ZA200308638B

ZA200308638B - 4(Phenyl-piperazinyl-methyl)benzamide derivatives and their use for the treatment of pain anxiety or gastrointestinal disorders.

Info

Publication number: ZA200308638B
Application number: ZA200308638A
Authority: ZA
Inventors: William Brown; Plobeck Niklas; Christopher Walpole
Original assignee: Astrazeneca Ab
Priority date: 2001-05-18
Filing date: 2003-11-05
Publication date: 2005-02-07
Also published as: SE0101772D0; UA77672C2

Description

4(Phenyl-piperazinyl-methyl) benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestinal disorders.

Field of the Invention

The present invention is directed to novel compounds, to a process for their preparation, . s their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain, anxiety and functional gastrointestinal disorders.

Background of the Invention

The 8 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the d receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the 6 receptor have also been shown to possess immunomodulatory activities.

The identification of at least three different populations of opioid receptors (, 6 and x) is "now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.

With few exceptions, currently available selective opioid J ligands are peptidic in nature and are unsuitable for administration by systemic routes. One example of a non-peptidic

S-agonist is SNC80 (Bilsky E.J. et al., Journal of Pharmacology and Experimental

Therapeutics, 273(1), pp. 359-366 (1995)). There is however still a need for selective

S-agonists having not only improved selectivity, but also an improved side-effect profile. . Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current 1 ) agonists, as well as having improved systemic efficacy.

Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred & agonist . compounds, described within the prior art, show significant convulsive effects when administered systemically. :

We have now found certain compounds that exhibit surprisingly improved properties, i.a. improved 8-agonist potency, in vivo potency, pharmacokinetic, bioavailability, in vitro stability and/or lower toxicity.

Outline of the Invention

The novel compounds according to the present invention are defined by the formula I 0)

R2 3 ~ R

NOP

R2 R4

N .

N

« wherein rR! is selected from any one of (i) phenyl; (ii) pyridinyl

B® =

N

(111) thienyl

S . (iv) furanyl

Oo (v) imidazolyl

M

\ J \ J : (vi) triazolyl :

WW

N— (vii) pyrrolyl

N

H

(viii) thiazolyl

J

\_J . (ix) pyridyl-N-oxide o ; N

AN

(J wherein each R' heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C,-Cg alkyl, halogenated C,-Cs alkyl, NO,, CF3, C,-Cg alkoxy, chloro, fluoro, bromo, and iodo; 5s Ris independently selected from ethyl and isopropyl, .

R® is independently selected from hydrogen and fluoro; : :

R* is independently selected from -OH, -NH, and -NHSO,R’; and

R’ is independently selected from hydrogen, -CF3 and C,-Cg alkyl, provided that when R? is ethyl and R® is hydrogen then R* cannot be -OH.

The substitutions on the heteroaromatic ring may take place in any position on said ring systems.

When the rR! phenyl ring and the R' heteroaromatic ring(s) are substituted, the preferred substituents are selected from any one of CF;, methyl, iodo, bromo, fluoro and chloro, of which methyl is most preferred.

A further embodiment of the present invention is thus a compound according to formula I wherein R' is as defined above and each R! phenyl ring and R! heteroaromatic ring may : independently be further substituted by a methyl group; 2s A further embodiment of the present invention is a compound according to figure I wherein

R'is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R* is ethyl or isopropyl; R?is hydrogen or fluoro; R* is -NH, or -NHSO,R; and R® is C,-Cg alkyl, optionally with 1 or 2 of the preferred substituents on the Rr! phenyl or Rr! heteroaromatic ring.

