HRP20020998A2 - 3-azabicyclo(3.1.0)hexane derivatives having opioid receptor affinity - Google Patents

Description

This invention relates to pharmaceutically useful compounds, particularly compounds that bind to opiate receptors (eg mu, kappa and delta opiate receptors). Compounds that bind to such receptors are likely to be suitable for the treatment of diseases regulated by opiate receptors, such as, for example, irritable bowel syndrome; constipation; nausea; vomit; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors are also indicated for the treatment of eating disorders, opiate overdose, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal cord damage, and head trauma.

There is a definite need to improve the treatment of pruritus. Itching or pruritus is a common dermatological symptom that can develop into a significant disorder in both humans and animals. Pruritus is often associated with skin inflammations that may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mites or pollen; with bacterial and fungal skin infections; or ectoparasitic infections.

Current treatments used to treat pruritus include the use of corticosteroids and antihistamines. However, both of these treatments are known to have unwanted side effects. Other therapies used include the use of essential fatty acids as dietary supplements, and if their drawback is that they are slow to act, and that they have only a limited effect on allergic dermatitis. Various emollients such as petroleum jelly, glycerin and lanolin have also been used, but with limited success.

Therefore, there is a continuing need for alternative and/or improved treatments for pruritus.

Certain piperidine-based 4-aryl compounds are disclosed inter alia in European patent applications EP 287339, EP 506468 and EP 506478 as opioid antagonists. Furthermore, International Patent Application WO 95/15327 describes azabicycloalkane derivatives which are suitable as neuroleptic agents.

International Patent Application WO00/39089, filed before the priority date of this patent application but published thereafter, is incorporated herein by reference in its entirety, and describes azabicycloalkanes of similar structure to the compounds described below, but with different R4 groups.

According to the invention, a compound of formula I was prepared,

[image]

where the "Ar" ring is preferably a phenyl fused to benzene or a 5- or 6-membered heteroaryl ring;

R1 when considered individually is H, halogen, NO2, NH2, NY2WY1, Hetl, AD, CO2R7, C(O)R8, C(=NOH)R8 or OE,

Y2 is H, C1-6 alkyl, C3-6 alkenyl (wherein both alkyl and alkenyl are optionally substituted with aryl, aryloxy or Hetl),

W is SO2, CO, C(O)O, P(Y1)=O, P(Y1)=S,

Y1 is C1-10 alkyl (optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, C1-4 alkoxy, C1-6 alkanoyloxy, CONH2, C1-6 alkoxycarbonyl, NH2, aryl, mono- or di - (C1-4 alkyl)amino, C3-8 cycloalkyl, phthalimidyl, Hetl), Hetl, aryl (preferably substituted with one or more substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl and halogen), NH2, N(C1-6 alkyl)2 or NH(C1-6 alkyl),

Het1 is a heterocyclic group containing up to 4 heteroatoms selected from the group consisting of N, O and S, which can contain up to 3 rings (preferably a heteroaryl group, preferably a heteroaryl fused to a benzene or pyridine group), optionally substituted with one or more substituents independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 haloalkyl, C3-6 halocycloalkyl, =O, OH, halogen, NO2, SiR19aR19bR19c . O2)- groups, and the carbon atom in the ring can be present as part of the carbonyl unit;

R19a, R19b, R19c independently of each other represent C1-6 alkyl or aryl,

R20a and R20b independently of each other represent H, C1-6 alkyl, aryl, (C1-4 alkyl) phenyl, wherein both alkyl, aryl and alkylphenyl are optionally substituted with one or more substituents such as C1-4 alkyl, C1-4 alkoxy, OH, NO2, NH2 and/or halogen,

or R20a and R20b can together with the nitrogen atom to which they are attached form a 4- to 6-membered ring optionally substituted with one or more substituents independently selected from the group consisting of one or more C1-4 alkyl, C1-4 alkoxy, OH, =O, NO2, NH2 and/or halogen,

R21a, b, c and d independently of each other represent H, C1-6 alkyl, aryl or C1-4 alkylphenyl, wherein both alkyl, aryl, and alkylphenyl are optionally substituted with one or more substituents such as C1-4 alkyl, C1-4 Alkoxy, OH, NO2, Halogen, NH2,

R22a, b and c independently of each other represent C1-6 alkyl, aryl or C1-4 alkylphenyl, wherein both alkyl, aryl, and alkylphenyl are optionally substituted with one or more substituents such as C1-4 alkyl, C1-4 alkoxy , OH, NO2, halogen, NH2,

A is C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene, each of which is optionally substituted with one or more substituents such as C1-4 alkyl, C1-4 alkoxy, halogen and/or OH,

D is H, OH, CN, NR25R26, CONR25R26, NHR27, CO2R28, COR29, C(=NOH)R29,

or AD is CN, NR25R26, CONR25R26,

where R25 and R26 are or independently of each other H, C1-3 alkyl, C3-8 cycloalkyl, aryl, C1-4 alkylphenyl (whereby C1-3 alkyl, C3-8 cycloalkyl, aryl, and C1-4 alkylphenyl preferably substituted with one or more substituents such as NO2, halogen, C1-4 alkyl and/or C1-4 alkoxy, (with the latter C1-4 alkyl and C1-4 alkoxy preferably substituted with one or more halogen of atoms)),

or R25 and R26 together with the nitrogen atom to which they are attached can form a 4- to 7-membered heterocyclic ring which preferably contains one or more further hetero atoms selected from the group consisting of N, O and S, wherein the ring is preferably substituted with one or more substituents such as C1-4 alkyl, OH, =O, NO2, NH2 and/or halogen,

R27 is COR30, CO2R31a, SO2R31b,

R28 and R29 are independently H, C1-6 alkyl, C3-8 cycloalkyl, aryl or C1-4 alkylphenyl, whereby C1-6 alkyl, C3-8 cycloalkyl, aryl and C1-4 alkylphenyl are optionally substituted with one or more substituents such as NO2, halogen, C1-4 alkyl C1-4 alkoxy (whereby both C1-4 alkyl and C1-4 alkoxy are preferably substituted with one or more halogen atoms),

R30 is H, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C3-8 cycloalkyloxy, aryl, aryloxy, C1-4 alkylphenyl, phenyl(C1-4)alkoxy, (wherein C1-4 alkyl . 4 Alkyl, C1-4 Alkoxy (wherein both Alkyl and Alkoxy are preferably substituted with one or more halogen atoms)),

R31a and R31b are independently C1-4 alkyl, C3-8 cycloalkyl, aryl or C1-4 alkylphenyl, each of which is optionally substituted with one or more substituents such as NO2, halogen, C1-4 alkyl or C1 -4 Alkoxy, wherein both the latter alkyl and Alkoxy are preferably substituted with one more halogen atom,

E is H, CONR32R33, CSNR32R33, COR34, CO2R34, COCH(R34a)NH2, R35, CH2CO2R35a, CHR35bCO2R35a, CH2OCO2R35C, CHR35dOCO2R35c, COCR36=CR37NH2, COCHR36CHR37NH2, or PO(OR38)2.

R32 and R33 are independently H, C3-10 alkylalkenyl, C3-7 cycloalkyl (preferably substituted with C1-4 alkyl), phenyl (preferably substituted with (X)n), C1-10 alkyl (preferably substituted with C4-7 cycloalkyl (preferably substituted with C1-4 alkyl) or phenyl preferably substituted with (X)n)

or R32 and R33 together with the nitrogen atom to which they are attached can form a 5- to 8-membered heterocycle which preferably contains further heteroatoms selected from the group consisting of N, O and S, wherein the heterocycle is preferably substituted with C1-4 alkyl, which is preferably substituted with one or more halogen atoms,

R34 is H, C4-7 cycloalkyl (preferably substituted with one or more C1-4 alkyl), phenyl (preferably substituted with (X)n, C1-4 alkanoyloxy, NR32R33, CONR32R33 and/or OH), or C1- 6 alkyl (preferably substituted with one or more halogen atoms, C4-7 cycloalkyl (preferably substituted with one or more C1-4 alkyl), or phenyl (preferably substituted with (X)n, C1-4 alkanoyloxy, NR32R33, CONR32R33 and/or OH)),

R34a is H, C1-6 alkyl (preferably substituted with one or more halogen atoms), C4-7 cycloalkyl (preferably substituted with one or more C1-4 alkyl), or phenyl (preferably substituted with (X)n , C1-4 alkanoyloxy, NR32R33, CONR32R33 and/or OH)), C4-7 cycloalkyl (preferably substituted with one or more C1-4 alkyl), phenyl (preferably substituted with (X)n, C1-4 alkanoyloxy, NR32R33, CONR32R33 and/or OH) or a natural amino acid substituent,

R35 is C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl (optionally substituted with one or more (X)n, C1-4 alkanoyl, NHR32, CON(R32)2, and/or OH) , C1-6 alkyl (preferably substituted with C4-7 cycloalkyl which is preferably substituted with one or more C1-4 alkyl, or phenyl (preferably substituted with one or more (X)n, C1-4 alkanoyl, NHR32, CON(R32)2, and/or OH)), C1-4 alkoxy(C1-4 alkyl), phenyl(C1-4)alkyloxy(C1-4)alkyl, tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl,

R35a, b, c and d are independently H, C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl optionally substituted with one or more (X)n or C1-6 alkyl (optionally substituted with C4-7 cycloalkyl which is preferably substituted with one or more C1-4 alkyl, or phenyl which is preferably substituted with one or more (X)n),

R36 and R37 independently represent H, C3-6 alkylalkenyl, C4-7 cycloalkyl, phenyl optionally substituted with one or more (X)n, or C1-6 alkyl (preferably substituted with C4-7 cycloalkyl which is optionally substituted with one or more C1-4 alkyl, or phenyl which is optionally substituted with one or more (X)n,

R38 is C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl optionally substituted with one or more (X)n, or C1-6 alkyl (optionally substituted with C4-7 cycloalkyl which is optionally substituted with one or more C1-4 alkyl, or phenyl optionally substituted with one or more (X)n,

R 2 taken individually is H or halogen;

or R1 and R2, when attached to adjacent carbon atoms, may represent together with the carbon atom to which they are attached Hetla;

Hetla is a heterocyclic group that contains up to 4 heteroatoms selected from the group consisting of N, O and S, and which can contain up to 3 rings (and preferably a 5- to 7-membered heterocyclic ring is connected to benzene), whereby is a group optionally substituted with one or more substituents independently selected from the group consisting of OH, =O, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy, wherein C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy groups can be optionally substituted with one or more C3-6 cycloalkyl, aryl(C1-6)alkyl, wherein the aryl group is optionally substituted with one or more halogen atoms, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy, whereby the latter C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy groups can optionally be substituted with one or more NR23R24, NR23S(O)nR24, NR23C(O)mR24, and if the S atom is present in the ring, it may be present as part of - S-, S(O)- or -S(O2)- groups,

wherein R23 and R24 considered individually independently represent H, C1-4 alkyl, or C1-4 haloalkyl,

or R23 and R24 can together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclic ring that preferably contains one or more further heteroatoms selected from the group consisting of, N, O, or S, wherein the heterocyclic ring is optionally substituted with one or more halogen atoms, and a C1-4 alkyl, C1-4 haloalkyl, C1-4 -4 alkoxy and/or C1-4 haloalkoxy group,

R3 is H, CN, halogen, C1-6 Alkoxy, C1-6 Alkoxycarbonyl, C2-6 Alkanoyl, C2-6 Alkanoyloxy, C3-8 Cycloalkyl, C3-8 Cycloalkyloxy, C4-9 Cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13, NY2WY1, C1-6 alkyl, C2-10 alkenyl, C2-10 alkynyl, (in which the alkyl, alkenyl, and alkynyl groups are preferably substituted with one or more substituents such as CN, halogen, OH , C1-6 Alkoxy, C1-6 Alkoxycarbonyl, C2-6 Alkyloxycarbonyloxy, C1-6 Alkanoyl, C1-6 Alkanoyloxy, C3-8 Cycloalkyl, C3-8 Cycloalkyloxy, C4-9 Cycloalkanoyl, Aryl, Aryloxy, Heteroaryl, Saturated Heterocycle, NR12R13, CONR12R13, and/or NY2WY1),

R4 is C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl, each of these groups being connected to the N atom via an sp3 carbon, and the group being substituted with one or more substituents selected from the group consisting of:

C2-6 Alkoxy [substituted with one or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 Alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO(heteroaryl1), CO(aryl1), CO2(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S(O)n(aryl1) , S(O)n(heteroaryl1), SO2NR25R26 and cycloalkyl1],

S(O)nC1-6 alkyl [optionally substituted with one or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN , CO(heteroaryl1), CO(aryl1), CO2(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S( O)n(aryl1), S(O)n(heteroaryl1), SO2NR25R26 and cycloalkyl1],

aryl2,

CO2CH2(heteroaryl1),

CO2CH2 (aryl1),

cycloalkyl1,

CO(heteroaryl1),

CO(aryl1),

OCO(aryl1),

OCO(heteroaryl1),

OCO(C1-6 alkyl),

OCOCH2CN,

CO2 (heteroaryl1),

CO2(aryl1),

COCH2(heteroaryl1),

S(O)naryl1,

S(O)nCH2aryl 1,

S(O)n(heteroaryl1),

S(O)nCH2(heteroaryl1),

NHSO2aryl1,

NHSO2(C1-6 alkyl),

NHSO2(heteroaryl1),

NHSO2CH2(heteroaryl1),

NHSO2CH2(aryl1),

NHCOaryl1,

NHCO(C1-6 alkyl),

NHCONHaril1,

NHCONH(C1-6 alkyl),

NHCOheteroaryl1,

NHCONHheteroaryl1,

NHCO2(aryl1),

NHCO2(C1-6 alkyl),

NHCO2(heteroaryl1),

aryl2oxy,

heteroaryloxy,

C1-6 alkoxycarbonyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26

C2-6 alkanoyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26,

C2-6 alkanoyloxy substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26,

cycloalkyl1oxy,

COcycloalkyl1,

heterocycle substituted with one or more substituents selected from the group consisting of C1-6 alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2( C1-6 alkyl), CH2CO2(C1-6 6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl,

heterocyclyloxy substituted with one or more substituents selected from the group consisting of C1-6 alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2( C1-6 alkyl), CH2CO2(C1-6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl,

