WO1999064420A1

WO1999064420A1 - β-CARBOLINE COMPOUNDS

Info

Publication number: WO1999064420A1
Application number: PCT/US1999/012874
Authority: WO
Inventors: Christophe Alain Thurieau; Lydie Francine Poitout; Marie-Odile Galcera; Christophe Philippe Moinet; Thomas D. Gordon; Barry A. Morgan; Dennis C. H. Bigg; Jacques Pommier
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1998-06-12
Filing date: 1999-06-08
Publication date: 1999-12-16
Anticipated expiration: 2000-12-12
Also published as: NZ508765A; NO20006268D0; NO20006268L; ES2188184T3; EP1086101A1; EP1086101B1; HUP0302962A2; AR019153A1; CN1169808C; DK1086101T3; US6586445B1; JP2002517500A; RU2233841C2; DE69904595D1; KR20010071461A; DE69904595T2; CN1308632A; CA2335339A1; PL345589A1; NO319532B1

Abstract

The present invention is directed to compounds of formula (I) wherein the variables are defined in the specification, which bind to somatostatin receptors and block Na channels.

Description

β-CARBOLINE COMPOUNDS Background of the Invention

The present invention is directed to compounds of formulas (I) and (II) and compositions containing said compounds which bind selectively to somatostatin receptor subtypes and the use of said compounds for treating medical disorders which are mediated by somatostatin receptor subtypes. Somatostatin (somatotropin release inhibiting factor, SRIF), a tetradecapeptide hormone, originally isolated from bovine hypothalami (Brazeau, P. et al., Science 179, 77-79, 1973) has been shown to have a wide range of regulatory effects on the release of a variety of hormones such as growth hormone, prolactin, glucagon, insulin, gastrin (Bloom, S.R. and Poldack, J.M., Brit. Med. J. 295, 288-289, 1987). In addition, antiproliferative properties (Reichlin, S., N. Engl. J . Med. 309, 1495-1501 , 1983) have been obtained with somatostatin analogs in metastatic prostatic cancer (Parmar, H. et al, Clin. Exp. Metastasis, 10, 3-1 1 , 1992) and in several other neuroendocrine neoplasms in man (Anthony, L. et al, Acta Oncol., 32, 217-223, 1993). Metabolism of somatostatin by aminopeptidases and carboxypeptidases leads to a short duration of action. The actions of somatostatin are mediated via membrane bound receptors. The heterogeneity of its biological functions has led to studies to identify structure-activity relationships of peptides analogs at the somatostatin receptors which resulted in the discovery of five receptor subtypes (Yamada, et al, Proc . Natl. Acad. Sci. U.S.A, 89, 251-255, 1992 ; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are under extensive investigation. Binding to the different types of somatostatin subtypes have been associated with the treatment of the following conditions and/or diseases. Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are restenosis, inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors, treatment of cancer such as hepatoma, inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis, chronic allograft rejection, angioplasty, preventing graft vessel and gastrointestinal bleeding Somatostatin agonists can also be used for decreasing body weight in a patient

In drug research, it is a key issue to minimize side effects by developing highly potent and selective drug molecules Recent work on the development of nonpeptide structures (Hirschmann, R et al, J Am Chem Soc 115, 12550-12568, 1993 , Papageorgiou, C and Borer, X , Bioorg Med Chem Lett 6, 267-272, 1996) have described compounds with low somatostatin receptor affinity

Further, compounds of Formula I and II are sodium channel blocker and, thus, exhibit useful pharmacological properties, especially utility for the alleviation of neuropathic pain Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperpathia

Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states They are in particular useful as local anesthetics, and in the treatment of arrhythmia It has also been reported for many years that sodium channel-blocking agents may be useful in the treatment of pain, including neuropathic pain, see, for example, Tanehan et al , Pain Forum , 4(2), 75-80, (1995) There is evidence that sodium channel-blocking agents selectively suppress ectopic neural firing in injured nerves, and it is via this mechanism that they are believed to be useful for relieving pain However, studies carried out on well known sodium channel- blocking agents, for example carbamazepine, phenytoin, docaine, mexiletine, and the like, indicate that these agents are not very effective for the treatment of neuropathic pain conditions at moderate dose levels, and that even at these moderate dose levels they are associated with a range of undesirable side effects, such as vertigo, nausea, sommolence, tremor, slurred speech, etc Pre-clinical evidence demonstrates that sodium channel-blocking agents selectively suppress abnormal ectopic neural firing in injured peripheral and central neurons, and it is via this mechanism that they are believed to be useful for relieving pain Consistent with this hypothesis, it has been shown that sodium channel accumulate in the peripheral nerve at sites of axonal injury (Devor et al , J Neurosci, 1993, 132, 1976-1992) Alterations in either the level of expression or distribution of sodium channels with an injured nerve, therefore, have a major influence on the pathophysiology of pain associated with this type of trauma This concept is supported by the relative success of employing sodium channel modulating agents (e g , anticonvulsants, local anesthesics) for the treatment of neuroplastic pain However, pain relief has often been obtained concomitantly with numerous adverse events and/or limitations in efficacy which have restricted tolerabi ty of these drugs It can be seen that a need still exists for an orally active agent that is effective for the treatment of neuropathic pain, but having fewer side effects Another aspect of this invention relates to the use of a compound of Formula I or

II for treating neuropathic pain conditions in a mammal that is responsive to sodium channel-blocking agents including peripheral neuropathies, such as trigemmal neuralgia, postherapeutic neuralgia, radiculopathy, and neuropathy secondary to metastatic infiltration, adiposis dolorosa and burn pain, and central pain conditions following stroke, thalamic lesions and multiple sclerosis, by administering a therapeutically effective amount of a compound of Formula I or II to the mammal

As a result, the compounds of the invention are indicated for the treatment of any pathology, disorder or clinical condition involving glutamate release in their etiology, including psychiatric disorders (such as schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive disorders, social withdrawal), hormonal conditions (excess GH, e g in the treatment of diabetes melhtus, angiopathy and acromegaly, or LH secretion, e g , prostrate hypertrophy, menopausal syndrome, corticosterone secretion in stress), metabolic inducted brain damage (hypoglycaemia, non-ketotic hyperglycmaemia (glycine encephalopathy), sulphite oxidase deficiency, hepatic encephalopathy associated with liver failure), emesis, spasticity, epilepsy, tinnitus, pain (e g cancer pain, arthritis) and drug (ethanol, opiates, including synthetics with opiate-like effects, e g pethidine, methadone etc , cocaine, amphetamine, barbiturates and other sedatives, benzodiazephines, abuse and withdrawal

Moreover, a compound of the present invention is indicated in the treatment of any pathology involving neuronal damage, for example neurodegenerative disorders such as Alzheimer's, Huntington's or Parkinson's diseases, virus (including HIV)- induced neurodegeneration, Amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, o voponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins Summary of the Invention

In one aspect the present invention is directed to a compound of formula (I),

(I) the racemic-diastereomeπc mixtures and optical isomers of said compound of formula (I), the pharmaceutically-acceptable salts or prodrugs thereof or a pharmaceutically acceptable salt of said prodrug, wherein represents an optional bond, X is N or N-R⁴, where X is N when both optional bonds are present and X is N-R⁴ when the optional bonds are not present,

R¹ is H -(CH₂)_m-C(0)-(CH₂)_m-Z¹, -(CH₂)_m-Z¹, -(CH₂)_m-0-Z¹ or (C₀-C₆)alkyl-C(O)-NH- (CH₂)_m-Z³,

Z¹ is an optionally substituted moiety selected from the group consisting of (C₁-C₁₂)alkyl, benzo[b]thιophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,

R² is (C_rC₁₂)alkyl, (C₀-C₆)alkyl-C(O)-O-Z⁵, (C₀-C₆)alkyl-C(O)-NH-(CH₂)_m-Z³ or optionally substituted phenyl,

Z⁵ is H, (C_rC₁₂)alkyl or (CH₂)_m-aryl,

Z³ is ammo, (C₁-C₁₂)alkylamιno, N,N-dι-(C_rC₁₂)alkylamιno, -NH-C(O)-0-(CH₂)_m- phenyl, -NH-C(O)-O-(CH₂)_m-(C_rC₆)alkyl or an optionally substituted moiety selected from the group consisting of imidazolyl, pyπdinyl and morpholinyl, piperidinyl, piperazinyl, pyrazolidinyl, furanyl and thiophene,

R⁴ is H -C(=Y)-N(X¹X²), C(=O)X² or X²,

X² is -(CH₂)_m-Y¹-X³;

X³ is H or an optionally substituted moiety selected from the group consisting of

(C_rC₁₂)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₁₂)alkoxy, aryloxy, (C₁-C₁₂)alkylamino, N,N- di-(C₁-C₁₂)alkylamino, -CH-di-(C₁-C₁₂)alkoxy or phenyl; R⁵ is (C_rC₁₂)alkyl, -(CH₂)_m-Y¹-(CH₂)_m-phenyl-(X¹)_n, (C₃-C₁₂)cycloalkyl, -(CH₂)_m-S-(C_r C₁₂)alkyl, (C₁-C₁₂)alkyl-S-S-(C₁-C₁₂)alkyl, -(CH₂)_m-(C₁-C₁₂)al enyl or an optionally substituted moiety selected from the group consisting of phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and

Y¹ is O, S, NH or a bond;

R⁶ is H or SO₂-phenyl;

R⁷ is H, alkyl optionally substituted with alkoxy or dialkylamino; wherein an optionally substituted moiety or optionally substituted phenyl is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF₃, NO₂, OH, SO₂NH₂, CN, N₃, -OCF₃, (C_rC₁₂)alkoxy, -(CH₂)_m-phenyl-(X¹)_n, -NH-CO-(C₁-C₆)alkyl, -S-phenyl-(X¹)_n, -O-(CH₂)_m-phenyl-(X¹)_n, -(CH₂)_m-C(O)-O-(C₁-C₆)alkyl, -(CH₂)_m-C(O)-(C₁-C₆)alkyl, -O-(CH₂)_m-NH₂, -O-(CH₂)_m-NH-(C_rC₆)alkyl, -0-(CH₂)_m-N-di-((C₁-C₆)alkyl) and -(C₀-C₁₂)alkyl-(X¹)_n;

X¹ for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, N0₂, OH, -CF₃, -OCF₃, (C_rC₁₂)alkyl, (C_rC₁₂)alkoxy, -S-(C_r

C₆)alkyl, -(CH₂)_m-amino, -(CH₂)_m-NH-(C₁-C₆)alkyl, -(CH₂)_m-N-di-((C₁-C₆)alkyl), -(CH₂)_m-phenyl and -(CH₂)_m-NH-(C₃-C₆)cycloalkyl; m for each occurrence is independently 0 or an integer from 1 to 6; and n for each occurrence is independently an integer from 1 to 5. A preferred compound of formula (I) is where X is NH; R¹ is H; R² is

-CH(CH₃)₂-CO-NH-(CH₂)_m-Z³ where m in the definition of R² is 1 , 2 or 3;

