HK1020345B - Aryl pyrimidine derivatives - Google Patents

Description

Aryl pyrimidine derivatives

The present invention relates to arylpyrimidine derivatives, and pharmaceutically acceptable salts and N-oxides thereof, which exhibit useful pharmacological properties, including being selective for 5HT_2BThe use of an antagonist. The invention also relates to their formulations and their use in the treatment of disease.

5-hydroxytryptamine, a neurotransmitter with mixed and complex pharmacological properties, was first discovered in 1948 and subsequently was the subject of research. 5-hydroxytryptamine, also known as 5-hydroxytryptamine (5-HT), acts on discrete 5-HT receptors via both central and peripheral pathways. Currently, 14 subtypes of 5-hydroxytryptamine receptors have been identified and described as 7 families, 5-HT₁To 5-HT₇. At 5-HT₂In family, 5-HT_2A，5-HT_2BAnd 5-HT_2CSubtypes are known to exist. These subtypes share sequence homology and show similarity in specificity for many ligands. The naming and classification of 5-HT receptors has recently been reviewed by Martin and Humphrey, Neuropharma, 33, 261-273(1994) and Hoyer et al, pharm. Rev., 46, 157-203 (1994). Mokrosz et al identified 5-HT of a model 1- (2-pyrimidinyl) piperazine derivative_1AAnd 5-HT_2AReceptor affinity (Mokrosz, J.L., et al, Pharmazie, (1994), 49, 801-.

5-HT_2BReceptors, originally designated 5-HT_2FOr 5-hydroxytryptamine-like receptors, first characterized in isolated gastric fundus of mice [ Clineschmidt et al (1985), j.pharmacol. exp. ther., 235, 696-708; cohen and Wittenauer, (1987), J.Cardiovasc.Pharmacol, 10, 176-]。

5-HT_2CReceptor, headFirst characterized as 5-HT_1CSubtype [ Pazos et al (1984), Eur.J.Pharmacol., 106, 539-]And then confirmed to belong to 5-HT₂Receptor family [ Pritchett et al (1988), EMBO J., 7, 4135-]Widely distributed in the human brain [ Pazos et al (1987), Neuroscience, 21, 97-122]. Current evidence strongly supports 5-HT_2CTherapeutic use of receptor antagonists in the treatment of: anxiety disorders (e.g., generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), alcoholism and addiction to other drugs of abuse, depression, migraine, sleep disorders, feeding disorders (e.g., anorexia nervosa), and priapism [ Kennett (1993), curr. opin. invest. drugs, 2, 317-]. Due to the fact that in 5-HT_2CAnd 5-HT_2BPharmacological similarity of ligand interactions at receptors is 5-HT_2CMany of the therapeutic targets suggested by receptor antagonists are also 5-HT_2BA receptor antagonist. In particular, several clinical observations have shown that 5-HT_2BThe therapeutic effect of receptor antagonists in the prevention of migraine, since the influx of 5-HT into the plasma may be a contributing factor to migraine. In addition, non-selective 5-HT_2BReceptor agonists trigger migraine attacks in susceptible individuals, not selective 5-HT_2BReceptor antagonists are effective in preventing migraine attack [ Kalkman (1994), Life Sciences, 54, 641-644)]。

Thus, it is clear that 5-HT is selective_2BReceptor antagonists offer particular therapeutic advantages in terms of power, rapidity of occurrence and absence of side effects. Also, such agents are expected to be useful in the treatment of hypertension [ Watts et al, J.pharm. exp.Ther, 277, 1056-]。

A number of aryl substituted pyrimidine compounds have been exemplified in the chemical and patent literature. For example, Budesinsky et al, Collection Czechosal v.chem.Commun., 26, 2865-2870(1961), disclose 2-amino-6-methyl-4- (naphthalen-1-yl) -pyrimidine as an intermediate for the preparation of antibacterial compounds.

