CZ20001716A3 - 5-HT1F agonists - Google Patents

Abstract

The present invention relates to 5-HT 1F agonists of formula (I), ve wherein A-B, X, and R are as defined in the specification. Solution it further relates to pharmaceutical compositions comprising the same the compounds of the present invention as well as methods of treating conditions associated with 5-HT1F activation using of these compounds or compositions.

Description

This invention relates to novel 5-HT _1F agonists, pharmaceutical compositions containing them and methods of treating conditions associated with activation of 5-HT _F using these compounds or compositions.

BACKGROUND OF THE INVENTION

Serotonin (5-HT) exhibits various physiological effects, mediated by at least seven classes of receptors, of which the 5-HT 1 class seems most heterogeneous. A human gene that expresses one of these 5-HT 1 receptor subtypes, referred to as

5-HTxF, isolated by Kao and co-workers (Proc. Natl. Acad. Sci. USA, 90, 408-412 (1993)). This _5-HTIF receptor exhibits a pharmacological profile distinct from any serotonergic receptors which have been described hitherto.

Moskowitz suggested the hypothesis that the currently unknown cause of pain stimulates trigeminal ganglia that innervate vasculature in brain tissue, leading to the release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a sequence of events that result in pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids through mechanisms that include 5-HT receptors, o ftft ftftftft ftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftft Which are thought to be closely bound to the 5-HT _1D subtype, located on trigeminovascular fibers (Neurology, 43 (suppl. 3)) S16-S20 (1993)). 5-HT 1F receptor agonists have been shown to inhibit peptide extravasation by stimulating the trigeminal ganglia (Audia and Nissen, US Patent No. 5,521,196).

Compounds which exhibit affinity for 5-HT receptors, _F represent a novel approach to the treatment of diseases related to abnormal serotonergic neurotransmission. Furthermore, compounds selective for the 5-HT subtype _F receptors are potentially useful for treating such diseases while causing fewer undesired side effects.

SUMMARY OF THE INVENTION

The present invention relates to 5-substituted-3- (piperidin-4-yl) - and 5-substituted-3- (1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridines of formula I :

I · _ · ♦ φ «φ φ φ • · · · · · · ve ve · · · · · · · ve ve ve ve ve

A-B is -C =CH- or -CH-CH 2 -;

R represents H, C 1 -C 6 alkyl, benzyl or phenylethyl;

X represents halogen, hydroxy, C 1 -C 4 alkoxy, -NHR ¹ , -C (O) OR ² , or -C (O) NHR ³ wherein:

R ¹ represents C 1 -C 4 alkyl, phenyl (C 1 -C 4 alkylenyl) or heteroaryl (C 1 -C 4 alkylenyl);

R ² represents a hydrogen atom or C1-C4 alkyl;

R ³ represents C 1 -C 4 alkyl, heterocycle or phenyl optionally monosubstituted with halogen or hydroxy; and pharmaceutically acceptable acid addition salts and solvates thereof, provided that when AB is -C =CH-, then X is not a hydroxy group, a halogen atom, or a C 1 -C 4 alkoxy.

The present invention also relates to a pharmaceutical composition which, together with a pharmaceutically acceptable carrier, diluent or excipient, also comprises a compound of formula I.

Another embodiment of the present invention is a method for increasing activation of the _5-HTIF receptor for treating a variety of disorders linked to decreased neurotransmission of serotonin in mammals. These disorders include depression, migraine pain, bulimia, premenstrual or late luteus syndrome, alcoholism, tobacco, panic disorder, anxiety, general pain, chronic pain, post-traumatic syndrome, memory loss, old-age dementia, social phobia, hyperactivity disorder Attention Deficit Disorder, Disruptive Behavioral Disorder, Impulse Control Disorder, Personality Uncertainty Disorder, Obsessive Compulsive Disorder, Chronic Fatigue Syndrome, Premature Ejaculation, Erectile Difficulties, Anorexia Nervosa, 0 · 4 · · · · · 4 4 · 4

4 4 4 · 4 4 4 44 • 4 Λ 9 _4 4 4 9 9 9 44

4 * 44 ·· · ···

9 9 tt 9 0 4 4 4 44 rhinitis, teeth or sleep disorders, autism, mutism, allergic trichothilomania, trigeminal neuralgia, pain temperomandibular pain in joint dysfunction. The compounds of the present invention are also useful as a prophylactic treatment of migraine. Any of these methods uses compounds of Formula II:

in which

AB is -C =CH- or -CH-CH ₂ -;

R is H, C1-4 alkyl, benzyl or phenylethyl;

X represents a halogen atom, hydroxy, C 1 -C ₄ alkoxy, -NHR ¹ , -C (O) OR ² , or -C (O) NHR ³ wherein:

R ¹ represents O ₄ -O ₄ alkyl, phenyl (O ₄ -O ₄ alkylenyl) or heteroaryl (C 1 -C 4 alkylenyl);

R ² represents a hydrogen atom or C1-C4 alkyl;

R ³ represents O ₄ -O ₄ alkyl, heterocycle or phenyl optionally monosubstituted with halogen or hydroxy; and pharmaceutically acceptable acid addition salts and solvates thereof.

Use of compounds of Formula II for the activation of 5-HT _F • ···· ·· ·· · β · «φ · · · · · · · · · • ···· · · • c * 9 9 9 9 9 The receptors, for inhibiting peptide extravasation in general or as a result of stimulating the trigeminal ganglion specifically and for treating any of the above disorders described above, represent various embodiments of the present invention.

The present invention also relates to methods and synthetic intermediates useful for preparing the compounds of the present invention.

The general chemical terms used in the above formulas have their usual meanings. For example, the term alkyl includes such groups as methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl-, 3-pentyl-, neopentyl, hexyl and the like. alike. The term alkoxy includes such groups as methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy and the like. The term halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.

The term phenyl (C 1 -C 4 alkylenyl) means a branched or linear C 1 -C 4 alkyl chain substituted at some position by the phenyl ring and includes such groups as benzyl, phenethyl, phenpropyl and phenbutyl.

The term heteroaryl (C 1 -C ₄ alkylenyl) means a branched or linear alkyl chain having 1 to 4 carbon atoms, substituted at some position by a heterocycle.

The term heterocycle means stable aromatic and non-aromatic 5- and 6-membered rings containing carbon and 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said rings are optionally monobenzocondensed. These rings include furyl, thienyl, pyridinyl, pyridinyl-N-oxide, piperidine, N-methylpiperidine, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like. Benzo-fused rings include isoquinolinyl, isoquinolinyl-N-oxide, benzoxazolyl, benzthiazolyl, quinolinyl, quinolinyl-N-oxide, benzofuranyl, thionaphthyl, indolyl and the like.

While all of the compounds of the present invention are useful as 5-HT _F agonists, certain classes of compounds are preferred. The following paragraphs describe such preferred classes.

a) A-B is -C =CH-;

b) A-B is -CH-CH 2 -;

c) R represents C 1 -C 6 alkyl;

d) R is methyl;

e) R is H;

f) X represents a halogen atom;

g) X is chlorine;

h) X is hydroxy;

i) X represents C 1 -C 4 alkoxy;

k) X is -C (O) OR ² ;

l) X is C (O) NHR ³ ;

m) R ¹ represents C 1 -C 4 alkyl;

n) R ¹ represents phenyl (C 1 -C 4 alkylenyl);

o) R ¹ represents heteroaryl (C 3 -C 4 alkylenyl);

p) R ² is hydrogen;

Λ 4 • · · · 4 ··· 44

44 444 444 • 4 4 4 4444 4 4 · ·

94 ^ 444 4,444 ·· * · “* 4/4 4 4 4 4 44 4

444 44 44 · · 44

q) R ² represents C 1 -C 4 alkyl;

r) R ³ represents C 1 -C 4 alkyl;

s) R ³ represents phenyl;

t) R ³ represents phenyl monosubstituted with halogen or hydroxy;

u) R ³ represents halophenyl;

v) R ³ represents hydroxyphenyl;

w) R ³ represents a heterocycle;

x) the compound is the free base;

y) the compound is a salt.

The compounds of the present invention, depending on their structure and method of synthesis and isolation, may exist as pharmaceutically acceptable solvates. These solvates include water, methanol and ethanol. The solvated forms of the compounds of the present invention are further embodiments of the present invention.

Compounds of the present invention wherein X is hydroxy may exist as a mixture of keto / enol tautomeric forms. The present invention includes the keto form, the enol form, and any tautomeric mixture thereof.

Compounds of the present invention are useful as a method for increasing activation of the _5-HTIF receptor for treating a variety of disorders linked to decreased neurotransmission of serotonin in mammals. A preferred mammal for treatment by administering the compounds of the present invention is a human.

Since the compounds of the present invention are amines, they are basic in nature and consequently react with an amount

creation

Advantageously acceptable «« · · and · ·· · ·

9 9 Inorganic and organic acid acids for pharmaceutically acceptable acid addition salts, convert free amines into their pharmaceutically acid addition salts to facilitate processing and administration . The acids commonly used to form such salts are inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric and the like and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromo- phenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Thus, examples of such pharmaceutically acceptable salts are sulfate, bisulfate, sulfite, bisulfite, monohydrogen phosphate, metaphosphate, pyrophosphate, pyrosulfate, phosphate, dihydrogen phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, acrylate, acrylate, acrylate, , malonate, succinate, suberate, sebacate, fumarate, formate, oxalate, maleic, butin-1,4-dioate, methylbenzoate, methoxybenzoate, phenylacetate, hexine-1, β-dioate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, phthalate, sulfonate , xylene sulfonate, phenylpropionate, phenylbutyrate, citrate, lactate, p-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelan and the like. Preferred pharmaceutically acceptable salts are those with hydrochloric acid.

The following group are illustrative compounds of formulas I and II which are within the scope of the subject matter.