An additional embodiment of the present invention is a compound according to figure 1 wherein R' is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R? is ethyl or isopropyl; R?is hydrogen; R* is -NHSO,R?; and R® is C;-Cg alkyl, optionally with 1 or 2 of the preferred substituents on the rR! phenyl or rR! heteroaromatic ring. . Other embodiments of the present invention are compounds according to Figure I wherein a) R'is phenyl, pyrrolyl, or furanyl; R? is ethyl or isopropyl; R? is hydrogen or fluoro; and ‘ 5s R'is -NH,; b) R' is thienyl or imidazolyl; R? is ethyl or isopropyl; Ris hydrogen or fluoro; and R* is -NH,; c)R'is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R? is ethyl or isopropyl; R’ is hydrogen or fluoro; R? is -NHSO,R>; and R’ is C;-C alkyl; and d) R' is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R? is ethyl or isopropyl; R? is hydrogen or fluoro; R* is -NHSO,R?; and R® is C,-Cg alkyl, wherein all embodiments a) to d) may - optionally be substituted with 1 or 2 of the preferred substituents on the R! phenyl or Rr! heteroaromatic ring. :

Within the scope of the invention are also separate enantiomers and salts of the compounds of the formula 1, including salts of enantiomers. Also within the scope of the present is invention are mixtures of the separate enantiomers, such as the racemic mixuture, as well ~ as salts of mixtures of separate enantiomers. :

Separation of racemic mixtures into separate enantiomers is well known in the art and may be accomplished for example by separation on a suitable chiral chromatography column.

Preparation of salts is well known in the art, and may be accomplished for example by mixing a compound of formula I in a suitable solvent with the desired protic acid and isolation by means standard in the art. Salts of compounds of formula I include pharmaceutically acceptable salts and also pharmaceutically unacceptable salts. 2s The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, : cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.

Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents. : 5s Compounds of the invention are useful in disease states where degeneration or dysfunction ) of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET). oo

Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, : generalized anxiety disorder, social phobia, and obesessive compulsive disorder; urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel

Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.

Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound : according to the formula I above, is administered to a patient in need of such treatment. ‘ 5 Methods of preparation

The compounds of the present invention can be prepared using the following general procedure.

Preparation of Phenols; Examples 1-3

The compounds of formula I wherein R* is —OH is prepared by reacting a compound of the general formula II : 0]

R2 3 ~N R

NSPS

Br ii wherein R* and R are as defined in Figure 1 and R* is OMe, with Boc-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the Boc protection group under standard conditions to give a compound of the

Formula II :

Oo

R2_ \ R3 : : R2 OMe 0)

N

H 0 which is thereafter alkylated under reductive conditions with a compound of the Formula

R'-CHO, followed by cleavage of the methyl ether using BBr3 in dichloromethane to give a compound of the Formula I wherein R* is -OH. i

Preparation of Anilines; Examples 4-6 >

The compound of formula I wherein R*is NH, is prepared by reacting a compound of the general formula IV

Oo :

R2 R3

Tod

R? R4 CL

Br Vv wherein R? and R® are as defined in Figure 1 and R* is NO», with Boc-piperazine in + acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the Boc protection group under standard conditions to give a compound of the

Formula V 5

RN R3 ke

NO, ®

N

H Vv : which is thereafter alkylated under reductive conditions with a compound of the Formula :

R'-CHO, followed by reduction of the nitro group using hydrogen and palladium on charcoal to give a compound of the Formula I wherein R* is -NH,.

Preparation of Methyl Sulfonanilides; Examples 7-8

The compound of formula I wherein R* is -NHSO,R® is prepared by reacting a compound . of the general formula VI

Oo

R? R3

TC QO

R? Rs

Br VI wherein R? and R® are as defined in claim 1 and R*is NO, with Boc-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed reduction of the nitro group by hydrogenolysis using palladium on charcoal as the catalyst, metanesulphonylation using methanesulphonylanhydride in dichloromethane in the presence of triethylamine, and thereafter removal of the Boc protection group under standard conditions to give a compound of the Formula VII : 0 : ™ SUSHI

Re NHSO,CH, 0)

N

H Ai which is thereafter alkylated under reductive conditions with a compound of the Formula ©

R'-CHO, followed by reduction of the nitro group using hydrogen and palladium on charcoal to give a compound of the Formula I wherein R* is -NHSO,R”.

Within the scope of the invention are also separate enantiomers and salts of the compounds of the Formula I, including salts of enantiomers. Compounds of Formula I are chiral compounds, with the diarylmethylpiperazine group being the stereogenic center, see Figure

I* below. oO

R2 3 ~N R

NOE

* ©

R? R4 . _N :

N

«

A further embodiment of the present invention is thus the (-)-enantiomer of a compound according to Formula I, as well as a salt of said compound.