Z³ is imidazolyl, pyridinyl, morpholino, or N,N-di-ethylamino; R⁵ is propyl, n-butyl, n-pentyl, -(CH₂)-O-(CH₂)-phenyl, 2-nitro-3-OMe-phenyl, p-t-Bu- phenyl, m-OMe-phenyl, o-OMe-phenyl, p-nitro-phenyl, -(CH₂)₂-S-Me, cyclohexyl, m-Br- phenyl, p-S-Me-phenyl, p-N,N-dimethylamino-phenyl, m-methyl-phenyl or

R⁶ is H, and R⁷ is H

Another preferred compound of formula (I) is where X is NH, R¹ is H, R² is phenyl,

R⁵ is propyl, n-butyl, n-pentyl, n-heptyl, isobutyl, neopentyl, cyclopropyl, cyclohexyl, -(CH₂)₂-S-Me, phenyl, -(CH₂)-0-(CH₂)-phenyl, 2-nιtro-3-OMe-phenyl, p-t-Bu-phenyl, o- OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, 3,4,5-tπ-OMe-phenyi, p-butoxy-phenyl, 3- ethoxy-4-methoxy-phenyl, o-nitro-phenyl, p-nitro-phenyl, p-OCF₃-phenyl, o-CF₃-phenyl, 3-F-4-OMe-phenyl, o-F-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2,4-dι-CI-phenyl, 3,4-dι-CI-phenyl, p-(3-(N,N-dιmethyiamιno)propoxy)phenyl, -(CH₂)₂-S-Me, cyclohexyl, p-(Me-CO-NH-)-phenyl, p-t-Bu-phenyl, p-OH-phenyl, p-(-S-Me)-phenyl, p(-S-t-Bu)- phenyl, p-N,N-dιmethylamιno-phenyl, m-methyl-phenyl, 3-OH-4-Ome-phenyl, p-phenyl- phenyl,

Another preferred compound of formula (I) is where X is NH, R¹ is H, R² is p- OMe-phenyl or p-nitro-phenyl,

R⁵ is n-butyl, n-pentyl, n-hexyl, isobutyl, cyclohexyl, -(CH₂)₂-S-Me. phenyl, m-OMe- phenyl, 2-nιtro-3-OMe-phenyl, p-nitro-phenyl, p-t-Bu-phenyl, p-thiomethyl-phenyl, m-Br- phenyl, 2-OMe-4-dιmethylamιno-phenyl, p-(3-(N N-dιmethylamιno)propoxy)phenyl, p-

dimethylamino-phenyl, 3-nιtro-4-CI-phenyl, -(CH₂)-0-(CH₂)-phenyl or

In another aspect, the present invention is directed to a compound of formula (ID,

the racemic-diastereomeπc mixtures and optical isomers of said compound of formula (II), the pharmaceutically-acceptable salts or prodrugs thereof or a pharmaceutically acceptable salt of said prodrug, wherein represents an optional bond,

J¹ is N-R⁶ or S,

J² is N-R¹ O or S,

X is N or N-R⁴, where X is N when both optional bonds are present and X is N-R⁴ when the optional bonds are not present,

R¹ is H -(CH₂)_m-C(0)-(CH₂)_m-Z¹, -(CH₂)_m-Z¹, -(CH₂)_m-0-Z¹ or (C₀-C₆)alkyl-C(O)-NH-

(CH₂)_m-Z³,

Z¹ is an optionally substituted moiety selected from the group consisting of (C_rC₁₂)alkyl, benzo[b]thιophene, phenyl, naphthyl, benzo[b]furanyl thiophene, isoxazolyl, indolyl,

R² is (C₁-C₁₂)alkyl, (C₀-C₆)alkyl-C(O)-O-Z⁵, (C₀-C₆)alkyl-C(O)-NH-(CH₂)_m-Z³ or optionally substituted phenyl,

Z⁵ is H, (C₁-C₁₂)alkyl or (CH₂)_m-aryl,

Z³ is ammo, (C₁-C₁₂)alkylamιno, N,N-dι-(C,-C₁₂)alkylamιno -NH-C(O)-0-(CH₂)_m- phenyl, -NH-C(O)-0-(CH₂)_m-(C₁-C₆)alkyl or an optionally substituted moiety selected from the group consisting of phenyl, imidazolyl, pyridinyl and morpholinyl, piperidinyl, piperazmyl, pyrazolidinyl furanyl and thiophene,

R³ is H, (C_rC₆)alkyl or optionally substituted phenyl;

X² is H or -(CH₂)_m-Y¹-X³;

(C₁-C₁₂)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₁₂)alkoxy, aryloxy, (C₁-C₁₂)alkylamino, N,N- di-(C₁-C₁₂)alkylamino, -CH-di-(C C₁₂)alkoxy or phenyl; R⁵ and R⁸ are each independently selected from the group consisting of H, (C_rC₁₂)alkyl, -(CH₂)_m-Y¹-(CH₂)_m-phenyl-(X¹)_n, (C₃-C₁₂)cycloalkyl, (C₃-C₁₂)cycloalkenyl, -(CH₂)_m-S-(C_rC₁₂)alkyl, (C₁-C₁₂)alkyl-S-S-(C₁-C₁₂)alkyl, -(CH₂)_m-(C₁-C₁₂)alkenyl and an optionally substituted moiety selected from the group consisting of phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and

, provided that R⁵ and R⁸ are not both H at the same time; or R⁵ and R⁸ are taken together with the carbon atom to which they are attached to form

Y¹ is O, S, NH or a bond; A is a bond, -CO-, -C(0)0-, -C(O)NH-, -C(S)NH-, or -S0₂-;

B is a bond or -(CH₂)_q-, where q is an integer from 1 to 6 ; J³ is H, (C₁-C₆)alkyl, optionally substituted phenyl, optionally substituted heteroaryl or N(R⁹R¹⁰), where R⁹ and R¹⁰ are each independently selected from the group consisting of (C₁-C₆)alkyl, and optionally substituted phenyl, or R⁹ and R¹⁰ are taken together with the nitrogen to which they are attached to form a ring having 5 to 8 members including the nitrogen atom that R⁹ and R¹⁰ are attached to, where one of the ring members may optionally be an oxygen atom or NR¹¹ , where R¹¹ is (C₁-C₆)alkyl, -C(O)-(C C₆)alkyl, -C(O)-N(V¹V²), -C(S)- N(V¹V²), or optionally-substituted-phenyl-(C₀-C₆)alkyl-, where V¹ and V² are each independently H, (C₁-C₆)alkyl or optionally-substituted-phenyl-(C₀-C₆)alkyl;

R⁶ is H or SO₂-phenyl;

R⁷ is H, Cl, F, Br, I, CF₃, NO₂, OH, SO₂NH₂, CN, N₃, -OCF₃, (C₁-C₁₂)alkoxy, -(CH₂)_m-phenyl-(X¹)_n, -NH-CO-(C_rC₆)alkyl, -S-(C_rC₁₂)alkyl, -S-phenyl-(X¹)_n, -O-(CH₂)_m- phenyl-(X¹)_n, -(CH₂)_m-C(O.)-O-(C₁-C₆)alkyl, -(CH₂)_m-C(O)-(C_rC₆)alkyl, -O-(CH₂)_m-NH₂, -O-(CH₂)_m-NH-(C₁-C₆)alkyl, -O-(CH₂)_m-N-di-((C₁-C₆)alkyl) and -(C₀-C₁₂)alkyl-(X¹)_n; wherein an optionally substituted moiety or optionally substituted phenyl is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF₃, N0₂, OH, S0₂NH₂. CN, N₃, -OCF₃, (C_rC₁₂)alkoxy, -(CH₂)_m-phenyl-(X¹)_n, -NH-CO-(C₁-C₆)alkyl, -S-(C₁-C₁₂)alkyl, -S-phenyl-(X¹)_n, -O-(CH₂)_m- phenyl-(X¹)_n, -(CH₂)_m-C(0)-0-(C₁-C₆)alkyl,

-O-(CH₂)_m-NH₂, -O-(CH₂)_m-NH-(C₁-C₆)alkyl, -0-(CH₂)_m-N-dι-((C_rC₆)alkyl) and -(C₀-C₁₂)alkyl-(X¹)_n,

X¹ for each occurrence is independently selected from the group consisting of hydrogen, Cl. F, Br, I, NO₂, OH, -CF₃, -OCF₃, (C_rC₁₂)alkyl, (C_rC₁₂)aikoxy, -S-(C_r C₆)alkyl, -(CH₂)_m-amιno, -(CH₂)_m-NH-(C_rC₆)alkyl, -(CH₂)_m-N-dι-((C_rC₆)alkyl), -(CH₂)_m-phenyl and -(CH₂)_m-NH-(C₃-C₆)cycloalkyl, m for each occurrence is independently 0 or an integer from 1 to 6, and n for each occurrence is independently an integer from 1 to 5

A preferred group of compounds of the compounds of formula (II) are those having the formula (lla)

wherein R³ is H or methyl ,

R⁴ is H or methyl ,

R⁵ is H, methyl, ethyl, butyl, pentyl or hexyl,

R⁸ is ethyl, butyl, pentyl, hexyl, or cyclohexyl , or R⁵ and R⁸ are taken together with the carbon to which they are attached to form

spirocyclohexyl, spirocycloheptyl, spiroadamantyl or / \

N-A-B-

\ where A is a bond or -C(0)0- B is a bond -(CH₂)- or -(CH₂ 2)/₂

J³ is H, or phenyl , and

R⁷ is H, Me, F, Cl, OH, -O-methyl or -0-CH₂-phenyl

A more preferred group of compounds of the formula (lla) are those compounds wherein

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together V and the imidazolyl is in the R-configuration ,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together

and the imidazolyl is in the R-configuration

\ /

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R^a are together and the imidazolyl is in the R-configuration ,

/^~Λ

R³, R⁴ and R⁷ are each hydrogen R⁵ and R⁸ are together and the imidazolyl is in the R-configuration, or its hydrochloπde salt

R³ is methyl R⁴ and R⁷ are each hydrogen R⁵ and R⁸ are each n-butyl and the imidazolyl is in the R-configuration,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together and the imidazolyl is in the R-configuration, or its hydrochloπde salt,

R³ and R⁴ are each hydrogen, R⁷ is 6-0-CH₂-phenyl, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together

the imidazolyl is in the R-configuration, or its hydrochloπde salt,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together

/ \

N-(CH₂)₂-Phenyl and the imidazolyl is in the R-configuration, R³ and R⁷ are each hydrogen, R⁴ is methyl, R⁵ and R⁸ are each n-butyl and the imidazolyl is in the R-configuration,

R³, R⁴ and are each hydrogen, R⁷ is 7-fluoro, R⁵ and R⁸ are each n-pentyl and the imidazolyl is the racemic mixture of the S- and R-configurations,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each n-hexyl and the imidazolyl is in the R-configuration

R³, R⁴ and R⁷ are each hydrogen R⁵ is hydrogen and R⁸ is hexyl in the S- configuration and the imidazolyl is in the R-configuration or its fumarate salt,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each n-butyl and the imidazolyl is in the R-configuration, or its fumarate salt,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together and the imidazolyl is in the R-configuration,

R³, R⁴ and R⁷ are each hydrogen R⁵ and R⁸ are each n-butyl and the imidazolyl is in the S-configuration,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each ethyl and the imidazolyl is in the R-configuration,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each n-pentyl and the imidazolyl is in the R-configuration,

