WO2002057275A1 - Boron-containing nicotine analogs for use in the treatment of cns pathologies - Google Patents

Abstract

Boron-containing nicotine analogs that have a selective partial agonist or antagonist property at the α7-containing nicotinic receptor subtypes are provided together with pharmaceutical compositions containing these compounds. Methods for the treatment of pathologies related to the central nervous system is also provided.

Description

BORON-CONTAINING NICOTINE ANALOGS FOR USE IN THE TREATMENT

OF CNS PATHOLOGIES

Field of the Invention

This invention relates to boron-containing nicotine analogs that have selective partial

agonist or antagonist properties at α -containing nicotinic receptor subtypes, and to a method of using such compounds to treat pathologies of the central nervous system. The present invention also relates to pharmaceutical compositions containing these compounds, as well as various uses thereof.

Background of the Invention

Formula (I) below shows the structure of S-(-)-nicotine (NIC), which activates neuronal nicotinic receptors which, for example, evoke the release of dopamine (DA) from presynaptic terminals in the central nervous system (CNS). NIC is a legal substance of dependence that produces many of its effects on the CNS, some of which may be considered to be beneficial, e.g., mood elevation, arousal and learning and memory enhancement. NIC produces its effect by binding to a family of ligand-gated ion channels. Stimulation by acetylcholine (ACh) or NIC causes the ion channel to open,

I S-(-)-Nicotine

and cations to flux with a resulting rapid (in msec) depolarization of the target cell membrane.

Over the last 12 years, there has been a substantial increase in studies on brain nicotinic receptors. Nicotinic receptors are composed of four subunit domains: 2α, β, γ and δ or ε.

Neuronal nicotinic receptors are composed of only types of two subunits, α and β, and are

believed to assemble with the general stoichiometry of 2α and 3β. Nine subtypes of the α

subunit (α₂ to αio) and three subtypes of the β unit (β₂ to β₄) are found in CNS. The most

common nicotinic receptor species in the brain is composed of two α₄ and three β₂ subunits, i.e.,

α₄β . These subunits display different, but overlapping, patterns of expression in the brain.

For the most part, the actual subunit compositions and stoichiometries of nicotinic receptors in the brain remains to be elucidated. Thus, neuronal nicotinic receptor subtype diversity originates from differences in the amino acid sequence at the subunit level and from the multiple combinations of assemblies of subunits into functional receptor proteins, which affords wide diversity of pharmacological specificity.

In spite of the extensive diversity in neuronal nicotinic receptor messenger RNA expression, only a limited number of tools are available to study the pharmacology of native nicotinic receptors. Radioligands are used in many such studies. [³H]NIC appears to label the same sites in the brain as [³H]ACh. It has been estimated that over 90% of [³H]NIC binding in the brain is due to association with a receptor that is composed of ₄ and β₂ subunits. Also, nicotinic receptor subtypes can be studied using an assay such as NIC-evoked [³H]DA release from rat straital slices. Nicotinic receptors are located in the cell body and terminal areas of the nigrostriatal dopaminergic system, NIC facilitates DA release from striatal nerve terminals. Studies strongly suggest that the [³H]DA release assay is useful to probe the α₃β -containing

subtype of the nicotinic receptor. Additionally, al, α8, and α9 subunits form functional

homomeric receptors. The receptor subtype is located on glutamergic terminals and elicit

glutamate release in hippoampus and striatum. α receptors are important receptors in the brain, and exhibit high permeability to calcium. This receptor subtype has been implicated as having an important role in nicotine-induced improvement of learning and memory as well as the nicotine- induced slowing of neuronal degeneration, as may occur in aging, dementia, and neurodegenerative diseases. The activation of α₇ receptors has also been suggested as a possible therapeutic approach for treating schizophrenia.

The structural and functional diversity of CNS nicotinic receptors has stimulated a great deal of interest in the development of novel, subtype-selective agonists. Some of these agonists are currently being evaluated in clinical trials for cognitive enhancement and neuroprotective effects of potential benefit in the treatment of diseases such as schizophrenia, Alzheimer's and Parkinson's Disease. Surprisingly, little attention has focused on developing subtype-selective antagonists for neuronal nicotinic receptors. We have carried out in vitro binding experiments and functional assays using native nicotinic receptors, and have expressed a variety of nAChR subtypes using a cell expression system. We have found that boron-containing nicotine analogs have selective affinity for α7 receptor subtypes and will produce significant activation or partial agonism of only α7 receptor subtypes of nicotinic receptors.

The invention disclosed herein is directed to novel class of efficacious and subtype- selective full agonists, partial agonists or antagonists at α -nicotinic receptors in the CNS. These compounds comprise boron-containing analogs of nicotine.

Summary of the Invention

The present invention provides for boron-containing nicotine analogs having selective full agonist, partial agonist or antagonist activity at neuronal α nicotinic receptor subtypes.

A preferred embodiment of the invention provides for a method of innervating as a full agonist, partial agonist, or antagonist of the α₇ nicotinic receptor subtype, comprising administering of a pharmaceutically effective amount of a compound of the invention.

Still another embodiment the invention provides a method for the treatment of psychostimulant abuse (including nicotine abuse, amphetamine abuse, methamphetamine abuse, and cocaine abuse), alcohol abuse, as a smoking cessation therapy, as an antidote for mcotine intoxication comprising administering of a pharmaceutically effective amount of a compound according to the invention, as a therapeutic agent for the treatment of pathologies of the GI tract, including but not limited to irritable bowel syndrome, colitis and related disorders.

This invention further provides a method of treatment of CNS disorders associated with the alteration of normal neurotransmitter release in the brain, including conditions such as schizophrenia, Alzheimer's disease, as well as other types of dementia, Parkinson's disease, cognitive dysfunction (including disorders of attention, focus and concentration), attention deficit syndrome, affective disorders, mood and emotional disorders such as depression, panic anxiety and psychosis, Tourette's syndrome, eating disorders, the control of pain, and stroke or other neuro-degenerative deseases, comprising administering of a pharmaceutically effective amoimt of a compound according to the invention.

The above and other objects of the invention will become readily apparent to those of skill in the relevant art from the following detailed description and figures, wherein only the preferred embodiments of the invention are shown and described, simply by way of illustration of the best mode of carrying out the invention. As is readily recognized the invention is capable of modifications within the skill of the relevant art without departing from the spirit and scope of the invention.

Detailed Description of the Invention

The present invention provides novel compounds corresponding to the schematic structure formula 2 below:

wherein X is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, C(S), S, S(O) or S(O)₂ containing alkylene moiety, provided however, that any heteroatom contained in X is separated from N by at least one carbon atom;

R¹ is selected from hydrogen, lower straight chain or branched alkyl (e.g., CpCio _. preferably Cι-C₆ , and more preferably methyl, ethyl,, isopropyl or isobutyl) or cycloalkyl (d- C₆), an aromatic, aralky, or heteroaromatic group;

R², Z¹ and Z⁴ are each independently selected from hydrogen, lower alkyl, lower branched alkyl, lower alkenyl, lower branched alkenyl; a and b are selected from nitrogen or carbon with the proviso that when a or b is nitrogen, R³ or R⁴ cannot be present.

R³, R⁴, Z² and Z³ are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, alkenyl; substituted alkenyl; alkynyl; substituted alkynyl; aryl; substituted aryl; alkylaryl; substituted alkylaryl; arylalkyl; substituted arylalkyl; aryialkenyi; substituted aryialkenyi; arylalkynyl; substituted arylalkynyl; heterocyclic; substituted heterocyclic; trifluoromethyl; halogen; cyano; nitro; S(O)Y¹, S^Y¹, S^OY¹ or S(O)₂NHY¹, wherein each Y¹ is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl, provided, however, that when R³, R⁴ or R⁵ is S(O)Y^[, Y^l is not hydrogen, and further provided that when Y¹ is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; C(O)Y², wherein Y² is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryialkenyi, substituted aryialkenyi, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality; OY³ or N(Y³)₂ wherein each Y³ is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryialkenyi, substituted aryialkenyi, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, that the OY³ or N(Y³)₂ functionality is not conjugated with an alkenyl or alkynyl functionality; SY⁴ wherein Y⁴ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryialkenyi, substituted aryialkenyi, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the SY⁴ functionality is not conjugated with an alkenyl or alkynyl functionality;

Or R³ and R⁴, together with the carbons to which they are attached, form a four to seven membered ring that can be saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said rings may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said rings may optionally be substituted with one or more substituents that are defined as Z³ and Z⁴ hereinbefore.

