AU706436B2 - Novel compounds with analgesic effect - Google Patents

Description

WO 97/23467 PCT/SE96/01636 1 NOVEL COMPOUNDS WITH ANALGESIC EFFECT Field of the invention The present invention is related to novel compounds which are substituted 7-membered nitrogen rings, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are used in therapy, and in particular for the treatment of pain.

Background and prior art The 5 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the 8 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the 6 receptor have also been shown to posess immunomodulatory activities.

The identification of at least three different populations of opioid receptors 6 and K) 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 6 ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic 6 antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol.

Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor 10-fold) selectivity for the 8 receptor vs t receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective nonpeptidic 8 ligands.

WO 97/23467 PCTISE96/01636 2 Recently, a non-peptidic 5 agonist, BW 373U86, was described by Chang et al., 1993, J.

Pharmacol. Exp. Ther., 267: 852-857., as the first 6-selective non-peptide with analgesic activity, however, it shows significant affinity for the i receptor.

Thus, the problem underlying the present invention was to find new analgesics having excellent analgesic effects, but also with an improved side-effect profile over current ji agonists and potential oral 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 compounds, described within the prior art, show significant convulsive effects when administered systemically.

In WO 93/15062 and WO 95/045051, some diarylmethylpiperazine and diarylmethylpiperidine compounds, including BW 373U86, are disclosed, but these prior art compounds are structurally distinct from the compounds acccording to the present invention.

The problem mentioned above has been solved by developing novel compounds which are 7-membered nitrogen rings, as will be described below.

_1 WO 97/23467 PCr/SE96/01636 Outline of the invention The novel compounds according to the present invention are defined by the general formula

(I)

R'

I

wherein 4 a 4 1 4 4 a 4 4 A is a substituted or unsubstituted aromatic; an optionally substituted C 5

-CO

0 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to atoms selected from any of C. S, N and 0, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH 3

(CH

2 )oCF 3 halogen, 6 5 5 5656

CONR

5

R

6

C

2 R CORS, (CH 2 )oNR R (CH 2 )oCH 3 (CH2 OSOR5 R 2 )OSOR (C2 0 oSO 2 (2 O 0

SO

2 N5, 0 NR 5DR and -NR5 (C21oCR 1 1 5 6 6a r eie eowmpcicy wherein o is 0, 1, or 2, and R R and R are as defined below respectively; R is selected from hydrogen, a branched or straight C 1

-C

6 alkyl, (12

CH=CH

2

C

3

-C

8 cycloalkyl, C 4 -Cg (alkyl-cycloalkyl) wherein alkyl is

C

1

-C

2 alkyl and cycloalkyl is C 3 -C cycloalkyl; C 6 -Cj 0 aryl; and heteroaryl having fran 5 to 10 ataoms selected from any of C, S, N and 0;

R

5 and R 6 is each and independently as defined for R 1 above; or R 5 and

R

6 taken together is r- wherein r is 4 or

R

2 is selected fran hydrogen, C3,OR 1 CD2j 1 and CH2C2R1 wherein R1 is as defined above; WO 97/23467 PCT/SE96/01636 4 B is a substituted or unsubstituted aromatic; an optionally substituted C 5 -C 10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to atoms selected from any of C, S, N and 0, optionally substituted by 1-2 substituents each and independently selected from hydrogen, CH 3

CF

3 halogen, (CH 2 )pCONR R 6 6 5 5 5 55

(CH

2 )pNR R (CH 2 )pCOR (CH 2 )pCO 2 R OR (CH 2 )pSQR (CH 2 )pSQ2R5 and

(CH

2 )pSO 2 NR 5R 6 5 6 wherein p is 0, 1, 2 or 3 and wherein R and R are as defined above; R 3 and R 4 is each and independently selected from R (CH 2 )pCONR R (CH 2 )pNR R (CH 2 pCO 2 R (CH 2 P Ph,

(CH

2 )p(p-OH Ph), (CH 2 )p-3-indolyl, (CH 2 )pSR 5or (CH 2 )pOR51 wherein p is 0, 1, 2, 3, or 4, and wherein R 5and R 6are as defined above.

Within the scope of the invention are also pharmnaceutically acceptable salts of the compounds of the formula aI), as well as isomers, hydrates, isoforms and prodrugs thereof.

Preferred compounds according to the invention are compounds of the formula (T) wherein A is selected from phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and pyrrolidinyl;, wherein each A group being optionally substituted by 1 or 2 substituents independently selected 56 5 5 from hydrogen, CE! 3

(CH

2 0

CF

3 F, Cl, CON'R R C0 2 R COR (CH2) 0

SOR,

5 6 5 6 (CH2)oSO 2 R5, (CH2)SO 2 NR (CH 2 )oNR COR and NR (CH 2 0 COR wherein R and R 6are as defined below, and ois 0orl1; WO 97/23467 PCT/SE96/01636 R R 5 and R 6 is each and independently selected from hydrogen, a branched or straight

CI-C

4 alkyl, C 3

-C

5 cycloalkyl, C 4 -C8 (alkyl-cycloalcyl) wherein alkyl is CI-C 2 ailkyl and cycloallcyl is C 3

-C

6 cycloalkyl, and phenyl; R 2 is hydrogen, methyl, or OR 1 I wherein R I is as defined above; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinoliyl, isoquinolinyl, cyc ,lohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl. indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuiranyl, pyrrolidinyl, indazolinyl, and 0 each B group being optionally substituted by 1-2 substituents independently selected from hdoeC .CF.hlgn56 5 6 15hdoeC3 Fhlgn (CH 2 )pCONR R C 2 R ,(H 2 )pCOR *(CH 2 )pCOiR 5, and 3 4* 5 6 (C2Rwherein p is 0 ,2 or 3, and wherein R and R ar as dfined above.

