkyl radical is a Ci-C ₆ alkyl radical;

mono-, bi- or tricyclic heteroarylacyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the acyl radical is a Ci-C ₆ - acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C ₆ -alkyloxy, COO(Ci-C ₆ -alkyl), NH ₂ , NH(C C ₅ -alkyl), N(CrC ₅ -alkyl) ₂ , CONH ₂ , CONH(C C ₆ -alkyl), CON(C C ₆ -alkyl) ₂ , OH, CF ₃ , CN, N0 ₂ , and/or S0 ₂ NH ₂ ;

mono-, bi- or tricyclic (heteroaryl) alkenylacyl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S, wherein the acyl radical is a Ci-C ₆ -acyl radical and the alkenyl radical is a C ₂ -C ₆ -alkenyl radical;

C(0)NH(C Cio-alkyl); C(O)N(C ₁ -C ₁₀ -alk l) ₂ , wherein the two alkyl radicals may form a saturated substituted or unsubstituted ring with the N atom; C(0)NH(aryl); C(0)NH(benzyl); C(O)(C ₃ -Ci ₀ -cycloalkyl); COO(aryl); COO(benzyl); COO(C ₃ -Ci ₀ - cycloalkyl);

(CH ₂ ) _g -COOH, wherein g is 1, 2, 3 or 4; (CH ₂ ) _h -COO(Ci-C ₆ -alkyl), wherein h is 1, 2, 3 or 4; (CH ₂ )i-CONH ₂ , wherein i is 1, 2, 3 or 4;

C(0)NH-(CH ₂ ) _j -COOH, wherein j is 0, 1, 2, 3 or 4; C(0)NH-(CH ₂ ) _k -COO(Ci-

C ₆ -alkyl), wherein k is 0, 1, 2, 3 or 4; C(0)NH-(CH ₂ )i-CONH ₂ , wherein 1 is 0, 1, 2, 3 or 4;

COO-(CH ₂ ) _m -COOH, wherein m is 0, 1, 2, 3 or 4; COO-(CH ₂ ) _n -COO(C C ₁₀ - alkyl), wherein n is 0, 1, 2, 3 or 4; COO-(CH ₂ ) _p -C(0)NH ₂ , wherein p is 0, 1, 2, 3 or 4; C(O)- (CH ₂ ) _q -COOH, wherein q is 0, 1, 2, 3 or 4; C(O)-(CH ₂ ) _r -COO(Ci-Ci ₀ -alkyl), wherein r is 0, 1, 2, 3 or 4; C(0)-(CH ₂ ) _s -C(0)NH ₂ , wherein s is 0, 1, 2, 3 or 4; C(0)-(CH ₂ ) _t -C(0)NH(C ₁ -C ₆ - alkyl), wherein t is 0, 1, 2, 3 or 4; C(0)-(CH ₂ ) _u -C(0)N(C C ₆ -alkyl) ₂ , wherein u is 0, 1, 2, 3 or 4;

C(0)-(CH ₂ ) _v -NH ₂ , wherein v is 0, 1, 2, 3 or 4; C(0)-(CH ₂ ) _w -OR', wherein w is 0, 1, 2, 3 or 4 and R' is H or C C ₆ -acyl; C(0)-(CH ₂ ) _x -C(0)NH-(CH ₂ ) _y C(0)NH ₂ , wherein x is 0, 1, 2 or 3 and wherein y is 0, 1, 2 or 3;

S0 ₂ (Ci-C ₆ -alkyl); S0 ₂ -(CH ₂ ) _z -heteroaryl, wherein z is 0, 1, 2 or 3; S0 ₂ (CH ₂ ) _a - heterocyclyl, wherein a is 0, 1, 2 or 3 and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising halogen, OH, CN, oxo and/or Ci-C ₆ -alkoxy; S0 ₂ N(Ci-C ₆ -alkyl) ₂ or S0 ₂ NH(Ci-C ₆ -alkyl), wherein the alkyl radical can be substituted by halogen, Ci-C4-alkoxy and/or OH; S0 ₂ NH(C ₃ -C ₆ - cycloalkyl); S0 ₂ NH-C(0)0(C ₁ -C ₆ -alkyl);

R 2 , R 3 are in each case identical or independent of each other and are chosen from the group comprising H; Ci-Cio-alkyl; C ₃ -Cio-cycloalkyl,

or

R 2 and R 3 form, together with the nitrogen to which they are bonded, a saturated or unsaturated 3- to 8-membered N-heterocycle, wherein this can be substituted by one or more identical or different groups chosen from the group comprising halogen, OH, Cp C ₄ -alkyloxy, COOH, COO(C C ₁₀ -alkyl), CONH ₂ , CONH(C C ₁₀ -alkyl), CON(C C ₁₀ - alkyl) ₂ , CN, and/or 0-C(0)(Ci-C ₆ alkyl); A is chosen from the group comprising (CH ₂ ) _b , wherein b is 0, 1, 2, 3, 4, 5, or 6;

C ₂ -C5 alkylene, which can be substituted by at least one C ₁ -C3 alkyl radical; O; S; NH and/or aryl; Z is chosen from the group comprising H; NH ₂ ; COOH; COO(Ci-Cs-alkyl);

CH(NH ₂ )COOH; Ci-C ₆ -acyl;

phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising halogen, C C ₅ -alkyl, C C ₅ -alkoxy, NH ₂ , NH(C C ₅ -alkyl), N(C C ₅ - alkyl) ₂ , OH, S0 ₂ (Ci-C ₅ -alkyl), SO(Ci-C ₅ -alkyl), CF ₃ , CN, N0 ₂ , S0 ₂ N(Ci-C ₅ -alkyl) ₂ , SO ₂ NH ₂ , S0 ₂ NH(Ci-C ₅ -alkyl), S0 ₂ NH(aryl), S0 ₂ NH(phenyl) and/or S0 ₂ NH(heteroaryl), wherein the substituents may form a ring;

a mono- or bicyclic aryl or heteroaryl containing one or two hetero atoms chosen from the group comprising N, O and/or S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising halogen, Ci-C ₄ -alkoxy, NH ₂ , NH(Ci-C ₅ -alkyl), N(Ci-C ₅ -alkyl) ₂ , OH, S0 ₂ (Ci-C ₅ -alkyl), SO(Ci-C ₅ -alkyl), CF ₃ , CN, N0 ₂ , S0 ₂ N(Ci-C ₅ -alkyl) ₂ , S0 ₂ NH ₂ , S0 ₂ NH(Ci-C ₅ -alkyl), S0 ₂ NH(aryl), S0 ₂ NH(phenyl) and/or S0 ₂ NH(heteroaryl).

The perhydroquinoxaline compounds of formula (1) according to the invention are named following the IUPAC nomenclature. In addition, the stereochemistry of the compounds of formula (1) follow the CIP nomenclature (Cahn-Ingold-Prelog) and may be specified as (4aS,5R,8aR) as long as the radical R ¹ has the highest priority. Alternatively, if the priority under IUPAC of the C(0)AZ moiety is higher than the one of R ¹ the stereochemistry is defined as (4aR,8R,8aS). In the following general description, in the absence of any definition to the contrary, whenever the stereochemistry of the compounds of formula (1) in general is referred to, it is assumed that the radical R ¹ has the highest priority and, thus, the (4aS,5R,8aR) definition applies. Consequently, the enantiomer of the compounds of formula (1) is referred to as the (4aR,5S,8aS) form. It has been found, surprisingly, that the compounds according to the invention have an improved action in treating and/or preventing analgesic opioid induced side effects and diseases having the same or similar symptoms (i.e. the same or a similar pathology). Without wishing to be bound by a particular theory, it is assumed that not only the perhydroquinoxaline ring structure of the compounds according to the invention has a considerable influence on the advantageous properties of the compounds, but in particular the specific stereochemistry in the perhydroquinoxaline ring structure as shown in formula (1). In particular, the compounds according to the invention have been shown to act as μ opioid receptor antagonists. This action is assumed to be responsible for the pharmaceutical efficacy.

In the context of the present invention, unless stated otherwise, the term "heteroaryl" is to be understood as meaning mono-, bi- or tricyclic heteroaryl containing one, two, three or four hetero atoms chosen from the group comprising N, O and/or S.

Preferred heteroaryl radicals are chosen from the group comprising pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, pyridazinyl, 1,3,5-triazinyl, quinolyl, isoquinolyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, thiazolyl, oxazolyl, isoxazolyl, oxazolidinyl, pyrrolyl, carbazolyl, indolyl, isoindolyl, furyl, benzofuryl, benzofuranyl, 1,3-benzodioxolyl, thienyl and/or benzothienyl.

The term "Ci-Cio-alkyl" according to the invention includes, unless stated otherwise, straight- chain, branched or cyclic alkyl groups, preferably chosen from the group comprising methyl, ethyl, n-/i-propyl, n-/i-/tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl and/or decyl.

The term "heterocyclyl" according to the invention includes saturated, mono- or diunsaturated cyclic alkyl radicals having 3 to 10 carbon atoms that contain one, two, three or four hetero atoms chosen from the group comprising NH, O and/or S. Ci-C6-alkoxy groups according to the invention are preferably chosen from the group comprising methoxy, ethoxy, linear or branched propoxy and/or butoxy. The term "halogen" according to the invention includes fluorine, chlorine, bromine and iodine, fluorine or chlorine being preferred, in particular chlorine.

The term "aryl" according to the invention includes aromatic radicals having 6 to 20 carbon atoms, preferably phenyl, naphthyl, indenyl, and biphenyl. The term "aryl" also includes carbocycles.