Further examples of these compounds are described in WO-A-8500603, WO-A-8500604, WO-A-8604583, WO-A-8907599, WO-A-8911279, US-A-3965101, DE-A-1921049, DE-A-3029871, DE-A-2750288, DE-A-4237768, WO-A-9632384, EP-A-0459830, DE-A-2255525 and EP-A-0114770. In addition, WO-A-9639400 discloses pyrimidine derivatives which are CRF receptor antagonists. Other pyrimidine derivatives are described in Mariella et al, j.org.chem., 25, 647-; zagluyaeva et al, izv.sib.otd.akad.nauk SSSR, ser.khim.nauk, 4, 27-31 (1990); essawy et al, egypt.j.chem., 37(4), 423-31 (1994); U.S. patents nos. nj0 s.4,543,248, 4,619,933, 4,665,077, 5,002,951, 5,147,876 and 5,223,505, and european patent publication No. [ EP ] 459830; EP-A-0210044; a-0521471.

One aspect of the invention relates to compounds represented by formula I:wherein: r¹Is hydrogen, alkyl, hydroxyalkyl, cycloalkyl lower alkyl, alkenyl, lower thioalkoxy, halogen, fluoroalkyl, optionally substituted phenyl lower alkyl, -NR⁶R⁷，-CO₂R⁸，-O(CH₂)_nR⁹Wherein

n is 1, 2, or 3;

R⁶and R⁷Independently hydrogen or lower alkyl;

R⁸is hydrogen or lower alkyl; and

R⁹is hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, or lower alkoxy; r²Is hydrogen, lower alkyl, lower alkoxy, halogen, or lower fluoroalkyl; r³Is optionally substituted aryl other than pyridyl, thienyl, or furyl; r⁴Is hydrogen, lower alkyl, optionally substituted phenyl-lower alkyl, hydroxy-lower alkyl, acyl, or- (CH)₂)_mNR⁶R⁷(ii) a Wherein

m is an integer of 1 to 6; and

R⁶and R⁷Is hydrogen or lower alkyl; and R⁵Is hydrogen or lower alkyl; the precondition is that:

(i) when R is³Is naphthyl, indol-1-yl, or 2, 3-indolin-1-yl, and R²，R⁴And R⁵When all are hydrogen, R¹Is not methyl;

(ii) when R is³When it is phenyl or naphthyl, R¹Is not-NR⁶R⁷；

(iii) When R is³When it is phenyl, R²Is not lower alkoxy, and R¹And R²Is not a halogen;

(iv) when R is³Is phenyl and R¹When is H, R²Is not methyl; and

(v) when R is³When it is 1, 2, 3, 4-tetrahydroquinolyl, R⁴And R⁵Is hydrogen; or a pharmaceutically acceptable salt or N-oxide thereof.

In another aspect, the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or N-oxide thereof, in admixture with one or more pharmaceutically acceptable non-toxic carriers.

In another aspect, the invention relates to methods of treating a mammal having a disease state that can be treated with 5HT_2BAntagonist therapy for alleviation, by administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or N-oxide thereof.

A compound of formula I, a pharmaceutically acceptable salt or N-oxide thereof for the manufacture of a medicament for the treatment of a disease state which is treatable by treatment with 5HT_2BAntagonist therapy to alleviate) is a further object of the invention.

The following definitions are used throughout the description of the present invention:

"alkyl" refers to a branched or unbranched saturated hydrocarbon chain containing 1-12 carbon atoms, such as methyl, ethyl, propyl, t-butyl, n-hexyl, n-octyl, n-dodecyl and the like.

"alkenyl" refers to unsaturated monovalent hydrocarbon radicals of 1 to 12 carbon atoms. The term is further exemplified by groups such as vinyl, prop-2-enyl, pent-3-enyl, hex-5-enyl, oct-2-enyl, and the like.

"cycloalkyl" refers to a monovalent saturated carbocyclic group containing no unsaturated bonds and having 3 to 8 carbon atoms, such as cyclopropyl, 2-methylcyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

"lower alkyl" refers to a branched or unbranched saturated hydrocarbon chain containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, tert-butyl, n-hexyl, and the like, unless otherwise specified.