444 of the present invention .;

5-fluoro-3- (1-hexylpiperidin-4-yl) pyrrolo [3,2-b] pyridine; 5-Bromo-3- (1-benzyl-piperidin-4-yl) -pyrrolo [3,2-b] pyridine; 5-Iodo-3- (1- (1-phenyleth-2-yl) piperidin-4-yl) pyrrolo [3,2-b] pyridine;

5-ethoxy-3- (1-pentylpiperidin-4-yl) pyrrolo [3,2-b] pyridine; 5-Propoxy-3- (1-butylpiperidin-4-yl) pyrrolo [3,2-b] pyridine; 5-isopropoxy-3- (1-isobutylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [methyl] amino) -3- (1-isopropylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [propyl] amino) -3- (1-ethylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [isopropyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [butyl] amino) -3- (1-benzylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [phenethyl] amino) -3- (1- (1-phenyleth-2-yl) piperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [phenopropyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [phenbutyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [3-furylmethyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [pyridin-2-ylethyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [3- (pyridin-4-yl-N-oxide) prop-1-yl] amino) 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [4- (2-Piperidin) but-1-yl] amino) -3- (1-methylpiperidine)

4-yl) pyrrolo [3,2-b] pyridine;

• 0 · «♦ <··· • · · · · · ·

4. LQ *

5- (N- [3-furylmethyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(oxazol-2-yl) methyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(pyrimidin-4-yl) methyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(indol-4-yl) methyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(quinolin-6-yl) methyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine;

N- [3-furyl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine

5-carboxamide;

N- [pyridin-2-yl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyridin-4-yl-N-oxide] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyrrol-2-yl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyrazol-3-yl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [oxazol-2-yl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyrimidin-4-yl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [indol-4-yl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [quinolin-6-yl] -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

5-fluoro-3- (1-hexyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5-bromo-3- (1-benzyl-1,2,3,6-tetrahydropyridine)

I I - e * e e--------

4-yl) pyrrolo [3,2-b] pyridine;

5-iodo-3- (1- (1-phenyleth-2-yl) -1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5-ethoxy-3- (1-pentyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5-Propoxy-3- (1-butyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5-isopropoxy-3- (1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [methyl] amino) -3- (1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [propyl] amino) -3- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [isopropyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [butyl] amino) -3- (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [phenethyl] amino) -3- (1- (1-phenyleth-2-yl) 1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [phenopropyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [phenbutyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridine)

4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [3-furylmethyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [pyridin-2-ylethyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N- [3- (pyridin-4-yl-N-oxide) prop-1-yl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3] 2-b] pyridine;

5- (N- [4- (2-piperidin) but-1-yl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine ;

99 »♦ <

I 9 9 <

r · · <

· · · · · · ·

998 9 9 9

5- (N- [3-furylmethyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(oxazol-2-yl) methyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(pyrimidin-4-yl) methyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(indol-4-yl) methyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

5- (N - [(quinolin-6-yl) methyl] amino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine;

N- [3-furyl] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyridin-2-yl] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyridin-4-yl-N-oxide] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyrrol-2-yl] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyrazol-3-yl] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [oxazol-2-yl] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [pyrimidin-4-yl] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [indol-4-yl] -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

N- [quinolin-6-yl] -3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide;

The compounds of the present invention are prepared by the methods ft ft ftft # ** ftft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft described in Synthetic Scheme I wherein X 'represents a halogen atom or C1-C4 alkoxy; and R is as defined above.

Synthetic Scheme I

The 5-substituted-pyrrolo [3,2-b] pyridine is condensed with 4-piperidone in lower alkanols, typically methanol or ethanol, in the presence of a suitable base. Suitable bases include potassium hydroxide or sodium hydroxide and sodium alkoxides such as sodium methoxide. The reaction is carried out at reflux to give the corresponding 5-substituted 3- (1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridines of the present invention. The product can be isolated by filtration or extraction and can be purified by recrystallization or chromatography if necessary;

4 4

4 4 4

4 · • 44 4 • 4 4 14 14:

444 44

4 · · 4 · · 4 · «· ♦

4 4

9 4

4 4 4 # required.

The 5-substituted-3- (1,2,3, β-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridines of the present invention, which are themselves useful as 5-HT _1F agonists, can be hydrogenated to yield 5-substituted 3- (piperidin-4-yl) pyrrolo [3,2-b] pyridines according to the present invention. Typically, the conversion is carried out under standard hydrogenation conditions, for example, by hydrogenating a substrate solution in a lower alkanol, typically methanol or ethanol, or a mixture of a lower alkanol and tetrahydrofuran, in the presence of a noble metal catalyst, typically either platinum or palladium on carbon.

Compounds representing intermediates of the present Scheme II, R ³ have the above according to the present invention in which X 1 -C ₄ alkoxy are also useful as for the preparation of other compounds of the invention as illustrated in Synthetic wherein R ² 'represents C 1 -C 4 alkyl and AB, R, and as defined.

It is this »♦ ·« ·· r 15J ^Λ • · a * «♦ ♦ It ·· · t

To toto to to to to to toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto

Synthetic Scheme II

OH

A suitable 5-alkoxypyrrolo [3,2-b] pyridine is heated with an aqueous acid, typically hydrobromic acid, to prepare the corresponding 5-hydroxypyrrolo [3,2-b] pyridine. This 5-hydroxy derivative is then treated with trifluoromethanesulfonic anhydride in a suitable solvent, typically pyridine, to afford the corresponding triflate of formula III. The triflates of formula (III) are novel and represent further embodiments of the present invention.

• 44

4444 • 4 4 444 · · __ 4 4

4 ··

44

4 4 · 4 4

4 ·

The triflates of formula III are useful for preparing compounds of the present invention wherein X is -C (O) NHR ³ or C (O) OR ^{2 by} subjecting triflates to palladium catalyzed carbonylation conditions in the presence of a suitable amine or alcohol. A mixture of triflates, palladium acetate, 1,1'-bis (diphenylphosphine) ferrocene and a proton scavenger such as triethylamine or potassium carbonate and the appropriate amine or alcohol is mixed in a suitable solvent, typically acetonitrile or dimethylformamide. The mixture was saturated with carbon monoxide and then heated to completion. The corresponding amides or esters are typically isolated by standard extraction processing and purified by crystallization or chromatography. One skilled in the art will appreciate that compounds of the present invention in which X is -C (O) OH are prepared by subjecting a suitable ester of the present invention to acidic or basic hydrolysis conditions.

Compounds of the present invention wherein X represents -C (O) OH, although valuable 5-HT _1F agonists, are also useful intermediates for the preparation of compounds of the present invention wherein X represents C (O) NHR ³ . These compounds are prepared by reacting an amine of formula R ³ NH ₂ with a suitable carboxylic acid or carboxylic acid derivative under standard amide bond formation conditions.

Compounds of the present invention wherein X is -NHR ¹ are prepared by functionalizing the corresponding 5-aminopyrrolo [3,2-b] pyridine under standard acylation / reduction or reduction alkylation conditions.

ft * ····

Ftft ft ft ft ft ft ft ft

Briefly, a solution of 5-aminopyrrolo [3,2-b] pyridine in a suitable solvent such as tetrahydrofuran, dioxane or diethyl ether, at a temperature ranging from ambient to about 0 ° C, is reacted with a suitable acylating agent in the presence of a suitable base such as is pyridine or triethylamine. The acylated product is then dissolved in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature from ambient to about 0 ° C and treated with a suitable hydride reducing agent such as diborane or lithium ammonium hydride. The reaction mixture was stirred for 1 to 24 hours and then treated with aqueous sodium sulfate. The resulting suspension is filtered and the filtrate is concentrated under reduced pressure to obtain the desired product.

Alternatively, a solution of 5-aminopyrrolo [3,2-b] pyridine in a solvent suitable for azeotropic removal of water, such as toluene, benzene or cyclohexane, is reacted at reflux with the appropriate aldehyde or ketone in the presence of 0.1-10% proton sources such as ptoluenesulfonic acid. When the reaction is complete, the volatiles are removed under reduced pressure and the residue redissolved in an alkanol such as methanol or ethanol. This solution is then subjected to hydrogenation conditions or treated with a suitable hydride reducing agent such as sodium borohydride or preferably sodium cyanoborohydride in the presence of an anhydrous acid such as hydrogen chloride. The product is isolated by normal extraction treatment.

The desired 5-substituted pyrrolo [3,2-b] pyridines necessary for the preparation of the compounds of the present invention can be prepared as described in Synthetic Scheme III, as described in Synthetic Scheme III. · ·· · · · · · · · ·

4 4 4 4 4 4 4 4 4 4 4 • 4 9 4 9 4 9 9 9 4 ** X is a halogen atom or a C1-C4 alkoxy group.

Synthetic scheme III

The 2-methyl-3-nitro-6-substituted pyridine can be reacted either with dimethylformamide dimethylacetal in dimethylformamide or with tris (dimethylamino) methane in toluene at elevated temperature to prepare the corresponding iminoenamine. If X represents C 1 -C 4 alkoxy, then the iminoenamine in lower alkanol, typically ethanol, or a mixture of lower alkanol and tetrahydrofuran, is then hydrogenated on Raney nickel or a noble metal catalyst, typically platinum or palladium on carbon, to yield the corresponding

5- (C 1 -C ₄ alkoxy) pyrrolo [3,2-b] pyridine. When X represents a halogen atom, the iminoenamine is reacted with metal iron in toluene / acetic acid to give the desired 5-halopyrrolo [3,2-b] pyridine. The 5-substituted pyrrolo [3,2-b] pyridines may be purified by recrystallization or chromatography, if necessary or desired, prior to use in the preparation of the compounds of the present invention.

The β-substituted 3-nitro-2-picolines required to prepare the corresponding 5-substituted-pyrrolo [3,2-b] pyridines are:

9

9 · 99 99

9 9 9 9 9

9 9 9 9 99

9 9 9 9

9 9 9 9 9

99-99 99 99 99 99 either commercially available or may be prepared in a manner well known to the person skilled in the art.

The desired 5-substituted-pyrrolo [3,2-b] pyridine required for the preparation of compounds of the present invention in which X represents -NHR ¹ may be prepared as described in Synthetic Scheme IV.