R⁵, R⁶ and R⁷ are each individually selected from hydrogen; lower alkyl; halogen; cyano; aryl; C(O)Y¹, wherein Y¹ is selected from hydroxy, alkoxy, alkylamino, aryloxy and arylamino;

Either Z¹ and Z² or Z¹ and Z³ and their associated carbon atoms can combine to form a fused ring structure. The junction between rings can be either cis or trans geometry. Either Z² and Z⁴ or Z³ and Z⁴ and their associated carbon atoms can combine to form a spiro ring structure. The present invention includes all possible diastereomers and all enantiomeric forms as well as racemic mixtures. The compounds can be separated into substantially optically pure compounds by means of standard methods.

It is preferred that X is either CH₂, CH₂CH₂, CH=CH-, C(CH₃)=CH, CH=(C(CH₃), or C(CH₃)=C(CH₃); A and B are each carbon; R¹ is a Ci- o alkyl or more preferably a Cι-C₆ alkyl or even more preferably a C1-C4 alkyl such as methyl, ethyl, isopropyl or isobutyl; R² is hydrogen; R³ and R⁴ are individually selected from the group consisting of hydrogen, halogen, alkyl or alkanoyl; R⁵, R^δ and R⁷ are each hydrogen or R⁵ and R⁶ are hydrogen, and R⁷ is cyano; Z¹, Z², Z³ and Z⁴ are each hydrogen, or Z³ and Z⁴ axe hydrogen, Z¹ and Z² and their associated carbon atoms combine to form a five or six membered fused ring structure, or Z² and Z⁴ are hydrogen, Z¹ and Z³ and their associated carbon atoms combine to form a five or six membered fused ring structure, or Z¹ and Z³ are hydrogen, Z² and Z⁴ and their associated carbon atoms combine to form a five or six membered spiro ring structure, or Z¹ and Z² are hydrogen, Z³ and Z⁴ and their associated carbon atoms combine to form a five or six membered spiro ring structure,

As employed herein, the meaning of the aforementioned terms are defined as follows:

"lower alkyl" refers to straight or branched chain alkyl radicals having in the range of about 1 up to 4 carbon atoms;

"alkyl" refers to straight or branched chain alkyl radicals having in the range of about 1 up to 19 carbon atoms and "substituted alkyl" refers to alkyl radicals further bearing one or more substituents such as hydroxy, alkoxy (of a lower alkyl group), mercapto (of a lower alkyl group), aryl, heterocyclic, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbarnate, sulfonyl, sulfonamide, and the like.

"cycloalkyl" refers to cyclic ring-containing moieties containing in the range of about 3 up to 8 carbon atoms and "substituted cycloalkyl" refers to cycloalkyl moieties further bearing one or more substituent as set forth above;

"alkenyl" refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and having in the range of about 2 up to 19 carbon atoms and "substituted alkenyl" refers to alkenyl groups further bearing one or more substituents as set forth above;

"alkynyl" refers to straight or branched chain hydrocarbyl moieties having at least one carbon-carbon triple bond, and having in the range of about 2 up to 19 carbon atoms and "substituted alkynyl" refers to alkynyl moieties further bearing one or more substituents as set forth above;

"aryl" refers to aromatic groups having in the range of 6 up to 24 carbon atoms and "substituted aryl" refers to aryl groups further bearing one or more substituents as set forth above;

"alkylaryl" refers to alkyl-substituted aryl groups and "substituted alkylaryl" refers to alkylaryl groups further bearing one or more substituents as set forth above;

"arylalkyl" refers to aryl-substituted alkyl groups and "substituted arylalkyl" refers to arylalkyl groups further bearing one or more substituents as set forth above;

"aryialkenyi" refers to aryl-substituted alkenyl groups and "substituted aryialkenyi" refers to aryialkenyi groups further bearing one or more substituents as set forth above; "arylalkynyl" refers to aryl-substituted alkynyl groups and "substituted arylalkynyl" refers to arylalkynyl groups further bearing one or more substituents as set forth above;

"aroyl" refers to aryl-substituted species such as benzoyl and "substituted aroyl" refers to aroyl moieties further bearing one or more substituents as set forth above;

"heterocyclic" refers to cyclic moieties containing one or more heteroatoms as part of the ring structure, and having in the range of 3 up to 24 carbon atoms and "substituted heterocyclic"refers to heterocyclic moieties further bearing one or more substituents as set forth above; "acyl" refers to alkyl-carbonyl species;

"halogen" refers to fluoride, chloride, bromide or iodide groups.

Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, salicylate, propionate, ascorbate, aspartate, fumarate, galactarate, maleate, citrate, glutamate, glycolate, lactate, malate, maleate, tartrate, oxalate, succinate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2. (1977) which are hereby incorporated by reference. The above salt forms may be in some cases hydrates or solvates with alcohols and other solvents.

When used in reference to compounds of the invention, "an effective amount" refers to doses of compound sufficient to provide circulating concentrations high enough to impart a beneficial effect on the recipient thereof for alleviating a disease or pathological symptom of a CNS pathology. The amount to be administered depends to some extent on the lipophilicity of the specific compound selected, since it is expected that this property of the compound will cause it to partition into fat deposits of the subject. The precise amount to be administered can be determined by the skilled practitioner in view of desired dosages, side effects and medical history of the patient and the like. It is anticipated that the compound will be administered in the amount ranging 1 x IO^"5 to about 100 mg/kg/day, with amounts in the range of about 1 x IO^"2 up to 1 mg/kg/day being preferred.

A pharmaceutical composition containing a compound of the invention is also contemplated, which may include a conventional additive, such as a stabilizer, buffer, salt, preservative, filler, flavor enhancer and the like, as known to those skilled in the art. Representative buffers include phosphates, carbonates, citrates and the like. Exemplary preservatives include EDTA, EGTA, BHA, BHT and the like. A composition of the invention may be administered by inhalation, i.e., intranasally as an aerosol or nasal formulation; topically, i.e., in the form of an ointment, cream or lotion; orally, i.e., in solid or liquid form (tablet, gel cap, time release capsule, powder, solution, or suspension in aqueous or non aqueous liquid; intravenously as an infusion or injection, i.e., as a solution, suspension or emulsion in a pharmaceutically acceptable carrier; transdermally, e.g., via a transdermal patch; rectally as a suppository and the like.

The novel compounds of this invention are substantially optically and/or diastereometrically pure.

Certain preferred compounds of the present invention can be represented by the formula:

where X, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined hereinbefore.

Certain other preferred compounds of the present invention can be represented by the formula:

where X, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined hereinbefore.

Certain other preferred compounds of the present invention can be represented by the formula:

where X,

R° and R' are as defined hereinbefore.

EXAMPLE 1

(S)-nicotine cyanoborane hydrobromide salt

3 a. (S)-nicotine cyanoborane

(S)-Nicotine dihydrochloride salt (1.78 g, 7.57 mmol) and sodium cyanoborahydride (0.52 g, 8.33 mmol) were placed in a three-necked round-bottomed flask, equipped with a reflux condenser, a N -gas inlet and a gas bubbler, the setup having been previously flushed with N₂. THF (15 mL) was then added through a side arm and the suspension was refluxed under N₂ overnight. The reaction mixture was cooled. THF was evaporated in vacuo and water was added to the residue. The mixture was extracted three times with methylene chloride. The combined organic phases were dried over Na₂SO₄ and evaporated The residue was chromatographed on silica (CH₂Cl :MeOH 50:1) to furnish (S)-nicotine cyanoborane (1.21 g, 80%) as a colorless oil: H MR (300 MHz, CDC1₃) δ 8.51 (1H, s), 8.45 (1H, d, J = 6.0 Hz), 8.09 (1H, dt, J = 8.1, 1.5 Hz), 7.60 (1H, dd, J = 8.1, 6.0 Hz), 3.23 (2H, m), 2.35 (1H, m), 2.25 (1H, m), 2.16 (3H, s), 1.86 (2H, m), 1.62 (1H, m); ¹³C NMR (75 MHz, CDC1₃) δ 146.49, 145.71, 144.22, 140.34, 126.20, 67.93, 56.97, 40.65, 36.03, 23.21; MS: m/z 202 (MH^). 3b. (S)-nicotine cyanoborane hydrobromide salt

(S)-Nicotine cyanoborane (1.21 g, 6.02 mmol) was dissolved in isopropanol (50 mL) and to which HBr (30% in AcOH) was added. The solution was concentrated in vacuo to give a brown solid which was recrystallized in isopropanol to give (S)-nicotine cyanoborane hydrobromide salt (1.35 g, 79%) as white needles: mp 150-151 °C; IR (KBr): 2422 (BH), 2200 (CN); ^lH NMR (300 MHz, dmso-d₆) δ 10.25 (1H, br s), 8.91(1H, s), 8.80 (1H, d, J = 5.7 Hz), 8.65 (1H, ), 8.04 (1H, dd, J = 8.1, 5.7 Hz), 4.69 (1H, ), 3.81 (1H, m), 3.25 (1H, m), 2.75 (3H, d, J = 4.2 Hz), 2.10-2.70 (4H, m); ¹³C NMR (75 MHz, dmso-dβ) δ 147.99, 147.61, 142.68, 132.72, 127.35, 67.83, 55.75, 38.48, 30.66, 21.47; ^UB NMR (64 MHz, dmso-d₆) δ -15.93. Anal. Calcd for C_uHι₇BBrN₃: C, 46.85; H, 6.08; N, 14.90. Found: C, 46.77; H, 6.11; N, 14.79.