"lower alkenyl" refers to monovalent unsaturated hydrocarbon groups of 1 to 6 carbon atoms. The term is further exemplified by groups such as vinyl, prop-2-enyl, pent-3-enyl, hex-5-enyl.

"cycloalkyl lower alkyl" as defined herein refers to a cycloalkyl group as defined above attached to a lower alkyl group as defined above, such as cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl and the like.

"phenyl lower alkyl" refers to a phenyl group attached to a lower alkyl group as defined above, e.g., phenylmethyl (benzyl), phenylethyl, phenylpropyl, and the like.

"fluoroalkyl" refers to an alkyl group as defined above substituted at any position by 1 to 5 fluorine atoms, for example trifluoromethyl, pentafluoroethyl, 1, 1, 1-trifluoro-n-propyl, 1-fluoro-n-butyl, 1, 2-difluoro-3-methylpentane, 1-fluorooctane, and the like.

"lower fluoroalkyl" refers to a lower alkyl group as defined above substituted at any position by 1 to 5 fluorine atoms, for example, trifluoromethyl, pentafluoroethyl, 1, 1, 1-trifluoro-n-propyl, 1-fluoro-n-butyl, 1, 2-difluoro-3-methylpentane, and the like.

"acyl" refers to the group-C (O) -R ', wherein R' is lower alkyl as defined herein.

"lower alkoxy" refers to the group-O-R ', where R' is lower alkyl as defined herein. Similarly, "lower thioalkoxy" refers to the group-S-R'.

"hydroxyalkyl" refers to an alkyl group as defined above substituted with 1, 2 or 3 hydroxy groups, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 1-hydroxyisopropyl, 2-hydroxyisopropyl, 1, 2-dihydroxyisopropyl, 1-hydroxybutyl, 1, 3-dihydroxybutyl and the like. Similarly, "hydroxy lower alkyl" refers to a lower alkyl group as defined above substituted with 1, 2 or 3 hydroxy groups.

"halogen" means fluorine, chlorine, bromine, or iodine unless otherwise specified.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description herein includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted phenyl" or "optionally substituted aryl" means that the phenyl or aryl group is substituted or unsubstituted with the following substituents: lower alkyl, lower alkoxy, hydroxy, nitro, lower fluoroalkyl, and halogen, and includes unsubstituted phenyl and unsubstituted aryl, and all possible mono-, di-, or tri-substituted isomeric phenyl and aryl groups.

The term "aryl" as used herein refers to a monocyclic aromatic ring, or a 9-14 membered bicyclic or tricyclic ring system, wherein at least one ring is aromatic in nature and includes carbocyclic rings and heterocyclic rings having one or two heteroatoms selected from nitrogen, oxygen and sulfur. Examples of aryl groups include, but are not limited to, phenyl, thiophene, naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, 1, 2, 3, 4-tetrahydroquinoline, indole2, 3-indoline, 1H-benzo [ b ]]Azadipine, 2, 3, 4, 5-tetrahydro-1H-benzo [ b]Azepines, 2H-benzo [1, 4]]Oxazines, 3, 4-dihydro-2H-benzo [1, 4]]Oxazines, 1H, 3H-benzo [ de ]]Isochroman, 6, 7,8, 9-tetrahydro-5-oxa-9-benzocycloheptane, 2, 3 dihydro-1, 4-benzodioxan, and the like. More specifically, the term aryl includes the following structures:for example, naphthalen-1-yl and naphthalen-2-yl, and derivatives thereof;for example, quinolin-2-yl, quinolin-4-yl, quinolin-8-yl, and the like and derivatives thereof;for example, isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-8-yl and the like and derivatives thereof;for example, 1, 2, 3, 4-tetrahydroquinolin-1-yl, 1, 2, 3, 4-tetrahydroquinolin-5-yl, and derivatives thereof;for example, 3, 4-dihydro-2H-benzo [1, 4]]Oxazin-1-yl, 3, 4-dihydro-2H-benzo [1, 4]]Oxazin-5-yl, and derivatives thereof;wherein the dotted line represents an optional double bond, e.g., indol-1-yl, 1H-indol-4-yl, 2, 3-indolin-1-yl, and derivatives thereof;for example, 2, 3, 4, 5-tetrahydro-1H-benzo [ b ]]Azepines, and derivatives thereof;for example, 7,8, -dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl, 7,8, -dihydro-6H-5-oxa-9-aza-benzocyclohepten-4-yl, and derivatives thereof;for example, benzo-1, 4-dioxane and derivatives thereof.