WHEREIN aryl1 represents phenyl which is preferably attached to a C5-7 carboxyl ring, the group of which is preferably substituted with one or more substituents selected from the group consisting of C1-6 alkyl (preferably substituted with OH, CN or halogen), C1 -6 HaloAlkoxy, OH, =O, NY2WY1, Halogen, C1-6 Alkoxy, CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R2, CO(C1-6 Alkyl), COaryl, COheteroaryl, SO2NR25R26, S(O)n(C1-6 Alkyl) ), S(O)n(aryl), S(O)n(heteroaryl), CO2(C1-6 alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)1-4CO2(C1-6 alkyl), (CH2)1-4CO2H, (CH2)1-4CO2(aryl), (CH2)1-4CO2 (heteroaryl), O(CH2)1-4CO2(C1-6 alkyl), O(CH2)1- 4CO2H; O(CH2)1-4CO2(aryl), O(CH2)1-4CO2(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(CH2)1-4CONR25R26 and C3 -7 cycloalkyl,

aryl2 is phenyl preferably attached to a C5-7 carboxyl ring, which group is optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl (preferably substituted with OH), CONR25R26, CH2CONR25R26, NR25R2, NHCONR25R26 , CO(C1-6 alkyl), COaryl, COheteroaryl, SO2NR25R26, S(O)n(C1-6 alkyl), S(O)n(aryl), S(O)n(heteroaryl), CO2(C1-6 alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)1-4CO2(C1-6 alkyl), (CH2)1-4CO2H, (CH2)1-4CO2(aryl), (CH2)1- 4CO2 (heteroaryl), O(CH2)1-4CO2(C1-6 alkyl), O(CH2)1-4CO2H; O(CH2)1-4CO2(aryl), O(CH2)1-4CO2(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(CH2)1-4CONR25R26 and C3 -7 cycloalkyl,

heteroaryl1 is a heteroaryl preferably attached to a C5-7 carboxyl ring, the group of which is optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl (preferably substituted with OH, CN or halogen), C1-6 haloalkoxy, OH, =O, NY2WY1, halogen, C1-6 Alkoxy, CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), COaryl, COheteroaryl, SO2NR25R26, S(O)n(C1-6 alkyl), S(O)n(aryl), S(O)n(heteroaryl), CO2(C1-6 alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)1-4CO2(C1-6 alkyl) , (CH2)1-4CO2H, (CH2)1-4CO2(aryl), (CH2)1-4CO2 (heteroaryl), O(CH2)1-4CO2(C1-6 alkyl), O(CH2)1-4CO2H; O(CH2)1-4CO2 (aryl), O(CH2)1-4CO2(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(CH2)1-4CONR25R26 and C3 -7 cycloalkyl,

cycloalkyl1 is a C3-10 carboxyl system with one or two rings, which is substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26 ,

with the condition that there are no N-R4 groups where the hetero atom is connected to another hetero atom through one sp3 carbon

Z is a direct bond, CO or S(O)n group,

B is (CH2)p,

R12 and R13 independently of each other represent H or C1-4 alkyl,

or R12 and R13 can together with the N atom to which they are connected form a 4- to 7-membered heterocycle which preferably contains a further hetero unit selected from the group consisting of NR16, O and/or S, which is preferably substituted with one or more C1-4 alkyl,

R14 and R15 independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, aryl or heteroaryl,

or R14 and R15 can together with the N atom to which they are connected form a 4- to 7-membered heterocycle which preferably contains a further hetero unit selected from the group consisting of NR16, O and/or S, which is preferably substituted with one or more C1-4 alkyl,

R16 is H, C1-6 alkyl, C3-8 cycloalkyl, (C1-6 alkylene), (C3-8 cycloalkyl) or (C1-6 alkylene)aryl,

R 5 and R 8 when considered separately independently of each other are H, C 1-6 alkyl,

R5 and R8 together with the carbon atom to which they are attached can form a C3-8 cycloalkyl ring,

R6, R7, R9 and R10 when considered separately are H,

R5 and R6 or R7 together with the carbon atom to which they are attached can form a C3-8 cycloalkyl ring,

X is halogen C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy,

m is 1 or 2;

n is 0, 1 or 2;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

q is 0 or 1;

"Natural amino acid substituent" means an α-substituent occurring in any of the following naturally occurring amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid acid, asparagine, glutamine, lysine, arginine or proline;

"Heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from the group consisting of N, O and S, and if an S atom is present in the ring, it may be present as part of -S-, S(O)- or -S( O)2- groups, which can be connected to the rest of the compound via any available atom(s);

"Heterocycle" is a group containing 1, 2 or 3 rings, with up to 4 ring heteroatoms selected from the group consisting of N, O and S, and up to 18 ring carbon atoms;

"Aryl", included in the definitions of "aryloxy", etc., means a group containing a phenyl ring, which may incorporate a further carboxyl ring attached to said phenyl ring, which may be attached to the rest of the compound via any available ) atoms (examples of such groups include naphthyl, indanyl, etc.);

"Alkyl", "alkenyl" and "alkynyl" groups can be straight or branched if the number of carbon atoms allows;

"Cycloalkyl" groups may be polycyclic if the number of carbon atoms permits;

or its pharmaceutical or veterinary acceptable derivatives or prodrugs.

If a fused heterocyclic group is present, it may be attached to the rest of the compound by any available atom(s).

"Haloalkyl", "haloalkoxy" groups and the like may contain more than one halogen atom, and may be, for example, per-halogenates.

Certain compounds of the invention may exist in one or more geometric and/or stereoisomeric forms. This invention includes all such individual isomers and salts, and prodrugs thereof.

Certain compounds of the present invention may exist in more than one tautomeric form. Similar suitable compounds of the invention may be in zwitterionic form. It should be understood that the invention encompasses all such tautomers, zwitterions and their derivatives.

Pharmaceutically acceptable salts of the compounds of formula (I) include their acid salts and their base salts. Suitable acid addition salts are formed from acids which form non-toxic salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulfonate, benzenesulfonate and p-toluenesulfonate salts. Suitable base salts are formed from bases which form non-toxic salts such as, for example, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. For a review of suitable salts, see Berge et al., J. Pharm. Sci., 66, 1-19 (1977).

Experts believe that it is convenient that certain protected derivatives of the compounds of formula (I), which can be made before the final stage of deprotection, do not have a pharmacological action in themselves, but can be transformed under certain conditions after administration in or on the body, for example through metabolism , thereby creating compounds of formula (I) that are pharmacologically active. Such derivatives are included in the term "prodrug". Those skilled in the art further consider that it is convenient that certain units, known in the art as "pro-units", as described for example in "Design of Prodrugs" by H Bundgaard (Elsevier) 1985, can be placed on the corresponding functional groups, if such functional groups present in the compounds of formula (I), in order to also create a "prodrug". Furthermore, certain compounds of formula I can act as prodrugs of other compounds of formula I. All protected derivatives and prodrugs of compounds of formula I are included within the scope of the invention.

Suitably, the "Ar" ring represents phenyl or pyridyl.

It is most convenient that the "Ar" ring represents a group of the formula:

[image]

Suitably R 1 , when considered individually, is OH, CN, halogen, NO 2 , NH 2 , NY 2 WY 1 or Het 1 . More preferably R 1 , when considered individually, is OH, CN, I, Cl, NH 2 , NO 2 , preferably heteroaryl fused to benzene, NHSO 2 Y 1 , NHCOY 1 or NHCO 2 Y 1 .

More preferably, R 1 , when considered individually, is OH, CN, I, Cl, NH 2 , NO 2 , 1,2,3-triazolyl, 1,2,4-triazolyl, imidazol-2-yl, pyridine-2- yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO2(C1-6 alkyl), NHSO2(C1-6 alkyl) substituted with methoxy, CONH2, OH, CO2(C2-6 alkyl) , phthalimido, NH2 or halogen), NHSO2NH2, NHSO2NH(C1-6 alkyl), NHSO2N(C1-6 alkyl)2, NHSO2Het1a, NHCO(C1-6 alkyl) or NHCO2(C1-6 alkyl).

More preferably, R1 is OH, NHSO2CH3, NHSO2C2H5, NHSO2(n-C3H7), NHSO2(i-C3H7), NHSO2 (n-C4H7), NHSO2NH(i-C3H7), NHSO2(N-methylimidazol-4-yl) , NHSO2(CH2)2OCH3, NHSO2(CH2)2OH, 1,2,4-triazolyl or imidazol-2-yl.

Most preferably, R 1 is OH, NHSO 2 CH 3 , NHSO 2 C 2 H 5 or imidazol-2-yl.

Suitably R 2 , when considered individually, is H.

It is convenient that R1 and R2 together with the carbon atom to which they are connected form a 5- to 7-membered heteroaryl ring, preferably fused with benzene, which is preferably substituted with C1-4 alkyl or C1-4 haloalkyl.

It is more convenient that R1 and R2 together with the carbon atom to which they are connected form a 5-membered heteroaryl unit, preferably substituted with C1-4 alkyl or C1-4 haloalkyl.

It is even more convenient that R1 and R2 together with the carbon atom to which they are connected form an imidazole group preferably substituted at position 2 with CF3.

It is convenient for X to be Cl.

It is convenient for n to be 0.

It is convenient for q to be 0.

It is convenient for R3 to be H, CN, C1-6 alkyl (preferably substituted with one or more halogen atoms, OH, C1-6 alkoxy, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C2-6 alkyloxycarbonyloxy , NR12R13, CONR12R13 and/or NY2WY1).

More preferably R 3 is H, CH 3 , C 2 H 5 , i-C 3 H 7 , n-C 3 H 7 or CH 2 OCH 3 .

It is most convenient that R 3 is CH 3 .

It is convenient for R4 to be C1-10 alkyl substituted with one or more substituents selected from the group consisting of:

C2-6 Alkoxy [substituted with one or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 Alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO(heteroaryl1), CO(aryl1), CO2(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S(O)n(aryl1) , S(O)n(heteroaryl1), SO2NR25R26 and cycloalkyl1],

S(O)nC1-6 alkyl [optionally substituted with one or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN , CO(heteroaryl1), CO(aryl1), CO2(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S( O)n(aryl1), S(O)n(heteroaryl1), SO2NR25R26 and cycloalkyl1],

aryl2,

CO2CH2(heteroaryl1),

CO2CH2 (aryl1),

cycloalkyl1,

CO(heteroaryl1),

CO(aryl1),

OCO(aryl1),

OCO(heteroaryl1),

OCO(C1-6 alkyl),

OCOCH2CN,

CO2 (heteroaryl1),

CO2(aryl1),

COCH2(heteroaryl1),

S(O)naryl1,

S(O)nCH2aryl 1,

S(O)n(heteroaryl1),

S(O)nCH2(heteroaryl1),

NHSO2aryl1,

NHSO2(C1-6 alkyl),

NHSO2(heteroaryl1),

NHSO2CH2(heteroaryl1),

NHSO2CH2(aryl1),

NHCOaryl1,

NHCO(C1-6 alkyl),

NHCONHaril1,

NHCONH(C1-6 alkyl),

NHCOheteroaryl1,

NHCONHheteroaryl1,

NHCO2(aryl1),

NHCO2(C1-6 alkyl),

NHCO2(heteroaryl1),

aryl2oxy,

heteroaryloxy,

C1-6 alkoxycarbonyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26

C2-6 alkanoyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26,

C2-6 alkanoyloxy substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26,

cycloalkyl1oxy,

COcycloalkyl1,

heterocycle substituted with one or more substituents selected from the group consisting of C1-6 alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2( C1-6 alkyl), CH2CO2(C1-6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl,

heterocyclyloxy substituted with one or more substituents selected from the group consisting of C1-6 alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2( C1-6 alkyl), CH2CO2(C1-6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl,

More preferably, R 4 is C 1-10 alkyl substituted with cycloalkyl 1 .

Even more preferably, R 4 is C 2-4 alkyl substituted with cycloalkyl 1 .

And it is even more convenient for R4 to be propyl substituted with cycloalkyl.

It is even more convenient for R4 to be propyl substituted with a C3-10 carboxyl system with one or two rings, which is substituted with OH.

And it is even more convenient for R 4 to be propyl substituted with (cyclohexyl substituted with OH).

R4 is most preferably (1-hydroxycyclohexyl)prop-3-yl.

A further suitable group of compounds is that in which R 4 has such values as specified in Examples 145-203 below.

It is convenient that R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are taken individually and that they are H.

A suitable group of substances is one in which the "Ar" ring, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, q and (X)n have such values as specified in the Examples below.

The invention further describes synthetic procedures for the preparation of the compounds and salts of the invention, which are described below in the Examples and in the Preparations. Those skilled in the art will appreciate that the compounds of the invention can be prepared using procedures other than those described herein, by adapting the procedures described herein and/or by adapting procedures known in the art, for example the professional procedure described herein, or by using standard professional books such as

"Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, VCH (1989 or later editions),

"Advanced Organic Chemistry - Reactions, Mechanisms and Structure", J. March, Wiley-Interscience (3rd edition or later editions),

"Organic Synthesis - Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions),

"Guidebook To Organic Synthesis" by RK Mackie and DM Smith (Longman) (1982 or later editions), etc.,

and the references cited therein are provided as guidelines.

It is necessary to understand that the synthetic transformation procedures mentioned here are only examples, and that the leg should be carried out on different sequences so that the desired compounds can be efficiently combined. A skilled chemist will use his judgment and knowledge regarding the most efficient reaction sequences for the synthesis of a given target compound. For example, substituents can be added to the intermediates and/or chemical transformations can be performed on the intermediates, which are mentioned below in connection with the corresponding reaction. This will depend, among others, on factors such as the nature of other functional groups present in the respective substrate, the availability of key intermediates and the protecting group selection strategy (if any) to be adopted. Clearly, the type of chemistry involved will affect the choice of reagents used in said synthetic step, the need, and type of protecting group used, and the sequence in which the synthesis is attempted. The procedures may be adapted as required by the reactants, reagents, and other reaction parameters so that they are clear to the skilled person, and in accordance with the references in standard technical books, as well as the examples described hereinbelow.

It is obvious to a person skilled in the art that it is necessary to protect sensitive functional groups, as well as to remove the protection during the synthesis of the compound of the invention. This can be accomplished by conventional procedures as described, for example, in "Protective Groups in Organic Synthesis", TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein. Suitable groups that are preferably protected include oxo, hydroxy, amino and carboxylic acid. Suitable oxo protecting groups include acetals, ketals (eg ethylene ketals) and dithianes. Suitable hydroxy protecting groups include trialkylsilyl and diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable amino protecting groups include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Appropriate protecting groups for the carboxylic acid include C1-6 alkyl or benzyl esters.

In the procedures below, unless otherwise specified, the substituents are as defined above for compounds of formula (I).

The invention describes processes for the preparation of compounds of formula I as defined above, or their pharmaceutically or veterinary acceptable derivatives, which include:

(a) for compounds of formula I where q is 0 and R1 represents NY2WY1, the reaction of compound of formula II,

[image]

with a compound of formula III,

Z1-WY1 III

where Z1 is a suitable leaving group, such as halogen or Y1SO2O-;

(b) for compounds of formula I where q is 0, and both R6 and R7 represent H, reduction of compound of formula IV,

[image]

by using the appropriate reducer;

(c) for compounds of formula I where q is 0, and both R9 and R10 represent H, reduction of compound of formula V,

[image]

by using the appropriate reducer;

(d) for compounds of formula I in which q is 0, and R1 and R2 are connected to adjacent carbon atoms, and together with the carbon atoms to which they are connected represent Het1a, in which Het1a represents an imidazolo unit, the reaction of the corresponding compound of formula VI,

[image]

with a compound of formula VII,

RYCO2H VII

where RY represents H or any possible substituent on Het1a (as defined above), suitably being H, C1-4 alkyl or C1-4 haloalkyl;

(e) where q is 0, the reaction of the compound of formula VIII,

[image]

with a compound of formula IX,

R4-Lg IX

where Lg is the leaving group;

(f) for compounds of formula I where q is 0 and R6, R7, R9 and R10 are all H, reduction of compound of formula X,

[image]

with appropriate reduction;

(g) for compounds of formula I wherein q is 0 and R 1 is OH, reaction of a compound of formula II wherein Y 2 is H, as defined above, with fluoroboric acid and isoamyl nitrite;

(h) for compounds of formula I wherein q is 0 and R1 is Cl, reaction of a compound of formula II wherein Y2 is H, as defined above, with sodium nitrite in the presence of dilute acid, followed by reaction with copper(I) - chloride in the presence of concentrated acid;

(i) for compounds of formula I where q is 1, reaction of a compound of formula I where q is 0 with a suitable oxidant such as hydrogen peroxide;

(j) for compounds of formula I where q is 0, reduction of the corresponding compound of formula XXXI,

[image]

wherein R4aCH2 has the same meaning as R4 as defined above; or

(k) for compounds of formula (I) where q is 0, the reductive amination reaction of the above amine of formula VIII with an aldehyde of formula R4a-CHO, where R4aCH2 has the same meaning as R4 as defined above, and where desired or necessary, converting the resulting compound of formula I into pharmaceutical or veterinary acceptable derivatives or vice versa.