A further embodiment of the present invention is thus the (+)-enantiomer of a compound according to Formula I, as well as a salt of said compound.

EXAMPLES

The invention will now be described in more detail by the following Examples, which are not to be construed as limiting the invention.

Scheme 1: Preparation of Fluoro Phenols; Examples 1-3 ey OL om

H AL ep— PN o SOB, CHC < i 2) Boc-piperazine, 3) TFA, CH,Cl, (81%)

Oo o ’ PR F

A Qeee

N

TOC eo on . 0 N 1. 1)BnBr, TEA, ACN

N CH; 2) BBr,, CH,C, (50%) (2 C ) N

N of Example 1 . _H : 1) thiophene-3-carboxaldehyde,

NaBH,CH, MeOH, HOAc 1) imidazole-2-carboxaldehyde, 2) BBr,, CH,Cl,, 26% NaBH,CN, MeOH, HOAc : 2) BBr,, CH,Cl,, 25% . I °

A OH A OH

0) | 0)

SN N

- os E

S B xample 2 « N Example 3

Intermediate 1: 4-] (4-fluoro-3-methoxyphenyl )(hydroxy)methyl]-N,N-diisopropyl- benzamide.

N,N-Diisopropyl-4-iodobenzamide (6.0 g, 18 mmol) was dissolved in THF (200 mL) and cooled to -78 °C under nitrogen atmosphere. n-BuLi (14 mL, 1.3 M solution in hexane, 18 : mmol) was added dropwise during 10 min at -65 to -78 °C. 4-fluoro-3- methoxybenzaldehyde (2.8 g, 18 mmol) was added dropwise dissolved in THF (5 mL). ) NH,Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc / water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0 — 75% EtOAc/heptane) to yield the desired product (3.9 g, ’

60%)."H NMR ( CDCl3) 8 1.0-1.6 (m, 12H), 2.65 (d, J = 4Hz, 1H), 3.4-3.9 (m, 2H), 3.80 (s, 3H), 6.10 (d, J = 4Hz, 1H), 6.76 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 6.76 (m, 1H), 7.25, 7.40 (24, J = 7.5Hz, 4H). : 5s Intermediate 2: 4-[(4-fluoro-3-methoxyphenyl)( I-piperazinyl)methyl]-N.N- diisopropylbenzamide.

Intermediate 1 (3.9 g, 11 mmol) was dissolved in dry CH,Cl; (50 mL) and treated with

SOB, (0.88 mL, 11 mmol) at 0 to 25 °C for 30 min. Neutralization with KHCO, (aq.) and drying (K2COs) of the organic phase was followed by solvent evaporation in vacuo. The residue and EN (1.8 mL, 13 mmol) was dissolved in MeCN (50 mL) and stirred with

Boc-piperazine (2.1 g, 11 mmol) at 25 °C for 12 h. Concentration in vacuo and ~~. chromatography on silica (0 to 50% EtOAc in heptane) gave 4.6g. 1.6g was treated with

TFA in CH,Cl; (1:1), concentrated in vacuo, extracted CH,Cly/ K2CO4 (aq.), dried (K:CO.) and evaporated in vacuo to give Intermediate 2 (1.3 g, 81% from intermediate 1).

MS (ES) 428.21 (MH+).

Example 1: 4-[1-(4-Benzyl-piperazin-1-yl)-1-(4-fluoro-3-hydroxy-phenyl }-methyl]-N,N- diisopropyl-benzamide.

Intermediate 2 (0.41 g, 0.96 mmol) and triethylamine (0.20 mL, 1.4 mmol) were dissolved 2 in MeCN (10 mL). Benzyl bromide (0.14 mL, 1.1 mmol) was added with stirring at 25 °C.