In the context of the present invention, if not indicated otherwise, the term "acyl" means "Cr Cio-acyl", namely including the groups HC(O)- (formyl) and (Ci-Cc))-C(0)-, wherein (C1-C9) means linear, branched or cyclic alkyl or alkenyl groups. HC(O)- (formyl) and CH ₃ -C(0)- (acetyl) are preferred.

In preferred embodiments of the compounds of formula (1) the residues R 1 , R 2 , R 3 and Z are as defined in the dependent claims 2 to 5.

Preferably in the compound according general formula (1)

R ¹ is chosen from the group comprising H; Ci-C ₃ -alkyl; COO(Ci-C ₄ -alkyl);

benzyl;

Ci-C ₄ -acyl; C(0)(C ₄ -C6-cycloalkyl); heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Ci-acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(C C ₃ -alkyl) and CONH ₂ ;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

mono-cyclic heteroarylalkyl containing one or two hetero atom chosen from the group of N, O and S, wherein the alkyl radical is a C1-C3 alkyl radical;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(Ci-C ₃ -alkyl) and CONH ₂ ;

mono-cyclic (heteroaryl) alkenylacyl containing one hetero atom chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the alkenyl radical is a C ₂ -C ₄ - alkenyl radical; C(0)NH(Ci-C ₃ -alkyl); C(0)N(Ci-C ₃ -alkyl) ₂ , wherein the two alkyl radicals may form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH(phenyl); C(0)NH(benzyl); C(0)(C ₃ -C ₆ -cycloalkyl); COO(benzyl);

(CH ₂ ) _g -COOH, wherein g is 1, 2, 3 or 4; (CH ₂ ) _h -COO(C C ₆ -alkyl), wherein h is 1, 2, 3 or 4; (CH ₂ )i-CONH ₂ , wherein i is 1, 2, 3 or 4;

C(0)NH-(CH ₂ ) _j -COOH, wherein j is 0 or 1; C(0)NH-(CH ₂ ) _k -COO(Ci-C ₃ - alkyl), wherein k is 0 or 1; C(0)NH-(CH ₂ ) _r CONH ₂ , wherein 1 is 0 or 1;

COO-(CH ₂ ) _m -COOH, wherein m is 0 or 1; COO-(CH ₂ ) _n -COO(C C ₃ -alkyl), wherein n is 0 or 1; COO-(CH ₂ ) _p -C(0)NH ₂ , wherein p is 0 or 1; C(0)-(CH ₂ ) _q -COOH, wherein q is 0 or 1; C(0)-(CH ₂ ) _r -COO(Ci-C ₃ -alkyl), wherein r is 0 or 1; C(0)-(CH ₂ ) _s - C(0)NH ₂ , wherein s is 0 or 1; C(0)-(CH ₂ ) _t -C(0)NH(C C ₃ -alkyl), wherein t is 0 or 1; C(O)- (CH ₂ ) _u -C(0)N(C C ₃ -alkyl) ₂ , wherein u is 0 or 1;

C(0)-(CH ₂ ) _v -NH ₂ , wherein v is 0 or 1 ; C(0)-(CH ₂ ) _w -OR', wherein w is 0 or 1 and R' is H or C acyl; C(0)-(CH ₂ ) _x -C(0)NH-(CH ₂ ) _y C(0)NH ₂ , wherein x is 0 or 1 and wherein y is 0 or 1 ;

S0 ₂ (Ci-C ₆ -alkyl); S0 ₂ -(CH ₂ ) _z -heteroaryl, wherein z is 0 or 1; S0 ₂ (CH ₂ ) _a - heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C ₃ -alkoxy; S0 ₂ N(Ci-C ₃ - alkyl) ₂ or S0 ₂ NH(Ci-C ₃ -alkyl), wherein the alkyl radical can be substituted by F, CI, Ci-C ₃ - alkoxy and/or OH; S0 ₂ NH(C ₃ -C ₆ -cycloalkyl); S0 ₂ NH-C(0)0(C C ₃ - alkyl);

R 2 , R 3 are identical or different and are chosen from the group comprising H, methyl, ethyl, n-propyl, and i-propyl,

or

R 2 and R 3 form, together with the nitrogen to which they are bonded, a saturated or mono-unsaturated 4- to 6-membered N-heterocycle, wherein this can be substituted by one or more identical or different groups chosen from the group comprising F, CI, OH, CONH ₂ , CN, and/or 0-C(0)(C C ₃ alkyl);

A is (CH ₂ )b, wherein b is 1;

Z is chosen from the group comprising phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C3-alkyl, Ci-C3-alkoxy, OH, CF ₃ , and N0 ₂ , wherein two OH substituents may be connected by an ether bridge to form a ring or wherein two Ci-C ₃ -alkyl groups may be connected to form a saturated ring; and

a mono- or bicyclic aryl or heteroaryl containing one hetero atom chosen from the group of N and S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C ₃ -alkyl, Ci-C ₃ - alkoxy, OH, CF ₃ , and N0 ₂ . More preferably in the compound according to general formula (1):

R ¹ is chosen from the group consisting of

Ci-acyl (formyl); heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Ci-acyl radical and the phenyl radical is substituted by one or more of COO(C C ₃ -alkyl) and CONH ₂ ;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the heteroaryl radical is substituted by one or more of COO(Ci-C ₃ -alkyl) and CONH ₂ ;

mono-cyclic (heteroaryl) alkenylacyl containing one hetero atom chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the alkenyl radical is a C ₂ -C ₄ - alkenyl radical;

C(0)NH(C C ₃ -alkyl); C(0)N(C C ₃ -alkyl) ₂ , wherein the two alkyl radicals form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH (phenyl); C(0)NH(benzyl); COO(benzyl);

(CH ₂ ) _g -COOH, wherein g is 1, 2, 3 or 4; (CH ₂ ) _h -COO(Ci-C ₆ -alkyl), wherein h is 1, 2, 3 or 4; (CH ₂ )i-CONH ₂ , wherein i is 1, 2, 3 or 4;

C(0)NH-(CH ₂ ) _j -COOH, wherein j is 0 or 1; C(0)NH-(CH ₂ ) _k -COO(C C ₃ - alkyl), wherein k is 0 or 1; C(0)NH-(CH ₂ ) _r CONH ₂ , wherein 1 is 0 or 1;

COO-(CH ₂ ) _m -COOH, wherein m is 0 or 1; COO-(CH ₂ ) _n -COO(C C ₃ -alkyl), wherein n is 0 or 1; COO-(CH ₂ ) _p -C(0)NH ₂ , wherein p is 0 or 1; C(0)-(CH ₂ ) _s -C(0)NH ₂ , wherein s is 0 or 1; C(0)-(CH ₂ ) _t -C(0)NH(Ci-C ₃ -alkyl), wherein t is 0 or 1; C(0)-(CH ₂ ) _u - C(0)N(Ci-C ₃ -alkyl) ₂ , wherein u is 0 or 1;

C(0)-(CH ₂ ) _v -NH ₂ , wherein v is 1 ; C(0)-(CH ₂ ) _w -OR', wherein w is 1 and R' is

H or Ci-acyl; S0 ₂ (Ci-C ₆ -alkyl); S0 ₂ -(CH ₂ ) _z -heteroaryl, wherein z is 0 or 1; S0 ₂ (CH ₂ ) _a - heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C ₃ -alkoxy; S0 ₂ N(Ci-C ₃ - alkyl) ₂ or S0 ₂ NH(Ci-C ₃ -alkyl), wherein the alkyl radical can be substituted by F, CI, C ₁ -C ₃ - alkoxy and/or OH; S0 ₂ NH(C ₃ -C ₆ -cycloalkyl); S0 ₂ NH-C(0)0(Ci-C ₃ - alkyl);

R 2 , R 3 are identical or different and are chosen from the group comprising H, methyl, ethyl, n-propyl, and i-propyl,

or

R 2 and R 3 form, together with the nitrogen to which they are bonded, a saturated or mono-unsaturated 4- to 6-membered N-heterocycle, wherein this can be substituted by one or more identical or different groups chosen from the group comprising F, CI, OH, CONH ₂ , CN, and/or 0-C(0)(C C ₃ alkyl);

A is (CH ₂ )b, wherein b is 1;

Z is chosen from the group comprising

phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy, OH, CF ₃ , and N0 ₂ , wherein two OH substituents may be connected by an ether bridge to form a ring or wherein two C ₁ -C ₃ - alkyl groups may be connected to form a saturated ring; and

a mono- or bicyclic aryl or heteroaryl containing one hetero atom chosen from the group of N and S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C ₃ -alkyl, C ₁ -C ₃ - alkoxy, OH, CF ₃ , and N0 ₂ .

