JP2003501416A - Pharmaceutical compositions and uses thereof - Google Patents

Abstract

  (57) [Summary] The pharmaceutical composition incorporates an aryl-substituted olefinamine compound. Representative compounds are (2S)-(4E) -N-methyl-5- [3- (5-isopropoxy-1-oxopyridinyl) yl)]-4-penten-2-amine, (3E)- N-methyl-4- (3- (1-oxopyridin) yl) -3-buten-1-amine, (4E) -N-methyl-5- (3- (1-oxopyridin) yl) -4- Penten-2-amine, (4E) -N-methyl-5- (3- (5-((carboxymethyl) oxy) pyridin) yl) -4-penten-2-amine, (3E) -N-methyl- 4- [3- (5-nitro-6-aminopyridin) yl] -3-buten-1-amine, (3E) -N-methyl-4- [3- (5- (N-benzylcarboxamido) pyridine ) Yl] -3-buten-1-amine, (4E) -N-methyl-5- [5- 2-aminopyrimidin) yl] -4-penten-2-amine, (4E) -N-methyl-5- (3- (5-aminopyridin) yl) -4-penten-2-amine, (3E)- N-methyl-4- (3- (5-isobutoxypyridin) yl) -3-buten-1-amine, (3E) -N-methyl-4- (3- (5-ethylthiopyridin) yl)- 3-buten-1-amine, (4E) -N-methyl-5- (3- (5-trifluoromethylpyridin) yl) -4-penten-2-amine, (4E) -5- (3- ( 5-isopropoxypyridin) yl) -4-penten-2-amine and (4E) -5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION The present invention relates to pharmaceutical compositions, and in particular to pharmaceutical compositions incorporating compounds capable of affecting nicotinic cholinergic receptors. More particularly, the invention relates to compounds capable of activating nicotinic cholinergic receptors, eg, as agonists of specific nicotinic receptor subtypes. The present invention also relates to methods of treating various conditions and diseases, particularly conditions and diseases associated with central and autonomic nervous system dysfunction.

Nicotine has been proposed to have many pharmacological actions. For example, Pulla
n et al. Engl. J. Med. 330: 811-815 (1994).
Certain of these effects may be associated with effects upon neurotransmitter release. For example, the neuroprotective effects of nicotine have been proposed, Sjak-shie et al., Brai.
n Res. 624: 295 (1993). Release of acetylcholine and dopamine by nerves upon administration of nicotine has been reported by Rowell et al. Neuro
chem. 43: 1593 (1984); Rapier et al., J. Am. Neuroch
em. 50: 1123 (1988); Sandor et al., Brain Res. 5
67: 313 (1991) and Vizzi, Br. J. Pharmacol. Four
7: 765 (1973). Release of norepinephrine by nerves upon administration of nicotine was reported by Hall et al., Biochem. Pharmacol
． 21: 1829 (1972). Neuronal release of serotonin upon administration of nicotine has been reported by Hery et al., Arch. Int. Pharmacod
yn. Ther. 296: 91 (1977). Neuronal release of glutamate upon administration of nicotine was reported by Toth et al., Neurochem R.
es. 17: 265 (1992). In addition, nicotine
Reportedly, it enhances the pharmacological behavior of certain pharmaceutical compositions used in the treatment of certain diseases. Sanberg et al., Pharmacol. Biochem. & Beha
vior 46: 303 (1993); Harsing et al. Neuroch
em. 59:48 (1993) and Hughes, Proceedings.
from Intl. Symp. Nic. See S40 (1994). In addition, various other beneficial pharmacological effects of nicotine have also been proposed. Decina et al., Bio
l. Psychiatry 28: 502 (1990); Wagner et al., Ph.
armacopsychiatry 21: 301 (1988); Pommerl
eau et al., Additive Behaviors 9: 265 (1984).
Onavii et al., Life. Sci. 54 (3): 193 (1994); Tr
ipati et al., JPET 221: 91-96 (1982) and Hamon,
Trends in Pharmacol. Res. See 15:36.

Various nicotine compounds have been reported to be useful in the treatment of a wide variety of conditions and diseases. For example, Williams et al., DN & P7 (4): 205-22.
7 (1994), Arneric et al., CNS Drug Rev. 1 (1): 1
~ 26 (1995), Arneric et al., Exp. Opin. Invest. D
rugs 5 (1): 79-100 (1996), Bencherif et al., JP.
ET 279: 1413 (1996); Lippiello et al., JPET 27.
9: 1422 (1996), Damaj et al., Neuroscience (199).
7), Holladay et al. Med. Chem 40 (28): 4169-
4194 (1997), Bannon et al., Science 279: 77-80.
(1998), PCT WO94 / 08992, PCT WO96 / 31475.
And Bencherif et al., US Pat. No. 5,583,140, Dull et al., US Pat. No. 5,597,919, Smith et al., US Pat. No. 5,604,2.
31, Dull et al., US Pat. No. 5,616,716, and Cosford.
See U.S. Pat. No. 5,852,041. Nicotine compounds are reported to be useful in the treatment of a wide variety of central nervous system (CNS) disorders.

CNS disease is a type of neurological disease. CNS disease can be drug-induced,
It may be attributed to a genetic predisposition, infection or trauma, or the etiology may be unknown. CNS disorders include neuropsychiatric disorders, neurological disorders and psychoses, including neurodegenerative disorders, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders in which the clinical manifestations are attributed to CNS dysfunction (ie, inappropriate levels of neurotransmitter release, inappropriate neurotransmitter receptor properties, and / or neurotransmitters and neurotransmitters). Diseases resulting from inappropriate interactions between receptors). Several CNS
The disease can be attributed to cholinergic deficiency, dopaminergic deficiency, adrenergic deficiency, and / or serotonergic deficiency. CNS disorders that occur relatively often include presenile dementia (early-onset Alzheimer's disease), senile dementia (Alzheimer-type dementia), Parkinson's syndrome including Parkinson's disease, Huntington's disease, tardive dyskinesia, hyperactivity, mania, and attention. Includes deficiency, anxiety, dyslexia, schizophrenia and Tourette's syndrome.

It is desirable to provide a useful method of preventing and treating a condition or disease by administering a nicotine compound to a patient susceptible to or suffering from such condition or disease. It has a nicotine pharmacological effect and has a beneficial effect (eg C
(For NS function) but without any significant associated side effects,
It is highly beneficial to administer a pharmaceutical composition containing an active ingredient to an individual suffering from a particular disease (eg, CNS disease), resulting in a severance of the symptoms of such disease. Although it is highly desirable to provide a pharmaceutical composition incorporating a compound that interacts with the nicotine receptor, such as a compound that can affect the function of the CNS, such a compound is sufficient to affect the function of the CNS. Even when used in different amounts, it does not significantly affect receptor subtypes that may induce unwanted side effects such as recognizable activity at skeletal muscle and ganglion sites.

SUMMARY OF THE INVENTION The present invention relates to aryl-substituted amine compounds, most preferably aryl-substituted olefin amine compounds. Representative preferred compounds of the invention are (3E) -N
-Methyl-4- [3- (5-nitro-6-aminopyridin) yl] -3-buten-1-amine, (3E) -N-methyl-4- [3- (5- (N-benzylcarboxy) Amido) pyridin) yl] -3-buten-1-amine, (4E) -N-methyl-5- [5- (2-aminopyrimidin) yl] -4-penten-2-amine,
(4E) -N-methyl-5- (3- (5-aminopyridin) yl) -4-penten-2-amine, (2S)-(4E) -N-methyl-5- [3- (5- Isopropoxy-1-oxopyridin) yl)]-4-penten-2-amine, (3E)
-N-methyl-4- (3- (5-isobutoxypyridin) yl) -3-butene-
1-amine, (3E) -N-methyl-4- (3- (1-oxopyridin) yl)
-3-Butene-1-amine, (4E) -N-methyl-5- (3- (1-oxopyridin) yl) -4-penten-2-amine, (3E) -N-methyl-4- ( Three
-(5-Ethylthiopyridin) yl) -3-buten-1-amine, (4E) -N
-Methyl-5- (3- (5-trifluoromethylpyridin) yl) -4-penten-2-amine, (4E) -N-methyl-5- (3- (5-((carboxymethyl) oxy)) (Pyridin) yl) -4-penten-2-amine, (4E) -5- (
3- (5-isopropoxypyridin) yl) -4-penten-2-amine, and (4E) -N-methyl-5- (3- (5-hydroxypyridin) yl) -4-.
Includes penten-2-amine.

The present invention also relates to methods of synthesizing certain aryl-substituted amine compounds, such as the compounds of the present invention. Of particular interest are isolated enantiomeric compounds (ie, compounds in substantially pure form as opposed to racemic mixtures), and methods of synthesizing such enantiomeric compounds in substantially pure form. The present invention also relates to prodrug derivatives of the compounds of this invention.

The present invention also relates to the prevention of a wide variety of conditions or disorders, particularly those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission, including those involved in neuromodulation of neurotransmitter release, such as dopamine release. Or regarding the cure. The present invention also provides
Central nervous system (CNS), characterized by alterations in normal neurotransmitter release
The present invention relates to a method for preventing or treating diseases such as diseases. The present invention also relates to the treatment of certain conditions (eg, pain relief). The method comprises administering to the subject an effective amount of a compound of the invention.

The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of a compound of the invention. Such a pharmaceutical composition, when used in an effective amount, is capable of interacting with the relevant nicotine receptor site of a subject (patient) and is therefore subject to a wide variety of conditions and diseases, especially changes in normal neurotransmitter release. It incorporates a compound that can act as a therapeutic agent for the prevention or treatment of the disease being characterized. A preferred pharmaceutical composition comprises a compound of the invention.

The pharmaceutical composition of the present invention is useful for the prevention and treatment of diseases such as CNS diseases characterized by altered normal neurotransmitter release. The compounds in such compositions, when used in effective amounts, exhibit (i) nicotine pharmacological effects, affecting relevant nicotine receptor sites (eg, acting as pharmacological agonists, Activating nicotine receptors), and (ii) inducing neurotransmitter secretion, and thus having the effect of preventing and suppressing the symptoms associated with such diseases, pharmaceutical compositions are provided for such diseases. To provide a therapeutic benefit to individuals who are afflicted with the disease and who present with clinical signs of such disease. Furthermore, the compounds (i) increase the number of nicotinic cholinergic receptors in the brain of the patient and (ii) do not cause any discernible adverse side effects when used in effective amounts (eg blood pressure and heart rate). Significant increase, a significant negative effect on the digestive tract, and a significant effect on skeletal muscle). The pharmaceutical compositions of the present invention are believed to be safe and effective in the prevention and treatment of a wide variety of conditions and diseases.

The above and other aspects of the present invention are described in detail in the detailed description and examples set forth below.

[0012]     (Detailed Description of the Invention)   The compounds of the present invention include compounds of the formula:

[Chemical 7] Here, X, X ′, X ″, Y ′ and Y ″ independently of each other are nitrogen, nitrogen bonded to oxygen (eg, oxidized N (N—O) functional group), or Hans.
ch et al., Chem. Rev. 91: 165 (1991), greater than or equal to 0, often greater than or equal to 0.1, typically greater than or equal to 0.2, and even greater than or equal to 0.3, or less than 0 and generally less than -0.1. A carbon bonded to a substituent species characterized by having a sigma m value of 1 or 0. Preferably X, X
Less than 4, more preferably less than 3, most preferably 1 or 2 of ', X'',Y'andY''are nitrogen or nitrogen bonded to oxygen. Furthermore, X, X
It is highly preferred that no more than one of ', X'',Y'andY''is nitrogen bound to oxygen, and if one of those species is nitrogen bound to oxygen, then that species is X ″ is preferred. Typically, X'is CH, CBr or COR
'Is. Typically X is CH. Most preferably X ″ is nitrogen. In certain preferred environments, both X'and X '' are nitrogen. Typically, Y ′ and Y ″ are each a carbon bonded to a substituent species, Y ′ and Y ″
Both ″ are preferably carbon bonded to a substituent species such as hydrogen. Furthermore, the sum of m and n is 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3.
, Is most preferably 2 or 3, m is an integer and n is an integer.
It is highly preferred that m is 1 and n is 1. When any of X, X ', X ", Y'and Y" is a carbon attached to a substituent species, those substituent species are often about -0.3 to about 0.75. , Often about -0.25 to about 0.
Has a sigma m value of 6 and each sigma m value independently of one another is 0 or 0
Need not be equal to.

B ′ is a substituted or unsubstituted two carbon atom bridging species (
bridging species) and can be selected from the following.

[Chemical 8] B ′ may be saturated or unsaturated (eg with R ′ and R ″) and may be part of a substituted or unsubstituted cycloalkyl ring (eg cyclopropyl, cyclobutyl). , Cyclopentyl, etc.). B ′ substituent (eg R ′ or R ″) and X or Y ″ associated substituent species (ie,
Related X and Y ″ are each a carbon atom attached to a substituent species) together are a ring structure such as a 5- or 6-membered ring structure (eg, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl) Can be formed. Typically, in such circumstances, a substituent species of a carbon atom of a bridging species immediately adjacent to the aromatic ring, together with X or Y ″, forms such a ring. Furthermore, B
', The substituents, at least one of E, E ^I , E ^II and E ^III , and the intervening atom are both monocyclic ring structures (eg cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl structures) or bicycles. A formula ring structure can be formed.

E, E ^I , E ^II and E ^III independently of one another are hydrogen, alkyl (eg C ₁
-C _8, preferably a linear or branched alkyl containing C ₁ -C _5, such as methyl,
Ethyl or isopropyl), substituted alkyl, halo-substituted alkyl (eg C ₁
-C _8, preferably comprises a C ₁ -C _5, linear or branched alkyl, such as trifluoromethyl or trichloromethyl), cycloalkyl, substituted cycloalkyl,
Heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl, all of E, E ^I , E ^II and E ^III may be hydrogen, or E, E ^I
, E ^II and E ^III are not hydrogen (eg, alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, Arylalkyl or substituted arylalkyl), the remainder E
, E ^I , E ^II and E ^III are hydrogen and E and E ^I or E ^II and E ^III and their associated carbon atoms together can form a ring structure such as cyclopentyl, cyclohexyl or cycloheptyl, and E and E ^II or E ^I and E ^III and their associated carbon atoms can together form a ring structure such as cyclopentyl, cyclohexyl or cycloheptyl, Z and Z ^I being independently of one another hydrogen or alkyl (eg C _1- C _8, preferably a linear or branched alkyl containing C ₁ -C _5, for example shows methyl, ethyl or isopropyl), at least one hydrogen of preferably Z and Z ', most preferably Z is hydrogen And Z ^I is methyl, and alternatively Z is hydrogen, and Z ^I is a ring structure (cycloalkyl, heterocyclyl, aryl or aryl). Alkylaryl), for example cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl, pyridinyl, quinolinyl, pyrimidinyl, phenyl, benzyl, thiazolyl or oxazolyl, methylpyridine, ethylpyridine, methylpyrazine or ethylpyrazine (any of the above is at least one substituent, Optionally substituted with, for example, an alkyl, alkoxy, halo or amino substituent), alternatively Z is hydrogen, Z ^I is propargyl, and alternatively Z, Z ^I and the associated nitrogen atom are ring structures. , Aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, iminothiazolinyl or iminooxazolinyl (optionally pyridyl, such as 3-pyridinyl, or pyrimidinyl, such as 5-pyridinyl. Substituted with rimidinyl), Z ^I and E ^I and the associated carbon and nitrogen atoms together can form a monocyclic ring structure such as pyrazolyl or isoxazolaminyl, Z ^I and E ^I and associated carbon And the nitrogen atom is
Together, a monocyclic ring structure such as azetidinyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl or piperazinyl or a bicyclic ring structure such as 3-([
4.2.0] -2-azabicyclooctyl), 3-([2.2.2] -2-azabicyclooctyl) or 3-([2.2.1] -2-azabicycloheptyl).
Z, Z ^I and E ^III and the associated carbon and nitrogen atoms together form a bicyclic ring structure such as quinuclidinyl, 2-([2.2.1] -1-azabicycloheptyl), or 2 -([3.3.0] -1-azabicyclooctyl), or a tricyclic ring structure, such as azaadamantyl, can be formed and Z ^I and E ^II and E ^III and the associated carbon and nitrogen atoms are both divalent. Cyclic ring structure, for example 1-([2.2
． 1] -2-Azabicycloheptyl) and Z, Z ^I , E ^II and E ^III and associated carbon and nitrogen atoms can together form a tricyclic ring structure. In the situation where B ′ is an olefin and its associated R ^I substituent forms with X or Y ^I a 5-membered heterocyclic aromatic ring (eg, furan, pyrrole or thiophene), Z, Z ^I
, E, E ^I , E ^II and E ^III most preferably do not together form a ring structure, ie in such circumstances Z and Z ^I are most preferably independently hydrogen or alkyl. And much less preferred, Z and Z ^I , together with the associated nitrogen atom, can simply form a ring structure. More specifically, X, X ',
X ″, Y ′ and Y ″ independently of each other include an aromatic carbon atom having N, N—O, or one of the following substituent species: H, alkyl, substituted alkyl, alkenyl, Substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br,
I, NR′R ″, CF ₃ , OH, CN, NO ₂ , C ₂ R ′, SH, SCH ₃ , N ₃
, SO ₂ CH ₃ , OR ', (CR'R'') _q OR', O (CR'R '') _q C ₂ R
', SR', C (= O) NR'R '', NR'C (= O) R '', C (= O) R
', C (= O) OR', OC (= O) R ', (CR'R'') _q OCH ₂ C ₂ R'
, (CR'R '') _q C (= O) R ', (CR'R'') _q C (CHCH ₃ ) OR
', (CR'R'') _q C (= O) OR', (CR'R '') _q C (= O) NR '
R '', (CR'R '') _q NR'R '', CH = CHR ', OC (= O) NR
“R” and NR′C (═O) OR ″, where q is an integer from 1 to 6, and R ′ and R ″ are independently of each other hydrogen or alkyl (eg, C ₁ -C). _Ten
Alkyl, preferably C ₁ -C ₅ alkyl, more preferably methyl, ethyl, isopropyl, tert-butyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or isobutyl), cycloalkyl (eg cyclopropyl, cyclobutyl). , Cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl), non-aromatic heterocycles, where the heteroatoms of the heterocycle moiety are at least 2 carbon atoms away from any other nitrogen, oxygen or sulfur atom. (Eg, quinuclidinyl, pyrrolidinyl and piperidinyl), aromatic group-containing species (eg, pyridyl, quinolinyl, pyrimidinyl, furanyl, phenyl, and benzyl, where any of the above is at least one substituent, eg, Alkyl, alkoxy, it may be suitably substituted with halo or amino substituents). Other representative aromatic ring systems are described by Gibson et al., J. Am. M
ed. Chem. 39: 4065 (1996). R ′ and R ″ may be straight or branched, or R ′ and R ″ and the intervening atom together form a ring structure (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl, adamantyl or quinuclidinyl) can be formed. X, X '
, X ″, Y ′ and Y ″, the substituent species for the aromatic carbon atom, when adjacent, together are one or more saturated or unsaturated, substituted or unsubstituted carbocycles. Or it can form a heterocycle, which includes but is not limited to ether, acetal, ketal, amine, ketone, lactone, lactam, carbamate, or urea functional groups. Furthermore, it is highly preferred that Y ′ is a carbon bonded to hydrogen and X is preferably C—H. Preferably E
, E ^I and E ^II are hydrogen. In one preferred embodiment, n is 1, m is 1 or 2, E, E ^I and E ^II are each hydrogen and E ^III is alkyl (eg methyl). In another preferred embodiment, n is 1,
m is 1 or 2 and E, E ^I , E ^II and E ^III are each hydrogen. Depending on the identity and position of E, E ^I , E ^II and E ^III independent of each other, certain compounds may be optically active. In addition, the compounds of this invention may have chiral centers in their side chains (eg compounds may have the R or S configuration). Depending on E, E ^I , E ^II and E ^III , the compounds of the invention have chiral centers and the invention relates to racemic mixtures of such compounds as well as enantiomeric compounds. Typically n, m
, E, E ^I , E ^II and E ^III are selected for up to 4 of the substituents designated E, E ^I , E ^II and E ^III , often up to 3, usually 0, 1 or 2. , Non-hydrogen substituents (ie, substituents such as alkyl or halo-substituted alkyl).

“Alkyl” as used herein means a straight or branched chain alkyl group containing C _{1 to} C ₈ , preferably C _{1 to} C ₅ , such as methyl, ethyl, or isopropyl. “Substituted alkyl” means 1 such as hydroxy, alkoxy, mercapto, aryl, heterocyclo, halo, amino, carboxyl, carbamyl, cyano and the like.
Means an alkyl group further having one or more substituents, “alkenyl” means C _1-
C _8, preferably comprises a C ₁ -C _5, at least one carbon - means carbon double bond, straight or branched chain hydrocarbon radical, "substituted alkenyl" as defined above Means an alkenyl group further having one or more substituents, "cycloalkyl" contains 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms,
“Substituted cycloalkyl” means a saturated or unsaturated ring-containing group, “substituted cycloalkyl” means a cycloalkyl group further having one or more substituents as defined above, and “aryl” means 6 to 10 carbon atoms. Means an aromatic group having atoms, "substituted aryl"
Means an aryl group further having one or more substituents as defined above, "alkylaryl" means an alkyl substituted aryl group and "substituted alkylaryl" is as defined above. By "arylalkyl" is meant an alkylaryl group further having one or more substituents, "arylalkyl" is an aryl-substituted alkyl group, and "substituted arylalkyl" is one or more substituents as defined above. Further means an arylalkyl group having, "heterocyclyl" includes one or more heteroatoms (eg, O, N, S) as part of the ring structure and has 2 to 7 carbon atoms in the ring, saturated or An unsaturated ring group is meant, and “substituted heterocyclyl” means a heterocyclyl group further having one or more substituents as defined above.

