AU725403B2 - Thrombin inhibitors - Google Patents
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- AU725403B2 AU725403B2 AU44117/97A AU4411797A AU725403B2 AU 725403 B2 AU725403 B2 AU 725403B2 AU 44117/97 A AU44117/97 A AU 44117/97A AU 4411797 A AU4411797 A AU 4411797A AU 725403 B2 AU725403 B2 AU 725403B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
WO 98/10763 PCT/US97/15989 -1- TITLE OF THE INVENTION THROMBIN INHIBITORS BACKGROUND OF THE INVENTION Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.
Edwards et al., J. Amer. Chem. Soc., (1992) vol. 114, pp.
1854-63, describes peptidyl a-ketobenzoxazoles which are reversible inhibitors of the serine proteases human leukocyte elastase and porcine pancreatic elastase.
European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety.
Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or a-keto carboxyl derivatives.
Thrombin inhibitors described in prior publications contain sidechains of arginine and lysine. These structures show low selectivity for thrombin over other trypsin-like enzymes. Some of them show toxicity of hypotension and liver toxicity.
European Publication 601 459 describes sulfonamido heterocyclic thrombin inhibitors, such as N-[4-[(aminoiminomethyl)amino]butyl]- 1 -[N-(2-naphthalenylsulfonyl)-L-phenylalanyl]-Lprolinamide.
WO 94/29336 describes compounds which are useful as thrombin inhibitors.
V
2 A first aspect of the present invention provides a compound having the following structure:
J-A
R
R2
R
3
I
and pharmaceutically acceptable salts thereof wherein J is (CH 2 1
(CH
2 )mNH, or SO 2 where m is 1 or 2; R1 and R 2 are independently selected from hydrogen, aryl, or in cyclo C3- 7 alkyl unsubstituted with one or more of C1-4 alkyl, C1- 4 alkoxy, benzyl, cyclohexylmethyl or aryl; R3 is hydrogen,
C
14 alkyl, or C1-4 alkenyl; A is selected from one of the following fragments NH HN N -N N H 2 N N-
NH
2
H
2 N B or wherein B is N or CH.
The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood
S
products, or mammalian organs in order to effect the desired inhibitions.
1 The invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a S npound of the invention in a pharmaceutically acceptable carrier. These compositions may I A .\YI.1I3\M Ili. I I 13272.~,pe-oc L WO 98/10763 PCT/US97/15989 -3optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.
The invention also includes the use of a compound of the invention in the manufacture of a medicament for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal.
The invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION Compounds of the invention have the following structure: X J-A
I
and pharmaceutically acceptable salts thereof wherein X is -S02-,
-SO-,
-OCH2(CH2)n aryl-, or -OCH2(CH2)n C3-8cycloalkyl-, wherein n is I or 2; WO 98/10763 WO 9810763PCTIUS97/15989 -4- J is -(CH2)m-, -(CH2)mNll-, -SO2NHI-, -S02(CH2)m-, -NIISO2-, -802-, or -(CH2)mSO2-, wherein m is 1 or 2; R 1, R 2 and R 4 are independently selected from hydrogen, aryl, -C02R 5 aryl C1-4 alkyl, diaryl CI-4 alkyl, dicyclo C3-8 alkyl Cl-4 alkyl, cyclo C3 -g alkyl C 1-4 alkyl,
CNR
-CO 'R 6 wherein R 5 and R 6 are independently hydrogen or C 1 4 alkyl, substituted aryl with one or two substituents selected from Cl-4 alkyl, Cl1 -4 alkoxy,
R
COR 6 wherein
R
5 and R 6 are independently hydrogen or CI1-4 alkyl, aryloxy, cyclo C3-8 alkoxy, methylenedioxy, halogen, or hydro xy, WO 98/10763 PCT/US97/15989 heteroaryl with one or two heteroatoms selected from N, O, and S, cyclo C3-7 alkyl unsubstituted or substituted with one or more of C 1-4 alkyl, C -4 alkoxy, benzyl, cyclohexylmethyl or aryl, a C4-10 carbocyclic or bicyclic ring, or
R
1 and R 2 along with the carbon to which they attach form a cyclo C3- 7 alkyl ring;
R
3 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy,
-NHR
7 wherein R 7 is hydrogen or Cl-4 alkyl, or -NHSO2CH2aryl; A is selected from one of the following fragments NH HN H 2 N4 S -N
NH
2
,,N
HN
H
2 N H2 N ,wherein B is N or CH.
One group of compounds of the invention have the following structure:
O
J A RR L- R 3 WO 98/10763 PCT/US97/15989 -6and pharmaceutically acceptable salts thereof wherein J is (CH2)m, (CH2)mNH, or S02, where m is 1 or 2; RI and R 2 are independently selected from hydrogen, aryl, or cyclo C3-7 alkyl unsubstituted or substituted with one or more of C1-4 alkyl, Cl-4 alkoxy, benzyl, cyclohexylmethyl or aryl;
R
3 is hydrogen, Cl-4 alkyl, or C1-4 alkenyl; A is selected from one of the following fragments
NH
-N N4
NH
2
H
2 N CN- HN
H
2 N B wherein B is N or CH.
One class of this group of compounds has the following structure: WO 98/10763 PCT/US97/15989 -7and pharmaceutically acceptable salts thereof wherein J is CH2, CH2NH, or S02;
R
1 and R 2 are independently selected from hydrogen, aryl, or cyclohexyl;
R
3 is hydrogen, -CH=CH2, or -CH2CH3; and A is selected from one of the following fragments NH HN C N -N N4O
H
N
NH
2 or H 2
N
Specific exemplifications of this class are
NH
NH
2
CH
3 0 NH ONH N O S-N N
NH
2 WO 98/10763 WO 9810763PCTIUS97/15989 8- 0H and
CH
2 C r
H
and pharmaceutically acceptable salts thereof.
ABBREVIATIONS
Designation BOC (Boc) HBT(HOBT or HOBt) BBC reagent PyCRJ
EDC
DMF
Et3N or TEA t-butyloxycarbonyl 1 -hydroxybenzotriazole hydrate benzotriazolyloxy-bis (pyrrolidino)carboniumn hexafluorophosphate 1, 1,3,3-bis(tetramethylene)chiorouronium hexafluorophosphate 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride di-t-butyl dicarbonate dimethylformamnide triethylamine WO 98/10763 PCT/US97/15989 -9- EtOAc
TFA
DMAP
DME
BH3-THF D-Phe(3,4-C12) D-3,3-dicha Pro Arg Gly D-3,3,-diphe ethyl acetate trifluoroacetic acid dimethylaminopyridine dimethoxyethane Borane-tetrahydrofuran complex D-3,4-Dichlorophenylalanine D-3,3-Dicyclohexylalanine Proline Arginine Glycine D-3,3-Diphenylalanine The compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
When any variable occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, except where noted, "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having 1-8 carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl). "Alkenyl" is intended to include both branched- and straight-chain unsaturated aliphatic hydrocarbon groups having 1-8 carbon atoms, e.g. ethenyl, propenyl, etc. "Cycloalkyl" includes cyclic saturated aliphatic hydrocarbon groups having 3-8 carbon atoms. "Aryl" means a 6-membered organic radical derived from an aromatic hydrocarbon by removal of one hydrogen atom.
"Heteroaryl" means a 5- or 6- membered organic radical having 1 or 2 heteroatoms selected from N, 0, and S. "Alkoxy" represents an alkyl group having 1-8 carbon atoms attached through an oxygen bridge.
"Halo", as used herein, means fluoro, chloro, bromo and iodo.
WO 98/10763 PCT/US97/15989 "Counterion" is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluroacetate, perchlorate, nitrate, benzoate, maleate, tartrate, hemitartrate, benzene sulfonate, and the like.
Under standard nonmenclature used throughout this disclosure unless specified otherwise, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. For example, an ethyl substituent substituted with "methylcarbonylamino" is equivalent to
HO
I II -CH2CH2-N-C-CH3 The term heterocycle or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
Examples of such heterocyclic elements include piperidinyl, piperazinyl-, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, WO 98/10763 PCT/US97/15989 11 -llthiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The pharmaceutically-acceptable salts of the compounds of Formula I (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts which are formed, from inorganic or organic acids or bases.
Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-Dglucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or l-ethyl-3-(3dimethylaminopropyl) carbodiimide. Other methods of forming the amide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester.
Typically, solution phase amide coupling are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead.
WO 98/10763 PCT/US97/15989 12- The addition and removal of one or more protecting groups is also typical practice.
Compounds of the invention can be prepared according to the general procedures outlined in Schemes I-VI.
Compounds found in table 1 were synthesized by the general method outlined in Scheme I and are exemplified by, but not limited to the examples 1-9. A phenolic ester such as ethyl 4hydroxybenzoic acid is alkylated with an alkyl bromide such as benzyl bromide by using a base such as cesium carbonate to afford the product 1-3. The ester group is then reduced with a hydride reducing agent such as lithium aluminum hydride to afford the benzylic alcohol I- 4. The benzylic alcohol is converted into a leaving group (such as a bromide or triflate) and the benzylic leaving group is reacted with 4aminopyridine to afford the final product.
WO 98/10763 WO 9810763PCT/tJS97/15989 13 SCHEME I
OH
CO
2
CH
2
CH
3 1-1 Cs 2 C0 3
/DMF
\/CH Br 1-2
LAH
THF
CO
2
CH
2
CH
3 1-3 TH F/C Br 4 (C 6
H
5 3
P
CH
3 CN
P
4-aminopyridine
CH
2 0H 1-4 BrO WO 98/10763 PCT/US97/15989 14- A general method for synthesizing compounds found in tables 2 and 3 is outlined Scheme II. A benzoic acid such as II-1 (obtained in standard fashion) is coupled to 4-amino-pyridine under standard amide bond coupling conditions. The resultant amide 11-2 is then reduced with lithium aluminum anhydride to afford the desired product 11-3.
SCHEME I
EDC/HOBT
O -CO 2
H
0 C 2E t 3 N D M F 11-1 4-AP 1) (COCI) 2
-CH
2
CI
2 Et 3 N- DMF 2) 4-AP (7 LiAIH 4
/THF
600 0 WO 98/10763 PCT/US97/15989 A general method for synthesizing compounds found in table 2 is outlined Schemes II and III. A benzoate ester such as 1I-4 (obtained in standard fashion) is reacted with an alkylating reagent (such as bromomethyl cyclohexane) to afford O-alkylated product III-5. The ester is hydrolyzed with an aqueous base and is coupled to 4aminopyridine under standard amide bond coupling conditions. The resultant amide III-7 is then reduced with lithium aluminum hydride to afford the desired product III-8.
WO 98/10763 WO 9810763PCT/US97/15989 16 SCHEME 111 ~B r
S
2 00 3
DMF
COOCH
3 111-1 111-2 230 0 C
HO
COOCH
3
H
2 /Pd (C) EtOAc 111-3
COOCH
3
CS
2 00 3
/DMF
111-4
MCOOCH
3 111-5 NaOH /MeOH WO 98/10763 WO 9810763PCT[US97/15989 17 SCHEME fI (CONTINUED)
MCOOH
111-6 1. (0100)2 DCE 2.
H
2 N <\74 0
H
LiAI Hj/ TH F 111-7 0N 111-8 WO 98/10763 WO 9810763PCTIUS97/15989 18 SCHEME TV HO~ a C O
H
~rBr /7%a
OOCO
CS
2 0- 3 DMF
COH
'v-1 IV-2 Br 2 Fe!/ HCOOH 10000C IV-3 Pd(PPh 3 4 /dioxane SSnBU 3 11 a COOCH 3 IV-4 WO 98/10763 WO 9810763PCTIUS97/15989 19 SCHEME-IV (CONTINUED)
H
2 /Pd (C) EtOAc LIOH/TH F
H
2 0
COOCH
3 1. (Cico) 2
DCM
COOH 2. H 2 N- C\ IV-6 LiAIH 4
/THF
N 50 0
C
IV-7
H
'v-8 WO 98/10763 PCT/US97/15989 A method for preparing compounds found in table 4 is outlined in Scheme V. Substituted benzene compound such as 4benzyloxy-benzene is reacted with sulfuryl chloride at 80-120°C to give a sulfonyl chloride. The sulfonyl chloride is reacted with Boc-piperazine and the Boc protecting group is removed with a strong acid to afford the deprotected piperazine. The free nitrogen is converted to the amidine with a guanylating reagent such as amidinosulfonic acid.
WO 98/10763 PTU9/58 PCTIUS97/15989 21 SCHEME V S0 2 C1 2
/DMF
1 00 0 C /2 h V-2 N0 V-3 HN NBOC Et 3 N 0H 2
C
2 EtOAc N. -250C
NH
H
2 N 1 S0 3
H
Et 3 N /DMF V-4
H*HCI
CF
3
COOH
WO 98/10763 PCT/US97/15989 -22- A general method for synthesizing compounds found in table 5 is outlined in Scheme VI. The ketone of a cyano-benzophenone such as 1 is reduced with a metal hydride reagent such as sodium borohydride and the resultant alcohol is removed by treatment with dimethyldichlorosilane to afford the diphenylmethane VI-3. The methoxy group is removed with borontribromide and the phenol is alkylated with an alkylating reagent such as benzyl bromide. The cyano group is then treated with sodium hexamethyldisilazane and the silylimidate is hydrolyzed with an acidic workup to afford the final product.
WO 98/10763 WO 9810763PCTIUS97/15989 23 SCHEME VI NaBH 4 I H 3 C00 vI-1 VI-2 (Me) 2 SiCI 2 aH 3 0 0
ON
B Br 3 VI-3 HOO ON VI-4 NaN(TMS)2
CS
2
CO
3
ON
*HCI
VI-6 Unless otherwise shown, NMR data for the compounds identified below was obtained using a field strength of 400 MHz.
WO 98/10763 WO 9810763PCT/US97/15989 -24- Preparation of compounds found in Table I EXAMPLE 1 Preparation of 4-amino-i .1-diphenylmethoxy)benzylpyridinium bromide (1 -6)
OH
CO
2
CH
2
CH
3 1 -1 Cs 2
CO,
3 /DM F
LAH
THF
CO
2
CH
2 C H 3 1-3 TH F/C Br4 (06 H 6 3
P
CH
3
CN
4-AP Br G
CH
2 0H Step A: Preparation of ethyl 1,1-diphenylmethoxy)benzoate (1-3) Under N2, a mixture of ethyl 4-hydroxybenzoic acid g, 15 mmol) 1-1I and Cs2CO3 (5.0 g, 15 mmol) in DMF (50 ml) was stirred at room temperature. After 15 min, diphenylmethyl bromide WO 98/10763 PCT/US97/15989 1-2 (4.0 g, 16 mmol) was added and then heated at 60 0 C. After 18h, saturated Na2CO3 was added and the mixture extracted with EtOAc The combined extracts were washed with H20, dried, filtered and concentrated to dryness to yield 1-3.
1 H NMR (CDCI3) 5 1.3 (3H, 4.3 (2H, 6.95 (2H, 7.3 (10H, m) and 7.95 (2H, d).
Step B: Preparation of 4-(1,1 -diphenylmethoxy)benzyl alcohol (1-4) To a suspension of LAH (3.2 g, 0.084 mmol) in THF (400 ml) under N2 was added dropwise a solution of 1-3 (21 g, 0.063 mol) in THF (100 ml). After stirring overnight at room temperature, saturated Na2SO4 was added to the reaction until a white suspension was observed. The mixture was filtered and the filtrate was combined with and CHC13, separated, and extracted further with CHC13 (2x).
The combined organic extracts were dried, filtered and concentrated to dryness. The residue was triturated with hexane to yield 1-4.
1 H NMR 8 1.6 (1H, bs), 4.55 (2H, 6.2 (1H, 6.95 (2H, and 7.3 (12H, m).
Step C: Preparation of 4-(1,1-diphenylmethoxy)benzyl bromide A solution of 1-4 (3.6 g, 12 mmol), triphenyl phosphine (3.1 g, 11.8 mmol) in THF (100 ml) was treated with carbon tetrabromide (3.9 g, 11.8 mmol). After 12h additional triphenylphosphine (3.1 g, 11.8 mmol) was added and the mixture allowed to stir at room temperature overnight. Some triphenyl phosphine oxide was then filtered off and the filtrate concentrated to dryness. The residue was chromatographed on a Still column (70 mm) and the product eluted with 5% EtOAc-hexane to yield 1H NMR (CDC13) 5 4.4 (2H, 6.2 (1H, 6.9 (2H, d) and 7.35 (12H, m).
WO 98/10763 PCT/US97/15989 -26- Step D: Preparation of 4-amino-1-(4-(1,1 -diphenylmethoxy)benzvl)pyridium bromide (1-6) A solution of 1-5 (0.58 g, 1.6 mmol) in CH3CN (25 ml) was treated under N2 with 4-aminopyridine (0.16 g, 1.7 mmol). After stirring overnight at room temperature, the solid was filtered off to yield 1-6. An analytical sample was crystallized from CH3CN.
mp: 254-5°.
Analysis calculated for C25H23BrN20 C, 67.12; H, 5.18; N, 6.26 Found: C, 67.25; H, 5.07; N, 6.25 1H NMR (d6-DMSO) 8 5.2 (2H, 6.55 (1H, 6.8 (2H, 7.05 (2H, 7.3 (8H, 7.47 (4H, 8.13 (2H, bs exch) and 8.25 (2H, d).
EXAMPLE 2 Preparation of 4-amino- 1-(4-(2-phenyl-1-ethoxy)benzyl)pyridinium bromide (2-2) 2-2 was prepared as described for the preparation of 1-6 except 2-phenyl-l-bromoethane was used in place of 1-2 in Step A and synthesized. mp: 170-1°C (CH3CN); 1H NMR (d6-DMSO) 8 3.0 (2H, 4.2 (2H, 5.3 (2H, 6.82 (2H, 6.96 (2H, 7.3 (7H, 8.15 (2H, exch bs) and 8.27 (2H; d).
Analysis calculated for C20H21BrN20 C, 59.96; H, 5.71; N, 6.99 Found: C, 59.62; H, 5.22; N, 7.14 WO 98/10763 PCT/US97/15989 -27- EXAMPLE 3 Preparation of 4-amino-l-(4-(cyclohexylmethoxy)benzyl)pyridinium bromide (3-3) 3-3 was prepared as described for the synthesis of 1-6 except 4-hydroxy-benzyl alcohol and cyclohexylmethyl bromide were used in Step A to yield 4-(cyclohexylmethoxy)benzyl alcohol directly. mp: 241-3 0
C;
IH NMR (d6-DMSO) 5 1.2 (5H, 1.75 (6H, 3.8 (2H, 5.28 (s, 2H), 6.8 (2H, 6.95 (2H, 7.34 (2H, 8.1 (2H, exch bs), 8.25 (2H, d).