Particularly preferably in the compound according to general formula (1):

R ¹ is chosen from the group comprising H; Ci-C ₃ -alkyl; COO(Ci-C4-alkyl);

benzyl;

Ci-C ₄ -acyl; C(0)(C ₄ -C6-cycloalkyl); heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Ci-acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(Ci-C ₃ -alkyl) and CONH ₂ ;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

mono-cyclic heteroarylalkyl containing one or two hetero atom chosen from the group of N, O and S, wherein the alkyl radical is a Ci-C ₃ alkyl radical;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(Ci-C ₃ -alkyl) and CONH ₂ ;

mono-cyclic (heteroaryl) alkenylacyl containing one hetero atom chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the alkenyl radical is a C ₂ -C ₄ - alkenyl radical;

C(0)NH(C C ₃ -alkyl); C(0)N(C C ₃ -alkyl) ₂ , wherein the two alkyl radicals may form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH(phenyl); C(0)NH(benzyl); C(0)(C ₃ -C ₆ -cycloalkyl); COO(benzyl);

(CH ₂ ) _g -COOH, wherein g is 1, 2, 3 or 4; (CH ₂ ) _h -COO(C C ₆ -alkyl), wherein h is 1, 2, 3 or 4; (CH ₂ )i-CONH ₂ , wherein i is 1, 2, 3 or 4;

C(0)NH-(CH ₂ ) _j -COOH, wherein j is 0 or 1; C(0)NH-(CH ₂ ) _k -COO(Ci-C ₃ - alkyl), wherein k is 0 or 1 ; C(0)NH-(CH ₂ )i-CONH ₂ , wherein 1 is 0 or 1 ;

COO-(CH ₂ ) _m -COOH, wherein m is 0 or 1; COO-(CH ₂ ) _n -COO(C C ₃ -alkyl), wherein n is 0 or 1; COO-(CH ₂ ) _p -C(0)NH ₂ , wherein p is 0 or 1; C(0)-(CH ₂ ) _q -COOH, wherein q is 0 or 1; C(0)-(CH ₂ ) _r -COO(Ci-C ₃ -alkyl), wherein r is 0 or 1; C(0)-(CH ₂ ) _s - C(0)NH ₂ , wherein s is 0 or 1; C(0)-(CH ₂ ) _t -C(0)NH(Ci-C ₃ -alkyl), wherein t is 0 or 1; C(O)- (CH ₂ ) _u -C(0)N(Ci-C ₃ -alkyl) ₂ , wherein u is 0 or 1 ;

C(0)-(CH ₂ ) _v -NH ₂ , wherein v is 0 or 1 ; C(0)-(CH ₂ ) _w -OR', wherein w is 0 or 1 and R' is H or C acyl; C(0)-(CH ₂ ) _x -C(0)NH-(CH ₂ ) _y C(0)NH ₂ , wherein x is 0 or 1 and wherein y is 0 or 1 ;

S0 ₂ (C C ₆ -alkyl); S0 ₂ -(CH ₂ ) _z -heteroaryl, wherein z is 0 or 1; S0 ₂ (CH ₂ ) _a - heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C ₃ -alkoxy; S0 ₂ N(Ci-C ₃ - alkyl) ₂ or S0 ₂ NH(Ci-C ₃ -alkyl), wherein the alkyl radical can be substituted by F, CI, C ₁ -C3- alkoxy and/or OH; S0 ₂ NH(C ₃ -C ₆ -cycloalkyl); S0 ₂ NH-C(0)0(Ci-C ₃ - alkyl);

2 3

R and R form, together with the nitrogen to which they are bonded, a mono- unsaturated 6-membered N-heterocycle, that may be substituted by one or more of F, CI, OH, CONH ₂ , CN, and/or 0-C(0)(Ci-C ₃ alkyl);

A is (CH ₂ ) _b , wherein b is 1; Z is chosen from the group comprising

phenyl, which can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy, OH, CF ₃ , and N0 ₂ , wherein two OH substituents may be connected by an ether bridge to form a ring or wherein two Ci-C ₃ - alkyl groups may be connected to form a saturated ring; and

a mono- or bicyclic aryl or heteroaryl containing one hetero atom chosen from the group of N and S, wherein the aryl or heteroaryl group can be substituted by one or more identical or different groups chosen from the group comprising F, CI, Ci-C ₃ -alkyl, Ci-C ₃ - alkoxy, OH, CF ₃ , and N0 ₂ . Particularly preferably in the compound according to general formula (1):

R ¹ is chosen from the group comprising H; Ci-C ₃ -alkyl; COO(Ci-C4-alkyl);

benzyl;

Ci-C ₄ -acyl; C(0)(C ₄ -C6-cycloalkyl); heterocyclylacyl containing NH or O in the ring; phenylacyl, wherein the acyl radical is a Ci-acyl radical and the phenyl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(C C ₃ -alkyl) and CONH ₂ ;

mono-cyclic heteroaryl containing one hetero atom chosen from the group of

N, O and S;

mono-cyclic heteroarylalkyl containing one or two hetero atom chosen from the group of N, O and S, wherein the alkyl radical is a Ci-C ₃ alkyl radical;

mono-cyclic heteroarylacyl containing one or two hetero atoms chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the heteroaryl radical can be substituted by one or more identical or different groups chosen from the group comprising COO(Ci-C ₃ -alkyl) and CONH ₂ ;

mono-cyclic (heteroaryl)alkenylacyl containing one hetero atom chosen from the group of N, O and S, wherein the acyl radical is a Ci-acyl radical and the alkenyl radical is a C ₂ -C ₄ - alkenyl radical;

C(0)NH(Ci-C ₃ -alkyl); C(0)N(Ci-C ₃ -alkyl) ₂ , wherein the two alkyl radicals may form a saturated halogen substituted or unsubstituted ring with the N atom; C(0)NH(phenyl); C(0)NH(benzyl); C(0)(C ₃ -C ₆ -cycloalkyl); COO(benzyl);

(CH ₂ ) _g -COOH, wherein g is 1, 2, 3 or 4; (CH ₂ ) _h -COO(Ci-C ₆ -alkyl), wherein h is 1, 2, 3 or 4; (CH ₂ )i-CONH ₂ , wherein i is 1, 2, 3 or 4;

C(0)NH-(CH ₂ ) _j -COOH, wherein j is 0 or 1; C(0)NH-(CH ₂ ) _k -COO(C C ₃ - alkyl), wherein k is 0 or 1; C(0)NH-(CH ₂ ) _r CONH ₂ , wherein 1 is 0 or 1;

COO-(CH ₂ ) _m -COOH, wherein m is 0 or 1; COO-(CH ₂ ) _n -COO(C C ₃ -alkyl), wherein n is 0 or 1; COO-(CH ₂ ) _p -C(0)NH ₂ , wherein p is 0 or 1; C(0)-(CH ₂ ) _q -COOH, wherein q is 0 or 1; C(0)-(CH ₂ ) _r -COO(Ci-C ₃ -alkyl), wherein r is 0 or 1; C(0)-(CH ₂ ) _s - C(0)NH ₂ , wherein s is 0 or 1; C(0)-(CH ₂ ) _t -C(0)NH(Ci-C ₃ -alkyl), wherein t is 0 or 1; C(O)- (CH ₂ ) _u -C(0)N(C C ₃ -alkyl) ₂ , wherein u is 0 or 1;

C(0)-(CH ₂ ) _v -NH ₂ , wherein v is 0 or 1 ; C(0)-(CH ₂ ) _w -OR', wherein w is 0 or 1 and R' is H or Ci-acyl; C(0)-(CH ₂ ) _x -C(0)NH-(CH ₂ ) _y C(0)NH ₂ , wherein x is 0 or 1 and wherein y is 0 or 1 ;

S0 ₂ (C C ₆ -alkyl); S0 ₂ -(CH ₂ ) _z -heteroaryl, wherein z is 0 or 1; S0 ₂ (CH ₂ ) _a - heterocyclyl, wherein a is 0 or 1, wherein the heteroatoms are O, N, and/or S and wherein the heterocyclyl residue may be substituted by one or more identical or different substituents chosen from the group comprising F, CI, OH, CN, oxo and/or Ci-C ₃ -alkoxy; S0 ₂ N(Ci-C ₃ - alkyl) ₂ or S0 ₂ NH(Ci-C ₃ -alkyl), wherein the alkyl radical can be substituted by F, CI, Ci-C ₃ - alkoxy and/or OH; S0 ₂ NH(C ₃ -C ₆ -cycloalkyl); S0 ₂ NH-C(0)0(C C ₃ - alkyl);

R 2 , R 3 are identical or different and are chosen from the group comprising H, methyl, ethyl, n-propyl, and i-propyl,

or

R 2 and R 3 form, together with the nitrogen to which they are bonded, a saturated or mono-unsaturated 4- to 6-membered N-heterocycle, wherein this can be substituted by one or more identical or different groups chosen from the group comprising F, CI, OH, CONH ₂ , CN, and/or 0-C(0)(Ci-C ₃ alkyl);

A is (CH ₂ )b, wherein b is 1;

Z is either a tetrahydronaphthyl or a 2,3-dihydrobenzo-l,4-dioxinyl residue, optionally substituted by one or more of F, CI, Ci-C ₃ -alkyl, Ci-C ₃ -alkoxy, OH, CF ₃ , and N0 ₂ .

Particularly preferred radicals R ¹ according to the invention are as follows:

Particularly preferred radicals NR 2 R 3 according to the invention are as follows:

Particularly preferred radicals Z according to the invention are as follows: Without being bound by a particular theory, it is assumed that the action of the compounds according to the invention is not only based on the steric action of the perhydroquinoxaline group, in particular in combination with the structural element R ¹ , but even more on the specific cis-trans stereochemistry and the (4aS,5R,8aR) form of the compounds as indicated in formula (1). Reference is made to the Biological Assay section of the application.

The compounds according to the invention can furthermore be used in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular their hydrates.

The pharmaceutically acceptable salts can be base addition salts. These include salts of the compounds according to the invention with inorganic bases, such as alkali metal hydroxides, alkaline earth metal hydroxides, or with organic bases, such as mono-, di- or triethanolamine. Acid addition salts, in particular with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, or with amino acids, can further advantageously be used.