The term "inert organic solvent" or "inert"polar solvent" refers to a solvent that is inert under the reaction conditions described [ including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform ("CHCl"), and mixtures thereof₃"), methylene chloride (or methylene chloride or" CH₂Cl₂"), diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like]. Unless indicated to the contrary, the solvent used in the reaction of the present invention is an inert solvent.

"pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable and are formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

'N-oxide' refers to a stable amine oxide formed on one of the pyrimidine nitrogen atoms.

The term "treatment" as used herein includes any treatment of a disease in a mammal, particularly a human, including:

(i) preventing the occurrence of a disease in a subject who is predisposed to the disease but has not yet been diagnosed as having the disease;

(ii) inhibiting the disease, i.e., limiting its development; or

(iii) Alleviating the disease, i.e. causing remission of the disease.

The term "therapeutically effective amount" refers to an amount of a compound of formula I, as defined above, sufficient to effect treatment when administered to a mammal in need of such treatment. The therapeutically effective amount will depend upon the subject being treated and the symptoms of the disease, the severity of the condition and the mode of administration, and can be routinely determined by one of ordinary skill in the art.

The term "by using 5 HT" as used herein_2BAntagonist treatment of disease states that can be alleviated "is intended to include conditions known in the art to be treatable for 5HT_2BAll diseases that are treated by compounds with affinity for the receptor, and those disease states that have been found to be effectively treated with a particular compound of the invention (a compound of formula I). Such disease states include, but are not limited to, anxiety disorders (e.g., generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), alcoholism and addiction to abuse of other drugs, depression, migraine, hypertension, sleep disorders, feeding disorders (e.g., anorexia nervosa), and priapism.

The compounds of formula I listed below will be named using the indicated numbering system:

a compound of formula I, wherein R¹Is isopropyl, R²，R⁴And R⁵Is hydrogen, and R³Is a 1-naphthyl group, designated:

2-amino-6-isopropyl-4- (naphthalen-1-yl) -pyrimidine.

A compound of formula I, wherein R¹Is isopropyl, R²，R⁴And R⁵Is hydrogen, and R³Is a 1H-indol-4-yl group, designated:

2-amino-4- (1H-indol-4-yl) -6-isopropylpyrimidine.

A compound of formula I, wherein R¹Is methyl, R²And R⁴Is hydrogen, R⁵Is methyl, and R³Is 1, 2, 3, 4-tetrahydroquinolin-1-yl, designated as:

6-methyl-2- (methylamino) -4- (1, 2, 3, 4-tetrahydroquinoline 1-yl) -pyrimidine.

1-N-oxides of compounds of formula I wherein R¹Is chlorine, R²Is methyl, R⁴And R⁵Is hydrogen, and R³Is a 4-methoxyphenyl group, designated:

2-amino-6-chloro-4- (4-methoxyphenyl) -5-methyl-pyrimidine-1-N-oxide.

Within the family of compounds of the present invention, a preferred class comprises compounds of formula I, wherein R is⁴And R⁵Is hydrogen or lower alkyl. Within this class, a preferred group includes those compounds wherein R is¹Is lower alkyl, fluoroalkyl or hydroxyalkyl and R³Is optionally substituted aryl, in particular wherein R³Is optionally substituted 1-naphthyl or indol-4-yl, or a pharmaceutically acceptable salt or N-oxide thereof.