Analysis calculated for C 19H25BrN20 C, 60.47; H, 6.68; N, 7.42 Found: C, 60.57; H, 6.70; N, 7.15 EXAMPLE 4 Preparation of 4-amino-l-(4-(1-phenyl-l-carbomethoxy)methoxybenzvl)pyridinium bromide (4-2) 4-2 was prepared as described for the synthesis of 1-6 except methyl I-bromo-l-phenylacetate was used in place of 1-2 in Step A. The compound was crystallized from CH3CN; mp:. 188- 0
C;
1 H NMR (d6-DMSO) 8 3.65 (3H, 5.27 (2H, 6.05 (IH, 6.83 (2H, 7.2 (2H, 7.34 (2H, 7.42 (3H, 7.54 (2H, 8.14 (2H, exch bs) and 8.27 (2H, d).
Analysis calculated for C21H21BrN20-0.25 C, 58.14; H, 5.00; N, 6.46 Found: C, 57.77; H, 4.94; N, 6.69 WO 98/10763 WO 9810763PCTIUS97/15989 28 EXAMPLE Preparation of 4-amnino-i -(4-(2,2-dicyclohexyl -1-ethoxy)benzyl)pyridinium bromide C02H
LAH
00 2 H THF 5-2 100%
DEAD/TPP
N
2
/THF
HO -0 CO 2 Et 5-3 0-0 CO 2 Et 5-4 52% Step A: Preparation of 1.1 -dicyclohexyl-2-hydroxy ethane (5-2) A solution of 1, 1-di cyc lohexylIacetic acid (2.8 g, 12.5 mmol) in THF (5 ml) under N2 was cooled in an ice bath and then M borane in THF (17 ml, 17 mmol) was added dropwise. After addition, the solution was stirred at room t emperature and then a 1: 1 mixture of THFfH2O (10 ml) was added carefully. The mixture was WO 98/10763 PCT/US97/15989 -29added to saturated Na2CO3 and extracted with EtOAc The organic extracts were dried, filtered and concentrated to dryness to yield 5-2.
1 H NMR (CDC13); 8 1.1 (11H, 1.6 (12H, 3.65 (2H, d).
Step B: Preparation of ethyl 1,1-dicyclohexyl)ethoxybenzoate (5-4) Under N2, 5-2 (1.1 g, 5.2 mmol), ethyl 4-hydroxybenzoate (0.9 g, 5.2 mmol), triphenylphosphine (1.6 g, 5.2 mmol), diethyl azodicarboxylate (1.1 g, 6.2 mmol) in THF (15 ml) were placed in a flask and stirred at room temperature. After 2 days, water and were added and separated. The aqueous layer was further extracted with Et20 (2x) and the combined layers backwashed with saturated Na2CO3, brine, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (40 mm) and the product eluted with 20% EtOAc/hex to yield 5-4.
5-4 was converted to 5-5 as described in Example 1; mp: 223-5 0
C;
IH NMR (d6-DMSO) 8 1.4 (23 H, 3.93 (2H, 5.26 (2H, 6.85 (2H, 6.95 (2H, 7.37 (2H, 8.15 (2H, exch bs) and 8.3 (2H, d).
Analysis calculated for C26H37N20Br*0.75 C, 64.12; H, 7.97; N 5.75 Found: C, 64.25; H, 7.66; N 5.83 WO 98/10763 PCT/US97/15989 EXAMPLE 6 Preparation of 4-amino-1-[4-(1,3-diphenyl-l-propoxy)benzyl]pyridinium bromide (6-8) Step A: Preparation of 1.3-diphenvlpropanol (6-2)
OH
6-1
N
2 NaBH 4 EtOH (-Phenylpropiophenone (7.5 g, 36.0 mmol) was suspended in ethanol (100 ml) and sodium borohydride (0.68 g, 18.0 mmol) was added under N2. The resulting solution was stirred at ambient temperature overnight. The ethanol was removed in vacuo and the residual oil-solid was taken up in ethyl acetate (100 ml) and water (30 ml). The ethyl acetate layer was removed, washed with water, dried, filtered and concentrated in vacuo to give 6-2 as a colorless oil.
1H NMR (d6-DMSO) 5 1.88 (2H, 2.6 (2H, 4.51 (1H, 5.28 (IH, 7.1-7.37 (10H, m).
WO 98/10763 PCT/US97/15989 Step B: -31 Preparation of ethyl 4-(1,3-diphenyl-l -propoxy)benzoate (6-4) 6-2
OH
Ph 3 P
N
2 OH DEAD 1 6-3 COOC 2
H
COOC
2
H
6-4 To 6-2 (2.12 g, 10.0 mmol) in tetrahydrofuran (25 ml) under a nitrogen atmosphere was added ethyl 4-hydroxybenzoate (6-3) (1.66 g, 10.0 mmol) followed by triphenyl phosphine (3.15 g, 12.0 mmol). The mixture was cooled in an ice bath and diethyl azodicarboxylate (2.09 g, 12 mmol) was added. This mixture was stirred overnight at ambient temperature and the solvent was removed in vacuo. The residue was taken up in the water and the ether layer was separated, washed with sodium bicarbonate and water, dried, filtered and concentrated in vacuo to yield an oil. Chromatographic purification on silica gel gave 6-4 as a colorless oil.
1H NMR (d6-DMSO) 8 1.25 (3H, 2.1 (1H 2.25 (1H, 2.66 (IH, 2.75 (1H, 4.22 (2H, 5.4 (1H, 6.99 (2H, 7.12-7.44 7.8 (2H, d).
WO 98/10763 PCT/US97/15989 -32- Preparation of 4-(1,3-diphenyl- l-propoxy)benzyl alcohol LAH N 2 0
COOC
2
H
5 Et 2 0
OH
A solution of 6-4 (2.46 g, 6.8 mmol) in ether (30 ml) was added dropwise under nitrogen atmosphere to a stirred cold suspension of lithium aluminum hydride (0.285 g, 7.5 mmol) in ether (5 ml). The mixture was stirred for 3 hrs at ambient temperature and was decomposed by carefully adding water and sodium hydroxide. This mixture was extracted with ethyl acetate. The extract was washed with water, dried, filtered and concentrated in vacuo to yield 6-5 as a colorless viscious oil.
1H NMR (d6-DMSO) 8 2.05 (1H, 2.2 (1H, 2.66 (1H, 2.75 (1H, 4.34 (2H, 4.99 (1H, 5.26 (1H, 6.81 (2H, 7.04-7.4 (12H, m).
WO 98/10763 PCT/US97/15989 -33- Step D: Preparation of 4-(1,3-diphenyl-l-propoxy)benzyl bromide (6-6) Ph 3 PBr 2
N
2
CH
3 CN Py.
OH
Br To an ice cold solution of 6-5 (1.19 g, 6.0 mmol) in acetonitrile (15 ml) was added pyridine (0.76 g, 9.6 mmol) and then triphenylphosphine dibromide (3.29 g, 7.8 mmol). The mixture was stirred at ice bath temperature for 1/4 hr under N2 and at ambient temperature for 1 &3/4 hrs and then was filtered. Concentration of the filtrate in vacuo gave a crude oil. The pure product 6-6 was obtained after three silica gel chromatographic separations.
1 H NMR (d6-DMSO) 8 2.06 (IH, 2.2 (1H, 2.66 (1H, 2.75 (1H, 4.62 (2H, 5.3 (1H, 6.82 (2H, 7.16-7.4 (12H, m).
WO 98/10763 PCT/US97/15989 -34- Step E: Preparation of 4-amino-l-[4-(1,3-diphenyl-l-propoxy)benzyllpyridinium bromide (6-8) O 0CH3CN NH 2 6-6 Br 6-7
N
vjo0y GBr( 6-8
NH
2 To a solution of 4-(1,3-diphenyl-l-propoxy)benzyl bromide 6-6 (0.381 g, 1.0 mmol) in acetonitrile (7 ml) was added 4aminopyridine (94 mg, 1.0 mmol) with stirring at room temperature. The mixture was stirred for 3 hrs and the resulting white suspension was filtered. The white solid obtained 6-8, melted at 215- 216.5 0 C. Recrystallization from acetonitrile raised the melting point to 218.5-220 0
C.
1H NMR (d6-DMSO) 8 2.06 (1H, 2.2 (IH, 2.65 (1H, 2.75 (IH, 5.2 (2H, 5.3 (1H, 6.8 (2H, 6.9 (2H, 7.16-7.41 (12H, 8.12 (2H, 8.24 (2H, d).
Analysis calculated for C27H27N20Br C, 68.21; H, 5.73; N, 5.89 Found: C, 68.48; H, 5.68; N, 5.98 WO 98/10763 WO 9810763PCTIUS97/15989 35 EXAMPLE 7 Preparation of 4-amino-I- [4-(2,2-diphenylethoxy)benzyllpyridinium bromide (7-7) Step A: Preparation of ethyl 4-(2..2-diphenylethoxv)benzoate (7-3) CH -CH 2 0H 7-1 Ph 3 P N 2 OH DEAD 7-2
C
2
H
CH-CH
2 -O /COOC 2
H
C 7-3 2,2-Diphenylethanol (5.95 g, 30 mmol) and ethyl 4hydroxybenzoate (5.48 g, 30 minol) were reacted, as in Example- 6. 7-3 was obtained after chromatography as a colorless oil.
I H NMR (CDCl3): 5 1.36 (3H, 4.33 (2H, 4.52 (3H, 6.9 (2H, 7.2-7.36 (10 H, in), 7.96 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 36 Step B: Preparation of ethyl 4-(2,2-diphenylethoxy)benzyl alcohol (7-4) O C 2 O/ OCH LAH N 2 COC2H5 Et 2
O
7-3 CH-0H 2 0
\H
7-4 7-3 (0.757 g, 2.2 inmol) was dissolved in ether (20 ml) and was reduced with lithium aluminum hydride (92 mg, 2.4 mmol) under nitrogen as in Example 6, Step B. 7-4 was obtained as a colorless oil.
IH NMR (d6-DMSO) 8 1.55 (1H, 4.45-4.52 in), 4.61 (2H, d), 6.88 (2H, 7.2-7.35 (12H, mn).
1 t WO 98/10763 PCT/US97/15989 -37- Step C: Preparation of 4-(2.2-diphenvlethoxy)benzyl bromide r\
CH-CH
2 -O PBr 3 OH 7-4 C
HH
2
-O
CH-CH2-0- C 7-4 (0.572 g, 1.9 mmol) was dissolved in ether (10 ml).
The solution was cooled in ice and phosphorus tribromide (0.204 g, 0.75 mmol) was added. After 1/2 hr. the reaction was diluted with methanol (2 ml) and water (5 ml). The ether layer was separated, washed with sodium bicarbonate and water, dried and filtered.
Concentration of the filtrate in vacuo gave 7-5 as a white solid.
mp: 70-73°C.
1 H NMR (d6-DMSO): 8 4.43-4.62 (3H, 4.64 (2H, 6.9 (2H, d), 7.15-7.4 (12H, m).
WO 98/10763 WO 9810763PCTJUS97/15989 38 Step D: Preparation of 4-amino-1-[4-(2,2-diphenyl-ethoxy)benzyllpyridinium bromide (7-7) C H 5 Br
NH
2
N
CH-CH
2 O0 NBr 7-7
NH
2 (100 mg, 0.27 mimol) was reacted with 4aminopyridine 7-6 (28 mg, 0.30 mmol) in acetonitrile (3 ml) as in Example 6, Step E. The white solid product 7-7 was obtained.
mp: 137-139'C.
I H NMR (d6-DMSO) 8: 4.45-4.59 (3H, in), 5.27 (2H, 6.82 (2H, d), 6.98 (2H, 7.17-7.4 (12H, mn), 8.13 (2H, 8.27 (2H, d).
Analysis calculated for (C26H25N2OBr-O.5 C, 66.38; H, 5.57; N, 5.96 Found: C, 66.57; H, 5.42; N, 5.98 WO 98/10763 WO 9810763PCTIUS97/15989 39 EXAMPLE8 Preparation of 4-amino-i 4-(dicyclohexylrnethoxy)benzyllpyridinium bromide (8-7) Step A: Preparation of ethyl 4-(dicyclohexylmethoxy)benzoate (8-3) O\Ph 3 P N 2 OH-OH OH
DEAD
8-1 8-2 OC00 2
H
OH-C COOC 2
H
(D/8-3 Dicyclohexylmethanol (4.91 g, 25 mmol) and ethyl 4hydroxybenzoate (4.15 g, 25 mmol) were reacted, as in Example 6, Step B, to obtain a colorless oil 8-3 after chromatography. IH NMR (CDCl3): 8 0.98-1.3 (1IH, in), 1.36 1.58-1.86 (1L1H, mn), 4.02 (1H, 4.33 (2H, 6.92 7.94 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 40 Ste B: Preparation of 4-(dicyclohexylmethoxy)benzyl alcohol (8-4) CH-O 0 COOC 2
H
5 LAH N 2 Et 2
O
0/ 8-3 CH-O
O
8-4 Reduction of 8-3 (2.8 g, 8.1 mmol) with lithium aluminum hydride (0.338 g, 8.9 mmol) in ether (30 ml) as in Example 6 gave 8-4 as a colorless oil.
I H NMR (CDC13): 8 1.01-1.31 (1IH, in), 1.45-1.86 (1L1H, in), 3.91 (I H, 4.6 (2H, 6.9 (2 H, 7.23 (2 H, d).
WO 98/10763 WO 9810763PCT/US97/15989 -41 Step C: Preparation of 4-(dicyclohexylmethoxy)benzyl bromide O\ PBr 3 CH-O OH Et 2
O
CY 8-4 CH-O
B
0a 8-4 (1.93 g, 6.4 mmol) was converted to the bromide using phosphorus tribromide (1.69 g, 2.6 mmol) in ether (25 ml) as in Example 7. Recovered 8-5 liquid.
I H NMR (CDCl3) 5 1.0-1.32 (11LH, in), 1.53-1.84 (l11H, in), 3.91 (1 H, 4.49 (2H1, 6.85 (2H, 7.25 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 Step D: 42 Preparation of 4-amino-i -[4-(dicyclohexylmethoxy)benzyllpyridinium bromide (8-7) CH-O
B
0/
B
CH
3
CN
NH
2 I8-6
N
9BrQ
CH-O-
NH
2 (183 mg, 0.5 mmol) and 4-aminopyridine 8-6 (47 mg, mmol) were reacted in acetonitrile (4 ml) as in Example 1: Recovered white solid 8-7. mp: 248-249'C I H NMR (d6-DMSO) 8 0.94-1.28 (11 H, in), 1.5-1.75 (11 H, in), 4.1 (I1H, 5.24 (2H, 6.83 (2H, 6.98 7.28 (2H, 8.14 (2H, 8.3 (2H, d).
Analysis calculated for C25H35N2OBr C, 65.35; H, 7.68; N, 6.10 C, 65.45; H, 7.62; N, 6.17 Found: WO 98/10763 WO 9810763PCTIUS97/15989 43 EXAMPLE 9 Preparation (9-7) of 3 ,4-diamino-l1-(4-benzyloxybenzyl)pyridinium bromide Step A: Preparation of 4-benzyloxvbenzyl bromide (9-2) P Br 3 O Et 2
O
OH
9-1
O
9-2 To a cold suspension of 4-benzyloxybenzyl alcohol 9-1 (21.4 g, 0.10 mol) in ether (250 ml) was added phosphorus tribromide (10.8 g, 40 mmol) as in Example 7. Recovered 27.2 g of white solid which was recrystallized from hexane (200 ml). Obtained pure bromide 9-2.
1H NMR (CDCl3) 854.5 (2H, 5.05 6.94 (2H, 7.26-7.45 (7H, in).
WO 98/10763 PCT/US97/15989 -44- Preparation of 3,4-diamino-l-(4-benzyloxybenzyl)pyridinium bromide (9-4) Step B:
O
CH
3
CN
N
Br
SNH
2
NH
2
TNH
2
NH
2 9-2 (1.38 g, 5.0 mmol) was reacted with 3,4diaminopyridine (0.573 g, 5.25 mmol) in acetonitrile (50 ml) as in Example 1. Recovered white solid 9-4. Recrystallized from acetonitrile, mp: 240-241 C.
1 H NMR (d6-DMSO) 8 5.1 (2H, 5.25 (2H, 5.56 (2H, s),'6.74 (1H, 7.05 (2H, 7.24-7.46 (9H, 7.61 (1H, 7.96 (1H, d).
Analysis calculated for (C19H2oN30+Br-): (0.25 C, 59.09; H, 5.22; N, 10.88 Found: C, 59.33; H, 5.60; N, 10.38 The compounds shown in the table below are exemplary compounds of the present invention. The range of Ki values associated with the specifically listed compounds is represented as follows: <0.1 .M >0.1 tM and <1.0 pM >1.0 .M WO 98/10763 WO 9810763PCTIUS97/15989 45 TABLE I z-Y
NH
2 Z Y R 2 Ki (thr)
H
2 0-
H
2 0- CH CH H CH CH H N CH H C CH Q-H
CHO-
O-CH 2
CH
2
O-
/CH 2
CHZ-CHO
CH CiH CHi CH H 254- 170to 218.5- 2200
H
/CH 2 CH CH H 241- WO 98/10763 WO 9810763PCTIUS97/15989 46 Z Y R 2 Ki (thr) a~m mp /CH(CH 2
CH
3
H
H
\/CH
2
CH
2
H
(HH(-
2
H
2 0-H CH CHI H CHCH H CH GIH Gi N H CH CH- H 188- 1 900 137- 223- 212- 248- 183- 125-
-CHO-
/CH 2
O-
G?-CH 2
O-
/CH 2
O-
-OCH3 CH&CHH CH CH H
-OCH
2 -0 CH CR NH2 240- WO 98/10763 WO 9810763PCTIUS97/15989 U. 47 The general procedure outlined in Scheme II can be used to make the following compounds.
EXAMPLE ,Prep~aration of N-4-(4-benzyloxvbenzyl)aminopyridine (10-3) Step A: 0 0 NH 10-2
N
Method 1: Preparation of 4-(4-benzyloxyphenyl)carboxamidop2yridine (10-2) A solution of 0 O\/C
C
2
H
10-1 (1.1 g, 4.8 mmol), 1-hydroxybenzotriazole (H-OBT) (1.0 g, 7.4 mmol), l-ethyl-3-(3-dimethylaminopropyl) carbodiiniide-HC1 (EDC) (1.4 g, 7.3 mmrol), Et3N (1 ml, 7.6 mmol) in DMF (40 ml) was treated under N2 with 4-ammnopyridine (4-AP) (0.54 g, 5.0 mmol). After stirring overnight at room temperature, the reaction was poured into saturated NaHCO3 and extracted with EtOAc The organic layers were washed with H20 and brine, dried, filtered and concentrated to dryness.