[0016]   Of particular interest are compounds of the formula:

[Chemical 9] Where X, X ′, X ″, Y ′, Y ″, E, E ^I , Z, Z ^I , m and R ′.
Is as defined hereinabove. The wavy line in the structure indicates that the compound is cis (Z
) Or a trans (E) form, preferably a trans (E) form. Preferably both R'is hydrogen or one or both R'is methyl. Preferably Z is hydrogen and Z'is hydrogen or methyl. Preferably m is 1 or 2. Preferably each E is hydrogen, preferably each E ^I is hydrogen or methyl, but most preferably all of E and E ^I are hydrogen. Preferably Y'is a carbon attached to a substituent species, most preferably the substituent species is hydrogen, halo, NR'R '' or OR '''. Preferably X
″ Is nitrogen or carbon attached to a substituent species such as NR′R ″, NO ₂ or OR ″, but most preferably nitrogen. Preferably, 'but is nitrogen, preferably hydrogen, R' X is halo, OR ', NR'R'', CN, bonded to a substituent species such as C ₂ R' or CHCHR 'carbon . Preferably, X is a carbon bonded to a substituent species such as hydrogen.

A representative compound of the invention is (3E) -N-methyl-4- [3- (5-nitro-6-aminopyridin) yl] -3-buten-1-amine, (3E)-. N-methyl-4- [3- (5- (N-benzylcarboxamido) pyridin) yl] -3
-Buten-1-amine, (4E) -N-methyl-5- [5- (2-aminopyrimidin) yl] -4-penten-2-amine, (4E) -N-methyl-5- (3-
(5-Aminopyridin) yl) -4-penten-2-amine, (2S)-(4E
) -N-Methyl-5- [3- (5-isopropoxy-1-oxopyridin) yl)]-4-penten-2-amine, (3E) -N-methyl-4- (3- (5- Isobutoxypyridin) yl) -3-buten-1-amine, (3E) -N-methyl-4- (3- (1-oxopyridin) yl) -3-buten-1-amine, (4E)
) -N-Methyl-5- (3- (1-oxopyridin) yl) -4-pentene-2
-Amine, (3E) -N-methyl-4- (3- (5-ethylthiopyridin) yl) -3-buten-1-amine, (4E) -N-methyl-5- (3- (5- Trifluoromethylpyridin) yl) -4-penten-2-amine, (4E) -N-methyl-5- (3- (5-((carboxymethyl) oxy) pyridin) yl) -4.
-Penten-2-amine, (4E) -5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine, and (4E) -N-methyl-5- (3
-(5-hydroxypyridin) yl) -4-penten-2-amine.

The following compounds are also representative compounds of the present invention: 4- (N-methylamino)-
1- (3- (5-isopropoxypyridin) yl) -1-pentan-1-ol, (2R)-(4E) -N-methyl-5- (5-pyrimidinyl) -4-penten-2-amine , (2S)-(4E) -N-methyl-5- (5-pyrimidinyl)-
4-Penten-2-amine, (2R)-(4E) -N-methyl-5- [3- (5
-Methoxypyridin) yl] -4-penten-2-amine, (2S)-(4E).
-N-methyl-5- [3- (5-methoxypyridin) yl] -4-pentene-2
-Amine, (4E) -N-methyl-5- [3- (5-cyclopentyloxypyridin) yl] -4-penten-2-amine, (4E) -N-methyl-5- [3-
(5-Cyclohexyloxypyridin) yl] -4-penten-2-amine, (
4E) -N-methyl-5- [3- (5-cyanopyridin) yl] -4-penten-2-amine, (4E) -N-methyl-5- [3- (5-ethynylpyridin) yl]. -4-Penten-2-amine, (4E) -N-methyl-5- [3- (5-phenylethynylpyridin) yl] -4-penten-2-amine, (4E) -N-
Methyl-5- [3- (5- (4-methoxyphenylethynyl) pyridin) yl]
-4-Penten-2-amine, (4E) -N-methyl-5- [3- (5-trans-β-styrylpyridin) yl] -4-penten-2-amine, (4E) -N
-Methyl-5- [3- (6-methoxypyridin) yl] -4-penten-2-amine, (4E) -N-methyl-5- [3- (5-phenylpyridin) yl] -4
-Penten-2-amine, (4E) -N-methyl-5- [3- (5- (4-methoxyphenyl) pyridin) yl] -4-penten-2-amine, (4E) -N-.
Methyl-5- [3- (5- (4-hydroxyphenyl) pyridin) yl] -4-
Penten-2-amine, (4E) -N-methyl-5- [3- (5- (4-fluorophenylpyridin) yl] -4-penten-2-amine, (4E) -N-methyl-5- [3- (5- (3,4-methylenedioxyphenylpyridin) yl]-
4-Penten-2-amine, (4E) -N-methyl-5- [3- (5-phenoxypyridin) yl] -4-penten-2-amine, (4E) -N-Methyl-5-
[3- (5- (4-Methoxyphenoxy) pyridin) yl] -4-pentene-2
-Amine, (4E) -N-methyl-5- [3- (5- (4-hydroxyphenoxy) pyridin) yl] -4-penten-2-amine, (4E) -N-methyl-5.
-[3- (5- (4-Fluorophenoxy) pyridin) yl] -4-pentene-
2-Amine, (4E) -N-methyl-5- [3- (5- (3,4-methylenedioxyphenoxy) pyridin) yl] -4-penten-2-amine, (4E) -N.
-Methyl-5- [3- (5-benzyloxypyridin) yl] -4-pentene-
2-Amine, (4E) -N-methyl-5- [3- (5- (4-methoxybenoxyoxy) pyridin) yl] -4-penten-2-amine, (4E) -N-methyl-5. -[3- (5- (4-hydroxybenzyloxy) pyridin) yl] -4-
Penten-2-amine, (4E) -N-methyl-5- [3- (5- (4-fluorobenzyloxy) pyridin) yl] -4-penten-2-amine, and (4
E) -N-methyl-5- [3- (5- (3,4-methylenedioxybenzyloxy) pyridin) yl] -4-penten-2-amine.

Yet another representative compound of the present invention includes: (1-methyl-4- (3
-Pyridyl) 3-butenyl) (3-pyridylmethyl) amine, methyl (1-methyl-4- (2- (prop-2-ynyloxymethyl) pyrimidin-5yl) 3
-Butenyl) amine, and methyl (1-methyl-4- (2- (2-phenylvinyl) pyrimidin-5-yl) 3-butenyl) amine.

There are various methods for synthetically producing the aryl-substituted olefin amine compounds of the present invention. Examples of techniques and procedures for providing the compounds of the present invention are set forth in US Pat. No. 5,616,716 to Dull et al. And US patent application Ser. No. 09 / 098,285 filed June 16,1998. Which are incorporated herein by reference.

Compounds of the (E) -metanicotine type are described in Loffler et al., Chem. Ber.
42, 3431-438 (1909) and Laforge, J. et al. A. C. S
． 50, 2477 (1928), can be used to prepare substituted nicotine-type compounds. Certain 6-substituted metanicotine-type compounds have the corresponding 6-
From substituted nicotine-type compounds, see Acheson et al. Chem. Soc. , Pe
It can be prepared using the general method of rkin Trans 1, 2, 579-585 (1980). 6-Substituted nicotine-type compounds, which are the necessary precursors for such compounds, are prepared from 6-substituted nicotinic acid esters by Rondahl, Acta P.
harm. Suec. 14, 113-118 (1977). The preparation of certain 5-substituted metanicotine-type compounds was performed from the corresponding 5-substituted nicotine-type compounds by Acheson et al. Chem.
Soc. , Perkin Trans, 1, 2, 579-585 (1980). 5-Halo-substituted nicotine-type compounds (eg, fluoro- and bromo-substituted nicotine-type compounds) and 5-aminonicotine-type compounds are described by Rondahl, Acta Pharm. Suec. 14,113
~ 118 (1977) can be used to prepare the general procedure. 5
-Trifluoromethylnicotine-type compounds are described in Ashimori et al., Chem. P
harm. Bull. 38 (9) 2446-2458 (1990) and Ron.
dahl, Acta Pharm. Suec. 14, 113-118 (1977
) Can be prepared using the techniques and materials shown in.

Further, the preparation of certain metanicotine-type compounds uses an aromatic halide and palladium-catalyzed coupling of a terminal olefin containing a protected amine substituent to remove the protecting group to obtain a primary amine. And optionally by alkylation 2
This can be achieved by providing a secondary or tertiary amine. In particular, certain metanicotine-type compounds include 3-halo-substituted, 5-substituted pyridine compounds or 5-halo-substituted pyrimidine compounds with protected amine functional olefins (e.g., phthalimide salts;
Halo-1-propene, 4-halo-1-butene, 5-halo-1-pentene or 6
-Halo-1-hexenes such as the olefins provided by the reaction) and subjected to a palladium catalyzed coupling reaction. Frank et al., J
． Org. Chem. 43 (15), 2947-2949 (1978) and M
alek et al. Org. Chem. 47, 5395-5397 (1982). Alternatively, a particular metanicotine-type compound is 4- (N-methyl-N-ter
can be prepared by coupling an N-protected modified amino acid residue such as t-butyloxycarbonyl) aminobutyric acid methyl ester with an appropriate aryl halide and an aryllithium compound as can be obtained from butyllithium. . The resulting N-protected aryl ketone is then chemically reduced to the corresponding alcohol and converted to an aryl halide, followed by dehydrohalogenation to introduce an olefinic functional group. The N-protecting group is then removed to give the desired metanicotine-type compound.

There are many different ways to provide (Z) -metanicotine-type compounds. In one method, a (Z) -metanicotine-type compound is converted from a nicotine-type compound into E and Z.
It can be synthesized as a mixture of isomers and the (Z) -metanicotine-type compound can then be chromatographed by Sprouse et al., Abstract of the article, 32, Co.
It can be separated using techniques of the type disclosed in the resta / TCRC Joint Conference (1972). Alternatively, the metanicotine-type compound is a corresponding acetylene compound (eg, N-methyl-4- (3-pyridinyl)-
3-butyn-1-amine type compounds) can be prepared by controlled hydrogenation. For example, certain 5-substituted (Z) -metanicotine type compounds and certain 6-substituted (Z)
-Metanicotine-type compounds can be prepared from 5-substituted-3-pyridinecarboxaldehyde and 6-substituted-3-pyridinecarboxaldehyde, respectively. (Z
) -A representative synthetic technique for metanicotine-type compounds is described in US Pat.
No. 597,919, the disclosure of which is incorporated herein by reference.

There are many ways in which the (Z) -olefin isomers of aryl-substituted olefin amine compounds can be synthetically produced. In one approach, the (Z) -isomer of an aryl-substituted olefin amine compound is a controlled alkynyl compound (eg, N-methyl-5- (3-pyridyl) -4-butyn-2-amine type compound). H by using a commercially available Lindlar catalyst (Aldrich Chemical Co.)
． Lindler et al., Org. Syn. 46:89 (1966). The required alkynyl compound is an aromatic halide, preferably a 3-bromopyridine type or 3-iodopyridine type compound, an alkynyl side chain compound (for example, N-methyl-4-pentyn-2-amine type compound) and a palladium catalyst. It can be prepared by coupling. Typically, L. Bleach
er et al., Synlett. 1115 (1995), copper iodide (
Used for palladium-catalyzed coupling of aryl halides with monosubstituted alkynes in the presence of I) and triphenylphosphine as base and potassium carbonate. Alkynyl compounds such as N-methyl-4-pentyn-2-amine were generated from commercially available 4-pentyn-2-ol (Aldrich Chemical Co.), followed by treatment with p-toluenesulfonyl chloride in pyridine. 4-pentin-2
It can be prepared by reaction of all-p-toluenesulfonate with an excess of methylamine as a 40% aqueous solution or a 2.0 M solution in tetrahydrofuran. In some cases, the amino functionality of the N-methyl-4-pentyn-2-amine type compound is protected by treatment with di-tert-butyl dicarbonate to give tert-
It may be necessary to obtain butoxycarbonyl protected amine type compounds. Such protected amine compounds may more readily undergo palladium-catalyzed coupling with aryl halides followed by controlled hydrogenation of alkynyl compounds than unprotected amine compounds. The tert-butoxycarbonyl protecting group can be easily removed using a strong acid such as trifluoroacetic acid to give an aryl-substituted olefin amine compound (Z).
-Olefin isomers can be obtained.

There are various methods by which the aryl-substituted olefin amine compounds of the present invention can be synthetically produced. Olefin alcohols such as 4-penten-2-ol condense with aromatic halides such as 3-bromopyridine or 3-iodopyridine. Typically, Frank et al., J. et al., Which includes palladium catalyzed coupling of olefins with aromatic halides. Org. Chem. 43, 2947-2949 (1978
) And Malek et al. Org. Chem. 47, 5395-5397 (1
982) is used. The olefin alcohol can optionally be protected as t-butyldimethylsilyl ether prior to coupling. Subsequent desilylation gives the olefin alcohol. The alcohol condensation product was then purified by de Costa et al. Org. Chem. 35, 4334-4
Conversion to the amine using a procedure of the type shown in 343 (1992). Typically, alcohol condensation products use methanesulfonyl chloride or p-toluenesulfonyl chloride to activate the alcohol, followed by ammonia or primary or secondary amines for mesylate or tosylate substitution. Thereby, it is converted into an aryl-substituted olefin amine. Thus, when the amine is ammonia, an aryl-substituted olefin primary amine compound is provided, and when the amine is a primary amine such as methylamine or cyclobutylamine, an aryl-substituted olefin secondary amine compound is provided and the amine is dimethyl. When a secondary amine, such as an amine or pyrrolidine, an aryl substituted olefin tertiary amine compound is provided. Other representative olefin alcohols are 4-penten-1-ol, 5-hexen-2-ol, 5-hexen-3-ol, 3-methyl-3.
-Buten-1-ol, 2-methyl-3-buten-1-ol, 4-methyl-4
-Penten-1-ol, 4-methyl-4-penten-2-ol, 1-octen-4-ol, 5-methyl-1-hepten-4-ol, 4-methyl-5-hexen-2-ol , 5-methyl-5-hexen-2-ol, 5-hexene-
Includes 2-ol and 5-methyl-5-hexen-3-ol. 1,1,1-
Trifluoromethyl-substituted olefin alcohols such as trifluoro-4-penten-2-ol have been prepared from 1-ethoxy-2,2,2-tolufluoro-ethanol and alkyltrimethylsilanes by Kubota et al., Tetrahedron.
Letters, 33 (10), 1351-1354 (1992) or from trifluoroacetic acid ethyl ester and alkyltributylstannane, Ishihara et al., Tetrahedron Letters,
No. 33 (56), 5777-5780 (1993). Certain olefin alcohols are optically active and can be used as a mixture of enantiomers or as a pure enantiomer to provide the corresponding optically active forms of the aryl-substituted olefin amine compounds. When an olefin allyl alcohol, such as methallyl alcohol, is reacted with an aromatic halide, an aryl-substituted olefin aldehyde is produced, and the resulting aldehyde is subjected to reductive amination (for example using alkylamine and sodium cyanoborohydride). Can be converted to an aryl-substituted olefin amine compound by treatment. Preferred aromatic halides are 3-bromopyridine type compounds and 3-iodopyridine type compounds. Typically, such 3-halopyridine-type compound substituents are contacted with the chemicals such groups encounter during preparation of the aryl-substituted olefin amine compounds (eg, tosyl chloride and methylamine) and reaction conditions. Even though it continues to exist. Separately, -OH, -N
Substituents such as H ₂ and —SH can also be protected as the corresponding acyl compounds,
Or substituents such as -NH ₂ can also be protected as a phthalimide functionality. In the case of dihaloaromatics, continuous palladium catalysis (He) to two different olefin side chains.
ck type) coupling is also possible.

Certain optional aryl-substituted olefin amine compounds having a branched chain, such as (
There are also various ways to provide 4E) -N-methyl-5- (5-isopropoxy-3-pyridyl) -4-penten-2-amine. By using one synthetic approach, the latter compound was substituted with the side chain N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine, 3-substituted 5-halo-substituted pyridine,
It can be synthesized in a convergent manner by coupling with 5-bromo-3-isopropoxypyridine under Heck reaction conditions followed by removal of the tert-butoxycarbonyl protecting group. W. W., typically involving palladium-catalyzed coupling of olefins with aromatic halides. C. Frank et al. Org. Chem. 43:29
47 (1978) and N.M. J. Malek et al. Org. Chem. 47:
A procedure of the type shown in 5395 (1982) is used. Necessary N-methyl-N-
(Tert-Butoxycarbonyl) -4-penten-2-amine can be synthesized as follows: (i) Commercially available 4-penten-2-ol (Aldrich Chemical Co., Lancaster Synthesis Co.) in p-toluene in pyridine. Treatment with sulfonyl chloride to give T.I. Michel et al., Liebigs Ann. 11: 1811 (
1996) makes it possible to obtain the 4-penten-2-ol p-toluenesulfonates previously described. (Ii) heating the obtained tosylate with 20 molar equivalents of methylamine as a 40% aqueous solution to give N-methyl-4-pentene-
The 2-amine can be obtained. (Iii) A. Viola et al. Ch
em. Soc. Chem. Commun (21): 1429 (1984), the resulting amine was reacted with 1.2 molar equivalents of di-tert-butyl dicarbonate in dry tetrahydrofuran to give the side chain N-methyl-N. −
(Tert-Butoxycarbonyl) -4-penten-2-amine can be obtained. Halo-substituted pyridines (eg 5-bromo-3-isopropoxypyridine) can be synthesized by two different routes. In one method, 3,5-dibromopyridine was present at 140 ° C. for 14 hours in the presence of 2 molar equivalents of potassium isopropoxide in dry isopropanol and copper powder (5% w / w of 3,5-dibromopyridine). Under heating in a sealed glass tube gives 5-bromo-3-isopropoxypyridine. A second method of preparing 5-bromo-3-isopropoxypyridine from 5-bromonicotinic acid can be carried out as follows: (i) 5-bromonicotinic acid is treated with thionyl chloride and then the intermediate The acid chloride of is converted to 5-bromonicotinamide by reacting with aqueous ammonia. (Ii) C.I. V. Grec
o et al. Heterocyclic Chem. 7 (4): 761 (1970)
), The resulting 5-bromonicotinamide, as previously described by), is subjected to Hofmann degradation by treatment with sodium hydroxide and 70% calcium hypochlorite solution. (Iii) C.I. V. Greco et al. Heterocyclic Ch
em. 7 (4): 761 (1970), the resulting 3-amino-5-bromopyridine was diazotized with isoamyl nitrite under acidic conditions and then the intermediate diazodium salt was removed. It can be converted to 5-bromo-3-isopropoxypyridine by treatment with isopropanol to obtain 5-bromo-3-isopropoxypyridine. Palladium-catalyzed coupling of 5-bromo-3-isopropoxypyridine and N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine was performed using acetonitrile-triethylamine (2
: 1, v, v), 1 mol% palladium (II) acetate and 4 mol% tri-
It is carried out using a catalyst consisting of o-tolylphosphine. The reaction is carried out at 80 ℃
By heating for 20 hours at (4E) -N-methyl-N- (ter
t-butoxycarbonyl) -5- (5-isopropoxy-3-pyridyl) -4-
Penten-2-amine can be obtained. Removal of the tert-butoxycarbonyl protecting group was performed by treatment with 30 molar equivalents of trifluoroacetic acid in anisole at 0 ° C. to give (4E) -N-methyl-5- (5-isopropoxy-3-
Pyridyl) -4-penten-2-amine can be obtained. A variety of N-methyl-5- (5-alkoxy or 5-aryloxy-3-pyridyl) -4-penten-2-amines from 3,5-dibromopyridine using this type of technique (ie Treatment with sodium or potassium alkoxides or aryl oxides followed by Heck coupling and deprotection).

There are various ways in which a particular aryl-substituted olefin amine compound having a branched chain may be provided. Using one synthetic approach, (4E) -N-methyl-5-
Compounds such as (5-methoxy-3-pyridyl) -4-penten-2-amine,
A halo-substituted pyridine, 5-bromo-3-methoxypyridine, could be synthesized and obtained by coupling it with an olefin having a secondary alcohol functional group, 4-penten-2-ol, under Heck reaction conditions. The pyridyl alcohol intermediate can be converted to its p-toluenesulfonic acid ester by treatment with methylamine. W. W., typically involving palladium coupling of olefins with aromatic halides. C. Frank et al. Org. Chem. 43: 2947 (
1978) and N.N. J. Malek et al. Org. Chem. 47: 539
5 (1982). The required halo-substituted pyridine, 5-bromo-3-methoxypyridine, was converted to H.C. J. den Hertog et al., Re
cl. Trav. Chim. Using a method similar to that described by Pays-Bas 67: 377 (1948), i.e. 3,5-dibromopyridine was treated with copper powder (5% of 3,5-dibromopyridine in dry methanol, w / w
) In a sealed glass tube at 150 ° C. for 14 hours by heating with 2.5 molar equivalents of sodium methoxide to produce 5-bromo-3-methoxypyridine. D. L. Comins et al. Org. Chem. 55
: 69 (1990), the resulting 5-bromo-3-methoxypyridine was treated with 4-penten-2-ol (1: 1: 1, v / v) in acetonitrile-triethylamine to give 1 Mol% palladium (II) acetate and 4 mol%
Can be coupled using a catalyst consisting of tri-o-tolylphosphine. The reaction was carried out by heating the components in a sealed glass tube at 140 ° C. for 14 hours to give (4E) -N-methyl-5- (5-methoxy-3-pyridyl) -4-penten-2-ol. To get The alcohol obtained is 2 molar equivalents of p- in dry pyridine.
Treatment with toluenesulfonyl chloride at 0 ° C., (4E) -N-methyl-5- (5
-Methoxy-3-pyridyl) -4-penten-2-ol p-toluenesulfonate is obtained. The tosylate intermediate with a small amount of ethanol as a cosolvent, 40
Treatment with 120 molar equivalents of methylamine as an aqueous solution gives (4E) -N-methyl-5- (5-methoxy-3-pyridyl) -4-penten-2-amine.
Heck coupling of 3,5-dibromopyridine with N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine under the conditions described above gave N-methyl-N- (tert-. Butoxycarbonyl) -5- (5-bromo-3-pyridyl) -4-penten-2-amine is formed. This is the subsequent H
In the eck reaction, coupling with styrene and deprotection as described previously (t
removal of ert-butoxycarbonyl group), (4E) -N-methyl-5- [3- (
5-trans-β-styrylpyridin) yl] -4-penten-2-amine is obtained. A similar second coupling with ethynylbenzene and subsequent deprotection gave (4E) -N-methyl-5- [3- (5-phenylethynylpyridine).
Ill] -4-penten-2-amine is obtained.