In process (a), the reaction can be carried out between 0°C and room temperature in the presence of a suitable base (eg pyridine) and a suitable organic solvent (eg dichloromethane).

Compounds of formula II can be prepared by reduction of the corresponding compound of formula XI or formula XII,

[image]

in the presence of a suitable reductant, such as lithium aluminum hydride. The reaction can be carried out between room temperature and reflux temperature in the presence of a suitable solvent (eg tetrahydrofuran).

Compounds of formulas XI and XII can be prepared by reduction of the corresponding -NO2 compounds under conditions well known to those skilled in the art (e.g. using H2/Raney Ni or in the presence of CaC12 and iron powder, in the presence of a suitable solvent mixture (e.g. EtOH, EtOAc and/ or water)). A person skilled in the art will find it convenient to carry out the two above-mentioned reduction steps in the same step or sequentially in any order when preparing the compound of formula II, where Y2 is H, and starting from the corresponding - NO2 compound.

Said corresponding -NO2 compounds can be prepared by reacting a compound of formula XII or formula XIV, as already required,

[image]

wherein L 1 represents a suitable leaving group [such as halo (eg chloro or bromo)], L 2 represents a suitable leaving group (such as C 1-3 alkoxy) and R 3 is as defined above, with a compound of formula XV,

R4NH2 XV

The reaction can be carried out in the range between room temperature and reflux temperature in the presence of a suitable base (e.g. NaHCO3) and a suitable organic solvent (e.g. dimethylformamide), or at a higher temperature (e.g. between 50 and 200°C, it is more convenient to be between 100 and 160°C) in the presence of the pure compound of formula XV.

Compounds of formula XIII and XIV can be prepared according to standard techniques. For example, compounds of formula XIII and XIV can be prepared by reacting the corresponding compound of formula XVI or XVII,

[image]

with a compound of formula XVIII or XIX respectively,

N2CHR5COL2 XVIII

N2CHR8COL2 XIX

where L2 is as defined above. The reaction can be carried out at room temperature in the presence of a suitable catalyst [e.g. Rh2(OAc)4] and a suitable non-protic solvent (e.g. dichloromethane).

Compounds of formula XVI and formula XVII are available or can be prepared using known techniques. Compounds of formula XVI and formula XVII can be prepared, for example, from the corresponding compounds of formula XX,

[image]

for example by carrying out the Wittig reaction using the appropriate carrier of the nucleophilic group RO2C-CR5H- or RO2C-CR8H- (where R represents eg a lower C1-3 alkyl), under conditions well known to the person skilled in the art. The CO2R group of the resulting compound can be converted to the corresponding -CH2L1 group using standard techniques (e.g., reduction of the ester to a primary alcohol and conversion of the latter to an alkyl halide under conditions well known to the skilled person.

In procedures (b) and (c), lithium aluminum hydride is included in the corresponding reducers. The reaction can be carried out in the range between room temperature and reflux temperature in the presence of a suitable solvent (eg tetrahydrofuran).

Compounds of formula II can be prepared by reduction of the corresponding compound of formula XXX,

[image]

analogous to the steps from the procedure mentioned above.

Compounds of formulas IV and V can be prepared respectively from compounds of formulas XXI and XXII,

[image]

where L3 represents a group capable of undergoing functional group transformation (eg, cyano) using standard functional group substitution or conversion techniques.

For example:

(1) Compounds of formula IV and V, where R1 represents 1,2,4-triazol-3-yl, can be prepared by reacting the corresponding compound of formula XXI or XXII where L3 represents -CN with HCl (gas) in the presence of a corresponding lower alkyl alcohol (e.g. ethanol), for example in the range between 0°C and room temperature, followed by reaction of the resulting intermediate with formic acid hydrazide (e.g. at reflux temperature, with or without a suitable organic solvent (e.g. methanol), followed by , if necessary, removing the solvent and heating the resulting residue at a high temperature (eg around 150°C)).

(2) Compounds of formula IV and V, where R1 represents imidazol-2-yl, can be prepared by reacting the corresponding compound of formula XXI or XXII where L3 represents -CN with HCl (gas) in the presence of a corresponding lower alkyl alcohol (e.g. ethanol), for example in the range between 0°C and room temperature, followed by reaction of the resulting intermediate with an aminoacetaldehyde dialkyl acetal (eg dimethyl acetal) (eg at or around reflux temperature, in the presence of a suitable solvent, such as methanol).

(3) Compounds of formula IV and V, where R1 represents 1,2,3-triazol-5-yl, can be prepared by reacting the corresponding compound of formula XXI or XXII, where L3 represents –CN with diazomethane, or its protected derivative (e.g. trialkylsilyl), for example in the range between 0°C and room temperature, in the presence of a suitable base (eg n-BuLi), and preferably a suitable organic solvent (eg THF), followed by deprotection if necessary.

(4) Compounds of formula IV and V, where R1 represents benzimidazol-2-yl, can be prepared by reacting the corresponding compound of formula XXI or XXII, where L3 represents C=NH(OEt), with 1,2-diaminobenzene. The reaction can be carried out in a solvent such as methanol at an elevated temperature (such as the reflux temperature of the solvent). Preparations 81, etc. describe further details. Compounds of formula IV and V, where R1 represents Het1, can also be prepared respectively from compounds of formula XI and XII according to the following scheme:

[image]

where Het1 is defined above. Further details can be found in Preparations 67, 68, etc. in WO00/39089, which is incorporated herein by reference in its entirety.

Compounds of formula XXI and XXII may be prepared in an analogous manner to the procedures described herein, for example as to the procedures previously described herein for the preparation of compounds of formula II.

Other compounds of formula (IV) and (V) can be prepared analogously to the procedures described here (eg analogously to the procedures previously described here for the preparation of compounds of formula XI and XII (and especially the corresponding -NO2 compound)).

In process (d), the reaction can be carried out by heating at reflux, with or without a suitable organic solvent.

Compounds of formula VI can be prepared using known techniques. For example, compounds of formula VI can be prepared by nitration (at the 4-position) of the corresponding 3-aminobenzene compound (compound of formula II), wherein the latter compound can be activated by conversion of the 3-amino group to a 3-amido group, followed by hydrolysis of the amide and reduction of the 4-nitrobenzene compound. All of these reactions can be carried out using techniques known to those skilled in the art and are shown in Preparations 45-48, etc. below.

In process (e), suitable leaving groups, which may be represented by Lg, include a halogen such as bromine, or a sulfonate group such as tosylate, mesylate or triflate. The reaction can be carried out in a polar solvent that does not inhibit the reaction, at a suitable temperature, eg 0-150°C, in the presence of a base. A catalyst such as sodium iodide may optionally be added.

It is convenient to choose an approach where a slight excess of R4-Lg is used, where Lg = Cl or Br, and the excess base (2.0-4.0 equiv.) is made up of compounds such as K2CO3, NaHCO3, or tertiary amines, such as triethylamine or Hunigs base, in a polar solvent, such as THF, DMF, or MeCN, in the range between 40 and 120°C, preferably in the presence of a catalyst such as NaI or KI, for 2-24 hours.

see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", VCH, (1989), p. 397, and the references there.

Compounds of formula VIII can be prepared from compounds of formula XXV,

[image]

where Pg represents the corresponding protecting group. Suitable protecting groups include allyl which can be removed using a palladium(0) catalyst and N,N-dimethylbarbituric acid (see Preparation 53, etc. below). Compounds of formula XXV can be prepared using procedures analogous to those described herein for the preparation of compounds of formula I.

In procedure (f), lithium aluminum hydride is included in the corresponding reducers. The reaction can be carried out in a solvent that does not inhibit the reaction (for example tetrahydrofuran), at an elevated temperature (for example the reflux temperature of the solvent).

Compounds of formula X can be prepared by reacting a compound of formula XXVI with a compound of formula XXVII in the presence of an oxidant. Suitable oxidants include manganese dioxide. The reaction can be carried out in a solvent that does not inhibit the reaction (for example dioxane), at an elevated temperature such as the reflux temperature of the solvent (for example see Preparation 77, WO00/39089). Intermediates XXIX can be isolated using appropriate conditions (eg, see Preparation 58, WO00/39089).

[image]

Compounds of formula XXVI can be prepared from compounds of formula XXVIII by reacting the appropriate ketone with hydrazine monohydrate using known techniques (as described in Preparation 76, etc. WO00/39089).

Process (f) is particularly suitable if Ar represents a 5- or 6-membered heteroaryl ring which is preferably fused to benzene. A similar methodology can be used to prepare compounds of formula II: a nitro compound precursor can be prepared from a compound of formula XX, as defined above, using the steps described above (see for example Preparations 57-61, WO00/39089).

In process (g), the reaction can be carried out in a solvent that does not inhibit the reaction (for example ethanol), first below room temperature, and then at elevated temperature (Examples 79, etc. WO00/39089 gives further details).

In process (h), the appropriate acids include dilute aqueous hydrochloric acid and concentrated hydrochloric acid, respectively. The reaction can be carried out at or around room temperature and is completed at an elevated temperature (for example 90°C. Example 51 of WO00/39089 gives further details).

In process (j), a compound of formula XXXI may be prepared by acylating a compound of formula VIII, as defined above, with an acylating agent of the formula R4aCo-Lg, where Lg is the appropriate leaving group, as defined above under (e), and includes halogen, (alkyl, haloalkyl, or aryl)sulfonates, OCOR4a (eg, acid anhydride), and the like, which are well known to those skilled in the art. See for example the conditions used for the preparation of 47. The coupling can preferably be carried out in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", Second Edition, (1999), p. 1941-1949, and the references mentioned there. Conveniently, carboxylic acid (0.9-1.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (1-1.5 eq.) and 1-hydroxybenzotriazole (1.0 eq.) stirred in DMF or DCM at room temperature for 5-15 min., and then amino salt (1 eq.) and base (NaHCO3 or organic base, Et3N or Hunigs base (2-4 eq.)) are added, whereby the reaction takes place for 2-24 hours at room temperature.

The amide bond can be reduced with an appropriate reductant, for example lithium aluminum hydride or borane, in an ethereal solvent such as THF at 0-100°C to give the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", VCH, (1989), p. 432-434, and the references there. Conveniently, the amide (1.0 eq.) is treated with lithium aluminum hydride (1.0-3 eq.), at 0°C to room temperature, in THF for 1-24 hours.

In process (k), the corresponding aldehyde is reacted with an amine, preferably present as an acid addition salt, in the presence of a suitable reductant (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt or Ni catalysts). Conveniently, the reaction is carried out in the presence of acetic acid at 0-100°C in THF, methanol, DCM (dichloromethane), or DCE (1,2-dichloroethane), for a suitable time of 1-24 hours.

Conveniently, an amino salt, such as a trifluoroacetic acid (TFA) salt, is treated with an organic base (1-3 mol equivalents), such as triethylamine or Hunigs base, and then with an aldehyde (1-1.5 mol equivalents), followed by sodium triacetoxyborohydride (1-2.0 mol equivalents), in DCM or DCE, at room temperature for 1-24 hours - see RC Larrock; "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", second edition, (1999), p. 835-842, and references therein, as well as Abdel-Magid et al., J. Org. Chem., 1996, 61, 3849.

Aldehydes used in this process can be prepared from suitable alcohols by using a suitable oxidant; see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", Second Edition, (1999), p. 1234-1236 and 12381247, and the references there. Suitable oxidants are tetrapropylammonium perutenate (Ley, et al., Synthesis, 1994, 639-666), Swern oxidation and related procedures (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinane reagent (Dess et al. , J. Org. Chem., 1983, 48, 4155-4156).

Various interconversions of the functional group can be carried out on the compounds of formula (I) or their intermediates, resulting in various compounds of formula (I) or intermediates. Some of them are mentioned below.

Anilines can be converted to urea using potassium cyanate (excess) in an aqueous acid solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432.

Esters can be converted to the corresponding Alcohols using the appropriate reductant, see Larock, Comprehensive Organic Transformations - A Guide to Functional Group Preparations, second edition, (1999), p. 1117-1120 and the references there. Suitable reductants include diisobutylaluminum hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminum hydride (LiAlH4, see Brown, Org. Reactions, 1951, 6, 469) - see a reaction of the type:

[image]

Alcohols can be prepared from a suitable acid by using a suitable reducing agent; see Larock, Comprehensive Organic Transformations - A Guide to Functional Group Preparations, Second Edition, (1999), p. 1114-1116. Conveniently, the reductant is either borane (BH3 (1-2 eq.), J. Org. Chem., 1973, 38, 2786) or LiAlH4 (1-4 eq.), in an ethereal solvent, such as THF, at 0-80°C, for 1-24 hours - see type reaction::

[image]

Direct procedures for the preparation of alkyl halides and allyl sulfonates from their alcohols are described in RC Larrock, Comprehensive Organic Transformations - A Guide to Functional Group Preparations, second edition, (1999), p. 689-700, and the references mentioned there.

Benzyl acetals can be treated with a suitable reductant in the presence of a Lewis acid or an organic acid to give benzyloxyalcohols.

For representative examples, see Organic Preparations and Procedures, Int., 1991, 23,4, 427431, ZrCl4/LiAlH4; J. Org. Chem., 1987, 52, 2594, Zn(BH4)2/Me3SiCl; and Organic Preparations and Procedures, Int., 1985, 17(1), 11-16, NaBH4/TFA. see reaction type:

[image]

It is obvious to a person skilled in the art that compounds of formula I can be converted into other compounds of formula I using known techniques. For example, compounds of formula I, where Y1 is alkoxycarbonyl, can be converted by reduction using LiAlH4 to compounds where Y1 is alkyl substituted with OH (Example 57 provides further details). Similarly, intermediates can be interconverted using known techniques (see for example Preparation 85).

Intermediates with formulas III, XV, XVIII, XIX, XX, VII, IX, XXVI, XXVII and XXVIII, as well as their derivatives, if not commercially available or not described below, can be obtained either analogously to the procedures described here, or by conventional synthetic procedures, in accordance with standard techniques from readily available starting reagents, using appropriate reagents and reaction conditions.

The invention further describes intermediates of formulas II, IV, V, VI, X, Xa, XI, XII, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX, and XXXI as defined above.

Where desired or necessary, a compound of formula (I) may be converted into a pharmaceutically acceptable salt thereof, usually by mixing solutions of a compound of formula (I) and the desired acid or base, as appropriate. The salt can be precipitated out of solution and collected by filtration, or it can be collected by other means such as evaporating the solvent. Both types of salts can also be formed or interconverted using ion exchange resin techniques.

The compounds of this invention can be purified by conventional methods, for example the separation of diastereomers can be achieved by conventional techniques, eg by fractional crystallization, chromatography or by HPLC of a stereoisomeric mixture of a compound of formula (I) or a salt thereof. A single enantiomer of a compound of formula (I) can also be prepared from a suitable optically pure intermediate or by separation, such as by HPLC of the suitable racemate using a suitable chiral support or by fractional crystallization of the diastereomeric salt formed in the reaction of the suitable racemate with a suitable optically active base or acid.