WO 97/23467 PCT/SE96/01636 6 Especially preferred compounds according to the invention are compounds of the formula wherein A is selected from 12 R K

O

wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from H, CH 3

(CH

2 )oCF 3 F, Cl, CONR5R 6

CO

2

R

5

(CH

2 )oSOR5, (CH 2 )oSO 2

R

5

(CH

2 )oSO 2 NR5R 6

(CH

2 )oNR5COR 6 and NR (CH 2 )oCOR6; wherein R 5 and R 6 are as defined below, and o is 0, 1 or 2; is R is selected from hydrogen, methyl, ethyl, CH 2

CH=CH

2 or CH2-cyclopropyl; R and R is each and independently selected from phenyl, methyl and ethyl; or

R

5 and R taken together is -(CH 2 wherein r is 4 or

R

2 is H, methyl, or OR1; 7 8 9 10 11 12 13 14 15 16

R

7 R, R R, R R R R R and R is each and independently as defined for R 1 above; WO 97/23467 WO 9723467PCT/SE96/01636 7 B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dillydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, t-trahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and 0 each B group being optionally substituted by 1-2 substituents independently selected from 5 6 5 65 hydrogen, methyl, CF 3 halogen, (CH 2 )pCONR R (CH 2 )pNR R (CH 2

(CH

2 )pCO 2 R5, and OR wherein p is 0, 1, or 2, and wherein R 5and R 6are as defined above; R3and R 4are each and independently selected from H, CH 3 CH(Me) 2

CH-

2 CH(Me) 2 CH(Me)CH 2

CH

3

(CH

2 )pCONR 5R 6, (CH 2 )PNR5 R 6, (CH 2 )pCONR 5R 6,(CH--)pCO 2 R

(CH

2 )pPh, (CH 2 )p(p-OH Ph), (CH 2 )p-3-ndolyl,

(CH

2 )pSR and (CH 2 )pOR: wherein p is 0, 1, 2, or 3, and wherein R 5and R 6are as defined above.

Even more preferred is to use a compound where the A substituent is 9K 0

R

110 o 0 and wherein R R 10

R

1 and R' 2 are as defined above.

WO 97/23467 PCT/SE96/01636 8 The substituents A and B respectively, may optionally be substituted at any position of the ring.

By "halogen" we mean chloro, fluoro, bromo and iodo.

By "aryl" we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.

By "heteroaryl" we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and 0.

By "hydroaromatic" we mean a partly or fully saturated aromatic ring structure having 5-10 carbon atoms in the ring.

By "heterohydroaromatic" we mean a partly or fully saturated aromatic ring structure in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and 0.

By "isomers" we mean compounds of the formula which differ by the position of their functional group and/or orientation. By "orientation" we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.

By "isoforms" we mean compounds of the formula which differ by their crystal lattice, such as crystalline compound and amorphous compounds.

By "prodrug" we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated.

WO 97/23467 PCT/SE96/01636 9 The novel compounds of the present invention are useful in therapy, especially for the treatment of pain.

s A further aspect of the invention is the use of a compound of the formula for the manufacture of a medicament for use in any of the diseases disclosed below.

The compounds are useful for modulating the analgesic effects acting at the 4 opioid receptor subtype, including for modulating side effects seen with agents acting at the i opioid receptor subtype such as morphine, especially respiratory depression, gut motility and abuse liability.

Compounds of the invention are also 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.

Compounds of the invention are useful also in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, 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.

WO 97/23467 PCT/SE96/01636 Methods of preparation Generalized Method A An aldehyde or ketone is treated with a nucleophile such as a Grignard or organolithium species to produce the corresponding alcohol. This alcohol may then be converted into a suitable leaving group such as an ester, sulphonate or halide which may in turn be displaced with a nucleophilic species such as a substituted or unsubstituted piperazine. N- (4)-unsubstituted piperazine derivatives may then be suitably substituted with a variety of groups via their organo halide or equivalent species, or acylated with a number of different acylating compounds. This sequence of events will give rise to compounds according to general formula I.

Generalized Method B An N-protected amino acid, as its activated ester, may be reacted with a second amino acid ester. On treatment with an acid this species may then cyclize to form a piperazinedione.

This dione may be reduced via a number of standard methods to the corresponding piperazine a reducing agent such as lithium aluminium hydride, by conversion to the thioamide and subsequent desulphuization, hydrogenation in the presence of POC1 3 etc.) This piperazine may then be alkylated or acylated on one or more of the nitrogens and/or may be used subsequently in generalized method A.

Deprotection of functional groups or further modifications may then be necessary, these are described for each individual case. Specific examples for the above transformations are given in the experimental.

WO 97/23467 PCT/SE96/01636 11 All transformations contemplated use reagents (including salts) and solvents known to the art of chemistry and to biotransformations carried out in a suitable biological medium to bring about these transformations and includes all reaction enhancing agents

HMPA),

and chiral resolutions using chiral salt formation and chiral biological resolutions.

The best mode of carrying out the invention known at present is to use the compounds 1, 2, 3, 4, 9 and Detailed description of the invention The invention will now be described in more detail by the following examples, which are not to be construed as limiting the invention.

WO 97/23467 PCT/SE96/01 636 12

EXAMPLES

The compounds according to Examples 1-3 were synthesized as shown in Scheme 1 below.

Scheme 1 l-lomoioerazinvI)-3-methoxvbenz D-.NNdiethvllbenzaride 2 and 3).

Homnopiperazine or N-methylhomopiperazine 0I

(A)

R=H (1) R=Me (2) cyclopropylmiethyl chloride Et 2

N'

'OMe

A)

L Pretnaration of 4 -(a-HvdroxvI-3methoxvbenzv).NNdiethIben 2 aim-de To a solution of 3-bromoanisole (5.61 g, 30.0 mmol) in dry THF (100 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 20 mL, 32 mmol) under nitrogen at -78'C The mixture was stirred for 1 hr at the same temperature prior to the addition of 4formyl-N,N-diethyl-benzaniide (6.15 g, 30.0 mmol) in dry THF (2OmL). The reaction WO 97/23467 WO 9723467PCT/SE96/O1 636 13 mixture was allowed to warm up to r.t (4 and then quenched with ammonium chloride The solvent was removed in vacuo, the residue dissolved in ethyl acetate/heptane, 1: 1, washed with brine and dried (MgSQ 4 Evaporation of solvent in vacuo gave a crude product, which was purified by column chromatography on silica gel to afford 4-(ahydroxyl-3-methoxybenzyl)-N,N-diethylbenzamide (6.15 g, 1H-NMR (400 MHz,

CDCI

3 8 1.10 (3 H, br, CH 3

CH

2 1.22 (3 H, br, CH 3

CH

2 2.60 (1H, br, OH), 3.24 (2 b, C 3

C

2 3.52 (2 H, br, CH 3

CH

2 3.79 (3H, s, OCki3),.80 (1H, s, CHN, 6.81 (1 H, m, ArH), 6.93 (1 H, m, ArM), 6.94 (1lH, m, ArH), 7.25 (1 H, m, An-I), 7.31 (2H, m, Arki), 7.39 (2 H, mn, ArH).