(2S)-(4E) -N-methyl-5- (3-pyridyl) -4-pentene-2
There are various ways in which optically active forms of certain aryl-substituted olefin amine compounds, such as amines, are provided. In one synthetic approach, the latter class of compounds was prepared by combining a halo-substituted pyridine, 3-bromopyridine, with a chiral secondary alcohol functional olefin, (2R) -4-penten-2-ol, and Heck.
Synthesized by coupling under reaction conditions. The resulting chiral pyridyl alcohol intermediate (2R)-(4E) -5- (3-pyridyl) -4-pentene-
The 2-ol is converted to its corresponding p-toluenesulfonic acid ester, which is subsequently treated with methylamine to displace the tosylate with a configuration inversion. Typically, W. W., which includes palladium-catalyzed coupling of aromatic halides and olefins. C. Frank et al. Org. Chem. 43: 2947
(1978) and N.M. J. Malek et al. Org. Chem. 47:53
95 (1982). (2R) -4- of the chiral side chain
Penten-2-ol is a chiral epoxide (R)-(+)-propylene oxide (commercially available from Fluka Chemical) in vinyl magnesium bromide in tetrahydrofuran at low temperature (-25 to -10 ° C). A. Kal
ivretenos, J .; K. Stille and L.C. S. Hegedus, J
． Org. Chem. Prepared by work up using the general synthetic method of 56: 2883 (1991) to give (2R) -4-penten-2-ol. The resulting chiral alcohol was treated with 3% in acetonitrile-triethylamine (1: 1, v / v) using a catalyst consisting of 1 mol% palladium (II) acetate and 4 mol% tri-o-tolylphosphine. -Heck reaction with bromopyridine. The reaction is carried out by heating the components at 140 ° C. for 14 hours in a sealed glass tube, which is the Heck reaction product, (2R)-(4E)-.
This produces 5- (3-pyridyl) -4-penten-2-ol. Treatment of the resulting chiral pyridyl alcohol with 3 molar equivalents of p-toluenesulfonyl chloride at 0 ° C. in dry pyridine provides the tosylate intermediate. The p-toluenesulfonic acid ester was heated with 82 molar equivalents of methylamine as a 40% aqueous solution containing a small amount of ethanol as a co-solvent to give (2S)-(4E) -N-methyl-5- (3 -Pyridyl) -4-penten-2-amine is produced.

Similarly, (2R)-(4E) -N-methyl-5- (3-pyridyl) -4-
The corresponding aryl-substituted olefin amine enantiomers, such as pentene-2-amine, are 3-bromopyridine and Hec of (2S) -4-penten-2-ol.
It can be synthesized by k-coupling. The resulting intermediate (2S)-(4E)-
5- (3-Pyridyl) -4-penten-2-ol is converted to its p-toluenesulfonate, which is subjected to methylamine displacement. Is a chiral alcohol (
2S) -4-Penten-2-ol is (S)-(−)-propylene oxide (
Commercially available from Aldrich Chemical Company). Kalivreten
os, J. K. Stille, and L.L. S. Hegedus, J. Org. C
hem. 56: 2883 (1991) as reported by (R)-(+)-.
Prepared using a procedure similar to that described for the preparation of (2R) -4-penten-2-ol from propylene oxide.

In another approach to the compounds of the present invention, (3E) -N-methyl-4- (
Compounds such as 3- (6-aminopyridin) yl) -3-buten-1-amine,
3-Halo- such as 2-amino-5-bromopyridine (Aldrich Chemical Co.)
Substituted pyridines can be prepared by subjecting them to palladium-catalyzed coupling with olefins having a protected amine functionality such as N-methyl-N- (3-buten-1-yl) benzamide. Removal of the benzoyl protecting group from the resulting Heck reaction product was carried out by heating with acidic water to give (3E) -N-methyl-
4- (3- (6-Aminopyridin) yl) -3-buten-1-amine can be obtained. The required olefin, N-methyl-N- (3-buten-1-yl)
Benzamide was prepared by adding 4-bromo-1-butene to an excess of concentrated methylamine and N, N
-N-methyl-3-buten-1-amine can be prepared by reacting in dimethylformamide in the presence of potassium carbonate. Treatment of the latter compound with benzoyl chloride in dichloromethane containing triethylamine provides the olefinic side chain N-methyl-N- (3-buten-1-yl) benzamide.

The compounds of the present invention may contain cyclic functional groups containing nitrogen atoms such as pyrrolidine or quinuclidine. There are various methods for synthesizing such compounds. In one way,
The Heck reaction can be used to couple vinyl-substituted or allyl-substituted nitrogen heterocycles to 3-halopyridines. For example, N- (tert-butoxycarbonyl) -2-allylpyrrolidine and 3-bromopyridine (Aldrich Chemical Co.) were used as W.I. C. Frank et al. Org.
Chem. 43: 2947 (1978) and N.M. J. Malek et al. Or
g. Chem. 47: 5395 (1982). Removal of the protecting groups using trifluoroacetic acid gave 2- (3- (3
-Pyridyl)-(2E) -propen-1-yl) pyrrolidine is obtained. The required N- (tert-butoxycarbonyl) -2-allylpyrrolidine is commercially available 2-
It can be prepared from pyrrolidine methanol (Aldrich Chemical Co.). 2-pyrrolidinemethanol was treated with di-tert-butyl dicarbonate to give its t
The amine is protected as an ert-butoxycarbonyl derivative. Subsequent reaction with p-toluenesulfonyl chloride in pyridine, followed by reaction with sodium iodide in acetone gives 2- (iodomethyl) -N- (tert-butoxycarbonyl) pyrrolidine. This compound can be coupled with vinylmagnesium bromide in the presence of copper iodide to give N- (tert-butoxycarbonyl) -2-allylpyrrolidine. Enantiopure 2-
The use of pyrrolidinemethanol (both the R and S isomers are obtained from Aldrich Chemical Company) prepares each enantiomer of N- (tert-butoxycarbonyl) -2-allylpyrrolidine. Subsequent reactions outlined above prepare each enantiomer of 2- (3- (3-pyridyl)-(2E) -propen-1-yl) pyrrolidine. The secondary amino compound was prepared according to the method of M.M., using formaldehyde and aqueous sodium cyanoborohydride. A. Abreo et al., J
． Med. Chem. 39: 817-825 (1996) and N-methylated using a method similar to that described by 2- (3- (3-pyridyl)-.
Each enantiomer of (2E) -propen-1-yl) -1-methylpyrrolidine can be obtained.

Similarly, when 2-allylquinuclidine is coupled with 3-bromopyridine under Heck conditions, 2- (3- (3-pyridyl)-(2E) -propene-1-
Il) quinuclidine can be obtained. The required 2-allylquinuclidine is 3
-Can be prepared from quinuclidinone (Aldrich Chemical Company) by alkylation and deoxygenation. Thus, 3-quinuclidinone can be converted to its isopropylimine using isopropylamine and molecular sieves. Treatment of the imine with lithium diisopropylamide and allyl bromide, followed by hydrolysis,
2-allyl-3-quinuclidinone is obtained. Deoxygenation by conversion of the ketone to its p-toluenesulfonylhydrazone and reduction with sodium borohydride gives 2-allylquinuclidine.

The compounds of the invention may contain a pyrazine or pyradazine ring. M. Haseg
2-Methylpyrazine or 3-methylpyrazine (both available from Aldrich Chemical Co.) was added to N-methyl-N- (tert- using the procedure reported by Awa et al. When condensed with butoxycarbonyl) -3-aminobutanal, (4E) -N-methyl-N
-(Tert-Butoxycarbonyl) -5- (2-pyrazinyl) -4-penten-2-amine and (4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (3-pyridazinyl) -4 -Penten-2-amine can be obtained respectively. Removal of the tert-butoxycarbonyl group with trifluoroacetic acid gave (4E) -N-methyl-5- (2-pyrazinyl) -4-penten-2-amine and (4E) -N-methyl-5- (3. -Pyridazinyl) -4-pentene-2
-Amine is obtained respectively. The required N-methyl-N- (tert-butoxycarbonyl) -3-aminobutanal can be obtained from the corresponding alcohols in PCT International Patent Application WO 9212122 by M.P. Adamczyk and Y. Y. It can be manufactured using the technique described by Chen. Alcohol, N-methyl-N
-(Tert-Butoxycarbonyl) -3-amino-1-butanol was prepared by continuous reductive amination (Org. Syn. 52, 124 (1974) from commercially available 4-hydroxy-2-butanone (Lancaster Synthesis Co.). At R. F. Borch
By using methylamine and sodium cyanoborohydride) and protection with di-tert-butyl dicarbonate.

Methods of preparing a particular compound of the invention vary. For example, a compound having a specific fused ring heterocycle can be prepared by the Heck reaction. Such compounds are
A bromoheterocyclic compound such as 6-bromo-2-methyl-1H-imidazo [4,5-b] pyridine and the previously described olefin amine side chain N-methyl-N.
It can be synthesized by palladium-catalyzed coupling of-(tert-butoxycarbonyl) -4-penten-2-amine. W. W., typically involving palladium-catalyzed coupling of olefins with aromatic halides. C. Frank et al. Org
． Chem. 43: 2947 (1978) and N.M. J. Malek et al. O
rg. Chem. 47: 5395 (1982), a type of procedure is used for the coupling reaction. The resulting tert-butoxycarbonyl protected (Boc protected) intermediate was treated with a strong acid such as trifluoroacetic acid to give (4E) -N-methyl-5- (6- (2-methyl-1H-imidazo [4 , 5-b] Pyridin) yl) -4-penten-2-amine can be obtained. The required bromo-imidazopyridine, 6-bromo-2-methyl-1H-imidazo [4,5-b] pyridine, was obtained from 2,3-diamino-5-bromopyridine with polyphosphoric acid in a yield of 82%. With acetic acid in the medium, P. K. Dubay et al., Indian J. Chem. 16B (6
): 531-533 (1978). 2,3-diamino-5-bromopyridine was obtained in a yield of 97%.
2-Amino-5-bromo-3-nitropyridine (commercially available from Aldrich Chemical Co. and Lancaster Synthesis Co.) with tin (II) chloride dihydrate in boiling ethanol in S. X. Cai et al. Med. Chem. 40 (
22): 3679-3686 (1997) by heating according to the technique described.

In another example, a bromo-fused ring heterocycle such as 6-bromo-1,3-dioxolo [4,5-b] pyridine is substituted with the previously described olefin amine side chain N-methyl-N. -(Tert-butoxycarbonyl) -4-penten-2-amine and H
The eck reaction can be used to couple. The resulting Boc protected intermediate was deprotected with a strong acid such as trifluoroacetic acid to give (4E) -N-methyl-5- (6- (1
, 3-Dioxolo [4,5-b] pyridin) yl) -4-penten-2-amine can be prepared. The required bromo compound, 6-bromo-1,3-dioxolo [4
, 5-b] Pyridine is treated with 5-bromo- via a methyleneation procedure using bromochloromethane in the presence of potassium carbonate and N, N-dimethylformamide.
5-bromo-2, also known as 3-hydroxy-2 (1H) -pyridinone,
From 3-dihydroxypyridine, F.I. Dallacker et al., Z. Nature
orsch 34b: 1729 to 1736 (1979). 5-Bromo-2,3-dihydroxypyridine is obtained from furfural (2-furaldehyde, commercially available from Aldrich Chemical Co. and Lancaster Synthesis Co.) from F.F. Dallacker et al., Z. Natureforsch 3
4b: 1729-1736 (1979). Separately, 5-bromo-2,3-dihydroxypyridine was prepared from D.I. Rose and N.N. It can be prepared according to the technique described in Maak EP0081745.

Another example of a compound having a fused ring heterocycle is a bromo compound, 7-bromo-2,3-dihydro-1,4-dioxino [2,3-b] pyridine (7-bromo-5 -Also known as aza-4-oxachroman) using the Heck reaction with the olefin amine side chain N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine described previously. Can be condensed. The resulting Boc-protected compound was deprotected with a strong acid such as trifluoroacetic acid to give (4E) -N-methyl-
5- (7- (2,3-dihydro-1,4-dioxino [2,3-b] pyridine)
Il-4-penten-2-amine can be produced. 7- which is a necessary bromo compound
Bromo-2,3-dihydro-1,4-dioxino [2,3-b] pyridine is 5
-Bromo-2,3-dihydroxypyridine was treated with 1,2-dibromoethane and potassium carbonate in N, N-dimethylformamide in F.I. Dallacker et al., Z. Natureforsch. 34: 1729-1736 (1979). 5-Bromo-2,3-dihydroxypyridine can be prepared from furfural as described above.

Other polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction. Thus, certain compounds are 6-bromo-1H-imidazo [4,5-b] pyridine-2-
It can be synthesized by a palladium-catalyzed coupling of a bromo fused ring heterocycle such as a thiol with an olefin amine side chain N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine as previously described. When the Boc-protected intermediate obtained from the Heck reaction is subjected to treatment with a strong acid such as trifluoroacetic acid, (
4E) -N-methyl-5- (6- (2-thio-1H-imidazo [4,5-b] pyridin) yl) -4-penten-2-amine can be produced. The required bromo compound, 6-bromo-1H-imidazo [4,5-b] pyridine-2-thiol, is
6-Bromo-1H-imidazo [4,5-b] pyridine with sulfur at 230-260
C., Y. M. Yutilov, Khim. Geterotsikl Doed
in 6: 799-804 (1988). 6-Bromo-1H-imidazo [4,5-b] pyridine can be obtained from Sigma-Aldrich Chemical Company. Separately, 6-bromo-1H
-Imidazo [4,5-b] pyridine was prepared by reacting 2,3-diamino-5-bromopyridine with formic acid and polyphosphoric acid in P.I. K. Dubay et al., Indian J. Ch
em. 16B (6): 531-533 (1978) and can be prepared by treatment using a method similar to that described. 2,3-Diamino-5-bromopyridine is a 97% yield of 2-amino-5-bromo-3-nitropyridine (commercially available from Aldrich Chemical and Lancaster Synthesis) with tin chloride ( II) dihydrate and S. X. Cai et al. Med. Chem. 40 (22): 3679-3686 (1997) by heating according to the technique described. Alternatively, 6-bromo-1H-imidazo [4,5-b] pyridine-2-thiol was prepared by treating 2,3-diamino-5-bromopyridine with K ⁺ -SCSOEt in ethanolic water in T.
C. Kuhler et al. Med. Chem. 38 (25): 4906-491.
6 (1995) by heating using a method similar to that described. 2,3-diamino-5-bromopyridine has the same 2
It can be prepared from -amino-5-bromo-3-nitropyridine.

In a related example, 6-bromo-2-phenylmethylthio-1H-imidazo [4
, 5-b] Pyridine can be coupled via the Heck reaction with the previously described olefinamine side chain N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine. The resulting Boc protected intermediate is subjected to treatment with a strong acid such as trifluoroacetic acid to give (4E) -N-methyl-5- (6-
(2-Phenylmethylthio-1H-imidazo [4,5-b] pyridin) yl)-
4-Penten-2-amine can be produced. The required bromo compound, 6-bromo-2-phenylmethylthio-1H-imidazo [4,5-b] pyridine, is the previously described 6-bromo-1H-imidazo [4,5-b] pyridine-2- The thiol can be prepared by alkylation with benzyl bromide in the presence of potassium carbonate and N, N-dimethylformamide.

In another example, 6-bromooxazolo [4,5-b] pyridine is N
Upon palladium-catalyzed coupling to -methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine and deprotection with trifluoroacetic acid, (4E) -N-methyl-5- (6- Oxazolo [4,5-b] pyridinyl)-
4-Penten-2-amine is obtained. Required 6-Bromooxazolo [4,5-
b] Pyridine is prepared from 2-amino-5-bromo-3-pyridinol by condensation with MC or formic acid or trialkylorthoformic acid. Viaud et al., Hetero
It can be prepared using a method similar to cycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo [4,5-b] pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Co.). Therefore, 5-bromo-3-pyridinol (prepared from furfurylamine as described in U.S. Pat. No. 4,192,946) was used to Koch
Et al., Synthesis, 499 (1990), can be chlorinated to give 2-chloro-5-bromo-3-pyridinol which is then treated with ammonia to give 2-chloro-5-bromo-3-pyridinol. Amino-5-bromo-3-pyridino-
Can be converted to

5-Bromooxazolo [5,4-b] pyridine, which is isomeric due to the orientation of the ring condensation to 6-bromooxazolo [4,5-b] pyridine described previously, also
For Heck coupling, N-methyl-N- (tert-butoxycarbonyl)
Can be used with -4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group resulted in (4E) -N-methyl-5- (5-oxazolo [
5,4-b] Pyridinyl) -4-penten-2-amine is provided. 5 required
-Bromooxazolo [5,4-b] pyridine is 3-amino-5-bromo-2-
It is synthesized from pyridinol (3-amino-5-bromo-2-pyridone) by condensation with formic acid (or a derivative thereof) as described above. 3-amino-5-bromo-2-pyridinol is a commercially available bromination of 3-nitro-2-pyridinol (Aldrich Chemical Co.) (T. Batkowski, Rocz. Chem.
41: 729-741 (1967)) followed by tin (II) chloride reduction (SX Cai et al., J. Med. Chem. 40 (2).
2): 3679-3686 (1997)).

Other polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction. Therefore, 5-bromofuro [2,3-b] pyridine and 5-bromo-1H-pyrrolo [
Both 2,3-b] pyridines are N-, which are the olefinic side chains previously described.
Following palladium-catalyzed coupling with methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine, (4E) -N-methyl-N- (tert.
-Butoxycarbonyl) -5- (5-furo [2,3-b] pyridinyl) -4-penten-2-amine and (4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (5 -1H-pyrrolo [2,3-b] pyridinyl) -4-penten-2-amine can be obtained respectively. Subsequent removal of the tert-butoxycarbonyl group with trifluoroacetic acid gave (4E) -N-methyl-5-
(5-furo [2,3-b] pyridinyl) -4-penten-2-amine and (4
E) -N-methyl-5- (5-1H-pyrrolo [2,3-b] pyridinyl) -4
-Penten-2-amine is provided. The required 5-bromofuro [2,3-b] pyridine and 5-bromo-1H-pyrrolo [2,3-b] pyridine are 2,3-
Dihydrofuro [2,3-b] pyridine and 2,3-dihydropyrrolo [2,3
-B] pyridine by bromination (bromine and sodium bicarbonate in methanol) and dehydrogenation (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), respectively, to give E. C. Taylor et al., Tetrahedron 43:51.
45-5158 (1987).
2,3-Dihydrofuro [2,3-b] pyridine and 2,3-dihydropyrrolo [2,3-b] pyridine were then prepared from 2-chloropyrimidine (Aldrich Chemical Co.) from A. E. Frissen et al., Tetrahedron 45: 8.
03-812 (1989) as described by Nucleophilic Substitution of Chlorides (
It is prepared by using the sodium salt of 3-butyn-1-ol or 4-amino-1-butyne) and subsequent intramolecular Diels-Alder reaction. Using similar chemistries, 2,3-dihydrofuro [2,3-b] pyridine and 2,3-dihydropyrrolo [2,3-b] pyridine are also 3-methylthio-1,2,4-. Triazene (EC Taylor et al., Tetrahedron 43: 5145-.
5158 (1987)), which is then glyoxal and S-methylthiosemicarbazide (W. Paudler et al., J. Heterocycle).
c Chem. 7: 767-771 (1970)).

Brominated dihydrofuropyridine, dihydropyrrolopyridine and dihydropyranopyridine are also substrates for palladium catalyzed coupling. For example, 5-bromo-2,3-dihydrofuro [2,3-b] pyridine and 5-bromo-2,3-dihydropyrrolo [2,3-b] pyridine (as described above, 2,3-dihydrofuro). Both [2,3-b] pyridine and 2,3-dihydropyrrolo [2,3-b] pyridine (from bromination) can be coupled with the previously described olefinamine side chains in the Heck process. . Corresponding by subsequent deprotection (4E)
-N-methyl-5- (5- (2,3-dihydrofuro [2,3-b] pyridin) yl) -4-penten-2-amine and (4E) -N-methyl-5- (5- ( Two
, 3-Dihydropyrrolo [2,3-b] pyridin) yl) -4-pentene-2-
The amine is obtained. By similarly treating 6-bromo-2,3-dihydrofuro [3,2-b] pyridine (isomerically ring-fused with the [2,3-b] system),
(4E) -N-methyl-5- (6- (2,3-dihydrofuro [3,2-b] pyridin) yl) -4-penten-2-amine is provided. Required 6-Bromo-2
, 3-Dihydrofuro [3,2-b] pyridine is 5-bromo-2-methyl-3-
It can be prepared from pyridinol by sequential treatment with 2 equivalents of lithium diisopropylamide (producing 2-methylenyl, 3oxydianion) and 1 equivalent of dibromomethane. Separately, M. U. Koller et al., Synth. Comm
un. 25: 2963-74 (1995), using a chemistry similar to that described in silyl protected pyridinol (5-bromo-2-methyl-3-trimethylsilyloxypyridine), 1 equivalent of lithium diisopropylamide and alkyl. Alternatively, successive treatments with aryl aldehydes can produce 2- (2- (1-alkyl- or 1-aryl-1-hydroxy) ethyl) -5-bromo-3- (trimethylsilyloxy) pyridine. Such materials are prepared by methods known to those skilled in the art (eg acid catalyzed cyclisation or Williamson synthesis) to the corresponding cyclic ethers (2-alkyl- or 2-aryl-6-bromo-2,3-dihydrofuro [ 2,2-b] pyridines can be converted to 2-alkyl- and 2-aryl-7-bromo-2,3 by a similar chemistry using an epoxide (instead of an aldehyde) for reaction with pyridylmethyl carbanion. -Dihydropyrano [3,2-
b] Pyridine is obtained. These 2-substituted and brominated dihydrofuro- and dihydropyranopyridines are also substrates for the Heck reaction. For example, 6-bromo-2,3-dibromo-2-phenylfuro [3,2-b] pyridine is N-methyl-N- (tert-butoxycarbonyl) -4-in a palladium catalyzed process.
It can be coupled with penten-2-amine and the coupled product is treated with trifluoroacetic acid (on removal of the tert-butoxycarbonyl group) to give (4E)-
N-methyl-5- (6- (2,3-dihydro-2-phenylfuro [3,2-b]
Pyridin) yl) -4-penten-2-amine is obtained.