• this • to • to • - • to 20 - this to this • to this • to • this • to

Synthetic Scheme IV

Nitration is carried out by adding an equivalent of 90% nitric acid dissolved in an equal volume of concentrated sulfuric acid. previously cooled to 0 ° C into solution

Of 6-amino-2-picoline (6-amino-2-methylpyridine) in five volumes (relative to the volume of the nitric acid solution) of concentrated sulfuric acid at -6 ° C. The nitric acid solution was added at a rate such that the temperature of the reaction mixture was maintained at about -2 ° C. The reaction mixture is stirred at about 0 ° C for one hour and then allowed to warm to about 10 ° C over one hour. The temperature of the reaction mixture is maintained at about 10 ° C for one hour, and then the mixture is allowed to warm to about 20 ° C over one hour. The reaction mixture is maintained at about 20 ° C for 2 hours. The reaction mixture is then poured onto ice, rendered basic (pH about 9) by addition of a suitable hydroxide base, typically potassium, sodium or ammonium hydroxide, maintaining the temperature at about 20 ° C by adding ice if necessary. The resulting slurry was filtered, washed with water and dried to give a 2: 1 mixture of 3-nitro-: 5-nitro-6-amino-2-picoline.

The undesired 5-nitro-6-amino-2-picoline isomer can be removed by steam distillation, sublimation, or fractional crystallization from a suitable solvent, preferably toluene. The desired 3-nitro-6-amino-2-picoline is then reacted with dimethylformamide dimethylacetal or tris (dimethylamino) methane in a suitable solvent, typically dimethylformamide. Once the reaction is complete, the reaction mixture is treated with either water or isopropanol to precipitate the desired intermediate IV, which is isolated by filtration. Alternatively, intermediate IV can be prepared directly by exposure of the nitration isomer mixture described above to dimethylformamide dimethylacetal or tris (dimethylamino) methane. Processing the resulting reaction ·· * «

• 4,444 ·

4 4

4 44 «

4 ·· * »

4 4 · · »

44

4 4 4

4 4 4

4 4 4 4

4 4 4

44 of the mixture with water results in the precipitation of intermediate IV, which can be isolated by filtration.

Once it is and the filtrate is desired it can be

Intermediate IV may then be hydrogenated in a lower alkanol, typically ethanol, in the presence of a palladium catalyst, typically 10% palladium on charcoal hydrogenation, the reaction mixture is filtered, concentrated under reduced pressure.

5- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine used as obtained in subsequent reactions or first purified by slurry washing or silica gel chromatography, if necessary or desired. Exposure

5- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine according to the reaction conditions described in Synthetic Scheme I gives 5-aminopyrrolo [3,2-b] pyridines necessary for the preparation of the corresponding compound of the present invention.

Alternatively, compounds of the present invention wherein X is -NHR ¹ may be prepared as described in the Synthetic Scheme.

IN.

Intermediate IV is hydrogenated in hydrogen chloride-containing methanol in the presence of a palladium catalyst, typically 10% palladium on carbon. The resulting 1-hydroxy-5- (dimethylaminomethanimino) -pyrrolo [3,2-b] pyridine dihydrochloride is isolated by filtration of the reaction mixture and can be further purified and removed from the catalyst by recrystallization. The amidine functional group at the 5-position of the pyrrolo [3,2-b] pyridine may be a to 4-to-one. · 9 /? - · · · ·· ·· that • "• * Z ⁴ · 4 4 4 this personal identification ·· 949 94 94 removed to give the corresponding amine by heating the amidine substrate in ethanol under acidic conditions or under neutral hydrogenation conditions. The amidine functionality at the 5-position can be removed either before or after reaction with the appropriate 4-piperidone under the conditions described for Synthetic Scheme I to obtain the desired 5-aminopyrrolo [3,2-b] pyridines. Regardless of when the amidine functional group is removed, the 1-hydroxy substituent is removed by hydrogenation in a lower alkanol, typically methanol, in the presence of a palladium catalyst, typically 10% palladium on carbon.

DETAILED DESCRIPTION OF THE INVENTION

The ability of the compounds of the present invention to bind to the 5-HT _1F receptor subtype was measured essentially as described in US Patent No. 5,521,196.

Preparation of membranes:

Membranes were prepared from transfected Ltk cells grown to 100% confluence. Cells were washed twice with phosphate buffered saline scraped from culture dishes into 5 ml phosphate buffered saline centrifuged at 200 g for 5 minutes at 4 ° C.

The cell residue was resuspended in 2.5 ml of ice-cold Tris buffer (20 mM Tris HCl, pH = 7.4 at 23 ° C, 5 mM EDTA) and homogenized with a Wheaton tissue shredder. The lysate was then centrifuged at 200 g for 5 minutes at 4 ° C to obtain a cell residue whose large fragments were a solution of ice solution and an ice solution. ·· ··· «removed. The supernatant was collected and centrifuged at 40,000g for 20 minutes at 4 ° C. The cell residue resulting from this centrifugation was washed once in ice-cold Tris wash buffer and resuspended in final buffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH = 7.4 at 23 ° C. The membrane preparations were stored on ice and used within two hours for radioligand binding assays. Protein concentrations were determined according to the method of Bradford (Anal. Biochem., 72, 248-254 (1976)).

Radioligand binding:

^[3 H-5-HT] binding was performed using a slightly modified assay conditions, 5-HT _D reported by Herrick-Davis and Titeler (J. Neurochem., 50, 1624-1631 (1988)) with the omission of masking ligands.

Radioligand binding studies were performed at 37 ° C with a total volume of 250 μΐ buffer (50 mM Tris, 10 mM MgCl ₂ , 0.2 mM EDTA, 10 μmηοΐη pargylin, 0.1% ascorbate, pH = 7.4 at 37 ° C. ° C) in 96 well microtiter plates.

Saturation studies were performed using [ ³ H] 5-HT at 12 different concentrations ranging from 0.5 nM to 100 nM. Relocation studies were performed using 4.5-5.5 nM [ ³ H] 5-HT. The binding profile of the substances tested in the competition experiments was obtained using 10-12 concentrations of the compound. Incubation times were 30 minutes for both saturation and displacement experiments based on initial investigations that determined equilibrium binding conditions. Non-specific binding was determined in the presence of 10 μιηοΐη 5-HT. Binding was initiated by the addition of 50 μΐ membrane homogenates (10-20 μς). The reaction was terminated by rapid filtration through pre-wetted (0.5% polyethyleneimine) filters using a 48R Cell Brandel Harvester (Gaithersburg, MD). Subsequently, the filters were washed for 5 seconds with ice buffer (50 mM Tris HCl, pH = 7.4 at 4 ° C), dried and placed in containers containing 2.5 ml Readi-Safe (Beckman, Fullerton, CA) and radioactivity was measured using a Beckman LS 5000TA liquid scintillation counter. [ ³ H] 5-HT counting efficiency averaged 45-50%. Binding data was analyzed using computer-aided non-linear regression analysis (Accufit and Accucomp, Lunden Software, Chagrin Falls, OH). IC ₅₀ values were converted to K ± values using the Cheng-Prusoff equation (Biochem. Pharmacol., 22, 3099-3108 (1973). All experiments were performed in triplicate.

Representative compounds of the present invention were found to have affinity for 5-HT _1F receptors, as measured in the manner described above.

As described by RL Weinshank, et al., WO93 / 14201, the 5-HT _f is functionally coupled to a G-protein as measured by the ability of serotonin and serotonergic drugs to inhibit forskolin stimulated cAMP production in NIH3T3 cells transfected with the _5-HTlF. Activation of G-protein coupled receptor agonists results in the release of GDP from the α-subunits of G protein and subsequent GTP binding. Binding of the stable [ ³⁵ S] GTPγS analogue is an indicator of this receptor activation.

φ φ ♦ ·

· Φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Preparation of membranes

Mouse LM (tk-) cells stably transfected with human 5-HT _1F receptor and grown in suspension were collected by centrifugation, resuspended in 50 mM Tris-HCl, pH 7.4, in 2 x 10 ⁸ aliquots and frozen at -70. ° C until the day of the experiment. On the day of the experiment, aliquots of the cells were thawed, resuspended in 35 ml of 50 mM Tris-HCl, pH 7.4, and centrifuged at 39800 g for 10 minutes at 4 ° C.

The resulting pellet was resuspended in 50 mM Tris-HCl, pH 7.4, incubated for 10 minutes at 37 ° C and centrifuged at 39800 g for 10 minutes at 4 ° C. The pellet was resuspended and centrifuged once more, the final pellet was resuspended in 4 mM MgCl ₂ , ISO mM NaCl, 0.267 mM EGTA, 67 mM Tris-HCl, pH 7.4 so that a 200 μΐ aliquot contained approximately 15-25 μg protein .

[ ³⁵ S] GTPγS binding

All incubations were performed in triplicate in a total volume of 800 μΐ. Dilute in different ratios in water, 200 μϊ, with concentrations over 6 log units, was added to 400 μΐ Tris-HCl, pH 7.4, containing 3 mM MgCl ₂ , 120 mM NaCl, 0.2 mM EGTA, 10 μΜ GDP and 0.1 nM [ ³⁵ S] GTPγS. Membrane homogenate, 200 μϊ was added, and then the tubes were incubated for 30 minutes at 37 ° C. Using a Brandel cell harvester (model MB-48R, Brandel, Gaithersburg, MD), incubations were then terminated by vacuum filtration through Whatman GF / B filters moistened with 20 mM Na ₄ P ₂ O7 and pre-cooled with 4 mL ice-cold 50 mM Tris. • 9 · 9 · 4 · 4 · 4 · 9 · 1 · 4 · 9 · 1 · 4 · 9 ·

9 4 9 9 9 9 9 9 9 9

HCl, pH 7.4. The filters were then washed rapidly with 4 ml of ice-cold 50 mM Tris-HCl, pH 7.4. The amount of radioactivity captured by the filters was determined by liquid scintillation spectrometry using the LS60001C instrument (Beckman Instruments, Fullerton, CA). GTPyS, 10 μΜ, defined non-specific binding. Protein was determined by the method of Bradford (Anal. Biochem., 72, 248-254 (1976)).

Statistical analysis

Efficacy values for test compounds were expressed as percent binding relative to 10 μΜ 5-HT. Non-linear regression analysis was performed on concentration-response curves using the four parameter logistic equation described by De Lean et al. (Mol. Pharmacol., 21, 5-16 (1982)). Variance analysis, followed by the Tukey-Kramer Honestly Significant Difference (JMP; SAS Institute Inc., Cary, NC), was performed on pEC ₅₀ and Emax values.

In the test of ^[35 S] GTP? S were investigated representative compounds of the present invention and were found to be agonists at the _5-HTIF receptor.