HI. Preparation of 4-(ac-Chloro-3-methoxvbenzvl)-NN-diethvt benzamide (comoound A in Scheme 1) To a solution of 4-(a-hydroxyl-3-methoxybenzyl)-N,N-diethylbenzamide (3.13 g. 10.0 mmol), in AcOEt (2OrmL) was added 35% hydrochloric acid (20 m.L) at 0' C. The reaction mixture was stirred for 12 hr at r.t. and extracted with AcOEt. The organic layers was washed with saturated ammonium chloride solution and brine, dried over MgSO 4 and evaporated to give a crude product, which was purified by column chromatography on silica gel to afford 4-(cx-chloro-3-methoxybenzyl)-N,N-diethylbenzamide (compound A) (1.82 g, GC-MS: 331, 330, 296, 259, 224, 196, 165, 152, 112.

Example 1 Prevaration of 4-(ct-(l-Homooi perazin-vi)3-methoxvbenzvl)-N,N..diethyibenz.ajnde (compound 1) A mixture of homopiperazine (200 mg, 2.0 mmol), 4-(a-chloro-3-methoxybenzyl)-NNdiethylbenzamide (331 mg, 1.0 mmol) and K 2 C0 3 (276 mg, 2.0 mmol) in dry acetonitrile (50 mL) was refluxed for 2 hr under nitrogen, after cooling down to the reaction WO 97/23467 WO 9723467PCT/SE96/01636 14 mixture was quenched with IN aqueous NH 4 0H solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous NH 4 CI and brine, dried over MgSO 4 Removal of solvents gave 4 -(cx-(1-homopiperazinyl)-3methoxybenzyl)-N,N-diethylbenzan-de (compound which was purified by silica gel column eluting with MeOH-CH 2

CI

2 98 -4 10: 90) to provide the title compound (254 mg, 64%).

GC-MS (Rt 17.35 min) 396.30 395.30 380.25 337.20 325.25 297.15 251.10 224.10 196.10 165.15 i0 15 2.10 112.15 99.20 (100); 5H (400 MHz, CDC1 3 1. 10 (brs, 3H), 1. (brs, 3H), 1.82 (in, 2H), 2.66 J=6.0 Hz, 2H), 2.72 (in, 2H), 2.97 J=5.2 Hz, 2H), 3.12 J=6.0 Hz, 2H), 3.23 (brs, 2H), 3.51 (brs, 2H), 3.77 3H), 4.60 1H), 5.26 (brs, 1H), 6.72 (in, 1H), 6.99 (in, 2H), 7.18 J=8.0 Hz, 1H), 7.28 J=8.0 Hz, 2H), 7.46 Hz, 2H); 8C- 13 (100 MHz, CDCl 3 12.8, 14.2, 29.0, 39.2, 43.3.46.0, 48.6, 53.0, 53.6, 55.2, 1s 74.9, 112.3, 113.5, 120.2, 126.7, 127.8, 129.5, 135.9. 144.3, 144.4, 159.7, 17 Its HBr salt: in.p. 137-140.5'C (AcOEt-Ether); v. (KBr) cm- 1 3500, 1600, 1288; Anal.Calcd.for C 24

H

33

N

3 0 2 .1.5HBr.0.8H 2 0: C, 54.25; H, 6.85; N, 7.91. Found: C, 54.36; H, 6.89; N, 7.78.

Example 2 Prevaration of 4-(a-(4-Meth- il-homoiierazinvI)-3rmthoxvbenz yflN..

diethvlbenzamide (compound 2) A mixture of homopiperazine (114 mg, 1. 14 mmol), 4 -(a-chloro-3-methoxybenzyl)-N,Ndiethylbenzamnide (compound A)(100 ing, 0.3 inmol) and K 2 C0 3 (138 mg, 1.0 inmol) in dry acetonitrile (10 mL) was refluxed for 5 hr under nitrogen. after cooling down to r.t, the reaction mixture was quenched with IN aqueous NH 4 0H solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous WO 97/23467 WO 9723467PCT/SE96/01636

NH

4 Cl and brine, dried over MgSO 4 Removal of solvents gave 4-(a-(4-metbyl-1Ihomopiperaznyl)-3-methoxybenzyl)N,Ndiethylbenzn-lide which was purified by silica gel column eluting with MeOH-CH 2

C

2 (5 :95 10 :90) to provide the title compound (82 mg, 67%).

GC-MS (Rt 16.19 min) 410. 10 409.20 351.15 324.15 296.15 264.10 237.00 224.05 196.05 152.00 113.15 (100); 5H (400 MHz, CDCl 3 1. 10 (brs, 3H), 1.20 (brs, 3H), 1.79 (in, 2H), 2.38 (s, 3H), 2.59 (in, 2H), 2.65 (mn, 4H), 2.72 J=6.0 Hz, 2H), 3.24 (brs, 2H), 3.54 (brs, 2H), 3.7 8 3H), 4.54 I1H), 6.72 (dt, J=8.0, 1.2 Hz, IlH), 6.99 (in, 2H), 7.18 (dt, J=8.0, 1.2 Hz, I1H), 7.27 (dd, J=8.4, 1.6 Hz, 2H), 7.44 (dd, J=8.4, 1.6 Hz, 2H); 8C1 (100 MHz, CDCl 3 12.9, 14.2, 27.7, 39.1, 43.2, 46.9, 52.7, 52.8, 55.2, 56.3, 59.1, 75.3, 112.0, 113.7, 120.4, 126.6, 127.9, 129.4, 135.7, 144.7, 144.8, 159.7, 17 1.1.

Its HBr salt: m.p. 165-178'C (AcOEt-Ether); vm,, (KBr) cm'1 3400, 1603, 1286; Anal.Calcd.for C 25

H

35

N

3 0 2 .2.OHBr .0.61+2O: C, 51.57; H, 6.61: N, 7.22. Found: C, 51.88; H, 6.56; N, 6.92.

Example 3 Preparation of 4 4 -CVC]ODrovmethvI-1.homopiperazinvi)-3.mthoxvbenzvI).