Required for the synthesis of brominated dihydrofro- and dihydropyranopyridines,
5-Bromo-2-methyl-3-pyridinol is prepared by standard conversion of commercially available material. Therefore, 2-methylnicotinic acid (Aldrich Chemical Company)
Thionyl chloride, bromine and ammonia (C. V. Greco et al., J. Heter.
ocyclic Chem. 7: 761-766 (1970)) can be converted to 5-bromo-2-methylnicotinamide. 5-bromo-
By the Hofmann rearrangement of 2-methylnicotinamide with hypochlorite, 3-
Amino-5-bromo-2-methylpyridine is obtained, which can be converted to 5-bromo-2-methyl-3-pyridinol by diazotization with sodium nitrate in sulfuric acid. Separately, alanine ethyl ester (Aldrich Chemical Co.)
Converted to its N-formyl derivative (using ethyl formate), which then
Converted to 5-ethoxy-4-methyloxazole using phosphorous oxide (N.
Takeo et al., Japanese Patent Publication No. 45-012732). The Diels-Alder reaction of 5-ethoxy-4-methyloxazole with acrylonitrile gives 5-hydroxy-5-methylnicotine nitrile (T. Yoshikawa et al., Ch.
em. Pharm. Bull. 13: 873 (1965)), which is converted to 5-amino-2-methyl-3-pyridinol by hydration (nitrile to amide) and Hoffmann rearrangement (Y. Morisawa et al., Agr. Biol. Chem.
． 39: 1275-1281 (1975)). 5-Amino-2-methyl-3-pyridinol can then be converted to the desired 5-bromo-2-methyl-3-pyridinol by diazotization in the presence of copper bromide.

Alternatively, the aryl-substituted olefin amine compounds of the present invention can be prepared by coupling an aryl protected lithium with an N-protected amino aldehyde such as 4- (N-methyl-N- (tert-butoxycarbonyl) amino) pentanal. The required aldehydes are described by Otsuka et al. Am. Chem. Soc. 112: 838
~ 845 (1990), commercially available 1,5-dimethyl-2
It can be prepared starting from pyrrolidinone (Aldrich Chemical Company). Therefore,
By heating 1,5-dimethyl-2-pyrrolidinone with 6N hydrochloric acid, 4
-(Methylamino) pentanoic acid is formed, which can be easily esterified to ethyl 4- (methylamino) pentanoate. The latter compound has 1 equivalent of di-te
Upon treatment with rt-butyl dicarbonate, 4- (N-methyl-N- (tert
Ethyl-butoxycarbonyl) amino) pentanoate can be obtained which is then reduced with DIBAL to give 4- (N-methyl-N- (tert-butoxycarbonyl) amino) pentanal. Reaction of this aldehyde with aryllithium yields an alcohol, which subsequently converts the alcohol to an alkyl halide (eg, with carbon tetrachloride and triphenylphosphine), followed by dehydrohalogenation (1,2). 8-diazabicyclo [5.4.0] undec-7-ene) can be used to convert to the N-protected olefin amine. te
Removal of the rt-butoxycarbonyl protecting group with trifluoroacetic acid afforded the desired (E
) -5-Aryl-4-penten-2-amine is obtained. Therefore, 3-lithio-5-isopropoxypyridine (from 3-bromo-5-isopropoxypyridine and n-butyllithium) is condensed with 4- (N-methyl-N- (tert-butoxycarbonyl) amino) pentanal. Then 1- (3- (5-isopropoxypyridin) yl) -4- (N-methyl-N- (tert-butoxycarbonyl) amino) -1-pentanol can be obtained, which in turn is (4E)-
It can be converted to N-methyl-5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine.

The R and S enantiomers of 1,5-dimethyl-2-pyrrolidinone can be prepared from commercially available (R)-and (S) -5- (hydroxymethyl) -2-pyrrolidinone (Aldrich Chemical Co.). Thus, reaction of enantiopure hydroxymethylpyrrolidinone with carbon tetrabromide and triphenylphosphine in acetonitrile yielded the corresponding 5- (bromomethyl) -2-pyrrolidinone (Pf
altz et al., Helv. Chim. Acta 79: 961 (1996)), which is reduced to 5-methylpyrrolidinone by tri-n-butyltin hydride in toluene (Otsuka et al., J. Amer. Chem. Soc.
． 112: 838 (1990)). Subsequent methylation with sodium hydride and methyl iodide in tetrahydrofuran gives enantiopure 1,5-dimethyl-2-pyrrolidinone.

There are various methods for synthesizing enantiomerically pure 4- (N-methyl-N- (tert-butoxycarbonyl) amino) pentanal. Schessinge
r et al., Tetrahedron Lett. 28: 2083-2086 (198)
N-Methyl-L-alanine or N-methyl-D-alanine (commercially available from Sigma) was continuously treated with lithium aluminum hydride (corresponding N -Methylaminopropanol is obtained), di-tert-butyldicarbonate (protecting the amino group), and p-toluenesulfonyl chloride (esterifying the alcohol). Obtained (S)-or (R) -1-p-toluenesulfonyloxy-N-methyl-N-
Alkylation of lithium acetylide using (tert-butoxycarbonyl) -2-propanamine to give the corresponding (S)-or (R) -N-methyl-N
It is possible to obtain-(tert-butoxycarbonyl) -4-pentyn-2-amine. These are then described in H.264. C. Brown et al. Amer. Chem.
Soc. 97: 5249 (1975) for hydroboration and oxidation.

The fused ring heterocycle is also lithiated to give 4- (N-methyl-N- (tert-
It can be condensed with butoxycarbonyl) amino) pentanal. For example, 6-chloro-2-phenylfuro [3,2-b] pyridine is treated sequentially with n-butyllithium and 4- (N-methyl-N- (tert-butoxycarbonyl) amino) pentanal. , 1- (6- (2-phenylfuro [3,2-b] pyridine)
Yl) -4- (N-methyl-N- (tert-butoxycarbonyl) amino)-
1-Pentanol can be obtained. Conversion of the alcohol to an alkyl halide followed by dehydrohalogenation and deprotection gives (4E) -N-methyl-5.
-(6- (2-phenylfuro [3,2-b] pyridin) yl) -4-pentene-
The 2-amine is obtained. A. Reaction of 5-chloro-2-iodo-3-pyridinol with phenylacetylene in the presence of palladium (II) acetate and copper iodide. The required 6-chloro-2-phenylfuro [3,2-b] was prepared using a method similar to that described by Arcadi et al., Synthesis, 749 (1986).
Pyridine can be produced. 5-chloro-2-iodo-3-pyridinol was then added to V.I. It can be prepared by iodination of commercially available 5-chloro-3-pyridinol (Aldrich Chemical Co.) using the method described by Koch et al., Synthesis, 497 (1990).

The present invention relates to methods of providing prevention of a condition or disease to a subject susceptible to such a condition or disease, and methods of providing treatment to a subject suffering from it. For example, the method provides a patient with an amount of a compound effective to provide some degree of prevention (ie, providing a protective effect) of CNS disease progression, amelioration of symptoms of CNS disease, and amelioration of relapse of CNS disease. Including administration. The method comprises administering an effective amount of a compound selected from the above general formula. The present invention relates to pharmaceutical compositions incorporating a compound selected from the general formula shown above.
The optically active compounds can be used as a racemic mixture or as an enantiomer. The compounds can be used in the free base form or salt forms (for example as pharmaceutically acceptable salts). Examples of suitable pharmaceutically acceptable salts are inorganic acid addition salts, for example hydrochlorides, hydrobromides, sulphates, phosphates and nitrates, and organic acid addition salts, For example, acetate, galactate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluene. Sulfonates, ascorbates and salts with acidic amino acids, such as aspartates and glutamate, alkali metal salts such as sodium and potassium salts, and alkaline earth metal salts such as magnesium salts and Calcium salts, ammonium salts, and organic basic salts such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, Cyclohexylamine salt, and N, and N'- Jin dibenzylethylenediamine salt, further comprising the salts with basic amino acids, such as lysine salt and arginine salt. These salts may in some cases be hydrates or ethanol solvates. US Pat. No. 5,597,9 to Dull et al.
Representative salts as described in No. 19, Dull et al., 5,616,716, and Ruecroft et al., No. 5,663,356 are provided.

The compounds of the present invention are also useful in conditions and disorders of the type where other types of nicotine compounds are proposed as therapeutic agents. For example, Williams et al., DN & P
7 (4): 205-227 (1994), Arneric et al., CNS Drug.
Rev. 1 (1) 1: 1 to 26 (1995), Arneric et al., Exp. O
pin. Invest. Drugs 5 (1): 79-100 (1996), B
encherif et al., JPET 279: 1413 (1996), Lippie.
Ilo et al., JPET 279: 1422 (1996), Damaj et al., Neur.
Oscience (1997), Holladay et al., J. Am. Med. Chem.
40 (28): 4169-4194 (1997), Bannon et al., Science.
279: 77-80 (1998), PCT WO94 / 08992, PC
T WO 96/31475, and Bencherif et al., US Pat. No. 5,58.
See 3,140, Dull et al., 5,597,919, and Smith et al., 5,604,231. The compounds of the present invention can be used as analgesics to treat ulcerative colitis or convulsions, a symptom of epilepsy. CNS diseases that can be treated by the present invention include presenile dementia (early onset Alzheimer's disease) and senile dementia (
Alzheimer-type dementia), Parkinson's syndrome including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperactivity, mania, attention deficit, anxiety, dyslexia, schizophrenia and Tourette's syndrome.

The pharmaceutical composition may include various other ingredients as additives or auxiliaries. Examples of pharmaceutically acceptable ingredients or adjuvants used in relevant settings include antioxidants, free radical scavengers, peptides, growth factors, antibiotics, bacteriostats, immunosuppressants, anticoagulants, Includes buffers, anti-inflammatory agents, antipyretics, time release binders, anesthetics, steroids and corticosteroids. Such ingredients may provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or protect against any potential side effects that may be imposed as a result of administration of the pharmaceutical composition. Can act like In certain circumstances, the compounds of the invention may be used as part of a pharmaceutical composition with other compounds for the purpose of preventing or treating the particular disease.

There are various methods of administering the compound. The compounds may be administered topically (eg, in a lotion form) by inhalation (eg, in the form of an aerosol to the nasal cavity or using a delivery article of the type shown in Brooks et al., US Pat. No. 4,922,901). Orally (eg, in a solvent such as an aqueous or non-aqueous liquid, or in liquid form in a solid carrier), intravenously (eg, in dextrose or saline solution), as an infusion or infusion (eg, It can be administered as a suspension in a pharmaceutically acceptable liquid or liquid mixture or as an emulsion), by intrathecal injection, intraventricularly intracerebroventricularly, or transdermally (eg, using a transdermal patch). While it is possible for a compound to be administered in the form of an active chemical mass, it is preferable to present each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration. Examples of methods of administering such compounds are known to those of skill in the art. For example, the compounds can be administered in the form of tablets, hard gelatin capsules or as time-release capsules. As another example, the compounds can be delivered transdermally using a type of patch technology available from Novartis and Alza. Administration of the pharmaceutical composition of the present invention, to a homeothermic animal (for example, a mammal such as mouse, rat, cat, rabbit, dog, pig, cow or monkey),
It may be intermittent or stepwise, continuous, constant or controlled rate, but is advantageously administered to humans. Further, the time of day and the number of times per day that the pharmaceutical preparation is administered varies. Administration is preferably such that the active ingredient of the pharmaceutical formulation is C
It interacts with the receptor site in the body of the subject that affects the function of NS. More particularly, in the treatment of CNS disorders, administration preferably optimizes effects on related receptor subtypes that have an effect on CNS function while minimizing effects on muscle type receptor subtypes. It is a thing. Other suitable methods for administering the compounds of the present invention are described in Smith et al., US Pat.
No. 231, the disclosure of which is incorporated herein by reference.

A suitable dose of the compound is an amount effective to prevent the onset of symptoms of the disease or to treat some symptoms of the disease affecting the patient. By "effective amount,""therapeuticamount," or "effective dose amount" is meant an amount that elicits the desired pharmacological or therapeutic effect, thus effecting effective prevention or treatment of the disease. Thus, when treating a CNS disorder, an effective amount of a compound crosses the subject's blood-brain barrier, binds to relevant receptor sites in the subject's brain, and activates relevant nicotine receptor subtypes (eg,
A sufficient amount to provide neurotransmitter secretion, thus providing effective prevention or treatment of the disease. Prevention of the disease manifests by delaying the onset of symptoms of the disease. Treatment of a disease manifests by a reduction in the symptoms associated with the disease or an amelioration of the recurrence of the symptoms of the disease.

Effective doses may vary depending on such factors as the patient's condition, the severity of the symptoms of the disease, and the manner in which the pharmaceutical composition is administered. For human patients, an effective dose of a typical compound will generally activate a related receptor to activate a neurotransmitter (eg, dopamine).
It is necessary to administer a sufficient amount of the compound to effect release, but the amount should be insufficient to induce effects on skeletal muscle and ganglia to any significant degree. Effective doses of compounds will, of course, vary from patient to patient, but in general, C
Including the amount at which the NS effect or other desired therapeutic effect begins to occur, but below the amount at which muscle action is observed.

Typically, an effective dose of the compound generally requires administering an amount of the compound less than 5 mg / kg (patient body weight). Often, the compound of the invention is about 1
less than mg / kg (patient weight), usually less than about 100 μg / kg (patient weight), but often less than about 10 μg to 100 μg / kg (patient weight), preferably about 10 μg to about 50 μg / kg (patient weight) Dose. Preferred compounds of the present invention that do not induce an action on muscle type nicotine receptors at low concentrations,
An effective dose is less than 5 mg / kg (patient body weight), and often such compounds are administered in amounts from 50 μg to less than 5 mg / kg (patient body weight). The effective doses are typically presented as the dose administered as a single dose or as one or more doses administered over 24 hours.

For human patients, an effective dosage of typical compounds will generally be at least about 1.
Often, it will be necessary to administer an amount of the compound of at least about 10, and frequently at least about 25 μg / 24 hours / patient. For human patients, an effective dosage of typical compounds will include administering no more than about 500, often no more than about 400, and often no more than about 300 μg / 24 hours / patient. Moreover, administration of an effective dose is such that the compound concentration in the patient's plasma is usually no more than 500 ng / ml, and often no more than 100 ng / ml.

Compounds useful according to the methods of the present invention are capable of crossing the blood-brain barrier of a patient. Thus, such compounds can penetrate the central nervous system of a patient. The log P values for typical compounds useful in the practice of this invention are generally about 0 or greater, often about 0.5 or greater,
Frequently about 1 or more. The logP values for such typical compounds are generally:
It is less than about 3.5, often less than about 3, and sometimes less than about 2.5. The LogP value is
It provides an indication of a compound's ability to cross a diffusion barrier such as a biological membrane. Hansch
Et al., J. Med. Chem. 11: 1 (1968).

Compounds useful according to the methods of the invention are capable of binding to and causing activation of nicotinic cholinergic receptors (eg, those that regulate dopamine release) in the brain of a patient in most circumstances. Therefore, such a compound may act as a nicotine agonist, which expresses nicotine pharmacological action. Receptor binding constants for typical compounds useful in the practice of the present invention are generally greater than about 1.0 nM, often greater than about 1 nM, and often greater than about 10 nM. Receptor binding constants for such exemplary compounds are generally less than about 1 μM, often less than about 100 nM, and often less than about 50 nM. Receptor binding constants provide an indication of a compound's ability to bind to half of the relevant receptor sites on a patient's specific brain cells. Cheng et al., Bioc
hem. Pharmacol. 22: 3099 (1973).

Compounds useful in accordance with the methods of the present invention effectively induce ionic influx and / or neurotransmitter secretion from nerve ending preparations (eg, thalamus or striatal synaptosomes), thereby exerting nicotine function. I can prove it. Thus, such compounds cause the associated nerves to become activated, acetylcholine,
It can release dopamine or other neurotransmitters. In general, typical compounds useful in the practice of this invention will be at least about 30%, often at least about 50%, and often at least about 75% of the amount maximally provided by (S)-(−)-nicotine. Efficiently provides relevant receptor activation in the amount of%. In general, typical compounds useful in the practice of the present invention will induce (S)-(-
) -More powerful than nicotine. In general, a typical compound useful in the practice of the present invention is at least about 50 in an amount maximally provided by (S)-(−)-nicotine.
%, Often at least about 75%, and often at least about 100%, efficiently providing secretion of dopamine. Certain compounds of the invention may provide secretion of dopamine in amounts that may exceed that maximally provided by (S)-(−)-nicotine. In general, typical compounds useful in the practice of the present invention are less potent than (S)-(−)-nicotine in inducing neurotransmitter secretion, such as dopamine secretion.

The compounds of the present invention are not capable of inducing human muscle nicotine receptor activation to any significant extent when used in effective amounts according to the methods of the present invention. In this respect, the compounds of the present invention demonstrate poor ability to cause isotopic rubidium ion influx through nicotine receptors in cell preparations expressing muscle type nicotinic acetylcholine receptors. Thus, such compounds have extremely high (ie, greater than or equal to about 100 μM) receptor activation constants or EC50 values (ie, concentrations of the compound required to activate half of the relevant receptor sites in the patient's skeletal muscle). Provide an indicator). In general, typically preferred compounds useful in the practice of this invention are S
(-) Activates the isotope rubidium ion influx less than 10%, often less than 5% of the amount maximally provided by nicotine.

The compounds of the invention, when used in an effective amount according to the methods of the invention, are selective for certain related nicotine receptors but have significant activation of the receptors associated with undesirable side effects. Does not cause. By this is meant that the dose of the particular compound that results in the prevention and / or treatment of CNS disorders is substantially ineffective at inducing the activation of certain ganglion-type nicotine receptors. This selectivity of the compounds of the invention for receptors involved in cardiovascular side effects is demonstrated by the inability of these compounds to activate the nicotine function of adrenal chromaffin tissue. Therefore, such compounds are less capable of causing isotopic rubidium ion influx through the nicotine receptor in cell preparations obtained from the adrenal gland. In general, typical preferred compounds useful in the practice of the present invention activate the isotopic rubidium ion influx less than 10%, and often less than 5% of the amount maximally provided by S (−) nicotine.

The compounds of the invention, when used in an effective amount according to the methods of the invention, provide some prevention of progression of CNS disease, amelioration of symptoms of CNS disease, and some amelioration of recurrence of CNS disease. It is effective for However, such an effective amount of the compound is sufficient to elicit any discernible side effects, as demonstrated by a reduced effect on the specimen that is believed to reflect effects on the cardiovascular system or on skeletal muscle. is not. Thus, administration of the compounds of the present invention provides a treatment window for certain CNS disorders and provides a therapeutic window in which side effects are avoided. That is, an effective amount of a compound of the invention is sufficient to provide the desired effect on the CNS,
Insufficient to provide undesired side effects (ie not high enough levels). Preferably, effective administration of a compound of the invention that results in the treatment of a CNS disorder is less than 1/3 of an amount sufficient to cause any side effects to a significant extent,
Frequently less than 1/5, often less than 1/10, occurs with administration.

The pharmaceutical composition of the present invention can be used for the prevention or treatment of certain other conditions, diseases and disorders. Examples of such diseases and disorders are inflammatory bowel disease, acute cholangitis, aphthous stomatitis, arthritis (eg rheumatoid arthritis and osteoarthritis), neurodegenerative diseases,
It includes cachexia secondary to infection (such as occurs in AIDS, AIDS-related complications and neoplasia), as well as the symptoms set forth in PCT WO 98/25619. The pharmaceutical composition of the present invention can be used for ameliorating the symptoms associated with their conditions, diseases and disorders. Accordingly, the pharmaceutical composition of the present invention is useful for treating genetic diseases and disorders, for treating autoimmune diseases such as lupus, and as an anti-infective agent (eg, bacterial, fungal and viral infections, and other types such as sepsis). For the action of the toxins of E. coli, as an anti-inflammatory agent (eg, for the treatment of acute cholangitis, aphthous stomatitis, asthma and ulcerative colitis), and as an inhibitor of cytokine release (eg, cachexia, inflammation). ,
Can be used (as desired in the treatment of neurodegenerative diseases, viral infections and neoplasia). The compounds of the present invention can also be used as adjuvant therapy in combination with existing therapeutic agents for the management of the above-mentioned types of diseases and disorders. In such situations, administration preferably results in an effect on the abnormal cytokine production while the active ingredient of the pharmaceutical formulation has a minimal effect on receptor subtypes such as those associated with muscle and ganglion. To act to optimize. Administration is preferably such that the active ingredient interacts with the area where cytokine production is affected or occurs. In treating such conditions or disorders, the compounds of the invention are very potent (ie, affect cytokine production and / or secretion at very low concentrations) and highly efficacious (ie, cytokine production). And / or significantly inhibit secretion to a relatively high degree).

The effective dose for such applications is most preferably the very low concentration at which maximum effect is observed. The concentration, determined as the amount of compound per volume of relevant tissue, typically provides an indication of the extent to which the compound affects cytokine production. Typically, an effective dose of the compound is generally 100 μg / k
It is necessary to administer an amount of the compound that is much less than g (patient body weight), or even less than 10 μg / kg (patient body weight). The effective doses are typically presented as the dose administered as a single dose or as one or more doses administered over 24 hours.