R³, R⁴ and R⁷ are each hydrogen, R⁵ is methyl and R⁸ is cyclohexyl and the imidazolyl is in the R-configuration. R³ and R⁴ are each hydrogen, R⁷ is 6-methyl R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 7-fluoro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, R³ and R⁴ are each hydrogen, R⁷ is 6-methoxy R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 6-hydroxy, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, R³ and R⁴ are each hydrogen, R⁷ is 6-fluoro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, or its hydrochloπde salt,

R³ and R⁴ are each hydrogen, R⁷ is 8-methyl, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 6-methyl, R⁵ and R⁸ are each n-pentyl and the imidazolyl is a racemic mixture of the S- and R-configurations, or

R³ and R⁴ are each hydrogen, R⁷ is 6-chloro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations

An even more preferred group of compounds of the formula (lla) are those compounds selected from the group consisting of R³, R⁴ and R⁷ are each hydrogen, R⁵ is hydrogen and R⁸ is hexyl in the S- configuration and the imidazolyl is in the R-configuration, or its fumarate salt,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each ethyl and the imidazolyl is in the R-configuration, R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each n-pentyl and the imidazolyl is in the R-configuration,

R³, R⁴ and R⁷ are each hydrogen, R⁵ is methyl and R⁸ is cyclohexyl and the imidazolyl is in the R-configuration,

R³ and R⁴ are each hydrogen, R⁷ is 6-methyl R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, R³ and R⁴ are each hydrogen R⁷ is 7-fluoro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 6-methoxy, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, R³ and R⁴ are each hydrogen, R⁷ is 6-hydroxy, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 6-fluoro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, or its hydrochloπde salt,

R³ and R⁴ are each hydrogen, R⁷ is 6-methyl, R⁵ and R⁸ are each n-pentyl and the imidazolyl is a racemic mixture of the S- and R-configurations, and

R³ and R⁴ are each hydrogen, R⁷ is 6-chloro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations In another aspect, this invention is directed to a pharmaceutical composition comprising one or more of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as defined heremabove, and a pharmaceutically acceptable carrier

In yet another aspect, the present invention is directed to a method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, as described heremabove, to said subject

In still another aspect, the present invention is directed to a method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, as described heremabove, to said subject

In a further aspect, the present invention is directed to a method of binding one or more somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof , as described heremabove, to said subject

In an even further aspect, this invention is directed to a method of treating acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hypeπnsulinism, gastπnoma, Zolimger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux duodenogastπc reflux, Cushing s Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas and TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, as described heremabove to said subject Another aspect of this invention provides a method of treating diabetes mel tus, hyper pidemia, insulin insensitivity, Syndrome X, angiopathy, pro ferative retmopathy, dawn phenomenon and Nephropathy, inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis chronic allograft rejection, angioplasty, preventing graft vessel and gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, as described heremabove to said subject

In still another aspect, this invention provides a method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, as described heremabove, to said subject

In still another aspect, this invention provides a method of blocking sodium channel in a subject in need thereof, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, to said subject In still another aspect, this invention provides a method of blocking sodium channel in a subject in need thereof, which comprises administering a compound of formula (II) or a pharmaceutically acceptable salt thereof, to said subject

In still another aspect, this invention provides a method of alleviating neuropathic pain in a subject in need thereof, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, to said subject

In still another aspect, this invention provides a method of alleviating neuropathic pain in a subject in need thereof, which comprises administering a compound of formula (II) or a pharmaceutically acceptable salt thereof, to said subject In still another aspect, this invention provides a pharmaceutical composition for use as a local anesthetic, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable diluent

In still another aspect, this invention provides a pharmaceutical composition for use as a local anesthetic, comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable diluent

In still another aspect, this invention provides a method of treating any pathology, disorder or clinical condition involving glutamate release in their etiology in a subject in need thereof, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, to said subject A preferred method of the immediately foregoing method is wherein the pathology, disorder or clinical condition is selected from the group consisting of psychiatric disorders, hormonal conditions, metabolic inducted brain damage, sulphite oxidase deficiency, hepatic encephalopathy associated with liver failure, emesis, spasticity, epilepsy, tinnitus, pain and drug abuse and withdrawal

In still another aspect, this invention provides a method of treating any pathology, disorder or clinical condition involving glutamate release in their etiology in a subject in need thereof, comprising administering a compound of formula (II) or a pharmaceutically acceptable salt thereof, to said subject A preferred method of the immediately foregoing method is wherein the pathology, disorder or clinical condition is selected from the group consisting of psychiatric disorders, hormonal conditions, metabolic inducted brain damage, sulphite oxidase deficiency, hepatic encephalopathy associated with liver failure, emesis, spasticity, epilepsy, tinnitus, pain and drug abuse and withdrawal In still another aspect, this invention provides a method of treating any pathology involving neuronal damage in a subject in need thereof, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, to said subject A preferred method of the immediately foregoing method is wherein the pathology is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's diseases, virus (including HIV)-ιnduced neurodegeneration, amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, oiivoponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins

In still another aspect, this invention provides a method of treating any pathology involving neuronal damage in a subject in need thereof, comprising administering a compound of formula (II) or a pharmaceutically acceptable salt thereof to said subject A preferred method of the immediately foregoing method is wherein the pathology is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's diseases, virus (including HIV)-ιnduced neurodegeneration, amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, oiivoponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins

In still another aspect, this invention provides a method of treating arrhythmia in a subject in need thereof, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, to said subject In still another aspect, this invention provides a method of treating arrhythmia in a subject in need thereof, comprising administering a compound of formula (II) or a pharmaceutically acceptable salt thereof, to said subject

In still another aspect, this invention provides a method of treating epilepsy in a subject in need thereof, comprising administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject

In still another aspect, this invention provides a method of treating epilepsy in a subject in need thereof, comprising administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof, to said subject

Detailed Description of the Invention One of ordinary skill will recognize that certain substituents listed in this invention may have reduced chemical stability when combined with one another or with heteroatoms in the compounds Such compounds with reduced chemical stability are not preferred

In general, the compounds of Formula (I) and (II) can be made by processes which include processes known in the chemical arts for the production of compounds Certain processes for the manufacture of Formula (I) and (II) compounds are provided as further features of the invention and are illustrated by the following reaction schemes and examples

All of the references and patents cited throughout this disclosure are incorporated herein by reference

In the above structural formulae and throughout the instant application, the following terms have the indicated meanings unless expressly stated otherwise

The alkyl groups are intended to include those alkyl groups of the designated length in either a straight or branched configuration Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl tertiary butyl, pentyl, isopentyl, hexyl, isohexyl and the like

When the definition C₀-alkyl occurs in the definition, it means a single covalent bond The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like

The term halogen or halo is intended to include the halogen atoms fluorine, chlorine, bromine and iodine

The term cycloalkyl is intended to include a mono-cycloalkyl (e g , cyclopentyl, cyclohexyl, etc ), a bi-cycloalkyl (e g , bιcyclo[2 2 1]hepta-2,5-dιene, etc ) or a tπ- cycloalkyl group (e g , adamantyl, etc ) of the indicated carbon number known to those of skill in the art, optionally having double or triple bonds therein The term aryl is intended to include aromatic rings known in the art which can be mono-cyclic, bi-cyclic or tπ-cyclic, such as phenyl, naphthyl indenyl, azulenyl and anthracene

The term heterocycle includes mono-cyclic, bi-cyclic and tπ-cyclic systems having one or more heteroatoms, such as oxygen, nitrogen and/or sulfur The ring systems may be aromatic, for example pyridine, indole, qumolme, pyrimidine thiophene (also known as thienyl), furan, benzothiophene, tetrazole dihydromdole, dazole, N- formylmdole, benzimidazole, thiazole, and thiadiazole The ring systems may be non- aromatic, for example pyrrolidme, pipeπdine morpholine and the like

What is meant by the following description, which appears in the claims "R⁹ and R¹⁰ are taken together with the nitrogen to which they are attached to form a ring having 5 to 8 members including the nitrogen atom that R⁹ and R¹⁰ are attached to, where one of the ring members may optionally be an oxygen atom or NR¹¹ , where R¹¹ is (C₁-C₆)alkyl,

-C(0)-(C₁-C₆)alkyl, -C(O)-NH₂, -C(O)-NH-(C₁-C₆)alkyl, -C(O)-N((C_r C₆)alkyl)₂, -C(S)-NH₂, -C(S)-NH-(C₁-C₆)alkyl, -C(S)-N((C_rC₆)alkyl)₂, or optιonally-substιtuted-phenyl-(C₀-C₆)alkyl-" is that the following types of moities result

where R¹¹ is as defined heremabove and the arcs represent the carbon members of the ring (however, the symmetry of the arcs is not intended to indicate that they are necessarily of equal number of carbons)

The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituents listed in this invention define compounds which will be less stable under physiological conditions Accordingly, such compounds are less preferred

When a chemical structure as used herein has an arrow emanating from it, the arrow indicates the point of attachment For example, the structure

is a pentyl group When an arrow is drawn through a cyclic moiety, the arrow indicates that the cyclic moiety can be attached at any of the available

bonding points, for example

means that the phenyl can be bonded ortho, meta or para to the X group When an arrow is drawn through a bi-cyclic or a tπ-cyclic moiety, the arrow indicates that the bi-cyclic or tπ-cyclic ring can be attached at any of

the available bonding points in any of the rings for example means that the indole is bonded either through the phenyl portion of the ring or the nitrogen containing ring portion

In the definition for formula (II) when R⁵ and R⁸ are taken together with the carbon atom to which they are attached is defined to be, for example

N-A-B-J

, the * in the ring indicates that it is the carbon atom that R⁵ and R⁸ are attached to, thus, forming a spiro compound Compounds of the present invention having the following core structure are

numbered according to the following scheme

"Treatment" means any treatment of a condition in a mammal, particularly a human, and includes (i) preventing the disease from occurring in a subject which may be predisposed to the disease, but has not yet been diagnosed as having it, (II) inhibiting the condition, / e , arresting its development, or

(ui) relieving the condition, / e relieving the symptom of pain

The term "subject" means the recipient of a compound of the present invention, preferrably a mammal and most preferrably a human

"Disease state which is treatable by administration of a sodium channel blocker" is intended to cover all disease states which are generally acknowledged in the art to be usefully treated with sodium channel blockers in general, and those disease states which have been found to be usefully treated by the specific sodium channel blocker of our invention, the compounds of formula (I) or (II) Such disease states include, but are not limited to peripheral neuropathies, such as tπgeπnal neuralgia, postherapeutic neuralgia, diabetic neuropathy, glossopharymgeal neuralgia, lumbar and cervical radiculopathy, reflex sympathetic dystrophy and causalgia, and neuropathy secondary to metastatic infiltration, adiposis dolorosa and burn pain, and central pain conditions following stroke thal ic lesions and multiple sclerosis

"Therapeutically effective amount" refers to that amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment The therapeutically effective amount will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, and may be determined routinely by one of ordinary skill in the art The term "therapeutically effective amount" is implicitly incorporated in the amount of compound administered in a method of the present invention or when said compound is a component in a pharmaceutical composition of the present invention The compounds of the instant invention have at least one asymmetric center as noted by the asterisk in the structural formula (I) and (II), above Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the scope of the instant invention