N.N-diethvlbenzamjde (compound 3) A mixture of 4 -homopiperaziny)-3-iethoxybenzy)Ndiethyeza-tde (compound 1) (119 mg, 0.3 mmol), (chloromethyl)cyclopropane (45 mg, 0.5 mmol), sodium iodide (75 mg, 0.5 mmol) and K 2 C0 3 (138 mg, 1.0 mmol) in MeCN (10 mnL) was refluxed for 2 hr. after cooling down to the reaction midxture was quenched with iN aqueous NH 4 0H solution and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous NH 4 C1 and brine, dried over MgS 04.

Removal of solvents gave 4 4 -cyclopropylrnethyl-1-homopiperazinyl)-3 WO 97/23467 PCT/SE96/01636 16 methoxybenzy)-N,Ndietlyleziide (compound which was purified by silica gel column eluting with MeOH-CH 2

CI

2 99 10 :90) to provide the title compound (125 mg, 93%).

GC-MS (Rt 25.44 mini) 377.15 365.10 352.25 337.20 323.15 296.15 259.10 237.05 224.00 196.10 153.20 (100), 110. 10 8H (400 MHz, CDCl 3 0.33 (in, 2H), 0.69 (in, 2H), 1. 11 (in, 3H), 1.20 (in, 4H), 2.11 (mn, 2H), 2.69 J=6.4 Hz, 2H), 2.81 J=6.6 Hz, 2H), 2.90 (in, 2H), 3.13 (brs, 2H), 3.25 (brs, 2H), 3.30 (in, 2H), 3.51 (brs, 2H), 3.79 3H), 4.59 1H), 6.75 (ddd, J=8.4, 2.4, 1.2 Hz, 1H), 6.98 (mn, 2H), 7.21 J=8.0 Hz, 1H4), 7.30 J=8.0 Hz, 2H), 7.44 J=8.0 Hz, 2H); 5C2.13(1 00 MHz, CDCl 3 4.6, 6.5, 12.8, 14.1, 24.9, 39.1, 43.3, 48.8, 52.4, 52.5, 55.2, 55.5, 62.3, 74.9, 112.2, 113.8, 120.2, 126.7, 127.8, 129.6, 136.1, 143.6, 143.7, 159.8, 170.9.

Its HBr salt: m.p. 138-147 0 C (AcOEt-Ether); (KBr) cm-1 3435, 1606, 1287; Anal.Calcd.for

C

2 8H 39

N

3 0 2 .1.2OHBr. 1.40H 2 0: C, 58.80; H, 7.58;, N, 7.35. Found: C, 58.82; H, 7.58; N, 7.24.

WO 97/23467 PCT/SE96101 636 17 Schem 2 4-(a-(l-Homopj Derazinvl)benzvl )-N.N-diethvlbenzamide hydrochloride (compound Homopiperazine (4) The compound according to Example 4 was synthesized as shown in Scheme 2 above.

B)

1. Preparation of 4-(Phenv-hydroxvmethvl )-N.N-diethylbenzamide 4 -Formyl-N,N-diethylibenzaniide (19.5 g, 95 mmnol) was dissolved in dry THF, cooled to -78* C under nitrogen. Phenyl magnesium bromide (104 m.L, 1.OM in THF) was added dropwise at -78' C. The temperature was allowed to rise slowly until reaction complete (1 The reaction was quenched with ammonium chloride The solvent was removed in vacuc, the residue dissolved in ethyl acetate/heptane, 1:1, washed with brine and dried (MgSO 4 Evaporation of solvent in vacuo gave 26.5 g of 4-(phenylhydroxymethyl)-N,N-diethylbenzamide MS: 282, 211, 165, 105, 1H NMR: (CDCl 3 7.38-7.20 (in, 9H), 5.80 J=3.5Hz, 1 3.5, 3.2 (2br.s, 4H), 1.2, 1.05 (2br. s, 6H).

WO 97/23467 PCT/SE96/oI 636 18 II. -Pre~aration of 4 -(Chloro-Rhenvl-methvfl).N.N-diethlbenzamide (compound B in Scheme 2) 4 -(Phenyl-hydroxymethyl)-N,N-diethyllbenzamide (24.5 g, 93 mmol) was dissolved in s dichioromethane (300mL), dried with 4A molecular sieves, and transferred to a dry flask under nitrogen. Thionyl chloride (7.5 mL, 103 mmol) was added at 0' C. Solution stirred at 250 C for 1 h. Solvent evaporated in vacuo. Residue dissolved in toluene and solvent evaporated again. 4 -(Chloro-phenyl-methyl)-N,N..diethylbenzamide (compound B) was obtained as an oil 100%) which crystallized in the freezer. GC-MS (2 peaks): 296, 225, 165, 121 and 300, 266, 229, 195, 165. 1HNMR: (CDCl 3 8 7.45-7.20 (in, 9H), 6.09 (s, I1H), 3.4 (br. mn, 4H), 1. 1 (br. m, 6H).

Example 4 1s Preparation of I -omotiierazin-vl)benzvl).N.N..diethvl benzamide (comoound 4) This compound was prepared as described for Example I (compound but substituting compound A for compound B.

4 -(a-(l-homopiperaznyl)benzyl)NNdiethylbena-Lde (compound 4) as an oil. GC-MS: 365.30 322.25 295.15 281.20 267.15 236.10 194.15 165.15 99.20 (100); 5H (4.00 MHz, CDC1 3 1.08 (brs, 3H), 1. 18 (brs, 3H), 1.69 (mn, 2H), 2.56 1H), 2.62 (mn, 4H), 2.85 (mn, 2H), 2.97 (in, 2H), 3.23 (brs, 2H), 3.50 (brs, 2H), 4.63 1H), 7.16 (mn, lH), 7.26 (in, 4H), 7.40 J=8.0 Hz, 2H), 7.44 J=8.0 Hz, 2H); 5 C-13 (100 MHz, CDC1 3 8: 12.6, 14.0, 30.7, 39.0, 43.1, 46.9, 49.6, 52.9, 56.1, 74.9, 126.4, 126.7, 127.6, 127.7, 128.3, 135.5, 142.9, 144.8, 17 WO 97/23467 WO 9723467PCT/SE96/O1 636 19 Its HCI salt (compound m.p. 155-165 0 C (AcOEt-Ether); (KBr) cm'1 3418, 1628, 1591, 1074; Anal.Calcd.for

C

23

H

31

N

3 0.2.50HCl..90H 2 0: C, 58.42; H, 7.52; N, 8.89.