Pharmaceutically acceptable salts of the compounds according to the invention are chosen, for example, from the group comprising chlorides, bromides, iodides, hydrochlorides, hydrobromides, sulfonates, methanesulfonates, sulfates, hydrogen sulfates, sulfites, hydrogen sulfites, phosphates, nitrates, methanoates, acetates, proprionates, lactates, citrates, glutarates, maleates, malonates, malates, succinates, tartrates, oxalates, fumarates, benzoates, p- toluenesulfonates and/or salts of amino acids, preferably the proteinogenic amino acids.

The compounds according to the invention are suitable for use as medicaments.

The compounds according to the invention can be used in particular for therapeutic and/or prophylactic treatment of side effects associated with opioid administration (opioid induced side effects) and diseases having the same or similar symptoms.

The side effects and/or diseases to be treated according to the invention preferably are selected from gastrointestinal dysfunction, inhibition of intestinal motility, constipation, GI sphincter constriction, nausea, emesis, biliary spasm, opioid bowel dysfunction, colic, dysphoria, pruritus, urinary retention, depression of respiration, papillary constriction, cardiovascular effects, chest wall rigidity and cough suppression, depression of stress response, and immune suppression associated with use of narcotic analgesia, or combinations thereof.

The side effects and/or diseases to be treated according to the invention may also be selected from irritable bowel syndrome, opioid-induced bowel dysfunction, colitis, post-operative or postpartum ileus, nausea and/or vomiting, decreased gastric motility and emptying, inhibition of the stomach, and small and/or large intestinal propulsion, increased amplitude of nonpropulsive segmental contractions, constriction of sphincter of Oddi, increased anal sphincter tone, impaired reflex relaxation with rectal distention, diminished gastric, biliary, pancreatic or intestinal secretions, increased absorption of water from bowel contents, gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominal or epigastric pain and discomfort, constipation, idiopathic constipation, post-operative gastrointestinal dysfunction following abdominal surgery, and delayed absorption of orally administered medications or nutritive substances.

The compounds according to the invention may further be used as a medicament in the treatment of pain, in the treatment of inflammatory conditions such as inflammatory bowel syndrome, in the treatment of infectious diseases, in the treatment of diseases of the musculoskeletal system such as osteoporosis, arthritis, osteitis, periostitis, myopathies, treatment of autoimmune diseases and immune suppression, therapy of post-operative gastrointestinal dysfunction following abdominal surgery, idiopathic constipation, and ileus, and in the treatment of disorders such as cancers involving angiogenesis, chronic inflammation and/or chronic pain, sickle cell anemia, vascular wounds, and retinopathy.

The patients suffering from the diseases to be treated according to the invention are preferably those receiving acute opioid therapy, such as a patient suffering from post-operative gastrointestinal dysfunction receiving acute opioid administration, or a subject receiving opioids chronically such as an AIDS patient, a cancer patient, a cardiovascular patient; a subject receiving chronic opioid therapy for pain management; or a subject receiving opioid therapy for maintenance of opioid withdrawal. The compounds according to the invention can furthermore be used for treatment and/or prevention of pruritus, psoriasis, psoriatic arthritis, contact dermatitis, atopic eczema, scleroderma, systemic lupus erythematous, urticaria, lichen planus, lymphoma and/or allergies.

The compounds according to the invention or compositions containing these can be administered systemically or topically. Preferably, the compounds or compositions according to the invention are administered topically, in particular in the form of creams, ointments, plasters or tinctures.

In the context of the present invention, the term "prophylactic treatment" is understood as meaning in particular that the compounds according to the invention can be administered before symptoms of a disease occur or the risk of a disease exists.

The medicaments according to the invention may further comprise at least one opioid receptor agonist. Suitable are the opioids selected from the group consisting of alfentanil, anileridine, asimadoline, bremazocine, burprenorphine, butorphanol, codeine, CR845, dezocine, diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levomethadon. levorphanol. loperamide, meperidine ( pethidine), methadone, morphine. morphine-6-glucoronide, nalbuphine, nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papavereturn, pentazocine, pethidin. piritramid. propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol. More preferably the opioid is chosen from the group consisting of tramadol, pethidin. codein. piritramid. morphin, levomethadon. fentanyl. alfentanil.. remifentanyl and/or sufentanil.

The medicaments according to the invention may further comprise at least one steroidal antiinflammatory drug, preferably chosen from the group of hydrocortisone, hydrocortisone acetate, prednisolone, methylprednisolone, prednisone, betamethasone, hydrocortisone- 17- valerate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17- butyrate flunisolide, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate, budesonide and/or hydrocortisone- 17-butyrate and/or a nonsteroidal anti- inflammatory drug (NSAID), preferably chosen from the group of aspirin, ibuprofen, diclofenac and/or naproxen, and/or an antibiotic.

The compounds according to the invention can be administered according to conventional methods, for example orally, dermally, intranasally, transmucosally, pulmonally, enterally, buccally, rectally, intraurethral, aural, by inhalation, by means of injection, for example intravenously, parenterally, intraperitoneally, intradermally, subcutaneously, topically and/or intramuscularly and/or locally, for example on painful areas of the body. Oral administration is particularly preferred.

The compounds according to the invention can be used in particular for the preparation of medicaments by being brought into a suitable dosage form together with at least one carrier substance or auxiliary substance, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules.

Pharmaceutical dosage forms with delayed release (sustained release formulation) are furthermore preferred for oral administration of the compounds according to the invention. Examples of formulations with delayed release are sustained release matrix tablets, multilayered tablets, the coating of which can be, for example, constructed to be resistant to gastric juice, such as coatings based on shellac, sustained release capsules or formulations using biodegradable polymers, for example poly(lactic acid) polymers. Conventional physiologically acceptable pharmaceutical auxiliary substances, preferably chosen from the group comprising carrier materials, fillers, solvents, diluents, wetting agents, emulsifiers, dyestuffs, preservatives, disintegrating agents, lubricants, salts for influencing the osmotic pressure, buffer substances, aromas and/or binders, can be used for the preparation of the medicaments.

The compounds according to the invention can be prepared by a process comprising the following steps: a) reacting 5,6,7,8-tetrahydroquinoxalin-5-ol with a protection agent X-PG in the presence of a base to introduce a protecting group PG at the alcohol function, wherein X is a suitable leaving group; b) catalytically hydrogenating the PG protected 5,6,7, 8-tetrahydroquinoxalin-5-ol obtained in step a) under stereoselective reduction of the pyrazine ring to obtain PG protected cis-cis 5-hydroxy-decahydroquinoxaline; c) reacting the PG protected cis-cis 5-hydroxy-decahydroquinoxaline obtained in step b) with a reagent X-R ¹ to regioselectively introduce the substituent R ¹ at the 1-N atom of the cis-cis 5-hydroxy-decahydroquinoxaline, wherein X is a suitable leaving group; d) deprotecting the PG protected hydroxy group in the product obtained in step c) to provide for the corresponding α,β-aminoalcohol; e) reacting the α,β-aminoalcohol obtained in step d) with sulfuryl chloride in the presence of a base to provide for the corresponding 1,2,3-oxathiazolidine 2,2-dioxide; f) reacting the 1,2,3-oxathiazolidine 2,2-dioxide obtained in step e) with an amine HNR 2 R 3 , followed by treatment with an acid to introduce the residue -NR 2 R 3 under inversion of the stereogenic center to provide for cis,trans 5-amino-octahydroquinoxaline; g) reacting the cis,trans 5-amino-octahydroquinoxaline obtained in step f) with an activated species ZACOY, wherein Y is a suitable leaving group, preferably with an acid chloride Z-ACOC1, under acylation in 4-position to provide for the compound of formula (1).

By this reaction (shown in Reaction Scheme 1 below in more detail) a racemate comprising two enantiomers is formed, namely next to the (4aS,5R,8aR) form of formula (1) also the enantiomeric (4aR,5S,8aS) form is obtained. In a preferred embodiment of the invention the process further comprises the step of separating the compound of formula (1) from its enantiomeric (4aR,5S,8aS) form. The separation of the enantiomers can be carried out by known methods, in particular chromatography methods, preferably by means of high performance liquid chromatography (HPLC) or column chromatography or flash chromatography (FC), even more preferably by chiral chromatography methods, in particular chiral high performance liquid chromatography.

The separation of the enantiomers can also be carried out by reaction of a racemic mixture of an organic acid with a pure enantiomer of an acid. The diastereomeric salts formed can be separated by fractional crystallization. The splitting of the racemate is preferably carried out by reacting the racemate with an enantiomerically pure acid. The separation is then carried out by fractional recrystallization or chromatography methods, it being possible for the methods to be combined and carried out several times.

The compound of formula (1) may be obtained in enantiomerically pure (4aS,5R,8aR) form by the process described above when subjecting enantiomerically pure (S)-5, 6,7,8- tetrahydroquinoxalin-5-ol to the reaction steps a) to g). (S)-5,6,7,8-tetrahydroquinoxalin-5-ol may be obtained according to the invention by

(al) oxidizing 5,6,7,8-tetrahydroquinoxalin-5-ol to the corresponding ketone with an oxidizing agent;

(a2) subjecting the ketone obtained in step (al) to an asymmetric hydrogen transfer reaction using a hydrogenation agent and a chiral catalyst to provide for enantiomerically pure (S)-5,6,7,8-tetrahydroquinoxalin-5-ol.