The compounds of the invention are suitable because they exhibit pharmacological activity in animals, especially mammals including humans. They can therefore be used as medicines, especially as medicines for animals.

According to a further aspect of the invention, compounds of the invention are described which are used as drugs, such as pharmaceutical and animal drugs, which are used to treat diseases and conditions regulated by opiates.

Under the term "treatment", this term includes both therapeutic (curative) treatment and prophylaxis.

In particular, it has been found that the substances of this invention are suitable for the treatment of diseases and conditions regulated via opiate receptors, such as irritable bowel syndrome; constipation; nausea; vomit; pruritus; eating disorder; opiate overdose; depression; addiction to smoking and alcohol; sexual dysfunctions; juice; drop; spine damage and/or head trauma; and conditions in which it is characteristic that pruritus appears as a symptom.

It is therefore expected that the compounds of the invention are suitable for the curative treatment or prophylaxis of pruritic dermatoses including allergic dermatitis and atopy in animals and humans. Other diseases and conditions that may be mentioned include contact dermatitis, psoriasis, eczema and insect bites.

Therefore, the invention describes a method of treating or preventing a disease regulated via opiate receptors. Furthermore, the treatment procedure for irritable bowel syndrome is described; constipation; nausea; vomiting; pruritus; eating disorders; opiate overdoses; depression; addiction to smoking and alcohol; sexual dysfunctions; of shock; drops; spine damage and/or head trauma; and conditions characterized by pruritus as a symptom in animals (eg, mammals), comprising administering a therapeutically effective amount of a compound of the present invention to animals in need of such treatment.

The compounds of the invention are usually administered orally or by any parenteral route, in the form of pharmaceutical preparations containing the active substance, preferably in the form of a non-toxic organic or inorganic acid or base, addition salt, in a pharmaceutically acceptable dose. Depending on the disorder and the patient being treated, as well as the route of administration, specimens may be administered at different doses (see below).

Although it is possible to administer the compound of the invention directly without any formulation, it is convenient to administer the compounds in the form of pharmaceutical or veterinary formulations with a pharmaceutical or veterinary acceptable carrier, diluent or excipients, and with the compound of the invention. The carrier, diluent or excipient can be selected with regard to the intended route of administration and standard pharmaceutical and/or veterinary practice. Pharmaceutical preparations that include the compounds of the invention may contain from 0.1 percent to 90.0 percent by weight of the active substance.

Methods of administration of compounds for veterinary use include oral administration via capsules, bolus, tablets or solution, topical administration in the form of ointment, pour-on, spot-on, dip, spray, foam, shampoo, collar or powder formulation, or alternatively, they can be administered by injection (eg subcutaneously, intramuscularly or intravenously), or as an implant. Such preparations can be prepared in the usual way in accordance with standard veterinary practice.

The preparations differ in the mass of the active substance they contain, which depends on the type of animal being treated, the severity and type of infection, and the animal's body weight. For parenteral, topical and oral administration, the usual dose range of the active substance is from 0.01 to 100 mg per kg of the animal's body weight. It is convenient for the range to be from 0.1 to 10 mg per kg.

In any case, a veterinarian or a professional person is able to determine the right dose that will be most suitable for an individual patient, which may vary depending on the species, age, weight and reaction of a particular patient. The above doses serve as examples for average cases; but of course there may be individual examples where higher or lower doses are needed, and they are also within the scope of the invention.

When used for veterinary purposes, the compounds of the invention are particularly suitable for the treatment of pruritus in domestic animals such as cats, dogs and horses.

Alternatively, for the treatment of animals, the compounds can be administered together with animal feed, and for this purpose, concentrated food additives or mixtures mixed with normal animal feed can be prepared.

When used on humans, the compounds are applied in the form of pharmaceutical formulations containing the active substance together with a pharmaceutically acceptable diluent or carrier. Such preparations include conventional tablets, capsules and ointments formulated according to standard pharmaceutical practice.

The compounds of the present invention may be administered either alone or in combination with one or more agents used for the treatment or prophylaxis of a disease or for the reduction or suppression of symptoms. Examples of such agents (which are described by way of illustration, and should not be considered a limiting factor) include anthelmintics, eg, fipronil, lufenuron, and midacloprid, avermectins (eg, abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, eg chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antimycotics, eg fluconazole, ketoconazole, and traconazole, griseofulvin, amphotericin B; chemotherapeutics, eg enrofloxacin, marbofloxacin, ampicillin, amoxicillin; antiphlogistics, eg prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, eg gamma-linoleic acid; and softeners. Therefore, the invention describes a product containing the compound of the invention and one or more selected compounds from the above list in the form of a multicomponent preparation for simultaneous, separate or sequential use for the treatment of diseases regulated by opiate receptors.

One skilled in the art will appreciate that the compounds of this invention can be taken as a single dose or "as required" (eg, as needed or desired).

Therefore, according to the following aspect of the invention, a pharmaceutical or veterinary formulation is described, including a compound of the invention in admixture with a pharmaceutical or veterinary acceptable adjuvant, diluent or carrier.

The advantage of the compounds of this invention can also be that they are more effective in the treatment of humans and/or animals, less toxic, have a wider area of action, are more potent, cause fewer side effects, can be more easily absorbed, or can have other useful pharmacological properties in compared to previously known compounds.

The biological activity of the compounds of this invention was determined using the following test procedures.

Biological testing

The compounds of this invention were found to exhibit activity in three opioid receptor selective binding assays for mu, kappa and delta opioid receptors in the canine brain. The tests were carried out according to the following procedure.

Laboratory hunting dogs are used as a source of canine brain tissue. Animals are euthanized, their brains are removed, and the cerebellum is discarded. The remaining brain tissue is dissected into small pieces weighing about 3 g, and homogenized in 50 mM Tris buffer pH 7.4 at 4°C using a Kinematica Politron tissue homogenizer. The resulting homogenate is centrifuged at 48,400 g for 10 minutes, and the supernatant is discarded. The pellet is resuspended in Tris buffer and incubated at 37°C for 10 minutes. The stages of centrifugation, resuspension and incubation are repeated two more times, and the resulting pellet is resuspended in Tris buffer and stored at -80°C. The membrane prepared in this way can be stored for up to four weeks before use.

In mu, kappa and delta tests, the experimental compound whose concentrations increase (5 × 10-12 to 10-5 M), Tris buffer and 3H ligand, (mu = [D-Ala2,N-Me-Phe4,Gly-ol5 ]-Enkephalin, DAMGO; kappa = U-69,593; delta = Enkephalin, [D-pen2,5] DPDPE) are mixed in polystyrene tubes. The reaction starts by adding tissue, and the mixture is incubated at room temperature for 90 minutes. The reaction is terminated by rapid filtration using a Brandel Cell Harvester™ through a Betaplate™ GF/A glass wool filter presoaked in 50 mM Tris pH 7.4, 0.1% polyethyleneimine buffer. The filters are then washed three times with 0.5 ml of ice-cold Tris pH 7.4 buffer. For mu and delta tests, washed filters are placed in bags, and Starscint™ scintillation agent is added, and for kappa testing, Meltile™ B/HS solid scintillation agent is used. Bags containing filters and scintillation agent are heat sealed and counted using a Betaplate™ 1204 beta counter.

Duplicates were made from each sample for each test compound, and the resulting data were analyzed using the Graphpad Prism IC50 analysis program. Ki values were calculated using the Graphpad Prism program according to the following formula:

Ki = IC50/1 + [3H ligand]/KD

where IC50 represents the concentration at which 50% of the 3H ligand is free in relation to the tested compound, and KD is the dissociation constant for the 3H ligand at the receptor site.

Biological activity

The Ki values of the corresponding compounds of this invention were determined when tested for binding to opioid receptors, and the Ki values were found to be 4000 nM or less for μ receptors.

The procedures used in the following Examples are believed to produce compounds with the relative stereochemistry shown below, with such compounds being preferred:

[image]

where R1-4 and (X)n are as defined above.

The invention is illustrated by the following Examples and Preparations in which the following abbreviations may be used:

APCI = atmospheric pressure chemical ionization

DMF = dimethylformamide

DMSO = dimethylsulfoxide

d (related to time) = day

d (related to NMR) = doublet

ES (related to MS) = Electron spray

EtOAc = ethyl acetate

EtOH = ethanol

h = hour

MeOH = methanol

min = minutes

MS = mass spectrum

n-BuOH = n-butanol

ODS = octadecylsilyl

THF = tetrahydrofuran

TSP = thermal spray

Melting points were determined using a Gallenkamp melting point apparatus and were not corrected. Nuclear magnetic resonance (NMR) spectral data are for 1H and were obtained using a Varian Unity 300 or 400 spectrometer, and chemical shifts (δ) were obtained consistent with the proposed structures. Mass spectrum (MS) data were obtained on a Fisons Instruments Trio 1000, or Fisons Instruments Trio 1000 APCI, or Finnigan Navigator MS, or Micromass Platform LC spectrometer. The calculated and obtained ions refer to the isotopic mixture of the smallest mass. Room temperature means 20 to 25°C. The mass spectrometer used as the detector of the analytical HPLC-MS system is the Micromass VG Platform II, which uses the Masslynx/Openlynx program. The system can process positive and negative ions using Electronspray or APCI probe, and is calibrated up to 1972 Daltons, and collects complete Diode array data from 190 nm to 600 nm.

HPLC stands for high-performance liquid chromatography. HPLC is performed under the following conditions:

Condition 1: Rainin Dynamax™ column, 8μ ODS, 24 × 300 mm, column temperature 40°C, flow rate 45 ml/min.., elution using a mixture of methanol : water (70 : 30), UV detection of the product at 246 nm.

Condition 2: Rainin Dynamax™ column, 5μ ODS, 21.6 × 250 mm, column temperature 40°C, flow rate 5 ml/min., elution using a mixture of acetonitrile : water (50 : 50), UV product detection at 246 nm .

Condition 3: Rainin Dynamax™ column, 8μ ODS, 41 × 250 mm, column temperature 40°C, flow rate 45 ml/min, elution using a mixture of acetonitrile : 0.1M aqueous ammonium acetate buffer (50 : 50), UV detection product at 235 nm.

Condition 4: Phenomenex Magellan™ column, 5μ C18 silica gel, 21.2 × 150 mm, column temperature 40°C, flow rate 20 ml/min, elution using a gradient mixture of acetonitrile : 0.1M aqueous ammonium acetate buffer (30 : 70 up to 95 : 5 during 10 min.), UV detection of the product at 220 nm.

Condition 5: Phenomenex Magellan™ column, 5μ ODS, 21.2 × 150 mm, column temperature 40°C, flow rate 20 ml/min, elution using a gradient mixture of acetonitrile : 0. 1M aqueous ammonium acetate buffer (5 : 95 to 95: 5 for 20 min.), UV detection of the product at 215 nm.

Condition 6: Phenomenex Magellan™ column, 5μ C18 silica gel, 4.6 × 150 mm, column temperature 40°C, flow rate 1 ml/min, elution using a gradient mixture of acetonitrile: 0.1M aqueous heptanesulfonic acid (10 : 90 up to 90 : 10 for 30 min.), UV detection of the product at 220 nm.

Condition 7: Phenomenex Magellan™ column, 5μ C18 silica gel, 21.2 × 150 mm, column temperature 40°C, flow rate 20 ml/min, elution using a gradient mixture of acetonitrile : 0.05M aqueous ammonium acetate buffer (50 : 50 during 15 min., and then 50 : 50 to 90 : 10 during 5 min.),

UV product detection at 220 nm.

Condition 8: Phenomenex Magellan™ column, 5μ C18 silica gel, 21.2 × 150 mm, column temperature 40°C, flow rate 20 ml/min, elution using a gradient mixture of acetonitrile : 0.1M aqueous ammonium acetate buffer (15 : 85 up to 85 : 15), UV product detection at 220 nm.

Condition 9: Phenomenex Magellen™ column, 5μ ODS, 10 × 150 mm, column temperature 40°C, flow rate 5ml/min., elution using a gradient mixture of acetonitrile : 0.1M aqueous ammonium acetate buffer (5 : 95 to 30 : 70 during 5 min., and then 30 : 70 for the next 20 min.), UV detection of the product at 225 nm.

Condition 10: Phenomenex Magellan™ column, 5μ C18 silica gel, 21.2 × 150 mm, column temperature 40°C, flow rate 20 ml/min, elution using a gradient mixture of acetonitrile : 0.1M aqueous ammonium acetate buffer (5 : 95 to 40 : 60 for 5 min, and then 40 : 60 for the next 25 min.), UV detection of the product at 210 nm.

Condition 11: Phenomenex Magellan™ column, 5μ ODS, 10 × 150 mm, column temperature 40°C, flow rate 5 ml/min, elution using a gradient mixture of acetonitrile : water (5 : 95 to 55 : 45 over 5 min.) , UV detection of the product at 210 nm.

Azabicyclo compounds in the form of a free base can be obtained from hydrochloride or acetate salts, for example in the following way. The salt (0.3 mmol) is dissolved in dichloromethane (20 ml) and washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The alkaline mixture was separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). The combined organic extracts are dried (Na2SO4) and concentrated under vacuum to obtain the free base.

SPE tank refers to solid phase extraction tanks. These can be obtained commercially from Varian (Megaveza Elut®) or Isolute™.

"Examples" numbered 1-144 are compounds related to this invention, but have different R4 groups, and as such are published in international patent application no. WO00/39089, which is incorporated herein by reference in its entirety.

A number of the following Examples, such as the examples described below, can be prepared using procedures A-K listed below, and the experimental details found in the table.

Procedure A

Alkylation

Alkylation of an amine of formula VIII or a salt thereof with R4Lg, where Lg is a suitable leaving group, such as halogen, triflate, mesylate, etc., in the presence of a base, preferably in the presence of a catalyst, in a polar solvent, between 0 and 150°C.

Alkylation is conveniently carried out with R4Lg (slight excess), where Lg = Cl or Br, and the base in excess (2.0-4.0 equiv.) is K2CO3, NaHCO3, or a tertiary amine, such as triethylamine or Hunigs base, in a polar solvent, such as THF, DMF or MeCN, between 40 and 120°C, preferably in the presence of a catalyst such as NaI or KI, for 2-24 hours.

see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", VCH, (1989), p. 397, and the references cited there.

For example:

[image]

Conditions: Amino salt (1.0 equiv), RX (1.1 equiv), NaHCO3 (2-4.0 equiv), DMF, NaI (cat), 40

Procedure B

Reductive amination

Treatment of the appropriate aldehyde R4aCHO with an amine of formula VIII in the presence of a suitable reductant (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catalytic hydrogenation with Pd, Pt, or Ni catalysts). The reaction is often carried out in the presence of acetic acid at 0-100°C in THF, MeOH, DCM, or DCE (1,2-dichloroethane), for 1-24 hours.

Conveniently, the amino salt is treated with an organic base (1-3 equiv), such as triethylamine or Hunigs base, and then with an aldehyde (1-1.5 equiv), followed by sodium triacetoxyborohydride (1-2, 0eq), in dichloromethane or DCE, at room temperature for 2-24 hours, see RC Larrock; "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", second edition, (1999), p. 835-842, and the references cited therein, as well as Abdel-Magid et al., J. Org. Chem., 1996, 61, 3849.