Found: C, 58.35; H, 7.52; N, 8.62.

Scheme 3 4 -(a-(l.HomoniperazinyI)ary)..NN.diethvlbenzamide hydrochloride (com]Dounds -9 and 01 :-1 0 Et 2 NH 1 t-Bu Li 2. ArCHO 0 ~Et 2 N -r

OH

and (6) Ar=4-diethylaminocarbonylphenyl Ar=2-naphthyl (6) SOC1 2 Homopiperazine and (8) Ar=4-diethylaminocarbonylphenyl (7) Ar=2-naphthyl (8) and Ar=4-diethylaminocarbonylphenyl (9) Ar=2-naphthyl The compounds according to Examples 5-10 were synthesized as shown in Scheme 3 above.

WO 97/23467 WO 9723467PCT/SE96/O1 636

C)

I. -Preparation of 4-Iodo-N.N-diethYlbeDznywde (compound C in Scheme 3) To a solution 4-iodobenzoyl chloride (13.3 g, 50 mmol) in dry dichioromethane (50 ML) was slowly added diethylamine (30 mL) at 0 0 C. After addition, the reaction mixture was warmed to r.t. and stirred for one hour at and then quenched with aqueous

K

2 C0 3 solution, extracted with diethyl ether (2 x 200 mL). The organic phases were washed with brine, dried over MgSO 4 Evaporation of solvents gave the crude product, which were puried by silica gel column eluting with MeOH-CH 2

CI

2 99) to provide 4-iodo-N,Ndiethylbenzamide (14.5 g, 95 GC-MS: 303.00 302.00 231.85 230.85 (100), 203.85 1).

H. Preparation of Di-( 4 .N.N-diethylaminocarbonvlphenvI)methanoI (compound To a solution of 4 -iodo-N,,N-diethylbenzamide (1.51 g, 5.0 mrnol) in dry THE (10 rnL) was slowly added t-butyilithiurn (5 mL, 1.7 M, 8.5 mmol) at -78 0 C. After 10 mmd, 4-formyl- N,N-diethylbenzamide (1.03 g, 5.0 mmol) in THF (5 mL) was dropwise added. the reaction mixture was warmed to r.t. and then quenched with aqueous NH 4 C1 solution and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over MgSO 4 Removal of solvents gave a crude product, which was purified by silica gel column eluting with MeOH-CH 2

CI

2 99 5: 95) to provide Di-(4-N,Ndiethylamidnocarbonylphenyl)methanoI (725 mg, 38 GC-MS: 382.20 364.15 310.05 283.15 204.05 154.55 119.05 (100); 8H (400 MHz, CDCl 3 1.06 (brs, 6H), 1. 19 (brs, 611), 3.20 (brs, 411), 3.48 (brs, 4H), 5.26 (s, 11H), 5.66 I 7.21 J=8.0 Hz, 4H), 7.31 (di, J=8.0 Hz, 411); 6C2.13 (100 MHZ, CDCI 3 12.5, 13.9, 3 9.0, 43.0, 74.5, 125.9, 126.2, 135.3, 145.3, 17 WO 97/23467 WO 9723467PCT/SE96/O1 636 21 Ml. Pre~aration of 4-(a-chloro-4-N.N-diethlaminocarbonylbenzvl).N.N.

diethvlbenzamnide (comound 7) To a solution of di-(4-N,N-diethylaminocarbonylphenyl)methanoI (400 mg, 1.05 mmol) in dry dichioromethane (10 m.L) was dropwise added thionyl chloride (1.0 m1L, 13.7 mmol) at r.t. The reaction mixture was stirred for one hour at r.t. Evaporation of solvents gave 4-(achoo4NNdehlmncroybny)N,-itybnafie which was used directly in the next step: N~ (400 MHz, CDCL 3 1.16 (brs, 12 3.38 (brs, 8H), 6.15 1H), 7.35 J=8.0 Hz, 4H), 7.44 J=8.0 Hz, 4H); 8C&13 (100 MHz, CDC1 3 5: 13.1, 39.1, 42.5, io 62.7, 126.3, 127.5, 136.2, 141.3, 170.3.

Example Premaration of I-HomoDiverazinyl )-4-N.N-diethylaminocarbonyl benzvl)-N.Ndiethlbnzamide hyvdrochloride (compound 9) This compound was prepared as described for compounds 1 and 4.

GC-MS: 407.20 (1.5 3 94.25 366.15 293.15 265.15 165.15 99. 10 (100); 8H 4 0 0 MHz, CDCl 3 1.11 (brs, 6H), 1.21 (brs, 6H), 1.69 (in, 2H), 2.36 (brs, 111), 2.63 (in, 4H1), 2.97 (mn, 2H), 3.00 (mn, 2H), 3.25 (brs, 4H1), 3.52 (brs, 4H), 4.63 I1H), 7.27 J=8.4 Hz, 4H), 7.43 J=8.4 Hz, 411); 8C-13 (100 MHz, CDC1 3 12.8, 14.1, 30.9, 39.1, 43.2, 47.1, 49.7, 53.0, 56.4, 74.9, 126.5, 127.7, 135.8, 144.5, 17 1. 1.

Its HCI salt: in.p. 158-164 0 C (AcOEt-Ether); v. (KBr) cin' 3498, 1627, 1047; Anal.Calcd.for C~gH4N 4 0 2 2.7OHC1 0.30H120: C, 59.16; H, 7.68; N, 9.86. Found: C, 59.25; H, 7.66; N, 9.63.

WO 97/23467 WO 9723467PCT/SE96/O1 636 22 rV.. Pregaration of 4 -(ca-hvdroxv-2naphthvlmethy)NA-itjhIbenzamide (comnound 6) This compound was prepared as described for compounds 1 and 4.

GC-MS: 333.20 332.20 (100), 316.15 261.10 215.05 (18.8), 155.05 127.10 SH (400 MHz, CDCI 3 0.93 (brs, 3H), 1. 11 (brs, 3H), 3.08 (brs, 2H), 3.38 (brs, 2H), 4.80 (brs, 1H), 5.73 1H), 7.13 J=8.0 Hz, 2H), 7.27 (d, Hz, 2H), 7.30 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (in, 2H), 7.63 J=8.4 Hz, IH), 7.70 (in, 2H), 7.74 IlH); 8C- 13 (100 MHz, CDC1 3 8& 12.5, 13.8, 39.0. 43.0, 75.0, 124.7, 124.8, 125.5, 125.7, 126.0, 126.3, 127.3, 127.6, 127.7, 132.4, 132.7, 135.2, 141.3, 145.2, 17 1. 1.