The residue was triturated with hexane to yield 10-2. mp: 126-7 0
C;
I H NMR (CDCl3) 8 5.15 (2H, 7.04 (2H, 7.4 (5H, in), 7.6 (2H, 7.84 (2H, 8.12 (1H, exch bs), 8.42 (2H, d).
WO 98/10763 PCT/US97/15989 -48- Method 2: Oxalyl chloride (3.3 g, 26 mmol) was added under N2 dropwise to a suspension of 10-1 (5.0 g, 22 mmol) in CH2C12 (75 ml) with 4 drops of DMF. After 1 h the solution was concentrated to dryness and flushed once with CHC13. The residue was dissolved in CHC13 (60 ml) and added dropwise to a suspension of 4-AP (6.2 g, 66 mmol) in CHC13 (100 ml). After 1 h at room temperature the solution was poured into saturated Na2CO3 and separated. The aqueous was further extracted with EtOAc The combined extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (80 mm) and the product eluted with 10% CHC13 to yield 10-2.
H SN
N
10-3 Preparation of 10-3: A solution of 10-2 (3.5 g, 11.5 mmol) in THF (40 ml) was treated dropwise under N2 with 1.0 M LAH in THF (17 ml, 17 mmol).
After addition, the solution was heated at 60 0 C. After 18 h, the solution was treated with saturated Na2SO4 to a white suspension. The mixture was filtered and the pad washed with EtOAc (200 ml). The organic extracts were washed with saturated Na2CO3, dried, filtered and concentrated to dryness to yield 10-3. An analytical sample was crystallized as the HC1 salt from EtOH-Et20; mp: 224-6 0
C;
1 H NMR (d6-DMSO) 8 4.45 (2H, 5.1 (2H, 6.95 (4H, d and m), 7.4 (7H, 8.2 (2H, 9.2 (1H, exch bs).
Analysis calculated for Cl9H18N20-HC1-0.25 C, 68.87; H, 5.93; N, 8.46 Found: C, 68.49; H, 5.80; N, 8.25 WO 98/10763 WO 98/ 0763PCTIUS97/15989 49 EXAMPLE 11I Preparation of 1.1 -diphenvlmethoxy)benzvlaminopvyri dine (I1I- 1) The desired compound was prepared as described in Example 10 using Method 1 in Step A and then Step B; mp: 220-l' (EtOH*Et2O); IH NMR (d6-DMSO) 8 3.4 (1H, exch bs), 4.4 (2H, 6.5 (11H, 6.9 (2H, dd), 7.05 7.6 (8H, in), 7.5 (4H, 8.15 (2H, dd), 9.1 (1 H, exch t).
Analysis calculated for C25H22N20*HCl'3/4 C, 72. 10; H, 5.93; N, 6.75 Found: C, 72.35; H, 5.71; N, 6.97 EXAMPLE 12 Preparation of N-4-(cyclohexvlmethoxy)benzylaminopyridine (12-1') The desired compound was prepared as described for 10-3 in Example 10 using Method I in Step A and then Step B; mp: 273-4'C (EtOH); I H NMR (d6-DMSO) 8 1.1 (5H, in), 1.7 rn), 3.75 (2H, 4.4 (2H1, 6.9 (4H, bd), 7.28 bd), 8.15 (2H, bd), 9.25 (111, exch bs).
Analysis calculated for C1I9H24N20*HCI C 68.55, H 7.57, N 8.42 Found: C 68.35, H 7.53, N 8.33 WO 98/10763 PCT/US97/15989 EXAMPLE 13 Preparation of 4-[4-(2-methyl-l-pheriylpropoxy)benzylamino]pyridine (13-2) Step A: Preparation of 1-phenvl-2-methyl- -propanol (13-2) SNaBH 4 EtOH
N
2 13-1 13-2 Isobutyrophenone 13-1 (29.6 g, 0.20 mmol) was dissolved in ethanol (300 ml) and was reduced under N2 with sodium borohydride (7.57 g, 0.20 mmol) for 4 hrs. at room temperature. The ethanol was removed in vacuo and the residue was taken up in ethyl acetate (200 ml) and water (100 ml). The ethyl acetate extract was washed with water, dried, filtered and concentrated in vacuo to obtain alcohol 13-2.
1 H NMR (CDC13): 8 0.82 (3H, 1.0 (3H, 1.83 (1H, 2.0 (1H, 4.4 (1H, 7.26 (5H, m).
WO 98/10763 PCT/US97/15989 -51 Step B: Preparation of ethyl 4-(2-methyl-1-phenylpropoxy)benzoate (13-5)
NH
SOH O /"CC1 3 NaH
CI
3 CCN
N
2 13-2 13-3 cyclohex. 0 COC2H
CH
2
CI
2
OH
13-5 13-4 COOC 2
H
Sodium hydride (60% in mineral oil) (200 mg, 5 mmol) was washed with hexane under nitrogen and was suspended in anhydrous ether (30 ml). To the stirred suspension was added 13-2 g, 50 mmol) in ether (10 ml) and the mixture was stirred at RT for 1/2 hr. After cooling to -5 0 C, trichloroacetonitrile (7.58 g, 52.5 mmol) was added. Stirring was continued for 1/2 hr. at 0°C and at ambient temperature for 1 hr. The ether was removed in vacuo and the residual oil 13-3 was taken up in cyclohexane (20 ml) and methylene chloride ml). To this solution was added ethyl 4-hydroxybenzoate (13-4) (8.3 g, 50 mmol) followed by methylene chloride (25 ml) and trifluoromethanesulfonic acid (0.2 ml). The mixture was stirred at ambient temperature overnight and was filtered and concentrated to an oil. Chromatography on silica gel gave 13-5.
1H NMR (CDC13) 5 0.91 (3H, 1.05 (3H, 1.32 (3H, 2.15 (1H, 4.3 (2H, 4.88 (IH, 6.83 (2H, 7.2-7.4 (5 H, 8.7 (2H, d).
WO 98/10763 PCT/US97/15989 Step C: -52 Preparation of 4-(2-methyl-l-phenylpropoxy)benzoic acid (13-6) 0-0 COOC 2
H
5 0 13-5
KOH
EtOH/H 2 0
COOH
13-6 To 13-5 (8.89 g, 29.8 mmol) was added 2N potassium hydroxide (100 ml) and ethanol (50 ml). The mixture was stirred at 100 0 C overnight. The ethanol was removed in vacuo and the aqueous solution was cooled in ice and acidified with 6N HC1 (35 ml, 0.21 mol).
The acid was extracted into ethyl acetate (50 ml) and the extract was washed with water, dried, filtered and concentrated in vacuo to obtain the oil 13-6, which solidified. The white solid melted at 125-129 0
C.
1 H NMR (CDC13) 8 0.91 (3H, 1.05 (3H, 2.15 (1H, 4.9 (1H, 6.85 (2H, 7.2-7.35 (5H, 7.91 (2H, d).
WO 98/10763 WO 9810763PCT/US97/15989 53 Step D: Preparation of 4-(2-methyl-1 -phenylpropoxy)benzoyl chloride 013-7) 0 COOH oxalyl chloride 13-6 0H 2 C1 2 0 13-7 .13A6 (0.54 1 g, 2.0 rnmol) was stirred in methylene chloride (3 ml) at room temperature and oxalyl chloride (0.38 1 g, 3.0 mmol) was added. After 3 hirs. at room temperature the solution was concentrated in vacuo to a pale yellow liquid 13-7. The acid chloride was used without purification.
WO 98/10763 PCT/US97/15989 -54- Step E: Preparation of 4-(2-methyl-l-phenylpropoxy)-N-(4pyridvl)benzamide (13-9)
II
O -C--CI Et.N THF 13-7 NH 2 S 13-8
N.-H
13-9
N
To an ice cold stirred solution of 13-8 (0.188 g, 2.0 mmol) and triethylamine (0.233 g, 2.0 mmol) in tetrahydrofuran (10 ml) was added a solution 13-7 (0.54 g, 2.0 mmol) over a 5-10 min period. The reaction was stirred at ambient temperature overnight. Then the THF was removed in vacuo and the residue was taken up in ethyl acetate ml) and water (25 ml). The ethyl acetate extract was separated, washed with water, dried and concentrated in vacuo to yield the oil 13-9.
1H NMR (d6-DMSO) 8 0.84 (3H, 1.02 (3H, 2.12 (1H, 5.2 (1H, 7.0 (2H, 7.2-7.4 (5H, 7.72 (2H, 7.82 (2H, 8.42 (2H, 10.33 (1H, s).
WO 98/10763 PCT/US97/15989 Step F: Preparation of 4-[4-(2-methyl-l-phenylpropoxy)benzylaminolpyridine (13-10) N.H LiAIH 4
N
2 13-9
N
NOH
13-10 N
N
To a stirred suspension of lithium aluminum hydride (0.152 g, 4.0 mmol) in ether (5 ml) under nitrogen was added a solution of 13-9 (0.71 g, 2.0 mmol) in tetrahydrofuran (5 ml) over a 5 min period. The mixture was stirred at ambient temperature overnight and then was decomposed by adding water and sodium hydroxide. Ethyl acetate (25 ml) was added and the mixture was filtered. The filtrate was dried, filtered and concentrated in vacuo to 620 mg of colorless oil which was chromatographed on silica gel. 13-10 was obtained as an oil.
The hydrochloride salt melted at 186-188°C.
1 H NMR (d6-DMSO) 8 0.5 (3H, 0.99 (3H, 1.16 (1H, 4.15 (2H, 4.99 (1H, 6.47 (2H, 6.82 (2H, 7.05 (1H, 7.12 (2 H, 7.2-7.25 (1H, 7.25-7.36 (4H, 7.96 (2H, d).
Analysis calculated for (C22H24N20-HC1* 0.2 C, 70.93; H, 6.87; N, 7.52 Found: C, 70.99; H, 6.79; N, 7.62 WO 98/10763 PCT/US97/15989 56 EXAMPLE 14 Preparation of 4-[4-(2,2-dipheiiylethoxv)benzylaminolpyridine (14-7) Step A: Preparation of ethyl 4-(2.2-diphenylethoxv)benzoate (14-3) Ph 3 P N 2
THF
CH-CH
2 OH OH
DEAD
14-1 1 14-2
COOC
2
H
CH-CH
2
COOC
2
H
0/ 14-3 To 2,2-diphenylethanol (14-1) (5.95 g, 30 mmol) .was added ethyl 4-hydroxybenzoate (14-2) (5.40 g, 30 mmol), triphenylphosphine (8.66 g, 33 mmol) and tetrahydrofuran (125 ml).
The mixture was cooled in ice and diethyl azodicarboxylate (5.75 g, 33 mmol) was added. The reaction mixture was stirred under nitrogen at ambient temperature overnight and then the volatile components were removed in vacuo. The oil-solid residue was taken up in ethyl acetate (100 ml) and water (50 ml). Work up of the ethyl acetate portion give crude solid. The product 14-3 was purified by silica gel chromatography.
1 H NMR (CDC13) 8 1.37 (3H, 4.33 (2H, 4.52 (3H, 6.9 (2H, 7.4-7.66 (10H, 7.96 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 57 Step B: Preparation of 4-(2.2-dip~henylethoxy)benzoic acid (14-4)
O\C
2 O/ 0CH NaOH CH -CH2- COO 2H5 EtOH/H 2 0 14-3 CH -0H 2 -0 COOH K2-,'14-4 A suspension of 14-3 '(346 mg, 1.0 minol) in 10% aqueous sodium hydroxide (15 ml) and ethanol (5 ml1) was stirred at 100'C overnight. The resulting solution was cooled and acidified with excess HCl. A gum separated which was extracted into ethyl acetate (15 ml), washed with water, dried, filtered and concentrated in vacuo. The acid 14-4 was a pale yellow solid, mp: 140-146'C.
1H NMR (CDCI3) 8 4.55 (3H1, 6.94 (2H, 7.21-7.37 (10H, in), 8.04 (2H, d).
WO 98/10763 PCT/US97/15989 58 Step C: Preparation of 4-(2,2-diphenylethoxy)-N-(4-pyridyl)benzamide (14-6) HOBT EDC TEA CH-CH2-O- COOH HOBT EDC TEA H C H NH 2
DMF
S
1 4 4 14-5 N 14-5 CH-CH2-O
V
/H
14-6
N
To 14-4 (125 mg, 0.393 mmol), 4-aminopyridine (56 mg, 0.59 mmol), 1-hydroxybenzotriazole hydrate (80 mg, 0.59 mmol) and triethylamine (60 mg, 0.59 mmol) in DMF (5 ml) under nitrogen was added 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (113 mg, 0.59 mmol). The mixture was stirred at ambient temperature overnight and the DMF was removed under high vacuum. The residual oil was taken up in ethyl acetate (15 ml) and washed with water and saturated sodium chloride, dried, filtered and concentrated to an amber gum 14-6.
WO 98/10763 PCT/US97/15989 -59- Step D: Preparation of 4-[4-(2,2-diphenylethoxy)benzylaminolpyridine (14-7) O LAH N2
CH-CH
2 -O H L 14-6 N THF-Et2 0
N
CH-CH
2 -O N
H
14-7
N
To a solution of 14-6 (0.144 g, 0.365 mmol) in tetrahydrofuran (1 ml) and ether (3 ml) under nitrogen was added lithium aluminum hydride (30 mg, 0.79 mmol). The mixture was stirred at room temperature overnight and then was decomposed with water and sodium hydroxide. The mixture was filtered and concentrated in vacuo to a colorless oil 14-7 which was purified by silica gel chromatography and converted to the HCI salt, mp: 213- 214.5 0
C.
1H NMR (d6-DMSO) 8 3.36 (1H, 4.36-4.58 (6H, d, 6.84-7.0 (3H, d, bm), 7.16-7.4 (11H, 8.06-8.25 (2H, 9.08-9.24 (1H, bs).
Analysis calculated for (C22H24N20*HC1) C, 74.48; H, 6.10; N, 6.74 Found: C, 74.89; H, 6.04; N, 6.72 WO 98/10763 WO 9810763PCTIUS97/15989 EXAMPLE Preparation of 4-[4-(2-cyclohekylethoxv)benzylaminolpvyridine (15-8) Step A: Preparation of ethyl 4-(2-cyclohexylethoxy)benzoate (15-3) Ph 3 P THF N 2 15-1 OH DEAD 1 15-2 COOC 2
H
O0 COOC 2
H
15-3 2-Cyclohexylethanol 15-1 (3.2 g, 25 mmol) and ethyl 4hydroxybenzoate 15-2 (4.15 g, 25 mmol) were reacted as in Example 14. The product 1-5-3 was obtained as a waxy solid.
I H NMR (CDCI3) 8 1.04 (2H, in), 1.08-1.3 (3H, in), 1.39 (3H, 1.42- 1.58 (1H, in), 1.62-1.81 (7H, in), 4.04 (2H, 4.35 6.9 (2H, d), 7.98 (2H, d).
WO 98/10763 WO 9810763PCT/US97/15989 -61- Preparation of 4-(2-cyclohexylethoxy)benzoic acid (15-4) Step B: o COOC 2
H
15-3
KOH
H
2 0/EtOH (D \o
COOH
15-4 Hydrolysis of 15-3 (1.13 g, 3.1 mmol) as in Example 14 gave the acid 15-4 as a white solid. mp, 129-132'C.
IH NMR (CDCl3) 5 0.9-1.07 (2H, in), 1.08-1.36 (3H, in), 1.43-1.6 (IH, in), 1.6-1.82 (7H, mn), 4.06 (2H, 6.92 (2H, 8.03 (2H, d).
Step C: Preparation of 4-(2-cyclohexy lethoxy)benzoyl chloride (15-5) 0--C COO H 15-4 15-5
CH
2
GI
2 oxalyl chloride.
The acid chloride was prepared from 15-4 (0.497 g, 2 inmol) as in Example 13. Crude product was obtained as an oil in quantitative yield and was used without fuirther purification.
WO 98/10763 WO 9810763PCTIUS97/15989 -62- Step D: Preparation of 4-(2-cyclohexylethoxy)-N-(4-pyridyl)benzamide (15-7) 0 c C Et 3 N THF N H 2 15-5 N 2 15-6
N
15-7
N
This amnide was prepared from 15-5 (0.53 g, 2 mmol) and 4-aminopyridine (15-6) (0.188 g, 2 mmol) as in Example 13. The solid obtained, 15-7, melted at 123-125'C.
I H NMR (d6-DMSO) 8 0.88-1.03 (2H, in), 1.05-1.3 (311, in), 1.4-1.56 (lH, in), 1.56-1.8 (7H, in), 4.1 (2H, 7.08 (2H, 7.78 (2H, 7.95 (2H, 8.45 (2H, 10.42 (I11, s).
WO 98/10763 WO 9810763PCTIUS97/15989 63 Preparation of 4- [4-(2-cyclohexylethoxy)-benzylaminollpyridine (15-8) Step E: C) 0- 0- 15-7
N
6N
LAH
TH F/Et 2
O
15-8 Reduction of 15-7 (0.52 g, 1.6 mmol) as in Example 13 gave the product 1-5-8 as a white solid mp I 15-120'C. The hydrochloride melted at 227-228'C.
I H NMR (d6-DMSO) 8 0.8 1 -1.0 (3H, in), 1.02-1.3 (3H, in), 1.37-1.52 (1H, in), 1.53-1.78 (7H, in), 3.95 (2H, 4.43 (2H, 6.91 (2H, d), 6.82-7.04 (2H, in), 7.28 (2H, 8.15 (2H, 9.25 (LH, t); Analysis calculated for C20H26N20-HCl C, 69.24; H, 7.58; N, 8,08 Found: C, 69.16; H, 7.80; N, 8.08 WO 98/10763 WO 9810763PCTIUS97/15989 64 EXAMPLE 16 Preparation of 4- [4-(dicyclohexylmethoxy)-benzylamfilpyridifle (16-8) Step A: Preparation of ethyl 4-(dicyclohexylmethoxy)belzoate (1-6-3) OII\ C OHPh 3 P THF N 2
OH-OHOH
DEAD
(D 16-1 1- 0000 2
H
C/ CH-O-0 000C 2
H
0/ 16-3 Dicyclohexylmethanol (16-1) (6.97 g, 35.5 mmol) and ethyl 4-hydroxybenzoate (16-2) (5.9 g, 35.5 inmol) were reacted as in Example 14 -and the product 16-3 was isolated as a colorless oil.