The instant compounds can be generally isolated in the form of their pharmaceutically acceptable acid addition saits, such as the salts derived from using inorganic and organic acids Examples of such acids are hydrochloric, nitric, sulfuπc, phosphoric, acetic, propionic, maleic, succmic, D-tartaπc, L-tartaπc, malonic, methane sulfonic and the like In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium calcium, magnesium and the like, as well as from organic bases

The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of formula (I) or (II) and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art As is known in the art, agonists and antagonists of somatostatin are useful for treating a variety of medical conditions and diseases, such as inhibition of H pylori proliferation, acromegaiy, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hypeπnsulinism, gastπnoma Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastπc reflux and in treating endocπnological diseases and/or conditions, such as Cushmg's Syndrome, gonadotropmoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, and polycystic ovary disease, in treating various types of cancer such as thyroid cancer, hepatome, leukemia, meningioma and conditions associated with cancer such as cancer cachexia, in the treatment of such conditions as hypotension such as orthostatic hypotension and postprandial hypotension and panic attacks; GH secreting adenomas (Acromegaiy) and TSH secreting adenomas Activation of type 2 but not type 5 subtype receptor has been associated with treating prolactin secreting adenomas Other indications associated with activation of the somatostatin subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperhpidemia, insulin insensitivity, Syndrome X, angiopathy, prohferative retmopathy, dawn phenomenon and Nephropathy, inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors, inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis, chronic allograft rejection, angioplasty, preventing graft vessel and gastrointestinal bleeding Somatostatin agonists can also be used for decreasing body weight in a patient Accordingly, the compounds of the instant invention are useful for the foregoing methods

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula (I) or (II) in association with a pharmaceutically acceptable carrier The compounds of this invention can be administered by oral, parenteral (e g , intramuscular, intrapeπtoneal intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublmgual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e g , lubricating agents such as magnesium stearate In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents Tablets and pills can additionally be prepared with enteric coatings

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents

Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions Examples of non-aqueous solvents or vehicles are propylene glycol polyethylene glycol vegetable oils, such as olive oil and corn oil, gelatin and injectable organic esters such as ethyl oleate Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax

Compositions for nasal or sublmgual administration are also prepared with standard excipients well known in the art

Further, a compound of this invention of formula (I) or (II) can be administered in a sustained release composition such as those described in the following patents U S Patent No 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester U S Patent No 5 595 760 teaches sustained release compositions comprising a bioactive agent in a gelable form U S Application No 08/929 363 filed September 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan U S Application No 08/740,778 filed November 1 , 1996, teaches sustained release compositions comprising a bioactive agent and cyclodextπn U S Application No 09/015 394 filed January 29, 1998, teaches absorbable sustained release compositions of a bioactive agent The teachings of the foregoing patents and applications are incorporated herein by reference In general, an effective dosage of a compound of the present invention of the formula (I) or (II) in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment, all of which are within the realm of knowledge of one of ordinary skill in the art Generally, dosage levels of between 0 0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e g , mammals

A preferred dosage range is 0 01 to 10 0 mg/kg of body weight daily, which can be administered as a single dose or divided into multiple doses Compounds of the instant invention can be and were assessed for its ability to bind to a somatostatin subtype receptor according to the following assays Human somatostatin subtype receptor binding studies

The affinity of a compound for human somatostatin subtype receptors 1 to 5 (sst,, sst₂, sst₃, sst₄ and sst₅, respectively) is determined by measuring the inhibition of [¹²⁵l- Tyr¹¹]SRIF-14 binding to CHO-K1 transfected cells

The human sst, receptor gene was cloned as a genomic fragment A 1 5 Kb Psfl-Xmπl segment containg 100 bp of the 5'-untranslated region, 1 17 Kb of the entire coding region, and 230 bp of the 3'-untranslated region was modified by the Bg1 ll linker addition The resulting DNA fragment was subcloned into the BamH\ site of a pCMV-81 to produce the mammalian expression plasmid (provided by Dr Graeme Bell, Univ Chicago) A clonal cell line stably expressing the sst₁ receptor was obtained by transfection into CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method (1) The plasmid pRSV-neo (ATCC) was included as a selectable marker Clonal cell lines were selected in RPMI 1640 media containing 0 5 mg/ml of G418 (Gibco), ring cloned and expanded into culture

The human sst₂ somatostatin receptor gene, isolated as a 1 7Kb Sa/nHI-H/ndlll genomic DNA fragment and subcloned into the plasmid vector pGEM3Z (Promega), was kindly provided by Dr G Bell (Univ of Chicago) The mammalian cell expression vector is constructed by inserting the 1 7Kb BamHI-H/ndll fragment into compatible restriction endonuclease sites in the plasmid pCMV5 A clonal eel! line is obtained by transfection into CHO-K1 ceils using the calcium phosphate co-precipitation method The plasmid pRSV-neo is included as a selectable marker

The human sst₃ was isolated at genomic fragment, and the complete coding sequence was contained within a 2 4 Kb SamHl/H/ndlll fragment The mammalian expression plasmid, pCMV-h3 was constructed by inserting the a 2 0 Kb Λ/col-H/ndlll fragment into the EcoRI site of the pCMV vector after modification of the ends and addition of EcoRI linkers A clonal cell line stably expressing the sst₃ receptor was obtained by transfection into CHO-K1 ceils (ATCC) using the calcium phosphate co- precipitation method The plasmid pRSV-neo (ATCC) was included as a selectable marker Clonal cell lines were selected in RPMI 1640 media containing 0 5 mg/ml of G418 (Gibco), ring cloned and expanded into culture

The human sst₄ receptor expression plasmid, pCMV-HX was provided by Dr Graeme Bell (Univ Chicago) The vector contains the 1 4 Kb Nhe\-Nhe\ genomic fragment encoding the human sst₄ 456 bp of the 5 -untranslated region and 200 bp of the 3'-untranslated region clone into the Xoal/EcoR1 sites of PCMV-HX A clonal cell line stably expressing the sst₄ receptor was obtained by transfection into CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method The plasmid pRSV-neo (ATCC) was included as a selectable marker Clonal cell lines were selected in RPMI 1640 media containing 0 5 mg/ml of G418 (Gibco) ring cloned, and expanded into culture

The human sst₅ gene was obtained by PCR using a λ genomic clone as a template, and kindly provided by Dr Graeme Bell (Univ Chicago) The resulting 1 2 Kb PCR fragment contained 21 base pairs of the 5'-untranslated region, the full coding region, and 55 bp of the 3'-untranslated region The clone was inserted into EcoRI site of the plasmid pBSSK(+) The insert was recovered as a 1 2 Kb H/ndlll-Xbal fragment for subclonmg into pCVM5 mammalian expression vector A clonal cell line stably expressing the SST₅ receptor was obtained by transfection into CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method The plasmid pRSV-neo (ATCC) was included as a selectable marker Clonal cell lines were selected in RPMI 1640 media containing 0 5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture

CHO-K1 cells stably expressing one of the human sst receptor are grown in RPMI 1640 containing 10% fetal calf serum and 0 4 mg/ml geneticm Cells are collected with 0 5 mM EDTA and centπfuged at 500 g for about 5 mm at about 4°C The pellet is resuspended in 50 mM Tris pH 7 4 and centπfuged twice at 500 g for about 5 mm at about 4°C The cells are lysed by sonication and centπfuged at 39000 g for about 10 mm at about 4°C The pellet is resuspended in the same buffer and centπfuged at 50000 g for about 10 mm at about 4°C and membranes in resulting pellet are stored at - 80°C Competitive inhibition experiments of [¹²⁵l-Tyr¹¹]SRIF-14 binding are run in duplicate in polypropylene 96 well plates Cell membranes (10 μg protein/well) are incubated with [¹²⁵l-Tyr¹¹]SRIF-14 (0 05 nM) for about 60 mm at about 37°C in 50 mM HEPES (pH 7 4), 0 2% BSA 5 mM MgCI₂, 200 KlU/ml Trasylol, 0 02 mg/ml bacitracm and 0 02 mg/ml phenylmethylsulphonylfluoπde Bound from free [^{1 5}l-Tyr¹¹]SRIF-14 is separated by immediate filtration through

GF/C glass fiber filter plate (Unifilter, Packard) presoaked with 0 1 % polyethylenimine (P E I ), using Filtermate 196 (Packard) cell harvester Filters are washed with 50 mM HEPES at about 0-4°C for about 4 sec and assayed for radioactivity using Packard Top Count Specific binding is obtained by subtracting nonspecific binding (determined in the presence of 0 1 μM SRIF-14) from total binding Binding data are analyzed by computer- assisted nonlinear regression analysis (MDL) and inhibition constant (Ki) values are determined The determination of whether a compound of the instant invention is an agonist or an antagonist is determined by the following assay Functional assay Inhibition of cAMP intracellular production

CHO-K1 Cells expressing human somatostatin (SRIF-14) subtype receptors are seeded in 24-well tissue culture multidishes in RPMI 1640 media with 10% FCS and 0 4 mg/ml geneticm The medium is changed the day before the experiment

Cells at 10⁵ cells/well are washed 2 times by 0 5 ml and fresh RPMI with 0 2% BSA supplemented with 0 5 mM (1) 3-ιsobutyl-1-methylxanthιne (IBMX) and incubated for about 5 mm at about 37°C

• Cyclic AMP production is stimulated by the addition of 1 mM forskolm (FSK) for about 15-30 minutes at about 37°C

• The agonist effect of a compound is measured by the simultaneous addition of FSK (1 μM) , SRIF-14 (10 ¹² M to 10 ^δ M) and a test compound (10 ¹⁰ M to 10⁵ M)

• The antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μM) , SRIF-14 (1 to 10 nM) and a test compound (10 ¹⁰ M to 10⁵ ) The reaction medium is removed and 200 ml 0 1 N HCl is added cAMP is measured using radioimmunoassay method (Kit FlashPlate SMP001A New England Nuclear)

The compounds of the present invention can be tested for activity in blocking Na channels The compounds of the invention display binding to the veratπdine-sensitive sodium channel For the binding procedure see for example J B Brown Journal of Neuroscience 6,. 2064-2070 (1986), the contents of which are incorporated herein by reference They block veratπdine-induced glutamate release in rat hippocampal slice preparations The experiment is performed according to a modification of M J Leach et al , in Epiiepsia 27, 490-497 (1986) and Stroke 24 1063-1067 (1993), using exogenous glutamate The compounds of the instant invention are synthesized according to the following procedures and examples β-CARBOLINES Tetrahydro-β-carbolines

General procedure An amine of formula (a) is treated with an aldehyde in a protic or aprotic solvent with or without an acid preferrably chloroform with TFA, at about 20-80°C for about 5-72 hours The resulting carboline (obtained as a mixture of diastereoisomers) can be isolated either by aqueous work-up followed by flash chromatography on silica gel, or by addition to the reaction mixture of a nucleophile supported on polymer (to trap the excess of aldehyde) such as aminomethylpolystyrene resm followed by filtration and then rapid purification of the resulting residue on a silica gel pad (using Alltech silica cartridge and Alltech manifold)

Example 1 Diastereomic mixture at C₁ of 1 2,3,4-tetrahydro-1-(4-methoxyphenyl)-3(S)-(4-phenyl- 1 H-ιmιdazol-2-yl)-9H-pyπdo[3, 4-b]ιndole

To 2-[1 (S)-amιno-2-(3-ιndolyl)ethyl]-)-4-phenyl-1 H-ιmιdazole (100 mg, 1 eq) in solution in chloroform (0 8 mL) were successively added p-anisaldehyde (80 mL, 2 eq) and TFA (256 mL. 10 eq). After about 2 days of stirring at about 20°C. the mixture was concentrated under reduced pressure and the residue was dissolved in THF (5 mL). Aminomethylpolystyrene resin (Novabiochem, loading = 1.2 mmol/g, 550 mg, 2eq) was added and the mixture was stirred overnight at about 20°C and then filtered. The filtrate was then concentrated under reduced pressure and then purified by a rapid filtration on a silica gel pad (Alltech silica cartridges) with ethylacetate as eluent to afford the tetrahydro-β-carboline as a mixture of diastereoisomers (65 :35) (yield = 78%). NMR (¹H, 400 MHz, CDCI₃) ^■ 12.2 (m, 1 H, NH), 7.77-6.83 (m, 15H, Harom, NH), 5.29, 5.17 (2s, 1 H, H-), 4 42 (m, 1 H, H₃), 3.82, 3.78 (2s, 3H, OCH₃), 3.49 (m, 1 H, H₄), 3.17 (m, 1 H, H₄), 1.90 (s, 1 H, NH). LC/MS: calculated MW= 420.51 , m/z= 421.05 (M+H), m/z= 419.07 (M-H)

Examples 2 - 1303 The following compounds can be prepared analogously to the procedure described for Example 1 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R² and R⁵, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R² (21 substιtuents))(R⁵ (62 substituents)) = 1302.