This reaction is shown in Reaction Scheme 2 below in more detail. As the chiral catalyst dichloro(p-cymene)ruthenium(II) dimer with enantiomeric (lS,2S)-N-p- tosyl-l,2-diphenylethylenediamine or enantiomeric (R)-Me-CBS-oxazoborolidine as the ligand may be used.

Finally, the compounds of formula (1) obtained may be converted to pharmaceutically acceptable salts by reaction with the corresponding acid in a common way.

In the following the preparation of the compounds of formula (1) according to the present invention and of related reference compounds is described in more detail. In the schemes, preparations and examples below, various reagent symbols and abbreviations have the following meanings:

Alloc Allyloxycarbonyl

Boc tert-butoxycarbonyl

Bn benzyl

Cbz benzyloxycarbonyl

DCM dichloromethane

DIEA ethyl-diisopropylamine

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

DMS dimethylsulfide

DMSO dimethyl sulfoxide

ee enantiomeric excess

Et ₂ 0 diethyl ether

EtOAc ethyl acetate

EtOH ethanol

h hour(s)

HOAc acetic acid

m/z mass-to-charge ratio

mCPBA 3-chloroperbenzoic acid

min minute(s)

NBS N-bromosuccinimide

MeCN acetonitrile

MeOH methanol

mp melting point

MW molecular weight

PG protecting group

Ph phenyl

RT room temperature

T temperature

TBDMS tert-butyldimethylsiliyl

TEA triethylamine TFA trifluoroacetic acid

TFAA trifluoroacetic acid anhydride

THF tetrahydrofuran

TLC thin layer chromatography

tR (min) HPLC retention time

Reaction Scheme 1:

Synthesis of perhydroquinoxalines with cis,trans stereochemistry (racemates)

rac. R rac. rac.

rac.

Optionally substituted perhydroquinoxalines with cis,trans stereochemistry can be obtained as shown in Reaction Scheme 1. 5,6,7,8-Tetrahydroquinoxaline can be oxidized with a peracid such as meta-chloroperbenzoic acid in a solvent like DCM to yield the corresponding N- oxides. Acylation with a reagent such as trifluoroacetic anhydride in a solvent like DCM followed by treatment with a base like lithium hydroxide in a mixture of water and DCM yields racemic 5,6,7,8-tetrahydroquinoxalin-5-ol. The alcohol function in benzylic position can be protected with a bulky protecting group PG by reaction with a reagent X-PG such as tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of a base like 2,6-lutidine in a solvent such as DCM. A stereoselective reduction of the pyrazine ring can be achieved by hydrogenating the protected 5,6,7,8-tetrahydroquinoxalin-5-ol with 5 bar hydrogen in the presence of a catalyst like platinum dioxide in a solvent such as a mixture of acetic acid and methanol. The product with cis,cis configuration, O-protected (4aSR,5RS,8aSR)-5-hydroxy- decahydroquinoxaline, is obtained exclusively. Various substituents R ¹ can be introduced regioselectively by reacting O-protected (4aSR,5RS,8aSR)-5-hydroxy-decahydroquinoxaline with reagents X-R ¹ in an inert solvent like DCM or THF with or without a base such as triethylamine. Subsequently the hydroxy group is deprotected. A tert-butyldimethylsilyl protecting group, for example, can be removed by reaction with a reagent such as ammonium fluoride in a solvent like methanol at elevated temperature. The α,β-aminoalcohol thus obtained is reacted with sulfuryl chloride in the presence of a base like triethylamine in an inert solvent such as DCM at reduced temperature to yield the corresponding 1,2,3- oxathiazolidine 2,2-dioxide. The residue -NR 2 R 3 can be introduced by reacting optionally substituted 1,2,3-oxathiazolidine 2,2-dioxide with an amine HNR 2 R 3 in a solvent like acetonitrile at elevated temperature followed by treatment with an acid such as aqueous hydrochloric acid. The reaction takes place under inversion of the stereogenic center. Therefore, a compound with cis,trans substitution, optionally substituted (4aRS,5SR,8aSR)-5- amino-octahydroquinoxaline, is obtained exclusively. Acylation in 4-position can be performed by reacting optionally substituted (4aRS,5SR,8aSR)-5-amino- octahydroquinoxaline with a reagent Z-A-COC1 in a solvent like DCM with or without the presence of a base such as DIEA. The target compounds can be used as such or being converted to pharmaceutically acceptable salts such as a hydrochloride by reacting the free base with the corresponding acid, e.g. hydrogen chloride in diethyl ether in a suitable solvent like DCM.

R ¹ can be a protecting group, e.g. a Boc, Cbz, benzyl, allyl, Alloc group, which is orthogonal to PG and can be cleaved once the residues -NR 2 R 3 and -CO-A-Z have been introduced. Subsequent reaction with reagents X-R ¹ as described above yields the target compounds. Reaction Scheme 2:

Synthesis of enantiomerically pure perhydroquinoxalines with cis,trans stereochemistry

Enantiomerically pure, optionally substituted (4aS,5R,8aR)-octahydroquinoxalines with cis,trans stereochemistry can be obtained as shown in Reaction Scheme 2. Racemic 5,6,7,8- tetrahydroquinoxalin-5-ol can be oxidized to the corresponding ketone with a reagent such as Dess-Martin periodinane in a suitable solvent like wet DCM. Subsequently, the ketone is subjected to a asymmetric hydrogen transfer reaction with dichloro(p-cymene)ruthenium(II) dimer, (lS,2S)-N-p-tosyl-l,2-diphenylethylenediamine and triethylammonium formate in DMF to yield enantiomerically pure (S)-5,6,7,8-tetrahydroquinoxalin-5-ol. Alternatively, the reaction can be carried out using borane DMS complex or boran THF complex in the presence of (R)-Me-CBS-oxazoborolidine in a solvent like THF. All following steps are performed as described above for the racemate. Reaction Scheme 3:

Debenzylation

Optionally substituted benzyl-protected perhydroquinoxazoline can be deprotected by hydrogenation in the presence of a catalyst such as palladium on charcoal in the presence in a suitable solvent like a mixture of THF and aqueous hydrochloric acid.

Reaction Scheme 4:

Boc-deprotection

Optionally substituted Boc-protected perhydroquinoxazoline can be deprotected with trifluoroacetic acid in DCM. Alternatively, reagents such as HCl in suitable solvents like dioxane, diethyl ether and THF may be applied.

Reaction Scheme 5:

Cbz-deprotection

Optionally substituted Cbz-protected perhydroquinoxazoline can be deprotected by hydrogenation in the presence of a catalyst such as palladium on charcoal in the presence in a suitable solvent like a THF or ethyl acetate. Alternatively, the unprotected compound can be obtained by reaction with an acid like trifluoroacetic acid in the presence of a reagent such as thioanisole.

Reaction Scheme 6:

Introduction of R ¹

Optionally substituted [8-aminooctahydroquinoxalin-l(2H)-yl]ethanones obtained as described in Reaction Schemes 1 to 5 can be reacted with various reagents for introduction of R ¹ as shown in Reaction Scheme 6.

Reaction with optionally substituted acid chlorides in an inert solvent like DCM with or without a base yields compounds wherein R ¹ is chosen from Q-Qo-acyl, C3-Cio-cycloacyl, phenylacyl, heteroarylacyl, C(O)COO(C ₁ -C ₁₀ -alk l) and C(O)-(CH ₂ ) COO(C ₁ -C ₁₀ -a]k l). Carbamates in which R ¹ is selected from COO(Ci-Cio-alkyl), COO(aryl) and COO(C ₃ -d ₀ - cycloalkyl) can be obtained by reacting the starting material with the corresponding optionally substituted alkyl-, aryl- and cycloalkylchloroformates in an inert solvent such as DCM.

Compounds in which R ¹ represents Ci-Cio-alkyl, phenylalkyl and heteroarylalkyl can be obtained using two different methodologies. The corresponding optionally substituted aldehydes can be subjected to a reductive amination reaction with optionally substituted [8- aminooctahydroquinoxalin-l(2H)-yl]ethanones to yield the alkylated compounds. The reaction is performed in a suitable solvent like MeOH in the presence of a reducing agent like NaBH ₃ CN with pH adjustment by concentrated acetic acid. Alternatively, above mentioned residues can also be introduced in an alkylation reaction using appropriate optionally substituted Ci-Cio-alkylhalogenides, C ₃ -Cio-cycloalkylhalogenides, phenylalkylhalogenides and heteroarylalkylhalogenides. Alkylation reactions can be conducted in a solvent like MeCN in the presence of a base such as NaHC0 ₃ or in a solvent like DCM or chloroform in the presence of a base such as DIEA.

2 3 1

If NR R contains functional groups, these can be protected before R is introduced and deprotected in a subsequent reaction step.

EXAMPLES

The following describes the preparation of the detailed examples of the invention via the above reaction schemes and their analysis.

Analytical LC-MS

Analytical conditions summary:

LC system: Agilent 1100; binary pump: Agilent G1312A; degasser; auto sampler; column heater.