The observation that the pain associated with migraine and associated disorders is inhibited by activation of the 5-HT _1F receptor by administration of 5-HT agonists _f required analysis of data from diverse assays of pharmacological activity. To determine whether 5-HT receptor subtype _F causes mediating neurogenic meningeal extravasation which leads to the pain of migraine, the binding affinity measured first panel of compounds to serotonin -: 23receptorům, using standard procedures. For example, the ability of compounds to bind to 5-HT receptor subtype _F was determined by the methods described above. For comparative purposes, also the above-described method of detecting the binding affinities of compounds to the 5-HT _D 5-HT and _{5-B ΗΤχ} Ε only were used different receptor clone instead of the above-described clone the 5-HT _1F receptor. 5-ΗΤχ _Β and 5-HT _1B receptors were recently renamed, their original names were 5-HT _1Dot and 5-ΗΤ ₁₀ β, respectively. (Hartig et al., Trends in Pharmaceutical Science, 17, 103-105 (1996)). The same panel was then tested in the cAMP assay to determine their agonistic or antagonistic character. Finally, the ability of these compounds to inhibit neuronal protein extravasation, a functional assay for migraine pain, was measured.

The panel of compounds used in this study represented various structural classes of compounds which were shown to exhibit a wide range of affinities for the serotonin receptors tested. In addition, panel compounds have been shown to have a wide range of efficacy in the neuronal protein extravasation assay. A panel of compounds selected for this study is described below.

Compound I

1- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (1: 1) (sumatriptan succinate) butane-1,4-dioate

:: -: 3α · · <

• to ··

Sumatriptan succinate is commercially available as Imitrex ™ or may be prepared as described in U.S. Patent 5,037,845, issued August 6, 1991, which is incorporated herein by reference in its entirety.

Compound II

5-Fluoro-3- (1- (2- (1-methyl-1H-pyrazol-4-yl) ethyl) -4-piperidinyl) -1H-indole hydrochloride

HCl

I · ftftft * • · • ftftft

32:

· Ft ft 9 9 9 9 9 9 9 9 9 9 ft 9 9

Compound III

5-Hydroxy-3- (4-piperidinyl) -1H-indole oxalate

Compound IV

8-Chloro-2-diethylamino-1,2,3,4-tetrahydronaphthalene hydrochloride

Cl

N (CH ₂ CH ₃ ), ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft 99

Compound V

6-hydroxy-3-dimethylamino-1,2,3,4-tetrahydrocarbazole

H

The preparation of compounds II-V is described in U.S. Patent 5,521,196, issued May 28, 1996, which is incorporated herein by reference in its entirety.

Binding tests

The binding affinities of compounds for various serotonin receptors were determined essentially as described above except that used different cloned receptors rather than receptor clone 5-HT _F. The results of these binding experiments are summarized in Table I.

4 ♦ · 4 44 444 * 4 4 4 44 44 44

4 4 «449 4 44 4 • •• * o ^J 5» · · · · · · · · · · · 4 «<· 4 4 4 4 4 4 4» 4

Table I

Binding to serotonin (5-HT 1) receptor subtypes (Ki nM)

Compound 5- HT _1Da 5- HTinp 5- HT _1e 5- HT _1F AND 4.8 9, 6 2520.0 25, 7 II 21.7 53.6 50.3 2.5 III 163.2 196, 5 3.9 22, 0 IV 13.5 145.3 813, 0 129.2 IN 791.0 1683.0 73.6 10.3 Creating cAMP As described by R.L Weinshank et al., WO93 / 14201 receptor

5-HT _F is functionally coupled to a G-protein as measured by the ability of serotonin and serotonergic drugs to inhibit forskolin stimulated cAMP formation in cells transfected with receptor ΝΙΗ3Τ3 _5-HTlF. Adenylate cyclase activity was determined using standard techniques. The maximal effect was achieved with serotoninin. E _max was determined as the ratio of inhibition of test compound to maximal effect and expressed as percent inhibition. (N. Adham et al., Supra; RL Weinshank et al., Proceedings of the National Academy of Sciences (USA), 89, 3630-3634 (1992)) and references cited therein.

Measurement of cAMP formation

Transfected NIH3T3 cells (estimated B _max from a single point competition study = 488 fmol / mg protein) were incubated in DMEM, 5 mM theophylline, 10 mM HEPES (4- [2-hydroxyethyl] 1-piperazinethanesulfonic acid) and 10 μΜ pargylin for < · «· * 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 :: :: :: ::

* 9 9 9 9 0 9 9 9 0 9 0 0 9 for 20 minutes at 37 ° C, 5% CO ₂ . Dose-response curves of the substance were then obtained by adding 6 different final concentrations of the substance followed by immediate addition of forskolin (10 μΜ). The cells were then incubated for an additional 10 minutes at 37 ° C, 5% CO ₂ . The medium was aspirated and the reaction was stopped by the addition of 100 mM HCl. To demonstrate competitive antagonism, dose-response curves for 5-HT were measured concurrently using a fixed dose of methiothepin (0.32 pinol). Plates were stored at 4 ° C for 15 minutes and then centrifuged for 5 minutes at 500 g per cell residue, and aliquots of supernatant were created and stored at -20 ° C before determining cAMP formation by radioimmunoassay (cAMP radioimmunoassay). kit; Advanced Magnetics, Cambridge, MA). Radioactivity was measured with a Packard COBRA Auto Gamma computer equipped with data reduction software.

All compounds of the panel were tested in the above assay of cAMP, and it was found that all receptor agonists 5-HT _F.

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) were anesthetized with sodium pentobarbital intraperitoneally (65 mg / kg and 45 mg / kg, respectively) and placed in a stereotaxic frame (David Kopf Instruments) with an incision knife set at -3.5 mm for rats or -4.0 mm for guinea pigs. After medial sagittal scalp incision, two pairs of bilateral holes were drilled through the skull (6 mm posterior, 2.0 and 4.0 mm lateral in rats; 4 mm posterior and 3.2 and 5.2 mm lateral in guinea pigs, all coordinates relative to bregma).

* · • · of the · · · · · ⁹ • f- «U ® -« «» »·«

Through the holes in both hemispheres, pairs of stainless steel stimulation electrodes (Rhodes Medical Systems, Inc.) Were introduced to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from drows.

The femoral vessel was exposed and a dose of test compound (1 ml / kg) was injected intravenously. Approximately 7 minutes later, a dose of 50 mg / kg of Evans Blue, a fluorescent dye, was injected intravenously. Evans Blue complexes with proteins in the blood and acts as a marker for protein extravasation. Exactly 10 minutes after injection of the test compound, the left trigeminal ganglion was stimulated for 3 minutes with a current intensity of 1.0 mA (5 Hz, 4 msec duration) using a Model 273 potentiostat / galvanostat (EG&G Princeton Applied Research).

Fifteen minutes after stimulation, the animals were killed and bled with 20 ml of saline. The upper part of the skull was removed to facilitate removal of the dural membrane. The membrane samples were taken from both hemispheres, rinsed with water and spread on microscope slides. After drying, the tissues were covered with a 70% glycerol / water solution.

A fluorescence microscope (Zeiss), equipped with a grid monochromator and spectrophotometer, was used to measure the amount of Evans blue in each sample. An excitation wavelength of approximately 535 nm was used and the emission intensity at 600 nm was determined. The microscope was equipped with a motorized support and connected to a personal computer. This made it possible to perform computer-controlled movements, support and fluorescence measurements at 25 points (500 μιη step) on each dural sample. Mean a

The standard deviation of the measurement was determined by the computer. I J J ΦΦ ΦΦ ΦΦ »» »»

Extravasation induced by electrical stimulation of the trigeminal ganglion had an ipsilateral effect (ie, occurred only on the side of the dura where the trigeminal ganglion was stimulated. This allowed the second (unstimulated) half of the dura to be used as a control. Controls represented by saline gave a ratio of approximately 2.0 for rats and 1.8 for guinea pigs, compared with a compound that effectively prevents extravasation in the dock on the stimulated side should be approximately 1 The dose response curve was determined and the dose that inhibited extravasation by 50% (ID ₅₀ ) was approximated.

Table II.

Table II

Inhibition of protein extravasation (ID ₅₀ mmol / kg)

compound iv ID ₅₀ (mmol / kg) AND 2, 6x10 ⁸ II 8,6x10 ¹⁰ III 8.9x10 ' ⁹ IV l, 2x10 ⁷ IN 8.7x10 ' ⁹

To determine the relative binding of various serotonin receptors to inhibition of neuronal protein extravasation, the binding affinity of the compounds to each of the receptors 5-HT _D, 5-HT _1B

5-HT _1E and 5-HT against _F illustrated _ID50 in the protein extravasation model. A linear regression analysis on each set of data and a correlation factor R calculated ^second

The results of this analysis are summarized in Table III.

• · · φφφ Φ · 1—9

9

Table III

Correlation Factor (R ²⁾ a specific binding affinity for subtypes of 5-HT due to the inhibition of protein extravasation

5-HT 1 subtype

5-HTid

5-HT _1b

5-HTie

5-HT _1f

Correlation factor (R ² ) 0.07 0.001

0.31, 94

An ideal linear dependence would give a correlation factor of 1.0, indicating the cause-effect relationship between the two variables. The experimentally determined correlation factor between inhibition of neuronal protein extravasation and 5-HT _1F binding affinity is 0.94. This nearly ideal dependence of the _ID50 in the protein extravasation model on binding affinity to the 5-HT _1F clearly demonstrates that the _5-HTIF mediates the inhibition of protein extravasation resulting from stimulation of the trigeminal ganglia.

Sumatriptan shows low bioavailability and relatively short duration of action. Its affinity for a number of serotonin receptor subtypes causes undesirable side effects, especially vasoconstrictors, which severely limit its usefulness for treating migraine. The compounds of the present invention, however, have a high biological level of ftft ftftft ftftftft ftftftft ftft ft. V. 3 · _ · # · · · · · Availability through a variety of routes of administration, including, but not limited to, oral, buccal, intravenous, subcutaneous, intranasal, intraocular, transdermal, rectal and inhalation routes. They exhibit rapid onset and long duration of action, and typically require only one dose per day to maintain therapeutic levels. Since the compounds of this invention are potent agonists of the 5-HT _f, required to maintain therapeutic levels, extremely low doses. Furthermore, due to the high selectivity of compounds of the present invention to the 5-HT _F are excluded complications due to vasoconstriction. The compounds of the present invention also inhibit protein extravasation when administered before or after stimulation of the trigeminal ganglion, suggesting that they can be administered prior to the anticipated migraine attack to prevent pain or during the migraine attack for pain relief.