R²

R⁵

N-SUBSTITUTEDTETRAHYDRO-β-CARBOLINES

General procedure A compound of formula (b) can react with isocyanates, isothiocyanates, Λ/-succιnιmιdyl carbamates, acyl chlorides or activated carboxylic acids in aprotic solvent at 20-70°C for 2-18 hours The resulting derivative can be isolated by evaporation of the mixture followed by flash chromatography on silica gel or by addition to the mixture of a nucleophile supported on polymer such as ammomethyl or thiomethyl polystyrene resm followed by filtration

For protected basic derivatives (R⁴ = (CH₂)_nNHBoc), the corresponding deprotected compounds (R⁴ = (CH₂)_nNH₂) were obtained by treating the Λ/-protected compound under acidic conditions (DCM/TFA 10%) Example 1304

Diastereomic mixture at C₁ of 1,2 3,4-tetrahydro-1-(4-methoxyphenyl)-2- [(phenylamιno)carbonyl]-3(S)-(4-phenyl- 1 H-ιmιdazol-2-yl)-9H-pyrιdo[3, 4-b]ιndole

To a solution of a diastereomeric mixture of 1 2,3 4-tetrahydro-1-(4- methoxyphenyl)-3(S)-(4-phenyl-1 H-ιmιdazol-2-yl)-9H-pyπdo[3 4-b]ιndole (50 mg) in chloroform (700 mL) was added benzyl isocyanate The mixture was stirred overnight at about 20°C and then diluted with chloroform (2 mL) Aminomethylpolystyrene resin (Novabiochem, loading 1 2 mmol/g, 198 mg, 2eq) was added to the mixture After about 15 hours of shaking at about 20°C, the mixture was filtered and the filtrate concentrated under reduced pressure to yield the title compound (60 mg, 92%yιeld)

NMR (¹H, 400 MHz, CDCI₃) δ 9 2-6 7 (m, 22H, arom H, NH), 6 25 (m, 1 H, H,), 5 80 (m, 1 H, H₃), 4 52-4 32 (m, 2H, CH₂Ph), 3 81-3 28 (m, 5H OCH₃, H₄, H₄) LC/MS calculated MW 553 66, m/z = 554 2 (M+H)

Examples 1305-1332 The following compounds can be prepared analogously to the procedure described for Example 1304 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein Each combination of R⁴ and R⁵, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R⁴ (9 substιtuents))(R⁵ (3 substituents)) = 27

β-carbolines

General procedure The tetrahydro-β-carbolme of formula (c) is oxidized to the corresponding fully aromatised β-carboimes using palladium on carbon or DDQ in an aprotic solvent such as toluene or xylene, chromic acid in a protic solvent, KMnO₄ in THF or manganese dioxide in an aprotic solvent preferrably chloroform at 20-80°C for 2-48 hours

Example 1333 1-Butyl-3-(4-phenyl- 1 H-ιmιdazol-2-yl)-9H-pyπdo[3, 4-b]ιndole

A mixture of 1 ,2,3,4-tetrahydro-1-butyl-3(R)-(4-phenyl-1 H-ιmιdazol-2-yl)-9H- pyπdo[3,4-b]ιndole (100 mg, 1 eq) and manganese dioxide (600 mg) in chloroform (7 mL) was heated at about 40°C for about 3 hours The mixture was cooled down to about 20°C and filtered over a CELITE® pad The filtrate was concentrated under reduced pressure to yield quantitatively the fully aromatized β-carbolme (97 mg)

NMR (¹H, 400 MHz, CDCI₃) 10 8 (s, 1 H, NH), 8 77-7 25 (m, 11 H, arom H, NH), 3.07 (f, 2H, ³J = 8Hz, CH₂), 1 85 (m, 2H, CH₂), 2 42 (m, 2H, CH₂), 0 91 (t, 3H, ³J = 8Hz , CH₃) LC/MS calculated MW = 366 46, m/z = 367 19 (M+H), m/z = 479 15 (M+TFA)

Example 1334-1336 The following compounds were prepared analogously to the procedure described for Example 1333 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein

Example 1337-1493 The following Examples can be made substantially according to the procedure of Example 1333 using the appropriate starting materials, which are commercially available or can synthesized according to literature methods known to those skilled in the art or as enabled by the teachings herein. The number of examples are calculated as follows (R2 (4 substituents))(R5(39 substituents)) = 156.

-^^s*s' Example 1494 (1 R)-1 -(4,5-Dimethyl-1 ,3-oxazol-2-yl)-2-(1 H-indol-3-yl)-1 -ethanamine hydrochloride

A solution of tert-butyl(1 R)-1-(4,5-dimethyl-1 ,3-oxazol-2-yl)-2-(1 H-indol-3-yl)ethyl- carbamate (3g, 8 4mmol) in HCI/AcOEt 1N (80ml) was stirred at room temperature for about 2 5 hours The mixture was concentrated under reduced pressure, diethyl ether (100ml) added and the white precipitate collected by filtration and washed with diethyl ether to afford the hydrochloride salt of the desired product (2 4g) Melting point 172- 174°C

(3R)-1 ,1 -Dibutyl-3-(4,5-dimethyl-1 ,3-oxazol-2-yl)-2,3,4,9-tetrahydro-1 H-β-carboline hydrochloride

To a solution of (1 R)-1-(4,5-dimethyl-1 ,3-oxazol-2-yl)-2-(1 H-indol-3-yl)-1 -ethanamine hydrochloride (1 2g, 3 6mmol) in isopropanol (20ml) was added 5-nonanone (3 1 ml, 20mmoi) and the mixture was refluxed for about 24 hours The solvent was evaporated under reduced pressure To the residue was added water (20ml) followed by NaHCO₃ (10%) solution until neutral pH, followed by ethyl acetate (3x15ml) After decantation and extraction the combined organic extracts were washed with water (20ml) and dried over MgS0₄ The solvent was evaporated under reduced pressure to afford an oil which was purified by column chromatography on silica gel using ethyl acetate/heptane 7 3 as eluent The resulting oil was dissolved in ethyl acetate (15ml) and a solution of HCl in ethyl acetate (1 N) was slowly added at about 20°C to give a precipitate The suspension was stirred a few minutes and the precipitate collected by filtration washed with diethyl ether and dried to afford 0 14g the desired product as the hydrochloride salt Melting point 128-134°C

Example 1495

(3R)-3-(4-Phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-1 '-benzoyl-spiro[1 H-β- carboline-1 ,4'-piperidine] hydrochloride

To a solution of (1 R)-2-(1 H-indol-3-yl)-1-(4-phenyl-1 H-imidazol-2-yl)-1 -ethanamine hydrochloride (1g, 2 65mmol) in isopropanol (15ml) was added N-benzoyl-4- pipeπdone (2 64g, 13mmol) The solution was refluxed for about one hour and cooled to about 20°C The solvent was removed under reduced pressure The residue was treated with dichloromethane (30ml) and stirred for about 30 m at about 20°C The resulting precipitate was collected by filtration, washed with dichloromethane and diethyl ether, and dried to afford 1 2g of the title product as the hydrochloride salt Melting point 240-244°C

Example 1496

(3R)-3-(4-Phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-1 '-(tert-butoxycarbonyl)- spiro[1 H-β-carboline-1 ,4'-piperidine]

To a solution of (1 R)-2-(1 H-indol-3-yl)-1-(4-phenyl-1 H-imidazol-2-yl)-1 -ethanamine hydrochloride (14g, 35mmol) in isopropanol (210ml) was added 1-tert-butoxycarbonyl- 4-pιperιdone (35g, 170mmol) and the mixture refluxed for about two hours The solvent was evaporated under reduced pressure Water (150ml) was added to the residue followed by 10% NaHC0₃ solution until neutral pH and extracted by ethyl acetate (4x50ml) The combined organic extracts were washed with water (2x50ml) and dried over MgS0₄ The solvent was removed under reduced pressure to afford an oil which solidified on addition of diisopropyl ether (150ml) The precipitate was collected by filtration, washed with diisopropyl ether and dried to afford 13 5g of the desired product Melting point 1 18-120°C

Example 1497 (3R)-3-(4-Phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-spιro[1 H-β-carboline-1 ,4'- piperidine

A solution of (3R)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-1 '-(tert- butoxycarbonyl)-spiro[1 H-β-carboline-1 ,4'-piperidine] (13 5g, 28mmol) in ethyl acetate (400ml) was cooled to about 0°C with an ice-bath and treated by a stream of anhydrous HCl gas for two hours The solvent was removed under reduced pressure to afford a semi-solid Tπturation with acetone gave a white solid which was collected by filtration and washed with acetone and diethyl ether The hydrochloride salt was converted to the free base with NaHC0₃ 10% solution and the aqueous layer was extracted with ethyl acetate (3x50ml) The combined organic extracts were washed with water (2x50ml), dried (MgS0₄), filtered and evaporated to afford 10g of the desired product Melting point >250°C

Example 1498 (1 R)-2-(1 -Benzothiophen-3-yl)-1 -(4-phenyl-1 H-imidazol-2-yl)-1 -ethanamine HCl

A solution of tert-butyl (1 R)-2-(1-benzothiophen-3-yl)-1 -(4-phenyl-1 H-imidazol-2-yl) ethylcarbamate (4g, 9 5mmol) in 70ml of 1 N HCI/AcOEt was warmed up to about 50°C for one hour The mixture was concentrated and diethyl ether (50ml) added The resulting white precipitate was collected by filtration and washed with diethyl ether to afford the hydrochloride salt of the desired product (3g) Melting point 190-192°C (3R)-3-(4-Phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-1'-tN-(3-pyridinyl)carbothio amide]spiro[1 H-β-carboline-1 ,4'-pιperidine]