After 12 h the solution was concentrated and purified by reverse phase chromatography (LiChroprep RP-18, 10-80 % MeCN in water, 0.1 % TFA). 0.53 g of free base was obtained after extraction with CH,Cly/ K,COj4 (aq.), drying (K2COs) and evaporation in vacuo. Treatment with boron tribromide ( 4 eq., IM solution in CH,Cl,) in CHCl, at —78 °C, addition of water, concentration in vacuo and reverse phase chromatography gave

Example 1 as the trifluoroacetate (0.35 g, 50%). MS (ES) 504.22 (MH+). IR (NaCl) 3222, 1677, 1592, 1454, 1346, 1201, 1135 (cm-1). '"H NMR (CD;0D) § = 1.1, 1.5 (m, 12H), 2.3 (m, 3H), 2.9-3.8 (m, 7H), 4.33 (s, 2H), 4.75 (s, 1H), 6.60 (m, 1H), 6.83 (m, 1H), 6.94 (m, 1H), 7.24 (d, J = 8 Hz, 2H), 7.47 (m, 7TH). Anal. Calc. for C3;H3sFN302 x0.8C4HoFsO4 .

C:59.87,H:5.82,N:6.12. Found C:60.06, H:5.83, N:6.19. :

Example 2: 4-[1-(4-Fluoro-3-hydroxy-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)- methyl]-N, N-diisopropyl-benzamide.

Intermediate 2 (0.43 g, 1.0 mmol) was dissolved in MeOH (5 mL) with 3-thiophene- } 5 carboxaldehyde (0.11 mL, 1.2 mmol) and HOAc (57 pL, 1.0 mmol) and stirred for 1 h.

Sodium cyanoborohydride (63 mg, 1.0 mmol) was added in portions over 6 h and the reaction was stirred at 25 °C for an additional 12 h before working up by concentration ir vacuo and extraction (CHCl, /K2COj3(aq)). Purification by reverse phase chromatography as for Example 1 to give 0.32 g (0.62 mmol) as free base. Treatment with boron tribromide as for Example 1 and chromatography gave Example 2 (0.20 g, 26%) as the . trifluoroacetate. MS (ES) 510.17 (MH+). IR (NaCl) 3281, 1674, 1606, 1454, 1346, 1200, 1135 (cm-1). "TH NMR (CD;0OD) § = 1.1, 1.5 (m, 12H), 2.30 (m, 2H), 2.9-3.7 (m, 10H), R 4.37 (s, 2H), 4.75 (s, 1H), 6.60 (m, 1H), 6.84 (m, 1H), 6.94 (m, 1H), 7.18 (m, 1H), 7.25, 7.48 (2d, J = 8.0Hz, 4H), 7.55 (m, 1H), 7.65 (m, 1H). Anal. Calc. for CoH36FN30,S x0.8 1s C4H,Fs04 x0.5 H,0, C:55.16, H:5.55, N:5.99. Found, C:55.12, H:5.39, N:6.07.

Example 3: 4-{1-(4-Fluoro-3-hydroxy-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1- : yll-methy1}-N. N-diisopropyl-benzamide.

Employing the same procedure as for Example 2 reaction with 2-imidazole-carboxaldehyde (0.10 g, 1.1 mmol) followed by treatment with boron tribromide (6 eq.) gave Example 3 (0.18 g, 25%) as the trifluoroacetate. MS (ES) 494.23 (MH+). IR (NaCl) 3123, 1673, 1592, 1454, 1350, 1201, 1135 (cm-1). "H NMR (CD;0D) §=1.1, 1.5 (m, 12H), 2.7-3.8 (m, 10H), 3.95 (s, 2H), 5.20 (m, 1H), 6.70 (m, 1H), 6.94 (m, 1H), 7.02 (m, 1H), 7.32, 7.58 (2d, 2s J=8.0Hz, 4H), 7.46 (s, 1H). Anal. Calc. for CasH3FN;O, x1.2 C4HaF604 x0.7 HO,

C:50.51, H:5.14, N:8.98. Found, C:50.44, H:5.18, N:9.11.

Scheme 2: Preparation of Anilines; Examples 4-6

A

=" OL vee

H 4-Pr,NCOPhI PN No. 1) SOBra, CH.Cl,

NO, 2 0 2 2) Boc-piperazine, o oC n-BuLi, THF (37%) OH ACN. TEA (3) 3) TFA, CH,CI, (81%) : . | 0 0 : ) PN . LAC

Pid N )

PN 9g ( c AN NF,

NO, TT > N 1) BnBr, TEA, ACN } - N 2) H,-Pd/C, EtOH, 30% ( ) (4) ) N

N Example 4 1) thiophene-3-carboxaldehyde,

NaBH,CH, MeOH, HOAc 1) imidazole-2-carboxaldehyde, 2) H2-Pd/C, EtOH, 20% NaBH,CN, MeOH, HOAc 2) H2-Pd/C, EtOH, 7%

Pe 0 LL 0

QGUS!