EXAMPLE 2 cw-2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[3,2-b]isoquinoline cyanoborane hydrobromide

4a. cw-2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[3,2-/ι]isoquinoline cyanoborane cw-2,3,3a,4,5,9b-Hexahydro-l-methyl-lH-pyrrolo[3,2-Λ]isoqιιinoline dihydrobromide salt (170 mg, 0.49 mmol) and sodium cyanoborahydride (49 mg, 0.83 mmol) were placed in a three-necked round-bottomed flask, equipped with a reflux condenser, a N₂-gas inlet and a gas bubbler, the setup having been previously flushed with N₂. TΗF (2 mL) was then added through a side arm and the suspension was refluxed under N overnight. The reaction mixture was

cooled. THF was evaporated in vacuo and water was added to the residue. The mixture was extracted three times with methylene chloride. The combined organic phases were dried over Na₂SO₄ and evaporated. The residue was chromatographed on silica (CH₂Cl₂:MeOH 50:1) to furnish ctj-2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[3,2-/z]isoquinoline cyanoborane (81 mg, 74%) as a colorless oil: 1H NMR (300 MHz, CDC1₃) δ 8.34 (IH, d, J = 5.7 Hz), 8.26 (IH, s), 7.39 (IH, d, J = 5.7 Hz), 3.12 (IH, d, J = 8.4 Hz), 3.06 (IH, m), 2.94 (IH, m), 2.6-2.7 (2H, m), 2.2-2.4 (4H, m), 2.16 (IH, m), 1.80 (IH, m), 1.5-1.7 (2H, m); ¹³C NMR (75 MHz, CDC1₃) δ 157.3, 146.8, 145.3, 136.6, 125.8, 64.3, 55.9, 40.7, 36.0, 30.1, 28.8, 26.9. 4b. cis-2,3 ,3 a,4,5 ,9b-hexahydro- 1 -methyl- lHrpyrrolo [3 ,2-Λ ]isoquinoline cyanoborane hydrobromide salt cw-2,3,3a,4,5,9b-Hexahydro-l-me1hyl-lH-pyrrolo[3,2-b]isoqιιinoline cyanoborane (81 mg, 0.36 mmol) was dissolved in isopropanol (5 mL) and to which ΗBr (30% in AcOΗ) was added. The solution was concentrated in vacuo to give a brown solid which was recrystallized in isopropanol to give cz 2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[3,2-Λ]isoquinoline cyanoborane hydrobromide salt (97 mg, 88%) as white needles: mp 202-204 °C; IR (KBr): 2426,

2411 (BΗ), 2206 (CN); 1H NMR (300 MHz, dmso-dβ) δ 10.11 (IH, br s), 8.34 (IH, s), 8.64 (IH, d, J = 6.0 Hz), 7.83 (IH, d, J = 6.0 Hz), 4.75 (IH, t, J = 7.5 Hz), 3.64 (IH, m), 3.25 (IH, m), 3.13 (IH, m), 2.92 (3H, s), 2.70-3.00 (2H, m), 2.38 (IH, m), 1.89 (2H, m), 1.75 (IH, m); ¹³C NMR (75 MHz, dmso-dβ) δ 157.62, 148.34, 146.92, 128.40, 127.15, 63.71, 54.09, 39.02, 34.41, 27.58,

26.33, 24.22; ^UB NMR (64 MHz, dmso-d₆) δ -16.02. Anal. Calcd for C₁₃Hι₉BBrN₃: C, 50.69; H, 6.22; N, 13.64. Found: C, 50.55; H, 6.22; N, 13.48.

Table 1 : Crystal Data and Structure Refinement for Compound 4b

Empirical formula Cι₃ Hι₉ B Br N₃

Formula weight 308.03

Temperature 173(1) K

Wavelength 0.71073 A

Crystal system, space group Triclinic, P -l

Unit cell dimensions a = 7.8780(10) A alpha =76.980(10) deg. b = 12.702(2) A beta =87.990(10) deg. c = 15.069(2) A gamma =88.670(10) deg.

Volume 1468.0(4) A^A3

Z, Calculated density 4, 1.394 Mg/m^Λ3

Absorption coefficient 2.786 mm^Λ-l F(000) 632

Crystal size 0.35 x 0.12 x 0.07 mm

Theta range for data collection 1.90 to 25.00 deg.

Limiting indices -9<=h<=9, - 15<=k<= 15, -17<=1<= 17

Reflections collected / unique 9878 / 5174 [R(int) = 0.0261]

Completeness to theta = 25.00 99.9 %

Absorption correction None

Refinement method Full-matrix least-squares on F^A2

Data / restraints / parameters 5174 / 0 / 326

Goodness-of-fit on F^Λ2 1.088

Final R indices |T 2sigma(I)] Rl = 0.0278, wR2 = 0.0613 >

R indices (all data) Rl = 0.0357, wR2 = 0.0643

Extinction coefficient 0.0031 (3)

Largest diff. peak and hole .490 and -.376 e.A^A-3

Table 2. Atomic coordinates ( 10^Λ4) and equivalent isotropic displacement parameters (A^Λ2 x 10^A3) for Compound 4b. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

U(eq)

Br(l) -1566(1) 2004(1) 4315(1) 25(1)

> Br(2) -6540(1) 2905(1) 425(1) 28(1)

> N(l) -2633(2) 3486(2) 198(1) 20(1)

> C(10) -2680(3) 4151(2) -749(2) 30(1)

> C(2) -2377(3) 4138(2) 907(2) 32(1)

> C(3) -1128(3) 3485(2) 1576(2) 27(1)

> C(3A) -1100(3) 2356(2) 1382(2) 22(1)

> C(4) -2561(3) 1659(2) 1866(2) 25(1)

> C(5) -2664(3) 591(2) 1569(2) 28(1)

> C(5A) -2399(3) 692(2) ^• 562(2) 23(1)

> C(6) -2731(3) -176(2) 170(2) 29(1)

> ^' C(7) -2415(3) -99(2) -739(2) 30(1)

> N(8) -1767(2) 798(2) -1286(1) 25(1)

> B(l l) -1445(4) 873(3) -2344(2) 35(1)

> C(12) -3186(4) 1232(2) -2830(2) 32(1)

> N(13) -4439(4) 1458(2) -3178(2) 51(1)

> C(9) -1426(3) 1644(2) -924(2) 22(1)

> C(9A) -1754(3) 1628(2) -11(2) 19(1)

> C(9B) -1280(3) 2591(2) 355(2) 18(1)

> N(l) 2323(2) 1484(2) 4752(1) 19(1)

> C(10) 2101(3) 1009(2) 5742(2) 27(1)

> C(2) 2778(3) 666(2) 4190(2) 30(1) > C(3) 3968(3) 1234(2) 3418(2) 27(1)

> C(3A) 3942(3) 2422(2) 3475(2) 22(1)

> C(4) 2503(3) 3068(2) 2947(2) 27(1)

> C(5) 2328(3) 4200(2) 3111(2) 30(1)

> C(5A) 2521(3) 4266(2) 4084(2) 25(1)

> C(6) 2159(3) 5224(2) 4362(2) 33(1)

> C(7) 2437(3) 5304(2) 5235(2) 32(1)

> N(8) 3082(2) 4469(2) 5854(1) 26(1)

> B(l l) 3423(4) 4557(3) 6870(2) 33(1)

> C(12) 1841(4) 4089(2) 7497(2) 32(1)

> N(13) 701(3) 3773(2) 7960(2) 49(1)

> C(9) 3438(3) 3533(2) 5602(2) 22(1)

> C(9A) 3156(3) 3397(2) 4740(2) 20(1)

> C(9B) 3673(3) 2350(2) 4492(2) 19(1) >

>

> Table 3. Bond len gths [A] and ar

>

>

> N(l)-C(10) 1.486(3)

> N(l)-C(2) 1.514(3)

> N(1)-C(9B) 1.524(3)

> N(1)-H(1N) 0.9300

> C(10)-H(10A) 0.9800

> C(10)-H(10B) 0.9800

> C(10)-H(10C) 0.9800

> C(2)-C(3) 1.526(3)

> C(2)-H(2A) 0.9900 > C(2)-H(2B) 0.9900

> C(3)-C(3A) 1.526(3)

> C(3)-H(3A) 0.9900

> C(3)-H(3B) 0.9900

> C(3A)-C(9B) 1.520(3)