The ability of agonists of the _5-HTIF receptor in general, and the compounds of the present invention specifically alleviate pain is demonstrated by testing in a standard model of chronic pain (Calvino, et al., Behavioral Brain Research, 24, 11-29 (1987); Colpaert, Pain, 28, 201 -222 (1987)). For example, arthritis-like conditions may be induced in rats for several days after a single injection of Freund's complete adjuvant or synthetic adjuvant such as lipoidal amine (N, N-dioctyldecyl N ', N-bis (2-hydroxyethyl) propanediamine) in oil (Benslay and Bendele, Agents Actions 34 (1-2), 254-6, (1991); Bendele et al., J. Pharmacol. Exp. Ther. 260 (1), 300-5 (1992); Meacock et al., Ann. Rheum. Dis. 53 (10), 653-8 (1994)). Animals treated in this way develop chronic swelling and pain in the hind limbs, resulting in an increase in • 4 4

I 44 4444

4 4 4 • 44 444 * 4 4 4

Irritability and decreased mobility. An ideal analgesic should increase the exploratory activity of arthritic animals towards normal without leading to an increase or decrease in this activity in normal animals. Analgesic compounds such as morphine and citalopram have been shown to improve the exploratory behavior of these animals (Larsen and Arnt, Acta Pharmacol. Toxicol. (Copenh) 57 (5), 345-51 (1985)).

Analgesic test

Male Lewis rats (Harlan-Sprague Dawley, Inc., Indianapolis, IN) weighing approximately 225 grams were housed in transparent plastic cages and had ad libidum access to food and water. Rats were kept on a 12 hour light and 12 hour dark cycle.

To obtain polyarthritis, half rats were injected subcutaneously into the dorsal tail base with a dose of 7.5 mg / rat of lipoidal amine in 0.1 ml of incomplete Freund's Adjuvant. This single injection of lipoidal amine resulted in hind limb inflammation, which was evident after about ten days. The other half rats received vehicle injection. Eleven days after injection of the lipoidal amine or vehicle, the animals were either administered orally or subcutaneously with test compound or an aqueous vehicle. One hour after drug administration, the animals were placed individually in an activity monitor (Omnitech Electronics, Columbus, OH) representing a new environment. Activity monitors have an open area of 42 x 42 cm and quantify exploratory behavior using infrared light rays and photocells. This is accomplished by using a grid of photosensors located at level

Ft ftft ft ftft ft ft ♦ ftft ♦ floor, for measuring horizontal activity. The computer analyzes the sensor array data. Exploratory behavior is quantified within the first 5 minutes in the chamber. The measured parameter used in this study is the total distance traveled by the animal in the first 5 minutes of the test.

While it is possible to administer the compounds of the present invention directly, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes such as oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds of the present invention are effective in both injectable and oral compositions. Such compositions are prepared in a manner well known to those skilled in the art of pharmacy and comprise at least one active compound. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCE, (16th ed. 1980).

In forming the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted with an excipient, or surrounded by a carrier, which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which serves as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may take the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight. To soft and hard gelatine capsules, injectable solutions and sterile; to this to this this to

•. The active compound, suppositories, sterile packaged powders are used.

When formulating the formulation, it may be necessary to grind the active compound to achieve a suitable particle size prior to combining it with the other ingredients. If the active compound is substantially insoluble, it is usually ground to particles having a mesh size of 200 mesh. If the active compound is substantially water-soluble, the particle size is normally adjusted to achieve a substantially uniform distribution in the formulation, for example to a size corresponding to a 40 mesh screen.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoate; sweeteners; and flavoring agents. The compositions of the present invention may be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to a patient using procedures well known to those skilled in the art.

The compositions are preferably formulated in a unit dosage form and each dose contains from about 0.001 to about 100 mg, more usually from about 1.0 to about 30 mg, of the active ingredient. Expression • · • 9 9 9

• · · 9

"Unit dosage form" refers to a physically discrete unit, aqueous as a unit dosage for humans or other mammals, and each unit contains a predetermined amount of active material intended to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient .

The active compounds are generally effective over a wide dosage range. For example, daily dosages normally fall within the range of about 0.0001 to about 30 mg / kg body weight. In the treatment of an adult human, a range of about 0.1 to about 15 mg / kg / day, in single or divided doses, is particularly preferred. However, it will be appreciated that the amount of the compound to be actually administered will be determined by the physician depending on the relevant circumstances, including the condition to be treated, the route of administration chosen, the particular compound or compounds to be administered, the age, weight and response of the individual. patient and the severity and severity of the patient's symptoms, and therefore the above dosages are not intended to limit the scope of the present invention in any way. In some cases, doses below the lower limit of the above range may be more appropriate, while in other cases even larger doses may be used without deleterious side effects, provided such high doses are subdivided into smaller doses administered several times a day.

Example of preparation 1

Hard gelatin capsules were prepared containing the following ingredients:

• • • •

Component

Quantity (mg / capsule)

Example 7 Starch

Magnesium stearate

30.0 305.0 5.0

The above ingredients were mixed and filled into hard gelatin capsules in an amount of 340 mg.

Example of preparation 2

Tablets were prepared containing the following ingredients:

Component

Quantity (mg / tablet)

Example 9 Microcrystalline Cellulose Colloidal Silicon Dioxide Stearic Acid

25.0

200.0

10.0

5.0

The above ingredients were mixed and compressed into 240 mg tablets.

Example of preparation 3

Suppositories, each containing 25 mg of active ingredient, were prepared as follows:

t • ·

Amount (mg / suppository)

• · · · · · · · · ·

Example 3 compound

Saturated fatty acid glycerides up to mg 2,000 mg

The active ingredient is sieved through a 60 mesh U.S. sieve. and suspended in saturated fatty acid glycerides, previously melted using minimal heat. The mixture is then poured into a suppository mold with a nominal capacity of 2 g and allowed to cool.

Example of preparation 4

An intravenous formulation can be prepared as follows:

Component Quantity

Example 13 250.0 mg

Isotonic saline 1000 ml

Other preferred formulations of the present invention employ transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the administration of pharmaceutical agents is well known to those skilled in the art, see for example U.S. Pat. No. 5,023,252, issued Nov. 11, 1993;

· 4 · 4 · 4

• Φ • Φ Φ Φ

Φ Φ φ • • • «

ΦΦ uvedený Φ Φ • Φ ΦΦ June 1991, incorporated herein by reference. Such patches may be designed to provide administration of a pharmaceutical agent that is continuous, burst, or on demand.

It is often desirable or necessary to incorporate the pharmaceutical compositions into the brain, either directly or indirectly. Direct techniques usually involve placing the drug delivery catheter into the recipient's ventricular system to bypass the blood-brain barrier. One such implicit delivery system used to transfer biological factors to specific anatomical areas of the body is described in U.S. Pat. No. 5,011,472, issued April 30, 1991, and incorporated herein by reference.

Indirect techniques, which are usually preferred, usually involve the formation of compositions that achieve the latency of the substances by converting them from hydrophilic to soluble lipids or precursors thereof. Latency is usually achieved by blocking the hydroxy, carbonyl, sulfate, and primary amino groups of the substance to make the substance more lipid soluble and more suitable for transmission across the blood-brain barrier.

Alternatively, the delivery of hydrophilic substances may be improved by intraarterial infusion of hypertonic solutions, which may temporarily open the blood-brain barrier.

The type of general formulation selected for administration of the compounds of the present invention may be dictated by the choice of a particular compound, the type of pharmacokinetic course

44

4 4 4

4 4 4 4

4 4 ·

44 given the route of administration by the condition of the patient.

and choice • 4 «

4 • 4

4

4 4

4 · 4

444 »

4 4

4 * 4 *: 4¾

the profile desired for the compound or compounds; and

Preparation

5-Trifluoromethanesulfonyloxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine

A solution of 0.90 g (3.89 mmol) of 5-hydroxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine in 80 mL of pyridine was cooled to 0 ° C. To this solution was then added 1.71 mL (10.13 mmol) of trifluoromethanesulfonic anhydride and the reaction mixture was allowed to warm gradually to ambient temperature. After four hours, the reaction was quenched by addition of saturated aqueous sodium bicarbonate, and the reaction mixture was then concentrated under reduced pressure. The residue was dissolved in 3: 1 chloroform: isopropanol and this solution was washed with saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with dichloromethane containing 0-20% methanol. Product containing fractions were combined and concentrated under reduced pressure to give 1.12 g (79%) of the title compound.

Melting point = 171-174 ° C (decomposition)

MS (m / e): 364 (M ⁺ 1).

Calcd. For C 14 H 16 N 3 O 3 SF 3. 0.25 H ₂ 0:

Theoretical: C, 45.73; H, 4.52; N, 11.42.

Found: C, 45.63; H, 4.45; N, 11.20.

Preparation II φ · φ φ · φ φ · φ

• · · · · · · · · · · ·

5-chloropyrrolo [3,2-b] pyridine

6-hydroxy-3-nitro-2-picoline

A suspension of 3.0 g (19.6 mmol) of 6-amino-3-nitro-2-picoline in 50 mL of water containing 3.5 mL of concentrated sulfuric acid was heated to form a solution. The resulting solution was cooled to 0 ° C, and a solution of 2.0 g (29.4 mmol) of sodium nitrite in 10 mL of water was added with vigorous stirring at a rate such that the reaction mixture was maintained at a maximum of 10 ° C. After 4 hours, the reaction mixture was filtered. The solid was washed with water and dried under reduced pressure to give 2.4 g (80%) of the title compound as a pale yellow solid.