To a solution of (3R)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-spiro[1 H-β- carboline-1,4'-piperidine] (0 38g, 10mmol) in dichloromethane (5ml) was added 3- pyπdyl isothiocyanate (0 136g, 10mmol) The mixture was stirred for about 30 mm at about 20°C and the resulting precipitate was collected by filtration and washed with dichloromethane and diethyl ether to afford 0 38g of the desired product Melting point 234-236°C

Example 1499 (3R)-1,1-Dibutyl-3-(4-phenyl-1 H-imidazol-2-yl)-1 ,2.3,4-tetrahydro[1]benzothieno

[2,3-c] pyridine

To a solution of (1 R)-2-(1-benzothiophen-3-yl)-1-(4-phenyl-1 H-imidazol-2-y1 )-1- ethanamine (1 g, 2 5mmol) in n-butanol (20ml) was added 5-nonanone (2 2ml, 13mmol) and the mixture refluxed overnight The solvent was removed under reduced pressure To the residue was added water (15ml) followed by a 10% NaHC0₃ solution until neutral pH and extracted with ethyl acetate (3x20ml) The combined organic extracts were washed with water (2x10ml) dried over MgS0₄, filtered The solvent was evaporated under reduced pressure to afford an oil which was purified by column chromatography on silica gel using ethyl acetate/heptane 1 1 as eluent After removing the solvent, diisopropyl ether was added to the residue The resulting white precipitate was filtered off and washed with diisopropyl ether to afford 0 1g of the title product Melting point 198-200°C

Example 1500 (3R)-1 ,1 -Dibutyl-3-(4-phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-1 H-β-carboline fumarate

A mixture of (10g, 33mmol) of (1 R)-2-(1 H-indol-3-yl)-1-(4-phenyl-1 H-imidazol-2-yl)-1- ethanamine hydrochloride n-butanol (150ml) and 5-nonanone (23 44g, 165mmol) was refluxed for about 4 hours and then 10ml of n-butanol were removed using a Dean- Stark apparatus After refluxmg for about a further 2 hours, the mixture was heated at about 100°C overnight The solvent was evaporated and the resulting residue partitioned between ethyl acetate (100ml) and 10% NaHC0₃ solution (50ml) After decantation the organic layer was washed with 10% NaHC0₃ solution (50ml) and water and dried over MgS0₄ Evaporation of the solvent afforded a brown residue which was purified by flash chromatography on silica gel (eluent dichloromethane /ethylacetate

9 1) The pure fractions were collected and concentrated to give, after washing with diisopropyl ether, 3 6g of the title compound as the free base Melting point 160-162°C

The free base (1 3g, 3mmol) was dissolved in acetone (5ml) Fumaπc acid

(448mg, 3mmol) was added The mixture was warmed to about 50°C to obtain a solution On standing overnight, white crystals appeared Diethyl ether (20ml) was added and the dried compound (1 05g) was collected Dy filtration Melting point 168- 170°C

Example 1501 (3R)-3-(4-Phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-spiro[1 H-β-carboline-1 ,1 - cycloheptyl]

To (0.75g, 2.5mmol) of (1 R)-2-(1 H-indol-3-yl)-1-(4-phenyl-1 H-imidazol-2-yl)-1- ethanamine was added 20ml of 1 ,2-dichloroethane, thfluoroacetic acid (2ml, 25mmol) and cycloheptanone (560mg, 5mmol). The mixture was refluxed for about 4 hours. Further trifluoroacetic acid (1 ml) and cycloheptanone (560mg) were added and reflux was continued for about 4 hours. The solvent was removed under reduced pressure. To the residue was added 20ml of ethyl acetate and 10% NaHC0₃ solution. After decantation the organic layer was washed with water and dried over MgS0₄. Evaporation of the solvent afforded a residue which was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate 3:7). The pure fractions were collected and concentrated to give 80mg of the title compound. Melting point :208- 210°C.

Example 1502

(3R)-3-(4-Pheny 1-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-1 '-[3-(4methylphenyl)-1 - propionyl] spiro[1 H-β-carboline-1 ,4'-piperidine]

To 20ml of anhydrous tetrahydrofurane were added (192mg, 1 mmol) of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and (0.14mi, 1 mmol) of triethylamine The mixture was stirred for about 15 mm then (3R)-3-(4-phenyl-1 H- imidazol-2-yl)-2,3,4,9-tetrahydro-spiro[1 H-β-carboline-1 ,4'-piperidine] (383mg,

1 mmol) and 3-(4-methylphenyl) propionic acid (164mg, 1 mmol) were added The reaction mixture was warmed to about 40°C and stirred overnight at this temperature The solvent was removed under reduced pressure The residue was partitioned between ethyl acetate (20ml) and water (10ml) After decantation the organic layer was washed with 10% NaHC0₃ solution, water and dried over MgS0₄ Evaporation of the solvent afforded a residue which was purified by flash chromatography on silica gel (eluent ethyl acetate/dichloromethane 1 1 ) The pure fractions were collected and concentrated The white solid obtained was washed with diethyl ether and collected by filtration to give 100mg of the title compound Melting point 180-182°C

Example 1503

(3R)-3-(4-Phenyl-1 H-imidazol-2-yl)-2,3,4,9-tetrahydro-1'-[N-(4- trifluoromethylphenyl)carboxamide]spiro[1 H-β-carboiine-1 ,4'-piperidine]

To a solution of (383mg, 1 mmol) (3R)-3-(4-phenyl-1 H-imidazol-2-yl)-2,3,4,9- tetrahydro-spiro[1 H-β-carboline-1 ,4'-piperidine] in dichloromethane was added

(187mg, 1 mmol) of 4-tπfluoromethylphenyl isocyanate The mixture was stirred for about one hour and diluted with 20m! diethyl ether The light cream precipitate was collected by filtration, and washed with diethyl ether to give 140mg of the title product

Melting point 222-224

Example 1504 tert-Butyl (1 R)-2-amino-1 -(1 H-indol-3-ylmethyl)-2-oxoethylcarbamate

In a reactor under 200 psi of pressure was added (6 2g, 22mmol) of methyl (2R)-2- [(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate, and 120 ml of methanol saturated with NH₃ The solution was stirred at about 85°C for about 24 hours After cooling, the solution was evaporated and the residue precipitated by the addition of diisopropyl ether Filtration gave 5 4g of the title product as a white powder Melting point 142-143°C tert-Butyl (1 R)-2-amino-1 -(1 H-indol-3-ylmethyl)-2-thiooxoethylcarbamate

To a solution of (5g, 160mmol) of tert-butyl (1 R)-2-amino-1 -(1 H-indol-3-ylmethyl)-2- oxoethylcarbamate in 85ml of 1 ,2-dιmethoxyethane was added 5 2g (62mmol) of NaHC0₃ and then (7 3g 32mmol) of P₂S₅ over a period of about 45 mm The mixture was stirred overnight and the solvent was evaporated The residue was suspended in ethyl acetate and washed with water, 10% NaHC0₃ solution and water After drying over MgS0₄ the organic layer was concentrated and the crude product precipitated by addition of isopentane/dnsopropyl ether 1 1 Filtration gave 4 3g of the title product as a cream powder MS 320 2 (MH⁺) TLC R_f = 0 7 (CH₂CI₂/MeOH 90 10) tert-Butyl (1 R)-2-(1 H-indol-3-yl)-1 -(4-phenyl-1 ,3-thiazol-2-yl)ethylcarbamate

A mixture of (2.24g, 7mmol) of tert-butyl (1R)-2-amino-1-(1H-indol-3-ylmethyl)-2- thiooxoethylcarbamate and (1 4g, 7mmol) of α-bromoacetophenone was heated until complete melting (90°C) The temperature was mamtened at about 90°C for about 10 m and after cooling ethyl acetate (50ml) and water (25ml) were added The organic layer was decanted washed with 10% NaHC0₃ solution, water dried over MgSO₄ Evaporation of the solvent afforded a residue which was purified by flash chromatography on silica gel (eluent dichloromethane/ethyl acetate 95 5) The pure fractions were collected and concentrated to give 1 1g of the desired product as a cream powder MS 420 2 (MH⁺) , TLC. R, = 0 7 (SιO₂ , CH₂CI₂/EtOAc 95 5) (1 R)-2-(1 H-lndol-3-yl)-1 -(4-phenyl-1 ,3-thiazol-2-yl)-1 -ethanamine hydrochloride

To (1 2g, 2 85mmol) of tert-butyl (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2- yl)ethylcarbamate was added ethyl acetate (10ml) and 20ml of a 1 N HCl solution in ethyl acetate The solution was stirred for about 2 hours at about 20°C followed by about 2 hours at about 50°C The crystals which formed on cooling were collected by filtration and washed with diethyl ether to give 1g of the title product as an orange powder Melting point 170-172°C (3R)-1 ,1 -Dibuty l-3-(4-phenyl-1 ,3-thiazol-2-yl)-2,3,4,9-tetrahydro-1 H-β-carboline

To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)-1 -ethanamine hydrochloride (210mg, 0 59mmol) in n-butanol (15ml) was added 0 45ml (2 5mmol) of

5-nonanone The mixture was heated under reflux for about two hours and then 5ml of n-butanol was removed by Dean-Stark Reflux was continued for about 3 hours The mixture was concentrated under reduced pressure and the residue partitioned between

15ml ethyl acetate and 15ml 10% NaHC0₃ solution After decantation the organic layer was washed with water and dried over MgS0₄ Evaporation of the solvent afforded a residue which was purified by flash chromatography on silica gel (eluent dichloromethane/ethyl acetate 97 3) The pure fractions were collected and concentrated The residue was dissolved in diethyl ether, and 1 N HCl in ethyl acetate was added The hydrochloride was collected by filtration and washed with diethyl ether to give 85mg of the title product as an orange powder Melting point 134-136°C

Preparation 1

Tert-butyl(1 R)-2-(1-benzothiophen-3-yl)-1-(4-phenyl-1 H-imidazol-2-yl)ethyl carbamate

To a solution of Boc-D-3-benzothienylalanine (5g, 15mmol) in absolute ethanol (60ml) and water (20ml) was added cesium carbonate (2 4g, 7 5mmol) and the mixture stirred for about two hours at about 20°C The solvent was removed under reduced pressure to afford a white powder which was dissolved in dimethylformamide (100ml) and treated with 2-bromoacetophenone (3g, 15mmol) After stirring overnight at about 20°C, the solvent was concentrated under reduced pressure The residue was treated with ethyl acetate (100ml) and the precipitate thus obtained (CsBr) was filtered off, washed with ethyl acetate and the filtrate was concentrated under reduced pressure to afford a light brown solid This solid was dissolved in xylene (100ml) ammonium acetate (23g, 300mmol) was added and the mixture refluxed for about two hours After cooling to about 20°C, water (50ml) and ethyl acetate (100ml) were added The organic layer was decanted and washed with water (50ml) 10% NaHC0₃ solution (2x50ml), brine (50ml) and dried over MgS0₄ The solvent was evaporated under reduced pressure Isopentane (60ml) was added to the residue which was then filtered to afford 4g of the title compond as a white powder Melting point 116-120°C

Preparation 2 Tert-butyl (1 R)-1 -(4,5-dιmethyl-1 ,3-oxazol-2-yl)-2-(1 H-indol-3-yl)ethylcarbamate

To a solution of Boc-D-TRP-OH (15g, 34mmol) in absolute ethanol (80ml) was added cesium carbonate (5 5g, 17mmol) The mixture was stirred for about one hour at about 20°C and concentrated under reduced pressure to afford a white powder which was dissolved in dimethylformamide (100ml) and treated with 3-bromo-2-butanone (3 56ml 34mmol) After stirring for about two hours at about 20°C the solvent was removed under reduced pressure to afford a suspension which was treated with ethyl acetate The precipitate (CsBr) was filtered off and the filtrate evaporated to afford an oil which was dissolved in xylene (400ml) Ammonium acetate (52g, δδOmmol) was added and the mixture was refluxed for about 45 mm After cooling to about 20°C, water (150ml) and ethyl acetate (100ml) were added After decantation the organic layer was washed with water (100ml), NaHC0₃ 10% (2x100ml) and brine (100ml), dried over MgSO₄ and the solvent evaporated under reduced pressure The residue was purified by column chromatography on silica gel using ethyl acetate/heptane 1 1 as eluent to afford 3g of the desired product as a white powder Melting point 138-140°C The following tables of compounds illustrate some of the compounds of the present invention that were synthesized and provide the HPLC retention time in minutes and mass spectra results of each compound.