Particularly preferred compounds are:

2-amino-4- (2-methylnaphthalen-1-yl) -6-methylpyrimidine;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-1-N-oxide;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (2-methylpropyl) -pyrimidine;

2-amino-6- (tert-butyl) -4- (4-fluoronaphthalen-1-yl) -pyrimidine;

2-amino-4- (2-methylnaphthalen-1-yl) -6-methylpyrimidine;

2-amino-4- (1H-indol-4-yl) -6-methylpyrimidine;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (1-fluoro-1-methyl-ethyl) -pyrimidine; and

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (1-hydroxy-1-methyl-ethyl) -pyrimidine;

2-amino-4- (4, 6-difluoronaphthalen-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine;

2-methylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropyl-pyrimidine;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (2-methylpropyl) -pyrimidine.

A further preferred group of compounds of the invention are compounds of formula I, wherein R is⁴And R⁵Is hydrogen or lower alkyl, R¹Is lower alkyl and R³Is optionally substituted indole, such as 2-amino-4- (1H-indol-4 yl) -6-methylpyrimidine or a pharmaceutically acceptable salt or N-oxide thereof.

The following methods may be used to prepare compounds of formula I:

one such method starts with an intermediate of formula (4), the preparation of which is given in scheme I below.

Reaction scheme IWherein R is lower alkyl, R¹And R²As defined above for formula I, R⁴And R⁵Is hydrogen or lower alkyl.

The starting ketoester of formula (I) may be obtained commercially, for example from Aldrich Chemical co, inc. The compounds of formula (2) may be obtained commercially or prepared according to methods known in the art.

To prepare the compound of formula (3), the ketoester of formula (1) is treated with an excess of the guanidine derivative of formula (2) in a protic solvent, preferably ethanol, at reflux temperature for 6-24 hours, preferably about 16 hours. The product of formula (3), the 2-amino-4-hydroxypyrimidine derivative, is isolated by conventional methods and reacted in the next step without further purification.

The 2-amino-4-hydroxypyrimidine derivative of formula (3) is preferably converted into the corresponding 4-chloro compound of formula (4) by reacting the compound of formula (3) with a chlorinating agent, preferably phosphorus oxychloride, preferably in the absence of a solvent. The reaction is carried out at reflux temperature for about 30 minutes to 8 hours, preferably about 2 hours. The product of formula (4), the 2-amino-4-chloropyrimidine derivative, is isolated by conventional means, and preferably recrystallized prior to further reaction.

One method of converting the compound of formula (4) to the compound of formula I is given in scheme II below.

Reaction scheme II:

wherein R is¹，R²And R³As defined in formula I, R⁴And R⁵Is hydrogen or lower alkyl.

Reacting a 2-amino-4-chloropyrimidine derivative of formula (4) with a boronic acid derivative of formula (5) in an aqueous solvent, preferably a mixture of ethanol, water and dimethoxyethane, and containing a palladium catalyst, preferably tetrakis (triphenylphosphine) palladium, and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 80-90 deg.C, for about 5-30 hours, preferably about 14 hours. The product of formula I is isolated in a conventional manner and preferably purified by recrystallization.

Another method for converting the compound of formula (4) to the compound of formula I is given in scheme III below.

Reaction scheme III

Wherein R is lower alkyl, R¹，R²And R³As defined in formula I, R⁴And R⁵Is hydrogen or lower alkyl.

The bromoaryl derivative of formula (6) is reacted with a strong base such as a lower alkyl lithium, preferably n-butyl lithium. The reaction is carried out in an ether solvent (e.g., diethyl ether, dimethoxyethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran) at a temperature of about-50 to-150 c, preferably about-95 c for about 5-30 minutes, after which about 1 equivalent of trialkoxyborane, preferably trimethoxyborane, is added and the mixture is allowed to warm to room temperature. The product of formula (7), the dimethoxyborane complex, is isolated by removing the solvent and used in the next reaction without further purification.

The 2-amino-4-chloropyrimidine derivative of formula (4) is reacted with the boron complex of formula (7) obtained above in an inert solvent, preferably an aromatic solvent, most preferably toluene, and containing a palladium catalyst, preferably tetrakis (triphenylphosphine) palladium, and an inorganic base, preferably sodium carbonate/water. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 80-90 deg.C, for about 10 minutes to 10 hours, preferably about 1 hour. The product of formula I is isolated and purified by conventional means, preferably by chromatography.