Detector DAD: Agilent G1315D, 210 nm and 220-320 nm

MSD system: Agilent LC/MSD G6130B ESI (pos/neg) mass range: 100-800

Method Al:

Column Waters XBridge™ (C18, 50 x 2.1 mm, 3.5 μπι); temperature: 35°C; flow rate: 0.8 mL/min, gradient: t ₀ = 2% A, t _{3 5m} i _n = 98% A, t _m i _n = 98% A; post time: 2 minutes; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; 220 and 220-320 nm

Method A2:

Column Waters XSelect™ (C18, 50 x 2.1 mm, 3.5 μπι); temperature: 35°C; flow rate: 0.8 mL/min, gradient: t ₀ = 2% A, t _{3 5m} i _n = 98% A, t _m i _n = 98% A; post time: 2 minutes; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; 220 and 220-320 nm

Method A3:

Column Waters XSelect™ (C18, 150 x 4.6 mm, 3.5 μηι); temperature: 35°C; flow rate: 1 mL/min, gradient: to = 5% A, ti = 5% A tiomin = 98% A, ti5 _m i _n = 98% A; post time: 5 minutes; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; 220-320 nm Method Bl:

Column Waters XBridge™ (C18, 50 x 2.1mm, 3.5 μπι); temperature: 25°C, flow rate: 0.8 mL/min, gradient: t ₀ = 2% A, t ₃ . _5m i _n = 98% A, t min = 98% A; post time: 2 min, eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water in acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH=9.5); 220-320 nm

Method B2:

Column Waters XBridge™ (C18, 50 x 2.1mm, 3.5 μπι); temperature: 25°C, flow rate: 0.8 mL/min, gradient: to = 2% A, t ₃ .5 _m i _n = 98% A, t6min = 98% A; post time: 2 min, eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water in acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH=9.5); 220 nm

Method B3:

Column Waters XBridge™ (C18, 50 x 2.1mm, 3.5 μπι); temperature: 25°C, flow rate: 0.8 mL/min, gradient: to = 2% A, t ₃ .5 _m i _n = 98% A, t6min = 98% A; post time: 2 min, eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water in acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH=9.5); 210 nm

Method B4:

Column Waters XSelect™ column (C18, 50 x 2.1 mm, 3.5 μηι); temperature: 25°C, flow rate: 0.8 mL/min, gradient: t ₀ = 2% A, t _{3 5m} i _n = 98% A, t _m i _n = 98% A; post time: 2 min, eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water in acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH=9.5); 220-320 nm Method B5:

Column Waters XSelect™ column (C18, 50 x 2.1 mm, 3.5 μηι); temperature: 25°C, flow rate: 0.8 mL/min, gradient: t ₀ = 2% A, t _{3 5m} i _n = 98% A, t _m i _n = 98% A; post time: 2 min, eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water in acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH=9.5); 220 nm

Structures of all examples of the present invention were confirmed with 1H NMR experiments. The following describes the detailed examples of the invention which have been prepared reaction schemes 1 to 6.

Table 1:

ree ase Table 2:

The following examples are provided to illustrate the invention and are not limiting the scope of the invention in any manner.

Common Intermediates:

5,6,7,8-Tetrahydroquinoxaline 1-oxide

5,6,7,8-Tetrahydroquinoxaline (250 g) was dissolved in dichloromethane (3 1). The solution was placed under nitrogen, cooled to 3°C and 3-chloroperbenzoic acid (77%, 482 g) was added in small portions over a time period of 90 min. During addition the reaction mixture was kept below 5°C. When the addition was complete, the reaction mixture had turned into a turbid white slurry and the reaction mixture was then allowed to slowly reach ambient T overnight (18 hours reaction time). At 17°C 10% Na ₂ S ₂ 0 ₃ aq. (884 ml) was added drop wise to the stirring reaction mixture in 20 min time. A sample from the reaction mixture was checked for peroxides with a wet (water) peroxide strip. Next, sat. NaHC0 ₃ aq. (2 1) was added to the stirring reaction mixture in 30 min time and the mixture was stirred for an additional 30 min until no more gas evolved from the reaction mixture. The organic layer was divided into two portions and both portions were extracted with sat. NaHC0 ₃ aq. (500 ml). The aqueous layer from the reaction mixture was extracted three times with CH ₂ C1 ₂ (1 1) and each CH ₂ C1 ₂ layer was washed with sat. NaHC0 ₃ aq. (300 ml). All CH ₂ C1 ₂ layers were combined and dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. A sample from the residue was checked for peroxides (sample in CH ₂ C1 ₂ and wet peroxide strip). The residue was co-evaporated with Et ₂ 0 and heptane. This afforded the crude product (226.8 g). The crude product was crushed with mortar and pestle and triturated in heptane (480 ml) for 2 hours. The product was filtered off, washed with heptane (200 ml) and dried in vacuo at 50°C (rotating evaporator). This afforded 187.3 g of the N-oxide. (R,S)-5,6,7,8-Tetrahydroquinoxalin-5-ol

5,6,7,8-Tetrahydroquinoxaline 1-oxide (264.4 g) was dissolved in dichloromethane (2644 ml) and the flask was placed under nitrogen, cooled to 0°C and trifluoroacetic anhydride (1109 g) was added drop wise in 100 min time, while the temperature was kept below 5°C. Next, the cooling bath under the reaction mixture was slowly allowed to reach 18°C. The reaction mixture was stirred for 17 h at 18°C (ambient T). The reaction mixture was evaporated in vacuo and stripped with CH ₂ CI ₂ . This afforded 633 g residue (TFA salt of the TFA ester intermediate). The residue was dissolved in dichloromethane (2644 ml) and 2 N lithium hydroxide monohydrate sol. in water (1761 ml) was added drop wise, while keeping the temperature below 20°C with an acetone dry ice bath. The reaction mixture was stirred for 1 h at ambient T. The reaction mixture was filtered over a layer of diatomaceous earth and sand. The filtrate was left at 19°C overnight. To the filtrate sat. aq. NaCl (1.5 1) was added and the layers were stirred for 10 min and was then allowed to rest for 30 min. The bottom CH ₂ CI ₂ layer (-2.5 1) was isolated with a separating funnel, dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. This afforded 138.6 g of black oil which slowly solidified. The aqueous layer was extracted three times with EtOAc (1 1). The EtOAc layers were combined, dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. This afforded 45.0 g of black oil which slowly solidified. The aqueous layer was extracted four times with EtOAc (1 1). The EtOAc layers were combined, dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. This afforded 45.6 g of black oil which slowly solidified. The three batches were combined and used as such in the next step.

(R,S)-5-((tert-Butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro -quinoxaline DSM

(R,S)-5,6,7,8-tetrahydroquinoxalin-5-ol (9.63 g) was dissolved in dichloromethane (300 ml) and cooled to 0°C. 2,6-Lutidine (8.96 ml) was added, followed by drop wise addition of tert- butyldimethylsilyl trifluoromethanesulfonate (17.67 ml) over a 10 minute period. Stirring was continued at 0°C for 3 hours. The reaction mixture was washed with 300 ml saturated NaHCC"3 (aq.) and the organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo (2,6-lutidine was removed by concentration with an external oil pump). The crude product was coated on Isolute (30 g) and purified by flash column chromatography with 10%- 30% EtOAc in heptane as eluent to yield the product (11.6 g) as clear brown oil. cis,cis-5-(tert-Butyldimethylsilyloxy)decahydroquinoxaline

ce mate) To a nitrogen flushed solution of (R,S)-5-(tert-butyldimethylsilyloxy)-5,6,7,8- tetrahydroquinoxaline (11.6 g) in methanol (150 ml), a slurry of platinum (IV) oxide (1.992 g) in methanol (15 ml) was added. The reaction mixture was placed under 5 bar H ₂ pressure (in a glass hydrogenation autoclave) and was stirred at 50°C for 68 hours. GCMS-analysis showed 39% starting material was still present and 53% desired product. To the (nitrogen flushed) reaction mixture, platinum (IV) oxide (1.494 g) was added (as a slurry in 10 ml MeOH). The reaction was continued under 5 bar H ₂ pressure and at 50°C for another 22 hours, after which GCMS-analysis showed 15% starting material remained. Once again platinum (IV) oxide (280 mg) was added (as a slurry in 3 ml MeOH) and the reaction was placed under 5 bar H ₂ pressure and stirred at 50°C for 23 hours, after which GCMS-analysis showed complete conversion. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated in vacuo. This afforded 11.3 g product, which was used as such in the next step. cis,cis-tert-Butyl 5-(tert-butyldimethylsilyloxy)octahydroquinoxaline-l(2H)- carboxylate

To a solution of cis,cis-5-(tert-butyldimethylsilyloxy)decahydroquinoxaline (11.3 g) in dichloromethane (250 ml), di-tert-butyl dicarbonate (9.57 g) was added. The reaction mixture was stirred at RT overnight. After 18 h, the reaction mixture was diluted with 150 ml CH ₂ CI ₂ and washed with 150 ml water (2 x). The CH ₂ CI ₂ layer was dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. The crude material was purified by column chromatography to yield 13.9 g product. cis,cis-tert-Butyl 5-hydroxyoctahydroquinoxaline-l(2H)-carboxylate

(race mate)

To a solution of cis,cis-tert-butyl 5-(tert-butyldimethylsilyloxy)octahydroquinoxaline-l(2H)- carboxylate (13.9 g) in methanol (350 ml), ammonium fluoride (20.84 g) was added. The solution was kept under reflux conditions for 20 hours. To the reaction mixture 350 ml sat. Na ₂ CC"3 (aq.) was added (pH>10), after which MeOH was evaporated in vacuo. The alkaline aqueous solution was extracted with EtOAc (3 x). The combined EtOAc layers were dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo (1 x coevaporated with CH ₂ CI ₂ ). This afforded 10 g crude product, which was further purified by gravity column chromatography (10% MeOH in CH ₂ CI ₂ ). This afforded 7.47 g product that was used as such in the next step. tert-Butyl (6aSR,9aRS,9bSR)octahydro-6H-[l,2,3]oxathiazolo[3,4,5-de]qui noxaline-6- carboxylate 2,2-dioxide