Mass spectra were acquired on a single quadrupole electrospray mass spectrometer (Micromass, Platform model), 0.8 Da resolution. A monthly calibration, between 80 and 1000 Da, is performed with sodium and rubidium iodide solution isopropanol/water (1/1 Vol.).

HPLC retention times were acquired on an HPLC system: HP1 100 (Hewlett- Packard) equipped with a photodiode array UV detector.

The HPLC conditions are as follows and the conditions used for each of the following tables of compounds are indicated in the column heading.

Condition A :

Solvent A : Water + 0.02% Thfluoroacetic acid B : Acetonitrile

Flow rate : 1.1 l/min

Injection volume : 5 μL

Column : Uptisphere ODS 3μm 33^*4.6 mm i.d.

Temp. : 40 °C

Wavelength: 220 nm

Condition A was employed for the HPLC analysis of the compounds in the Tables of Compounds of Formulas 2, 3 and 4. Condition B :

Solvent : A : Water + 0.04% Thfluoroacetic acid B : Acetonitrile

Flow rate : 1.1 ml/min

Injection volume : 5 μL

Column : Uptisphere ODS 3μm 33^*4.6 mm i.d

Temp. : 40 °C

Wavelength: 220 nm

Condition B was employed for the HPLC analysis of the compounds in the Table of Compounds of Formula 1.

Condition C :

Solvent : A : Water + 0.04% Thfluoroacetic acid

B : Acetonitrile

Flow rate : 1.1 ml/min Injection volume : 5 μL Column : Uptisphere ODS 3μm 33^*4.6 mm i.d

Temp. : 40 °C Wavelength: 250 nm

Condition C was employed for the HPLC analysis of the compounds in the Table of Compounds of Formula 5.

R1

FORMULA 5

Analyses

R1 R2 Rt (mm) [M+H]+

(S)

71 53 3712

(R)

72 53 3712

73 ^ιx 53 3852

(R)

74 53 3852

(S)

75 53 3712

(R),

76 53 3712

(S)

77 53 3891

(R),

53 3891

(S)

79 56 4132

(R)

80 57 413.2

Claims

What is claimed is

A compound of formula (I),

the racemic-diastereomeπc mixtures and optical isomers of said compound of formula

(I), the pharmaceutically-acceptable salts or prodrugs thereof or a pharmaceutically acceptable salt of said prodrug, wherein represents an optional bond

X is N or N-R⁴, where X is N when both optional bonds are present and X is N-R⁴ when the optional bonds are not present, R¹ is H,

-(CH₂)_m-0-Z¹ or (C₀-C₆)alkyl-C(O)-NH-

(CH₂)_m-Z³,

Z¹ is an optionally substituted moiety selected from the group consisting of (Cι-C₁₂)alkyl, benzo[b]thιophene, phenyl, naphthyl, benzo[b]furanyl, thiophene isoxazolyl, indolyl,

R² is (C C₁₂)alkyl, (C₀-C₆)alkyl-C(O)-O-Z⁵, (C₀-C₆)alkyl-C(O)-NH-(CH₂)_m-Z³ or optionally substituted phenyl,

Z⁵ is H, (C C₁₂)alkyl or (CH₂)_m-aryl, is am o, (C C₁₂)alkylamιno, N,N-dι-(C₁-C₁₂)alkylamιno, -NH-C(0)-0-(CH₂) phenyl, -NH-C(0)-0-(CH₂)_m-(Ci-C₆)alkyl or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl and morpholinyl, piperidinyl, piperazinyl, pyrazolidmyl, furanyl and thiophene,

R⁴ is H, -C(=Y)-N(X¹X²), C(=0)X² or X²,

X² is -(CH₂)_m-Y -X³

(Cι-Cι₂)alkyl, (C₃-C₈)cycloalkyl, (Cι-C₁₂)alkoxy, aryloxy, (d-C₁₂)alkylamιno, N,N- dι-(C₁-C₁₂)alkylamιno, -CH-dι-(C₁-C₁₂)alkoxy or phenyl R⁵ is (d-CizJalkyl, -(CH₂)_m-Y¹-(CH₂)_m-phenyl-(X¹)_n, (C₃-C₁₂)cycloaikyl, -(CH₂)_m-S-(C C₁₂)alkyl, (C₁-C₁₂)alkyl-S-S-(C₁-C₁₂)alkyl, -(CH₂)_m-(d-C₁₂)alkenyl or an optionally substituted moiety selected from the group consisting of phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and

Y¹ is O, S, NH or a bond,

R⁶ is H or S0₂-phenyl,

R⁷ is H, alkyl optionally substituted with alkoxy or dialkylamino, wherein an optionally substituted moiety or optionally substituted phenyl is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF₃, N0₂, OH, S0₂NH₂, CN, N₃, -OCF₃, (C₁-C₁₂)alkoxy, -(CH₂)_m-phenyl-(X¹)_n, -NH-CO-(C₁-C₆)alkyl, -S-phenyl-(X¹)_n, -0-(CH₂)_m-phenyl-(X¹)_n, -(CH₂)_m-C(O)-O-(C₁-C_β)alkyl, -(CH₂)_m-C(OHC₁-C_β)alkyl, -O-(CH₂)_m-NH₂, -O-(CH₂)_m-NH-(Cι-C_β)alkyl, -0-(CH₂)_m-N-dι-((C₁-C₆)alkyl) and -(C₀-C₁₂)alkyl-(X¹)_n,

X¹ for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I N0₂, OH, -CF₃, -OCF₃, (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy, -S-(d-

C_β)alkyl, -(CH₂)_m-amιno, -(CH₂)_m-NH-(C C₆)alkyl, -(CH₂)_m-N-dι-((d-C₆)alkyl), -(CH₂)_m-phenyl and -(CH₂)_m-NH-(C₃-C₆)cycloalkyl, m for each occurrence is independently 0 or an integer from 1 to 6, and n for each occurrence is independently an integer from 1 to 5 2 A compound according to claim 1 wherein X is NH, R is H, R² is

-CH(CH₃)₂-CO-NH-(CH₂)_m-Z³ where m in the definition of R² is 1 , 2 or 3.

Z³ is imidazolyl, pyridinyl, morpholino, or N,N-dι-ethylamιno, R⁵ is propyl, n-butyl, n-pentyl, -(CH₂)-0-(CH₂)-phenyl, 2-nιtro-3-OMe-phenyl, p-t-Bu- phenyi, m-OMe-phenyl, o-OMe-phenyl, p-nitro-phenyl, -(CH₂)₂-S-Me, cyclohexyl, m-Br- phenyl, p-S-Me-phenyl, p-N,N-dιmethylamιno-phenyl, m-methyl-phenyl or

3 A compound according to claim 1 wnerein X is NH R' is H, R² is phenyl,

R⁵ is propyl, n-butyl, n-pentyl, n-heptyi, isobutyl neopentyl, cyclopropyl, cyclohexyl, -(CH₂)₂-S-Me, phenyl, -(CH₂)-0-(CH₂)-phenyl, 2-nιtro-3-OMe-phenyl, p-t-Bu-phenyl, o- OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, 3,4,5-tπ-OMe-phenyl, p-butoxy-phenyl, 3- ethoxy-4-methoxy-phenyl, o-nitro-phenyl, p-nitro-phenyl, p-OCF₃-phenyl, o-CF₃-phenyl, 3-F-4-OMe-phenyl, o-F-phenyi, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2,4-dι-CI-phenyl 3,4-dι-CI-phenyl, p-(3-(N,N-dιmethylamιno)propoxy)phenyl, -(CH₂)₂-S-Me, cyclohexyl, p- (Me-CO-NH-)-phenyl, p-t-Bu-phenyl, p-OH-phenyl, p-(-S-Me)-phenyl, p(-S-t-Bu)-phenyl, p-N,N-dιmethylamιno-phenyl, m-methyl-phenyl, 3-OH-4-Ome-phenyl, p-phenyl-phenyl,

4 A compound according to claim 1 wherein X is NH R is H R² is p-OMe- phenyl or p-nitro-phenyl,

R⁵ is n-butyl, n-pentyl, n-hexyl, isobutyl, cyclohexyl, -(CH₂)₂-S-Me, phenyl, m-OMe- phenyl, 2-nιtro-3-OMe-phenyl, p-nitro-phenyl, p-t-Bu-phenyl, p-thiomethyl-phenyl, m-Br- phenyl, 2-OMe-4-dιmethylamιno-phenyl, p-(3-(N N-dιmethylamιno)propoxy)phenyl, p-

dimethylamino-phenyl 3-nιtro-4-CI-phenyl, ~(CH₂)-0-(CH₂)-phenyl or

5 A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier

6 A method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject

7 A method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject 8 A method of binding one or more somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject

9 A method of treating acromegaiy, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VlPoma, nesidoblastosis, hypeπnsulinism, gastπnoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scieroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastπc reflux, Cushmg's Syndrome, gonadotropmoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas or TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject 10 A method of treating diabetes melhtus, hyperlipidemia, insulin insensitivity, Syndrome X angiopathy, pro ferative retmopathy, dawn phenomenon, Nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome watery diarrhea syndrome, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject

11 A method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound according claim 1 or a pharmaceutically acceptable salt thereof, to said subject

12 A compound of formula (II),

J¹ is N-R⁶ or S,

R¹ is H, -(CH₂)_m-C(0)-(CH₂)_m-Z\ -(CH₂)_m-Z¹ , -(CH₂)_m-0-Z¹ or (C₀-C₆)alkyl-C(O)-NH-

(CH₂)_m-Z³, Z¹ is an optionally substituted moiety selected from the group consisting of (Cι-C₁₂)alkyl, benzo[b]thιophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,

R² is (C C₁₂)alkyl, (C₀-C₆)alkyl-C(O)-O-Z⁵, (C₀-C₆)alkyl-C(O)-NH-(CH₂)_m-Z³ or optionally substituted phenyl, Z⁵ is H, (d-Cι₂)alkyl or (CH₂)_m-aryl,