N jqeVel PN NH, 2 0 >) - ~

S BD Example 5 w N Example 6

Intermediate 3: 4-[Thydroxy(3-nitrophenyl)methyl l-N.N-diisopropylbenzamide.

Procedure as for intermediate 1 but after addition of n-BuLi the solution was cannulated into a solution of 3-nitrobenzaldehyde (2.7 g, 18 mmol) in toluene/THF (approx. 1:1, 100 : 5. mL)at-78 °C. Workup and chromatography gave for intermediate 3 (2.4 g, 37%).'H NMR (CDCl) & 1.1-1.7 (m, 12H), 3.90 (d, J = 3.5 Hz, 1H), 3.4-3.9 (m, 2H), 5.91 (5, J =3.5Hz, 1H), 7.27, 7.35 (2d, I = 8Hz, 4H), 7.51 (m, 1H), 7.71 (m, 1H), 8.13 (m, 1H), 8.30 (s, 1H).

Intermediate 4: N.N-diisopropyl-4-[(3-nitrophenyl)(1-piperazinyl)methyllbenzamide.

Employing the same procedure as for intermediate 2, intermediate 3(2.4 g, 6.7 mmol) gave Boc-protected intermediate 4 (2.83 g, 81%). TFA treatment quantitatively gave intermediate 4. MS (ES) 425.23 (MH+).

Example 4: 4-[1-(3-Amino-phenyl)-1-(4-benzyl-piperazin-1-yl)-methyl]-N,N-diisopropyl- benzamide.

Reaction of 7 (0.40 g, 0.94 mmol) with benzyl bromide as for Example 1 was followed by hydrogenation (Hy, 40 psi) with 10% Pd/C (50 mg) in EtOH (25 mL) and 2 N HCI (1.2 mL, 2.4 mmol) for 2 h. Purification by reverse phase chromatography using the same conditions as for Example 1 gave Example 4 (0.20 g, 30%) as the trifluoroacetate. MS (ES) 485.40 (MH+). IR (NaCl) 3414, 1673, 1605, 1455, 1345, 1201, 1134 (cm-1). 'H NMR (CD;0D) § =1.1, 1.5 (m, 12H), 2.3 (m, 2H), 2.9-3.8 (m, 8H), 4.31 (s, 2H), 4.47 (s, 1H), 7.02 (m, 1H), 7.21-7.52 (m, 12H). Anal. Calc. for C3;HsN4O x1.2 C4H,F04 x0.5 H,0, C:56.04,

H:5.70, N:7.30. Found, C:56.06, H:5.67, N:7.41. - Example 5: 4-[1-(3-Amino-phenyl)-1-(4-thiophen-3-yimethyl-piperazin-1-yl )-methyl]-

N,N-diisopropvl-benzamide.

Reaction of intermediate 4 (0.40 g, 0.94 mmol) with 3-thiophene-carboxaldehyde as for example 2 was followed by hydrogenation (H;, 30 psi) with 10% Pd/C (50 mg) in EtOH (25 mL) and 2 N HCI (1.0 mL, 2.0 mmol) for 12 h. Purification by reverse phase chromatography using the same conditions as for Example 1 gave Example 5 (0.13 g, 20%) as the ditrifluoroacetate. MS (ES) 491.28 (MH+). IR (NaCl) 3408, 1673, 1605, 1455, 1345, 1201, 1134 (cm-1). "TH NMR (CD;0D) 6 = 1.1, 1.5 (m, 12H), 2.3 (m, 2H), 2.9-3.8 (m, 8H), 4.35 (s, 2H), 4.44 (s, 1H), 6.98 (m, 1H), 7.16-7.32 (m, 6H), 7.49 (d, J = 8Hz, 2H), 7.55 (m, 1H), 7.64 (m, 1H). Anal. Calc. for C2oH3sN4OS x1.3 C4H,Fs04 x0.6 H,0, C:51.48,

H:5.28, N:7.02. Found, C:51.51, H:5.20, N:7.01.