> C(3A)-C(4) 1.529(3)

> C(3A)-H(3AA) 1.0000

> C(4)-C(5) 1.526(3)

> C(4)-H(4A) 0.9900

> C(4)-H(4B) 0.9900

> C(5)-C(5A) 1.501(3)

> C(5)-H(5A) 0.9900

> C(5)-H(5B) 0.9900

> C(5A)-C(6) 1.397(3)

> C(5A)-C(9A) 1.398(3)

> C(6)-C(7) 1.365(4)

> C(6)-H(6A) 0.9500

> C(7)-N(8) 1.346(3)

> C(7)-H(7A) 0.9500

> N(8)-C(9) 1.346(3)

> N(8)-B(ll) 1.587(3)

> B(ll)-C(12) 1.587(4)

> B(11)-H(11A) 0.9900

> B(11)-H(11B) 0.9900

> C(12)-N(13) 1.134(3)

> C(9)-C(9A) 1.386(3)

> C(9)-H(9A) 0.9500

> C(9A)-C(9B) 1.511(3)

> C(9B)-H(9BA) 1.0000

> N(l)-C(10) 1.484(3)

> N(l)-C(2) 1.512(3) > N(1)-C(9B) 1.524(3)

> N(1)-H(1N) 0.9300

> C(10)-H(10D) 0.9800

> C(10)-H(10E) 0.9800

> C(10)-H(10F) 0.9800

> C(2)-C(3) 1.527(3)

> C(2)-H(2C) 0.9900

> C(2)-H(2D) 0.9900

> C(3)-C(3A) 1.529(3)

> C(3)-H(3C) 0.9900

> C(3)-H(3D) 0.9900

> C(3A)-C(4) 1.522(3)

> C(3A)-C(9B) 1.523(3)

> C(3A)-H(3AB) 1.0000

> C(4)-C(5) 1.516(3)

> C(4)-H(4C) 0.9900

> C(4)-H(4D) 0.9900

> C(5)-C(5A) 1.501(3)

> C(5)-H(5C) 0.9900

> C(5)-H(5D) 0.9900

> C(5A)-C(6) 1.393(3)

> C(5A)-C(9A) 1.401(3)

> C(6)-C(7) 1.369(4)

> C(6)-H(6B) 0.9500

> C(7)-N(8) 1.347(3)

> C(7)-H(7B) 0.9500

> N(8)-C(9) 1.347(3)

> N(8)-B(ll) 1.592(4)

> B(ll)-C(12) 1.581(4)

> B(11)-H(UC) 0.9900

> B(11)-H(11D) 0.9900 > C(12)-N(13) 1.140(3)

> C(9)-C(9A) 1.375(3)

> C(9)-H(9B) 0.9500

> C(9A)-C(9B) 1.505(3)

> C(9B)-H(9BB) 1.0000 >

> C(10)-N(l)-C(2) 113.72(19)

> C(10)-N(1)-C(9B) 115.05(17)

> C(2)-N(1)-C(9B) 106.24(17)

> C(10)-N(1)-H(1N) 107.1

> C(2)-N(1)-H(1N) 107.1

> C(9B)-N(1)-H(1N) 107.1

> N(1)-C(10)-H(10A) 109.5

> N(1)-C(10)-H(10B) 109.5

> H(10A)-C(10)-H(10B) 109.5

> N(1)-C(10)-H(10C) 109.5

> H(10A)-C(10)-H(10C) 109.5

> H(10B)-C(10)-H(10C) 109.5

> N(l)-C(2)-C(3) 105.99(19)

> N(1)-C(2)-H(2A) 110.5

> C(3)-C(2)-H(2A) 110.5

> N(1)-C(2)-H(2B) 110.5

> C(3)-C(2)-H(2B) 110.5

> H(2A)-C(2)-H(2B) 108.7

> C(2)-C(3)-C(3A) 105.02(19)

> C(2)-C(3)-H(3A) 110.7

> C(3A)-C(3)-H(3A) 110.7

> C(2)-C(3)-H(3B) 110.7

> C(3A)-C(3)-H(3B) 110.7

> H(3A)-C(3)-H(3B) 108.8

> C(9B)-C(3A)-C(3) 102.60(19) > C(9B)-C(3A)-C(4) 110.62(18)

> C(3)-C(3A)-C(4) 112.80(19)

> C(9B)-C(3A)-H(3AA) 110.2

> C(3)-C(3A)-H(3AA) 110.2

> C(4)-C(3A)-H(3AA) 110.2

> C(5)-C(4)-C(3A) 112.39(19)

> C(5)-C(4)-H(4A) 109.1

> C(3A)-C(4)-H(4A) 109.1

> C(5)-C(4)-H(4B) 109.1

> C(3A)-C(4)-H(4B) 109.1

> H(4A)-C(4)-H(4B) 107.9

> C(5A)-C(5)-C(4) 114.0(2)

> C(5A)-C(5)-H(5A) 108.7

> C(4)-C(5)-H(5A) 108.7

> C(5A)-C(5)-H(5B) 108.7

> C(4)-C(5)-H(5B) 108.7

> H(5A)-C(5)-H(5B) 107.6

> C(6)-C(5A)-C(9A) 117.4(2)

> C(6)-C(5A)-C(5) 120.5(2)

> C(9A)-C(5A)-C(5) 122.0(2)

> C(7)-C(6)-C(5A) 120.4(2)

> C(7)-C(6)-H(6A) 119.8

> C(5A)-C(6)-H(6A) 119.8

> N(8)-C(7)-C(6) 122.0(2)

> N(8)-C(7)-H(7A) 119.0

> C(6)-C(7)-H(7A) 119.0

> C(7)-N(8)-C(9) 118.8(2)

> C(7)-N(8)-B(ll) 121.0(2)

> C(9)-N(8)-B(l l) 120.2(2)

> C(12)-B(l l)-N(8) 107.4(2)

> C(12)-B(11)-H(11A) 110.2 > N(8)-B(11)-H(11A) 110.2

> C(12)-B(11)-H(11B) 110.2

> N(8)-B(11)-H(11B) 110.2

> H(11A)-B(11)-H(11B) 108.5

> N(13)-C(12)-B(l l) 178.0(3)

> N(8)-C(9)-C(9A) 122.1(2)

> N(8)-C(9)-H(9A) 119.0

> C(9A)-C(9)-H(9A) 119.0

> C(9)-C(9A)-C(5A) 119.2(2)

> C(9)-C(9A)-C(9B) 119.2(2)

> C(5A)-C(9A)-C(9B) 121.4(2)

> C(9A)-C(9B)-C(3A) 114.60(19) .

> C(9A)-C(9B)-N(1) 112.83(17)

> C(3A)-C(9B)-N(1) 102.31(17)

> C(9A)-C(9B)-H(9BA) 108.9

> C(3A)-C(9B)-H(9BA) 108.9

> N(1)-C(9B)-H(9BA) 108.9

> C(10)-N(l)-C(2) 113.89(18)

> C(10)-N(1)-C(9B) 115.48(17)

C(2)-N(1)-C(9B) 105.15(16)

> C(10)-N(1)-H(1N) 107.3

> C(2)-N(1)-H(1N) 107.3

> C(9B)-N(1)-H(1N) 107.3

> N(1)-C(10)-H(10D) 109.5

> N(1)-C(10)-H(10E) 109.5

> H(10D)-C(10)-H(10E) 109.5

> N(1)-C(10)-H(10F) 109.5

> H(10D)-C(10)-H(10F) 109.5

> H(10E)-C(10)-H(10F) 109.5

> N(l)-C(2)-C(3) 106.22(19)

> N(1)-C(2)-H(2C) 110.5 > C(3)-C(2)-H(2C) 110.5

> N(1)-C(2)-H(2D) 110.5

> C(3)-C(2)-H(2D) 110.5

> H(2C)-C(2)-H(2D) 108.7

> C(2)-C(3)-C(3A) 105.57(19)

> C(2)-C(3)-H(3C) 110.6

> C(3A)-C(3)-H(3C) 110.6

> C(2)-C(3)-H(3D) 110.6

> C(3A)-C(3)-H(3D) 110.6

> H(3C)-C(3)-H(3D) 108.8

> C(4)-C(3A)-C(9B) 110.48(19)

> C(4)-C(3A)-C(3) 112.7(2)

> C(9B)-C(3A)-C(3) 102.59(18)

> C(4)-C(3A)-H(3AB) 110.3

> C(9B)-C(3A)-H(3AB) 110.3

> C(3)-C(3A)-H(3AB) 110.3

> C(5)-C(4)-C(3A) 112.5(2)

> C(5)-C(4)-H(4C) 109.1

> C(3A)-C(4)-H(4C) 109.1

> C(5)-C(4)-H(4D) 109.1

> C(3A)-C(4)-H(4D) 109.1

> H(4C)-C(4)-H(4D) 107.8

> C(5A)-C(5)-C(4) 114.4(2)