At 0°C a solution of sulfuryl chloride (2.60 ml) in dichloromethane (125 ml) was added to a solution of cis,cis-tert-butyl 5-hydroxyoctahydroquinoxaline-l(2H)-carboxylate (7.47 g) and triethyl amine (11.18 ml) in dichloromethane (250 ml). The reaction mixture was slowly allowed to reach RT and stirred for 20 h. The reaction mixture was washed with 150 ml sat. NaHCC"3 (aq.) and 100 ml water. The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. This afforded 8.64 g crude product, which was further purified by flash column chromatography (30% EtOAc in heptane) to yield 5.53 g product, which was used as such in the next step. (4aRS,5SR,8aSR)-tert-But l-5-(pyrrolidin-l-yl)octahydroquinoxaline-l(2H)-carboxylate

A mixture of (31RS,6aRS,9aSR)-tert-butyl hexahydro-31H-[l,2,3]oxathiazolo[3,4,5-de]- quinoxaline-6(6aH)-carboxylate 2,2-dioxide (1.91 g) and pyrrolidine (1.478 ml) in anhydrous acetonitrile (50 ml) was stirred at 70°C for 22 hours. The reaction mixture was evaporated in vacuo, coevaporated with toluene and CH ₂ C1 ₂ (removal excess pyrrolidine). The residue was taken up in CH ₂ C1 ₂ , 50 ml 10% citric acid (aq.) was added and the mixture was shaken for 2 min, after which the layers were separated. The acidic aqueous layer was basified with IN NaOH (aq.) and extracted with CH ₂ C1 ₂ (2x 50 ml). The combined CH ₂ C1 ₂ extracts were dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. This afforded 1.92 g product, which was used as such in the next step. cis,cis-l-Benzyl-5-(tert-butyldimethylsilyloxy)decahydroquin oxaline

(race mate)

To a solution of cis,cis-5-(tert-butyldimethylsilyloxy)decahydroquinoxaline (3.0 g) in dry N,N-dimethylformamide (105 ml), potassium carbonate (3.07 g) and benzyl bromide (1.393 ml) were added. The reaction mixture was stirred at 80°C for 1 h. The reaction mixture was evaporated in vacuo. The residue was dissolved in EtOAc, washed with water and brine and dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (5% MeOH in CH ₂ C1 ₂ ) to yield 2.65 g of product. cis,cis-l-Benzyldecahydroquinoxalin-5-ol

To a solution of cis,cis-l-benzyl-5-(tert-butyldimethylsilyloxy)decahydroquin oxaline (2.65 g) in methanol (extra dry, 80 ml), ammonium fluoride (4.08 g) was added. The reaction mixture was kept under reflux conditions for 20 h. Saturated Na ₂ C0 ₃ (aq) was added and the mixture was evaporated in vacuo (coevaporated 4 x with MeOH). The solid residue was triturated (3 x) with 100 ml CH ₂ C1 ₂ . The combined CH ₂ C1 ₂ filtrates were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. This afforded 1.81 g product. The product was coevaporated once with CH ₂ C1 ₂ to remove Et ₂ 0 and was used as such in the subsequent step.

(6aSR,9aRS,9bSR)-6-Benzyloctahydro-4H-[l,2,3]oxathiazolo[ 3,4,5-de]quinoxaline 2,2- dioxide

The reaction was performed in the dark. A solution of sulfuryl chloride (0.591 ml) in dichloromethane (20 ml) was added drop wise to a solution of cis,cis-l- benzyldecahydroquinoxalin-5-ol (1.8 g) and triethyl amine (3.05 ml) in dichloromethane (60 ml) at 0°C. The solution was stirred at 0°C for 1 h and at RT for 4 h. The mixture was partially concentrated at 35°C, filtered and immediately purified by flash chromatography (EtOAc/heptane 1/1) to afford 442 mg product which was used right away for the next step. (4aRS,5SR,8aSR)-l-Benz l-5-(pyrrolidin-l-yl)decahydroquinoxaline

Pyrrolidine (0.589 ml) was added to a solution of (31RS,6aRS,9aSR)-6-benzyloctahydro- 31H-[l,2,3]oxathiazolo[3,4,5-de]quinoxaline 2,2-dioxide (442 mg) in anhydrous acetonitrile (10 ml) and the solution was stirred at 70°C for 20 h. The mixture was concentrated in vacuo, 10 ml 1M HC1 (aq.) was added and the mixture was stirred at 50°C for 1 h. The acidic aqueous layer was washed with Et ₂ 0 and basified with 2N NaOH (aq.). The basic aqueous layer was extracted with dichloromethane. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated to afford the crude product. The residue was triturated in Et ₂ 0, filtered and the filtrate was concentrated to give 360 mg product, which was used as such in the next step. cis,cis-Benzyl 5-(tert-butyldimethylsilyloxy)octahydroquinoxaline-l(2H)- carboxylate

Benzyl chloroformate (0.110 ml) was added to a solution of cis,cis-5-(tert- butyldimethylsilyloxy)decahydroquinoxaline (200 mg) in dichloromethane (4 ml) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM, washed with sat. Na ₂ C0 ₃ (aq.), dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was triturated in heptane, filtered and concentrated to afford 181 mg product. cis,cis-Benzyl 5-hydroxyoctahydroquinoxaline-l(2H)-carboxylate

(race mate)

Ammonium fluoride (249 mg) was added to a solution of cis,cis-benzyl 5-(tert- butyldimethylsilyloxy)octahydroquinoxaline-l(2H)-carboxylate (181 mg, 0.447 mmol) in methanol (extra dry, 5 ml) and the mixture was stirred under reflux conditions overnight. The reaction mixture was concentrated; the residue was taken in CH2CI2 and sat. Na ₂ C0 ₃ (aq) was added. After shaking, the biphasic mixture was concentrated; the residue was taken up in CH ₂ C1 ₂ , dried over Na ₂ S0 ₄ , filtered and concentrated to afford 110 mg of product.

Benzyl (6aSR,9aRS,9bSR)octahydro-6H-[l,2,3]oxathiazolo[3,4,5-de]qui noxaline-6- carboxylate 2,2-dioxide

A solution of sulfuryl chloride (0.032 ml) in dichloromethane (1 ml) was added dropwise to a solution of cis,cis-benzyl 5-hydroxyoctahydroquinoxaline-l(2H)-carboxylate (110 mg) and triethyl amine (0.158 ml) in dichloromethane (3 ml) at 0°C. The solution was stirred at 0°C for 1 h and at RT for 1 h. The mixture was diluted with CH ₂ C1 ₂ , hydrolysed with water and the organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. Purification by flash chromatography (EtO Ac/heptane 1/1) yielded 35 mg of product. (4aRS,5SR,8aSR)-Benz l-5-(pyrrolidin-l-yl)octahydroquinoxaline-l(2H)-carboxylate

Pyrrolidine (0.024 ml) was added to a solution of (31RS,6aRS,9aSR)-benzyl hexahydro-31H- [l,2,3]oxathiazolo[3,4,5-de]quinoxaline-6(6aH)-carboxylate 2,2-dioxide (35 mg) in anhydrous acetonitrile (1 ml) and the solution was stirred at 70°C for 20 h. The mixture was concentrated in vacuo, the residue was taken up in CH ₂ C1 ₂ , washed (after thorough shaking) with 10% aqueous citric acid solution, dried over Na ₂ S0 ₄ , filtered and concentrated to yield 34 mg of product.

2- (3,4-Dichlorophenyl)acetyl chloride

To a solution of 3,4-dichlorophenylacetic acid (400 mg) in dry diethyl ether (12 ml), N,N- dimethylformamide (catalytic) and oxalyl chloride (0.184 ml) were added. The reaction mixture was stirred at RT for 2 h, concentrated, coevaporated with dichloromethane (2 x) to afford 2-(3,4-dichlorophenyl)acetyl chloride. The product was used as such in the next step.

Synthesis of Example 1:

Example 1:

(racemate)

A solution of 2-(3,4-dichlorophenyl)acetyl chloride (403 mg) in dichloromethane (2 ml) was added to a solution of (4aRS,5SR,8aSR)-l-benzyl-5-(pyrrolidin-l-yl)decahydroquinoxa line (360 mg) in dichloromethane (6 ml) at RT and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and hydrolysed with water. The aqueous layer was basified with 0.5M NaOH (aq.). The organic layer was dried over Na ₂ SC"4, filtered and concentrated in vacuo. Purification by flash chromatography (eluent CH ₂ Cl ₂ /3-10% MeOH) yielded 460 mg product.

Synthesis of Example 2:

Example 2: (racemate)

A solution of 2-(3,4-dichlorophenyl)acetyl chloride (31.2 mg) in dichloromethane (1 ml) was added to a solution of (4aRS,5SR,8aSR)-benzyl-5-(pyrrolidin-l-yl)octahydroquinoxali ne- l(2H)-carboxylate (32 mg) and N,N-diisopropylethylamine (0.032 ml) in dichloromethane (2 ml) at RT. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with CH ₂ CI ₂ and hydrolysed with water. The aqueous layer was basified with 0.5 M NaOH (aq.), the organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (eluent CH ₂ Cl ₂ /5-10% MeOH) followed by trituration in Et ₂ 0 provided the final product.