In human patients, an effective dosage of typical compounds will generally be at least about 1.
Often, it will be necessary to administer an amount of the compound of at least about 10, and frequently at least about 25 μg / 24 hours / patient. In human patients, an effective dose of a typical compound is generally no more than about 1, often no more than about 0.75, often no more than about 0.5, often about 0.25 mg / 24 hours / It is necessary to administer a compound that does not exceed the patient. Moreover, the administration of an effective dose is such that the concentration of the compound in the patient's plasma usually does not exceed 500 pg / ml, often 300 pg / m 2.
It does not exceed 1 and often does not exceed 100 pg / ml. When used in such a method, the compounds of the invention are dose-dependent and thus cause inhibition of cytokine production and / or secretion when used at low concentrations, but at higher concentrations such Has no inhibitory effect. The compounds of the invention show an inhibitory effect on cytokine production and / or secretion when used in an amount less than that required to induce activation of the relevant nicotine receptor subtypes to any significant degree. .

The following examples are provided to illustrate the present invention and should not be taken as a limitation thereof. In these examples all parts and ratios are by weight unless otherwise stated. Reaction yields are reported in mol%. Several commercially available starting materials are used throughout the examples below. 3-bromopyridine, 2-amino-5
-Bromopyrimidine, 2-amino-5-bromo-3-nitropyridine, furfurylamine, 4-bromo-1-butene and 4-penten-2-ol were obtained from Aldrich Chemical Company. (R)-(+)-Propylene oxide is Fluk
a Obtained from Chemical Company. 5-bromonicotinic acid is Acros Or
Obtained from Ganics or Aldrich Chemical. 3,5-Dibromopyridine was obtained from Lancaster Synthesis or Aldrich Chemical. Three
-Chloro-5-trifluoromethylpyridine is a Strem Chemical
s company. Column chromatography is performed by Merck Silica Gel 60 (70-2
30 mesh) or aluminum oxide (activated, neutral, BlockmannI
, Standard grade, about 150 mesh). Pressurized reaction is Ace G
It was carried out in a heavy walled glass pressure tube (185 mL capacity) with Ace-Thread and stopper valve available from Lass. The reaction mixture is typically
Heated using a hot silicone oil bath, temperature means the temperature of the oil bath. The following abbreviations are used in the following examples: CHCl _{3 for} chloroform, CH ₂ Cl _{2 for} dichloromethane, CH ₃ OH for methanol, DMF for N, N-dimethylformamide, EtOAc for ethyl acetate, THF for tetrahydrofuran, and triethylamine. Then Et ₃ N.

Example Assay Determination of Binding to Related Receptor Sites Binding of compounds to related receptor sites is described by Dull et al., US Pat. No. 5,597,9.
It was determined according to the technique described in No. 19. The inhibition constant (Ki value) reported in nM is
Cheng et al., Biochem, Pharmacol. 22: 3099 (197
Calculated from IC ₅₀ values using the method of 3).

Determination of Dopamine Release Dopamine release was measured using the technique described in Dull et al., US Pat. No. 5,597,919. Release is expressed as% of the release obtained at the concentration of (S)-(−)-nicotine that produces the maximal effect. The reported EC ₅₀ value is nM
The E _max value represents the amount released relative to (S)-(−)-nicotine on a% basis.

Neurotransmitter release from brain synaptosomes Neurotransmitter release was measured using a technique similar to that previously published (Bencherif M et al., JEP 279: 1413-1421, 199).
6).

Rat brain synaptosomes were prepared as follows: Female Sprague Da
wley rats (100-200 g) were killed by decapitation after anesthesia with 70% CO ₂ . Brain dissected, hippocampus, striatum and thalamus isolated, 5 mM HEP
Homogenize using a glass / glass homogenizer in 0.32 M sucrose with ES (pH 7.4). The tissue was then centrifuged at 1000 xg for 10 minutes and the pellet discarded. The supernatant was centrifuged at 12000 xg for 20 minutes.
The obtained pellet was subjected to reflux buffer (128 mM NaCl, 1.2 mM KH ₂ P).
O ₄ , 2.4 mM KCl, 3.2 mM CaCl ₂ , 1.2 mM MgSO ₄ ,
25 mM HEPES, 1 mM ascorbic acid, 0.01 mM pargyline HCl
And 10 mM glucose (pH 7.4)) for 15 minutes at 25,000
It was centrifuged at xg. Resuspend final pellet in reflux buffer, water bath (37 ° C)
For 10 minutes. Add radiolabeled neurotransmitter (30L ³ HDA, 20
L ³ HNE, 10 L ³ H glutamate), final concentration 100 nM, vortexed and placed in a water bath for an additional 10 minutes. The tissue addition filter was placed on an 11 mm diameter Gelman A / E filter on an open air support. After a 10 minute wash period, fractions were collected to establish basal release and agonist was applied during reflux. Additional fractions were collected after agonist application to reestablish baseline. The perfusate was collected directly in scintillation vials and the radioactivity released was quantified using conventional liquid scintillation techniques. Release of neurotransmitters was determined in the presence of 10 M of various ligands and expressed as% of release obtained at a concentration of 10 M (S)-(−)-nicotine or 300 M TMA that produced maximal effect. did.

Determination of Rubidium Ion Release Rubidium release is described by Bencherif et al., JPET, 279: 1413-1.
421 (1996). The reported EC ₅₀ value is
Expressed in nM, E _max values indicate the amount of released rubidium ion compared to 300 μM tetramethylammonium ion on a% basis.

Determining Interactions with Muscle Receptors Determining the interaction of compounds with muscle receptors is described in Dull et al., US Pat. No. 5,597.
, 919. Maximum activation of individual compounds (E _max
) Was determined as% of the maximal activation induced by (S)-(−)-nicotine. The reported E _max values represent the amount released on a% basis compared to (S)-(−)-nicotine.

Determination of Interactions with Ganglion Receptors The determination of the interaction of compounds with ganglion receptors is described by Dull et al., US Pat. No. 5,59.
It was carried out according to the technique described in No. 7,919. Maximal activation (E _{ma x)} of the individual compound, (S) - (-) - it was determined as a percentage of the maximal activation induced by nicotine. The reported E _max values represent the amount released on a% basis compared to (S)-(−)-nicotine.

Example 1 Sample No. 1 is (3E) -N-methyl-4- [3- (5-nitro-6-aminopyridin) yl] -3-buten-1-amine, which is Prepared according to the following technique.

[0074]   N-methyl-3-buten-1-amine   Under a nitrogen atmosphere, anhydrous DMF (40 mL) was added at −78 ° C. via a syringe.
Added to methylamine (40 mL, 43.2 g, 1.4 mol, concentrated from gas phase)
. Anhydrous potassium carbonate (19.36 g, 140 mmol) was added to the stirred solution, and then
Then 4-bromo-1-butene (18.9 g, 140 mmol) was added. Obtained
The resulting mixture was slowly warmed to room temperature overnight. Pour the mixture into water (150 mL)
And extracted with ether (8 x 50 mL). The combined organic extracts are dried (Na ₂ SO_Four), Filtered and distilled at atmospheric pressure to a boiling point of 80-82 ° C (G. Courto
is et al., Bull. Soc. Chim. Fr. (3): 449-453 (198)
6.86 g of literature boiling point of 760 mm Hg and 87 ° C.) as reported by 6)
A colorless oil (57.6%) was obtained.

N-Methyl-N- (3-buten-1-yl) benzamide Under a nitrogen atmosphere, N-methyl-3-buten-1-amine (6.86 g, 80.
A solution of 6 mmol) in dichloromethane (100 mL) was cooled to 0 ° C. and triethylamine (17.39 g, 177.2 mmol) and 4- (N, N-dimethylamino) pyridine (207 mg) were added. Benzoyl chloride (11.89 g,
A solution of 84.6 mmol) in dichloromethane (60 mL) was added 1 via a dropping funnel.
It was added dropwise at 0-5 ° C over time. The resulting cloudy mixture was stirred for 3 hours at 0 ° C. The mixture was then continuously treated with 1M HCl solution (3 × 75 mL), 5% N 2
Washed with aHCO ₃ solution (3 × 100 mL), and water (100 mL). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated on a rotary evaporator to give a yellow oil (12.66 g). Vacuum distillation using a 6 inch Vigreaux column and a short path distillation apparatus yielded 8.58 g (56.3%) of a colorless oil with a boiling point of 100-103 ° C. at 0.1 mmHg.

(3E) -N-Methyl-N-benzoyl-4- [3- (5-nitro-6-aminopyridin) yl] -3-buten-1-amine Under nitrogen atmosphere, N-methyl-N -(3-buten-1-yl) benzamide (
2.25 g, 11.9 mmol), 2-amino-5-bromo-3-nitropyridine (2.67 g, 11.9 mmol) (Aldrich Chemical Co.), palladium (II) acetate (27.2 mg, 0.12 mmol). , Tri-o-tolylphosphine (74.6 mg, 0.24 mmol), and triethylamine (2.41 g.
, 24.0 mmol) was stirred and heated under reflux at 90-95 ° C. (oil bath temperature) for 20 hours. More triethylamine (2.18g, 21.5mmo
1), palladium (II) acetate (27.2 mg, 11.9 mmol), tri-o.
-Tolylphosphine (149.2 mg, 0.49 mmol) and acetonitrile (6.0 mL) were added, the mixture was stirred and at 90-100 ° C (oil bath temperature) 12
Heated for 0 hours. TLC analysis of the mixture _{(CHCl 3 -CH 3 OH, 98} : 2, v /
v) shows an incomplete reaction and therefore more palladium acetate (II
) (54.4 mg, 0.24 mmol), tri-o-tolylphosphine (295
． 0 mg, 0.97 mmol) and triethylamine (2.18 g, 21.5
mmol) was added. Reflux was continued for a further 192 hours at 110-115 ° C (oil bath temperature). The resulting dark brown solid mixture is cooled slightly and added to water (125 mL) and dichloromethane (150 mL) to form an emulsion. The aqueous layer was separated and extracted with dichloromethane (25 mL). The combined dichloromethane extracts were filtered and the filtrate washed with water (75 mL). The dark brown dichloromethane layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated on a rotary evaporator. The product obtained was dried in a vacuum oven at 30 ° C. for 16 hours to give 3.85 g of a brown solid. Dissolve the solid in dichloromethane (100 mL) and add 1M HCl solution (100 m).
L, 50 mL). The brown dichloromethane layer was separated and concentrated on a rotary evaporator to give a dark brown oily solid. 2-Propanol was added and the solution was concentrated by rotary evaporation. The resulting dark brown residue was dried in a vacuum oven at 40 ° C. for 16 hours to give 3.71 g of a brown solid. This solid was converted to silica gel (218
． By 2g) column _{chromatography, CHCl 3 -CH 3 OH (98} : 2,
Purified by elution with v / v). The fractions selected on the basis of TLC analysis were combined to give 2.00 g (51.7%) of a reddish orange powder.
An analytical sample was prepared by continuously recrystallizing 1.28 g of material from the following solvents: benzene-petroleum ether (1: 1, v / v), benzene (Da).
rco® G-60 charcoal (0.10 g) and Hyflo Super
Cel (including 0.10 g) treatment, and finally benzene (twice). The recrystallized product was air dried and further dried in a vacuum oven at 50 ° C. for 5 hours to give 0.
77 g of orange powder (melting point 162.5-164 ° C.) were obtained.

(3E) -N-Methyl-4- [3- (5-nitro-6-aminopyridin) yl] -3-buten-1-amine (6 mL of 6M HCl solution (20 mL) under a nitrogen atmosphere. 3E) -N-methyl-
N-benzoyl-4- [3- (5-nitro-6-aminopyridin) yl] -3-
A solution of buten-1-amine (130.0 g, 0.40 mmol) was stirred and heated under reflux at 145-150 ° C. (oil bath temperature) for 16 hours. The resulting bright yellow solution was cooled to room temperature and then to 0 ° C. 20% NaOH solution (30 mL
) Was added dropwise with stirring until a pH of 12 was reached. The solution was extracted with dichloromethane (100 mL), which produced an emulsion. A two-layer mixture,
The filter cake was filtered through a Buchner funnel precoated with Hyflo Super Cel filter aid, washing with dichloromethane (2 x 25 mL). Separate the yellow dichloromethane layer and separate the aqueous layer with dichloromethane (3 x 25
mL). The combined dichloromethane extracts were dried (Na ₂ SO ₄ ), filtered and concentrated by rotary evaporation to give a yellow powder (86.6 mg).
The crude product was subjected to silica gel (8.1 g) column chromatography to give THF.
-CH ₃ OH @ - conc _{NH 4 OH (22: 10:} 1, v / v / v) and purified eluting with. Based on TLC analysis, selected fractions containing product were combined and concentrated by rotary evaporation. The solid obtained was dissolved in dichloromethane and dried (Na ₂ SO ₄ ).
Filtered and concentrated by rotary evaporation. Further drying in a vacuum oven at 30 ° C. for 16 hours gave 59.1 mg (66.7%) of a dark orange powder (mp 118-1).
21 ° C.) was obtained.

Sample number 1 exhibits a Ki of 3 nM. The low binding constants suggest that the compounds show good high binding affinity for specific CNS nicotine receptors. Sample No. 1 showed an E _max value of 0% for dopamine release, indicating that the compound is selective for inducing neurotransmitter release. The sample had an EC ₅₀ value of 26,000 nM and 22 in the rubidium ion influx assay.
% E _max values are given. The sample exhibits a neurotransmitter free E _max value of 33%.

Sample No. 1 showed an E _max of 10% (at a concentration of 100 μM) at muscle-type receptors, indicating that the compound does not significantly induce activation of muscle-type receptors.
The sample exhibits an E _max (at a concentration of 100 μM) of 11% at the ganglion-type receptor.
The compounds have the ability to bind to the human CNS receptor without activating muscle and ganglionic nicotinic acetylcholine receptors to any significant extent. Thus, a therapeutic window useful for treating CNS disorders is provided. The compound begins to induce muscle and ganglion effects only when used in an amount greater than that required to bind to a particular CNS receptor, and is therefore desirable in subjects receiving this compound. It is shown that there are no side effects.

Example 2 Sample No. 2 is (3E) -N-methyl-N- [3- (5- (N-benzylcarboxamido) pyridin) yl] -3-buten-1-amine, which is Was prepared according to the following technique.

N-Methyl-3-buten-1-amine Under a nitrogen atmosphere, anhydrous DMF (40 mL) was added via syringe to methylamine (40 mL, 43.2 g, 1.4 mol, gas phase at −78 ° C.). From concentrated). Anhydrous potassium carbonate (19.36 g, 140 mmol) was added to the stirred solution, followed by 4-bromo-1-butene (18.9 g, 140 mmol). The resulting mixture was slowly warmed to room temperature overnight. The mixture was poured into water (150 mL) and extracted with ether (8 x 50 mL). The combined ether extracts were dried (N
a ₂ SO ₄ ), filtered and distilled at atmospheric pressure to give 6.86 g (57.6%) of a colorless oil (boiling point 80-82 ° C.) (G. Courtois et al., Bull. Soc. Ch.
im. Fr. (3): 449-453 (1986), the boiling point of the literature was 760 mmHg and 87 ° C.) was obtained.

N-methyl-N- (tert-butoxycarbonyl) -3-buten-1-amine Under a nitrogen atmosphere, ice-cooled (2 ° C.) N-methyl-3-buten-1-amine (4) under stirring. A solution of 0.78 g, 56.2 mmol) in dry THF (20 mL, freshly distilled from sodium and benzophenone) was added in portions with di-tert-butyl dicarbonate (12.26 g, 56.2 mmol) over 10 minutes to generate carbon dioxide. It was treated quietly during the addition. The resulting colorless solution was warmed to ambient temperature. The THF was removed by rotary evaporation and the resulting light yellow liquid was vacuum distilled using a 6 inch Vigreaux column and short path distillation apparatus. 3.5
Fractions with a boiling point of 70 ° C. at mmHg were collected to give 4.19 g (40.2%) of a colorless oil.

5-Bromo-3-N-benzylnicotinamide Under anhydrous conditions, thionyl chloride (4.12 g, 34.65 mmol) was added via a dropping funnel to 5-bromonicotinic acid (7.00 g, 34.65 g). 65 mmol) (Ac
ros Organics), pyridine (5.48 g, 69.28 mmol) and toluene (6 mL) were added dropwise to a cold (0 ° C.) stirred mixture. The stirred mixture is heated to 105 ° C. (oil bath temperature) and kept at this temperature for 1 hour, then 70-7
Cooled to 5 ° C. A solution of benzylamine (3.71 g, 34.65 mmol) in toluene (10 mL) was added via a dropping funnel at 70-75 ° C over 5 minutes, then more pyridine (9.14 g, 116. 0 mmol) was added.
The dark brown solution was heated to 90-95 ° C (oil bath temperature) for 3 hours and cooled to ambient temperature. The reaction mixture was poured into 1M HCl solution (150 mL) resulting in a bilayer mixture with solid present. The mixture was gently warmed and filtered to collect the solid. The product was vacuum dried at 45 ° C. for 15 hours to give 6.90 g of a cream colored solid. The crude product was recrystallized from a small amount of absolute ethanol. The recrystallized material is filtered,
Wash with cold ethanol (2 x 20 mL) and vacuum dry at 45 ° C for 15 hours to give 4
． 26 g of a light beige, slightly pink crystalline powder (melting point 118-120)
C) was obtained. More product was obtained from the HCl-toluene filtrate. The toluene layer was separated and extracted with 1M HCl solution (2 × 50 mL). Combined H
The Cl extract was cooled to 0 ° C. and basified to pH 9 with 18% Na ₂ CO ₃ solution,
It was extracted with toluene (50 mL) and CH ₂ Cl ₂ (4 × 50 mL). It was dried toluene -CH ₂ Cl ₂ extract of peach (Na ₂ SO _4), filtered, and concentrated on a rotary evaporator, and further dried under vacuum for 15 hours at 45 ° C.. The reddish-beige solid obtained was recrystallized from a minimum amount (about 5 mL) of absolute ethanol. The recrystallized second batch was filtered, washed with cold ethanol (2 x 10 mL), 45 ° C.
After vacuum drying for 3 hours, 2.09 g of a light beige, slightly pink crystalline powder (melting point: 118 to 120 ° C.) was obtained, and the total yield was 6.35 g (62.9%).
Met.

(3E) -N-methyl-4- (tert-butoxycarbonyl) -4- [3-
(5- (N-benzylcarboxamido) pyridin) yl] -3-butene-1-
Amine Under nitrogen atmosphere, 5-bromo-3-N-benzylnicotinamide (2.50 g
, 8.59 mmol), N-methyl-N- (tert-butoxycarbonyl)-
3-buten-1-amine (1.59 g, 8.59 mmol), palladium acetate (
II) (21.2 mg, 0.09 mmol), tri-o-tolylphosphine (1
15.0 mg, 0.38 mmol), triethylamine (2.39 g, 23.6)
A mixture of 6 mmol) and anhydrous acetonitrile (6.6 mL) was stirred and heated under reflux at 95-100 ° C (oil bath) for 24 hours and then at 85-90 ° C (oil bath temperature) for 60 hours. The dark brown mixture was cooled to ambient temperature and washed with water (20 m
L) and CH ₂ Cl ₂ (20 mL). The CH ₂ Cl ₂ layer of light brown were separated and the aqueous layer was extracted with _{CH 2 Cl 2 (2 × 20mL} ). The combined CH ₂ Cl ₂ extracts were washed with water (10 mL), dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and further vacuum dried at 0.6 mmHg for 3 hours to give 3.41 g. A brown oil was obtained. The crude product was purified by silica gel (150 g) column chromatography, eluting with 50-100% (v / v) ethyl acetate in hexane. Selected fractions containing the product ( _Rf 0.31 in EtOAc-hexane (3: 1, v / v)) were combined, concentrated by rotary evaporation and dried in vacuo to 2.17 g (6
A light yellow oil (3.9%) was obtained.

(3E) -N-methyl-N- [3- (5- (N-benzylcarboxamide)
Pyridin) yl "-3-buten-1-amine (3E) -N-methyl-N- (tert-butoxycarbonyl) -4- [3- (5- (N-benzylcarboxamido) pyridine) under a nitrogen atmosphere. Il] -3
-Butene-1-amine (1.27 g, 3.21 mmol), anisole (1.7
4 g, 16.06 mmol) and CHCl ₃ (12 mL) were treated with trifluoroacetic acid (14.80 g, 129.8 mmol). 1 to the resulting brown solution
Stir for hours, concentrate on a rotary evaporator, then dry further under high vacuum. 2 residues
Basify to pH 12 with 0% NaOH solution (5 mL), add saturated NaCl solution (3 mL), and extract the mixture with CHCl ₃ (4 × 10 mL). The combined CHCl ₃ extracts were washed with saturated NaCl solution (10 mL), dried (Na ₂ S
O ₄ ), filtered, concentrated by rotary evaporation, and then further dried under high vacuum,
0.98 g of a foamy brown residue was obtained. The crude product was purified by silica gel (45 g) column _{chromatography, CH 3 OH-Et 3 N} (97: 3, v / v) and purified eluting with. Selected fractions containing the product (R _f 0.24) were combined and concentrated on a rotary evaporator to give a yellow residue which was dissolved in CHCl ₃ (5 mL). The CHCl ₃ solution was dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and dried under high vacuum to give 30.1 mg (3.2%) of a light yellow oil. Sample number 2 shows a Ki of 192 nM, which is compound specific CNS.
It is suggested to show binding to the nicotine receptor. Sample number 2 shows an EC ₅₀ value of 100,000 nM and an E _max value of 12% for dopamine release.

Sample No. 1 showed an E _max (at a concentration of 100 μM) of 11% at muscle-type receptors, indicating that the compound does not significantly induce activation of muscle-type receptors.
The sample exhibits an E _max (at a concentration of 100 μM) of 16% at the ganglion-type receptor.
The compounds have the ability to bind to the human CNS receptor without activating muscle and ganglionic nicotinic acetylcholine receptors to any significant extent.

Example 3 Sample No. 3 is (4E) -N-methyl-5- [5- (2-aminopyrimidin) yl] -4-penten-2-amine hemigalactarate, which is Was prepared according to the technique of.