V. Preparation of 4-(a-chloro-2-naphth vl)-N.N-diethylbenzamide compound 8) This compound was prepared as described for compounds I and 4.

Used directly in the next step: 6H (400 MHz, CDC1 3 1.15 (brs, 6H), 3.38 (brs, 4H), 6.28 (s, lH), 7.35 (in, 2H), 7.47 (mn, 5H), 7.80 (in, 4H).

Example 6 Preparation of 4.%.IHnoieaiy)2nthhlehl-,-dehlezmd hydrochloride (compound This compound was prepared as described for compounds 1 and 4.

GC-MS: 415.15 400.20 356.20 345.25 317.15 (15.7), 244.00 215.15 99.15 (100); 8H (400 MHz, CDC1 3 1.07 (brs, 3H), 1. 17 (brs, 3H), 1.69 (in, 2H), 2.63 (brs, 1H), 2.67 (in, 4H), 2.86 (in, 2H), 2.98 (in, 2H), 3.20 (brs, 2H), 3.48 (brs, 2H), 4.80 1H), 7.30 J=8.0 Hz, 2H), 7.42 (mn, 2H), 7.52 J=8.0 Hz, 2H), 7.61 (mn, I1H), 7.78 (in, 4H), 13 (100 MHz, CDC1 3 8: 12.7, 14.0, 30.9, 39.0, 43. 1, WO 97/23467 PCT/SE96/01636 23 47.0, 49.6, 53.0, 56.2, 75.0, 125.5, 125.7, 125.8, 126.4, 126.5, 127.4, 127.6, 127.7, 128.1, 132.5, 133.2, 135.5, 140.6, 144.7, 171.0.

Its HCI salt: m.p. 165-172 oC (AcOEt-Ether); vm (KBr) cm 3462, 1612, 1106; Anal.Calcd.for C 27

H

33

N

3 0 2.0HC1. 1.60H 2 0: C, 62.69; H, 7.44; N, 8.12. Found: C, 62.80; H, 7.37; N, 8.03.

Pharmaceutical compositions The novel compounds according to the present invention may be administered orally, intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, intrathecally and intracerebroventricularly.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component In tablets, the active component is mixed with the carrier having the WO 97/23467 PCT/SE96/01636 24 necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, cetrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannata, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc.

Preferred pharmaceutically acceptable salts are the hydrochlorides and citrates.

The term composition is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it.

Similarly, cachets are included.

WO 97/23467 PCT/SE96/01636 Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid from compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Preferably the pharmaceutical compositions is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.

WO 97/23467 PCT/SE96/01636 26 Biological evaluation A) IN VITRO MODEL Cell culture Human 293S cells expressing cloned human 5, and c receptors and neomycin resistance were grown in suspension at 37 0 C and 5% CO 2 in shaker flasks containing calcium-free DMEMIO% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 pg/ml geneticin.

Membrane preparation Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min. then homogenized with a polytron for 30 sec. The suspension was spun at S. 5 1000g (max) for 10 min at 4 0 C. The supernatant was saved on ice and the pellets resuspended and spun as before. The supernatants from both spins were combined and spun at 46,000 g(max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris/C1. pH 7.0) and spun again. The final pellets were resuspended in membrane buffer mM Tris, 0.32 M sucrose, pH Aliquots (1 ml) in polypropylene tubes were frozen in 20 dry ice/ethanol and stored at -70°C until use. The protein concentrations were determined Sby a modified Lowry assay with SDS.

Binding assays *qP04

S.

Membranes were thawed at 37C, cooled on ice, passed 3 times through a needle, and diluted into binding buffer (50 mM Tris, 3 mM MgC1 2 1 mg/ml BSA (Sigma A- 7888), pH 7.4, which was stored at 4 0 C after filtration through a 0.22 m filter, and to which had been freshly added 5 pg/ml aprotinin, 10 pM bestatin, 10 pM diprotin A, no DTT).

Aliquots of 100 pl (for pg protein) were added to iced 12x75 an O polypropylene tubes containing 100 pl of the appropriate radioligand (see Table 1) and 100 WO 97/23467 PCT/SE96/01636 27 pl of test peptides at various concentrations. Total (TB) and nonspecific (NS) binding were determined in the absence and presence of 10 pM naloxone respectively. The tubes were vortexed and incubated at 25 0 C for 60-75 min, after which time the contents are rapidly vacuum-filtered and washed with about 12 ml/tube iced wash buffer (50 mM Tris, pH 7.0, 3 mM MgC12) through GF/B filters (Whatman) presoaked for at least 2h in 0.1% polyethyleneimine. The radioactivity (dpm) retained on the filters was measured with a beta counter after soaking the filters for at least 12h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 9 6-place PEIsoaked unifilters, which were washed with 3 x 1 ml wash buffer, and dried in an oven at 55 0 C for 2h. The filter plates were counted in a TopCount (Packard) after adding 50 pi scintillation fluid/well.

Data analysis The specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test peptides was expressed as percentage of control SB. Values of IC 50 and Hill coefficient (nH) for ligands in displacing specifically bound radioligand were calculated from logit plots or curve fitting programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit.

Values of Ki were calculated from the Cheng-Prussoff equation. Mean S.E.M. values of

IC

50 Ki and n H were reported for ligands tested in at least three displacement curves.

Receptor saturation experiments Radioligand Kg values were determined by performing the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated I5 (up to 10 times if amounts of radioligand required are feasable). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of K and Bmax from individual experiments were obtained from nonlinear fits of specifically bound vs. nM free radioligand from individual according to a one-site modeL WO 97/23467 PCT/SE96/01636 28 B) BIOLOGICAL MODEL (IN VIVO MODEL) The well characterized hot plate test (Jolicoeur et al., 1991, "Neurobehavioral evidence for kappa agonist activity of the morphinan derivation 1 4 -b-methyl 8 -oxacyclorphan [BC(3016)]": Pharmacol. Biochem. Behav. 38: 401-405.) and tail flick test (D'Amour, F.E. and Smith, D.L. (1941): "A method for determining loss of pain sensation",

J.