Synthesis of Example 3:

Example 3:

(racemate) To a solution of (4aRS,5SR,8aSR)-tert-butyl-5-(pyrrolidin-l-yl)octahydroquino xaline-l(2H)- carboxylate (1.92 g) and N,N-diisopropylethylamine (2.124 ml) in dichloromethane (160 ml), a solution of 2-(3,4-dichlorophenyl)acetyl chloride (2.080 g) in dichloromethane (80 ml) was added in 30-45 min time. The reaction mixture was stirred at RT for 1 h. The reaction mixture was washed with 2 x 50 ml 0.5N NaOH (aq.). The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo. The crude product was purified by flash chromatography (1% MeOH (7N NH ₃ ) in CH ₂ C1 ₂ ).

Synthesis of Example 9:

Intermediate 9a) (preparation 1):

(racemate)

To a solution of Example 3 (527 mg) in dichloromethane (5 ml), trifluoroacetic acid (2.358 ml) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was evaporated in vacuo and coevaporated with toluene and with CH ₂ C1 ₂ (2 x). The residue was dissolved in CH ₂ C1 ₂ and washed with 0.5N NaOH (aq.) and water. The CH ₂ C1 ₂ layer was dried over Na ₂ S0 ₄ , filtered and evaporated in vacuo.

Intermediate 9a) (preparation 2):

(racemate)

Concentrated HC1 (36% in H ₂ 0, 8 ml) and palladium, 10% on activated carbon (150 mg) were added to a degassed solution of Example 2 (380 mg) in tetrahydrofuran (40 ml) and water (40 ml). The mixture was stirred under H ₂ atmosphere (balloon, 1 bar) at RT for 4 h. Extra palladium, 10% on activated carbon (150 mg) was added and the stirring was continued under 1 bar H ₂ atmosphere for 1 h. The mixture was filtered and partially concentrated to remove THF. The acidic water layer was washed with Et ₂ 0, basified with 1M NaOH (aq.) and extracted with CH ₂ C1 ₂ . The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The crude product was purified by flash chromatography.

Example 9:

Intermediate 9a) (50 mg) was dissolved in dichloromethane (2 ml). Methyl 4-(chloro- carbonyl)benzoate (30.1 mg) and N,N-diisopropylethylamine (24.92 mg) were added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with dichloromethane (10 ml) and washed with 10 ml sat. NaHC0 ₃ (aq.) and brine (10 ml). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to yield 74 mg of crude product. Purification by flash column chromatography with 0-7% MeOH in CH ₂ C1 ₂ as eluent yielded 45.7 mg desired product. The product was converted to the corresponding HC1 salt. The free base was dissolved in CH ₂ C1 ₂ (2 ml), 1M HC1 in Et ₂ 0 (1 ml) was added and the mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo and coevaporated with Et ₂ 0 (3 x 2 ml). The product was dried under reduced pressure. Synthesis of Example 12:

Example 12:

Example 9 (31 mg) was dissolved in CH ₂ CI ₂ (3 ml) and washed with IN NaOH (aq., 2 ml). The organic layer was separated and concentrated in vacuo to yield the free amine. Enantiomers were separated using chiral preparative HPLC (OD column, flow rate: 18 mL/min, eluent heptane/EtOH 8:2 + 0.1% diethylamine). After concentration of the product fractions in vacuo, both enantiomers were lyophilized from acetonitrile/water (1:1) to give 9 mg of Example 12 (first peak) and 9 mg of its enantiomer (second peak). The ee for both enantiomers was >98%.

BIOLOGICAL ASSAYS

A. μ Opioid receptor binding assay (CHO-Kl cell membrane preparations)

Human opiate μ receptors expressed in CHO-Kl cells are used in modified Tris-HCl buffer pH 7.4. An 11 μg aliquot is incubated with 0.6 nM [ HJDiprenorphine for 60 minutes at 25°C. Nonspecific binding is estimated in the presence of 10 μΜ naloxone. Membranes are filtered and washed, the filters are then counted to determine [ HJDiprenorphine specifically bound. Test compounds are screened at various concentrations (see e.g. Wang, J.B. FEBS Lett. 1994;338:217-222).

B. μ Opioid receptor functional assay (GTPyS Binding) Human recombinant opiate μ receptors stably expressed in CHO-Kl cells are used. Test compound and/or vehicle is preincubated with the membranes (0.016 mg/ml) and 3 mM GDP in modified HEPES pH 7.4 buffer for 20 minutes at 25°C and SPA beads are then added for another 60 minutes at 30°C. The reaction is initiated by 0.3 nM [ 35 S]GTP S for an additional 30 minute incubation period. Test compound-induced inhibition of 0.1 μΜ DAMGO-induced increase of [ 35 S]GTP S binding response by 50 percent or more (>50%) indicates receptor antagonist activity. Compounds are screened at various concentrations.

Table 3: μ Opioid receptor binding (determination as described in biological assays A)

24 85

25 72

26 73

27 81

28 89

29 94

30 80

31 95

32 65

33 88

34 92

35 76

36 81

37 92

38 87

39 58

40 76

41 95

42 82

43 87

44 76

45 101

46 59

47 94

48 84

49 95

Table 4: μ Opioid functional activity (determination as described in biological assays B) IC ₅₀ values are grouped in three classes: a < 10 nM; b > 10 nM and < 100 nM; c >100 nM and < 1 μΜ

Example GTPyS % inhibition functional (nM) assay at 1 μΜ c 71 a 101 b 98 c 70 a 102 b 99 b 99 c 77 c 80 c 66 c 89 b 99 b 95 a 99 b 93 c 77 b 98 b 92 b 95 b 97 b 99 a 100 b 96 a 100 b 93 b 92 c 80 c 58 c 61 c 62 38 c 73

39 c 67

40 c 82

41 b 98

42 c 77

43 c 90

44 c 74

45 a 101

46 c 64

47 b 98

48 b 90

49 b 98

Table 5: μ Opioid functional activity for reference compounds from WO2009/080745 (determination as described in biological assays B)

The data in Table 5 show that all reference compounds of WO2009/080745 are no functional antagonists of the μ opioid receptor. Thus, the compounds of formula (1) according to the present invention (having the 4aS,5R,8aR stereochemistry) provide for improved and unexpected technical effects.

C. In vivo model for pruritus associated with the oxazolone model of a delayed type hypersensitivity reaction Scratching activity in mice is measured after topical application of the test compound. Ear thickness is measured and histology parameters are determined (see e.g. Elliott G.R. An automated method for registering and quantifying scratching activity in mice: use for drug evaluation. J. Pharmacol. Toxicol. Methods. 2000;44:453-459 and Gijbels M.J. Therapeutic interventions in mice with chronic proliferative dermatitis (cpdm/cpdm). Exp. Dermatol. 2000;9:351-358).

D. In vivo model of chronic oxazolone-induced ear inflammation

Mice are challenged several times with oxazolone following an initial sensitization. Ear thickness is measured daily during the treatment period with topical application of the test compound (see e.g. Ottosen E.R. J. Med. Chem. 2003;46: 5651-5662). At the end of the study ear weight is determined. Ears are characterized histologically and by immunofluorescence. Gene expression was quantified (RT-qPCR). E. Mouse model of topical arachidonic acid-induced ear inflammation Arachidonic acid in acetone is applied topically to the anterior and posterior surfaces of the right ear of mice. Test substances are similarly applied 30 minutes before and 15 minutes after arachidonic acid. Ear swelling is measured 1 h after application of arachidonic acid. Scratching activity is monitored for 1 h following the application of arachidonic acid. Ear weight and histology parameters are determined at the end of the study (see e.g. Chang J. Eur. J. Pharmacol. 1987;142: 197-205).

Treatment with examples 9 and 12, respectively, (topical) dose dependently prevented the increase in ear thickness observed for the vehicle control. F. Effects on chloroquine-induced scratching

Compounds are intrathecally injected in a volume of 5 μΐ, 10 min before the i.d. injection of chloroquine (100 μg/ 10 μΐ) in the rostral back. Following the i.d. cheek injection, mice are placed in an arena with a clear glass floor and videotaped from beneath for 30 min. Videotapes are reviewed by blinded investigators, who count the number of hindlimb scratch bouts.

Treatment with example 9 significantly inhibited chloroquine-evoked scratching. G. Pharmacokinetic studies, evaluation of clinical signs

The test items are administered intravenously to Wistar rats. Blood samples are taken after 15 minutes and after 1 h following administration. Perfused brains are collected 1 h following administration of the test item. Brain and plasma concentrations are measured. Clinical signs are monitored 15 minutes and 1 h after dosing.

Examples of a Pharmaceutical Composition

Composition Example 10:

Cream

Compound 10 1.00

Cetostearyl alcohol 7.00

Macrogol-6-cetostearyl ether 1.50

Macrogol-25-cetostearyl ether 1.50 Liquid paraffin 12.00

Propylene glycol 8.00

Methylparaben 0.15

Ethylparaben 0.08

Butylhydroxytoluene 0.04

Disodium edetate 0.05

Water 68.68

Composition Example 12:

Gel

Compound 12 0.50

Ethanol 15.00

Polyoxyl 40 Hydrogenated Castor Oil 1.00

Butylhydroxytoluene 0.04

Disodium edetate 0.05

Carbomer 0.50

Triethanolamine 0.70

Water 82.21 Composition Example 10:

As a specific embodiment of an oral composition of a compound of the present invention, 21 mg of Example 10 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatine capsule.

Composition Example 12:

As another specific embodiment of an oral composition of a compound of the present invention, 20 mg of Example 12 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatine capsule.