> C(5A)-C(5)-H(5C) 108.7

> C(4)-C(5)-H(5C) 108.7

> C(5A)-C(5)-H(5D) 108.7

> C(4)-C(5)-H(5D) 108.7

> H(5C)-C(5)-H(5D) 107.6

> C(6)-C(5A)-C(9A) 117.0(2)

> C(6)-C(5A)-C(5) 120.9(2)

> C(9A)-C(5A)-C(5) 122.0(2) > C(7)-C(6)-C(5A) 120.9(2)

> C(7)-C(6)-H(6B) 119.6

> C(5A)-C(6)-H(6B) 119.6

> N(8)-C(7)-C(6) 121.5(2)

> N(8)-C(7)-H(7B) 119.3

> C(6)-C(7)-H(7B) 119.3

> C(9)-N(8)-C(7) 118.7(2)

> C(9)-N(8)-B(l l) 119.4(2)

> C(7)-N(8)-B(l l) 121.9(2)

> C(12)-B(l l)-N(8) 108.5(2)

> C(12)-B(11)-H(UC) 110.0

> N(8)-B(11)-H(11C) 110.0

> C(12)-B(11)-H(11D) 110.0

> N(8)-B(11)-H(11D) 110.0

> H(11C)-B(11)-H(11D) 108.4

> N(13)-C(12)-B(l l) 178.3(3)

> N(8)-C(9)-C(9A) 122.4(2)

> N(8)-C(9)-H(9B) 118.8

> C(9A)-C(9)-H(9B) 118.8

> C(9)-C(9A)-C(5A) 119.4(2)

> C(9)-C(9A)-C(9B) 119.5(2)

> C(5A)-C(9A)-C(9B) 120.8(2)

> C(9A)-C(9B)-C(3A) 114.77(19)

> C(9A)-C(9B)-N(1) 113.12(17)

> C(3A)-C(9B)-N(1) 102.08(17)

> C(9A)-C(9B)-H(9BB) 108.9

> C(3A)-C(9B)-H(9BB) 108.9

> N(1)-C(9B)-H(9BB) 108.9

> > > Symmetry transformations used to generate equivalent atoms: > >

> Table 4. Anisotropic displacement parameters (A^Λ2 x 10^A3) for Compound 4b.

> The anisotropic displacement factor exponent takes the form:

> -2 pi^A2_.[ h^A2 a*^A2 UI 1 + ... + 2 h k a* b* U12 ] >

>

> > Ul l U22 U33 U23 U13 U12 >

>

> Br(l) 19(1) 24(1) 33(1) -6(1) -2(1) 0(1)

> Br(2) 19(1) 28(1) 36(1) -7(1) -1(1) -2(1)

> N(l) 16(1) 21(1) 23(1) -5(1) -id) -id)

> C(10) 35(2) 26(1) 24(1) 2(1) 2(1) 3(1)

> C(2) 36(2) 30(2) 34(2) -17(1) -8(1) 5(1)

> C(3) 27(1) 31(1) 26(1) -15(1) -3(1) -2(1)

> C(3A) 19(1) 28(1) 21(1) -6(1) -3(1) 1(1)

> C(4) 24(1) 34(1) 17(1) -4(1) -2(1) -id)

> C(5) 25(1) 30(1) 26(1) 0(1) 0(1) -6(1)

> C(5A) 15(1) 23(1) 30(1) -4(1) -4(1) 2(1)

> C(6) 26(1) 19(1) 40(2) -2(1) -2(1) -4(1)

> C(7) 26(1) 24(1) 43(2) -14(1) -7(1) -1(1)

> N(8) 22(1) 28(1) 29(1) -13(1) -6(1) 4(1)

> B(l l) 33(2) 45(2) 34(2) -22(2) -4(1) 4(2)

> C(12) 42(2) 29(2) 29(2) -12(1) -6(1) 3(1)

> N(13) 56(2) 52(2) 46(2) -10(1) -24(1) 12(1) > C(9) 18(1) 23(1) 26(1) -7(1) -4(1) 2(1)

> C(9A) 12(1) 20(1) 24(1) -5(1) -3(1) 2(1)

> C(9B) 14(1) 19(1) 22(1) -4(1) 1(1) 0(1)

> N(l) 17(1) 20(1) 20(1) -4(1) 0(1) -1(1)

> C(10) 31(1) 29(1) 21(1) -4(1) -1(1) -4(1)

> C(2) 36(2) 24(1) 32(2) -12(1) 7(1) -5(1)

> C(3) 28(1) 30(1) 27(1) -12(1) 4(1) -4(1)

> C(3A) 19(1) 26(1) 21(1) -4(1) 3(1) -3(1)

> C(4) 25(1) 34(2) 22(1) -2(1) -2(1) -5(1)

> C(5) 28(1) 32(2) 27(1) 1(1) -9(1) 1(1)

> C(5A) 16(1) 22(1) 34(1) -3(1) 1(1) -1(1)

> C(6) 30(2) 23(1) 43(2) -3(1) -1(1) 4(1)

> C(7) 28(1) 18(1) 50(2) -12(1) 7(1) 1(1)

> N(8) 24(1) 23(1) 34(1) -12(1) 6(1) -5(1)

> B(l l) 34(2) 35(2) 36(2) -21(2) 5(1) -9(1)

> C(12) 35(2) 28(2) 34(2) -14(1) 2(1) 2(1)

> N(13) 49(2) 43(2) 49(2) -1(1) 16(1) 0(1)

> C(9) 20(1) 19(1) 28(1) -6(1) 0(1) -1(1)

> C(9A) 15(1) 22(1) 24(1) -6(1) 0(1) -2(1)

> C(9B) 14(1) 21(1) 23(1) -5(1) -2(1) -2(1) >

>

> Table 5. Hydrogen coordinates ( x 10^A4) and isotropic

> displacement parameters (A^A2 x 10^Λ3) for Compound 4b. >

>

>

> U(eq) >

>

> H(1N) -3681 3156 328 24

> H(10A) -3589 4697 -789 45

> H(10B) -2893 3684 -1169 45

> • H(10C) -1588 4508 -913 45

> H(2A) -3469 4244 1224 38

> H(2B) -1909 4855 620 38

> H(3A) -1515 3460 2213 32

> H(3B) 15 3805 1475 32

> H(3AA) 14 1986 1554 27

> H(4A) -2408 1508 2532 30

> H(4B) -3645 2065 1735 30

> H(5A) -1796 83 1892 33

> H(5B) -3792 274 1758 33

> H(6A) -3180 -823 538 35

> H(7A) -2660 -696 -993 36

> H(11A) -557 1409 -2589 42

> H(11B) -1062 163 -2450 42

> H(9A) -945 2271 -1306 27

> H(9BA) -187 2888 53 22

> H(1N) 1291 1804 4550 23

> H(10D) 1192 477 5842 41

> H(10E) 1800 1582 6062 41 > H(10F) 3163 653 5977 41

> H(2C) 1744 426 3942 36

> H(2D) 3351 26 4567 36

> H(3C) 3563 1159 2822 33

> H(3D) 5132 925 3498 33

> H(3AB) 5059 2759 3257 27

> H(4C) 2714 3114 2287 33

> H(4D) 1423 2684 3128 33

> H(5C) 3195 4661 2728 36

> H(5D) 1198 4499 2910 36

> H(6B) 1712 5829 3939 39

> H(7B) 2170 5964 5410 38

> H(11C) 4463 4140 7089 40

> H(11D) 3589 5321 6890 40

> H(9B) 3901 2946 6037 27

> H(9BB) 4743 2073 4808 23

>

>

> Table 6. Torsion angles [deg] for Compound 4b. >

> > C(10)-N(l)-C(2)-C(3) -138.6(2)

> C(9B)-N(1)-C(2)-C(3) -11.0(2)

> N(1)-C(2)-C(3)-C(3A) -15.4(3)

> C(2)-C(3)-C(3A)-C(9B) 35.9(2)

> C(2)-C(3)-C(3A)-C(4) -83.1(2)

> C(9B)-C(3A)-C(4)-C(5) 58.0(3)

> C(3)-C(3A)-C(4)-C(5) 172.30(19) > C(3A)-C(4)-C(5)-C(5A) -42.3(3)

> C(4)-C(5)-C(5A)-C(6) -169.4(2)

> C(4)-C(5)-C(5A)-C(9A) 13.2(3)

> C(9A)-C(5A)-C(6)-C(7) 0.6(3)

> C(5)-C(5A)-C(6)-C(7) -177.0(2)

> C(5A)-C(6)-C(7)-N(8) 0.5(4)

> C(6)-C(7)-N(8)-C(9) -0.2(3)