Z³ is ammo, (d-C₁₂)alkylamιno, N,N-dι-(d-C₁₂)alkylamιno, -NH-C(0)-O-(CH₂)_m- phenyl, -NH-C(0)-O-(CH₂)_m-(d-C₆)alkyl or an optionally substituted moiety selected from the group consisting of phenyl, imidazolyl, pyridinyl and morpholinyl, piperidinyl, piperazmyl, pyrazolidmyl, furanyl and thiophene, R³ is H, (d-C₆)alkyl or optionally substituted phenyl; R⁴ is H, -C(=Y)-N(X¹X²), C(=0)X² or X²,

X² ιs H or -(CH₂)_m-Y¹-X³, X³ is H or an optionally substituted moiety selected from the group consisting of (d-C₁₂)alkyl, (C₃-C₈)cycloalkyl, (Cι-Cι₂)alkoxy, aryloxy (d-Cι₂)alkylamιno N,N- dι-(Cι-Cι₂)alkylamιno, -CH-dι-(d-C₁₂)alkoxy or phenyl,

R⁵ and R⁸ are each independently selected from the group consisting of H, (Cι-Cι₂)alkyl, -(CH₂)_m-Y¹-(CH₂)_m-phenyl-(X¹)_n, (C₃-C₁₂)cycloalkyl, (C₃-C₁₂)cycloalkenyl,

-(CH₂)_m-S-(d-Cι₂)alkyl, (d-C₁₂)alkyl-S-S-(d-C₁₂)alkyl, -(CH₂)_m-(d-C₁₂)alkenyl and an optionally substituted moiety selected from the group consisting of phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and

-*-(C C₄)alkyl- J^ >

X ^" O , provided that R⁵ and R⁸ are not both H at the same time, or R⁵ and R⁸ are taken together with the carbon atom to which they are attached to form

Y¹ is O, S, NH or a bond,

A is a bond, -CO-, -C(O)0-, -C(O)NH-, -C(S)NH-, or -S0₂-, B is a bond or -(CH₂)_q-, where q is an integer from 1 to 6 ,

J³ is H, (d-C₆)alkyl, optionally substituted phenyl, optionally substituted heteroaryl or N(R⁹R¹⁰), where R⁹ and R¹⁰ are each independently selected from the group consisting of (C C₆)alkyl, and optionally substituted phenyl, or R⁹ and R¹⁰ are taken together with the nitrogen to which they are attached to form a ring having 5 to 8 members including the nitrogen atom that R⁹ and R¹⁰ are attached to, where one of the ring members may optionally be an oxygen atom or NR¹¹, where R ¹ is (d-C₆)alkyl, -C(O)-(C₁-C_β)alkyl, -C(O)-N(V¹V²), -C(S)- N(V¹V²), or optιonaily-substιtuted-phenyl-(C₀-C₆)alkyl-, where V¹ and V² are each independently H, (C C₆)alkyl or optιonally-substιtuted-phenyl-(C₀-C₆)alkyl, R⁶ is H or SO₂-phenyl,

R⁷ is H, Cl, F, Br, I, CF₃, NO₂, OH, SO₂NH₂, CN, N₃, -OCF₃, (d-C₁₂)alkoxy, -(CH₂)_m-phenyl-(X¹)_n, -NH-CO-(C C₆)alkyl, -S-(d-C₁₂)alkyl, -S-phenyl-(X¹)_n, -0-(CH₂)_m- phenyl-(X¹)_n, -(CH₂)_m-C(O)-O-(d-C₆)alkyl, -(CH₂)_m-C(O)-(C₁-C₆)alkyl, -0-(CH₂)_m-NH₂, -O-(CH₂)_m-NH-(d-C₆)alkyl, -0-(CH₂)_m-N-dι-((d-C₆)alkyl) and -(C₀-C₁₂)alkyl-(X )_n, wherein an optionally substituted moiety or optionally substituted phenyl is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF₃, N0₂, OH, SO₂NH₂, CN, N₃, -OCF₃, (d-C₁₂)alkoxy, -(CH₂)_m-phenyl-(X¹)_n, -NH-CO-(d-C₆)alkyl, -S-(d-C₁₂)alkyl, -S-phenyl-(X¹)_n, -O-(CH₂)_m- phenyl-(X )_n, -(CH₂)_m-C(O)-O-(C C₆)alkyl, -(CH₂)_m-C(O)-(C₁-C₆)alkyl, -0-(CH₂)_m-NH₂, -0-(CH₂)_m-NH-(d-C₆)alkyl, -O-(CH₂)_m-N-di-((d-C₆)alkyl) and -(C₀-C₁₂)alkyl-(X¹)_n;

X¹ for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO₂, OH, -CF₃, -OCF₃, (d-C₁₂)alkyl, (d-C₁₂)alkoxy, -S-(C C₆)alkyl, -(CH₂)_m-amino, -(CH₂)_m-NH-(d-C₆)alkyl, -(CH₂)_m-N-di-((d-C₆)alkyl), -(CH₂)_m-phenyl and -(CH₂)_m-NH-(C₃-C₆)cycloalkyl; m for each occurrence is independently 0 or an integer from 1 to 6; and n for each occurrence is independently an integer from 1 to 5.

13. A compound according to claim 12 having the formula

wherein R³ is H or methyl ;

R⁴ is H or methyl ;

R⁵ is H, methyl, ethyl, butyl, pentyl or hexyl;

R⁸ is ethyl, butyl, pentyl, hexyl, or cyclohexyl ; or R⁵ and R⁸ are taken together with the carbon to which they are attached to form

spirocyclohexyl, spirocycloheptyl, spiroadamantyl, J or

N-A-B-J-

\ / where A is a bond or -C(O)O- ; B is a bond, -(CH₂)- or -(CH₂)₂

J³ is H, or phenyl ; and

R⁷ is H, Me, F, Cl, OH, -O-methyl or -0-CH₂-phenyl. 14 A compound according to claim 13 wherein

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together

and the imidazolyl is in the R-configuration ,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together and the imidazolyl is in the R-configuration ,

/ \

N

/ \ s

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together and the imidazolyl is in the R-configuration, or its hydrochloride salt, R³ is methyl, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each n-butyl and the imidazolyl is in the R-configuration,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together and the imidazolyl is in the R-configuration, or its hydrochloride salt,

R³ and R⁴ are each hydrogen, R⁷ is 6-0-CH₂-phenyl R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

/ \

N-COOEt

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are together

/ \

N-(CH₂)₂-Phenyl and the imidazolyl is in the R-configuration, R³ and R⁷ are each hydrogen, R⁴ is methyl, R⁵ and R⁸ are each n-butyl and the imidazolyl is in the R-configuration, R³, R⁴ and are each hydrogen, R⁷ is 7-fluoro, R⁵ and R⁸ are each n-pentyl and the imidazolyl is the racemic mixture of the S- and R-configurations,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each n-hexyl and the imidazolyl is in the R-configuration,

R³, R⁴ and R⁷ are each hydrogen, R⁵ is hydrogen and R⁸ is hexyl in the S- configuration and the imidazolyl is in the R-configuration, or its fumarate salt,

R³, R⁴ and R⁷ are each hydrogen, R⁵ and R⁸ are each n-butyl and the imidazolyl is in the S-configuration,

R³ and R⁴ are each hydrogen, R⁷ is 6-methyl R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 7-fluoro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 6-fluoro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations, or its hydrochloride salt, R³ and R⁴ are each hydrogen, R⁷ is 8-methyl, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations,

R³ and R⁴ are each hydrogen, R⁷ is 6-methyl, R⁵ and R⁸ are each n-pentyl and the imidazolyl is a racemic mixture of the S- and R-configurations, or R³ and R⁴ are each hydrogen, R⁷ is 6-chloro, R⁵ and R⁸ are each n-butyi and the imidazolyl is a racemic mixture of the S- and R-configurations

15 A compound according to claim 14 wherein said compound is selected from the group consisting of

R³, R⁴ and R⁷ are each hydrogen R⁵ and R⁸ are each n-butyl and the imidazolyl is in the R-configuration, or its fumarate salt,

R³ and R⁴ are each hydrogen, R⁷ is 6-methyl, R⁵ and R⁸ are each n-pentyl and the imidazolyl is a racemic mixture of the S- and R-configurations, and R³ and R⁴ are each hydrogen, R⁷ is 6-chloro, R⁵ and R⁸ are each n-butyl and the imidazolyl is a racemic mixture of the S- and R-configurations.

16. A pharmaceutical composition comprising a compound according to claim 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. A method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof to said subject. 18. A method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof to said subject.

19. A method of binding one or more somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim

12 or a pharmaceutically acceptable salt thereof to said subject.

20. A method of treating acromegaiy, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VlPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas or TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof to said subject.

21. A method of treating diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon, Nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof to said subject.

22. A method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof, to said subject.

23. A method of blocking sodium channel in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof, to said subject.

24. A method of blocking sodium channel in a subject in need thereof, which comprises administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof, to said subject. 25. A method of alleviating neuropathic pain in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof, to said subject.

26. A method of alleviating neuropathic pain in a subject in need thereof, which comprises administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof, to said subject.

27. A pharmaceutical composition for use as a local anesthetic, comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

28. A pharmaceutical composition for use as a local anesthetic, comprising a compound according to claim 12 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

29. A method of treating any pathology, disorder or clinical condition involving glutamate release in their etiology in a subject in need thereof, comprising administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject.

30. A method of treating any pathology, disorder or clinical condition involving glutamate release in their etiology in a subject in need thereof, comprising administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof to said subject. 31. A method according to claim 29 wherein the pathology, disorder or clinical condition is selected from the group consisting of psychiatric disorders, hormonal conditions, metabolic inducted brain damage, sulphite oxidase deficiency, hepatic encephalopathy associated with liver failure, emesis, spasticity, tinnitus, pain and drug abuse and withdrawal.

32. A method according to claim 30 wherein the pathology, disorder or clinical condition is selected from the group consisting of psychiatric disorders, hormonal conditions, metabolic inducted brain damage, sulphite oxidase deficiency, hepatic encephalopathy associated with liver failure, emesis, spasticity, tinnitus, pain and drug abuse and withdrawal.

33. A method of treating any pathology involving neuronal damage in a subject in need thereof, comprising administeπng a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject.

34. A method of treating any pathology involving neuronal damage in a subject in need thereof, comprising administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof to said subject.

35. A method according to claim 33 wherein the pathology is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's diseases, virus (including HIV)-induced neurodegeneration, amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, oiivoponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins.

36. A method according to claim 34 wherein the pathology is selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's diseases, virus (including HIV)-induced neurodegeneration, amyotrophic lateral sclerosis (ALS), supra-nuclear palsy, oiivoponto-cerebellar atrophy (OPCA), and the actions of environmental, exogenous neurotoxins.

37. A method of treating arrhythmia in a subject in need thereof, comprising administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof, to said subject. 38. A method of treating arrhythmia in a subject in need thereof, comprising administering a compound according to claim 12 or a pharmaceutically acceptable salt thereof, to said subject.

39. A method of treating epilepsy in a subject in need thereof, comprising administeπng a compound according to claim 1 or a pharmaceutically acceptable salt thereof, to said subject.

40. A method of treating epilepsy in a subject in need thereof, comprising administeπng a compound according to claim 12 or a pharmaceutically acceptable salt thereof, to said subject.