IH NMR (CDC13) 8 0.98-1.3 (1 1H, in), 1.35 (3H, 1.52-1.86 (1llH, mn), 4.02 (1lH, 4.33 (2H, 6.91 (2H, 7.94 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 65 Preparation of 4-(dicyclohexylmethoxy)benzoic acid -(16-4) Step 13: CH-O
COOC
2
H
16-3
KOH
EtOH/H 2 0 CH-O COOH 0/ 16-4 Hydrolysis of 16-3 (7.9 g, 23 rnmol) as in Example 14 produced slightly crude acid 16-4.
1 H NMR (CDCl3) 8 0.98 -1.32 (11 H, in), 1.54-1.84 (I11H, in), 4.05 (1 H, 6.92 (2H, 8.0 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 -66- Step C: Preparation of 4-(dicyclohexylmethoxy)benzyl chloride (16-5) CH -0 COOH C 16-4
CH
2
CI
2 oxalyl chloride -I0 CH-0 C 0C 16-5 Preparation of the acid chloride of 16-4 (1.54 g, 5 mmol) as in Example 13 gave the product 16-5 as a pale yellow oil. It was used without purification.
WO 98/10763 WO 9810763PCTIUS97/15989 StepD: 67 Preparation of 4-(4-dicyclohexylmethoxy)-N-(4pyridvl)benzamide (16-7) 0 O\ 11 CH-0-( C 01 0/ 16-5 O\ 0 CH-0-NH 16-7
N
Et 3 N THF N 2
NH
2
N
6-6 4-Aminopyridine 16-6 (0.47 g, 5 mmol) was acylated with 4-(dicyclohexylmethoxy)benzyl chloride 16-5 (5 mmol) as in Example 13 to give the amide 16-7 as a white solid.
I H NMR (d6-DMSO) 8 0.97-1.3 (11IH, in), 1.53-1.76 (11 H, mn), 4.25 (1H, 7.1 (2H1, 7.76 (2H1, 7.88 (2H, 8.43 (2H, 10.38 (11H, s).
WO 98/10763 WO 9810763PCTIUS97/15989 Step E: 68 Preparation of 4- [4-(dicyclohexylmethoxy)-benzylaminolpyridine (16-8)
OZ\
CH-O
LAH N 2 TH F/Et 2
O
16-7
O\O\
16-8 Lithium aluminum hydride reduction of 16-7 (1.28 g, 3.3 nimol) as in Example 14 gave product 16-8 as a colorless oil. .The hydrochloride melted at 213-215 0
C.
IH NMR (d6-DMSO) 5 0.93-1.28 (11 H, in), 1.5-1.77 (11 H, in), 4.04 (lH, 4.41 (2H, 6.95 (411, 7.22 (2H, 8.16 (2H, bd), 9.15 (I H, t).
Analysis calculated for C25H34N20*HCI C, 72.35; H, 8.50; N, 6.75 C, 72.63; H, 8.47; N, 6.76 Found: WO 98/10763 WO 9810763PCTIUS97/15989 69 EXAMPLE 17 Preparation (17-9)~ of 1,3 -diphenyl-2-propoxy)benzylaminolpyridine Step A: Preparation of 1,3-diphenvl -2-propanol (17-2) NaBH 4 EtOH N 2 17-1
OH
17-2 Reduction of 1,3-diphenylacetone 17-1 (21.0 g, 0.10 mole) was accomplished as in Example 13 in quantitative yield. The alcohol 17-2 was a colorless oil.
1 H NMR (CDCl3) 8 1.64 (IH, 2.7 1-2.91 (4H, dd), 4.07 (LH, in), 7.18-7.37 (10H, in).
WO 98/10763 WO 9810763PCT/US97/15989 Preparation of ethyl 1,3-diphenyl-2-propoxy)benzoate (17-4) Step B:
-OH
>17 -2 Ph 3 P THF N 2 OH DEAD 17-3
COOC
2
H
>0 C00 2
H
17,- 4 Reaction of 17-2 (5.3 g, 0.025 mol) and ethyl 4hydroxybenzoate 17-2 (6.56 g, 0.025 mol) as in Example 14 gave the product 17-4 as a colorless oil.
WO 98/10763 WO 9810763PCTIUS97/15989 Ste pC: -71- Preparation of 1,3-diphenyl-2-propoxy)benzoic acid (17-5) -0 00C 2
H
17-4
KOH
EtO H/H 2 0 0
\/COOH
17-5 Hydrolysis of 17-4 (7.47 g, 21 mmol) as in Example 14 gave the acid 17-5 as a viscious oil (4.28 g).
I H NMR (CDCI3) 5 2.9 1-3.08 (4H, in), 4.77 (1 H, in), 6.84 (2H, d), 7.16-7.33 (10H, in), 7.96 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 Step -D: 72 Preparation of I,3-diphenyl-2-propoxy)benzoyl chloride (17-6) 9~
>\/-COOH
"y 17-5 0H 2 C1 2 oxalyl chloride 17-6 17-5 .66 g, 5 mmol) was converted to the acid chloride 17-6 as in Example 13. The viscous oil was used without further purification.
WO 98/10763 WO 9810763PCTIUS97/15989 73 Step E: Preparation of 4-(1 ,3-diphenyl-2-propoxy)-N-(4- 12yridyl)benzamide (17-8') 0 17-6 Et 3 N THF
NH
2
A
N
17-7 17-8 4-Aminopyridine 17-7 (0.471 g, 5 mmnol) was acylated with 17-6 (1.75 g, 5 mimol) using the conditions of Example 13. The amnide 17-8 was obtained as a solid foam.
WO 98/10763 WO 9810763PCT/US97/15989 74 Step F: Preparation of 1,3-diphenyl-2-propoxy)-benzylaminolp~yridine (17-9) LAH N, 17-8
N
0 17-9 Lithium aluminum hydride reduction of 17-8 (1.36 g, 3.3 mmol) as described in Example 14 gave a quant. yield of the product 17-9 as a viscous oil. The hydrochloride melted at 151-154'C.
IH NMR (d6-DMSO) 5 2.88 (4H1, 4.41 (2H, 4.73 (11H, in), 6.9 (2H, 6.83-7.0 (2H, in), 7.16-7.82 (12H, in), 8.15 (211, bd), 9.15 (1H, 0).
Analysis calculated for C27H26N200HCl. 0.4 C, 74.00; H, 6.40; N, 6.39 Found: C, 73.94; H, 6.28; N, 6.30 WO 98110763 WO 9810763PCT/US97/15989 EXAMPLE 18 Preparation of ,4-methylenedioxybenzy loxy)benzylaminolpyridine (18-7) Step A: Preparation of ethyl 4-(3 ,4-methylenedioxybenzy Ioxv)benzoate (18-3) O's, Ph 3 P THE
OH
1 18
DEAD
18-1
OH
-2 C000 2
H
18-3 O COOC 2
H
3,4-Methylenedioxybenzyl alcohol 19-1 (6.2 g, 40.0 mmol) and ethyl 4-hydroxybenzoate 1-2 (6.65 g, 40.0 mmol) were reacted as in Example 14. The desired ester 18-3 was obtained as a white solid.
WO 98/10763 PCT/US97/15989 -76- Preparation of ethyl 4-(3,4-methylenedioxybenzyloxv)benzoic acid (18-4) Step B:
O
0- r 18-3
COOH
18-4 LiOH
DME/H
2 0 18-3 (2.5 g, 8.3 mmol) was hydrolyzed with lithium hydroxide (0.8 g, 33.4 mmol) in dimethoxyethane (60 ml) and water ml) at room temperature overnight. Then water (50 ml) was added and the solution was acidified with 6N HC1. Filtered the white solid which had precipitated and obtained a quantitative yield of crude acid which was recrystallized from butyl chloride-ethyl acetate. The pure products 18-4 melted at 192-194 0
C.
IH NMR (d6-DMSO) 5 5.06 (2H, 6.02 (2H, 6.9-6.99 (2H, m), 7.02-7.12 (3H, 7.9 (2H, d).
WO 98/10763 WO 9810763PCTIUS97/15989 Step C: 77 Preparation of 4-(3 ,4-methylenedioxybenzyloxy)-N-(4pvridvl~benzamnide (1 8-6)
C
1 8-6 EDO HOBT
COOH
18-4
NH
2 Et 3
N
N 18-5 To 19-4 (0.545 g, 2 mmol) was added 4-aminopyridine 18-5 (0.235 g, 2.5 mmol), 1-hydroxy-benzotriazole hydrate (0.338 g, mmol), 1 -ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (0.479 g, mmol) and dry DMF (5 ml) followed by triethylamine (0.35 ml, mmol). The mixture was stirred at ambient temperature overnight.
Then the DMF was removed under high vacuum. The residual oil was chromatographed on silica gel to obtain a white solid 18-6.
WO 98/10763 WO 9810763PCTIUS97/15989 78 Step D: Preparation of ,4-methylenedioxybenzyloxy)benzylaminolpyri dine 018-7) LAH
N
2 Et 2 O/TH F 0- 18-6 0 18-7 18-6 (0.32 g, 0.9 mmol) was reduced with lithium aluminum hydride (0.30 g, 8 mmol) as in Example 10. The product 18-7 was obtained as an oil. The hydroc-hloride salt melted at 190- 193 0
C.
I H NMR (d6-DMSO) 5 4.45 (2H1, 4.99 (2H, 6.02 (2H, 6.83- 7.06 (7H, in), 7.3 (2H, 8.16 (2H, bd), 9.2 (1 H, t).
Analysis calculated for C2oH1 8N203-HCI' 0.2 C 64.15, H 5.22, N 7.48 Found: C 63.82, H 5.16, N 7.5 1.
WO 98/10763 PCTIUS97/15989 -79- The compounds shown in the table below are exemplary compounds of the present invention. The range of Ki values associated with the specifically listed compounds is represented as follows: <0.1 M >0.1 ItM and <1.0 iM >1.0 gM WO 98/10763 WO 9810763PCTIUS97/15989 80 R-C H-X- TABLE 2 X Ki (thr) mp (HC1) 224-60
H
220-10 273-40 213-14.50
&~CH-
(CH3 )2CH-
H
186-80 227-80 WO 98/10763 WO 9810763PCTIUS97/15989 81 TABLE 2 (CONT'D) X Ki (thr) aim mp (HCI) <0 2
H
H
H
213-50 151-40 190-30 211-30 NH 202-50 171-30 NH NH 200-20 WO 98/10763 WO 9810763PCT/US97/15989 -92 X Ki (thr) aim mp (HC1) -CO2CH2 0 11
-CNH
2 182-50 (7- 176- 1820 C -CH 2
-CH
2
CH
2 101-20 (freebase) o' HaC yCH 3
CH
CH2CH2- CH3- 210-110 1 63-40 1 28-300 WO 98/10763 PCTUS97/15989 83 EXAMPLE 19 Preparation of 4-(4-cyclohexylmethyloxy-2-benzylphenylmethyl)aminopyridine (19-3) 19-3 Preparation of 4-cyclohexylmethyloxy-2-benzyl-benzoic acid (19-2) "O sec-
COOH
19-1 0.
3uLi, TMEDA; BnBr
'COOH
19-2 A solution of 4-cyclohexylmethyloxybenzoic acid (19-) (1.00 g, 4.27 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added to a solution of sec-butyllithium (1.3 M, 8.21 mL, 10.7 mmol, 2. 50 equiv) and N, N, N'-tetramethylethylenediamine (1.61 mL, 10.7 mmol, 2.50 equiv) in tetrahydrofuran (10 mL) at -100 C (ethanol-N2(1)).
The resultant orange suspension was stirred at -100 "C for 1 h, then warmed to -78 "C and held at that temperature for 15 min. Benzyl bromide (2.00 mL, 16.8 mmol, 3.93 equiv) was added to the cold reaction mixture, causing the color to change to light yellow. The suspension was stirred at -78 oC for 35 min, then was poured into water (150 mL). The aqueous mixture was acidified to approximately pH 2 WO 98/10763 PCT/US97/15989 84with an aqueous 1 N hydrochloric acid solution and was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography (40% hexanes in ethyl acetate initially, grading to 100% ethyl acetate) to afford the desired carboxylic acid 19-2 as a white solid.
The coupling 19-2 and 4-aminopyridine and subsequent reduction of the amide product were carried out as described in Example 14 to afford the final product 19-3.
1H NMR (400 MHz, CDC13), 6: 8.12 (br d, 2H, J=6.4 Hz, PyH), 7.26 2H, PhH), 7.20 1H, PhH), 7.20 1H J=8.4 Hz, ArH), 7.09 (br d, 1H, J=7.1 Hz, PhH), 6.80 1H, J=2.8 Hz, ArH), 6.75 (dd, 1H, J=8.4, 2.6 Hz, ArH), 6.26 (br d, 2H, J=6.4 Hz, PyH), 4.12 3H, CH2NH and NH), 4.00 2H, ArCH2Ph), 3.73 2H, J=6.4 Hz, OCH2Cy), 1.86 (br d, 2H, J=12.8 Hz, CyH), 1.81-1.65 4H, CyH), 1.37-1.13 3H, CyH), 1.05 (qd, 2H, J=12.1, 2.9 Hz, CyH); mp: 114- 116°C EXAMPLE Preparation of 4-(4-cyclohexylmethyloxy-2-benzyloxybenzyl)aminopyridine (20-6) U 0
H
0 N 20-6 WO 98/10763 PCT/US97/15989 Step A: Preparation of Methyl-(4-cyclohexylmethyloxy-2hydroxy)benzoate (20-2)
CO
2
CH
3 Br CO 2
CH
3 OH CS 2
CO
3
H
DMF
A
OH O 20-1 20-2 Cyclohexylmethyl bromide (4.56 mL, 32.67 mmol, 1.1 equiv) was added to a suspension of methyl 2,4-dihydroxy-benzoate (5.0 g, 29.7 mmol, 1 equiv) and cesium carbonate (33.9 g, 104.1 mmol, 3.5 equiv) in N, N-dimethylformamide (100 mL) at 23 0 C. The reaction mixture was heated to 70 0 C and was stirred at that temperature for 5 h. The solution was cooled to 23 0 C and was concentrated. The residue was diluted with ethyl acetate, and the resulting solution was washed with an aqueous saturated ammonium chloride solution (2 x mL). The combined aqueous layers were further extracted with ethyl acetate in hexane (2 x 100 mL). The combined organic layers were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography ethyl acetate in hexanes) to afford 20-2. TLC (30% EtOAc- hexane), Rf=0.35 (UV)TLC EtOAc- hexane), Rf= 0.51 (UV); 1 H NMR (400 MHz, CDC13), 6: 10.94 1H, OH), 7.71 1H, J 9.52 Hz, ArH [ortho to CO2CH3]), 6.41 2H, ArH [meta to CO2CH3]), 3.90 3H, CO2CH3), 3.76 2H, J=6.04 Hz, OCH2Cy), 1.77 6H, CyH), 1.26 3H, CyH), 1.05 2H, CyH).
WO 98/10763 PCT/US97/15989 -86- Step B: Preparation of Methyl(4-cyclohexylmethyloxy-2benzvloxy)benzoate (20-3)
CO
2
CH
3 Br CO 2
CH
3 -s H Cs 2
CO
3 0
DMF
20-2 20-3 Benzyl bromide (0.216 mL, 1.81 mmol, 1.2 equiv) was added to a suspension of 20-2 (400 mg, 1.51 mmol, 1 equiv) and cesium carbonate (1.72 g, 5.30 mmol, 3.5 equiv) in N, N-dimethylformamide mL) at 23 0 C. The reaction mixture was heated to 70 0 C and was stirred at that temperature for 2h. The solution was cooled to 23 0 C and was concentrated. The residue was diluted with ethyl acetate (60 mL), and the resulting solution was washed with an aqueous saturated ammonium chloride solution (2 x 30 mL). The organic layer was dried over magnesium sulfate and was concentrated to afford the product 20-3 as a pale yellow oil which was used without further purification.
1H NMR (400 MHz, CDC13), 5: 7.87 1H, J 8.61 Hz, ArH [ortho to CO2CH3]), 7.53 2H, J=7.32 Hz, PhH), 7.39 2H, J= 6.95 Hz, PhH), 7.32 1H, PhH), 6.53 IH, ArH [meta to CO2CH3]), 6.51 1H, J=8.79 Hz, ArH [meta to CO2CH3]), 5.17 2H, CH2Ph), 3.87 3H, CO2CH3), 3.77 2H, J=6.22 Hz, CH2Cy), 1.85 2H, J=13.36 Hz, CyH), 1.76 4H, CyH), 1.27 2H, CyH), 1.05 2H, CyH); TLC (10% EtOAc-hexane), Rf: 0.14 (UV) WO 98/10763 PCT/US97/15989 -87- Step C: Preparation of (4-cyclohexylmethyloxy-2-benzyloxy)benzoic acid (20-4)
CO
2
CH
3
CO
2
H
S NaOH 1,4-dioxane 0 0 20-3 20-4 A solution of sodium hydroxide (302 mg, 7.55 mmol, equiv) in water (3 mL) was added to a solution of 20-3 (1.51 mmol, 1 equiv) in 1,4-dioxane (7 mL). The reaction mixture was heated at reflux for 16 h. The solution was cooled to 23°C, and then was diluted with ethyl acetate (60 mL). The organic layer was washed with an aqueous 10% potassium hydrogen sulfate solution (2 x 30 mL) and was dried over magnesium sulfate and was concentrated to afford 20-4 as a white solid, which was used without further purification.
IH NMR (400 MHz, CD30D), 5: 7.85 1H, J 8.79 Hz, ArH [ortho to CO2H]), 7.51 2H, J 7.51 Hz, PhH), 7.35 3H, PhH), 6.65 1H, J 2.01 Hz, ArH [meta to C02H]), 6.57 (dd, 1H, J 8.79, 2.20 Hz, ArH [meta to CO2H], 5.25 2H, CH2Ph), 3.80 2H, J 6.22 Hz, CH2Cy), 1.85 2H, J 14.10 Hz, CyH), 1.76 4H, CyH), 1.29 3H, CyH), 1.10 2H, CyH).
WO 98/10763 WO 9810763PCTIUS97/15989 88 Step D: Preparation of N-4-pyridyl-(4-cyclohexylmethyloxy-2benzyloxv)benzamide (20-5) C0 2 H 0- 0 CICOCOCI;0
H
4-aminopyridine o b 6 20-5 20-4 Oxalyl chloride (0.391 mL, 4.49 mmol, 3 equiv) was added to a solution of 20A (509 mg, 1.49 mmol, 1 equiv) in dichioromethane (6 mL) at 23'C. Once gas evolution ceased (approximately 5 min after the addition of oxalyl. chloride), the volatiles were removed in vacuo.