> C(6)-C(7)-N(8)-B(l l) -178.8(2)

> C(7)-N(8)-B(l l)-C(12) 84.0(3)

> C(9)-N(8)-B(l l)-C(12) -94.6(3)

> N(8)-B(l l)-C(12)-N(13) -98(9)

> C(7)-N(8)-C(9)-C(9A) -1.4(3)

> B(11)-N(8)-C(9)-C(9A) 177.3(2)

> N(8)-C(9)-C(9A)-C(5A) 2.5(3)

> N(8)-C(9)-C(9A)-C(9B) 177.8(2)

> C(6)-C(5A)-C(9A)-C(9) -2.0(3)

> C(5)-C(5A)-C(9A)-C(9) 175.5(2)

> C(6)-C(5A)-C(9A)-C(9B) -177.2(2)

> C(5)-C(5A)-C(9A)-C(9B) 0.2(3)

> C(9)-C(9A)-C(9B)-C(3A) -159.4(2)

> C(5A)-C(9A)-C(9B)-C(3A) 15.8(3)

> C(9)-C(9A)-C(9B)-N(1) 84.0(2)

> C(5A)-C(9A)-C(9B)-N(1) -100.7(2)

> C(3)-C(3A)-C(9B)-C(9A) -164.65(18)

> C(4)-C(3A)-C(9B)-C(9A) -44.1(3)

> C(3)-C(3A)-C(9B)-N(1) -42.2(2)

> C(4)-C(3A)-C(9B)-N(1) 78.4(2)

> C(10)-N(1)-C(9B)-C(9A) -76.5(2)

> C(2)-N(1)-C(9B)-C(9A) 156.78(19)

> C(10)-N(1)-C(9B)-C(3A) 159.88(19)

> C(2)-N(1)-C(9B)-C(3A) 33.1(2) > C(10)-N(l)-C(2)-C(3) -145.5(2) > C(9B)-N(1)-C(2)-C(3) -18.1(2)

N(1)-C(2)-C(3)-C(3A) -8.6(3)

> C(2)-C(3)-C(3A)-C(4) -87.0(2)

> C(2)-C(3)-C(3A)-C(9B) 31.8(2)

> C(9B)-C(3A)-C(4)-C(5) 57.9(3)

> C(3)-C(3A)-C(4)-C(5) 171.97(19)

> C(3A)-C(4)-C(5)-C(5A) -41.6(3)

> C(4)-C(5)-C(5A)-C(6) -170.9(2)

> C(4)-C(5)-C(5A)-C(9A) 12.6(3)

> C(9A)-C(5A)-C(6)-C(7) 0.8(4)

> C(5)-C(5A)-C(6)-C(7) -175.8(2)

> C(5A)-C(6)-C(7)-N(8) 0.6(4)

> C(6)-C(7)-N(8)-C(9) -0.8(3)

> C(6)-C(7)-N(8)-B(l l) 179.5(2)

> C(9)-N(8)-B(l l)-C(12) -84.0(3)

> C(7)-N(8)-B(l l)-C(12) 95.7(3)

> N(8)-B(ll)-C(12)-N(13) -137(11)

> C(7)-N(8)-C(9)-C(9A) -0.5(3)

> B(11)-N(8)-C(9)-C(9A) 179.2(2)

> N(8)-C(9)-C(9A)-C(5A) 1.9(3)

> N(8)-C(9)-C(9A)-C(9B) 176.7(2)

> C(6)-C(5A)-C(9A)-C(9) -2.0(3)

> C(5)-C(5A)-C(9A)-C(9) 174.6(2)

> C(6)-C(5A)-C(9A)-C(9B) -176.7(2)

> C(5)-C(5A)-C(9A)-C(9B) -0.1(3)

> C(9)-C(9A)-C(9B)-C(3A) -157.7(2)

> C(5A)-C(9A)-C(9B)-C(3A) 17.0(3)

> C(9)-C(9A)-C(9B)-N(1) 85.7(3)

> C(5A)-C(9A)-C(9B)-N(1) -99.6(2)

> C(4)-C(3A)-C(9B)-C(9A) -45.0(3) > C(3)-C(3A)-C(9B)-C(9A) -165.36(19)

> C(4)-C(3A)-C(9B)-N(1) 77.7(2)

> C(3)-C(3A)-C(9B)-N(1) -42.6(2)

> C(10)-N(1)-C(9B)-C(9A) -71.9(2)

> C(2)-N(1)-C(9B)-C(9A) 161.66(19)

> C(10)-N(1)-C(9B)-C(3A) 164.22(19)

> C(2)-N(1)-C(9B)-C(3A) 37.8(2) >

>

> Symmetry transformations used to ι generate equivalent atoms:

>

> Table 7. Hydrogen bonds for Compound 4b [A and deg.].

>

>

> D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

EXAMPLE 3

cw-2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[2,3-/jquinoline cyanoborane hydrochloride. 5 a. cis-2, ,3 a,4,5,9b-hexahydro- 1 -methyl- 1 H-pyrrolo [2,3 -/jquinoline cyanoborane cw-2,3,3a,4,5,9b-Ηexahydro-l-methyl-lH-pyrrolo[2,3-/]quinoline dihydrochloride salt (160 mg, 0.46 mmol) and sodium cyanoborahydride (46 mg, 0.78 mmol) were placed in a three- necked round-bottomed flask, equipped with a reflux condenser, a N₂-gas inlet and a gas bubbler, the setup having been previously flushed with N₂. TΗF (2 mL) was then added through a _ side arm and the suspension was refluxed under N₂ overnight. The reaction mixture was cooled. TΗF was evaporated in vacuo and water was added to the residue. The mixture was extracted three times with methylene chloride. The combined organic phases were dried over Na SO₄ and evaporated. The residue was chromatographed on silica (CΗ Cl₂:MeOΗ 50:1) to furnish cw-2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[2,3-/]quinoline cyanoborane (70 mg, 68%) as a colorless oil: 1H NMR (300 MHz, CDC1₃) δ 8.58 (IH, dd, J = 4.8, 1.8 Hz), 7.78 (IH, dd, J = 7.8, 1.8 Hz), 7.39 (IH, dd, J = 7.8, 4.8 Hz), 3.16 (IH, d, J = 8.1 Hz), 3.0-3.4 (3H, ), 2.61 (IH, m), 2.30 (IH, m), 2.24 (3H, s), 2.12 (IH, m), 1.88 (IH, m), 1.6-1.8 (2H, m). 5b. cw-2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[2,3-/]quinoline cyanoborane hydrochloride c/5^,-2,3,3a,4,5,9b-Ηexahydro-l-methyl-lH-pyrrolo[2,3- ]qxιinoline cyanoborane (70 mg, 0.31 mmol) was dissolved in TΗF (5 mL) and to which ΗC1 (1.0 M in Et₂O) was added. The solvent was removed, and the solid was triturated with Et2O and dried to afford cw- 2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[2,3-/]quinoline cyanoborane hydrochloride as a white powder (61 mg, 74%): mp 178-179 °C; IR (KBr): 2431 (BΗ), 2221, 2194 (CN); 1H NMR (300 MHz, dmso-d_δ) δ 10.35 (IH, br s), 8.86 (IH, d, J = 5.7 Hz), 8.47 (IH, d, J = 7.8 Hz), 7.80 (IH, dd, J = 7.8, 6.0 Hz), 4.68 (IH, t, J = 7.5 Hz), 3.69 (IH, m), 3.05-3.35 (3H, m), 2.93 (3H, d, J = 4.2 Hz), 2.87 (IH, m), 2.36 (IH, m), 1.90 (3H, m); ¹³C NMR (75 MHz, dmso-d₆) δ 158.56, 149.31, 144.92, 128.32, 123.96, 65.81, 53.71, 39.04, 34.31, 27.46, 26.72, 23.76; ^πB NMR (64 MHz, dmso-dβ) δ -17.94. Anal. Calcd for Cι₃Hι₉BClN₃: C, 59.24; H, 7.27; N, 15.94. Found: C, 59.41; H, 7.39; N, 15.98. EXAMPLE 4 [³H]-DA Release Assay

Rat striatal slices (500 μm thickness, 6-8 mg wet weight) were incubated for 30 minutes in Kreb's buffer (118 n NaCl, 4.7 n KCl, 1.2 n MgCl₂, 1.0 n NaH₂PO₄, 1.3 n CaCl₂, 11.1 ΏM glucose, 25 n NaHCO₃, 0.11 n L-ascorbic acid, and 0.004 nM disodium EDTA; pH 7.4, and saturated with 95% O₂/5% CO₂) in a metabolic shaker at 34° C. Slices were rinsed with 15 ml of fresh buffer and incubated for an additional 30 minutes in fresh buffer containing 0.1 μM [³H]-DA (6 slices/3 ml). Subsequently, slices were rinsed with 15 ml of fresh buffer and transferred to a glass superfusion chamber. Slices were superfused (1.0 ml/min) for 60 minutes with Kreb's buffer containing nomifensine (10 μM) and pargyline (10 μM) and maintained at 34° C, pH 7.4, with continual aeration (95% O /5% CO₂). Two 5 minute samples (5 ml each) were collected to determine basal outflow of [³H]-DA. Boron-containing nicotine analogs were added to the superfusion buffer after the collection of the second sample and remained in the buffer until 12 consecutive 5 minute samples were collected. Subsequently, S-(-)-nicotine (10 μM) was added to the buffer and an additional 12 consecutive five minute samples were collected. At the end of the experiment, each slice was solubilized and the [³H] content of the tissue determined.