For example:

[image]

Conditions: Amino salt (1.0 equiv), RCHO (1-1.5 equiv), Et3N (1-3 equiv), Na(OAc)3BH (1-2 equiv), DCM, room temp.

Procedure C

Reduction of amide of formula XXXI

The amide carbonyl can be reduced with a suitable reductant, such as for example lithium aluminum hydride or borane, in an ethereal solvent such as THF, at 0-100°C, to produce the desired tertiary amine, see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", VCH, (1989), p. 432434, and the references cited there.

It is convenient to treat the amide (1.0 eq.) with lithium aluminum hydride (1.0-3 eq.), at 0°C - room temperature, in THF, for 1-24 hours, e.g.:

[image]

Procedure D

Oxidation

The aldehydes used in procedure B can be prepared by using a suitable oxidant; see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", Second Edition, (1999), p. 1234-1236 and 1238-1247, and the references cited there.

Suitable oxidants are tetrapropylammonium perutenate (Ley, et al., Synthesis, 1994, 639-666), Swern oxidation and related procedures (Tidwell, Organic Reactions, 1990, 39, 297-572), and Dess-Martin Periodinan reagent (Dess et al. , J. Org. Chem., 1983, 48, 4155-4156).

[image]

Procedure E

Coupling of acid/amino salt to obtain amides of formula XXXI

Using either an acid chloride + amine in a suitable solvent, or an acid activated by a suitable agent, preferably in the presence of a catalyst, for example DMAP, in a suitable solvent; see RC Larrock in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations", Second Edition, (1999), p. 1941-1949, and the references cited there. Conveniently, carboxylic acid (0.9-1.1 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (1-1.5 eq.) and 1-hydroxybenzotriazole (1.0 eq.) stir in DMF or DCM at room temperature for 5-15 min. An amino salt (1 eq.) and a base (NaHCO3 or an organic base, Et3N or Hunig's base (2-4 eq.)) are then added, and the reaction takes place for 2-24 hours at room temperature.

For example:

[image]

Procedure F

Obtaining urea

Anilines can be converted to urea using potassium cyanate (excess) in an acidified aqueous solution, see Cross et al., J. Med. Chem., 1985, 28, 1427-1432. see reaction type:

[image]

Procedure G

Ester to alcohol

Esters can be converted to the corresponding alcohol using the appropriate reductant, see Larock, Comprehensive Organic Transformations - A Guide to Functional Group Preparations, Second Edition, (1999), p. 1117-1120, and the references cited there. Suitable reductants include diisobutylaluminum hydride (DIBAL, see Winterfeldt, Synthesis, 1975, 617) and lithium aluminum hydride (LiAIH 4 , see Brown, Org. Reactions, 1951, 6, 469). see reaction type:

[image]

Procedure H

Acid to alcohol

It is convenient that the alcohols used in process D can be prepared from a suitable acid by using a suitable reducing agent; see Larock, Comprehensive Organic Transformations - A Guide to Functional Group Preparations, Second Edition, (1999), p. 1114-1116. Conveniently, the reducing agent is borane (BH3 (1-2 eq.), J. Org. Chem., 1973, 38, 2786), or LiAIH4 (1-4 eq.), in an ethereal solvent, such as THF, at 0-80°C, during 1-24 hours.

[image]

Procedure I

Alcohol to Halide

Conveniently, R4Lg, which is used in process A, can be prepared from the corresponding alcohol R4aOH.

Direct procedures for the preparation of alkyl halides and alkyl sulfonates from their alcohols are described in RC Larock, Comprehensive Organic Transformations - A Guide to Functional Group Preparations, second edition, (1999), p. 689-700, and the references cited there.

Procedure J

Benzyl halides to benzyloxy alcohols

Benzyloxyalcohols can be prepared by refluxing the corresponding benzyl halide with sodium or sodium hydride, and polymethylene glycol in xylene, see J. Am. Chem. Soc., 1951, 3159-3162. see reaction type:

[image]

Procedure K

Acetals to benzyloxyalcohols

Acetals can be treated with a suitable reduction agent in the presence of a Lewis acid or an organic acid to give benzyloxyalcohols.

For representative examples see Organic Preparations and Procedures, int., 1991, 23, 4, 427-431, ZrC14/LiAIH4; J. Org. Chem., 1987, 52, 2594, Zn(BH4)2/Me3SiCl; and Organic Preparations and Procedures, int. 1985, 17 (1), 11-16, NaBH4/TFA. see reaction type:

[image]

[image]

[image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image ]

Example 199

N-(3-{3-[3-(4-acetylphenyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide - and formate salt

[image]

To a solution of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenylmethanesulfonamide trifluoroacetate (106 mg, 0.27 mmol) in N,N-dimethylformamide (4 ml) was added sodium hydrogen carbonate (90 mg, 1.1 mmol), 1-[4-(3-chloropropyl)phenyl]ethanone (58 mg, 0.29 mmol), and sodium iodide (catalytic amount) and the reaction mixture is heated to 70°C during 20 hours. After cooling, the solvent is removed under vacuum to give a crude residue. It is purified (14 g) on a silica gel chromatography column by elution using a mixture of ethyl acetate:hexane (75:25), and then with pure ethyl acetate. A partially purified product was obtained by combining and evaporating the corresponding fractions. This substance was further purified by preparative HPLC (Condition 1) to give the formate salt of the title compound (16 mg, 12%) as a yellow oil.

1H-NMR (300MHz, CDCl3, data for formate salt): 0.85 (t, 3H), 1.70 (q, 2H), 2.05 (quintet, 2H), 2.15 (s, 2H), 2.55 (s, 3H), 2.70 (t, 2H), 2.80-2.85 (m, 4H), 2.95 (s, 3H), 3.70-3.80 (m, 2H), 7.00 (d, 1H), 7.05-7.10 (m, 2H), 7.20-7.28 (m, 3H), 7.90 (d, 2H), 8.40 (s, 1H).

MS (electron spray): M/Z (M-H) 439; C25H32N2O3S - H calculated 439.2.

Example 200:

N-(3-{3-[2-(benzyloxy)benzyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

[image]

N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide was added to a solution of 2-benzyloxybenzaldehyde (27mg, 0.13mmol) in dichloromethane (5ml) at room temperature. trifluoroacetate (50 mg, 0.13 mmol) and triethylamine (0.05 ml, 0.38 mmol). The reaction mixture was stirred at room temperature for 2 hours. At this point, sodium triacetoxyborohydride (40.8 mg, 0.19 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Then water (5ml) is added to the reaction mixture, and the two layers are separated using a Whatman filter tube (hydrophobic polytetrafluoroethylene membrane). The organic layer is then evaporated to dryness in a stream of nitrogen. The residue is purified on a chromatographic column using a Sep-Pak™ container packed with silica gel (10 g) eluting with a mixture of hexane:ethyl acetate (100:0, 1:1, 1:3, 1:6, 1:9 and 0: 100) to give the title compound (28 mg, 46%) as an oil.

1H-NMR (300MHz, CDCl3): 0.85 (t, 3H), 2.80 (s, 2H), 2.00-2.10 (m, 2H), 2.85 (d, 2H), 3 .00 (s, 3H), 3.10-3.20 (dd, 2H), 3.80 (s, 2H), 5.10 (s, 2H), 6.90-7.05 (m, 3H ), 7.10 (m, 2H), 7.20-7.30 (m, 3H), 7.40-7.50 (m, 6H).

MS (electron spray): M/Z (M+H) 477; C28H32N2O3S + H calculated 477.

Example 201

N-{3-[3-(4-cyanobenzyl)-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

[image]

The above compound was prepared by a similar procedure as in Example 167, using N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide trifluoroacetate (100 mg, 0.25 mmol) and 4-cyanobenzaldehyde (33 mg, 0.25 mmol) as starting materials. The product is purified using preparative HPLC (condition 3) to give the title compound (28 mg, 28 %) as an off-white solid.

1H-NMR (300MHz, CDCl3): 0.85 (t, 3H), 1.80 (s, 2H), 2.05 (q, 2H), 2.80 (d, 2H), 3.00 (s, 3H ), 3.10 (d, 2H), 3.70 (s, 2H), 7.00-7.20 (m, 3H), 7.20 (m, 1H), 7.40 (d, 2H) , 7.60 (d, 2H)

MS (electron spray): M/Z (M+H) 396; C22H25N3O2S - H calculated 396.

Example 202

N-(3-{-[2-(4-cyclopropylphenoxy)ethyl]-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

[image]

To a solution of N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide trifluoroacetate (75 mg, 0.19 mmol) in N,N-dimethylformamide (3 ml) was added sodium bicarbonate (64 mg, 0.8 mmol), 1-(2-chloroethoxy)-4-cyclopropylbenzene (41 mg, 0.21 mmol), and sodium iodide (3 mg, catalytic amount), and the reaction mixture was heated to 60°C for 20 hours. After cooling, the solvent is removed under vacuum to give a crude residue. It was purified by preparative HPLC (Condition 2) to give the formate salt of the title compound (4 mg, 5%) as a brown gum.

1H-NMR (300MHz, CDCl3, data for formate salt): 0.55-0.60 (m, 2H), 0.80-0.95 (m, 5H), 1.80-1.90 (m, 3H), 2.25 (bs, 2H), 2.95 (s, 3H), 3.15 (d, 2H), 3.45 (t, 2H), 3.803.90 (m, 2H), 4, 20 (t, 2H), 6.90 (d, 2H), 7.00 (d, 2H), 7.05-7.15 (t, 2H), 7.20 (s, 1H), 7.30 (t, 1H).

MS (electron spray): M/Z (M-H) 439; C25H32N2O3S - H calculated 439.2.

Example 203

N-(3-{6-ethyl-3-[(2-phenylcyclopropyl)methyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide

[image]

In the mixture of trans-2-phenylcyclopropylcarboxaldehyde {ref. J. Org. Chem., 1992, 57, 1526} (30 mg, 0.2 mmol) and trifluoroacetic acid salt of N-[3-(6-ethyl-3azabicyclo[3.1.0]hex-6-yl)phenylmethanesulfonamide (50 mg, 0 .13 mmol) in anhydrous 1,2-dichloroethane, Hunig's base (0.02 ml, 0.12 mmol) is added. The mixture was placed in an ultrasonic bath for 3 minutes, and then stirred for a further 30 minutes, followed by the addition of sodium triacetoxyborohydride (50 mg, 0.25 mol). After stirring for 72 hours, the reaction mixture was diluted with ethyl acetate (50 ml) and partitioned between saturated sodium bicarbonate solution (2 x 25 ml). The organic layer is washed with salt solution (2 x 20 ml), dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure, resulting in a yellow/brown oil. This oil was dissolved in a minimal amount of dichloromethane and purified using a Biotage™ 6 g container eluting with a gradient of ethyl acetate:hexane (30:70) to ethyl acetate (100%) to give the title compound (32 mg, 62%) as an oil.

1H-NMR (300MHz, CDCl3): 0.78-0.90 (m, 3H), 0.97 (m, 1H), 1.24 (m, 1H), 1.72 (m, 1H), 1 .76-1.79 (m, 2H) 1.90-2.05 (m, 2H) 2.45 (dd, 1H), 2.60 (dd, 1H), 2.84-2.95 (m , 2H), 2.99 (s, 3H), 3.02-3.08 (m, 2H) 6.89-7.3 (m, 9H).

MS (electron spray): M/Z (M+H) 411; C24H30SO2N2 + H calculated 411

PREPARATION

No. Preparations 1 through 148 of International Patent Application WO00/39089 are incorporated herein by reference in their entirety, and the same reference numerals are attached herein.

Preparation 149:

1-[4-(3-chloropropyl)phenyl]ethanone

[image]

Dissolve aluminum chloride (15.0 g, 0.11 mol) and acetyl chloride (16.0 g, 0.20 mol) in dichloromethane (50 mL) at room temperature. This mixture was then added dropwise to a solution of 1-chloro-3-phenylpropane (15.5 g, 0.10 mol) in dichloromethane (25 ml) at room temperature over 15 minutes. The mixture is stirred for 1 hour, and then carefully poured onto ice. The aqueous layer is extracted with dichloromethane (450 ml). The organic layer was washed with water and brine, then dried (MgSO4) and concentrated under reduced pressure to give the title compound (19.2 g, 98%) in the form of an oil.

1H-NMR (300MHz, CDCl3): 2.10 (quintet, 2H), 2.60 (s, 3H), 2.85 (t, 2H), 3.55 (t, 2H), 7.30 (d , 2H), 7.90 (d, 2H).

MS (thermospray): M/Z [M+NH4] + 214; C11H13ClO + NH4 calculated 214.1.

Preparation 150:

1-(2-chloroethoxy)-4-cyclopropylbenzene

[image]

4-Cyclopropylphenol (6.75 g, 50.3 mmol, reference: Horrom et al., Org. Prep. Proceed. Inf., 1992, 24 (6), 696-698), 2-chloroethyl p-toluenesulfonate (17, 71 g, 75.5 mmol), and potassium carbonate (10.4 g, 75.4 mmol) in anhydrous acetonitrile (500 ml) were stirred under nitrogen at reflux for 30 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer is washed with water (3 x 250 ml), dried (MgSO4), filtered and concentrated under reduced pressure. This raw material is purified on a silica gel chromatography column by eluting with a mixture of hexane:dichloromethane (4:1), and then using a mixture of hexane:dichloromethane (3:1), which gives the title compound (8.7 g, 88%) in the form of a solid .

T.p.: 47-48°C

1H-NMR (300MHz, CDCl3): 0.60-0.70 (m, 2H), 0.85-0.95 (m, 2H), 1.80-1.95 (m, 1H), 3, 81 (t, 2H), 4.21 (t, 2H), 6.82 (d, 2H), 7.02 (d, 2H).

MS (thermospray) M/Z (M) 196; C11H13OCl calculated 196.1.

Preparation 151:

1-Allyl-1H-pyrrole-2,5-dione (see J. Org. Chem., 1997, 62, 2652)

[image]

A solution of allylamine (57.1 g, 1.00 mol) in toluene (1000 ml) during one hour. The mixture was stirred at room temperature for 20 hours, then zinc chloride (136.3 g, 1.00 mol) was added and the reaction was heated to 80°C. Then 1,1,1,3,3,3-hexamethyldisilazane (242 g, 1.5 mol) in toluene (1000 ml) was added dropwise over one hour and the mixture was stirred at 80°C for the next 4 hours. The mixture is cooled to room temperature, and then poured into 1 N HCl (4000 ml). The two layers are separated and the organic layer is washed with water (2000 ml), saturated sodium bicarbonate solution (2000 ml) and brine (2000 ml). The organic layer was concentrated under vacuum to give the title compound (74 g, 54%) as a solid.

1H-NMR (300MHz, CDCl3): 4.05 (d, 2H), 5.00-5.15 (m, 2H), 5.60-5.80 (m, 1H), 6.65 (2H, s) .

Preparation 152:

1-(3-nitrophenyl)-1-propanone hydrazone

[image]

Hydrazine monohydrate (96.8 g, 1.93 mol) was slowly added to a solution of 3-nitropropiophenone (168 g, 0.93 mol) in ethanol (830 mL) at room temperature using an addition funnel. The reaction mixture is heated at reflux for 4 hours, and then cooled to room temperature. The solvent was removed under vacuum and the residue partitioned between dichloromethane (750 ml) and water (750 ml). The two layers are separated and the organic layer is washed with brine (250 ml), dried (Na2SO4), filtered and concentrated under vacuum to give an orange oil. This residue was recrystallized from diisopropyl ether at -20°C to give the title compound (110 g, 61%) as a yellow crystalline solid.