MS (m / e): 153 (M ^& lt ^{; +} & gt ^; )

6-chloro-3-nitro-2-picoline

A mixture of 2.42 g (15.7 mmol) of 6-hydroxy-3-nitro-2-picoline, 1.0 g of phosphorus pentachloride and 0.5 ml of phosphorus oxychloride was heated at 110 ° C for 2.5 hours. The reaction mixture was cooled to ambient temperature and then an additional 0.5 g of phosphorus pentachloride and 0.5 ml of phosphorus oxychloride were added. Heating was continued for one hour and then the reaction mixture was poured into 100 mL ice / water. The resulting slurry was filtered and the solid was dried under vacuum to give 2.3 g (85%) of the title compound as a brown solid.

2- (2-dimethylaminoethen-1-yl) -3-nitro-6-chloropyridine A solution of 5 g (29 mmol) of 6-chloro-3-nitro-2-picoline in 40 ml of dimethylformamide was treated with 5.83 ml (44 mmol) of ) dimethylformamide dimethylacetal and the resulting mixture was heated at 100 ° C for 1 hour. 5 hours. At this point, 2 drops of triethylamine were added followed by 1.9 mL of dimethylformamide dimethyl acetal and heating was continued for an additional 2 hours. The reaction mixture was concentrated under reduced pressure to give the desired compound.

• 44 44 44 ··· 44 4 «was washed and saturated

Reduction / ring closure

A mixture of 3.07 g (13.5 mmol) of 2- (2-dimethylamino-ethen-1-yl) 3-nitro-6-chloropyridine, 6.5 g (0.116 mol) of iron and 16.4 g of silica gel in 170 ml 5: 3 toluene: acetic acid was heated at 110 ° C for 1 hour. The reaction mixture was filtered through a pad of celite. The filtrate was sequentially aqueous sodium bisulfite aqueous sodium bicarbonate until the aqueous wash remained basic, and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residual solid was subjected to silica gel chromatography, eluting with dichloromethane containing 0-5% methanol. Product containing fractions were combined and concentrated under reduced pressure to afford the title compound.

MS (m / e): 153 (M ^& lt ^{; +} & gt ^; )

Preparation III

5-Methoxypyrrolo [3,2-b] pyridine

6-Methoxy-3-nitro-2-picoline

0.46 g (20 mmol) of sodium was dissolved in 15 ml of anhydrous methanol. To this solution was added portionwise 2.3 g of 6-chloro-3-nitro-2-picoline. The resulting mixture was stirred for 18 hours at ambient temperature and then for 1 hour at a temperature of <RTIgt; ft. </RTI> ftft. Ftft. Ftft. Ftftft. Ftftft. Ftft. ························ The reaction mixture was poured into 100 mL of ice water with vigorous stirring. The suspension was filtered and the solid was dried at 30 ° C under reduced pressure for 18 hours to give 2.04 g (91%) of the desired compound as a tan solid.

2- (2-dimethylaminoethen-2-yl) -3-nitro-6-methoxypyridine A mixture of 2.0 g (11.9 mmol) of 6-methoxy-3-nitro-2-picoline and 16 ml (119 mmol) of dimethylformamide dimethyl acetal in 20 ml of dimethylformamide was heated at 100 ° C for 7 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with toluene and concentrated under reduced pressure. The residual solid was dried at 50 ° C under reduced pressure for 1 hour to give 2.70 g (100%) of the title compound as a red solid.

Reduction / ring closure 2.5 g (11.2 mmol) mixture

2- (2-dimethylamino-ethen-2-yl) 3-nitro-6-methoxypyridine and 0.30 g of 10% palladium on carbon were hydrogenated at an initial hydrogen pressure temperature filtered

Residue for 18 hrs. The reaction mixture was ambient after 30 p.s.i.

and the filtrate was concentrated under reduced pressure, subjected to silica gel chromatography, eluting with dichloromethane. Product containing fractions were combined and concentrated under reduced pressure to give 1.22 g (74%) of the title compound as a colorless solid.

Preparation IV

5-Amino-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine

·· ···· ·· · ·

Nitration of 6-amino-2-picoline

110 g (1.02 mol) of molten 6-amino-2-picoline was added dropwise to 500 ml of concentrated sulfuric acid, which had been pre-cooled to -15 ° C, at such a rate that the temperature of the sulfuric acid solution was kept below Deň: 18 ° C. The solution was then cooled to about -6 ° C, and then a solution of 49 ml of 90% nitric acid (1.16 mol) in 49 ml of sulfuric acid, previously cooled to about 0 ° C, was added dropwise over about 30 minutes, maintaining the temperature at about 0 ° C. The reaction mixture was stirred at about 0 ° C for one hour and then allowed to warm to about 10 ° C over one hour. The temperature of the reaction mixture was maintained at about 10 ° C for one hour and the mixture was then allowed to warm to about 20 ° C over one hour. The reaction mixture was maintained at about 20 ° C for 2 hours. The reaction mixture was poured into 8 L of ice with vigorous stirring. The pH of the reaction mixture was then adjusted to about 9 by adding 1.5 L of concentrated ammonium hydroxide, keeping the temperature of the reaction mixture at about 24 ° C by adding ice if necessary. The resulting slurry was filtered and the solid was washed several times with water. The solid was dried at 70 ° C under vacuum for 3 days to give 135.4 g (87%) of a 2: 1 mixture of 3-nitro-: 5-nitro-6-amino-2-picoline.

Separation of nitration isomers by sublimation g of the nitration mixture were sublimated twice under vacuum at 125 ° C, each for 6 hours. The 5-nitro isomer was sublimed as a bright yellow powder and discarded.

The 3-nitro isomer remaining at the bottom of the sublimation apparatus was collected. A total of 121 g was sublimed to give 60.9 g (75.5%) of the crude 3-nitro isomers. 58 g of the crude 3-nitro isomers were suspended in 200 ml of hot 95: 5 ethanol: water. The mixture was cooled to ambient temperature and diluted with 200 mL of water. After two hours, the precipitate was collected by filtration and washed several times with water. The solid was dried under vacuum at ambient temperature to give 38 g (65% based on 58 g crude product) of 3-nitro-6-amino-2-picoline.

MS (m / e): 153 (M ^& lt ^{; +} & gt ^; )

Calcd. For C6H7N3O2:

Theoretical: C, 47.05; H, 4.61; N, 27.44.

Found: C, 47.08; H, 4.53; N, 27.53.

Separation of nitration isomers by recrystallization

A mixture of 20 g of the nitration mixture and 800 ml of toluene was heated to reflux for 15 minutes. The mixture was filtered at 95 ° C and the mother liquid was allowed to cool to ambient temperature. After 4 hours, the crystalline solid was collected, washed with 100 mL of toluene and dried under reduced pressure at 50 ° C for 16 hours to give 13.7 g (68%) of 3-nitro-6-amino-2-picoline.

Preparation of 2- (2-dimethylaminoethen-1-yl) -5-nitro-6- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine (Intermediate IV) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · To · to · this ··

A mixture of 60 g (0.39 mol) of 3-nitro-6-amino-2-picoline in 260 ml of dimethylformamide was treated with 260 ml (1.83 mol) of 94% dimethylformamide dimethyl acetal and the solution was heated to reflux for 48 min. hours. The reaction mixture was concentrated under reduced pressure and the residual solid was suspended with toluene. The toluene was evaporated under reduced pressure. This procedure was repeated five times. The resulting residue was suspended with 300 mL of methyl tert-butyl ether and then filtered. This solid was washed three times with 300 mL of methyl tert-butyl ether and the black solid was finally dried under reduced pressure to give 90.6 g (88%) of the title compound.

MS (m / e): 263.1 (M ^& lt ^{; +} & gt ^; )

Calcd. For C12H17N5O2:

Theoretical: C, 54.74; H, 6.51; N, 26.60.

Found: C, 54.84; H, 6.49; N, 26.79.

Preparation of 5- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine A mixture of 90 g (0.34 mol) of Intermediate IV and 6 g of 10% palladium on carbon in 650 ml of ethanol was hydrogenated at 50 p.s.i. for 45 hours. The reaction mixture was filtered and then concentrated under reduced pressure. The residual solid was suspended for 30 minutes with 70:30 methyl tert-butyl ether: ethyl acetate, filtered and rinsed with 3 x 300 mL of 70:30 methyl tert-butyl ether: ethyl acetate. The solid was sprayed and then suspended with 200 mL of 70:30 methyl tert-butyl ether: ethyl acetate. The solid was filtered and dried under reduced pressure to give 54.5 g (85%) of the title compound as a yellow solid.

MS (m / e): 188.2 (M ^& lt ^{; +} & gt ^; )

········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Condensation with 1-methyl-4-piperidone

A solution of 19.2 g (0.10 mol) of 5- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine in 208 ml of methanol was treated with 20 g (0.30 mol) of potassium hydroxide followed by 16.3 ml (0.13 mol) mmol) of 1-methyl-4-piperidone. The reaction mixture was heated at reflux for 24 hours and was then concentrated under reduced pressure. The residual solid was treated with 250 mL of 9: 1 ethyl acetate: tetrahydrofuran and 50 mL of methanol. The solution was cooled to 0 ° C and then 200 mL of cold water was added. The phases were separated and the aqueous phase was extracted with 9: 1 ethyl acetate: tetrahydrofuran. All organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residual solid was suspended repeatedly with 475 ml cold water to remove black impurities. The remaining solid was dried under reduced pressure to give 17 g (74%) of the title compound as a yellow powder.

MS (m / e): 228.1 (M ^& lt ^{; +} & gt ^; )

Calcd. For C ₁₃ H ₁₆ N ₄ :

Theoretical: C, 68.39; H, 7.06; N, 24.54.

Found: C, 68.13; H, 7.06; N, 24.38.

Preparation

5-Amino-3- (1-methyl-piperidin-4-yl) -pyrrolo [3,2-b] pyridine

A mixture of 21 g (89.9 mmol) of 5-amino-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine and 10% palladium on carbon moistened with 30 ml of ethanol in 180 mL of methanol was hydrogenated at 65 psi for 3 days. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residual solid was suspended in 120 mL of ethyl acetate, filtered and washed with 3 x 30 mL of ethyl acetate. The remaining solid was dried under reduced pressure to give 19 g (92%) of the title compound as a light brown solid.

MS (m / e): 230 (M ^& lt ^{; +} & gt ^; )

Calcd. For C 13 H 18 N 4:

Theoretical: C, 67.80; H, 7.88; N, 24.32.

Found: C, 67.21; H, 7.79; N, 24.24.