Another method for converting a compound of formula (4) to a compound of formula I, wherein R³Is a bicyclic ring system containing N as a point of attachment to the pyrimidine nucleus, i.e. R³Expressed as:wherein n is 0, 1 or 2 and Y is CH₂O, S or NH, the ring being optionally substituted as defined above. This process is given by the following scheme IV.

Reaction scheme IV:wherein n is 0, 1 or 2 and Y is CH₂O, S or NH, and R¹，R²，R⁴And R⁵As defined in formula I.

The 2-amino-4-chloropyrimidine derivative of the formula (4) is reacted with the compound of the formula (8) in a mixture of water and a strong acid, preferably sulfuric acid, as a solvent. The reaction is preferably carried out at about 100 ℃ for about 20 minutes to 10 hours, preferably about 2 hours. The product of formula I is isolated by conventional means and preferably purified by recrystallization.

Alternatively, the compounds of formula (4) and (8) are reacted together in a polar solvent, preferably dimethylformamide. The reaction is preferably carried out at about 70-90 deg.C for 12-72 hours, preferably about 24 hours. The product of formula I is isolated by conventional means and preferably purified by chromatography.

The compounds of formula I may also be prepared from acylaryl derivatives of formula (9), as shown in scheme V below.

Reaction process V:wherein R is lower alkyl, R⁴And R⁵Is hydrogen or lower alkyl, and R¹，R²And R³As defined above in formula I.

The acylaryl derivatives of formula (9) can be obtained commercially, for example from Aldrich chemical co., inc., or prepared according to methods well known in the art, for example a Friedel-Crafts reaction. In general, of the formula R³The aryl derivative of H is reacted with a carboxylic acid derivative such as acetic anhydride in the presence of a lewis acid (e.g., aluminum chloride). The reaction is carried out at a temperature of about-20 c to 20 c, preferably 0 c, for about 5 minutes to 3 hours, preferably 20 minutes. The acylaryl derivative product of formula (9) is isolated by conventional means and preferably purified by chromatography.

The acylaryl derivative of formula (9) is reacted with an excess of an ester of formula (10) in the presence of a strong base, preferably sodium hydride. The reaction is preferably carried out at a temperature of about 80 ℃ until the compound of formula (9) is consumed. The diketone of formula (11) is isolated by conventional means and preferably purified by chromatography.

Preparation of Compounds of formula I

The diketone of formula (11) is preferably reacted with the compound of formula (2) in the absence of a solvent. The reaction is carried out at a temperature of about 100 ℃ to 180 ℃, preferably about 150 ℃ for about 1 to 10 hours, preferably about 5 hours. The product of formula I is isolated by conventional means and preferably purified by chromatography. Preparation of a Compound of formula I from an acylaryl derivative of formula (9) (wherein R¹Hydrogen) is given by the following scheme VI.

Reaction scheme VI:wherein R is⁴And R⁵Is hydrogen or lower alkyl, R²And R³As defined above in formula I.

The acylaryl derivative of formula (9) is reacted with tert-butoxybis (dimethylamino) methane (Bredereck's reagent) in a protic solvent, preferably ethanol. The reaction is preferably carried out at about 80 ℃ for about 12 hours to 5 days, preferably about 2 days. The compound of formula (13) is isolated by conventional means and preferably used in the next reaction without further purification.

Reacting an alkenone of formula (13) with a compound of formula (2), preferably in the absence of a solvent. The reaction is carried out at a temperature of about 100 ℃ and 180 ℃, preferably about 120 ℃ for about 5to 24 hours, preferably about 14 hours. The product of formula I is isolated by conventional means and preferably purified by recrystallization.

An alternative method of preparing the compounds of formula I is from intermediates of formula (16), which is given in scheme VII below.

Reaction scheme VIIWherein R is lower alkyl, R¹And R²As defined above in formula I.