The residue was dissolved in dichloromethane (11 mL), and the resulting solution was transferred via cannula to a suspension of 4arninopyridine (704 mg, 7.47 mmol, 5 equiv) and triethylamine (1.67 mL, 11.96 mmol, 8 equiv) in dichioromethane (10 mL) at 23'C. The reaction mixture was stirred for 2 h at 23'C, then was concentrated in vacuc. The residue was purified by flash column chromatography hexanes in ethyl acetate) to afford the product 20-5 as a white solid.
I
1 H NMR (400 MHz, CDCl3), 8: 9.99 I1H, 8.34 2H, J 4.95 Hz, PyH), 8.24 I H, J 8.79 Hz, ArH [meta to OCH2Cy]), 7.55 2H, J 7.69 Hz, PhH), 7.52 (in, 3H, PhH), 7.06 (dd, 2H, J 4.95, 1.28 Hz, PyH), 6.68 IlH, J 8.79 Hz, ArH [ortho to OCH2Cy]), 6.65 I1H, ArH [ortho to OCH2Cy]), 5.19 2H, CH2Ph), 3.85 2H, J 6.23 Hz, CH2Cy), 1.89 2H, J 12.64 Hz, CyH), 1.77 (in, 4H, CyH), 1.29 (in, 2H, CyH), 1.09 (i,211, CyH); TLC (100% EtOAc), Rf. 0.38 (UV) WO 98/10763 PCT/US97/15989 -89- Step E: Preparation of 4-(4-cyclohexylmethyloxy-2-benzyloxybenzyl)aminopyridine (20-6)
P
S- N- N LAH H THF b
A
-20-5 SN
N
20-6 A solution of lithium aluminum hydride in tetrahydrofuran M, 4.12 mL, 4.12 mmol, 4 equiv) was added to a solution of 20-5 (430 mg, 1.03 mmol, 1 equiv) in tetrahydrofuran (3 mL) at 0°C. The reaction mixture was heated to 50 0 C and held at that temperature for 2 h. The mixture was cooled to 0°C, and excess lithium aluminum hydride was quenched by the consecutive addition of water (0.155 mL), aqueous 15% sodium hydroxide solution (0.155 mL), and water (0.467 mL). The resulting aluminum salts were removed by filtration. The filtrate was concentrated, and the residue was purified by flash column chromatography methanol in chloroform saturated with ammonia) to afford the product 20-6 as a white solid (mp 131-132 0
C,
330 mg, 1H NMR (400 MHz, CDC13), 5: 8.16 (dd, 2H, J 4.77, 1.46 Hz, PyH), 7.37 5H, PhH), 7.15 1H, J 8.24 Hz, ArH [meta to OCH2Cy]), 6.57 IH, J 2.02 Hz, ArH [ortho to OCH2Cy]), 6.46 WO 98/10763 PCT/US97/15989 (dd, 1H, J 8.24, 2.19 Hz, ArH [ortho to OCH2Cy]), 6.43 (dd, 2H, J 4.77, 1.46 Hz, PyH), 5.09 2H, CH2Ph), 4.50 (br s, 1H, NH), 4.32 2H, J 5.86 Hz, CH2NH), 3.73 2H, J 6.41 Hz, CH2Cy), 1.86 2H, J 12.27 Hz, CyH), 1.75 4H, CyH), 1.27 3H, CyH), 1.04 2H, CyH); TLC CH30H- CHC13 sat'd with NH3), Rf 0.19 (UV) EXAMPLE 21 Preparation of [3-amino-4-(cyclohexylmethyloxy)phenyl]methylamino pyridine dihydrochloride (21-6) Step A: Preparation of Ethyl nitrobenzoate (21-2) 4-(cyclohexylmethyloxy)-3-
NO
2
HO
CO
2 Et 21-1 )2 'I 02E To a mixture of ethyl 4-hydroxy-3-nitrobenzoate (21-1) (2.11g, 10.0 mmol), cesium carbonate (6.52 g, 20.0 mmol), and sodium iodide (0.15g, 1.0 mmol) in DMF (20 ml) under nitrogen was added cyclohexylmethylbromide (1.67 ml, 12.0 mmol). The mixture was stirred 48h at 60 0 C. The resulting mixture was evaporated under reduced pressure. To the residue was added water (100 ml), and the aqueous mixture was extracted with methylene chloride (2 x 200 ml).
The organic fraction was washed with saturated sodium carbonate solution (100 ml) and brine (100 ml), dried (sodium sulfate), and the WO 98/10763 PCT/US97/15989 -91 solvent was evaporated under reduced pressure. The residue was crystallized from ether/hexane to give product 21-2 as yellow crystals, mp: 79-80 0
C.
IH NMR (CDC13) 8.49 (1H, d, J=2 Hz), 8.19 (1H, dd, J=9, 2 Hz), 7.09 (1H, d, J=9 Hz), 4.39 (2H, q, J=7 Hz), 3.95 (2H, d, J=6 Hz), 1.69- 1.89 (6H, 1.40 (3H, t, J=7 Hz), 1.06-1.38 (5H, m).
Step B: Preparation of 4-(cyclohexylmethyloxy)-3-nitrobenzoic acid (21-3) To a solution of 21-2 (1.38 g, 4.50 mmol) in THF (22.5 ml) cooled in an ice-bath was added 1N lithium hydroxide solution (22.5 ml). The resulting solution was stirred 18h while warming to ambient temperature. The solution was partially evaporated at reduced pressure, and the remaining aqueous solution was washed with ethyl acetate (20 ml). The aqueous layer was cooled in an ice-bath, stirred rapidly, and concentrated hydrochloric acid (2 ml) was added dropwise, resulting in formation of a precipitate. The mixture was stirred Ih, the precipitate was collected and dried in vacuo to give product 21-3 as a white solid, mp: 200-202 0
C.
1 H NMR (CDC13) 8 8.56 (1H, d, J=2 Hz), 8.24 (1H, dd, J=9, 2 Hz), 7.13 (1H, d, J=9 Hz), 3.98 (2H, d, J=6 Hz), 1.70-1.90 (6H, 1.08- 1.40 (5H, m).
Step C: Preparation of N-(4-pyridyl)-4-(cyclohexylmethyloxy)- 3-nitrobenzamide (21-4) O
NO
2 I H
N
21-4 0 N To a mixture of 21-3 (0.307 g, 1.1 mmol) and DMF (I drop) in methylene chloride (3 ml) under nitrogen cooled in an ice-bath was added dropwise a solution of oxalyl chloride (0.113 ml, 1.3 mmol) WO 98/10763 PCTIUS97/15989 -92in methylene chloride (1 ml). The resulting solution was stirred lh with ice-bath cooling, lh at ambient temperature, then was evaporated at reduced pressure to give crude 4-(cyclohexylmethyloxy)-3nitrobenzoyl chloride as an oil.
To a mixture of the crude 4-(cyclohexylmethyloxy)-3nitrobenzoyl chloride in methylene chloride (2 ml) under nitrogen cooled in an ice-bath was added dropwise a solution of 4-aminopyridine (0.282 g, 3.0 mmol) in methylene chloride (1 ml). The resulting solution was stirred lh with ice-bath cooling, then 2h at ambient temperature. The mixture was diluted with methylene chloride (10 ml) and washed with saturated sodium bicarbonate solution (5 ml). The aqueous layer was extracted with methylene chloride (2 x 10 ml). The combined organic fractions were washed with water (10 ml), brine ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol:ethyl acetate to give a solid. The solid was recrystallized from ethyl acetate to give the product 21-4 as white crystals, mp: 197-198°C.
1 H NMR (CDC13) 8.57 (2H, d,J= 6 Hz), 8.37 (1H, d, J= 2 Hz), 8.14 (2H, 7.62 (2H, d, J= 8 Hz), 7.13 (1H, d, J= 9 Hz), 3.98 (2H, d, J= 6 Hz), 1.71-1.90 (6H, 1.08-1.38 (5H, m).
Analysis calculated for Cl9H21N304 C, 64.21; H, 5.96; N, 11.82 Found: C, 64.18; H, 5.97; N, 11.70 WO 98/10763 PCT/US97/15989 -93- Step D: Preparation of N-(4-pyridyl)-3-amino-4-(cyclohexylmethyloxy)benzamide (21-5)
H
NH N (21-5) 0 N A mixture of 21-4 (0.171g, 0.48 mmol) and 10% palladium on carbon (0.040g) in ethanol (50 ml) was shaken on a Parr hydrogenation apparatus under hydrogen (50 psi) for 20h. The mixture was filtered through filter aid and the filtrate was evaporated under reduced pressure to give a solid. The solid was dissolved in hot ethyl acetate (50 ml), treated with charcoal, and the mixture was filtered through filter aid. The filtrate was evaporated to one-third volume and cooled. The resulting precipitate was collected and dried in vacuo to give product 21-5 as a white crystalline solid, mp: 193-194°C.
1 H NMR (CDC13) 8 8.52 (2H, d, J=6 Hz), 7.89 (1H, br 7.58 (2H, d, J=6 Hz), 7.25 (1H, d, J=2 Hz), 7.20 (1H, dd, J=8, 2 Hz), 6.80 (1H, d, J= 8 Hz), 3.98 (2H, br 3.86 (2H, d, J=6 Hz), 1.66-1.91 (6H, 1.08- 1.38 (5H, m); Analysis calculated for C19H23N302-0.10 ethyl acetate C, 69.71; H, 7.18; N, 12.57 Found: C, 69.71; H, 7.17; N, 12.57 WO 98/10763 PCT/US97/15989 -94- Step E: Preparation of [3-amino-4-(cyclohexylmethyloxy)phenyllmethylamino pyridine dihydrochloride (21-6) S NH 2
H
21-6 N *2 HCI
"N
In a dry three-necked round bottom flask equipped with a condenser, nitrogen inlet, and septum, was placed a solution of 21-5 (0.059 g, 0.18 mmol) in anhydrous THF (2 ml). To the solution was added 2.0M borane-dimethylsulfide complex in THF (0.38 ml, 0.76 mmol) dropwise via syringe. The resulting mixture was stirred lh at 0 C. The mixture was cooled to ambient temperature, and 6N hydrochloric acid (1 ml) was added dropwise. The mixture was heated in a 60 0 C oil-bath for five minutes, cooled to ambient temperature, and poured into saturated sodium carbonate solution (10 ml). The mixture was extracted with ethyl acetate (3 x 20 ml). The combined organic fractions were washed with brine (20 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methanol:ethyl acetate (10:90), to give a gummy solid. The solid (0.052g) was suspended in ethanol (1 ml) and ethanolic HCI (6 M, 0.065 ml, 0.39 mmol) was added. The mixture was stirred, diluted with ether ml), and the resulting precipitate was collected and dried in vacuo to give 21-6, as a white solid, mp: 173-175 0
C.
1 H NMR (DMSO-d6) 8 9.26 (1H, t, J=6 Hz), 8.7-9.8 (2H, br 8.22 (1H, d, J=7 Hz), 8.11 (lH, d, J=7 Hz), 7.25 (lH, 7.19 (1H, d, J=8 Hz), 7.09 (IH, d, J=8 Hz), 7.00 (IH, dd, J=7, 2 Hz), 6.85 (IH, dd, J=7, 2 Hz), 4.47 (2H, d, J=6 Hz), 3.84 (2H, d, J=6 Hz), 3.3-4.1 (2H, br s), 1.86 (2H, d, J=12 Hz), 1.60-1.82 (4H, 1.11-1.32 (3H, 1.00-1.10 (2H, m); Analysis calculated for C 9H25N30*2 HC1*0.25 C, 58.68; H, 7.13; N, 10.81 WO 98/10763 PCT/US97/15989 Found: C, 58.64; H, 6.99; N, 10.72
S
H
N
H
21-7c NCI *2 HCI Step F: Preparation of 4- {[3-ethylamino-4-(cyclohexylmethyloxy)phenyllmethylamino pyridine dihydrochloride (21-7c) Step 1: To a mixture of N-(4-pyridyl)-3-amino-4-(cyclohexylmethyloxy)benzamide (21-7a) (0.065 g, 0.20 mmol) in methylene chloride (1 ml) under nitrogen cooled in ice-bath was added acetic anhydride (0.040 ml, 0.42 mmol). The resulting mixture was stirred with ice-bath cooling for 2 h. The mixture was diluted with methylene chloride (4 ml), washed with 10% citric acid solution (2 ml), water (2 ml), saturated sodium bicarbonate solution (2 ml), water (2 ml), and brine (2 ml), dried over sodium sulfate, and concentrated in vacuo to give N-(4-pyridyl)-3-amino-4-(cyclohexylmethyloxy)benzamide (21-7b) (0.060 g, 82%) as a foam.
dH(CDCl3) 8.84 (1H, d, J 2 Hz), 8.52 (2H, d, J 6 Hz), 8.46 (1H, br s), 7.81 (IH, br 7.76 (1H, dd, J9,2 Hz), 7.65 (2H, dd, J 5,1 Hz), 6.96 (1H, d, J 8 Hz), 3.91 (2H, d, J 6 Hz), 2.24 (3H, 1.70-1.95 (6H, m), 1.07-1.42 (5H, m).
Step 2: Employing the procedure substantially as described for the preparation of 21-6, but starting with 21-7b (0.055g, 0.15 mmol), 21-7c was obtained as a white solid, mp: 137-145 0
C.
dH(DMSO-d6) 9.16 (1H, bs), 8.22 (1H, 8.13 (1H, 6.95-7.15 (3H, 6.97 (1H, d, J 7 Hz), 6.87 (1H, d, J 7 Hz), 4.45 (2H, d, J 5 Hz), 3.83 (2H, d, J 5 Hz), 3.4-3.8 (2H, br 3.18 (2H, q, J7 Hz), 1.60-1.90 (6H, 1.17 (3H, t, J7 Hz), 1.04-1.82 (5H, m).
Analysis calculated for C21H29N30*2 HC1l0.50 WO 98/10763 PCT/US97/15989 -96- C, 59.85; H, 7.65; N, 9.97 Found: C, 59.90; H, 7.49; N, 9.94
HN'.S
H
21-7e N N *HC N Step G: 4- {[3-(phenylmethylsulfonamido)-4-(cyclohexylmethyloxv)phenvllmethylamino pyridine dihydrochloride (21-7e) Step 1: To a mixture of 21-7a (0.065 g, 0.20 mmol) and pyridine (0.032 ml, 0.40 mmol) in methylene chloride (2 ml) under nitrogen cooled in ice-bath was added alpha-toluenesulfonyl chloride (0.050 g, 0.26 mmol). The resulting mixture was stirred with ice-bath cooling for 3 h. The mixture was diluted with ethyl acetate (15 ml), washed with saturated sodium bicarbonate solution (5 ml) and brine (5 ml), dried over sodium sulfate, and concentrated in vacuo to give a gum (0.106g). The gum was flash chromatographed on silica gel eluting with ethyl acetate to give N-(4-pyridyl)-3-(phenylmethylsulforiamido)- 4-(cyclohexylmethyl-oxy)benzamide (21-7d) as a gum.
dH(CDCl3) 8.55(1H, d, J 6 Hz), 8.06 (1H, bs), 8.46 (1H, br 7.80 (1H, d, J 2 Hz), 7.71 (1H, dd, J9,2 Hz), 7.62 (2H, d, J 6 Hz),7.25-7.32 (3H, 7.26 (2H, 6.94 (IH, d, J 9 Hz), 6.83 (1H, bs), 4.39 (2H, s), 3.81 (2H, d, J 6 Hz), 1.65-1.82 (6H, 1.13-1.33 (3H, 0.90-1.08 (2H, m).
Step 2: Employing the procedure substantially as described for the preparation of 21-6, but starting with 21-7d (0.077 g, 0.16 mmol), 21- 7e, was obtained as a white solid, mp: 135-140°C.
dH(DMSO-d6) 9.07 (1H, bs), 8.79 (IH, bs), 8.17 (2H, d, J 6 Hz), 7.26- 7.35 (5H, 7.19 (1H, d, J 2 Hz),7.12 (1H, d, J 8 Hz), 7.03 (1H, d, J 8 WO 98/10763 PCTIUS97/15989 -97- Hz), 6.92 (2H, bs), 4.43 (4H, in), 3.80 (2H, d, J 6 Hz), 1.62-1.82 (6H, in), 1.12-1.30 (3H, in), 0.95-1.10 (2H, in).
Analysis calculated for C26H3 I1N303S -HCl: C, 62.20; H, 6.42; N, 8.37 Found: C, 62.31; H, 6.44; N, 8.36 WO 98/10763 WO 9810763PCT/US97/15989 98 EXAMPLE 22 Preparation of 4- {[3-propyl-4-(cyclohexylmethyloxv')DhenvllmethylaminolIpyridine (22-8) HOI:
COOCH
3 22-1
CS
2
CO
3
DMF
22-2 23000 HO
H
2 /Pd (C)
COOCH
3 EtOAc 22-3
COOCH
3 22-4
CS
2 00 3
DMF
0~ NaOH MeOH l
COOCH
3 22-5 1. (OICO) 2
/DCE
2.- COOH H 2 N -c 22-6 Iz~~O H LiAIH 4
/THF
22-7 0N 22-8 WO 98/10763 PCT/US97/15989 99 Step A: Preparation of Methyl 4-allyloxvbenzoate (22-2) 22-2
COOCH
3 To a solution of methyl 4-hydroxybenzoate (22-1) (9.72 g, 64.36 mmol) in 100 mL of DMF was added 24.8 g (76.0 mmol) of Cs2CO3 followed by 5.0 mL (58.5 mmol) of allyl bromide. The resulting solution was then heated at 50 0 C for 5h. The solvent was distilled under reduced pressure and the residue was taken up in 200 mL of EtOAc. The organic phase was extracted with IN NaOH (2 x mL), water (5 x 50 mL) and brine (50 mL), dried (MgSO4) and concentrated to afford product 22-2 as a white solid.
IH NMR (CDC13) 8 8.00 J=7.8 Hz, 2H), 6.95 J=7.8 Hz, 2H), 6.05 1H), 5.45 1H), 5.30 1H), 4.60 J=6.4 Hz, 2H), 3.85 3H).
Step B: Preparation of Methyl 4-hydroxv-3-allvlbenzoate (22-3)
HO
SCOOCH
3 22-3 The neat allyl ether 22-2 from Step A (7.0 g, 38.6 mmol) was heated in an oil bath at 230 0 C for Ih. The reaction was followed by NMR and was found to be complete after 90 min. The resulting brown oil was cooled and subjected to column chromatography (1:1 EtOAc Hexane) to afford 22-3 as a white solid.