Example 6: 4-{1-(3-Amino-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-vi]- 25s methyl}-N,N-diisopropyl-benzamide.

Employing the same procedure as for Example 2, reaction of intermediate 4 with 2- imidazole-carboxaldehyde (0.10 g, 1.1 mmol) followed by hydrogenation gave Example 6 : (45 mg, 7%) as ditrifluoroacetate salt. MS (ES) 475.30 (MH+). IR (2x TFA, NaCl) 3351, 1674, 1621, 1455, 1349, 1202, 1134 (cm-1). 'H NMR (2x TFA, CD;0D) §=1.1, 1.5 (m, 3 12H), 2.9-3.8 (m, 8H), 4.35 (s, 2H), 4.44 (5, 1H), 6.98 (m, 1H), 7.16-7.32 (m, 6H), 7.49 (d,

J = 8Hz, 2H), 7.55 (m, 1H), 7.64 (m, 1H). Anal. Calc. for C,5sH3sN¢O x1.6 C4HFs04 x0.8

H,0, C:48.39, H:5.05, N:9.84. Found, C:48.43, H:5.06, N:9.85. :

Scheme 3: Preparation of Methyl Sulfonanilides; Examples 7-8

JJ

H. 4-iPr,NCOPhI A NO. 1) SOBr, CHCl :

NO, B i THE (37% 2 2) Boc-piperazine, 0 n-BuLi, THF (37%) OH ACN, TEA (1) 0

A 9

N Py

XK oe LOC

N NO, 1) H,-Pd/C, HOAc, 12 h A NH : 2) (CH;S0,),0, TEA, CH,CI (4a) C ) 3) TFA, CH,Cl,. ’ N SOCH,

N (5)

A N

070 H 1) furan-3-carboxaldehyde, 1) thiophene-3-carboxaldehyde, NaBH,CN, MeOH, HOAc

NaBH,CH, MeOH, HOAc ~ {2) H2-Pd/C, EtOH, 7% . 2) H2-Pd/C, EtOH, 20% 0 PN 0 sqeN o $0,CH, N SO,CH,

Example 7 ( J Example 8 ( )

N N

Intermediate 5: N.N-diisopropyl-4-[{3-[(methylsulfonyl)amino]}phenyl }(1- piperazinylimethyllbenzamide. - s Intermediate 3 gave Boc-protected Intermediate 4 as described for Intermediate 4, above.

Boc-protected Intermediate 4 (1.21 g, 2.3 mmol) was hydrogenated under Hj at 30 psi with 10% Pd/C (150 mg) in AcOH (25 mL) for 12 h. Evaporation in vacuo and extraction with

CH,Cly/ K2CO4 (aq.) gave 1.1 g (2.3 mmol) of the intermediate aniline, which was dissolved in MeCN/CH,Cl; (1:1, 10 mL). Et;N (0.48 mL, 3.4 mmol), then . methanesulponylanhydride (0.41 g, 2.4 mmol) was added at 0 °C. After warming to room temperature the reaction was worked up by extraction CH,Cly/brine. Purification by chromatography on silica (0 — 5% MeOH/ CH,Cl,) gave Boc-protected Intermediate 5 (1.3 g, 97%). Treatment with TFA in CH,Cl, quantitatively gave Intermediate 5. MS (ES) 473.16 (MH).

Example 7: N,N-Diisopropyl-4-[1-(3-methanesulfonylamino-phenyl)-1-(4-thiophen-3- ylmethyl-piperazin-1-yl)-methyl]-benzamide.

Reductive amination procedure as for Example 2. Intermediate 5 (0.20 g, 0.43 mmol) gave . 5s Example 7 (90 mg, 26%) as ditrifluoroacetate salt. The dihydrochloride salt was obtained after extraction of the free base with CH,Cly/ K,COy4 (aq.) and treatment with 2 eq. HCI (aq.). MS (ES) 569.21 (MH+). IR (free base, NaCl) 1604, 1455, 1340, 1151 (cm-1). 'H

NMR (free base, CDCl3) 6 = 0.9- 1.7 (m, 12H), 2.5 (m, 8H), 2.85 (s, 3H), 3.55 (s, 2H), 3.8 (m, 2H), 4.22 (s, 1H), 7.00-7.40 (m, 12H). Anal. Calc. for C30HN4O3S; x2.6 HCI,

C:54.30, H:6.47, N:8.44. Found, C:54.33, H:6.20, N:8.32.