The starting ketoester of formula (I) may be obtained commercially, for example from Aldrich Chemical co, inc. The compounds of formula (14) may be obtained commercially or prepared according to methods well known in the art.

To prepare the compound of formula (15), the ketoester of formula (1) is treated with about 2 molar equivalents of the isothiourea derivative of formula (14) in an aqueous solution containing an excess of an inorganic base, preferably sodium carbonate. The reaction is carried out at a temperature of about 5 ℃ to 60 ℃, preferably about 25 ℃ for about 10 to 100 hours, preferably 60 hours. The product of formula (15), the 4-hydroxy-2-methylthiopyrimidine derivative, is isolated in a conventional manner and preferably reacted in the next step without further purification.

The 4-hydroxy-2-methylthiopyrimidine derivative of formula (15) is converted to the corresponding 4-chloro compound of formula (16) under conditions analogous to those described above for the preparation of the compound of formula (4) according to scheme I. The product of formula (16), a 4-chloro-2-methylthiopyrimidine derivative, is isolated by conventional means.

One method of converting the compound of formula (16) to the compound of formula I is given by scheme VIII below.

Reaction scheme VIII:wherein R is¹，R²And R³As defined above in formula I.

In a first step 1, a compound of formula (17) is prepared as follows:

a solution of the 6- (lower alkyl or lower alkoxy) -2-methylthiopyrimidine compound of formula (16) in an anhydrous ether solvent, preferably tetrahydrofuran, is reacted with a solution of an excess of a hindered base, preferably lithium diisopropylamide, in an anhydrous ether solvent, preferably tetrahydrofuran, at a temperature of about-90 c to 10 c, preferably about-70 c, for about 30 minutes. An excess of the bromoaryl derivative of formula (6) is added and the reaction mixture is then brought to ambient temperature. The product of formula (17), i.e. the 2-methylthiopyrimidine compound (17), is isolated again by conventional methods and preferably purified by chromatography.

Alternatively, using the procedure given in scheme III, a compound of formula (16) may be reacted with a compound of formula (7) to give a compound of formula (17).

In a second step 2, a compound of formula (18) is prepared as follows:

the 2-methylthiopyrimidine derivative of formula (17) is reacted with about 1-4 molar equivalents, preferably about 2 molar equivalents, of a strong oxidizing agent such as m-chloroperoxybenzoic acid. The reaction is carried out at a temperature of about 0 ℃ to 50 ℃, preferably about 25 ℃, in an inert solvent, preferably dichloromethane, for about 1 to 30 hours, preferably about 16 hours. The product of formula (18), the 2-methylsulfonylpyrimidine derivative, is isolated using conventional procedures.

In a third step 3, the compound of formula I is prepared as follows:

the 2-methylsulfonylpyrimidine derivative of formula (18) is reacted with an excess of a primary or secondary amine in a suitable solvent such as ethanol. The reaction is carried out at a temperature of about 10 c to 100 c, preferably 45 c, for about 1 to 10 hours, preferably 6 hours. The product, i.e., the compound of formula (1), is isolated and purified by conventional means.

Further routes for preparing compounds of formula I are given by the following scheme IX:

reaction scheme IX:wherein R is¹Is hydroxy wherein R¹Is chlorineWherein R is¹Is chlorine wherein R¹Is NR⁶R⁷Wherein R is¹Is chlorine wherein R¹Is hydrogen wherein R⁴And R⁵Is hydrogen or lower alkyl, R²And R³As defined above in formula I.

A compound of formula I (wherein R¹Is chloro) can be prepared from compounds of formula I (wherein R is R) in the same manner as given in step 2 of scheme I above¹Is a hydroxyl group).

Alternatively, compounds of formula I (wherein R is R) are prepared by reaction of a dichloro derivative in the same manner as in scheme II or III¹Is chlorine) can be derived from compounds of formula (4) (wherein R is¹Is chloro) (i.e., a 4, 6-dichloro-pyrimidine derivative).