T.p.: 32°C

1H-NMR (300MHz, CDCl3): 1.20 (t, 3H), 2.70 (q, 2H), 5.65 (broad s, 2H), 7.50 (t, 1H), 7.95 (d, 1H), 8.10 (d, 1H), 8.50 (s, 1H).

MS (Electronspray) M/Z [MH] 194; C9H11N3O2 + H calculated 194.1.

Preparation 153:

3-Allyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

[image]

To a stirred solution of 1-(3-nitrophenyl)-1-propanone hydrazone (84.7 g, 439 mmol) in 1,4-dioxane (1000 mL) was rapidly added manganese dioxide (grade CMD-1 from Sumitromo, 175 g, 2.01 mol), followed by a saturated solution of potassium hydroxide (40 ml) in ethanol at room temperature. The mixture is stirred at room temperature for 18 minutes, during which time the reaction temperature rises from 19°C to 25°C. Then the mixing is stopped and the mixture is allowed to settle. This mixture is then filtered through a Celite® column; dropwise, directly into a solution of 1-allyl-1H-pyrrole-2,5-dione (57.3 g, 418 mmol) in 1,4-dioxane (200 mL). The Celite® column is washed with 1,4-dioxane (100 ml) to ensure complete addition of the reactants. After stirring at room temperature for one hour, the mixture is heated at reflux for 20 hours. The mixture is cooled to room temperature and the solvent is removed under vacuum. The residue was then recrystallized from diisopropyl ether (1000 mL) at 0°C to give the title compound (83 g, 66%) as an off-white crystalline solid.

T.p.: 128-129°C

1H-NMR (300MHz, CDCl3): 0.90 (t, 3H), 1.80 (q, 2H), 2.80 (s, 2H), 4.05 (d, 2H), 5.20 (d , 1H), 5.30 (d, 1H), 5.75-5.85 (m, 1H), 7.55 (t, 1H), 7.70 (dd, 1H), 8.20 (dd, 1H), 8.25 (s, 1H).

Preparation 154:

3-allyl-6-(3-aminophenyl)-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

[image]

To a suspension of 3-allyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (93 g, 310 mmol) and iron powder (151 g, 2.70 mol) in stirring ethanol (6.75 L) was added with calcium chloride (16.7 g, 0.15 mol) in water (1.2 L). The mixture is heated at reflux for three hours, then cooled to room temperature before being filtered through Celite®. The filtrate is concentrated under vacuum to give a wet solid. This substance is dissolved in dichloromethane (500 ml), after which the two layers are separated. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to give a light yellow solid (81 g). This substance was recrystallized from ethyl acetate and hexane (1:1; 6 ml per gram) at room temperature to give the title compound (54 g, 65%) as a light yellow crystalline solid.

1H-NMR (300MHz, CDCl3): 0.90 (t, 3H), 1.75 (q, 2H), 2.75 (s, 2H), 3.95 (broad s, 2H), 4.05 ( d, 2H), 5.25 (d, 1H), 5.35 (d, 1H), 5.75-5.85 (m, 1H), 6.65 (d, 1H), 6 .70 (s, 1H), 6.75 (d, 1H), 7.10 (t, 1H).

Preparation 155:

3-(3-Allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)aniline

[image]

To a solution of lithium aluminum hydride (1 M solution in THF; 400 ml, 400 mmol) in tetrahydrofuran (400 ml), under a nitrogen atmosphere at -15°C, was added 3-allyl-6-(3-aminophenyl)-6- ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (44 g, 163 mmol) in tetrahydrofuran (250 mL) using an addition funnel over 0.5 h. The mixture is then slightly warmed to room temperature for one hour. The mixture is heated to 50°C for 3 hours, and then cooled to 5°C. Water (400 ml) is then carefully added to the cooled (5°C) reaction mixture. The solid is removed by filtration through a Celite® column, washed with ethyl acetate (400 ml). The filtrate was dried (MgSO4), filtered, and concentrated under vacuum to give the title compound (38.1 g, 96%) as a golden oil.

1H-NMR (300MHz, CDCl3): 0.85 (t, 3H), 1.80-1.95 (m, 4H), 2.85-3.00 (m, 4H), 3.15 (d, 2H), 3.60 (broad s, 2H), 5.10 (d, 1H), 5.20 (d, 1H), 5.80-5.95 (m, 1H), 6.50 (d, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 7.05 (t, 1H).

MS (AP+) M/Z [MH] + 243; C16H22N2 + H calculated 243.2.

Preparation 156:

N-[3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide

[image]

In a solution of 3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)aniline (41 g, 169 mmol) and triethylamine (34 g, 337 mmol) in dichloromethane (750 ml) at -40°C, methanesulfonyl chloride (23.7 g, 206 mmol) was added dropwise using an addition funnel. The reaction mixture was slowly warmed to room temperature for 2 hours and then stirred at room temperature for 20 hours. The organic layer was then washed with water (4 x 500 ml), dried (MgSO4), filtered and concentrated under vacuum to give the title compound (59.0 g) as a crude gum.

1H-NMR (300MHz, CDCl3): 0.85 (t, 3H), 1.85 (s, 2H), 1.95 (q, 2H), 2.80-3.20 (m, 9H), 5 .10-5.25 (m, 2H), 5.80-5.95 (m, 1H), 7.00-7.40 (m, 4H).

Preparation 157:

N-[3-(6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide

[image]

Into a degassed solution of N-[3-(3-allyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (54.0 g, 169 mmol) and 1,3-dimethylbarbituric acid (80.0 g, 512 mmol) in dichloromethane (500 mL), under a nitrogen atmosphere, was added tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol). The mixture is heated at reflux for 8 hours, and then stirred at room temperature for 20 hours. The organic layer was then extracted with 2M HCl (2 x 100 ml) and water (100 ml). The combined aqueous layers were then washed with dichloromethane (4 x 100 ml) and lyophilized to give a crude solid. This substance was purified by preparative HPLC (Condition 4) to give the trifluoroacetic acid salt of the title compound (25.2 g, 53%) as a gray solid.

1H-NMR (300MHz,, CD3OD): 0.90 (t, 3H), 1.65 (q, 2H), 2.30-2.40 (m, 2H), 2.90 (s, 3H), 3.25-3.35 (m, 2H), 3.70-3.80 (m, 2H), 7.10-7.15 (m, 2H), 7.20 (s, 1H), 7, 30 (t, 1H).

MS (AP+): M/Z [MH] + 281; C14H20N2O2S + H calculated 281.1.

Preparation 158:

3-Benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

MnO2 (350g, 2.3mol) was added to a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone (100g, 0.56mol) in dioxane (1 l) and the reaction mixture was stirred at room temperature for 30 min. The mixture is filtered through celite, and the celite column is washed with dioxane (200 ml). The filtrate is returned to the flask, and N-benzyl maleimide (110 g) is added in portions over 20 min. The reaction mixture was stirred at room temperature for 4 hours before being heated to reflux for 16 hours. The reaction mixture is cooled to room temperature, and the solvent is removed under vacuum. The residue is triturated in methanol (500 ml), and the product is isolated by filtration as a white crystalline solid (56%).

NMR (CDCl3) d: 1.31 (s, 3H), 1.55 (s, 3H), 2.80 (s, 2H), 4.63 (s, 2H), 7.28-7.34 (m, 3H), 7.43-7.45 (d, 2H), 7.52-7.56 (t, 1H), 7.63-7.65 (d, 1H), 8.13-8.16 ( d, 1H), 8.17 (s, 1H)

MS (APCI): m/z [MH+] 337.5 +H calculated 337.3

Preparation 159:

6-(3-Aminophenyl)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione

5% Pt was added to a mixture of 3-benzyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (30g, 89 mmol) in ethyl acetate (600 ml) /C (1.5g, 5% by weight). The mixture is hydrated at 4 atm. (=60 psi)/room temperature for 18 hours The mixture is filtered through Arbacel, and the resulting solution is evaporated under vacuum to give the product as a white crystalline solid (24 g, 88%).

NMR (CDCl3) d: 1.26 (s, 3H), 2.74 (s, 2H), 3.7 (2H, bs), 4.60 (s, 2H), 6.56-6.58 ( d, 1H), 6.60 (s, 1H), 6.65-6.67 (d, 1H), 7.07-7.11 (t, 1H), 7.26-7.33 (m, 3H), 7.42-7.44 (m, 2H).

MS (APCI): m/z [MH+] 307.5 +H calculated 307.4

Preparation 160:

N-{3-[3-Benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

Pyridine ( 9.5ml, 118 mmol) followed by the slow addition of methanesulfonyl chloride (9.1 ml, 118 mmol). The reaction was stirred at room temperature for 2.5 hours. The reaction mixture was washed successively with 1 M HCl solution (120 ml) and water (120 ml). Ethyl acetate is dried over MgSO4 and evaporated under reduced pressure to give the product as an orange solid (30 g, 99%).

NMR (CDCl 3 ) d: 1.27 (s, 3H), 2.77 (s, 2H), 3.02 (s, 3H), 4.61 (s, 2H), 7.08-7.14 ( m, 3H), 7.26-7.32 (m, 4H), 7.41-7.42 (d, 2H).

MS (APCI): m/z [MH+] 385.7 +H calculated 385.5

Preparation 161:

N-{3-Benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

In a solution of N-{3-[3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide (150 g, 391 mmol), under a nitrogen atmosphere sodium borohydride (31 g, 820 mol) was added. The reaction mixture was cooled to <10°C, and BF3OEt2 (138.6 ml, 1094 mmol) was added dropwise while maintaining the temperature at <10°C. The reaction mixture was warmed to room temperature over 2 hours before being refluxed for a further 8.5 hours. The reaction mixture was cooled between 0°C and 5°C, and an aqueous solution of piperazine (198.5 g, 2304 mol in 1.26 l of water) was added. The reaction mixture is then heated at reflux for 18 hours. The THF is removed under vacuum, ethyl acetate (900 ml) is added, and the phases are separated. The aqueous phase is extracted with an additional amount of ethyl acetate (450ml). The organic phases are combined and washed with water (750 ml). The organic layer is dried over MgSO4 and evaporated under vacuum to give the product as a white crystalline solid (129 g, 93%).

NMR (CDCl 3 ) d: 2.62 (s, 3H), 2.80-2.83 (d, 2H), 2.99 (s, 3H), 3.03-3.07 (d, 2H), 3.68 (s, 2H), 7.01-7.02 (s, 1H), 7.06-7.08 (m, 2H), 7.22-7.26 (m, 3H), 7, 30-7.32 (m, 3H).

MS (APCI): m/z [MH+] 357.5 +H calculated 357.5

Preparation 162:

N-{3-[6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

Ammonium formate (10.6 g, 168 mmol), and the reaction is stirred for 5 minutes. 10% Pd/C (8 g) is added, and the resulting mixture is heated at reflux for 16 hours. The mixture is cooled, and the catalyst is removed by filtering through celite. The solvent is removed under vacuum to give the product as a light yellow oil, which solidifies on standing (15.2 g, 85%).

NMR (CDCl3) d: 1.27 (s, 3H), 1.85-1.88 (d, 2H), 2.93 (s, 3H), 3.07-3.10 (d, 2H), 3.39-3.44 (d, 2H), 6.92-6.97 (m, 2H), 7.06 (s, 1H), 7.20-7.23 (m, 1H).

MS (APCI): m/z [MH+] 267.4 +H calculated 267.3

Preparation 163:

3-Benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

MnO2 (126 g, 144 0mol) was added to a solution of 1-(3-nitrophenyl)-1-propanone hydrazone (42.1 g, 217 mmol) in dioxane (630 ml) and the reaction mixture was stirred at room temperature for 20 min. The mixture is filtered through celite, and the celite column is washed with dioxane (200 ml). The filtrate was returned to the flask, and N-benzyl maleimide (44.9 g, 239 mmol) was added in portions over 20 min. The reaction mixture was stirred at room temperature for 60 hours before being heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue is heated under reflux in methanol (1200 ml) for 3 hours, and then cooled to room temperature. The product is isolated by filtration as a white crystalline solid (42.4 g, 56%).

NMR (CDCl3) d: 0.69-0.73 (t, 3H), 1.47-1.49 (q, 2H), 2.78 (s, 2H), 4.64 (s, 2H), 7.3-7.32 (m, 2H), 7.43-7.44 (d, 1H), 7.52-7.55 (t, 1H), 7.62-7.65 (d, 2H ), 8.17-8.18 (m, 3H).

MS (APCI): m/z [MH+] 351.5 +H calculated 351.3

Preparation 164:

6-(3-Aminophenyl)-3-benzyl-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione

To a mixture of 3-benzyl-6-ethyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (42.1 g, 120 mmol) in ethyl acetate (850 ml) was added 5% Pt/C (2.1 g, 5% by mass). The mixture is hydrated at 60psi/room temperature for 18 hours. The mixture is filtered through Arbacel, and the resulting solution is evaporated under vacuum to give the product in the form of a white crystalline solid (34.1 g, 89%).

NMR (CDCl3) d: 0.70-0.74 (t, 3H), 1.41-1.47 (q, 2H), 2.73 (s, 2H), 3.68 (bs, 2H), 4.61 (s, 2H), 6.55-6.57 (d, 1H), 6.60 (s, 1H), 6.66-6.68 (d, 1H), 7.07-7, 10 (t, 1H), 7.28-7.32 (m, 3H), 7.41-7.43 (d, 2H).

MS (APCI): m/z [MH+] 321.4 +H calculated 321.4

Preparation 165:

N-{3-[3-Benzyl-6-ethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6 yl]phenyl}methanesulfonamide

To a solution of 6-(3-aminophenyl)-3-benzyl-6-ethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (31.5 g, 98 mmol) in dichloromethane (250 ml) is added pyridine (9.5 mL, 118 mmol) followed by slow addition of methanesulfonyl chloride (9.1 mL, 118 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 1M HCl solution (250 ml) and water (120 ml). Dichloromethane is dried over MgSO4 and evaporated under vacuum to give the product as a pink waxy solid (38.2 g, 98%).

NMR (CDCl3) d: 0.68-0.72 (t, 3H), 1.42-1.47 (q, 2H), 2.75 (s, 2H), 3.02 (s, 3H), 4.62 (s, 2H), 7.13-7.18 (m, 3H), 7.29-7.42 (m, 4H), 7.41-7.43 (d, 2H).

MS (APCl): m/z [MH+] 399.6 +H calculated 399.5

Preparation 166:

N-{3-Benzyl-6-ethyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

In a solution of N-{3-[3-benzyl-6-ethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide (38.2 g, 95 mmol), in Sodium borohydride (7.46 g, 201 mmol) was added to THF (200 ml) under a nitrogen atmosphere. The reaction mixture was cooled to < 10 °C and BF 3 OEt 2 (38.1 ml, 268 mmol) was added dropwise, maintaining the temperature at < 10 °C. The reaction mixture is warmed to room temperature for 2 hours before being heated at reflux for the next 12 hours. 320 ml of water). The reaction mixture is then heated at reflux for 18 hours, the THF is removed under vacuum, ethyl acetate (200 ml) is added, and the phases are separated. The aqueous phase is extracted with an additional amount of ethyl acetate (200 ml). The organic phases are combined and washed with 3 separate amounts of water (3 x 400 ml). The organic layer is dried over MgSO4 and evaporated under vacuum to give the product in the form of a white crystalline solid (3.5g, 94%).