Radioactivity in the superfusate and tissue samples was determined by liquid scintillation spectroscopy. Fractional release for each tritium collected in each sample by the total tritium present in the tissue at the time of sample collection and was expressed as a percentage of total tritium. Basal [³H]outflow was calculated from the average of the tritium collected in the two five minute samples just before addition of the boron-containing nicotine analog. The sum of the increase in collected tritium resulting from either exposure to the test compound or exposure to nicotine in the absence and presence of the test compound equaled total [³H]overflow. [ HjOverflow was calculated by subtracting the [ H]outflow during an equivalent period of prestimulation from the values in samples collected during and after drug exposure. Inasmuch as the radiolabelled compounds were not separated and identified, the tritium collected in superfusate is referred to as either [ Hjoutflow or [ Hjoverflow, rather than as [ H]-DA. [ HjOverflow primarily represents [ H]-DA in the presence of nomifensine and pargyline in the superfusion buffer.

The boron-containing nicotine analog 4b was evaluated for its ability to evoke [³H] release from rat striatal slices at three concentrations (0.1, 1 and 10 μM). Compound 4b had no

significant [³H]-DA releasing properties in this assay at concentrations below lOμM, but

exhibited intrinsic activity at 10 μM . Since striatal NIC-evoked [ H]-DA release is thought to be

mediated through a mechanism involving the α₃β -containing receptor subtype, these

compounds do not possess significant agonist activity below 10 μM at this putative receptor

subtype.

The boron-containing nicotine analog 4b was also evaluated for its ability to inhibit NIC

evoked [³H]-DA release (putative α₃β₂ receptor subtype). In these experiments, the striatal slices

were superfused for 60 minutes with various concentrations of the analog prior to NIC (10 μM) exposure. Antagonist activity was evaluated by comparing the NIC-evoked [³H]overflow in the absence and presence of the analogs. No inhibition of S-(-)nicotine evoked [³H]dopamine release

at 10 μM was observed for compound 4b.

EXAMPLE 5 [³H]-NIC Binding Assay Striata from two rats were dissected, pooled, and homogenized with a Tekmar polytron in 10 volumes of ice-cold modified Krebs-HEPES buffer (20 mMHEPES, 1 18 m NaCl, 4.8 m KCl, 2.5 m CaCl , 1.2 m MgSO , adjusted to pH 7.5). The homogenates were incubated at

37° C for 5 minutes and centrifuged at 15,000 g for 20 minutes. The pellet was resuspended in

10 volumes of ice-cold MilliQ water, incubated for 5 minutes at 37° C, and centrifuged at 15,000 g for 20 mm. The second pellet was then resuspended in 10 volumes of fresh ice-cold 10%

Krebs-HEPES buffer, incubated at 37° C, and centrifuged at 15,000 g for 20 minutes. The latter sequence of resuspension, incubation, and centrifugation was repeated. The pellet was frozen

under fresh 10% Krebs-HEPES buffer and stored at -40° C until assayed. Upon assay, the pellet

was resuspended in the Krebs-HEPES buffer, incubated at 37° C for 5 minutes, and centrifuged at 15,000 g for 20 mm. The final pellet was resuspended in 3.6 ml ice-cold MilliQ water which provided for approximately 200 μg protein per 100 μl aliquot. Competition assays were performed in triplicate in a final volume of 200 μl Krebs-HEPES buffer containing 250 mmol Tris buffer (pH 7.5 at 4° C). Reactions were initiated by addition of 100 μl of membrane suspension to 3 nM [³H]-NIC (50 μl) and one of at least nine concentrations of analog (50 μl).

After a 90 min incubation at 4° C, reactions were terminated by dilution of the samples with 3 ml

of ice-cold Krebs-HEPES buffer followed immediately by filtration through Whatman GF/B glass fiber filters (presoaked in 0.5% polyethyleneimine) using a Brandel Cell Harvester. Filters were rinsed three times with 3 ml of ice-cold Krebs-HEPES buffer, transferred to scintillation vials, and 5 ml scintillation cocktail (Research Products International Corp., Mt. Prospect, IL) added. Nonspecific binding determined in triplicate was defined as binding in the presence of 10 μM NIC. Binding parameters were determined using the weighted, least squares regression analysis.

The boron-containing nicotine analogs were evaluated for their ability to displace [³H]~ NIC binding from rat striatal membranes. The results are summarized in Table 6. Furthermore,

the displacement by the analogs was compared to that produced by DHβE (Ki = 65 nM). All of

the compounds examined displaced [³H]-NIC binding with much lower affinities than DHβE.

Thus, these novel boron-containing nicotine analogs have relatively poor affinity for the α4β2

receptor subtype.

EXAMPLE 6 [³H]-MLA Binding Assay Whole rat brain tissue (without cortex, striatum and cerebellum) was homogenized with a Tekmar Polytron (setting 40) in 20 volumes of ice-cold hypotonic buffer (2 mMHEPES, 14.4 mMNaCl, 0.15 m KCl, 0.2 mM CaCl₂ and 0.1 mMMgSO₄, pH = 7.5). The

homogenate was incubated at 37° C for 10 minutes and centrifuged at 25,000 x g for 15 minutes at 40° C. The pellet was washed 3 times more by resuspension in the 20 volumes of the same

buffer and centrifugation at the above parameters. The final pellet was stored at -20° C under 4.6 ml of the incubation buffer and was suspended just before the incubation with radioligand.

The binding of [³H]methyllycaconitine ([³H]MLA), a probe for the α₇ neuronal nicotinic

acetylcholine receptor subtype, was determined using a modification of the method of Davies et al., "Characterisation of the binding of [³H]methyllycaconitine: a new radioligand for labelling

α7-type neuronal nicotinic acetylcholine receptors", Neuropharmacology, 38, 679-690 (1999).

[³H]-MLA (25.4 Ci mmol) was purchased from Tocris Cookson Ltd., Bristol, U.K. Binding was performed in duplicate, in a final volume of 250 μL of the incubation medium, containing 20 mM HEPES, 144 m NaCl, 1.5 mM KCl, 2 mM CaCI₂, 1 mM MgSO₄ and 0.05% BSA, pH = 7.5. Reaction was initiated by the addition of 100 μl of membrane suspension to the samples containing a desired concentration of test compounds and 2.5 nM [³H]-MLA (final concentration) and incubated for 2 hours at room temperature. Total binding was measured in the absence of unlabelled ligand, and nonspecific binding was determined in the presence of 1 μM unlabelled MLA. The binding reaction was terminated by dilution of samples with 3 ml of ice-cold incubation buffer followed by immediate filtration through presoaked in 0.5% polyetylenimine glass fiber filters (S&S, grade #32) using a Brandel harvester system. Filters were rinsed three times with 3 ml of ice-cold buffer, transferred to scintillation vials and 4 ml of scintillation cocktail was added. Protein was measured using the Bradford dye-binding procedure with bovine serum albumin as the standard.

In order to determine if these compounds had affinity for the α7 receptor subtype, the boron-containing analogs were evaluated for their ability to displace [³H]-MLA binding from rat

brain membranes (Table 1). In addition, the classical α7 receptor antagonist α-bungarotoxin was

also examined in this assay for comparison. α-Bungarotoxin afforded a Ki value of 28.6 ± 5.4

nM in the above assay. The results from the competition binding assay showed that compoxmds

3b, and 4b had Ki values of 15.2 and 2.2 μM. Compound 5b had a K-, greater than 100 μM for

this binding site.

Table 1 : K. Values for Compounds 3b. 4b, and 5b in the [ HI Nicotine and [ H] MLA Binding Assays.

EXAMPLE 7 Xenopus Oocyte Assay

Mature (49 cm) female Xenopus laevis African toads (Nasco, Ft. Atkinson, WI, U.S.A.) were used as a source of oocytes. Prior to surgery, frogs were anaesthetized by placing the animal in a 2 g/1 solution of MS222 (3-aminobenzoic acid ethyl ester). Eggs were removed from an incision made in the abdomen. Subsequently, stage five oocytes were isolated and injected with 50 nl of a mixture of the appropriate subunit cRNAs.