4-Penten-2-ol p-toluenesulfonate Tosyl chloride (16.92 g, 88.85 mmol) was added to 4-
Penten-2-ol (7.28 g, 84.52 mmol) pyridine (60 m
L) Medium cold (2 ° C.) was added to the stirred solution. The solution was stirred at 2-5 ° C for 2 hours and allowed to warm to ambient temperature over several hours. The mixture containing the white solid was treated with cold 3M HCl solution (2
50 mL) and extracted with CHCl ₃ (4 × 75 mL). Combined CHCl ₃ extracts with 3M HCl solution (4 × 100 mL), saturated HCl solution (2 × 50 mL).
), Dried (Na ₂ SO ₄ ), filtered, concentrated on a rotary evaporator and further dried under high vacuum to give 17.38 g (85.6%) of an amber oil. Was given.

N-Methyl-4-penten-2-amine In a 185 mL thick walled glass pressure tube, 4-penten-2-ol p-toluenesulfonate (17.30 g, 71.99 mmol) was added, followed by 40% aqueous methylamine solution. (111.85 g, 1.44 mol) was added. The tube was sealed, the mixture was stirred and heated at 122 ° C. (oil bath temperature) for 16 hours. Cool the solution to ambient temperature,
Further cooled to 0-5 ° C. The light yellow solution was saturated with NaCl and extracted with diethyl ether (6 x 40 mL, inhibitor free). The combined ether extracts (light yellow) were dried (Na ₂ SO ₄ ) and filtered. By distilling the ether at atmospheric pressure,
Removed using a 6 inch Vigreaux column and short path distillation apparatus.
The residual light yellow oil was distilled at atmospheric pressure, collecting 2.59 g (36.3%) of a colorless oil (boiling point 75-105 ° C).

N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine di-tert-butyl dicarbonate (6.84 g, 31.35 mmol) was added rapidly and in small portions to N-methyl-4. -Penten-2-amine (2.55g, 25
． 68 mmol) of THF (25 mL, freshly distilled from sodium and benzophenone) was added to a cold (0-5 ° C.) stirred solution. The resulting light yellow solution was stirred and warmed to ambient temperature over several hours. The solution was concentrated by rotary evaporation. The resulting oil was vacuum distilled using a short path distillation apparatus to 4.61 g (90.0%
) Was obtained as a nearly colorless oily substance (boiling point: 85-86 ° C at 5.5 mmHg).

(4E) -N-methyl-N- (tert-butoxycarbonyl) -5- [5-
(2-Aminopyrimidin) yl] -4-penten-2-amine In a 185 mL thick-walled glass pressure tube, 2-amino-5-bromopyrimidine (1
． 222 g, 7.025 mmol), palladium (II) acetate (15.77 mg)
, 0.070 mmol), tri-o-tolylphosphine (85.53 mg, 0.
281 mmol), N-methyl-N- (tert-butoxycarbonyl) -4-
Penten-2-amine (1.400 g, 7.025 mmol), triethylamine (2.5 mL, 1.815 g, 17.937 mmol) and acetonitrile (5 mL) were added. The tube is flushed with nitrogen, sealed and heated at 114 ° C (oil bath temperature)
Heated for hours. The mixture was cooled and additional palladium (II) acetate (15.77m) was added.
g, 0.070 mmol), tri-o-tolylphosphine (85.53 mg, 0
． 281 mmol), triethylamine (2.5 mL) and acetonitrile (
5 mL) was added. The tube was sealed and the mixture was heated at 115 ° C. for an additional 29 hours. The mixture was cooled to ambient temperature and solidified as a dark brown crystalline solid. The solid is put into water (2
5 mL) and CH ₂ Cl ₂ (25 mL). Separate the water layer, C
Extracted with H ₂ Cl ₂ (2 × 25 mL). The combined dark brown CH ₂ Cl ₂ extracts were washed with saturated NaCl solution (25 mL), dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and briefly dried under high vacuum to give a dark. Brown oily semi-solid (2.2
5 g) was obtained. The crude product was purified by silica gel (125 g) column chromatography, eluting with CHCl ₃ —CH ₃ OH (95: 5, v / v). Selected fractions containing the product (R _f 0.24) were combined and concentrated to 1.46.
g of a light yellow oil was obtained. The product was converted to EtOAc-hexane (9: 1, v
/ V) and rechromatographed on silica gel (100 g). Selected fractions containing product (R _f 0.17) were combined and concentrated to 0.5
9 g of a light yellow oil was obtained. The impure fraction was concentrated to an oil which was
Eluted with OAc-hexane (9: 1, v / v) again, silica gel (85 g
) Chromatography. Pure fractions were combined and concentrated to give an additional .0.
21 g of a light yellow oil was obtained for a total yield of 0.80 g (39.0%). On standing at ambient temperature the oil solidified as a waxy off-white glass (mp 84-92 ° C).

(4E) -N-methyl-5- [5- (2-aminopyrimidin) yl] -4-penten-2-amine Under a nitrogen atmosphere, (4E) -N-methyl-N- (tert- Butoxycarbonyl) -5- [5- (2-aminopyrimidin) yl] -4-penten-2-amine (0.78 g, 2.668 mmol) in CHCl ₃ (55 mL) was added to iodotrimethylsilane (0.83 mL). , 1.174 g, 5.869 mmol) was added dropwise at ambient temperature for treatment. The cloudy orange-brown solution was stirred for 30 minutes. The solution was treated with methanol (55 mL) and the resulting dark brown solution was stirred for 1 hour at ambient temperature. The solution was concentrated by rotary evaporation to a brown foamy residue. After cooling at 0 ° C., the residue was basified with 10% NaOH solution (15 mL) and saturated N 2
It was diluted with aCl solution (10 mL) and extracted with CHCl ₃ (10 × 10 mL).
The combined CHCl ₃ extracts (yellow) were dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and briefly dried under high vacuum to give a brown oil (0.57 g). . The crude product was purified by silica gel (65 g) column chromatography.
_{CH 3 OH-NH 4 OH (} 20: 1, v / v) and purified eluting with. Product (
Fractions containing R _f 0.29) were combined and concentrated to give 0.04 g of a tan semi-solid. Impure fractions were combined and concentrated to give a residue which was again chromatographed on silica gel (65 g) to give an additional 0.09 g of a tan semi-solid. The impure fractions were combined and concentrated to a yellow oil, which was
Elution with CH ₃ OH-NH ₄ OH (10: 1, v / v) was repeated while eluting with silica gel (
65 g) Chromatography. Fractions containing the product (R _f 0.48) were combined and concentrated to give an additional 0.07 g of a tan semi-solid. All purified material was dissolved in CHCl ₃ . The CHCl ₃ solution was dried (Na ₂ SO ₄ ), filtered and concentrated to a yellow oil which crystallized as oily light yellow crystals (
0.215 g, 41.9%).

(4E) -N-methyl-5- [5- (2-aminopyrimidin) yl] -4-pentene-2-amine hemigalactarate (4E) -N-methyl-5- [5- (2 -Aminopyrimidin) yl] -4-penten-2-amine (209.7 g, 1.091 mmol) in ethanol (3 m
To the L) solution was added galactaric acid (114.6 mg, 0.545 mmol).
Water (0.8 mL) was added dropwise while warming the solution to near reflux. To remove some white, insoluble crystals, the warm solution was filtered through a glass wool plug while washing the filter plug with a warm solution of ethanol-water (4: 1, v / v) (2 x 10 mL). did. The filtrate was diluted with ethanol (5 mL). The mixture was cooled to ambient temperature and further at 5 ° C. No solid settled. As a result, the solution was concentrated by rotary evaporation and the residue was further dried under high vacuum to give a yellow crisp solid. Heat the material with hot 2-propanol (about 10 mL) -water (1.3
Recrystallization from (mL) gave a brown oil with some solids. The mixture was cooled at 5 ° C. for 16 hours. The resulting solid was filtered and cold 2-propanol (4x
2 mL). The light beige solid was triturated and slurried in hot ethanol (5 mL). Cool the ethanol slurry to ambient temperature and then add 0 at 5 ° C.
． Cooled for 5 hours. The solid is filtered, washed with cold 2-propanol and washed at 40 ° C for 48 hours.
Vacuum drying for 24 hours yielded 258.6 mg (79.7%) of an off-white amorphous powder (mp 174.5-177 ° C. (decomposition)).

Sample number 3 shows a Ki of 542 nM. The low binding constants suggest that the compounds show good high binding affinity to specific CNS nicotine receptors.

Example 4 Sample No. 4 is (4E) -N-methyl-5- (3- (5-aminopyridin) yl) -4-penten-2-amine hemigalactarate, which is Was prepared according to the technique of.

(4E) -5- (3- (5-Bromopyridin) yl) -4-penten-2-ol 3,5-dibromopyridine (6.00 g, 25.42 mmol), 4-pentene-2- All (2.62 g, 30.50 mmol), palladium (II) acetate
(57 mg, 0.25 mmol), tri-o-tolylphosphine (309 mg,
A mixture of 1.01 mmol), triethylamine (16 mL, 114.40 mmol) and acetonitrile (20 mL) was heated in a sealed glass tube at 140 ° C for 14 hours. The reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with chloroform (3 x 100 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by column chromatography on neutral alumina eluting with ethyl acetate-hexane (2: 3) as eluent to give 4.20 g (68.2%) of a pale yellow liquid. Was given.

(4E) -5- (3- (5-Bromopyridin) yl-4-penten-2-ol p-toluenesulfonate (4E) -5- (3- (5-Bromopyridin) yl at 0 ° C. ) -4-Pentene-
2-ol (1.80 g, 7.40 mmol) in dry dichloromethane (15 mL)
) And pyridine (5 mL) in a stirred solution of p-toluenesulfonyl chloride (
2.82 g, 14.81 mmol) was added. The reaction mixture was stirred for 24 hours at ambient temperature. The solvent was removed under vacuum, toluene (10 mL) was added and removed on a rotary evaporator. The crude product was stirred with saturated sodium bicarbonate (100 mL) solution for 30 minutes and then extracted with chloroform (4 x 50 mL). The combined extracts were dried over sodium sulfate and filtered. 2.52 g of solvent removed on a rotary evaporator
A pale yellow oil (86.0%) was obtained.

(4E) -N-Methyl-5- (3- (5-bromopyridin) yl) -4-penten-2-amine (4E) -5- (3- (5-Bromopyridin) yl-4 A mixture of -penten-2-ol p-toluenesulfonate (2.52g, 6.36mmol) and methylamine (30mL, 40% aqueous solution) and methanol (10mL) was stirred at ambient temperature for 18 hours. Concentrate to 25 mL on an evaporator and extract with chloroform (4 x 50 mL) Combined extracts were concentrated on a rotary evaporator The crude product was treated with aqueous hydrochloric acid at 0-5 ° C (10%, 30 mL). And stirred for 30 minutes.The solution was extracted with chloroform (50 mL) .The aqueous layer was cooled (0-5 ° C).
), Basified to pH 8-9 with aqueous sodium hydroxide and chloroform (4 x
50 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator to give a pale yellow oil (0.94g, 58.1%).

(4E) -N-Methyl-5- (3- (5-aminopyridin) yl) -4-penten-2-amine (4E) -N-Methyl-5- (3- (5-bromopyridine) ) Yl) -4-Penten-2-amine (70 mg, 0.27 mmol), copper (I) bromide (43 mg,
A mixture of 0.30 mmol) and concentrated aqueous ammonia (30 mL) was heated in a sealed glass tube at 150-160 ° C. for 18 hours. The reaction mixture was cooled to ambient temperature and extracted with chloroform (4 x 40 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator to give 47 mg (89.5%) of a pale yellow oil.

(4E) -N-Methyl-5- (3- (5-aminopyridin) yl) -4-pentene-2-amine hemigalactarate (4E) -N-methyl-5- (3- (5 Galactaric acid (21 mg, 0.10 mmol) was added to a hot solution of -aminopyridinyl) -4-penten-2-amine (40 mg, 0.20 mmol) in ethanol (10 mL). The mixture was heated to reflux and water (6 drops) was added dropwise. The solution was filtered to remove some insoluble particles. The filtrate was concentrated to 5 mL and cooled to ambient temperature for 4 hours. The precipitate was filtered, washed with anhydrous ether and dried in a vacuum oven at 45 ° C for about 16 hours. The yield was 32 mg (52 mg) of a very bright yellow powder (mp 175-177 ° C).
． 5%).

Sample No. 4 shows a Ki of 1137 nM. The binding constants suggest that the compound exhibits binding to a particular CNS nicotine receptor.

Example 5 Sample No. 5 is (2S)-(4E) -N-methyl-5- [3- (5-isopropoxy-1-oxopyridin) yl)]-4-penten-2-amine Which was prepared according to the following technique.

5-Bromo-3-isopropoxypyridine Calcium metal (6.59 g, 168.84 mmol) was dried under nitrogen 2
-Dissolved in propanol (60.0 mL). Obtained potassium isopropoxide in a glass tube sealed at 140 ° C. with 3,5-dibromopydiline (20.00 g, 84.42 mmol) and copper powder (1 g, 5% by weight of 3,5-dibromopyridine). Heated at 14 hours. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4 x 200 mL). The combined ether extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The obtained crude product was subjected to column chromatography on aluminum oxide to obtain ethyl acetate-hexane (1: 9).
, V / v) for elution. Selected fractions were combined and concentrated by rotary evaporation to give a pale yellow oil (12.99g, 71.2%).

(2R) -4-Penten-2-ol (2R) -4-Penten-2-ol is (R)-(+) in 82.5% yield.
From propylene oxide, A. Kalivretenos, J .; K. Still
le and L.L. S. Hegedus, J. Org. Chem. 56: 2883 (
1991).

(2R)-(4E) -5- [3- (5-isopropoxypyridin) yl)]-
4-Penten-2-ol 5-Bromo-3-isopropoxypyridine (10.26 g, 47.50 mmo
l), (2R) -4-Penten-2-ol (4.91 g, 57.00 mmol)
), Palladium (II) acetate (106 mg, 0.47 mmol), tri-o-tolylphosphine (578 mg, 1.90 mmol), triethylamine (28.
A mixture of 46 mL, 204.25 mmol) and acetonitrile (30 mL) was heated at 140 ° C. for 14 hours in a sealed glass tube. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with chloroform (3 x 200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give a pale yellow oil (8.92 g, 85.0%).

(2R)-(4E) -5- [3- (5-isopropoxypyridin) yl)]-
4-Penten-2-ol p-toluenesulfonate (2R)-(4E) -5- [3- (5-isopropoxypyridin) yl)]-4-penten-2-ol (8.50 g, To a stirred solution of 38.46 mmol) of dry pyridine (30 mL) was added p-toluenesulfonyl chloride (14.67).
g, 76.92 mmol) was added. The reaction mixture was stirred for 24 hours at ambient temperature. Pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and removed by rotary evaporation. The crude product was stirred with saturated sodium bicarbonate (100 mL) and extracted with chloroform (3 x 100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give a dark brown viscous oil (11.75g, 81.5%).

(2S)-(4E) -N-Methyl-5- [3- (5-isopropoxypyridin) yl)]-4-penten-2-amine (2R)-(4E) -5- [3 -(5-isopropoxypyridin) yl)]-
4-Penten-2-ol p-toluenesulfonate (11.00 g, 29.3)
3 mmol), methylamine (200 mL, 40% aqueous solution), and ethyl alcohol (10 mL) were stirred at ambient temperature for 18 hours. The resulting solution was extracted with chloroform (3 x 100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was subjected to column chromatography on aluminum oxide to give ethyl acetate-methanol (7: 3).
, V / v) for elution. Selected fractions were combined and concentrated by rotary evaporation to give an oil. Further purification by vacuum distillation gave 2.10 g (3
1.0%) of a colorless oil (boiling point 90-100 ° C. at 0.5 mmHg) was obtained.

(2S)-(4E) -N-Methyl-5- [3- (5-isopropoxypyridin) yl)]-4-penten-2-amine hemigalactarate (2S)-(4E) -N -Methyl-5- [3- (5-isopropoxypyridin) yl)]-4-penten-2-amine (2.00 g, 8.55 mmol),
It was dissolved in ethyl alcohol (20 mL) while being heated to 70 ° C. and assisting.
The hot solution was treated with galactaric acid (900 mg, 4.27 mmol) in small portions, then water (0.5 mL) was added dropwise. The solution was filtered while hot to remove some insoluble material. The filtrate was cooled to ambient temperature. The resulting crystals were filtered, washed with anhydrous diethyl ether and dried under vacuum at 40 ° C to give a white powder (750mg, 26.0%) (mp 140-143 ° C).

(2S)-(4E) -N-methyl-N- (tert-butoxycarbonyl)-
5- [3- (5-isopropoxypyridin) yl] -4-penten-2-amine (2S)-(4E) -N-methyl-5- [3- (5-isopropoxypyridin) yl] -4 -Penten-2-amine hemigalactarate (225.0 mg, 0
． 663 mmol) was basified with saturated K ₂ CO ₃ solution (5 mL) and saturated NaC
1 solution (2 mL) and made basic with 50% NaOH solution (10 drops). The cloudy mixture was extracted with CHCl ₃ (10 × 7mL). The combined light yellow CHCl ₃ extracts were dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and dried under high vacuum (1 mmHg) for 1.5 h to give (2S)-(4E)- N-Methyl-5- [3- (5-isopropoxypyridin) yl] -4-penten-2-amine was obtained as a yellow oil (150.7 mg) (97.0%). The oil was immediately dissolved in dry THF (8 mL, freshly distilled from sodium and benzophenone) and the resulting solution was added to di-tert-butyl dicarbonate (15 mL) at 0 ° C.
Treated with 9.0 mg, 0.729 mmol) under nitrogen atmosphere. The resulting mixture was stirred and warmed to ambient temperature over 22 hours. The solution was concentrated by rotary evaporation and dried under high vacuum (1 mmHg) to give a yellow oil (232.5 mg). The crude product was purified by silica gel (20 g, Merck 70-230 mesh) column chromatography, eluting with CHCl ₃ —CH ₃ OH (95: 5, v / v). Selected fractions containing the product (Rf 0.55) were combined, concentrated by rotary evaporation and dried briefly in vacuo at 1 mm Hg to give 226.5 mg (quantitative yield) of a light yellow oil.

(2S)-(4E) -N-methyl-N- (tert-butoxycarbonyl)-
5- [3- (5-isopropoxy-1-oxopyridin) yl] -4-penten-2-amine (2S)-(4E) -N-methyl-N- (tert-butoxycarbonyl)-
5- [3- (5-isopropoxypyridin) yl] -4-penten-2-amine (218.8 mg, 0.654 mmol) in CH ₂ Cl ₂ (5 mL, LiAlH ₄
Ice-cooled (0 ° C.) solution of (3-chloroperoxybenzoic acid) (219
． 1 mg, 0.724-1.092 mmol) (57.86% pure) was added in small portions. The solution was stirred for 30 minutes at 0 ° C and stored at 5 ° C for 16 hours. TLC analysis: by _{(CHCl 3 -CH 3 OH, 95} 5, v / v), showed the reaction was complete.
The light yellow solution was treated with 1M NaOH solution (10 mL) and 10% NaHSO ₃ solution (2 mL). The CH ₂ Cl ₂ layer was separated and the aqueous layer was separated with CH ₂ Cl ₂ (2 × 10 m
L). All CH ₂ Cl ₂ extracts were combined, dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and briefly vacuum dried at 1 mm Hg to 221.7.
mg of a light yellow oil was obtained. The crude product was purified on silica gel (20.8 g, Merck 70-230 mesh) by column chromatography, EtOAc-CH ₃
Purified by eluting with OH (9: 1, v / v). Selected fractions containing the product (R _f 0.34) were combined, concentrated by rotary evaporation and briefly dried under vacuum at 1.3 mm Hg (1.5 h) to give 201.2 mg (89.9%). A pale yellow oil was obtained.

(2S)-(4E) -N-Methyl-5- [3- (5-isopropoxyl-oxopyridin) yl)]-4-penten-2-amine Under nitrogen atmosphere, (2S)- (4E) -N-Methyl-N- (tert-butoxycarbonyl) -5- [3- (5-isopropoxy-1-oxopyridin) yl] -4-penten-2-amine (191.6 mg, 0. A cold (0 ° C.) stirred solution of 547 mmol) anisole (2.5 mL) was treated dropwise with trifluoroacetic acid (2.5 mL, 32.5 mmol) over 3 minutes. The resulting light yellow solution was stirred for 45 minutes at 0-5 ° C. then concentrated by rotary evaporation using a 70 ° C. water bath. The resulting liquid was vacuum dried at 1 mmHg for 16 hours to give a yellow oil (25
4.5 mg) was produced. The oil was basified with 1M NaOH solution (2 mL) at 0-5 ° C. then treated with saturated NaCl solution (2 mL). CHC the mixture
and extracted with l ₃ (14 × 5mL). The combined CHCl ₃ extracts were dried (Na ₂ S
O ₄ ), filtered, concentrated by rotary evaporation and dried in vacuo to give 134.4 mg (98
． 2%) of a light yellow oil.

Sample number 5 shows a Ki of 1400 nM. Depending on the binding constant, the compound is C
It is suggested to show binding to the NS nicotine receptor. The sample exhibits a neurotransmitter free E _max value of 19%.

Sample No. 5 showed an E _max of 7% (at a concentration of 100 μM) at muscle-type receptors, indicating that the compound does not induce activation of muscle-type receptors. The sample exhibits an E _max (at a concentration of 100 μM) of 8% at the ganglion type receptor. The compound is
It has the ability to activate the human CNS receptor without activating the muscle and ganglion nicotinic acetylcholine receptors to any significant extent. Therefore, C
A therapeutic window useful for treating NS disorders is provided. That is, it shows that at certain levels the compounds show CNS effects to a significant extent, but do not show undesired muscle and ganglion effects to any significant extent.

Example 6 Sample No. 6 is (3E) -N-methyl-4- (3- (5-isopropoxypyridin) yl) -3-buten-1-amine hemigalactarate, which is Prepared according to the following technique.