1 H NMR (CDC13) 8 7.80 2H), 6.90 J=7.8 Hz, IH), 6.00 (m, 1H), 5.60 1H), 5.20 1H), 5.15 J=6 Hz, 1H), 3.85 3H), 3.45 J=6.4 Hz, 2H), WO 98/10763 PCT/US97/15989 100- Step C: Preparation of Methyl 4-hydroxy-3-propylbenzoate (22-4)
HO
I COOCH 3 22-4 To 22-3 (6.0 g, 33.2 mmol) in 50 mL of EtOAc was added mg of 5% Pd on carbon and the whole was hydrogenated at atmospheric pressure for 24h. Hydrogen was removed from the reaction mixture and the solution was filtered through Celite.
Evaporation of the solvent afforded product 22-4 as a white solid.
1 H NMR (CDC13) 8 7.84 J=1.9 Hz, 1H), 7.79 (dd, J=2.0, 8.3 Hz, 1H), 6.79 J=8.3 Hz, 1H), 5.49 1H), 3.88 3H), 2.60 J=7.8 Hz, 2H), 1.65 2H), 0.97 J=7.3 Hz, 3H).
Step D: Preparation of Methyl 4-(cyclohexylmethyloxy)-3propylbenzoate (22-5) M COOCH 3 22-5 To a solution of 22-4 (915 mg, 5.0 mmol) in 10 mL of DMF was added 1.78 g (5.50 mmol) of Cs2CO3 followed by 0.68 mL (4.9 mmol) of bromomethyl cyclohexane. The resulting solution was then heated at 50C for 24h. The solvent was distilled under reduced pressure and the residue was taken up in 20 mL of EtOAc. The organic phase was extracted with IN NaOH (2 x 50 mL), water (5 x 5 mL) and brine (5 mL), dried (MgSO4) and concentrated to afford 22-5 as an oil.
1H NMR (CDC13) 5 7.84 (dd, J=2.4, 8.8 Hz, 1H), 7.80 J=2.4, Hz, 1H), 6.80 J=8.8 Hz, 1H), 3.87 3H), 3.80 J=15.9 Hz, 2H), 2.60 J=7.8 Hz, 2H), 1.95-1.00 13H), 0.93 J=7.3 Hz, 3H).
WO 98/10763 PCT/US97/15989 101 Step E: Preparation of 4-(cyclohexylmethyloxy)-3-propylbenzoic acid (22-6)
COOH
22-6 To a solution of 22-5 (1.0 g, 3.44 mmol) in 10 mL of MeOH and 2 mL of THF was added 3.5 mL (14 mmol) of 4N NaOH.
The resulting solution was heated at 50 0 C for 24h, cooled and acidified by the addition of 15 mL of 1N HC1. The aqueous phase was extracted with 2 x 40 mL of EtOAc. The organic extracts were washed with brine mL) and dried over MgSO4. Evaporation of the solvent afforded 22-6 which was used without purification.
Step F: Preparation of N-(4-pyridyl)-3-propyl-4-(cyclohexylmethyloxy)benzamide (22-7) OY
H
/N
22-7 0 N To a solution of 22-6 (770 mg, 2.78 mmol) in 10 mL of (CH2C1)2 and 0.05 mL of DMF was added 0.26 mL (3.05 mmol) of oxalyl chloride. The resulting solution was heated at 50°C for 30 min, cooled to 0°C and treated with 1.20 g (13.8 mmol) of 4-aminopyridine.
Stirring was continued for 2h before the heterogeneous mixture was diluted with 50 mL of EtOAc and quenched with 25 mL of Na2CO3. The organic extract was washed with sat'd NH4CI (3 x mL), water (2x 25 mL), brine (25 mL) and dried over MgSO4.
Evaporation of the solvent and column chromatography (EtOAc) afforded product 22-7.
1H NMR (CDC13) 8 8.55 J=8.0 Hz, 2H), 8.10 (bs, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.70 1H), 7.60 J=8.0 Hz, 2H), 6.85 J=8.8 WO 98/10763 PCT/US97/15989 102- Hz, 1H), 3.80 J=15.9 Hz, 2H), 3.70 3H), 2.60 J=7.8 Hz, 2H), 1.95-1.00 13H), 0.90 J=7.3 Hz, 3H).
Step G: Preparation of 4- {[3-propyl-4-(cyclohexylmethyloxy)phenyllmethylamino I pyridine (22-8) 22-8 N To a solution of 22-7 (1.0 g, 2.8 mmol) in 30 mL of THF was added 10.0 mL (10.0 mmol) of LiAlH4 (1M in THF) and the resulting solution was stirred at room temperature for 16 h, cooled to 0°C and quenched with 1 mL of water, 1 mL of 15% NaOH then 3 mL of water. The heterogeneous mixture was diluted with 50 mL of EtOAc and washed with 3 x 5 mL of sodium potassium tartrate, water (2x mL), brine (5 mL) and dried over MgS04. Evaporation of the solvent and column chromatography (9:1 CHC13 (sat'd NH3)/isopropyl alcohol) afforded 22-8.
IH NMR (CDC13) 5 8.18 J=8.1 Hz, 2H), 7.10 J=7.5 Hz, 1H), 7.07 1H), 6.77 J=7.5 Hz, 2H), 6.41 J=8.1 Hz, 2H), 4,45 (bs, 1H), 4.24 J=15.9 Hz, 2H), 3.74 J=5.1 Hz, 2H), 2.57 J=7.8 Hz, 2H), 2.00-1.00 13H), 0.94 J=7.3 Hz, 3H); Analysis calculated for C22H30N20 C, 78.06; H, 8.93, N, 8.28 Found: C, 78.33; H, 8.99; N, 8.56 WO 98/10763 WO 9810763PCT/US97/15989 103- EXAMPLE 23 Preparation of 4- -ethyl-4-(cyclohexylmethyloxy)phenyllmethylamino lpyridine (23-8)
COOCH
3 B :Oa
COOCH
3 23-1 COOH S 2 C0 3 DMF 23-23 8r 2 Fe /HCOOH 1§Z7 a zzz 10000C Br C000H 3 23-3 Pd(PPh 3 4 dioxane SnBU 3
H
2 /Pd (C) EtOAc PI COOOH 3 0 23-4 N 0000H 3 23-5 LiOH THF
H
2 0 COOH 23-6 1. (0100)2 DCM 2.-
H
2
N\,N
23-7
N
LiAIH 4
THF
500C 23-8 WO 98/10763 PCT/US97/15989 104 Step A: Preparation of Methyl 4-cyclohexylmethyloxy-benzoate (23-2) 23-2
HCOOCH
3 To a solution of methyl 4-hydroxybenzoate 23-1 (24.3 g, 160 mmol) in 250 mL of DMF was added 62 g (190 mmol) of Cs2CO3 followed by 20.4 mL (146 mmol) of cyclohexylmethyl bromide. The resulting slurry was then heated at 50 0 C for 20 h. The solvent was distilled under reduced pressure and the residue was taken up in 500 mL of EtOAc. The organic phase was extracted with IN NaOH (2 x 150 mL), water (5 x 150 mL) and brine (150 mL), dried (MgSO4) and concentrated to afford product 23-2 as a white solid.
IH NMR (CDC13) 5 7.98 J=8.5 Hz, 2H), 6.90 J=8.5 Hz, 2H), 3.88 3H), 3.78 J=6.1 Hz, 2H), 2.00-1.00 11H).
Step B: Preparation of Methyl 4-cyclohexylmethoxy-3-bromobenzoate (23-3) 23-3 Br
COOCH
3 A solution of 23-2 (26.3 g, 106 mmol) was warmed on a steam bath in 110 mL of HCOOH with 592 mg (10.6 mmol) of Fe powder. Bromine (7.6 mL, 147.4 mmol) in 50 mL of HCOOH was added by dropping funnel over a period of 10 min. The reaction mixture was stirred an additional Ih cooled and poured onto ice. The resulting gum was taken up in 500 mL of EtOAc and washed with sat'd Na2S203 (2 x 150 mL), water (5 x 100 mL), sat'd NaHCO3 (3 x 100 mL) and brine (50 mL), dried (MgSO4) and concentrated to afford product 23-3 as a white solid.
1H NMR (CDC13) 5 8.22 1H), 7.98 J=8.5 Hz, IH), 6.90 Hz, 1H), 3.88 3H), 3.78 J=6.1 Hz, 2H), 2.00-1.00 11 H).
WO 98/10763 PCT/US97/15989 105- Step C: Preparation of Methyl 4-cyclohexylmethyloxy-3-ethenylbenzoate (23-4) 23-4 COOCH 3 23-4 To a solution of 23-3 (810 mg, 2.5 mmol) in 11.5 mL of dioxane was added 820 mg (2.6 mmol) of vinyltributyl tin followed by 58 mg (0.05 mmol) of Pd(PPh3)4. The resulting solution was then heated at 100 0 C for 20 h. The solvent was distilled under reduced pressure and the residue was chromatographed to afford product 23-4.
IH NMR (CDC13) 8.19 1H), 7.85 J=8.5 Hz, 1H), 7.00 (dd, J=, 1H), 6.92 1H), 5.85 J=Hz, 1H), 5.35 J=Hz, 1H), 3.88 3H), 3.78 J=6.1 Hz, 2H), 2.00-1.00 11H).
Step D: Preparation of Methyl 4-cyclohexylmethyloxy-3-ethylbenzoate (23-5) 23-5 COOCH3 To 23-4 (560 mg, 2.0 mmol) in 15 mL of EtOAc was added 56 mg of 10% Pd on carbon and the whole was hydrogenated at atmospheric pressure for 24h. Hydrogen was removed from the reaction mixture and the solution was filtered through Celite.
Evaporation of the solvent afforded 23-5 as a white solid.
1 H NMR (CDC13) 5 7.84 (dd, J=2.4, 8.8 Hz, 1H), 7.80 J=2.4 Hz, 1H), 6.80 J=8.8 Hz, 1H), 3.87 3H), 3.80 J=15.6 Hz, 2H), 2.60 J=7.5 Hz, 2H), 1.95-1.00 14H).
WO 98/10763 PCT/US97/15989 -106- Step E: Preparation of 4-cyclohexylmethyloxy-3-ethyl-benzoic acid (23-6) 23-6 COOH To a solution of 23-5 (290 mg, 1.0 mmol) in 7.6 mL of THF and 10 mL of water was added 210 mg (5.0 mmol) of LiOH. The resulting solution was stirred for 40h, then acidified by the addition of mL of IN HCI. The aqueous phase was extracted with 2 x 20 mL of EtOAc. The organic extracts were washed with brine (5 mL) and dried over MgSO4. Evaporation of the solvent afforded acid 23-6 which was used without purification.
Step F: Preparation of N-(4-pyridyl)-3-ethyl-4-(cyclohexylmethyloxy)benzamide (23-7) 0
H
23-7 O N 0 To a solution of 23-6 (270 mg, 1.0 mmol) in 3.6 mL of CH2C12 was added 0.13 mL (1.5 mmol) of oxalyl chloride. The resulting solution was stirred for lh, cooled to 0°C and treated with 380 mg (4.0 mmol) of 4-aminopyridine. Stirring was continued for Ih before the heterogeneous mixture was diluted with CH2C12 and quenched with sat'd NaHCO3. The organic extract was washed with water, brine and dried over Na2SO4. Evaporation of the solvent and column chromatography (3:1 EtOAc Hexane) afforded product 23-7.
1 H NMR (CDC13) 5 8.55 J=8.0 Hz, 2H), 8.10 (bs, 1H), 7.75 (dd, J=2.4, 8.8 Hz, 1H), 7.70 1H), 7.60 J=8.0 Hz, 2H), 6.85 J=8.8 WO 98/10763 PCT/US97/15989 107 Hz, 1H), 3.80 J=15.9 Hz, 2H), 2.60 J=7.8 Hz, 2H), 1.95-1.00 (m, 14H).
Step G: Preparation of 4- [3-ethyl-4-(cyclohexylmethyloxy)phenvllmethvlamino pyridine (23-8) /YO H 23-8
,N
To a solution of 23-7 (290 mg, 0.86 mmol) in 5 mL of THF was added 1.7 mL (1.7 mmol) of LiAlH4 (1M in THF) and the resulting solution was heated at 500C for 2 h, cooled to 0°C and quenched with 0.07 mL of water, 0.07 mL of 15% NaOH and 0.2 mL of water. The precipitate was filtered, concentrated and purified by column chromatography (94:6:0.6 CHC13 IPA NH40H) to afford product 23-8.
1H NMR (CDC13) 5 8.18 J=8.1 Hz, 2H), 7.10 J=7.5 Hz, 1H), 7.07 1H), 6.77 J=7.5 Hz, 1H), 6.41 J=8.1 Hz, 2H), 4.39 (bs, 1H), 4.24 J=15.9 Hz, 2H), 3.74 J=5.1 Hz, 2H), 2.60 J=7.8 Hz, 2H), 2.00-1.00 14H); Analysis calculated for C21H28N20 C, 77.72; H, 8.71, N, 8.63 Found: C, 77.53; H, 8.62; N, 8.56 The compounds shown in the table below are exemplary compounds of the present invention. The range of Ki values associated with the specifically listed compounds is represented as follows: <0.1 lM >0.1 M and <1.0 gM >1.0 pM and <10.0 tM >10.0 gM TABLE 3
R
0- 0- 0- 0- 0- H1
H
H
H
-CH2CH3 CH2CH2CH3 -CH2CH2OH CH2CH2CH3
R
3
R
4
H
H4
H
H
Ki(th)p.M 0.64 0.50 4.4 3.2 0.8 mp 116-90 113-50 oil
R
Q-
OH
2 Hl
H
H
H
H
H
RH2C(H) CH2CH2CH3 -CH=CH2
H
H
CH2CH2CH3
H
H3
H
H
0H 2 -Ph
H
H
H4
H
H
H
H
-CH2OH -CH2CH2 CH(CH3)2 Ki(th)g~M 1.3 0.26 1.8 6.4 3.8 3.2 mp 103-60 114-60 125-60 Ki(th)[tM mp O-
OH
2
H
H
-CH (CH3)2 CH2CH2CH3 CH2CH2CH3
H
CH2CH2CH3 0.22 0.74 H OCH3
H
3.2 0.5 128-90 1 79-800 0- 0- 0- 0-
OCH
2 Ph
OH
2 Ph CH2CH2CH3 1.8 >0.9 1.6 2.9 131-20 182-30 OH 15O0 -NH2 -NH2 173-50 Rl Ki(th)g~M mp 0- 0-
CH
3 -O CIJ2CH2CH3 CH2CH2CH3 CH2CH2CH3 0.32 1.8 140-30 94-60 (freebase) 85-70 (freebase) WO 98/10763 WO 9810763PCTIUS97/15989 -112- TABLE 4 x R W X Y Z Ki (thr) C -amyl H H H C)Ph H H H H H H O3 CH2NH2 H H H OCH2NHCH3 H H H Ol CONCH3 H H H CH2CH2Ot H H H C) Bu n-Pr piperidy H H a) 1-methyl n-Pr H Et H WO 98/10763 WO 9810763PCTIUS97/15989 113-
R
0 i-butyl w n-Pr n-Pr n-Pr n-Pr z CH3
H
Ki (thr) WO 98/10763 WO 9810763PCTIUS97/15989 114- EXAMPLE 24 Preparation of N-((4-benzyloxy)phenylsulfonyl)-N'-aminomethyliminopiperazine (24-5) 1!:r 24-1 S0 2 01 2
/DMF
10000 /2 h 24-2 24-3 HN NBOC Et 3 N CH 2 C1 2 HCI EtOAc -N
BOC
H- HCI 24-4
NH
H
2 N l S0 3
H
Et 3 N DMF N YNH2 *CF 3 000H
NH
24-5 1 I WO 98/10763 PCT/US97/15989 115- Step A: Preparation of 4-benzyloxyphenylsulfonyl chloride (24-2) 24-2 To a 0°C solution of sulfonyl chloride (1.9 mL, 23.8 mmol) in 2 mL of DMF was added 4.0 g (21.7 mmol) of benzyl phenyl ether The resulting solution was then heated at 100 0 C for 2h.
The reaction mixture was then cooled and poured onto crushed ice. The aqueous layer was extracted with CH2C12 The combined organic extracts were dried (Na2SO4) and concentrated. Column chromatography (95 5 Hexane EtOAc) and trituration (hexane) of the pure fractions afforded 24-2 as a pink solid.
1H NMR (CDCl3) 8 8.00 J=7.8 Hz, 2H), 7.45 5H), 7.10 (d, J=7.8 Hz, 2H), 5.15 2H).
Step B: Preparation of N-((4-benzyloxy)phenylsulfonyl)-N'-t- Butvloxvcarbonvlpiperazine (24-3) -°o
BOC
24-3 To a 0°C solution of 24-2 (250 mg, 1.0 mmol) in 3 mL of CH2C12 was added 0.15 mL (1.1 mmol) of Et3N followed by 204 mg (1.1 mmol) of BOC piperazine. The resulting solution was allowed to stir to rt over 72h. The reaction mixture was diluted with CH2C12 and washed with sat'd NaHCO3 (3 x 5 mL). The organic phase was dried (Na2SO4) and concentrated to afford product 24-3 which was used directly without any purification.
WO 98/10763 PCT/US97/15989 116- IH NMR (CDC13) 8 7.70 J=7.8 Hz, 2H), 7.40 5H), 7.10 (d, J=7.8 Hz, 2H), 5.18 2H), 3.58 J=7 Hz, 4H), 2.95 J=7 Hz, 4H), 1.40 9H).
Step C: Preparation of N-((4-benzyloxy)phenylsulfonyl)piperazine (24-4) 0,,0 0 S N 24-4 H *HCI A -25 0 C solution of crude 24-3 (390 mg, 0.94 mmol) in mL of EtOAc was treated with HCI gas for 5 min and then stirred for 2h at this temperature. Excess HCI was displaced from the solution by bubbling N2 through the reaction mixture. The resulting solution was concentrated to give the amine hydrochloride as a white solid which was triturated (EtOAc) to give product 24-4.
1H NMR (CDC13) 5 7.80 J=7.8 Hz, 2H), 7.40 5H), 7.20 (d, J=7.8 Hz, 2H), 5.10 2H), 3,30 4H), 3.20 4H).