Example 8: 4-({4-(3-furylmethyl)-1-piperazimyl}{3-[(methyisulfonyl)aminolphenyl }-N,N- diisopropyl-benzamide.

Employing the same procedure as for Intermediate 7. Intermediate 5 (0.21 g, 0.45 mmol) gave Example 8 (80 mg, 32%) as free base. MS (ES) 553.23 (MH+). IR (free base, NaCl) 1604, 1455, 1340, 1151 (cm-1). "H NMR (free base, CDCl3) § = 1.0- 2.6 (m, 20H), 2.91 (s, 3H), 3.40 (s, 2H), 4.22 (s, 1H), 6.39 (s, 1H), 7.06-7.42 (m, 11H). Anal. Calc. for

C30H40N404S x2.8 HCI, C:55.03, H:6.59, N:8.56. Found, C:54.93, H:5.93, N:8.49.

Claims

1. A compound of the formula I : LJ (0) . "R2 R3 ToCoLQ R2 RA N N™ A wherein rR is selected from any one of (i) phenyl; (ii) pyridinyl ~N Pr N i5 (iii) thienyl

Ss .

(iv) furanyl OF (v) imidazolyl H (J \_/ (vi) triazolyl N N—"

(vii) pyrrolyl N H (viii) thiazolyl S (J N (ix) pyridyl-N-oxide 0 N ES [J wherein each R' heteroaromatic ring may optionally and independently be further substituted . by 1, 2 or 3 substituents selected from straight and branched C;-Cs alkyl, halogenated C;-Cg alkyl, NO,, CF3, C;-Cg alkoxy, chloro, fluoro, bromo, and iodo;

C31 Ris independently selected from ethyl and isopropyl; . R’ is independently selected from hydrogen and fluoro; * 5s R'is independently selected from -OH, -NH, and -NHSO,R?; and Ris independently selected from hydrogen, -CF3 and C,-C alkyl, or salts thereof or separate enantiomers and salts thereof, provided that when R? is ethyl and R? is hydrogen then R* cannot be -OH.

3. A compound according to claim 1, wherein R! is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R? is ethyl or isopropyl; R? is hydrogen; R* is -NHSO,R’; and R® is C;-C; alkyl.

4. A compound according to claim 1, wherein the heteroaromatic ring(s) are substituted by CF3, methyl, iodo, bromo, fluoro or chloro. | . :

5. A compound according to claim 1, wherein the heteroaromatic ring(s) are substituted by methyl.

6. A compound according to claim 1, selected from any one of 4-[1-(4-Benzyl-piperazin-1-yl)-1-(4-fluoro-3-hydroxy-phenyl)-methyl}-N, N-diisopropyl- benzamide; 4-[1-(4-Fluoro-3-hydroxy-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl}-N, N- diisopropyl-benzamide; 4-{1-(4-Fluoro-3-hydroxy-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl}-methyl } - N,N-diisopropyl-benzamide; 4-[1-(3-Amino-phenyl)-1-(4-benzyl-piperazin-1-yl)-methyl}-N,N-diisopropyl-benzamide;

4-[1-(3-Amino-phenyl)- 1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N, N-diisopropyl- benzamide; 4-{1-(3-Amino-phenyl)-1-{4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl]-methyl }-N, N- diisopropyl-benzamide; N,N-Diisopropyl-4-[1-(3-methanesulfonylamino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin- 1-yl)-methyl}-benzamide; 4-([4-(3-furylmethyl)-1-piperazimyl]{3-[(methylsulfonyl)amino]phenyl }-N, N-diisopropyl- benzamide; 4-{(3-aminophenyl)[4-(3-thienylmethyl)-1-piperazinylJmethyl }-N,N-diethylbenzamide; 4-[(3-aminophenyl)(4-benzyl-1-piperazinyl)methyl]-N,N-diethylbenzamide, and ~ 4-((4-benzyl-1-piperazinyl){3-[(methylsulfonyl)aminolphenyl } methyl)-N,N- diethylbenzamide.