NMR (CDCl3) d: 0.84-0.88 (t, 3H), 1.76-1.77 (d, 2H), 2.06-2 12 (q, 2H), 2.79-2, 81 (d, 2H), 2.99 (s, 3H), 3.06-3.08 (d, 2H), 3.67 (s, 2H), 7.01-7.03 (d, 1H) , 7.08-7.10 (d, 2H), 7.22-7.26 (m, 3H), 7.30-7.32 (m, 3H).

MS (APCI): m/z [MH+] 371.3 +H calculated 371.5

Preparation 167:

N-{3-[6-Ethyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide

Ammonium formate ( 255 mg, 4.05 mmol) and the reaction mixture was stirred for 5 minutes. 10% Pd/C (200 mg) is added, and the resulting mixture is heated at reflux for 2 hours. The mixture is cooled, and the catalyst is removed by filtering through celite. The solvent is removed under vacuum to give the product as a light yellow oil which solidifies on standing (15.2 g, 85%).

NMR (CDCl3) d: 0.80-0.84 (t, 3H), 1.64-1.69 (q, 3H), 1.82-1.86 (d, 2H), 2.98 (s, 3H ), 3.12-3.18 (d, 2H), 3.21-3.26 (d, 2H), 7.01-7.06 (d, 1H), 7.10-7.14 (m , 2H), 7,257.28 (m, 1H).

MS (APCI): m/z [MH+] 281.7 +H calculated 281.4

Other suitable materials for the synthesis of compounds of formula (I) with different R 4 groups are available from the sources indicated in the table below, which also lists their routine derivatizations or analogous syntheses.

[image] [image] [image] [image] [image] [image] [image]

Claims (34)