Step D: Preparation of N-((4-benzyloxy)phenylsulfonyl)-N'aminomethyliminopiperazine (24-5) 4 ,,o S,
N
0 24-5 N NH 2
CF
3
COOH
24-5
NH
To a -25 0 C solution of 24-4 (300 mg, 0.90 mmol) in 10 mL of DMF and 0.25 mL (1.79 mmol) of Et3N was added 111 mg (0.895 mmol) of guanidine sulfonic acid. The resulting solution was allowed to stir to RT over 16h. The reaction mixture was concentrated and WO 98/10763 PCT/US97/15989 -117subjected to preparative HPLC to afford product 24-5 as its TFA salt.
IH NMR (CD30D) 8 7.80 J=7.8 Hz, 2H), 7.40 5H), 7.20 (d, J=7.8 Hz, 2H), 5.20 2H), 3,60 4H), 3.05 4H); MS (FAB) 375; Analysis calculated for C18H22N403S 0.4 H20 CF3COOH C, 48.46; H, 4.84, N, 11.30 Found: C, 48.76; H, 4.69; N, 10.94 EXAMPLE Preparation of N-((4-cyclohexylmethyloxy)-3-ethyl-phenylsulfonyl)- N'-aminomethyliminopiperazine (25-1) 25-1 was synthesized in the same manner as 24-5 by substituting 4-cyclohexylmethyloxy-3-ethylbenzene for 4benzyloxybenzene in Step A, Example 24.
The compounds shown in the table below are exemplary compounds of the present invention. The range of Ki values associated with the specifically listed compounds is represented as follows: <0.1 RM >0.1 lpM and <1.0 gM >1.0 iM and <10.0 [M >10.0 pM WO 98/10763 WO 9810763PCT/US97/15989 Rl
NH
R-CH
2 O S0 2 -N ~,NH 2 TABLE Ki(thr) iM_ R -CH2CH3 279 237-90 WO 98/10763 PCT/US97/15989 119- EXAMPLE 26 Preparation of [4-(Phenylmethyloxy)phenyl]methyl}benzamidine hydrochloride (26-6) Step A: Preparation of 4-[(4-Methoxyphenyl)hydroxymethyllbenzonitrile (26-2)
O
0 H OH
H
3 CO CN H 3 CO CN 26-1 26-2 To a suspension of 4-(4-methoxybenzoyl)benzonitrile 26-1 Med. Chem.. 1991, 34, 2768-2778) (0.783 g, 3.3 mmol) in ethanol ml) under nitrogen cooled in an ice-bath was added sodium borohydride (0.250g, 6.6 mmol). The mixture was stirred 4h with icebath cooling. To the resulting solution was added saturated ammonium chloride solution (35 ml). The mixture was partially evaporated under reduced pressure, and the resulting aqueous mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic fractions were washed with brine (50 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:6 increasing to to give product 26-2 as an oil.
NMR 8 H(CDCl3) 7.61 (2H, d, J=8 Hz), 7.50 (2H, d, J=8 Hz), 7.23 (2H, d, J=9 Hz), 6.87 (2H, dd, J=9, 2 Hz), 5.82 (lH, d, J=3 Hz), 3.79 (3H, s), 2.37 (lH, bs); IR 2227 cm- 1 WO 98/10763 PCT/US97/15989 -120- Step B: Preparation of 4-[(4-Methoxyphenyl)methyl]benzonitrile (26-3)
H
3 CO CN 26-3 To a mixture of 26-2 (0.622 g, 2.6 mmol) and sodium iodide (1.56 g, 10.4 mmol) in acetonitrile (7 ml) at ambient temperature in a 3-necked round bottom flask equipped with a nitrogen inlet and rubber septum was added dichlorodimethylsilane (0.63 ml, 5.2 mmol) via syringe. The resulting mixture was stirred 60 min. Saturated sodium bicarbonate solution (30 ml) was added and the mixture was extracted with ethyl acetate (2 x 90 ml). The combined organic fractions were washed with 10% sodium thiosulfate solution (30 ml), brine (30 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:6 increasing to to give product 26-3 as a white solid, mp: 41.5- 43.5 0
C.
dH(CDCl3) 7.56 (2H, d, J= 8 Hz), 7.27 (2H, d, J= 8 Hz), 7.07 (2H, d, J= 9 Hz), 6.85 (2H, d, J= 9 Hz), 3.97 (2H, 3.79 (3H, s).
IR 2224 cm- 1 Step C: Preparation of 4-[(4-Hydroxyphenyl)methyl]benzonitrile (26-4) HO" CN 26-4 To a solution of 26-3 (0.391 g, 1.75 mmol) in methylene chloride (6 ml) cooled in an ice-bath in a 3-necked round bottom flask equipped with a nitrogen inlet and rubber septum was added boron tribromide in methylene chloride (3.9 ml, 3.9 mmol) via syringe.
WO 98/10763 PCT/US97/15989 -121 The resulting mixture was stirred 18h while warming to ambient temperature. Water (7 ml) was added and the mixture was extracted with ether (35 ml). The organic fraction was washed with brine ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane increasing to to give product 26-4 as a white solid, mp: 163- 164 0
C.
S H(CDCl3) 7.56 (2H, d, J= 8 Hz), 7.26 (2H, d, J= 8 Hz), 7.02 (2H, d, J= 8 Hz), 6.78 (2H, d, J= 8 Hz), 4.78 (1H, 3.96 (2H, s).
IR 2230 cm- 1 Step D: Preparation of 4- {[4-(Phenylmethyloxy)phenyl]methyl benzonitrile (26-5) HON CN Br 26-4 26-5
CN
To a mixture of 26-4 (0.105 g, 0.50 mmol) and cesium carbonate (0.326 g, 1.0 mmol) in dimethylformamide (1 ml) under nitrogen was added benzyl bromide (0.071 ml, 0.60 mmol). The mixture was stirred 18h at ambient temperature. The resulting mixture was evaporated under reduced pressure. To the residue was added saturated sodium bicarbonate solution (15 ml), and the aqueous mixture WO 98/10763 PCT/US97/15989 122was extracted with methylene chloride (2 x 30 ml). The organic fraction was washed with brine (10 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:6 increasing to to give a white solid. The solid was recrystallized from ethyl acetate/hexane to give product 26-5 as white crystals, mp: 110-111 C.
8 H(CDCl3) 7.56 (2H, d, J=8 Hz), 7.32-7.44 (5H, 7.27 (2H, d, J=8 Hz), 7.07 (2H, d, J=9 Hz), 6.92 (2H, d, J=9 Hz), 5.04 (2H, 3.97 (2H, IR 2223 cm- 1 Analysis calculated for C21H 17NO C, 84.25; H, 5.72; N, 4.68 Found: C, 84.02; H, 5.66; N, 4.74 Step E: Preparation of [4-(Phenylmethyloxy)phenyl]methyl benzamidine hydrochloride (26-6) o 26-5 26-6
*HCI
CN
CN
H
2 N NH To a solution of 26-5 (0.081 g, 0.27 mmol) in anhydrous ether (4 ml) at ambient temperature in a 3-necked round bottom flask equipped with a nitrogen inlet and rubber septum was added 1.0 M lithium bis(trimethysilyl)-amide in THF (0.30 ml, 0.30 mmol) via syringe. The resulting solution was stirred 18h at ambient temperature.
To the solution was added ethanolic HCI (6M, 0.18 ml, 1.1 mmol, 4 equivalents). The mixture was stirred 4h and the resulting precipitate was filtered off to give a solid (0.094g). The solid was placed in saturated sodium bicarbonate solution (3 ml) and was extracted with WO 98/10763 PCT/US97/15989 123ethyl acetate (5 x 10 ml). The combined organic fractions were washed with brine (10 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue (0.017g) was suspended in ethanol (1 ml) and ethanolic HCI (6 M, 0.010 ml) was added. The mixture was stirred, diluted with ether (5 ml), and the resulting precipitate was collected. The precipitate was then stirred under water (1 ml) for lh. The resulting solid was collected and dried in vacuo to give product 26-6, as an off-white solid, mp: 234-236°C.
H(DMSO-d6) 9.30 (2H, br 9.09 (2H, br 7.74 (2H, d, J=8 Hz), 7.32-7.47 (7H, 7.17 (2H, d, J=8 Hz), 6.95 (2H, d, J=8 Hz), 5.06 (2H, 3.98 (2H, s).
Analysis calculated for C21H20N20-HCI*0.65 C, 69.18; H, 6.17; N, 7.68 Found: C, 69.24; H, 5.93; N, 7.40 EXAMPLE 27 Preparation of 4- [4-(Cyclohexylmethyloxy)phenyl]methyl)benzamidine hydrochloride (27-1) I Br- HO' CN 26-4 27-1 27-1 i WO 98/10763 PCT/US97/15989 -124- Step A: Preparation of [4-(Cyclohexylmethyloxy)phenyl]methyl lbenzonitrile (27-1) Employing the procedure substantially as described above, but substituting cyclohexylmethyl bromide for the benzyl bromide, the desired compound 27-1 was prepared: mp: 104-106°C; 1H NMR (CDC13) 7.56 (2H, d, J=8 Hz), 7.26 (2H, d, J=8 Hz), 7.05 (2H, d, J=8 Hz), 6.83 (2H, d, J=8 Hz), 3.96 (2H, 3.72 (2H, d, J= 6 Hz), 1.68-1.87 (6H, 1.17-1.38 (3H, 0.97-1.08 (2H, IR 2223 cm- 1 Step B: Preparation of 4- [4-(Cyclohexylmethyloxy)phenyl]methyl benzamidine hydrochloride (27-3) 27-1 27-2
*HCI
NH.
27-3
*HCI
H
2
N'
Into a suspension of 27-1 (0.101 g, 0.33 mmol) in ethanol (3 ml) under nitrogen cooled in an ice-bath was bubbled hydrogen chloride until the mixture was saturated. The mixture was stirred 18h while warming to ambient temperature. To the resulting solution was WO 98/10763 PCT/US97/15989 125added ether (12 ml) resulting in formation of a precipitate. The precipitate was collected and dried in vacuo to give ethyl (cyclohexylmethyloxy)pihenyl]-methyl }benzimidate hydrochloride 27-2 as a white solid. NMR 8 H(DMSO-d6) 11.0-11.8 (2H, br 7.98 (2H, d, J=8 Hz), 7.48 (2H, d, J=8 Hz), 7.13 (2H, d, J=8 Hz), 6.85 (2H, d, J=8 Hz), 4.57 (2H, q, J=7 Hz), 3.99 (2H, 3.72 (2H, d, J=6 Hz), 1.68-1.80 (6H, 1.47 (3H, t, J=7 Hz), 1.19-1.26 (3H, 0.99-1.06 (2H, m).
Into a suspension of 27-2 (0.101 g, 0.26 mmol) in ethanol ml) cooled in an ice-bath was bubbled ammonia until the mixture was saturated. The mixture was stirred 18h while warming to ambient temperature. The resulting solution was evaporated to one-half volume under reduced pressure. Addition of ether (2 ml) resulted in formation of a precipitate. The precipitate was filtered off. The filtrate was evaporated under reduced pressure, and the residue was stirred under ether (5 ml). The resulting precipitate was collected and dried to give a solid. The solid (0.042 g) was suspended in ethanol (1 ml) and ethanolic HCI (6 M, 0.025 ml) was added. The mixture was stirred, diluted with ether (10 ml), and the resulting precipitate was collected and dried in vacuo to give 27-3, as a white solid, mp: 257-258 0
C.
H(DMSO-d6) 9.1 (4H, br 7.73 (2H, d, J=8 Hz), 7.45 (2H, d, J=8 Hz), 7.14 (2H, d, J=8 Hz), 6.84 (2H, d, J=8 Hz), 3.97 (2H, 3.72 (2H, d, J=6 Hz), 1.63-1.80 (6H, 1.15-1.30 (3H, 0.95-1.10 (2H, m); Analysis calculated for C21H26N20*HCI*0.40 C, 68.89; H, 7.65; N, 7.68 Found: C, 68.84; H, 7.45; N, 7.75
R
x -CH2-
Y
-0- R-X-Y /CH 2
R'
TABLE 6 Rl R Ki( NH
H
-C N H 2 H
H
-G NH 2 NH -CH2CH2CH3
NH
2 thr) p.M 0.39 0.17 0.3 234-60 -CH2- -0- -CH2- -0- 257-80 241-20
R
0- 0- 0- 0- 0x
-COIH-
CH(CH
3 2
Y
-0- -CH2- -0- -CH2- -0-
NH
NH
2 -N NH2
NH
2 -0 -NH2
NH
2
NH
-NH
2
NH
NH
2 -CH2CH2CH3 -CH3 -CH2CH3 -CH3 -CH2CH3 0.28 0.102 0.077 0.020 0.020 172-1840 249-2500 252-30
-COIH-
CH(CH
3 2
-COIH-
CH(CH
3 2 -0- -0- 1 97-2000 198-90 WO 98/10763 WO 9810763PCTIUS97/15989 -128 EXAMPLE 28 Preyarati on of N-(4-Dhenioxvmethvlbenzvl )aminouvyridine (28-6)
-OH
28-1 ~00
L
28-3 Br
+I
C0 2
CH
3
CS
2
CO
3 D MF/r.t.
28-2 5 N NaOH/EtOH 28-4 C0 2
H
1 )(COCI) 2 /Cat.DMF I2) 4-AP
H
2C1 2
I
28-5
H
LAH/THF
600 0 7 Lc N
\N
H
28-6 WO 98/10763 PCT/US97/15989 129- Step A: Preparation of methyl 4-(phenoxymethyl)benzoate (28-3) In a round bottom flask under N2 was placed 28-1 (1.49 g, 15.9 mmol), Cs2CO3 (5.2 g, 16 mmol), 28-2 (3.6 g, 15.7 mmol) in DMF (250 ml) and the suspension stirred at room temperature. After 18 h, the mixture was poured into saturated Na2CO3 and extracted with EtOAc The organic extracts were dried, filtered and conc'd to dryness to yield 28-3.
1 H NMR (CDC13) 8 3.85 (3H, 5.05 (2H, 6.9 (3H, 7.2 (2H, d), 7.45 (2H, 8.0 (2H, d).
Step B: Preparation of 4-(phenoxymethvl)benzoic acid (28-4) Under N2, a mixture of 28-3 (4.1 g, 15.9 mmol) in EtOH (100 ml) and 5 N NaOH (100 ml) was stirred at room temperature.
After 18 h, the reaction was heated at 80 0 C for 1/2 h, cooled to room temperature and then acidified with 6 N HC1. The mixture was extracted with EtOAc (3x) and the combined organic layer was washed with brine, dried, filtered and concentrated to dryness. The residue was triturated with Et20 to yield 28-4.
1 H NMR (d6-DMSO) 8 5.5 (2H, 7.35 (3H, 7.6 7.9 (2H, 8.35 (2H, d).
Step C: Preparation of 4-(phenoxymethyl)benzcarboxamido)pyridine (28-5) To a suspension of 28-4 (2.5 g, 11 mmol) in CH2C12 ml) with 4 drops of DMF was added with stirring under N2 at room temperature oxalyl chloride (1.7 g, 14 mmol). After 2h, the solution was concentrated to dryness, flushed with CHC13 and then dissolved in CHC13 (30 ml). This solution was then added dropwise to a suspension of 4-aminopyridine (3.1 g, 33 mmol) in CHC13 (50 ml). After stirring at room temperature overnight, a sat'd solution of Na2CO3 was added and separated. The aqueous was further extracted with EtOAc (3x).
The combined extracts were backwashed with H20, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still WO 98/10763 PCT/US97/15989 130column (60 mm) and the product eluted with 10% CH30H/CHC13 to yield 2-5; mp: 195-197°C IH NMR (d6-DMSO) 5 5.2 (2H, 6.95 (1H, 7.03 (2H, 7.3 (2H, 7.62 (2H, 7.79 (2H, 7.99 (2H, 8.48 (2H, d).
Analysis calculated for C 19H 16N202 C 74.98, H 5.30, N 9.21 Found: C 74.63, H 5.32, N 9.17 Step D: Preparation of 4-phenoxymethylbenzyl)aminopyridine (28-6) Under N2, a solution of LAH 1.0 M in hexane (10 ml, mmol) was added dropwise to a suspension of 28-5 (1.75 g, 5.8 mmol) in THF (200 ml). After heating at 600 overnight with stirring, a sat'd solution of Na2SO4 was added until a white suspension was formed.
The mixture was poured through super cel and washed with EtOAc.
The organic layer was washed with water and the aqueous layer further extracted with EtOAc The combined organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (40 mm) and the product eluted with 10% CHC13. The hydrochloride salt was prepared from EtOH-HCI and the product crystallized from EtOH to yield 28-6; mp: 213-215 0 C. The compound analyzed for C9H 18N20-HC1; 1H NMR (d6-DMSO) 5 4.55 (2H, 5.05 (2H, 6.95 (5H, 7.25 (2H, 7.4 (4H, 8.15 (2H, bd).
Analysis calculated for C, 69.82; H, 5.86; N 8.57 C, 69.82; H, 5.86; N, 8.57 Found: C, 69.73; H, 5.88; N, 8.58 The compounds shown in the table below are exemplary compounds of the present invention. The range of Ki values associated with the specifically listed compounds is represented as follows: <0.1 iM >0.1 gM and <1.0 gM >1.0 pM and <10.0 gM >10.0 [M WO 98/10763 WO 9810763PCTfUS97115989 131- TABLE 7 R X Y. RI Ki(thr) mp -CH2- -CH2- 1 17-90 -CH2- 213-50
\N
EXAMPLE 29 Preparation of -cyclohexylmethyloxy-phenyl)ethyl)amninop2yridine (29-6 0 29-6 H K-N WO 98/10763 PCT/US97/15989 132- Step A: Preparation of ethyl 3-hydroxy-phenvlacetate (29-2) HO HO
H
2 S0 4 0 EtOH -0
A
OH
OCH
2
CH
3 29-1 29-2 Sulfuric acid (0.018 mL, 0.329 mmol, 0.1 equiv) was added to a solution of 3-hydroxy-phenylacetic acid (29-1) (500 mg, 3.29 mmol, 1 equiv) in ethanol (10 mL) at 23°C. The reaction mixture was heated at reflux for 1.5 h. The solution was cooled to 23°C, then was concentrated. The residue was diluted with ethyl acetate, and the resulting solution was washed with water (2 x 20 mL). The organic layer was dried over magnesium sulfate and was concentrated to afford the product as a colorless oil 29-2 which was used without further purification.