3-Bromo-5-isobutoxypyridine Under nitrogen, sodium metal (0.46 g, 20 mmol) was dried (distilled from sodium) in isobutanol (15 mL) until the sodium was completely dissolved (
Stir overnight at 25 ° C. and at reflux for 1 hour). The mixture solidified upon cooling. To this solid was added 3,5-dibromopyridine (3.16 g, 13.3 mmol) and anhydrous DMF (15 mL). The mixture is heated at reflux for 24 hours, cooled,
Poured into water (75 mL) and extracted with ether (3 x 75 mL). The ether extract was dried (Na ₂ SO ₄ ), evaporated and the residue vacuum distilled to give 1.45 g (47.
A 4% yield) of a colorless oil (boiling point 102-109 ° C at 2.0 mmHg) was obtained.

(3E) -N-methyl-N- (tert-butoxycarbonyl) -4- (3-
(5-isobutoxypyridin) yl) -3-buten-1-amine 3-bromo-5-isobutoxypyridine (690 mg, 3.00 mmol),
N-methyl-N- (tert-butoxycarbonyl) -3-buten-1-amine (574 mg, 3.10 mmol) prepared as previously described, palladium (II) acetate (7 mg, 0.03 mmol), A mixture of and tri-o-tolylphosphine (37 mg, 0.12 mmol) was diluted with acetonitrile (2 mL) and triethylamine (1 mL) and heated at 75 ° C. for 30 hours. The mixture was cooled, poured into water (10 mL) and extracted with chloroform (2 x 10 mL).
The extracts were dried (Na ₂ SO ₄ ) and evaporated. The residue is converted to 15-40% (
Column chromatography on v / v) ethyl acetate on Merck silica gel 60 (70-230 mesh) gave 754 mg (75.4% yield) of a viscous light yellow oil.

(3E) -N-methyl-4- (3- (5-isobutoxypyridin) yl) -3
-Buten-1-amine (3E) -N-methyl-N- (tert-butoxycarbonyl) -4- (3-
(5-isobutoxypyridin) yl) -3-buten-1-amine (748 mg,
2.24 mmol) was dissolved in THF (15 mL) and 6M aqueous HCl (15 mL) was added.
). The mixture was stirred at 25 ° C. for 1.5 hours, cooled to 0 ° C., at which point 5M aqueous NaOH (20 mL) and saturated aqueous NaCl (20 mL) were added.
The mixture was extracted with chloroform (3 x 35 mL) and the extracts dried (Na ₂ S).
O ₄ ) and evaporated. 10-20% (v / v) methanol in benzene,
Column chromatography on Merck silica gel 60 (70-230 mesh) with 2% (v / v) Et ₃ N gave 203 mg (38.7% yield).
A waxy white solid was obtained.

(3E) -N-methyl-4- (3- (5-isobutoxypyridin) yl) -3
-Butene-1-amine hemigalactarate (3E) -N-methyl-4- (3- (5-isobutoxypyridin) yl) -3
-Buten-1-amine (195 mg, 0.832 mmol) was dissolved in absolute ethanol (3 mL) and galactaric acid (90 mg, 0.42 mmol) and water (
1 mL) was added. The mixture was heated in a hot water bath until it became clear and then filtered through a glass wool stopper. The filtrate was diluted with ethanol (6 mL) and slowly cooled to 0 ° C. Vacuum filtration and vacuum oven drying yielded 38 mg of hemi-galactarate as a white powder, mp 146-149 ° C (decomposition). Evaporation of the filtrate and recrystallization from methanol (3 mL) gave a second product (24 mg) of the same purity as the first, giving a combined yield of 62 mg (22.0%).

Sample number 6 shows a Ki of 20 nM. The low binding constants indicate that the compounds show good high binding affinity to specific CNS nicotine receptors. Sample No. 6 has an EC ₅₀ and 25 of 15,000 nM for dopamine release.
% E _max values are given. The sample is 1 in the rubidium ion influx assay.
EC _{50 of} 1,000 nM and E _max value of 15% are shown.

Sample No. 6 shows an E _max of 6% (at a concentration of 100 μM) at muscle-type receptors. The sample exhibits an E _max (at a concentration of 100 μM) of 13% at the ganglion-type receptor.

Example 7 Sample No. 7 is (3E) -N-methyl-4- (3- (1-oxopyridin) yl) -3-buten-1-amine, which is prepared according to the following technique. Prepared.

(E) -Metanicotine (E) -Metanicotine is described in Ruecroft and Woods US Pat.
, 663, 356, prepared from nicotine.

(3E) -N-methyl-N- (tert-butoxycarbonyl) -4- (3-
Pyridinyl) -3-buten-1-amine di-tert-butyl dicarbonate (425 mg, 1.95 mmol)
(3E) -N-methyl-4- (3-pyridyl) -3-buten-1-amine ((E
) -Metanicotine)) (317 mg, 1.95 mmol) was added to a cold (ice bath) stirred solution in 2 mL of THF. The ice bath was removed and the solution was stirred at 25 ° C for 16 hours. Volatiles were removed and the residue was subjected to column chromatography on Merck silica gel 60 (70-230 mesh) with 1: 1 (v / v) ethyl acetate / hexane to give 413 mg (80.8% yield). A colorless oily substance was obtained.

(3E) -N-methyl-N- (tert-butoxycarbonyl) -4- (3-
(1-oxopyridin) yl) -3-buten-1-amine meta-chloroperoxybenzoic acid (57-86%) (425 mg, 1.40)
2.12 mmol) was added to (3E) -N-methyl-N- (tert-butoxycarbonyl) -4- (3-pyridinyl) -3-buten-1-amine (405 mg, 1
． 54 mmol) of dichloromethane (5 mL) was added to a cold (ice bath) stirred solution.
The mixture was maintained at 4 ° C. for 16 hours, then shaken with a mixture of 1M aqueous NaOH (10 mL) and 10% (w / v) aqueous NaHSO ₃ (2 mL). The organic layer was dried (Na ₂ SO ₄ ) and evaporated to give 416 mg (96.7% yield) of a colorless viscous oil (R _f 0.50 on silica gel with 5% methanol in chloroform).
) Remained.

(3E) -N-Methyl-4- (3- (1-oxopyridin) yl) -3-buten-1-amine (3E) -N-methyl-N in anisole (1 mL) at 0 ° C. -(Tert-Butoxycarbonyl) -4- (3- (1-oxopyridin) yl) -3-butene-
To 1-amine (126 mg, 0.453 mmol), trifluoroacetic acid (1 mL
) Was added. The mixture was stirred for 30 minutes at 0 ° C. then the volatiles were removed first by rotary evaporation and then under high vacuum. The residue is 10% (w / v) NaOH
It was mixed with water (2 mL) and saturated aqueous NaCl (2 mL) and the mixture was extracted with chloroform (3 x 3 mL). The extract was dried (Na ₂ SO ₄ ) and evaporated to give 47
mg (59% yield) of an off-white viscous oil (R _f 0.14 on silica gel with 1: 1 methanol / chloroform) remained.

[0126]   Sample number 7 shows a Ki of 47,220 nM.

Example 8 Sample No. 8 is (4E) -N-methyl-5- (3- (1-oxopyridin) yl) -4-penten-2-amine, which is prepared according to the following technique. Prepared.

(4E) -5- (3-Pyridyl) -4-penten-2-ol 3-bromopyridine (7.50 g, 47.46 mmol), 4-pentene-2.
-Ol (4.90 g, 56.96 mmol), palladium (II) acetate (10
6 mg, 0.47 mmol), tri-o-tolylphosphine (575 mg, 1.
89 mmol), triethylamine (28.4 mL, 204.11 mmol) and acetonitrile (25 mL) in a sealed glass tube at 140 ° C. 1
Heated for 4 hours. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with chloroform (3 x 200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give a pale yellow oil (7.50 g
, 81.0%) was obtained.

(4E) -5- (3-Pyridyl) -4-penten-2-ol p-toluenesulfonate (4E) -5- (3-pyridyl) -4-pentene in dry pyridine (30 mL) at 0 ° C. To a stirred solution of 2-ol (5.00 g, 30.67 mmol) was added p-toluenesulfonyl chloride (8.77 g, 46.01 mmol). The reaction mixture was stirred for 24 hours at ambient temperature. Pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue followed by rotary evaporation. The crude product was stirred with saturated sodium bicarbonate solution (100 mL) and chloroform (3 x 1
(00 mL). The combined chloroform extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography on aluminum oxide eluting with ethyl acetate-hexane (3: 7, v / v). Selected fractions were combined and concentrated by rotary evaporation to give a viscous brown oil (5.83 g, 60.1%).

(4E) -N-methyl-5- (3-pyridyl) -4-penten-2-amine (4E) -5- (3-pyridyl) -4-penten-2-ol p-toluenesulfonate ( 5.60 g, 17.66 mmol), methylamine (100 mL,
40% aqueous solution), and a mixture of ethyl alcohol (10 mL) at ambient temperature 1
Stir for 8 hours. The resulting solution was extracted with chloroform (3 x 100 mL).
The combined chloroform extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography on aluminum oxide eluting with ethyl acetate-methanol (7: 3, v / v). Selected fractions were combined and concentrated by rotary evaporation to give an oil. Colorless oil (boiling point 110-120 ° C at 0.1 mmHg) by further purification by vacuum distillation.
) Was obtained 1.60 g (51.6%).

(4E) -N-methyl-5- (3-pyridyl) -4-pentene-2-amine hemigalactarate (4E) -N-methyl-5- (3-pyridyl) -4-pentene-2 -Amine (
1.60 g, 9.10 mmol) was dissolved in ethyl alcohol (20 mL), assisted by warming to 60 ° C. The warm solution is converted to galactaric acid (955
mg, 4.54 mmol) in portions, then water (0.5 mL) was added dropwise. The solution was filtered while hot to remove some insoluble material. The filtrate was cooled to ambient temperature. The crystals obtained were filtered, washed with anhydrous diethyl ether and dried under vacuum at 40 ° C. to give 1.20 g (47.0%) of a white powder (melting point 1
48-150 ° C) was obtained.

(4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (3-
Pyridyl) -4-penten-2-amine (4E) -N-methyl-5- (3-pyridyl) -4-penten-2-amine hemigalactarate (255.0 mg, 0.906 mmol) was saturated with K ₂ Basified with CO ₃ solution (5 mL), treated with saturated NaCl solution (2 mL), 50% Na
It was made more basic with an OH solution (15 drops). The cloudy mixture was added to CHCl ₃ (10 ×
6 mL). The combined CHCl ₃ extracts were dried (MgSO ₄ ), filtered, concentrated by rotary evaporation and dried under high vacuum (0.8 mmHg) for 1 h.
4E) -N-methyl-5- (3-pyridyl) -4-penten-2-amine was obtained as a yellow oil (140.6 mg) (88.0%). The oil was immediately dissolved in dry THF (7 mL, freshly distilled from sodium and benzophenone) and the resulting solution was stirred at 0 ° C. for di-tert-butyl dicarbonate (191.5 m).
g, 0.878 mmol) under a nitrogen atmosphere. The resulting mixture was stirred and allowed to warm to ambient temperature for 16 hours. The solution was concentrated by rotary evaporation and dried under high vacuum for 1 hour to give a yellow oil (226.1 mg). Column chromatography of the crude product on silica gel (20 g, Merck 70-230 _{mesh), CHCl 3 -CH 3 OH (} 95: 5, v / v) and purified eluting with. Selected fractions containing the product (R _f 0.48) were combined, concentrated by rotary evaporation and briefly vacuum dried at 1 mm Hg to give 217.9 mg (98.8%) of a yellow oil. .

(4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (3-
(1-Oxopyridinyl) yl) -4-penten-2-amine (4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (3-
Pyridyl) -4-penten-2-amine (216.7 mg, 0.7841 mmo
1) CH ₂ Cl ₂ (5 mL) in ice-cooled (0 ° C.) solution (3-chloroperoxybenzoic acid) (154.7 mg, 0.511 to 0.771 mmol) (57 to 86%).
Purity). After stirring for 30 minutes at 0 ° C., TLC analysis showed that
Incomplete reaction was shown (R _f 0.5 for Boc protected amine, R _f 0.08-0.15 for Boc protected amine N-oxide) and additional 3-chloroperoxybenzoic acid (64.7 mg). , 0.2137-0.3224 mmol) was added. After storing at 5 ° C. for 16 hours, the solution was treated with 1M NaOH solution (10 mL) and 10% NaHCO ₃ solution (2 mL). The CH ₂ Cl ₂ layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 5 mL). All CH ₂ Cl ₂ extracts were combined, dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and briefly vacuum dried at 1.5 mm Hg to give 221.6 mg (96.7%) of yellow. An oily substance was obtained.

(4E) -N-Methyl-5- (3- (1-oxopyridin) yl) -4-penten-2-amine Under a nitrogen atmosphere, (4E) -N-methyl-N- (tert- Butoxycarbonyl) -5- (3- (1-oxopyridinyl) yl) -4-penten-2-amine (215.9 mg, 0.738 mmol) in a cold (0 ° C) stirred solution of anisole over 3 minutes. Treated with trifluoroacetic acid (2.5 mL, 32.5 mmol) dropwise. The resulting light yellow solution was stirred for 45 minutes at 0-5 ° C, then 70 ° C.
Concentrated by rotary evaporation using a water bath. The liquid obtained is 1 at 0.5 mmHg
After vacuum drying for 6 hours, a light yellow oily substance (302.5 mg) was obtained. The oil was basified with 1 M NaOH (2 mL) at 0-5 ° C. then treated with saturated NaCl solution (2 mL). The mixture was extracted with CHCl ₃ (14 × 5mL). The combined CHCl ₃ extracts were dried (Na ₂ SO ₄ ), filtered, concentrated by rotary evaporation and dried in vacuo to give 143.8 mg (quantitative yield) of a brown, syrupy semi-solid (CH ₃ OH- Rf 0.23) was obtained with Et ₃ N (97: 3, v / v).

Sample number 8 exhibits a Ki of 5900 nM. The binding constants suggest that the compound exhibits binding to a particular CNS nicotine receptor. Sample is 9%
2 shows the _Emax value of neurotransmitter release.

Sample No. 8 showed 0% E _max (at a concentration of 100 μM) at muscle-type receptors, indicating that the compounds do not induce activation of muscle-type receptors. The sample exhibits an E _max (at a concentration of 100 μM) of 8% at the ganglion type receptor. The compound is
It has the ability to activate the human CNS receptor without activating the muscle and ganglion nicotinic acetylcholine receptors to any significant extent. Therefore, C
A therapeutic window useful for treating NS disorders is provided. That is, it indicates that at certain levels the compounds show CNS effects to a significant extent, but do not show undesired muscle or ganglion effects to any significant extent.

Example 9 Sample No. 9 is (3E) -N-methyl-4- (3- (5-ethylthiopyridin) yl) -3-buten-1-amine hemigalactarate, which is Prepared according to the following technique.

3-Bromo-5-ethylthiopyridine Under a nitrogen atmosphere, NaOH (1.25 g, 31.3 mmol) was added to anhydrous DMF (
40 mL). Then ethanethiol (2.60 mL, 2.20 g, 3
5.5 mmol) is added by syringe and the mixture is stirred for 6 h at 25 ° C. with NaOH.
Stir until dissolved. The solution was cooled to 0 ° C. and 3,5-dibromopyridine (5
． 92 g, 25.0 mmol) was added. After stirring for 15 minutes at 0 ° C. and 45 minutes at 25 ° C., the mixture was poured into water (250 mL) and extracted with ether (2 × 100 mL). The ether was dried (Na ₂ SO ₄ ) and evaporated, then 4.39 (80.6%) of a colorless oil (boiling point 9 at 0.30 mm Hg 9 after vacuum distillation of the crude product).
1-95 ° C) was obtained.

(3E) -N-methyl-N- (tert-butoxycarbonyl) -4- (3-
(5-Ethylthiopyridin) yl) -3-buten-1-amine 3-bromo-5-ethylthiopyridine (1.09 g, 5.00 mmol), N-methyl-N-prepared as previously described. (Tert-Butoxycarbonyl) -3-buten-1-amine (945 mg, 5.10 mmol), palladium (II) acetate (11 mg, 0.049 mmol) and tri-o-tolylphosphine (61 mg, 0.20 mmol), Diluted with acetonitrile (3 mL) and triethylamine (1.5 mL) and heated at 75 ° C. for 40 hours. 11 more
mg of palladium (II) acetate and 61 mg of tri-o-tolylphosphine were added and heating was continued for a further 32 hours. Cool the mixture, pour into water (15 mL),
Extracted with chloroform (2 x 15 mL). The extracts were dried (Na ₂ SO ₄ ), evaporated and the residue column chromatographed on Merck silica gel 60 (70-230 mesh) using a 15-30% (v / v) gradient of ethyl acetate in hexanes. I went to This gave 1.28 g (79.5% yield) of a light yellow viscous oil (
R _f 0.10) was obtained with 17% ethyl acetate in hexane.

(3E) -N-methyl-4- [3- (5-ethylthiopyridin) yl] -3-
Butene-1-amine (3E) -N-methyl-N- (tert-butoxycarbonyl) -4- (3- (
5-Ethylthiopyridin) yl) -3-buten-1-amine (1.27 g, 3.
94 mmol) in THF (25 mL) and cooled to 0 ° C., at which point 6
M HCl water (25 mL) was added. The mixture is stirred for 75 minutes at 25 ° C., 5M
When aqueous NaOH (35 mL) was added, it was cooled again to ice bath temperature. Then saturated aqueous NaCl (35 mL) was added and the mixture was added to chloroform (3 x 100 mL).
). The extracts were dried (Na ₂ SO ₄ ) and evaporated, then 30 g of Merck silica gel 60 (70-230) using 25% (v / v) methanol in benzene, 2.5% (v / v) triethylamine. Column chromatography on (mesh) gave 190 mg of a light yellow oil. The recovered starting material was treated again with aqueous HCl in THF (2.5 ° C. for 2.5 hours) to give 82 mg of the desired product, total weight 272 mg (31.1% yield). It was

(3E) -N-methyl-4- (3- (5-ethylthiopyridin) yl) -3-
Butene-1-amine hemigalactarate (3E) -N-methyl-4- (3- (5-ethylthiopyridin) yl) -3-
Butene-1-amine (265 mg, 1.19 mmol) was added to absolute ethanol (4 m
L), galactaric acid (128 mg, 0.591 mmol) and water (1
mL) was added. The mixture was heated in a hot water bath until clear and then filtered through a glass wool plug to remove a small amount of insoluble material. The flask and filter were washed with 4: 1 (v / v) ethanol / water (2 mL) and the wash was added to the filtrate. The filtrate was diluted with ethanol (6 mL) and slowly cooled to 0 ° C. By vacuum filtration and vacuum oven drying (40 ° C., 24 hours), 281 mg (72
． 8% yield of white powder (melting point 162-164 ° C (decomposition)) was obtained.

[0142]   Sample number 9 exhibits a Ki of 28 nM. The low binding constant makes the compound unique.
It is suggested to show good high binding affinity to certain nicotine receptors. Sump
No. 9 has an EC of 875 nM for dopamine release.₅₀Value and E of 39% _max Values are shown, indicating that the compounds induce neurotransmitter release. Sun
Pull has a EC of 191 nM in the rubidium ion influx assay.₅₀Value and
40% E_maxIndicates a value.

Sample No. 9 exhibits an E _max of 7% (at a concentration of 100 μM) at muscle-type receptors. The sample exhibits an E _max (at a concentration of 100 μM) of 22% at the ganglion type receptor.

Example 10 Sample No. 10 is (4E) -N-methyl-5- (3- (5-trifluoromethylpyridin) yl) -4-penten-2-amine, which is Prepared according to the technique.

(4E) -5- (3- (5-Trifluoromethylpyridin) yl) -4-penten-2-ol 3-chloro-5-trifluoromethylpyridine (4.00 g, 22.03 mm
ol) (Stem Chemicals), 4-penten-2-ol (2.
28 g, 26.44 mmol), palladium (II) acetate (50 mg, 0.22)
mmol), tri-o-tolylphosphine (270 mg, 0.88 mmol),
A mixture of triethylamine (13.8 mL, 99.15 mmol) and acetonitrile (15 mL) was heated at 140 ° C. for 14 hours in a sealed glass tube. The reaction mixture was cooled to ambient temperature, diluted with water (40 mL) and chloroform (3 x
100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to give 2.31 g (45.2%) of a colorless viscous oil.

(4E) -5- (3- (5-Trifluoromethylpyridinyl) -4-penten-2-ol p-toluene sulfonate (4E) -5- (3- (5-tri Fluoromethylpyridin) yl) -4
-Penten-2-ol (2.10 g, 9.09 mmol) in dry pyridine (1
To a stirred solution in 5 mL), p-toluenesulfonyl chloride (5.20 g, 27.
27 mmol) was added. The reaction mixture was stirred for 24 hours at ambient temperature. Pyridine was removed under vacuum, toluene (20 mL) was added and removed on a rotary evaporator. The crude product was stirred with saturated sodium bicarbonate solution (100 mL) for 30 minutes and then extracted with chloroform (4 x 75 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated on a rotary evaporator to give a dark brown viscous oil (2.57 g,
73.5%) was obtained.

(4E) -5- (3- (5-Trifluoromethylpyridin) yl) -4-penten-2-amine (4E) -5- (3- (5-Trifluoromethylpyridinyl)- A mixture of 4-penten-2-ol p-toluenesulfonate (2.30 g, 5.97 mmol) methylamine (50 mL, 40% aqueous solution) and ethyl alcohol (5 mL) was stirred at ambient temperature for 18 hours. 3 × 100 mL) .The combined chloroform extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator.The crude product was purified by column chromatography on neutral alumina with ethyl acetate-methanol (3). : 7), eluting with a dark brown solid, the product was recrystallized from chloroform-hexane. Purified by 650 mg (44.4%) of a pale yellow crystalline solid, mp 144-14.
7 ° C.) was obtained.

Sample number 10 shows a Ki of 3942 nM. The binding constants suggest that the compounds show binding to specific CNS nicotine receptors. The sample had an EC ₅₀ value of 100,000 nM and 0% in the rubidium ion influx assay.
The E _max value of is shown. The sample exhibits a neurotransmitter free E _max value of 50%.