Preparation VI

Alternative isolation of intermediate IV

A solution of 38.8 g (0.25 mol) of 3-nitro-6-amino-2-picoline in 172 ml of dimethylformamide was treated with 172 ml of dimethylformamide dimethyl acetal and the mixture was heated at about 97 ° C for 42 hours. The reaction mixture was then cooled to ambient temperature and diluted with 650 mL of isopropanol. The reaction mixture was allowed to stand for 18 hours at ambient temperature and was then cooled to 3-5 ° C with stirring for an additional 2 hours. The slurry was filtered and the solid was washed with 2 x 75 mL isopropanol and dried under reduced pressure at 45 ° C for 16 hours to give 58.9 g (88%) of intermediate IV.

Preparation VII

Synthesis of intermediate IV from a mixture of nitration isomers

A mixture of 133 g (0.86 mol) of a 2: 1 mixture of 3-nitro: 5-nitro-6-amino-2-picoline in 500 ml of dimethylformamide was treated with 500 ml (3.5 mol) of 94% dimethylformamide dimethyl acetal and heated. · »!»! 00 • 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0000 0 0 00 00 0 0 0 at reflux for 40 hours. After cooling to ambient temperature, the reaction mixture was divided in half and each half was poured into 10 L of water at 0 ° C with vigorous stirring. After 10 minutes, the mixture was filtered and the solid was suspended / rinsed with 3 x 1 L of water. The solid was dried under vacuum at 65 ° C for 2.5 days to give 183 g (81%) of the title compound as a red solid.

Preparation VIII

Alternative synthesis of 5-amino-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine

Preparation of 1-hydroxy-5- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine dihydrochloride

A mixture of intermediate IV (23.4 g, 89 mmol) and 10% palladium on carbon (0.7 g) in anhydrous methanol (234 ml) was treated with 140 ml.

5.9 N ethanolic hydrogen chloride. The resulting mixture was hydrogenated for 1.5 hours at an initial hydrogen pressure of 30 p.s.i. The reaction mixture was diluted with 585 mL of ethanol and stirred at ambient temperature for 1 hour at ambient temperature. The precipitate was filtered and rinsed with 50 ml of ethanol. The solid was taken up in 1.1 L of methanol, filtered and then concentrated under reduced pressure. The residual solid was dried under reduced pressure to give 20.5 g (83%) of the desired compound (containing 5% 5- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine) as a yellow solid.

Preparation of 1-hydroxy-5- (dimethylaminomethylimino) -3- (1-methyl56)

4 9 9 9 4 5

4 94 4 9 4 4 4 4 4 4 4 4

444 44 49

1,2,3,6-tetrahydropyridin-4-yl] pyrrolo [3,2-b] pyridine

A mixture of 13.5 g (48.7 mmol) of 1-hydroxy-5- (dimethylaminomethylimino) pyrrolo [3,2-b] pyridine and 17.5 g (155 mmol) of 1-methyl-4-piperidone in 270 ml of anhydrous ethanol was stirred until homogeneous. At this point, 19.4 mL (109 mmol) of 5.6 N dimethylamine in ethanol was added and the reaction mixture was stirred at ambient temperature for 4 hours. The resulting yellow precipitate was filtered, washed with 2 x 27 mL ethanol and dried under reduced pressure at 45 ° C to give 13.4 g (92%) of the title compound as a yellow solid.

Hydrogenation / hydrogenolysis

A mixture of 0.28 g (0.94, / mol) of 1-hydroxy-5- (dimethylaminomethylimino) -3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine and 0.10 g of 10% palladium on carbon in 20 ml of methanol was hydrogenated for about 18 hours under an initial hydrogen pressure of 50 psi The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 0.21 g (96%) of the title compound.

EXAMPLE 1

5- (N- [ethyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine

A mixture of 0.200 g (0.74 mmol) of 5- (N- [acetyl] amino) 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine and 0.125 g (3.31 mmol) of lithium hydride -ammonium in 40 ml φ ♦ φ ♦ ♦ ♦ · φ φ φ φ φ φ

The tetrahydrofuran was heated at 75 ° C for 18 hours. Tetrahydr tetrahydr tetrahydr · · · φ φ φ tetrahydr tetrahydr tetrahydr tetrahydr tetrahydr tetrahydr tetrahydr The reaction mixture was cooled to 0 ° C and then treated with sodium sulfate decahydrate. After vigorous stirring, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 0-20% methanol. Product containing fractions were combined and concentrated under reduced pressure to give 0.10 g (54%) of the title compound. M.p. = 132.5-133.9 ° C

MS (m / e): 258 (M ^& lt ^{; +} & gt ^; )

EXAMPLE 2

5- (N- [benzyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine

A mixture of 0.25 g (1.09 mmol) of 5-amino-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine, 0.5 g of molecular sieves and 0.22 ml (2.17 mmol) of benzaldehyde in 10 ml of methanol was stirred at 40 ° C for 5 hours. The reaction mixture was then cooled to ambient temperature and 0.124 g (3.27 mmol) of sodium borohydride was added. The reaction mixture was then stirred for 30 minutes at ambient temperature and then quenched with 1N sodium hydroxide. The reaction mixture was concentrated under reduced pressure, and then the aqueous residue was extracted with 3: 1 chloroform: isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 0-10% methanol. The fractions containing the product were combined and concentrated 4444 44 44 4 4 # 4 4 4 4 44 4 4 444 44 4 concentrated under reduced pressure to obtain the title compounds.

MS (m / e): 321 (M ⁺ 1).

EXAMPLE 3

5- (N- [thien-2-ylmethyl] amino) -3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine

Starting from 0.25 g (1.09 mmol) of 5-amino-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine and 0.20 ml (2.17 mmol) of thiophene-2-carboxaldehyde , the title compound was prepared essentially as described in Example 2.

MS (m / e): 327 (M ⁺ 1).

EXAMPLE 4

5-chloro-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine

To a solution of 0.66 g (4.3 mmol) of 5-chloropyrrolo [3,2-b] pyridine in 50 mL of methanol was added 1.09 g (47.6 mmol) of sodium. The reaction mixture was stirred until all of the sodium had dissolved and then 1.6 ml (13 mmol) of 1-methyl-4-piperidone was added. The reaction mixture was stirred at reflux for 7.5 hours and was then cooled to 0 ° C. To the mixture was then added hydrochloric acid until the pH of the solution was approximately 8. The reaction mixture was then concentrated under reduced pressure to an oil. This oil was dissolved in 3: 1 chloroform: isopropanol and the resulting solution was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous chloride. • to • this • to • this • to • sodium. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 0-10% methanol. Product containing fractions were concentrated under reduced pressure to give 0.30 g (28%) of the title compound.

Melting point = 230 ° C (decomposition)

MS (m / e): 247 (M ^& lt ^{; +} & gt ^; )

Calcd. For C 13 H 14 N 3 Cl:

Theoretical: C, 63.03; H, 5.70; N, 16.96.

Found: C, 63.20; H, 5.90; N, 16.82.

EXAMPLE 5

5-methoxy-3- (1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine

A solution of 0.20 g (1.35 mmol) of 5-methoxypyrrolo [3,2-b] pyridine, 0.23 mg (4.05 mmol) of potassium hydroxide and 0.31 g (2.03 mmol) of 4- hydrochloride monohydrate piperidone in 5 mL of methanol was heated at reflux for 18 h. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between water and 3: 1 chloroform: isopropanol. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to radial chromatography (2 mm silica gel plate) eluting with dichloromethane containing 20-40% methanol and 1% ammonium hydroxide. Product containing fractions were combined and concentrated under reduced pressure to give 0.21 g (68%) of the title compound as a yellow solid. An analytical sample was crystallized from methanol.

··

- 60 «· · 8

9 9

4 49 4

444 44

4 4

444

N, 18.33. N, 18.50.

MS (m / e): 229 (M ^& lt ^{; +} & gt ^; )

Calculated for C13H15N3O:

Theoretical: C, 68.10; H, 6.59;

Found: C, 68.03; H, 6.74;

EXAMPLE 6

5-Methoxy-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine

Starting from 0.80 g (5.4 mmol)

Of 5-methoxypyrrolo [3,2-b] pyridine and 1.2 mL (10.1 mmol) of 1-methyl-4-piperidone, 1.1 g (84%) of the title compound was obtained as a yellow solid in principle as described in Example 5. The analytical sample was recrystallized from methanol.

Melting point = 202.9 ° C (sublimation)

MS (m / e): 243 (M ^& lt ^{; +} & gt ^; )

Calculated for C ₁₄ H ₁₇ N ₃ O:

Theoretical: C, 69.11; H, 7.04; N, 17.27.

Found: C, 69.22; H, 7.13; N, 17.47.

EXAMPLE 7

5-Methoxy-3- (1-methyl-piperidin-4-yl) -pyrrolo [3,2-b] pyridine

Starting from 0.50 g (2.1 mmol) of 5-methoxy-3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) pyrrolo [3,2-b] pyridine, 0.2 94 g (57%) of the title compound was prepared essentially as described in Preparation V. The analytical sample was crystallized from aqueous ethanol.

MS (m / e): 245 (M ^& lt ^{; +} & gt ^; )

Calculated for C14H19N3O:

• ·

• 4

• • 4 • 4 4

4 4

44

Theoretical: C, 68.54; H, 7.81; N, 17.13.

Found: C, 68.40; H, 7.52; N, 16.90.

EXAMPLE 8

5-Hydroxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine

A solution of 1.00 g (4.1 mmol) of 5-methoxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine in 20 mL of hydrogen bromide (30% in acetic acid) was heated at temperature reflux for 48 hours. An additional 5 ml aliquots of hydrogen bromide in acetic acid were added after about 8 and 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was treated with 1 mL of saturated aqueous sodium bicarbonate. The resulting mixture was taken up in methanol and passed through a VARIAN BOND ELUT SCX ™ ion exchange column (Varian, Harbor City, CA, U.S.A.) which was previously activated with 10% acetic acid in methanol. The column was washed with three volumes of methanol not used and then with ammonium-containing methanol. Product containing fractions were combined and concentrated under reduced pressure to afford 0.892 g (94%) of the title compound. The analytical sample was further subjected to flash silica gel chromatography, eluting with dichloromethane containing 10-40% methanol. Product containing fractions were combined and concentrated under reduced pressure. The residue was crystallized from methanol.