1H NMR (400 MHz, CDC13), 5: 7.17 1H, J 7.88 Hz, ArH [meta to 6.83 1H, J 7.51 Hz, ArH [ortho to 6.78 1H, ArH [ortho to 6.74 1H, J 8.05 Hz, ArH [para to OH]), 5.90 (br s, IH, ArOH), 4.17 2H, J 7.15 Hz, CO2CH2CH3), 3.57 2H, CH2CO2CH2CH3), 1.26 3H, J 7.14 Hz, CO2CH2CH3).
Step B: Preparation of ethyl 3-cyclohexylmethyloxy-phenylacetate (29-3) HO Br
CS
2
CO
3 S+ DMF
OCH
2
CH
3 0
OCH
2
CH
3 29-2 29-3 WO 98/10763 PCT/US97115989 133 Cyclohexylmethyl bromide (0.459 mL, 3.29 mmol, 1 equiv) was added to a suspension of 29-2 (592 mg, 3.29 mmol, 1 equiv) and cesium carbonate (1.07 g, 3.29 mmol, 1 equiv) in N, Ndimethylformamide (6 mL) at 23 0 C. The reaction mixture was heated to 70 0 C and was stirred at that temperature for 3h. The solution was cooled to 23 0 C and was concentrated. The residue was diluted with ethyl acetate, and the resulting solution was washed with an aqueous saturated ammonium chloride solution (2 x 20 mL). Organic layer was dried over magnesium sulfate and was concentrated. The resulting oil was purified by flash column chromatography ethyl acetate in hexane) to afford the product as a colorless oil 29-3 as well as recovered ethyl 3-hydroxy-phenylacetate.
IH NMR (400 MHz, CDC13), 7.21 1H, J 7.69 Hz, ArH [meta to OCH2Cy]), 6.81 2H, ArH [ortho and para to OCH2Cy]), 6.83 (s, 1H, ArH [ortho to the OCH2Cy]), 4.15 2H, J 7.14 Hz, CO2CH2CH3), 3.74 2H, J=6.40 Hz, OCH2Cy), 3.57 2H, CH2CO2CH2CH3), 1.86 2H, J=12.6 Hz, CyH), 1.74 4H, CyH), 1.24 3H, CyH), 1.25 3H, J=7.14 Hz, CO2CH2CH3), 1.05 2H, CyH); TLC (10% EtOAc-hexane), Rf: 0.50 (UV) Step C: Preparation of 3-cyclohexylmethyloxy-phenylacetic acid (29-4) 0 1 N NaOH t-BuOH o 0 29-3 OCH 2
CH
3 29-4 OH A solution of aqueous sodium hydroxide (IN, 14 mL, 14.0 mmol, 10 equiv) was added to a solution of ethyl 3-cyclohexylmethyloxy-phenylacetate 29-3 (384 mg, 1.39 mmol, 1 equiv) in a mixture of t-butanol (8 mL) and water (4 mL) at 23 0 C. The reaction WO 98/10763 PCT/US97/15989 134mixture was heated at reflux for 2h. The solution was cooled to 23°C and was diluted with ethyl acetate (50 mL). The organic layer was washed with an aqueous 10% potassium hydrogen sulfate solution (2 x mL), then was dried over magnesium sulfate and was concentrated to afford the product 29-4 as a white solid, which was used without further purification.
IH NMR (400 MHz, CD30D), 5: 7.19 1H, J= 7.88 Hz, ArH [meta to OCH2Cy]), 6.83 1H, ArH [ortho to OCH2Cy]), 6.79 2H, ArH [ortho and para to OCH2Cy]), 3.75 2H, J=6.04 Hz, OCH2Cy), 3.55 2H, CH2CO2H), 1.87 2H, J=12.5 Hz, CyH), 1.74 4H, CyH), 1.29 3H, CyH), 1.10 2H, CyH).
Step D: Preparation of N-4'-pyridyl-(3-cyclohexylmethyloxv)phenylacetamide (29-5) O 0 I CICOCOCI; 4-aminopyridine 29-4 0 Et 3
N
29- O H 29-5 HN
N
Oxalyl chloride (0.158 mL, 1.81 mmol, 3 equiv) and a catalytic amount of N, N-dimethylformamide (2 mL) were added consecutively to a solution of 29-4 (150 mg, 0.604 mmol, 1 equiv) in dichloromethane (2 mL) at 23 0 C. Once gas evolution ceased (approximately 2 min following the addition of the N, Ndimethylformamide), the volatiles were removed in vacuo. The residue was dissolved in dichloromethane (2 mL), and the resulting solution was transferred via cannula to a suspension of 4-aminopyridine (284 mg, 3.02 mmol, 5 equiv) and triethylamine (0.673 mL, 4.83 mmol, 8 equiv) in dichloromethane (2 mL) at 23 0 C. The reaction mixture was stirred for 2.5 h at 23°C and then was concentrated in vacuo. The residue was WO 98/10763 PCT/US97/15989 135 diluted with ethyl acetate (50 mL), and the resulting solution was washed with an aqueous saturated ammonium chloride solution (2 x mL). The organic layer was dried over magnesium sulfate and was concentrated. The residue was purified by flash column chromatography (100% ethyl acetate) to afford 29-5 as a yellow oil (36 mg, 18.4 IH NMR (400 MHz, CDC13 5: 8.46 (dd, 2H, J=4.86, 1.56 Hz, PyH), 7.36 (dd, 2H, J 4.85, 1.56 Hz, PyH), 7.32 IH, J=7.88 Hz, ArH [meta to OCH2Cy]), 7.17 IH, Amide 6.88 2H, ArH [ortho to OCH2Cy]), 6.84 IH, J= 1.83 Hz, ArH [para to OCH2Cy]), 3.76 (d, 2H, J=6.23 Hz, OCH2Cy), 3.72 2H, CH2-amide), 1.86 2H, J=13.18 Hz, CyH), 1.76 4H, CyH), 1.29 3H, CyH), 1.04 2H, CyH). TLC (EtOAc), Rf. 0.20 (UV).
Step E: Preparation of 4-(2-(3-cyclohexylmethyloxyphenyl)ethyl)aminopyridine (29-6)
LAH
0 THF HN N 2 HN N A solution of lithium aluminum hydride in tetrahydrofuran M, 0.308 ml, 0.308 mmol, 4 equiv) was added to a solution of 29-5 mg, 0.077 mmol, 1 equiv) in tetrahydrofuran (2 mL) at 0°C. The reaction mixture was heated to 50 0 C and was held at that temperature for 2 h. The mixture was cooled to 0°C, and excess lithium aluminum hydride was quenched by the consecutive addition of water (12 pl), aqueous 15% sodium hydroxide solution (12 pl), and water (36 pl).
The resulting aluminum salts were removed by filtration. The filtrate was concentrated, and the residue was purified by flash column WO 98/10763 PCT/US97/15989 136chromatography methanol in chloroform saturated with ammonia) to afford the product 29-6 as a pale yellow solid (mp: 81-83°C).
1 H NMR (400 MHz, CDC13 8: 8.20 (dd, 2H, J=4.94, 1.47 Hz, PyH), 7.23 1H, J=7.84 Hz, ArH [meta to OCH2Cy]), 6.78 3H, ArH [ortho and para to OCH2Cy]), 6.43 (dd, 2H, J=4.85, 1.56 Hz, PyH), 4.15 1H, NH), 3.74 2H, J=6.22 Hz, OCH2Cy), 3.44 2H, J=6.87 Hz, CH2NH), 2.89 2H, J=6.87 Hz, CH2CH2NH), 1.87 2H, J=13.37 Hz, CyH), 1.77 4H, CyH), 1.27 3H, CyH), 1.06 2H, CyH); TLC MeOH-CHCI3 sat'd with NH3), Rf 0.27 (UV) In vitro assay for determining proteinase inhibition Assays of human a-thrombin and human trypsin were performed at 25 0 C in 0.05 M TRIS buffer pH 7.4, 0.15 M NaCI, 0.1% PEG. Trypsin assays also contained 1 mM CaCl2.
In assays wherein rates of hydrolysis of a p-nitroanilide (pna) substrate were determined, a Thermomax 96-well plate reader was used to measure (at 405 nm) the time dependent appearance of pnitroaniline. sar-PR-pna (sarcosine-Pro-Arg-p-nitroanilide) was used to assay human a-thrombin (Km=125 pM) and human trypsin (Km=59 pM). p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm-1M- 1 In certain studies with potent inhibitors (Ki 10 nM) where the degree of inhibition of thrombin was high, a more sensitive activity assay was employed. In this assay the rate of thrombin catalyzed hydrolysis of the fluorogenic substrate Z-GPR-afc (Cbz-Gly- Pro-Arg-7-amino-4-trifluoromethyl coumarin) (Km=27 pM) was determined from the increase in fluorescence at 500 nm (excitation at 400 nm) associated with production of 7-amino-4-trifluoromethyl coumarin. Concentrations of stock solutions of Z-GPR-afc were determined from measurements of absorbance at 380 nm of the 7amino-4-trifluoromethylcoumarin produced upon complete hydrolysis of an aliquot of the stock solution by thrombin.
WO 98/10763 PCT/US97/15989 -137- Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration 0.5 Km into a solution containing enzyme or enzyme equilibrated with inhibitor.
Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (Vo) or presence of inhibitor (Vi) were measured. Assuming competitive inhibition, and that unity is negligible compared and (where and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (Ki) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of Vo/Vi on shown in equation 1.
Vo/Vi 1 [I]/Ki (1) The activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
Thrombin Inhibitors Therapeutic Uses Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
The term "patient" used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent WO 98/10763 PCT/US97/15989 138 coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus, thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems The thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions.
Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
The thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Coming Corporation.
The thrombin inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The thrombin inhibitors may also be coupled WO 98/10763 PCT/US97/15989 139with soluble polymers as targetable drug carriers. Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propylmethacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the thrombin inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
The dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
Oral dosages of the thrombin inhibitors, when used for the indicated effects, will range between about 0.1 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 100 mg/kg/day and most preferably 1-20 mg/kg/day. Intravenously, the most preferred doses will range from about 0.01 to about mg/kg/minute during a constant rate infusion. Advantageously, the thrombin inhibitors may be administered in divided doses of two, three, or four times daily. Furthermore, they can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
WO 98/10763 PCT/US97/15989 -140- For example, oral tablets can be prepared which contain an amount of active compound of between 100 and 500 mg, typically between 200 and 250 mg. Typically, a patient in need of thrombin inhibitor compound, depending on weight and metabolism of the patient, would be administered between about 100 and 1000 mg active compound per day. For a patient requiring 1000 mg per day, two tablets containing 250 mg of active compound can be administered in the morning and two tablets containing 250 mg of active compound can again be administered in the evening. For a patient requiring 500 mg per day, one tablet containing 250 mg of active compound can be administered in the morning and one tablet containing 250 mg of active compound can again be administered in the evening.
The thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators WO 98/10763 PCT/US97/15989 141 include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
The thrombin inhibitors can also be co-administered with suitable anti-coagulation agents or thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies. For example, thrombin inhibitors enhance the efficiency of tissue plasminogen activatormediated thrombolytic reperfusion. Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter. They may also be combined with heparin, aspirin, or warfarin.
EXAMPLE Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the following active compound is prepared as illustrated below: 4-amino-1 -diphenylmethoxy)benzylpyridinium bromide TABLE FOR DOSES CONTAINING
FROM
25-100MG OF THE ACTIVE COMPOUND Amount-mg Active Compound 25.0 50.0 100.0 Microcrystalline cellulose 37.25 100.0 200.0 Modified food corn starch 37.25 4.25 Magnesium stearate 0.50 0.75 WO 98/10763 PCT[US97/15989 -142- All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
Claims (12)
1. A compound having the following structure: and pharmaceutically acceptable salts thereof wherein J is (CH 2 (CH 2 )mNH, or SO 2 where m is 1 or 2; R' and R 2 are independently selected from hydrogen, aryl, or cyclo C3-7 alkyl unsubstituted or substituted with one or more of C-4 alkyl, C14 alkoxy, benzyl, cyclohexylmethyl or aryl; R3 is S.. S S S. S S hydrogen, C1-4 alkyl, or C1-4 alkenyl; A is selected from one of the following fragments NH S /N N N H 2 I ll-C 2 N N- HN H 2 N B 2' 'Z wherein B is N or CH.
2. A compound according to claim 1 having the following structure: J-A R 3 R2 R 3 and pharmaceutically acceptable salts thereof wherein J is CH 2 CH 2 NH, or SO 2 R' and R 2 are independently selected from hydrogen, aryl, or cyclohexyl; U- I II I I II \Ij| 3272 .dn lI'[' R3 is hydrogen, -CH=CH 2 or -CH 2 CH 3 and A is selected from one of the following fragments I, N -N N IH 2 H 2 ,or
3. A compound according to claim 2 which has the same structure: 0 NH H 2 .CH 3 0 N H N 0 0* 0 0 00 0 0000 0 N H 0 S-N N 0\/0 N N 0 NN and CH 2 HGH 1 1AD[AYIM3LIBA3.\O Io L1:I and pharmaceutically acceptable salts thereof.
4. A compound being the title compound substantially as hereinbefore described with reference to any one of the Examples. A process of preparing a compound of claim 1, wherein the process is substantially as hereinbefore described with reference to the procedures outlined in Schemes I-VI.
6. A composition comprising a compound of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
7. A method for inhibiting thrombin in blood in a mammal, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition of claim 6.
8. A method for inhibiting formation of blood platelet aggregates in blood in a mammal, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition of claim 6.
9. A method for inhibiting formation of fibrin in blood in a mammal, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition Sof claim 6. A method for inhibiting thrombus formation is blood in a mammal, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition of claim 6. l: 11. A method for inhibiting thrombin in stored blood, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition of claim 6.
12. A method for inhibiting formation of blood platelet aggregates in stored blood, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition of claim 6.
13. A method for inhibiting formation of fibrin in stored blood, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition of claim 6.
14. A method of inhibiting thrombus formation in stored blood, the method comprising administering to the mammal a compound of any one of claims 1 to 4 or a composition I :of claim 6. I ,15. The use of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a purpose in a mammal selected from a group consisting of inhibiting thrombus formation, preventing thrombus formation, inhibiting thrombin, inhibiting formation of fibrin and inhibiting formation of blood platelet aggregates.
16. A compound of any one of claims 1 to 4 or a composition of claim 6 when used LL r a purpose in a mammal selected from a group consisting of inhibiting thrombus formation, II I. LNI IIAIU27~i~cdoc FIA~ 146 preventing thrombus formation, inhibiting thrombin, inhibiting formation of fibrin and inhibiting formation of blood platelet aggregates. Dated 8 August, 2000 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON I A I) 3 7 2~I,~ci(Io~s lIT
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2603396P | 1996-09-13 | 1996-09-13 | |
| US60/026033 | 1996-09-13 | ||
| GBGB9624278.9A GB9624278D0 (en) | 1996-11-22 | 1996-11-22 | Thrombin inhibitors |
| GB9624278 | 1996-11-22 | ||
| PCT/US1997/015989 WO1998010763A1 (en) | 1996-09-13 | 1997-09-09 | Thrombin inhibitors |
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| AU725403B2 true AU725403B2 (en) | 2000-10-12 |
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| EP (1) | EP0927035A4 (en) |
| JP (1) | JP2001500864A (en) |
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| EP1981507A4 (en) * | 2006-02-01 | 2011-10-19 | Merck Sharp & Dohme | Potassium channel inhibitors |
| RU2354647C2 (en) * | 2007-06-28 | 2009-05-10 | Общество С Ограниченной Ответственностью "Бионика" | New compounds with thrombin inhibiting function, and based pharmaceutical compositions |
| RU2353619C2 (en) * | 2007-06-28 | 2009-04-27 | Общество С Ограниченной Ответственностью "Бионика" | Novel compounds possessing anticoagulant function, based on them pharmaceutical compositions for treatment of thrombotic conditions and plasma-substituting solution for correction of hypercoagulation disorders in hemodilution |
| RU2469029C2 (en) * | 2010-12-30 | 2012-12-10 | Закрытое Акционерное Общество "Вертекс" | Substance showing combined antiagregant, anticoagulant and vasodilator activities, n,n'-substituted piperazines and method for preparing them (versions) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5084466A (en) * | 1989-01-31 | 1992-01-28 | Hoffmann-La Roche Inc. | Novel carboxamide pyridine compounds which have useful pharmaceutical utility |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5283532A (en) * | 1976-01-01 | 1977-07-12 | Teijin Ltd | Novel aromatic compounds |
| IL87181A (en) * | 1987-08-07 | 1993-08-18 | Sanofi Sa | Aminoalkoxyphenyl derivatives, their preparation and pharmaceutical and veterinary compositions containing them |
| EP0511347A1 (en) * | 1990-11-15 | 1992-11-04 | Pentapharm A.G. | Meta-substituted phenyl alanine derivatives |
| GB9214120D0 (en) * | 1991-07-25 | 1992-08-12 | Ici Plc | Therapeutic amides |
| TW257757B (en) * | 1993-03-03 | 1995-09-21 | Boehringer Mannheim Gmbh | |
| US5530012A (en) * | 1994-12-22 | 1996-06-25 | Bristol-Myers Squibb Co. | 3-alkoxybenzylpiperidine derivatives as melatonergic agents |
| IL117149A0 (en) * | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
| US5612363A (en) * | 1995-06-02 | 1997-03-18 | Berlex Laboratories, Inc. | N,N-di(aryl) cyclic urea derivatives as anti-coagulants |
| ES2117950B1 (en) * | 1996-08-02 | 1999-09-16 | Univ Granada | NEW COMPOUNDS THAT BLOCK THE BIOSYNTHESIS OF PHOSPHORYLCHOLINE AND ITS USE AS A SECOND MESSENGER IN CELL PROLIFERATION. |
-
1997
- 1997-09-09 AU AU44117/97A patent/AU725403B2/en not_active Ceased
- 1997-09-09 EP EP97942415A patent/EP0927035A4/en not_active Withdrawn
- 1997-09-09 JP JP10513809A patent/JP2001500864A/en active Pending
- 1997-09-09 CA CA002264037A patent/CA2264037A1/en not_active Abandoned
- 1997-09-09 WO PCT/US1997/015989 patent/WO1998010763A1/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5084466A (en) * | 1989-01-31 | 1992-01-28 | Hoffmann-La Roche Inc. | Novel carboxamide pyridine compounds which have useful pharmaceutical utility |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0927035A4 (en) | 2002-11-13 |
| WO1998010763A1 (en) | 1998-03-19 |
| CA2264037A1 (en) | 1998-03-19 |
| EP0927035A1 (en) | 1999-07-07 |
| JP2001500864A (en) | 2001-01-23 |
| AU4411797A (en) | 1998-04-02 |
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| FGA | Letters patent sealed or granted (standard patent) |