Pharmacol. Exp. Ther. 72: 74-79; Nance, P.A. and Sanyor, J. (1987): "Substance

P-

induced long-term blockade of spinal adrenergic analgesia: reversal by morphine and naloxone"; J. Pharm. Exp. Ther. 340: 972-977) were used to evaluate the effectiveness of compounds of the present invention as potent analgesics.

Claims (17)

1. A cxround of the general formula (I) R' N R B wherein A is a substituted or unsubstituted aromatic; an optionally substituted C 5 -C 1 0 hydroaromaric; a heteroaromatic or a heterohydroaromatic moiety having from 5 to atoms selected from any of C, S, N and 0, each optionally and independently substituted by I or 2 substituents independently selected from hydrogen, C- 3 (CH 2 0 CF 3 halogen, CN 5 R 6 ,C 5 CR 5 56 6 CoNR R C02R COR (CH 2 )(NR R ,(CH 2 ))oCH 3, (l SoRR (CH 2 )0 SOR 5 56 5 1 .0 (C 2 So 2 R (CH 0 S 2 NR (CH)) 0 NR CXR and -NR (ai 2 (R wherein o is 0, 1, or 2, and R R and Rare as defined below respectively; SR' is selected frmn hydrogen, a branched or straight C-C 6 alkyl, Q§2 Gi=CU 2 1, C3- cycloalkyl, L 4 -L 8 (alkyl-cycloalkyl) wherein alkyl is C -C2 alkyl and cycloalkyl is C 3 -L 6 cycloalkyl; C-C10 aryl; and heteroaryl having fran 5 to 10 atomE selected fran any of C, S, N and 0; R 5 and R is each and i xependently as defined for R 1 above; or R5 and R 6 taken together is -(CH 2 werein r is 4 or R 2 is selected fran hydrogen, CM 3 I (7AIC22R and CH 2 2R 1 wtrein R 1 is as defined above; WD 97/23467 PCr/SE96/01636 B is a substituted or unsubstituted aromatic; an optionally substituted C 5 -CIO hydroaromaric; a heteroaromatic or a heterohydroaromaric moiety having from 5 to atom selected from any of C, S, N and 0, optionally substituted by 1-2 substituents each 5 6 and independently selected from hydrogen, CH 3 CF 3 halogen, (CH 2 )pCONR R (CH 2 )PNR 5 R 6 (CH 2 )pCOR 5,(CH 2 )PCO 2 R 5,OR5 (CH 2 )pSOR 5(CH 2 )pSO 2 R 5, and

6. wherein p is 0, 1, 2 or 3 and wherein R 5and R 6are as defined above; R 3and R 4is each and independently selected from 5 5 6 5 6 5 6 5 R (CH 2 )pCONR R (CH2)pNR R (CH 2 )pCONR R (CH 2 )pCO2R ,(CH2)pPh, (CH 2 )p(p-OH Ph), (CH 2 )p-3-indolyl, (CH 2 )pSR 5or (CH 2 wherein p is 0, 1, 2, 3, or 4, and wherein R 5and R 6are as defined above; as well as pharmaceutically acceptable salts of the compounds of the formula isomers, hydrates, isoforms and prodrugs thereof. 2. A*.ronlo h~euial acpal at riceso hyrae or 9sf=o rdusteefoftefr aIacrigt 2.c A group beng orptiona ebsiutedalby accetal s l ts orepnenl saerete or hydrates, or3 isof )onms or prtkug threo of th fo02Rl I acxrin toCH (caim 0R5 1,2)S0N whereinORadNR(H)OO ween n A i r s e fed rmbel, andphyo is dll 0ezfrnl orztiohnl py1: frnl WO 97/23467 PCT/SE96/01636 31 1 5 6 R R and R is each and independently selected from hydrogen, a branched or straight C 1 -C 4 alkyl, C 3 -C5 cycloalkyl, C 4 -C 8 (alkyl-cycloalyl) wherein ailcyl is CI-C 2 alkyl and cycloalkyl is C 3 -C 6 cycloalyl, and phenyl; 2 is hydrogen, methyl, or OR wherein R is as defined above; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetahydroquinyl, io tetrahydroisoquinoliny, tetrahydrofuranyl, pyrrolidinyl, indazolinyl, and 0 R each B group being optionally substituted by 1-2 substituents independently selected from 1 hyrgn56 5 6 hydrogen, CH 3 CF 3 halogen, (CH 2 )pCONR R (CH 2 NR R (CH 2 )pCOR 5 (CH 2 )pCO 2 R and OR whrein p is 0 or 1, and wherin R 5 and R 6 are as defined above; 3 4 :i 20 R3 and R4 are each and independently selected from hydrogen, CH3, CH(Me)2, CH2CH(Me)2, CH(Me)CH2CH3 (CH2)pCONR',, (CH2)NR5 (CH)pCONRR6, (CH2)pC2R 5, (CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR, and (CH)pOR whein p is0, 1, 2, or and wherein R5 and R6 are as defined above T 97/23467 PCr/SE96/01636 3. A compound or pharmaceutically acceptable salts or isomrrers or hydrates or isoforms or prodrugs thereof according to claim 2, wherein A is selected from 7 R K 9 N-S R o/ i 0F 12 R K O O Md R 16.,) wherein the phenyl ring of each A substituent may be optionally and independently 6 substituted by 1 or 2 substiments selected from H, CH 3 (CH 2 )oCF 3 F, Cl, CONR R, 5 5 5 6 5 6 CO 2 R (CH 2 )oSOR (CH)oSq 2 R (CH 2 )oSO 2 NR R (CH 2 )oNR COR and NR5(CH 2 )oCOR6 wherein R5 and R are as defined below, and o is 0, 1 or 2; RI is selected from hydrogen. methyl, ethyl, CH 2 CH=CH2, or CH2-cyclopropyl; 6 R and R is each and independently selected from phenyl, methyl and ethyl; or RS and R6 taken together is -(CH 2 wherein r is 4 or 2 1 R is H, methyl, or OR 7 8 9 10 11 12 13 14 15 16 R R R, R10, R11, R R R4, R5, and R 6, is each and independently as defined for R above; WD~ 97/23467 PCr/SE96/01636 33 B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobcnzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cycloh~enyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and each B group being optionally substituted by 1-2 substituents independently selected from 6 hydrogen, methyl, CF 3 halogen, (CH 2 )pCONR R (CH 2 )PNR 5 R (CH 2 )pCORS (CH 2 )pCQR 5, and wherein p is 0. 1, or 2, and wherein R 5 and R 6 are as defined above: 3t 4 Rand Rare each and independently selected from H, CH 3 CH(Me) 2 CH 2 CH(Me) 2 6 5 6 5 CH(Me)CH 2 CHI (CH 2 )pCONR R (CH 2 )pNR R ,(CH 2 )pCONP. R (CH 2 )pCO 2 R. (CH 2 )ph, (CH2)p(p-OH Ph), (CH 2 )p-3-indolyl, (CH 2 )pSR 5,and (CH 2 )pOR wherein p is 0, 1, 2, or 3, and wherein R 5and R 6are as defined above. 0 R. R 9 1 110 R1- 0 and wherein R R 1 0 R 1 and R 12 are as defieincam3 WJ 97/23467 PCT/SE96/01636 A ccnacund or pharaceutically acceptable salts or iscr~s or hydrates or isoforms or prodmxgs thereof according to any one of clainrE 1-4, in the form of its hydochloride salt. 6. A ccaTpond or pharnraceutically acceptable salts or isomers or hydrates or isofonrE or prcdnigs thereof of the fonrmla of claim 1, which ocximpon is a. *t S a S a a a a a a a a