MS (m / e): 231 (M ^& lt ^{; +} & gt ^; )

Calcd. For C 13 H 17 N 3 O:

Theoretical: C, 67.51; H, 7.41; N, 18.17.

Found: C, 67.24; H, 7.37; N, 18.38.

EXAMPLE 9 • φφ ·· φφφφ ·· ·· • φφφ · · · ΦΦΦΦ

· Φ Φ · ·· Φ Φ Φ Φ

ΦΦ ΦΦΦ Φ ΦΦΦ Φφ Φ

ΦΦΦΦ ΦΦ Φ ΦΦΦΦ

ΦΦ ΦΦ ΦΦ ΦΦΦ ΦΦ ΦΦ

Methyl 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxylate

A mixture of 0.225 g (0.62 mmol) of 5-trifluoromethanesulfonyloxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine, 0.035 g (0.15 mmol) of palladium acetate, 0.17 g (0, 31 mmol) of 1,1'-bis (diphenylphosphino) ferrocene, 0.17 ml (1.2 mmol) of triethylamine and 0.75 ml (18.5 mmol) of methanol in 15 ml of dimethylformamide were saturated with carbon monoxide by bubbling carbon monoxide through the reaction mixture. for about 5 minutes. The reaction mixture was heated at 60 ° C under a carbon monoxide atmosphere that was held from the balloon for 24 hours. The reaction mixture was diluted with saturated aqueous sodium chloride and then extracted with 3: 1 chloroform: isopropanol. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 0-20% methanol.

Product containing fractions were combined and concentrated under reduced pressure to afford 0.10 g (59.3%) of the title compound.

Mp = 199.7 - 201.0 ° C

MS (m / e): 273 (M ^& lt ^{; +} & gt ^; )

Calculated for C15H19N3O2:

Theoretical: C, 65.91; H, 7.01; N, 15.37.

Found: C, 65.62; H, 6.77; N, 15.07.

EXAMPLE 10

N- [ethyl] 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide • ftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftft • ft ftft ftft ft ftft ftft

A mixture of 0.150 g (0.41 mmol) of 5-trifluoromethanesulfonyloxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine, 0.023 g (0.10 mmol) of palladium acetate, 0.12 g (0, 21 mmol of 1,1'-bis (diphenylphosphino) ferrocene and 0.457 g (3.30 mmol) of potassium carbonate in 40 ml of acetonitrile were saturated with carbon monoxide at 0 ° C. To this mixture was added 0.202 g (2.48 mmol) of ethylamine hydrochloride and the reaction mixture was heated to 65 ° C under a carbon monoxide atmosphere maintained by a balloon. After 72 hours, the reaction mixture was diluted with water and then extracted once with ethyl acetate followed by 3: 1 chloroform: isopropanol. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 0-20% methanol. Product containing fractions were combined and concentrated under reduced pressure to give 0.10 g (84%) of the title compound.

Mp = 117-120 ° C

MS (m / e): 286 (M ^& lt ^{; +} & gt ^; )

Calcd for C16H22N4O:

Theoretical: C, 67.11; H, 7.74; N, 19.56.

Found: C, 67.17; H, 7.61; N, 19.43.

EXAMPLE 11

N- [phenyl] 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide

Starting from 0,125 g (0,34 mmol)

5-trifluoromethanesulfonyloxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine and 0.16 ml (1.72 mmol) of aniline;

· 4 · 4 · 4 · 9 9 9

9 9 9

0.065 g (56%) of the title compound was prepared essentially as described in Example 10.

MS (m / e): 334 (M ^& lt ^{; +} & gt ^; )

EXAMPLE 12

N- [2-hydroxyphenyl] 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide

Starting from 0,125 g (0,34 mmol)

5-trifluoromethanesulfonyloxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine and 0.19 mL (1.72 mmol) of 2-hydroxyaniline, 0.093 g (77%) of the title compound was prepared essentially in the manner described in Example 10.

MS (m / e): 351 (M ⁺ 1).

EXAMPLE 13

N- [4-fluorophenyl] 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxamide

Starting from 0.15 g (0.41 mmol)

5-Trifluoromethanesulfonyloxy-3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine and 0.12 mL (1.24 mmol) of 4-fluoroaniline, 0.058 g (40%) of the title compound was prepared essentially in the manner described in Example 10.

Mp = 114-116 ° C

MS (m / e): 353 (M ⁺ 1).

Calculated for C20H21N4OF:

Theoretical: C, 68.16; H, 6.01; N, 15.90.

Found: C, 68.40; H, 6.08; N, 16.07.

9 9

9999

9 9 • 9 9 9

9 9

9 9

999

9 9

9 · · · ·

9 9

EXAMPLE 14 Acid dihydrochloride

3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxylic acid

A solution of 0.125 g (0.46 mmol) of methyl 3- (1-methylpiperidin-4-yl) pyrrolo [3,2-b] pyridine-5-carboxylate in 30 ml of 1N hydrochloric acid was heated at reflux for 18 hours. The reaction mixture was concentrated under reduced pressure to give 0.10 g (87%) of the title compound.

MS (m / e): 259 (M ⁺ 1);

Represented by:

Dr. Otakar Švorčík

Thorns /

JUDr. Otakar Švorčík attorney

120 00 Prague 2, Halkova 2

Claims (11)

1. A compound of formula I: in which AB is -C =CH- or -CH-CH ₂ -; R represents H, C 1 -C 6 alkyl, benzyl or phenylethyl; X represents halogen, hydroxy, C 1 -C 4 alkoxy, -NHR ¹ , -C (O) OR ² , or -C (O) NHR ³ wherein: R ¹ represents C 1 -C 4 alkyl, phenyl (C 1 -C 4 alkylenyl) or heteroaryl (C 1 -C 4 alkylenyl); R ² represents a hydrogen atom or C1-C4 alkyl; R ³ represents C 1 -C 4 alkyl, heterocycle or phenyl optionally monosubstituted with halogen or hydroxy; and pharmaceutically acceptable acid addition salts and solvates thereof, provided that when AB is -C =CH-, then X is not a hydroxy group, a halogen atom, or a C 1 -C 4 alkoxy. • · A compound according to claim 1, wherein AB is -CHCH ₂ -. A compound according to claim 1, wherein X is -C (O) NHR ³ . 4. A pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula I: in which AB is -C =CH- or -CH-CH ₂ -; R represents H, C 1 -C ₆ alkyl, benzyl or phenylethyl; X is halogen, hydroxy, C 1 -C 4 alkoxy, -NHR ¹ , -C (O) OR ² , or -C (O) NHR ³ wherein: R ¹ represents C 1 -C 4 alkyl, phenyl (C 1 -C 4 alkylenyl) or heteroaryl (C 1 -C 4 alkylenyl); R ² represents a hydrogen atom or C1-C4 alkyl; R ³ represents C 1 -C 4 alkyl, heterocycle or phenyl optionally monosubstituted with halogen or hydroxy; and pharmaceutically acceptable acid addition salts thereof; and The solvates, provided that when A-B represents -C =CH-, then X is not a hydroxy group, a halogen atom or a C 1 -C 4 alkoxy. 5. A method of activating 5-HT _XF receptors in a mammal comprising administering to a mammal in need of such activation an effective amount of a compound of Formula II: in which AB is -C =CH- or -CH-CH ₂ -; R is H, C ₁ -C Alkyl, benzyl or phenylethyl; X represents halogen, hydroxy, C 1 -C 4 alkoxy, -NHR ¹ , -C (O) OR ² , or -C (O) NHR ³ wherein: R ¹ represents C ₁ -C ₄ alkyl, phenyl (C 1 -C 4 alkylenyl) or heteroaryl (C 1 -C 4 alkylenyl); R ² represents a hydrogen atom or C1-C4 alkyl; R ³ represents C 1 -C 4 alkyl, heterocycle or phenyl optionally monosubstituted with halogen or hydroxy; and pharmaceutically acceptable acid addition salts and solvates thereof. · 4 · β. Method according to claim 5, characterized in that the _{5-HTlF-mediated} disorder is migraine. 7. A method for the prevention of migraine in a mammal, comprising administering to a mammal susceptible to migraine an effective amount of a compound of formula II: in which AB is -C =CH- or -CH-CH ₂ -; R is H, C 1 -C ₆ alkyl, benzyl or phenylethyl; X represents a halogen atom, hydroxy, C 1 -C ₄ alkoxy, -NHR ¹ , -C (O) OR ² , or -C (O) NHR ³ wherein: R ¹ represents C 1 -C ₄ alkyl, phenyl (C 1 -C ₄ alkylenyl) or heteroaryl (C 1 -C ₄ alkylenyl); R ² represents a hydrogen atom or C 1 -C ₄ alkyl; R ³ represents C 1 -C ₄ alkyl, heterocycle or phenyl optionally monosubstituted with halogen or hydroxy; and pharmaceutically acceptable acid addition salts and solvates thereof. • · · · - 70 « 8. A method of preventing or inhibiting neuronal protein extravasation comprising administering to a mammal in need thereof an effective amount of a compound of Formula II: in which AB is -C =CH- or -CH-CH ₂ -; R represents H, C 1 -C 6 alkyl, benzyl or phenylethyl; X represents halogen, hydroxy, C 1 -C 4 alkoxy, -NHR ¹ , -C (O) OR ² , or -C (O) NHR ³ wherein: R ¹ represents C 1 -C 4 alkyl, phenyl (C 1 -C 4 alkylenyl) or heteroaryl (C 1 -C 4 alkylenyl); R ² represents a hydrogen atom or C1-C4 alkyl; R ³ represents C 1 -C 4 alkyl, heterocycle or phenyl optionally monosubstituted with halogen or hydroxy; and pharmaceutically acceptable acid addition salts and solvates thereof. 00 0 ·· 0000 0 0 0 000 00 000 9. Compound of formula III: wherein AB represents -C =CH- or -CH-CH ₂ -; and R represents H, C 1 -C 6 alkyl, benzyl or phenylethyl; and acid addition salts thereof. The compound of claim 9, wherein AB is -CHCH ₂ -. The compound of claim 10, wherein R is methyl.