7. A compound according to any of the preceding claims, in form of its hydrochloride, dihydrochloride, sulfate, tartrate, ditrifluoroacetate or citrate salts.

8. A process for preparing a compound of formula I wherein R* is -OH, comprising reacting a compound of the general formula II oO R2 R3 Tod R? RA Br J wherein R? and R® are as defined in claim 1 and R*is OMe, with Boc-piperazine in : acetonitrile in the presence of triethylamine under standard conditions, followed by removal of } the Boc protection group under standard conditions to give a compound of the Formula III

O R “N R3 R? OMe : . 4 ) N H Im which is thereafter alkylated under reductive conditions with a compound of the Formula R’- CHO, followed by cleavage of the methyl ether using BBr3 in dichloromethane to give a compound of the Formula I wherein R* is —OH.

9. A process for preparing a compound of formula I wherein R* is -NHa, comprising reacting a compound of the general formula IV ~~. Oo R2 R3 TOO Br Iv wherein R? and R’ are as defined in claim 1 and R* is NO,, with Boc-piperazine in acetonitrile : in the presence of triethylamine under standard conditions, followed by removal of the Boc protection group under standard conditions to give a compound of the Formula V 0 Tog R2 ~~ NG, 0) N H v which is thereafter alkylated under reductive conditions with a compound of the Formula R'- CHO, followed by reduction of the nitro group using hydrogen and palladium on charcoal to - give a compound of the Formula I wherein R? is ~NHj.

10. A process for preparing a compound of formula I wherein R* is -NHSO,R’, comprising reacting a compound of the general formula VI 0 R2 3 ~N R NYS R? R4 Br VI wherein R* and R® are as defined in claim 1 and R*is NO», with Boc-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed reduction of the nitro group by hydrogenolysis using palladium on charcoal as the catalyst, metanesulphonylation using methanesulphonylanhydride in dichloromethane in the presence of triethylamine, and 1s thereafter removal of the Boc protection group under standard conditions to give a compound of the Formula VII o

2 . Ra R® R? NHSO,CH, 8 N H VII which is thereafter alkylated under reductive conditions with a compound of the Formula R'- CHO, followed by reduction of the nitro group using hydrogen and palladium on charcoal to give a compound of the Formula I wherein R* is -NHSO,R® .

PCT/SE02/00956

11. A compound according to any of claims 1-7 for use in therapy.

12. Use of a compound according to formula I of claim 1 for the manufacture of a medicament for use in the treatment of pain, anxiety or functional gastrointestinal disorders.

13. A pharmaceutical composition comprising a compound of the formula I according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.

14. A method for the treatment of pain, whereby an effective amount of a compound of the formula I according to claim 1 is administered to a subject in need of pain management.

15. A substance or composition for use in a method for the treatment of functional gastrointestinal disorders, said substance or composition comprising a compound of the formula I according to claim 1, and said method comprising administering an effective amount of said substance or composition to a subject suffering from said functional gastrointestinal disorder.

16. Use of a compound according to any of claims 1-7 in the manufacture of a medicament for use in treatment.

17. A substance or composition for use in a method for the treatment of pain, said substance or composition comprising a compound of the formula I according to claim 1 and said method comprising administering an effective amount of said substance or composition to a subject in need of pain management.

18. A compound according to claim 1, substantially as herein described and illustrated.

19. A process according to any one of claims 8 to 10, substantially as herein described and illustrated. AMENDED SHEET

} 36 PCT/SE02/00956

20. A substance or composition for use in a method of treatment according to any one of claims 11, or 15, or 17, substantially as herein described and illustrated.

21. Use according to claim 12, or claim 16, substantially as herein described and illustrated. 22, A composition according to claim 13, substantially as herein described and illustrated.

23. A method according to claim 14, substantially as herein described and illustrated.

24. A new compound, a new process for preparing a compound, a substance or composition for a new use in a method of treatment, a new use of a compound of any of claims 1-7, a new composition, or a new non-therapeutic method of treatment, substantially as herein described. AMENDED SHEET