7. A ccound or phamceutically acceptable salts or isomers or hydrates or isoforms or prodrugs thereof of the fornula of claim 1, which ccupoun is WO 97/23467 PCr/SE96/01636

8. A ccmpomid or pharmaceutically acceptable salts or iscxs or hydrates or isoforns or prodrugs thereof of the formiula of claim 1, which compound is Kz~ a. 0e C S 0 .5 C *5 C C C 0*

9. C 9. A cxnpound or pharmaceutically acceptable salts or isomers or hydrates or isoforus or prodrugs thereof of the formula of claim 1, which carpounx is 0 Et 2 N-, WO 97/23467 PCr/SE96/01636 A ca~rxcpnd or pharmaceutically acceptable salts or iscars or hydrates or isofornm or piodugs thereof of the formula of claim i, which cmpouix is wherein Ar is 4-diethylamincartxylphenyl.

11. A ccnpcund or pharmaceutically acceptable salts or isamrs or hydrates or isoforms or prtdrugs thereof of the forrula of claim 1, which ccrpounrd is 0@ Se S .0 0 6 0 *S 00 0 0: 0 0@ 9 0@ 0 0: 0 0 00 0@ 0000 S S 0 0 *00L 0 050 wheein Ar is 2-naphthyl.

12. A ccnpound or phanaceutically acceptable salts or iscrerms or hydrates or isoforms or prodrugs thereof according to any cne of claims 1-11, which is in a form suitable for use in therapy. WO 97/23467 PCrT/SE96/01636

13. A compound or phanrmaceutically acceptable salts or iscmers or hydrates or isofonrms or prodrugs thereof according to claim 12, wherein the therapy is pain management.

14. A compound or hydrates or isoforms or the therapy is directed A compound or hydrates or isoforms or the therapy is directed

16. A cormpound or hydrates or isoforms or the therapy is directed phanrmaceutically acceptable salts or isomers or prodrugs thereof according to claim 12, wherein tcwards gastrointestinal disorders. pharmaceutically acceptable salts or iscmers or prodrugs thereof according to claim 12, wherein towards spinal injuries. pharmaceutically acceptable salts or iscmers or prodrugs thereof according to claim 12, wherein to disorders of the sympathetic nervous system. C C CC* *CC2 C C C C.. C. CI 4

17. A compound or pharmaceutically acceptable salts or isomers or hydrates or isoforms or prodrugs thereof according to any one of claims .5 1-11, further characterized in that it is isotopically labelled.

18. Use of a compound or pharmaceutically acceptable salts or isomers or hydrates or isoforms or prodrugs thereof according to any one S of claims 1-11, in the form of a diagnostic agent. S 19. Use of a compound or pharmaceutically acceptable salts or 20 isomers or hydrates or isoforms or prodrugs thereof according to any one S of claims 1-11, in the manufacture of a medicament, said medicament being formulated for use in the treatment of pain.

20. Use of a ccmpound or pharmaceutically acceptable salts or isomers or hydrates or isoforms or prodrugs thereof according to any one of claims 1-11, in the manufacture of a medicament, said medicament being formulated for use in the treatment of gastrointestinal disorders.

21. Use of a compound or pharmaceutically acceptable salts or iscirers or hydrates or isoforms or prodrugs thereof according to any one WO 97/23467 PCT/SE96/01636 38 of claims 1-11, in the manufacture of a medicament, said medicament being formulated for use in the treatment of spinal injuries.

22. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salts or isomers or hydrates or isoforms or prodrugs thereof of the formula I according to any one of claims 1-11 as an active ingredient, together with a pharmaceutically acceptable carrier.

23. A process for the preparation of a compound or pharmaceutically acceptable salts or isomers or hydrates or isoforms or prodrugs thereof according to the formula of any one of claims 1-11, where applicable, wherein: A) an aldehyde or ketone is treated with a nuclecphile, giving the corresponding alcohol; (ii) the alcohol is converted into a suitable leaving group, which in i turn is displaced with a homopiperazine derivative; and (iii) a N- -unsubstituted homopiperazine derivative is substituted via its organo halide or equivalent species, or acylated; or B) S: a N-protected amino acid ester is reacted with a second amino acid ester, and thereafter treated with an acid, giving a homopiperazinedione; (ii) the diane is reduced to the corresponding bhccpiperazine; and (iii) the hcumpiperazine is alkylated or acylated on one or more of the nitrogens.

24. A compound or pharmaceutically acceptable salts or isomers or hydrates or isoforms or prodrugs thereof according to the formula I of any one of claims 1-11, when obtained by the process of claim 23. NO 97/23467 PCT/SE96/01636 A nmethod for the treatment of pain, wherein an effective axnunt of a cnompound or pharmaceutically acceptable salts or isaomers or hydrates or isoforms or prodrugs thereof according to the formula I according to any one of claims 1-11 and 24, or a pharmraceutical carpositican according to claim 22, is administered to a subject in need of pain managerent. ITED this 21st day of April 1999 ASTRA PHARMA INC., By its Patent Attorneys, E. F. WEUIN=I(N CI), By: (Bruce Wellington) (Bruce Weklihtn) I S S S S *SS* S S A/KA/4700