After linearization and purification of cloned cDNA, cRNA transcripts of α4, β2, 3, β4,

al, γ and δ subunits of nAChRs were prepared in vitro using the appropriate mMessage mMachine kit from Ambion Inc. (Austin, TX, U.S.A.). Harvested oocytes were treated with collagenase from Worthington Biochemical Corporation (Freehold, NJ, U.S.A.) for 2 h at room temperature in calcium-free Barth's solution (in mM, 88 NaCl, 10 HEPES pH 7.6, 0.33 MgS0₄ and 0.1 mg/ml gentamicin sulphate).

Electrophysiological recordings were perfomed 7 days following injections. Recordings were made with a Warner Instruments (Hamden, CT, U.S.A.) OC-725C oocyte amplifer and RC- 8 recording chamber interfaced with National Instruments' LabView software. Current electrodes were filled with 250 mM CsCl, 250 mM CsF and 100 mM EGTA, pH 7.3 and had

resistances of 0.5-2.0 MΩ. Noltage electrodes were filled with 3 M KCl and had resistances of

1-3 MΩ. Oocytes with resting membrane potentials more positive than - 30 mV were not used. Oocytes were placed in a Warner recording chamber with a total volume of 0.6 ml and were perfused at room temperature with frog Ringer's (115 mM NaCl, 2.5 mM KCl, 10 mM HEPES, pH 7.3, 1.8 mM CaCl₂) plus 1 μM atropine to block potential muscarinic receptor responses.

Current responses to drug administration were studied under two electrode voltage clamp at a holding potential of- 50 mV. Drugs were diluted in perfusion solution and then applied for 20 sec. A Mariotte flask filled with Ringer's was used to maintain a constant hydrostatic pressure for drug deliveries and washes. The rate of drug delivery was 6 ml/min. Holding currents immediately prior to agonist application were subtracted from measurements of the peak response to agonist. All drug applications were separated by a wash period of 5 min. At the start

of recording, all oocytes received two initial control applications of 300 μM acetylcholine

(ACh). Drug responses were normalized for the level of channel expression in each cell by measuring the response to the second application of ACh. In order to measure residual recovery effects, an experimental application of an analog was followed by an application of ACh alone, and the result was compared to the pre-analog application of ACh (i.e. control response). Means and S.E.M. were calculated from the normalized responses of four oocytes for each experimental concentration.

Results from the Xenopus oocvte studies COMPOUND 4b

1) Activity in Oocytes Expressing Alpha-7 Receptor Sub-Types:

Concentration Effect of Analog Recovery of ACh Response

100 μM 0.079 ± 0.003 0.740 ± 0.09

300 μM 0.179 + 0.040 0.770 ± 0.18

2) Activity in Oocytes Expressing α2βγδ Receptor Sub-Types

Concentration Effect of Analog Recovery of ACh Response

1 μM O.0001 My lO μM O.001 fully

100 μM <0.0001 fully 3) Activity in Oocytes Expressing α4β2 Receptor Sub-Types:

Concentration Effect of Analog Recovery of ACh Response

100 μM 0.005 ± 0.002 0.970 ± 0.04

300 μM 0.001 ± 0.001 0.870 ± 0.02

4) Activity in Oocytes Expressing α3β4 Receptor Sub-Types:

Concentration Effect of Analog Recovery of ACh Response

100 μM 0.001 ± 0.002 0.997

Conclusions

Compound 4b selectively interacts with the α receptor subtype, and appears to be a potent partial agonist at α receptors expressed in Xenopus oocytes.

The purpose of the above description and examples is to illustrate some embodiments of the present invention without implying any limitation. It will be apparent to those of skill in the art that various modifications and variations may be made to the composition and method of the present invention without departing from the spirit or scope of the invention. All patents and publications cited herein are incorporated by reference in their entireties.

Claims

What is Claimed Is:

1. A pharmaceutical composition comprising a boron-containing nicotine analog having selective full agonist, partial agonist, or antagonist activity at neuronal α₇ nicotinic receptor subtypes or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

2. A compound having the following formula:

wherein A and B are carbon;

X is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, C(S), S, S(O) or S(O)₂ containing alkylene moiety, provided however, that any heteroatom contained in X is separated from N by at least one carbon atom;

R¹ is selected from hydrogen, lower straight chain or branched alkyl or cycloalkyl, an aromatic, aralky, or heteroaromatic group;

R², Z¹ and Z⁴ are each independently selected from hydrogen, lower alkyl, lower branched alkyl, lower alkenyl, lower branched alkenyl;

R³, R⁴, Z² and Z³ are each independently selected from hydrogen, alkyl, substituted alkyl; cocloalkyl, substituted cycloalkyl, alkenyl; substituted alkenyl; alkynyl; substituted arylalkyl; aryialkenyi; subsituted aryialkenyi; arylalkynyl, substituted arylalkynyl; heterocyclic; substitued heterocyclic; trifluoromethyl, halogen, cyano, nitro; S(O)Y', S(O)₂Y^l, S(O)₂OY' or S(O)₂NHY^!, wherein each Y¹ is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl, provided, however, that when R³, R⁴ or R⁵ is S(O)Y', Y¹ is not hydrogen, and further provided that when Y¹ is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; C(O)Y², wherein Y² is selected from hydrogen, alkyl, substituted alkyl, aloxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryialkenyi, substituted aryialkenyi, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality; OY³ or N(Y³)₂ wherein each Y³ is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryialkenyi, substituted aryialkenyi, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfony, provided that the OY³ or N(Y³)₂ functionality is not conjugated with an alkenyl or alkynyl functionality; SY⁴ wherein Y⁴ is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryialkenyi, substituted aryialkenyi, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided that the SY⁴ functionality is not conjugated with an alkenyl or alkynyl functionality; or R³ and R⁴, together with the carbons to which they are attached, form a four to seven membered ring that can be saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said rings may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said rings may optionally be substituted with one or more substituents that are defined as Z³ and Z⁴ hereinbefore;

R , R and R are each individually selected from hydrogen, lower alkyl, halogen, cyano, aryl, C(O)Y¹, wherein Y¹ is selected from hydroxy, alkoxy, alkylamino, aryloxy and arylamino; and wherein either Z¹ and Z² or Z¹ and Z³ and their associated carbon atoms can combine to form a fused ring structure.

3. The compound of claim 2, wherein X is either CH₂CH₂, CH=CH-, C(CH₃)=CH, CH=(C(CH₃), or C(CH₃)=C(CH₃); A and B are each carbon; R¹ is a Ci-Cio alkyl, R² is hydrogen; R³ and R⁴ are individually selected from he group consisting of hydrogen, halogen, alkyl or alkanoyl; R , R and R are each hydrogen or R⁵ and R⁶ are hydrogen, and R⁷ is cyano; Z¹, Z², Z³ and Z⁴ are each hydrogen, or Z³ and Z⁴ are hydrogen, Z¹ and Z² and their associated carbon atoms combine to form a five or six membered fused ring structure, or Z² and Z⁴ are hydrogen, Z¹ and Z³ and their associated carbon atoms combine to form a five or six membered fused ring structure, or Z¹ and Z³ are hydrogen, Z² and Z⁴ and their associated carbon atoms combine to form a five or six membered spiro ring structure, or Z¹ and Z² are hydrogen, Z³ and Z⁴ and their associated carbon atoms combine to form a five or six membered spiro ring stucture.

4. The compound of claim 2 having the following structural formula:

The compound of claim 2 having the structural formula:

The compound of claim 2 having the formula:

7. The compound of claim 2, wherein the compound is nicotine cyanoborane or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2, wherein the compound is cis- 2,3 ,3 a,4, 5 ,9b-hexahy dro- 1 -methyl- 1 H-pyrrolo [3 ,2-b]isoquinoline cyanoborane or a pharmaceutically acceptable salt thereof.

9. The compound of claim 2, wherein the compound is cis- 2,3,3a,4,5,9b-hexahydro-l-methyl-lH-pyrrolo[2,3- ]quinoline cyanoborane or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition containing the compound of claim 2 or a pharmaceutically acceptable salt thereof.

11. A method for the treatment of psychostimulant abuse comprising administering a pharmaceutically effective amount of the composition of claim 1 to a subject in need thereof to ameliorate the psychostimulant abuse.

12. The method of claim 11 comprising treating nicotine abuse, amphetamine abuse, methamphetamine abuse or cocaine abuse as the psychostimulant abuse.

13. A method for treating CNS disorders comprising administering a pharmaceutically effective amount of the composition of claim 1 to a subject in need thereof to ameliorate the CNS disorder.

14. The method of claim 13 comprising treating Schizophrenia, Alzheimer, Parkinson, Attention Deficit Syndrome, depression, or anxiety as the CNS disorder.