1. A substance representing a compound of formula I, [image] characterized in that the "Ar" ring is preferably a phenyl fused to benzene or a 5- or 6-membered heteroaryl ring; R1 when taken singly is H, halogen, NO2, NH2, NY2WY1, Het1, AD, CO2R7, C(O)R8, C(=NOH)R8 or OE, Y2 is H, C1-6 alkyl, C3- 6 alkenyl (wherein both alkyl and alkenyl are preferably substituted with aryl, aryloxy or Hetl), W is SO2, CO, C(O)O, P(Y1)=O, P(Y1)=S, Y1 is C1 -10 alkyl (preferably substituted with one or more substituents independently selected from the group consisting of halogen, OH, C1-4 alkoxy, C1-6 alkanoyloxy, CONH2, C1-6 alkoxycarbonyl, NH2, aryl, mono- or di- (C1 -4 alkyl)amino, C3-8 cycloalkyl, phthalimidyl, Hetl), Hetl, aryl (optionally substituted with one or more substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl and halogen), NH2, N (C1-6 alkyl)2 or NH(C1-6alkyl), Hetl is a heterocyclic group containing up to 4 heteroatoms selected from the group consisting of N, O and S, which can contain up to 3 rings (suitably it is a heteroaryl group, preferably a heteroaryl fused to a benzene or pyridine group), preferably substituted with one or more substituents independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 haloalkyl, C3-6 halocycloalkyl, =O, OH, halogen, NO2 , SiR19aR19bR19c, CON20aR20b, NR20aR20b, SR21a, NR21bSO2R22a, NR21cC(O)OR22b, NR21dCOR22d, and C1-6 alkoxycarbonyl, and if the S atom is present in the ring, it can be present as part of -S-, S(O)- or - S(O2)- groups, and the carbon atom in the ring may be present as part of the carbonyl unit; R19a, R19b, R19c independently represent C1-6 alkyl or aryl, R20a and R20b independently represent H, C1-6 alkyl, aryl, (C1-4 alkyl) phenyl, wherein alkyl, aryl and alkylphenyl optionally substituted with one or more substituents such as C1-4 alkyl, C1-4 alkoxy, OH, NO2, NH2 and/or halogen, or R20a and R20b can together with the nitrogen atom to which they are attached form 4- to 6 -membered ring optionally substituted with one or more substituents independently selected from the group consisting of one or more C1-4 alkyl, C1-4 alkoxy, OH, =O, NO2, NH2 and/or halogen, R21a, b, c and d independently one on the other, they represent H, C1-6 alkyl, aryl or C1-4 alkylphenyl, wherein both alkyl, aryl, and alkylphenyl are optionally substituted with one or more substituents such as C1-4 alkyl, C1-4 alkoxy, OH, NO2, halogen, NH2, R22a, b and c independently of each other represent C1-6 alkyl, aryl or C1-4 alkylphenyl, wherein both alkyl, aryl, and alkylphenyl are preferably with substituted with one or more substituents such as C1-4 alkyl, C1-4 alkoxy, OH, NO2, halogen, NH2, A is C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene, each of which is preferably substituted with one or more substituents such as C1-4 alkyl, C1-4 alkoxy, halogen and/or OH, D is H, OH, CN, NR25R26, CONR25R26, NHR27, CO2R28, COR29, C(=NOH)R29, or AD is CN, NR25R26, CONR25R26, where R25 and R26 are either independently H, C1-3 alkyl, C3-8 cycloalkyl, aryl, C1-4 alkylphenyl (wherein C1-3 alkyl, C3-8 cycloalkyl, aryl, and C1-4 alkylphenyl preferably substituted with one or more substituents such as NO2, halogen, C1-4 alkyl and/or C1-4 alkoxy, (wherein the latter are also C1-4 alkyl and C1-4 Alkoxy optionally substituted with one or more halogen atoms)), or R25 and R26 together with the nitrogen atom to which they are attached can form a 4- to 7-membered heterocyclic ring which optionally contains one or more further hetero atoms selected from the group consisting of N , O and S, wherein the ring is optionally substituted with one or more substituents such as C1-4 alkyl, OH, =O, NO2, NH2 and/or halogen, R27 is COR30, CO2R31a, SO2R31b, R28 and R29 are independently of each other H, C1-6 alkyl, C3-8 cycloalkyl, aryl or C1-4 alkylphenyl, wherein both C1-6 alkyl, C3-8 cycloalkyl, aryl and C1-4 alkylphenyl are optionally substituted with one or more substituents such as NO2, halogen, C1-4 alkyl C1-4 alkoxy (wherein both C1-4 alkyl and C1-4 alkoxy are preferably substituted with one or more halogen atoms), R30 is H, C1-4 alkyl, C3-8 Cycloalkyl, C1-4 Alkoxy, C3-8 Cycloalkyloxy, Aryl, Aryloxy, C1-4 Alkylphenyl, Phenyl(C1-4)Alkoxy, (where C1-4 Alkyl, C3-8 Cycloalkyl, C1-4 Alkoxy, C3-8 cycloalkyloxy, aryl, aryloxy, C1-4 alkylphenyl, and phenyl(C1-4)alkoxy optionally substituted with one or more substituents such as NO2, halogen, C1-4 alkyl, C1-4 alkoxy (at wherein both alkyl and alkoxy are preferably substituted with one or more ha logon atoms)), R31a and R31b are independently C1-4 alkyl, C3-8 cycloalkyl, aryl or C1-4 alkylphenyl, each of which is optionally substituted with one or more substituents such as NO2, halogen, C1 -4 alkyl or C1-4 Alkoxy, wherein both the latter alkyl and Alkoxy are preferably substituted with another halogen atom, E is H, CONR32R33, CSNR32R33, COR34, CO2R34, COCH(R34a)NH2, R35, CH2CO2R35a, CHR35bCO2R35a, CH2OCO2R35C, CHR35dOCO2R35c, COCR36=CR37NH2, COCHR36CHR37NH2, or PO(OR38)2, R32 and R33 are independently H, C3-10 alkylalkenyl, C3-7 cycloalkyl (preferably substituted with C1-4 alkyl), phenyl (per optionally substituted with (X)n), C1-10 alkyl (preferably substituted with C4-7 cycloalkyl (preferably substituted with C1-4 alkyl) or phenyl optionally substituted with (X)n) or R32 and R33 together with an atom of the nitrogen to which they are connected can form a 5- to 8-membered heterocycle, which preferably contains further hetero atoms selected from the group consisting of N, O and S, wherein the heterocycle is preferably substituted with C1-4 alkyl, which is preferably substituted with one or more halogen atoms, R34 is H, C4-7 cycloalkyl (preferably substituted with one or more C1- 4 alkyl), phenyl (preferably substituted with (X)n, C1-4 alkanoyloxy, NR32R33, CONR32R33 and/or OH), or C1-6 alkyl (preferably substituted with one or more halogen atoms, C4-7 cycloalkyl ( which is optionally substituted with one or more C1-4 alkyl), or phenyl (preferably substituted with (X)n, C1-4 alkanoyloxy, NR32R33, CONR32R33 and/or OH)), R34a is H, C1-6 alkyl (preferably substituted with one or more halogen atoms, C4-7 cycloalkyl (preferably substituted with one or more C1-4 alkyl), or phenyl (preferably substituted with (X)n, C1-4 alkanoyloxy, NR32R33, CONR32R33 and/or OH)), C4-7 cycloalkyl (preferably substituted with one or more C1-4 alkyl), phenyl (preferably substituted with (X)n, C1-4 alkanoyloxy, NR32R33, CO NR32R33 and/or OH) or a natural amino acid substituent, R35 is C4-7 cycloalkyl preferably substituted with one or more C1-4 alkyl, phenyl (preferably substituted with one or more (X)n, C1-4 alkanoyl, NHR32, CON(R32)2, and/or OH), C1-6 alkyl (preferably substituted with C4-7 cycloalkyl which is preferably substituted with one or more C1-4 alkyls, or phenyl (preferably substituted with one or more (X)n, C1-4 alkanoyl, NHR32, CON(R32)2, and/or OH)), C1-4 alkoxy(C1-4 alkyl), phenyl(C1-4)alkyloxy(C1-4)alkyl , tetrahydropyranyl, tetrahydrofuranyl, cinnamyl or trimethylsilyl, R35a, b, c and d are independently H, C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl optionally substituted with one or more (X)n or C1-6 alkyl (preferably substituted with C4-7 cycloalkyl which is preferably substituted with one or more C1-4 alkyl, or phenyl which is preferably substituted with one or more (X)n), R36 and R37 n are independently represented by H, C3-6 alkylalkenyl, C4-7 cycloalkyl, phenyl optionally substituted with one or more (X)n, or C1-6 alkyl (optionally substituted with C4-7 cycloalkyl which is optionally substituted with one or more C1-4 alkyl, or phenyl optionally substituted with one or more (X)n, R38 is C4-7 cycloalkyl optionally substituted with one or more C1-4 alkyl, phenyl optionally substituted with one or more (X)n, or C1-6 alkyl (preferably substituted with C4-7 cycloalkyl which is preferably substituted with one or more C1-4 alkyl, or phenyl which is optionally substituted with one or more (X)n, R2 considered singly is H or halogen; or R1 and R2, when attached to adjacent carbon atoms, may represent together with the carbon atom to which they are attached Hetla; Hetla is a heterocyclic group that contains up to 4 heteroatoms selected from the group consisting of N, O and S, and which can contain up to 3 rings (and preferably a 5- to 7-membered heterocyclic ring is connected to benzene), whereby is a group optionally substituted with one or more substituents independently selected from the group consisting of OH, =O, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy, wherein C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy groups can be optionally substituted with one or more C3-6 cycloalkyl, aryl(C1-6)alkyl, wherein the aryl group is optionally substituted with one or more halogen atoms, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy, whereby the latter C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy groups can optionally be substituted with one or more NR23R24, NR23S(O)nR24, NR23C(O)mR24, and if the S atom is present in the ring, it may be present as part of - S-, S(O)- or -S(O2)- groups, wherein R23 and R24 considered individually independently represent H, C1-4 alkyl, or C1-4 haloalkyl, or R23 and R24 together with a nitrogen atom on which are joined to form a 4- to 6-membered heterocyclic ring that preferably contains one or more further heteroatoms selected from the group consisting of, N, O, or S, wherein the heterocyclic ring is preferably substituted with one or more halogen atoms, and C1-4 alkyl, C1-4 haloalkyl, C1-4 -4 alkoxy and/or C1-4 haloalkoxy group, R3 is H, CN, halogen, C1-6 alkoxy, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C2- 6 alkanoyloxy, C3-8 cycloalkyl, C3-8 cycloalkyloxy, C4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13, NY2WY1, C1-6 alkyl, C2-10 alkenyl, C2-10 alkynyl, (at where the alkyl, alkenyl, and alkynyl groups are preferably substituted with one or more substituents such as CN, halogen, OH, C1-6 alkoxy, C1-6 alkoxycarbonyl, C2-6 alkyloxycarbonyloxy, C1-6 alkanoyl, C1-6 alkanoyloxy, C3-8 cycloalkyl, C3-8 cycloalkyloxy, C4-9 cycloalkanoyl, aryl, aryloxy, heteroaryl, saturated heterocycle, NR12R13, CONR12R13, and/or NY2WY1), R4 is C1-10 alkyl , C3-10 alkenyl or C3-10 alkynyl, wherein each of these groups is connected to the N atom through an sp3 carbon, and wherein the group is substituted with one or more substituents selected from the group consisting of: or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO(heteroaryl1), CO(aryl1), CO2(heteroaryl1 ), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S(O)n(aryl1), S(O)n(heteroaryl1 ), SO2NR25R26 and cycloalkyl1], S(O)nC1-6 alkyl [optionally substituted with one or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO(heteroaryl1 ), CO(aryl1), CO2(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S(O)n( aryl1), S(O)n(heteroaryl1), SO2NR25R26 and cycloalkyl1], aryl2, CO2CH2(heteroaryl1), CO2CH2 (aryl1), cycloalkyl1, CO(heteroaryl1), CO(aryl1), OCO(aryl1), OCO(heteroaryl1) , OCO(C1-6 alkyl), OCOCH2CN, CO2 (heteroaryl1), CO2(aryl1), COCH2(heteroaryl1), S(O)naryl1, S(O)nCH2aryl1, S(O)n(heteroaryl1), S( O)nCH2(heteroaryl1), NHSO2aryl1, NHSO2(C1-6 alkyl), NHSO2(heteroaryl1), NHSO2CH2(heteroaryl1), NHSO2CH2(aryl1), NHCOaryl1, NHCO(C1-6 alkyl), NHCONHaryl1, NHCONH(C1-6 alkyl ), NHCOheteroaryl1, NHCONHheteroaryl1, NHCO2(aryl1), NHCO2(C1-6 alkyl), NHCO2(heteroaryl1), aryl2oxy, heteroaryl1oxy, C1-6 alkoxycarbonyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26 C2-6 alkanoyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen , OH, CN and or NR25R26, C2-6 alkanoyloxy substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, cycloalkyl1oxy, COcycloalkyl1, heterocycle substituted with one or more substituents selected from the group consisting of C1-6 alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2(C1-6 alkyl), CH2CO2(C1-6 6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl, heterocyclyloxy substituted with one or more of substituents selected from the group consisting of C1-6 alkyl (substituted with OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2(C1-6 alkyl), CH2CO2(C1-6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl, WHEREIN, aryl1 is phenyl which is preferably attached with a C5-7 carboxyl ring, whose sku pin optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl (preferably substituted with OH, CN or halogen), C1-6 haloalkoxy, OH, =O, NY2WY1, halogen, C1-6 alkoxy, CONR25R26 , CH2CONR25R26, NR25R26, NHCONR25R2, CO(C1-6 alkyl), COaryl, COheteroaryl, SO2NR25R26, S(O)n(C1-6 alkyl), S(O)n(aryl), S(O)n(heteroaryl) , CO2(C1-6 alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)1-4CO2(C1-6 alkyl), (CH2)1-4CO2H, (CH2)1-4CO2(aryl) , (CH2)1-4CO2 (heteroaryl), O(CH2)1-4CO2(C1-6 alkyl), O(CH2)1-4CO2H; O(CH2)1-4CO2 (aryl), O(CH2)1-4CO2(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(CH2)1-4CONR25R26 and C3 -7 cycloalkyl, aryl2 is phenyl preferably attached to a C5-7 carboxyl ring, which group is preferably substituted with one or more substituents selected from the group consisting of C1-6 alkyl (preferably substituted with OH), CONR25R26, CH2CONR25R26 , NR25R2, NHCONR25R26, CO(C1-6 alkyl), COaryl, COheteroaryl, SO2NR25R26, S(O)n(C1-6 alkyl), S(O)n(aryl), S(O)n(heteroaryl), CO2 (C1-6 alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)1-4CO2(C1-6 alkyl), (CH2)1-4CO2H, (CH2)1-4CO2(aryl), ( CH2)1-4CO2 (heteroaryl), O(CH2)1-4CO2(C1-6 alkyl), O(CH2)1-4CO2H; O(CH2)1-4CO2 (aryl), O(CH2)1-4CO2(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(CH2)1-4CONR25R26 and C3 -7 cycloalkyl, heteroaryl1 is heteroaryl which is preferably connected to a C5-7 carboxyl ring, whose group is preferably substituted with one or more substituents selected from the group consisting of C1-6 alkyl (preferably substituted with OH, CN or halogen) . 6 alkyl), S(O)n(aryl), S(O)n(heteroaryl), CO2(C1-6 alkyl), CO2(aryl), CO2(heteroaryl), CO2H, (CH2)1-4CO2(C1 -6 alkyl), (CH2)1-4CO2H, (CH2)1-4CO2(aryl), (CH2)1-4CO2 (heteroaryl), O(CH2)1-4CO2(C1-6 alkyl), O(CH2) 1-4CO2H; O(CH2)1-4CO2 (aryl), O(CH2)1-4CO2(heteroaryl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN, O(CH2)1-4CONR25R26 and C3 -7 cycloalkyl, cycloalkyl1 is a C3-10 carboxyl system with one or two rings, which is substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH , CN or NR25R26, with the condition that there are no N-R4 groups in which the hetero atom is connected to another hetero atom through one sp3 carbon, Z is a direct bond, CO or S(O)n group, B is (CH2)p, R12 and R13 independently of each other represent H or C1-4 alkyl, or R12 and R13 can together with the N atom to which they are connected form a 4- to 7-membered heterocycle which preferably contains a further hetero unit selected from the group consisting of NR16, O and/or S, which is preferably substituted with one or more C1-4 alkyl, R14 and R15 independently of each other represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl , aryl or heteroaryl, or R 14 and R 15 may together with the N atom to which they are connected to form a 4- to 7-membered heterocycle which preferably contains a further hetero unit selected from the group consisting of NR16, O and/or S, which is preferably substituted with one or more C1-4 alkyl , R 16 is H, C 1-6 alkyl, C 3-8 cycloalkyl, (C 1-6 alkylene), (C 3-8 cycloalkyl) or (C 1-6 alkylene)aryl, R 5 and R 8 when considered separately are independently H , C1-6 alkyl, R5 and R8 can together with the carbon atom to which they are attached to form a C3-8 cycloalkyl ring, R6, R7, R9 and R10 when considered separately are H, R5 and R6 or R7 can together with the carbon atom on which are linked to form a C3-8 cycloalkyl ring, X is halogen C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy, m is 1 or 2; n is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; q is 0 or 1; "Natural amino acid substituent" means an α-substituent occurring in any of the following naturally occurring amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, histidine, serine, threonine, methionine, cysteine, aspartic acid, glutamic acid acid, asparagine, glutamine, lysine, arginine or proline; "Heteroaryl" represents an aromatic ring containing up to four heteroatoms independently selected from the group consisting of N, O and S, and if an S atom is present in the ring, it may be present as part of -S-, S(O)- or -S( O)2- groups, which can be connected to the rest of the compound via any available atom(s); "Heterocycle" is a group containing 1, 2 or 3 rings, with up to 4 ring heteroatoms selected from the group consisting of N, O and S, and up to 18 ring carbon atoms; "Aryl", included in the definitions of "aryloxy", etc., means a group containing a phenyl ring, which may incorporate a further carboxyl ring attached to said phenyl ring, which may be attached to the rest of the compound via any available ) atoms (examples of such groups include naphthyl, indanyl, etc.) ; "Alkyl", "alkenyl" and "alkynyl" groups can be straight or branched if the number of carbon atoms allows; "Cycloalkyl" groups may be polycyclic if the number of carbon atoms permits; or its pharmaceutical or veterinary acceptable derivatives or prodrugs. 2. The substance according to claim 1, characterized in that the "Ar" ring represents phenyl or pyridyl. 3. A substance according to any preceding claim, characterized in that R1 considered individually is OH, CN, halogen, NO2, NH2, NY2WY1 or Het1. 4. A substance according to any preceding claim, characterized in that R 2 considered individually is H. 5. A substance according to claim 1 or 2, characterized in that R1 and R2, together with the carbon atom to which they are connected, form a 5- to 7-membered heteroaryl ring, preferably connected with benzene, which is preferably substituted with C1-4 alkyl or C1-4 haloalkyl. 6. A substance according to any preceding claim, characterized in that X Cl. 7. A substance according to any preceding claim, characterized in that n is 0 and q is 0. 8. A substance according to any preceding claim, characterized in that R3 is H, CN, or C1-6 alkyl (preferably substituted with one or more halogen atoms, OH, C1-6 alkoxy, C1-6 alkoxycarbonyl, C2-6 alkanoyl , C2-6 alkanoyloxy, C2-6 alkyloxycarbonyloxy, NR12R13, CONR12R13, and/or NY2WY1). 9. A substance according to any preceding claim, characterized in that R4 is C1-10 alkyl, substituted with one or more substituents selected from the group consisting of: C2-6 Alkoxy [substituted with one or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 Alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN, CO(heteroaryl1), CO(aryl1), CO2(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S(O)n(aryl1) , S(O)n(heteroaryl1), SO2NR25R26 and cycloalkyl1], S(O)nC1-6 alkyl [optionally substituted with one or more groups selected from the group consisting of OH, NR25R26, CONR25R26, halogen, C1-6 alkoxy, C2-4 alkynyl, C2-4 alkenyl, heteroaryl1, aryl1, COCH2CN , CO(heteroaryl1), CO(aryl1), CO2(heteroaryl1), COCH2(aryl1), COCH2(heteroaryl1), CO2CH2(aryl1), CO2CH2(heteroaryl1), S(O)n(C1-6 alkyl), S( O)n(aryl1), S(O)n(heteroaryl1), SO2NR25R26 and cycloalkyl1], aryl2, CO2CH2(heteroaryl1), CO2CH2 (aryl1), cycloalkyl1, CO(heteroaryl1), CO(aryl1), OCO(aryl1), OCO(heteroaryl1), OCO(C1-6 alkyl), OCOCH2CN, CO2 (heteroaryl1), CO2(aryl1), COCH2(heteroaryl1), S(O)naryl1, S(O)nCH2aryl 1, S(O)n(heteroaryl1), S(O)nCH2(heteroaryl1), NHSO2aryl1, NHSO2(C1-6 alkyl), NHSO2(heteroaryl1), NHSO2CH2(heteroaryl1), NHSO2CH2(aryl1), NHCOaryl1, NHCO(C1-6 alkyl), NHCONHaril1, NHCONH(C1-6 alkyl), NHCOheteroaryl1, NHCONHheteroaryl1, NHCO2(aryl1), NHCO2(C1-6 alkyl), NHCO2(heteroaryl1), aryl2oxy, heteroaryloxy, C1-6 alkoxycarbonyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26 C2-6 alkanoyl substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, C2-6 alkanoyloxy substituted with substituents such as C1-6 alkyl, aryl, C1-6 alkoxy, CH2(aryl1), C1-4 haloalkyl, halogen, OH, CN or NR25R26, cycloalkyl1oxy, COcycloalkyl1, heterocycle substituted with one or more substituents selected from the group consisting of C1-6 alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2( C1-6 alkyl), CH2CO2(C1-6 6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl, heterocyclyloxy substituted with one or more substituents selected from the group consisting of C1-6 alkyl (substituted by OH), CONR25R26, CH2CONR25R26, NR25R26, NHCONR25R26, CO(C1-6 alkyl), SO2NR25R26, SO2(C1-6 alkyl), CO2( C1-6 alkyl), CH2CO2(C1-6 alkyl), OCH2CO2(C1-6 alkyl), aryl, heterocyclyl, aryloxy, aryl(CH2)oxy, aryl(CH2), CN and C3-7 cycloalkyl. 10. A substance according to any preceding claim, wherein R5, R6, R7, R8, R9 and R10 occur singly and are all H. 11. A substance according to any preceding claim, characterized in that the "Ar" ring represents a group of the formula: [image] 12. A substance according to any preceding claim, characterized in that R 3 is H, CH 3 , C 2 H 5 , i-C 3 H 7 , n-C 3 H 7 or CH 2 OCH 3 . 13. A substance according to any preceding claim except claim 5, characterized in that R 1 is OH, CN, I, Cl, NH 2 , NO 2 , preferably heteroaryl fused to benzene, NHSO 2 Y 1 , NHCOY 1 or NHCO 2 Y 1 . 14. A substance according to any preceding claim, characterized in that R4 is C1-10 alkyl substituted with cycloalkyl1. 15. A substance according to any preceding claim except claims 3, 4 and 13, characterized in that R1 and R2 together with the carbon atom to which they are connected form a 5- to 7-membered heteroaryl unit, preferably substituted with C1-4 alkyl or C1 -4 haloalkyl. 16. A substance according to any preceding claim, characterized in that R 3 is CH 3 or C 2 H 5 . 17. A substance according to any preceding claim except claims 5 and 15, characterized in that R1, when considered individually, is OH, CN, I, Cl, NH2, NO2, 1,2,3-triazolyl, 1,2,4 -triazolyl, imidazol-2-yl, pyridin-2-yl, thien-2-yl, imidazol-4-yl, benzimidazol-2-yl, NHSO2(C1-6 alkyl), NHSO2(C1-6 alkyl) substituted with methoxy, CONH2, OH, CO2(C2-6 alkyl), phthalimido, NH2 or halogen), NHSO2NH2, NHSO2NH(C1-6 alkyl), NHSO2N(C1-6 alkyl)2, NHSO2Het1a, NHCO(C1-6 alkyl) or NHCO2(C1-6 alkyl). 18. A substance according to claim 17, characterized in that R1 is OH, NHSO2CH3, NHSO2C2H5, NHSO2(n-C3H7), NHSO2(i-C3H7), NHSO2(n-C4H7), NHSO2NH(i-C3H7), NHSO2(N- methylimidazol-4-yl), NHSO2(CH2)2OCH3, NHSO2(CH2)2OH, 1,2,4-triazolyl or imidazol-2-yl. 19. A substance according to claim 18, characterized in that R1 is OH, NHSO2CH3, NHSO2C2H5 or imidazol-2-yl. 20. A substance according to claim 15, characterized in that R1 and R2, together with the carbon atom to which they are connected, form an imidazole group preferably substituted at position 2 with CF3. 21. A substance according to any preceding claim, characterized in that R4 is C2-4 alkyl substituted with cycloalkyl1. 22. A substance according to any preceding claim, characterized in that R4 is propyl substituted with cycloalkyl1. 23. A substance according to any preceding claim, characterized in that R4 is propyl substituted with a C3-10 carboxyl system with one or two rings, which is substituted with OH. 24. A substance according to any preceding claim, characterized in that R4 is propyl substituted with (cyclohexyl substituted with OH). 25. A substance according to any preceding claim, characterized in that R4 is (1-hydroxycyclohexyl)prop-3-yl. 26. A substance according to claim 1, characterized in that it has the following relative stereochemistry: [image] 27. The substance according to claim 1, characterized in that it is selected from the group consisting of the compounds of the Examples described here, and its salts and prodrugs 28. Pharmaceutical or veterinary preparation, characterized in that it contains a substance according to any of the previous requirements, and a pharmaceutical or veterinary acceptable carrier. 29. A substance according to any one of claims 1 to 26, characterized in that it is used in medicine. 30. A substance according to any one of claims 1 to 26, characterized in that it is used as a medicine suitable for the treatment of diseases or conditions controlled by an opiate. 31. Use of the substance according to any one of claims 1 to 26, characterized in that it is used in the production of a drug suitable for the treatment of diseases or conditions mediated by opiate. 32. A method of treating a condition mediated by an opiate receptor or receptors, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 26. 33. The procedure for preparing the substance according to claim 1, characterized by the fact that it includes: (a) for compounds of formula I where q is 0 and R1 represents NY2WY1, the reaction of compound of formula II, [image] with a compound of formula III, Z1-WY1 III where Z1 is a suitable leaving group, such as halogen or Y1SO2O-; (b) for compounds of formula I where q is 0, and both R6 and R7 represent H, reduction of compound of formula IV, [image] by using the appropriate reducer; (c) for compounds of formula I where q is 0, and both R9 and R10 represent H, reduction of compound of formula V, [image] by using the appropriate reducer; (d) for compounds of formula I in which q is 0, and R1 and R2 are connected to adjacent carbon atoms, and together with the carbon atoms to which they are connected represent Het1a, in which Het1a represents an imidazolo unit, the reaction of the corresponding compound of formula VI, [image] with a compound of formula VII, RYCO2H VII where RY represents H or any possible substituent on Het1a (as defined above), suitably being H, C1-4 alkyl or C1-4 haloalkyl; (e) where q is 0, the reaction of the compound of formula VIII, [image] with a compound of formula IX, R4-Lg IX where Lg is the leaving group; (f) for compounds of formula I where q is 0 and R6, R7, R9 and R10 are all H, reduction of compound of formula X, [image] with appropriate reduction; (g) for compounds of formula I wherein q is 0 and R 1 is OH, reaction of a compound of formula II wherein Y 2 is H, as defined above, with fluoroboric acid and isoamyl nitrite; (h) for compounds of formula I where q is 0 and R1 is Cl, reacting a compound of formula II where Y2 is H, as defined above, with sodium nitrite in the presence of dilute acid, followed by reaction with copper (I) - chloride in the presence of concentrated acid; (i) for compounds of formula I where q is 1, reaction of a compound of formula I where q is 0 with a suitable oxidant such as hydrogen peroxide; (j) for compounds of formula I where q is 0, reduction of the corresponding compound of formula XXXI, [image] wherein R4aCH2 has the same meaning as R4 as defined above; or (k) for compounds of formula (I) where q is 0, the reductive amination reaction of the above amine of formula VIII with an aldehyde of formula R4a-CHO, wherein R4aCH2 has the same meaning as R4 as defined above. 34. A compound of formula II, IV, V, VI, X, Xa, XI, XII, XXI, XXII, XXIII, XXIV, XXIX, XXIXa, XXX, or XXXI, or a salt thereof, as described herein.