Sample No. 10 exhibits 0% E _max (at a concentration of 100 μM) at muscle-type receptors. The sample exhibits 0% E _max (at a concentration of 100 μM) at the ganglion type receptors.

Example 11 Sample No. 11 is (4E) -N-methyl-5- (3- (5-((carboxymethyl) oxy) pyridin) yl) -4-penten-2-amine, which is Was prepared according to the following technique.

(4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (3- (5-hydroxypyridin) yl) -4-penten-2-amine (prepared as previously described. 156 mg, 0.534 mmol) was cooled to 0 ° C. and 5.0 M of 5.0 M NaOH aqueous solution (0.11 mL, 0.55 mmol) and iodoacetic acid solution (149 mg, 0.801 mmol) were successively added. NaOH water (
0.15 mL, 0.75 mmol) solution was added dropwise for treatment. A precipitate was formed. The mixture was warmed to 25 ° C. and sufficient water (about 0.5 mL) was added to dissolve the precipitate. The homogeneous solution was stirred for 24 hours and then another drop of 5.0 M N 2 was added.
Treated with aOH. After stirring for a further 24 hours, the mixture was concentrated and dried. The residue was dissolved in 6.0 M HCl (4 ml, 24 mmol) and stirred for 1 hour at 25 ° C. Volatile material was evaporated again and the residue was dissolved in 1% (v / v) acetic acid in water, Dow
Applied to ex50 column. After continuous washing with water and 1% (v / v) aqueous ammonia, 93 mg of off-white powder was obtained after lyophilization. Recrystallization from isopropanol gave 17 mg of white powder (mp 160-165).
C (decomposition) was obtained.

Sample number 111 was determined to exhibit a Ki of 100,000 nM. Example 12 Sample No. 12 is (4E) -5- (3- (5-isopropoxypyridine)
Yl) -4-penten-2-amine hemigalactarate, which was prepared according to the following technique.

N- (4- (1-Pentene) yl) phthalimide Under nitrogen, 4-penten-2-ol (5.00 g, 58.1 mmol) at 0 ° C.
To a stirred solution of phthalimide (8.55 g, 58.1 mmol) and triphenylphosphine (15.2 g, 58.1 mmol) in THF (40 mL), diethyl azodicarboxylate (10.1 g, 58.1 mmol) in THF ( 20m
L) The solution was added dropwise. The mixture was stirred at 0 ° C (12 hours) then at 25 ° C (12 hours).
Stir) for hours. The mixture was diluted with water and extracted 3 times with chloroform. The chloroform extract was dried (Na ₂ SO ₄ ), evaporated and subjected to column chromatography on Merck silica gel 60 (70-230 mesh) with chloroform to give 8.77 g (70.2% yield). A colorless oil was obtained.

(4E) -N-phthaloyl-5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine palladium (II) acetate (2.2 mg, 0.010 mmol), tri- of o-tolylphosphine (12 mg, 0.040 mmol), 3-bromo-5-isopropoxypyridine (216 mg, 1.00 mmol) and N- (4- (1-pentene) yl) phthalimide (215 mg, 1.00 mmol). The mixture was diluted with acetonitrile (1.0 mL) and triethylamine (0.5 mL) and heated under nitrogen (80 ° C. oil bath) for 25 hours. The mixture was cooled, poured into water (5 mL) and extracted with chloroform (3 x 5 mL). The extract is dried (Na ₂ SO ₄ ),
Evaporated and subjected to column chromatography on 15 g Merck silica gel 60 (70-230 mesh) with 1: 1: 3 (v / v) ethyl acetate / chloroform / hexane to yield 268 mg (76.6% yield). A very viscous light yellow oil was obtained.

(4E) -5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine (4E) -N-phthaloyl-5- (3- (5-isopropoxypyridin) yl ) -4-Penten-2-amine (258 mg, 0.736 mmol) was dissolved in methanol (4 mL), treated with hydrazine hydrate (0.15 mL, 3.1 mmol) and stirred under nitrogen at 25 ° C. for 36 hours. did. The reaction mixture is then treated with 1M Na
It was poured into a mixture of OH solution (15 mL) and saturated NaCl solution (15 mL) and extracted with benzene (3 x 15 mL). The benzene extract was dried (Na ₂ SO ₄ ), evaporated and 7 g of Merck Silica Gel 60 (70-70%) with 5-10% (v / v) methanol in benzene, 2.5% (v / v) triethylamine. Column chromatography (230 mesh). This gave 118 mg (72.8% yield)
A light yellow oil was obtained.

(4E) -5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine hemigalactarate (4E) -5- (3- (5-isopropoxypyridin) yl) -4-Penten-2-amine (112 mg, 0.508 mmol) in methanol (2.5 mL)
Dissolved in galactaric acid (53 mg, 0.25 mmol) and water (0.20 m
L). The mixture is warmed slightly, filtered through a glass wool plug, slowly warmed to 0 ° C and maintained at that temperature for 48 hours. By vacuum filtration and vacuum oven drying (40 ° C., 24 hours), 53 mg of a white solid (melting point 171.5-
173.5 ° C) was obtained. Second and third products, 50 mg and 5 m
g (mp 170-173 ° C and 169-172 ° C, respectively) were isolated by concentrating the supernatant, giving a total yield of 108 mg (65.5% yield). Three salt samples were slurried together in hot 100% ethanol, cooled and filtered to give 27 mg of an analytical sample of a fine white powder (mp 170-172 ° C).

Sample number 12 exhibits a Ki of 413 nM. The binding constants suggest that the compound exhibits binding to a particular CNS nicotine receptor.

Sample No. 12 is a muscle-type receptor with an E _max of 13% (at a concentration of 100 μM).
Indicates. The sample exhibits an E _max of 5% at the ganglion-type receptor (at a concentration of 100 μM). The sample exhibits 32% neurotransmitter E _max .

Example 13 Sample No. 13 is (4E) -N-methyl-5- (3- (5-hydroxypyridin) yl) -4-penten-2-amine sesquioxalate, which is Was prepared using the same technique.

3-Bromo-5-hydroxypyridine 3-Bromo-5-hydroxypyridine was obtained in 35.0% yield from furfurylamine as described in Clauson-Kaas et al., US Pat. No. 4,192,946. Prepared according to the procedure.

(4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (3-
(5-Hydroxypyridin) yl) -4-penten-2-amine Palladium (II) acetate (65 mg, 0.28 mmol), tri-o-tolylphosphine (354 mg, 1.11 mmol), 3-bromo-5-hydroxy. Pyridine (3.20 g, 18.4 mmol) and N-methyl-N- (tert-butoxycarbonyl) -4-penten-2-amine (3.66 g, 18.4 mmol) prepared as previously described, Diluted with triethylamine (8 mL) and acetonitrile (11 mL). The mixture was heated and stirred under nitrogen in a sealed tube at 120 ° C. for 24 hours. The mixture was cooled, poured into water and extracted with chloroform. The extracts were dried (Na ₂ SO _4), evaporated, chloroform 20-30%
Column chromatography on Merck silica gel 60 (70-230 mesh) with (v / v) acetone. This resulted in 3.6 g (67% yield) of a pale yellow oil.

(4E) -N-methyl-5- (3- (5-hydroxypyridin) yl) -4-
Penten-2-amine Gaseous HCl at 25 ° C. (4E) -N-methyl-N- (tert-butoxycarbonyl) -5- (3- (5-hydroxypyridin) yl) -4-pentene-2.
A solution of the amine (341 mg, 1.17 mmol) in anisole (1 mL) was bubbled. After a brief introduction period, rapid gas evolution and a gummy solid formed. The HCl flow was stopped and the volatiles were evaporated first with a nitrogen flow and then under high vacuum. The residue was dissolved in methanol and filtered. Rotary evaporation of the filtrate left 316 mg of dark semi-solid material still smelling of anisole. This substance is about 12
Combined with another preparation containing 0 mg of impure amine and chromatographed on 15 g Merck silica gel 60 (70-230 mesh) with 5:35:60 (v / v) triethylamine / methanol / chloroform. This allows
201 mg of a brown gum were obtained.

(4E) -N-methyl-5- (3- (5-hydroxypyridin) yl) -4-
Pentene-2-amine sesquioxalate (4E) -N-methyl-5- (3- (5-hydroxypyridin) yl) -4-
Penten-2-amine (83 mg, 0.43 mmol) in methanol (7 mL)
To the solution was added 38 mg (0.43 mmol) oxalic acid. The oxalic acid melted. The mixture was kept at 25 ° C. for 6 hours and the supernatant was aspirated. Vacuum sediment (4
After drying overnight at 0 ° C., 59 mg (49% yield) of fine, light yellow crystals (mp 161-163 ° C.) were obtained.

Sample number 13 shows a Ki of 504 nM. The binding constants suggest that the compound exhibits binding to a particular CNS nicotine receptor. Sample is 80
The% neurotransmitter release E _max values are shown.

Sample No. 13 is a muscular receptor with an E _max of 21% (at a concentration of 100 μM)
Indicates. Samples are 12% E _max at ganglion receptors (at a concentration of 100 μM)
Indicates.

The above is a description of the invention and is not to be construed as limiting. The invention is defined by the following claims, with equivalents of the claims to be included herein.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) A61P 25/08 A61P 25/08 25/14 25/14 25/18 25/18 25/22 25/22 25 / 28 25/28 43/00 111 43/00 111 C07D 213/38 C07D 213/38 213/65 213/65 213/70 213/70 213/82 213/82 213/89 213/89 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW) , EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, M), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Caldwell, William Scott 27106 Winston-Salem, Yorkshire USA 1270 (72) Inventor Lim, Dowo Ameri United States North Carolina 27103, Winston-Salem, Madison Avenue 801 (72) Inventor Batty, Balwinder Singh United States North Carolina 27106, Winston-Salem, Polo Road 2536 (72) Inventor Schmid, Jeffrey Daniels United States North Carolina State 27101, Winston-Salem, Laurel Streight 632 (72) Inventor Beard, Gary Dwight North Carolina, USA 27127, Winston-Salem, Vintage Avenue 204 (72) Inventor Haddy Mani, Sri Shalkumar Vassa Wannaappa United States North Carolina State 27105, Winston-Salem, Elsa Drive 5009, # E-F Term (reference) 4C055 AA01 AA17 BA01 BA02 BA51 BA52 CA02 CA03 CA13 CA27 CA34 CA42 CA47 CA52 CB02 CB04 CB14 DA01 FA03 FA11 FA13 FA15 4C086 AA01 AA02 AA03 BC17 BC19 MA01 MA04 MA13 MA17 MA22 MA23 MA32 MA35 MA37 MA41 MA43 MA52 MA56 MA59 MA63 MA66 NA06 NA14 ZA06 ZA08 ZA15 ZA16 ZA18 ZA22 ZC41

Claims (36)

[Claims] 1. The formula: [Wherein X, X ', X ", Y'and Y" independently of one another have nitrogen, nitrogen oxides, or sigma m values between about -0.3 and about 7.5. A carbon bonded to a substituent species characterized by having 3 of X, X ′, X ″, Y ′ and Y ″.
Less than one is nitrogen or a nitrogen oxide, one or less of X, X ′, X ″, Y ′ and Y ″ is a nitrogen oxide, and m and n are the sum of m and n is 1, 2, 3, 4,
Is an integer such that 5 or 6 is present, B'is a two carbon bridging species, Z and Z'are independently of each other hydrogen or methyl, and E, E ^I , E ^II and E ^III are independent of each other. And is hydrogen or methyl.]. 2. The formula: [Wherein X ′ and X ″ are, independently of each other, nitrogen, or a carbon bonded to a substituent species having a sigma m value of between about −0.3 and about 0.75. And X, Y ′ and Y ″ are, independently of each other, carbons attached to a substituent species characterized in that they have a sigma m value of between about −0.3 and about 0.75. , M and n are integers such that the sum of m and n is 1, 2, 3, 4, 5 or 6, B ′ is a two carbon bridging species and Z and Z ′ are independent of each other. Is hydrogen or methyl, and E, E ^I , E ^II and E ^III are each independently hydrogen or methyl]. 3. The compound according to claim 1, wherein X ′ and X ″ are each nitrogen. 4. A compound according to claim 1 or 2 wherein B'is CR '= CR' and R'independently of each other is hydrogen or methyl. 5. The compound according to claim 1 or 2, wherein each of Y ′ and Y ″ is a hydrogen-bonded carbon. 6. The compound according to claim 1 or 2, wherein X ″ is a nitrogen oxide. 7. The compound according to claim 1 or 2, wherein X ″ is nitrogen. 8. The compound according to claim 1 or 2, wherein the sum of m and n is 2 or 3. 9. The compound according to claim 1 or 2, wherein m is 1 and n is 1. 10. The compound according to claim 1 or 2, wherein X'is CH, CBr or COR 'and R'is hydrogen or alkyl. 11. (2S)-(4E) -N-methyl-5- [3- (5-isopropoxy-1-oxopyridin) yl)]-4-penten-2-amine, (3
E) -N-methyl-4- (3- (1-oxopyridin) yl) -3-butene-1
-Amine, (4E) -N-methyl-5- (3- (1-oxopyridin) yl)-
4-penten-2-amine, and (4E) -N-methyl-5- (3- (5- (
The compound according to claim 1, which is (carboxymethyl) oxy) pyridinyl) -4-penten-2-amine. 12. (3E) -N-Methyl-4- [3- (5-nitro-6-aminopyridin) yl] -3-buten-1-amine, (3E) -N-methyl-4-.
[3- (5- (N-benzylcarboxamido) pyridin) yl] -3-buten-1-amine, (4E) -N-methyl-5- [5- (2-aminopyrimidin) yl] -4- Penten-2-amine, (4E) -N-methyl-5- (3- (5-aminopyridin) yl) -4-penten-2-amine, (3E) -N-methyl-4
-(3- (5-isobutoxypyridin) yl) -3-buten-1-amine, (3
E) -N-methyl-4- (3- (5-ethylthiopyridin) yl) -3-buten-1-amine, (4E) -N-methyl-5- (3- (5-trifluoromethylpyridine) ) Yl) -4-penten-2-amine, (4E) -5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine, and (4E) -5.
The compound according to claim 2, which is-(3- (5-isopropoxypyridin) yl) -4-penten-2-amine. 13. An effective amount of a formula: ## STR00003 ## together with a pharmaceutically acceptable carrier. [Wherein X, X ', X ", Y'and Y" independently of one another have nitrogen, nitrogen oxides, or sigma m values between about -0.3 and about 7.5. A carbon bonded to a substituent species characterized by having 3 of X, X ′, X ″, Y ′ and Y ″.
Less than one is nitrogen or a nitrogen oxide, one or less of X, X ′, X ″, Y ′ and Y ″ is a nitrogen oxide, and m and n are the sum of m and n is 1, 2, 3, 4,
Is an integer such that 5 or 6 is present, B'is a two carbon bridging species, Z and Z'are independently of each other hydrogen or methyl, and E, E ^I , E ^II and E ^III are independent of each other. And is hydrogen or methyl]. 14. An effective amount of a compound of formula: ## STR00004 ## together with a pharmaceutically acceptable carrier. [Wherein X ′ and X ″ are, independently of each other, nitrogen, or a carbon bonded to a substituent species having a sigma m value of between about −0.3 and about 0.75. And X, Y ′ and Y ″ are, independently of each other, carbons attached to a substituent species characterized in that they have a sigma m value of between about −0.3 and about 0.75. , M and n are integers such that the sum of m and n is 1, 2, 3, 4, 5 or 6, B ′ is a two carbon bridging species and Z and Z ′ are independent of each other. Is hydrogen or methyl, and E, E ^I , E ^II, and E ^III are each independently hydrogen or methyl.]. 15. The pharmaceutical composition according to claim 13 or 14, wherein X ′ and X ″ are each nitrogen. 16. The pharmaceutical composition according to claim 13 or 14, wherein B'is CR '= CR' and R'independently of each other is hydrogen or methyl. 17. The pharmaceutical composition according to claim 13 or 14, wherein each of Y ′ and Y ″ is a hydrogen-bonded carbon. 18. The pharmaceutical composition according to claim 13 or 14, wherein X ″ is nitrogen oxide. 19. The pharmaceutical composition according to claim 13 or 14, wherein X ″ is nitrogen. 20. The pharmaceutical composition according to claim 13 or 14, wherein the sum of m and n is 2 or 3. 21. The pharmaceutical composition according to claim 13 or 14, wherein m is 1 and n is 1. 22. The pharmaceutical composition according to claim 13 or 14, wherein X ′ is CH, CBr or COR ′, and R ′ is hydrogen or alkyl. 23. The above compound is (2S)-(4E) -N-methyl-5- [
3- (5-isopropoxy-1-oxopyridin) yl)]-4-pentene-2
-Amine, (3E) -N-methyl-4- (3- (1-oxopyridin) yl)-
3-buten-1-amine, (4E) -N-methyl-5- (3- (1-oxopyridin) yl) -4-penten-2-amine, and (4E) -N-methyl-5-.
The pharmaceutical composition according to claim 13, which is selected from the group consisting of (3- (5-((carboxymethyl) oxy) pyridin) yl) -4-penten-2-amine. 24. The above compound is (3E) -N-methyl-4- [3- (5-
Nitro-6-aminopyridin) yl] -3-buten-1-amine, (3E) -N
-Methyl-4- [3- (5- (N-benzylcarboxamido) pyridin) yl] -3-buten-1-amine, (4E) -N-methyl-5- [5- (2-aminopyrimidine) Il] -4-penten-2-amine, (4E) -N-methyl-5-
(3- (5-aminopyridin) yl) -4-penten-2-amine, (3E)-
N-methyl-4- (3- (5-isobutoxypyridin) yl) -3-butene-1
-Amine, (3E) -N-methyl-4- (3- (5-ethylthiopyridin) yl) -3-buten-1-amine, (4E) -N-methyl-5- (3- (5- Trifluoromethylpyridin) yl) -4-penten-2-amine, (4E) -5- (
The group consisting of 3- (5-isopropoxypyridin) yl) -4-penten-2-amine, and (4E) -5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine. The pharmaceutical composition according to claim 14, which is selected from the group consisting of: 25. A method of treating a disease characterized by alterations in normal neurotransmitter release, wherein a subject in need thereof is treated with an effective amount of the formula: [Wherein X, X ', X ", Y'and Y" independently of one another have nitrogen, nitrogen oxides, or sigma m values between about -0.3 and about 7.5. A carbon bonded to a substituent species characterized by having 3 of X, X ′, X ″, Y ′ and Y ″.
Less than one is nitrogen or a nitrogen oxide, one or less of X, X ′, X ″, Y ′ and Y ″ is a nitrogen oxide, and m and n are the sum of m and n is 1, 2, 3, 4,
Is an integer such that 5 or 6 is present, B'is a two carbon bridging species, Z and Z'are independently of each other hydrogen or methyl, and E, E ^I , E ^II and E ^III are independent of each other. And is hydrogen or methyl]. 26. A method of treating a disorder characterized by alterations in normal neurotransmitter release, wherein a subject in need thereof is treated with an effective amount of the formula: [Wherein X ′ and X ″ are, independently of each other, nitrogen, or a carbon bonded to a substituent species having a sigma m value of between about −0.3 and about 0.75. And X, Y ′ and Y ″ are, independently of each other, carbons attached to a substituent species characterized in that they have a sigma m value of between about −0.3 and about 0.75. , M and n are integers such that the sum of m and n is 1, 2, 3, 4, 5 or 6, B ′ is a two carbon bridging species and Z and Z ′ are independent of each other. a Te hydrogen or methyl, E, E ^I, mETHOD E ^II and E ^III, including administering a compound represented by the mutually independently hydrogen or methyl. 27. The method according to claim 25 or 26, wherein X ′ and X ″ are nitrogen. 28. The method according to claim 25 or 26, wherein B'is CR '= CR' and R'independently of each other is hydrogen or methyl. 29. The method according to claim 25 or 26, wherein each of Y ′ and Y ″ is a hydrogen-bonded carbon. 30. The method according to claim 25 or 26, wherein X ″ is nitrogen oxide. 31. The method according to claim 25 or 26, wherein X ″ is nitrogen. 32. The method according to claim 25 or 26, wherein the sum of m and n is 2 or 3. 33. The method according to claim 25 or 26, wherein m is 1 and n is 1. 34. The method according to claim 25 or 26, wherein X'is CH, CBr or COR 'and R'is hydrogen or alkyl. 35. The above compound is (2S)-(4E) -N-methyl-5- [
3- (5-isopropoxy-1-oxopyridin) yl)]-4-pentene-2
-Amine, (3E) -N-methyl-4- (3- (1-oxopyridin) yl)-
3-buten-1-amine, (4E) -N-methyl-5- (3- (1-oxopyridin) yl) -4-penten-2-amine, and (4E) -N-methyl-5-.
26. The method of claim 25, selected from the group consisting of (3- (5-((carboxymethyl (oxy) pyridin) yl) -4-penten-2-amine. 36. The above compound is (3E) -N-methyl-4- [3- (5-
Nitro-6-aminopyridin) yl] -3-buten-1-amine, (3E) -N
-Methyl-4- [3- (5- (N-benzylcarboxamido) pyridin) yl] -3-buten-1-amine, (4E) -N-methyl-5- [5- (2-aminopyrimidine) Il] -4-penten-2-amine, (4E) -N-methyl-5-
(3- (5-aminopyridin) yl) -4-penten-2-amine, (3E)-
N-methyl-4- (3- (5-isobutoxypyridin) yl) -3-butene-1
-Amine, (3E) -N-methyl-4- (3- (5-ethylthiopyridin) yl) -3-buten-1-amine, (4E) -N-methyl-5- (3- (5- Trifluoromethylpyridin) yl) -4-penten-2-amine, (4E) -5- (
The group consisting of 3- (5-isopropoxypyridin) yl) -4-penten-2-amine, and (4E) -5- (3- (5-isopropoxypyridin) yl) -4-penten-2-amine. 27. The method of claim 26, selected from