Reacting a compound of formula I, wherein R¹Is chlorine, with the formula R⁶R⁷Primary or secondary amine of NH, wherein R⁶Is hydrogen or lower alkyl and R⁷Is a lower alkyl group, and is reacted in a high boiling protic solvent, preferably ethylene glycol. The reaction is preferably carried out at a temperature of about 100 ℃ for about 12 hours to 5 days, preferably about 2 days. Isolating the compound of formula I, wherein R is¹is-NR⁶R⁷。

In the presence of a palladium or platinum catalyst, preferably palladium supported on a carbon support, wherein R¹The compound of formula I, which is chlorine, is catalytically reduced with hydrogen. The reaction is carried out in a protic solvent, preferably methanol or ethanol, in the presence of a strong base, preferably aqueous sodium hydroxide. The reaction is preferably carried out at a temperature of about 10-40 c, preferably about room temperature, at about 1 atmosphere until the reduction reaction is complete, for about 1 hour. Wherein R is isolated by conventional means¹A compound of formula I which is hydrogen.

A compound of formula I (wherein R¹Is thioalkoxy) is given by the following scheme X.

Reaction process X:wherein R is⁴And R⁵Is hydrogen or lower alkyl, R²And R³As defined above in formula I.

An acylaryl derivative of formula (9), which is commercially available or prepared according to methods well known in the art, is mixed with carbon disulfide in an aprotic solvent such as diethyl ether, benzene, toluene, preferably diethyl ether, in the presence of a strong base, preferably potassium tert-butoxide, at a temperature of about 10-12 ℃. The reaction mixture was warmed to room temperature and then cooled to about 10-12 c, at which time 2 molar equivalents of methyl iodide were added dropwise. The mixture is maintained at a temperature of about 10-80 c, preferably about room temperature, for about 5-24 hours, preferably about 16 hours. The bis-methylsulfanyl compound of formula (19) is isolated by conventional means and preferably purified by crystallization.

The compound of formula (19) is reacted with the compound of formula (2) in the presence of a strong base, preferably sodium hydride, in a polar solvent, preferably dimethylformamide. The reaction is carried out at room temperature for about 1 hour, and then at about 100 ℃ and 180 ℃, preferably at about 150 ℃ for about 1-10 hours, preferably about 5 hours. The product of formula (I) is isolated by conventional means and preferably purified by chromatography.

The compound of formula (19) is reacted with a compound of formula (2) in the presence of a strong base, preferably sodium hydride, in a polar solvent, preferably dimethylformamide. The reaction is carried out at room temperature for about 1 hour, and then at about 100 ℃ and 180 ℃, preferably at about 150 ℃ for about 1-10 hours, preferably about 5 hours. The product of formula (I) is isolated by conventional means and preferably purified by chromatography.

The preparation of the N-oxides of the compounds of formula I is given in the following scheme XI.

Reaction scheme XI:wherein R is¹，R²，R³，R⁴And R⁵As defined above in formula I.

The compound of formula I is reacted with an oxidizing agent, preferably m-chloroperbenzoic acid, in an inert solvent, preferably chloroform or dichloromethane. The reaction is preferably carried out at a temperature of about 30 to 60 c, preferably about 40 c, for about 10 minutes to 2 hours, preferably about 30 minutes. The N-oxide of the compound of formula I is isolated using conventional methods.

Position of N-oxidation with the group R¹By a change in steric hindrance ofAnd (4) changing. For example, when R is¹In the case of the methyl group, the N-oxidation reaction (formula Ia) occurs almost exclusively at the 1-position. However, when R is¹As the group increases in size, an increased amount of 3-N-oxide (formula Ib) will be found. For example, when R is¹In the case of the tert-butyl group, the majority of the oxidation takes place in the 3-position. For the oxidation reaction to obtain a mixture of N-oxides, the 1-N-oxide and 3-N-oxide can be separated by chromatography or by selective crystallization from a suitable solvent, e.g. a mixture of ethanol/diethyl ether.

Preparation of a compound of formula I from an N-oxide of formula I (wherein R¹Is hydroxyalkyl or alkenyl) is given in scheme XII below.

Reaction scheme XII:wherein, in the formulae Ia and Ib, R¹Is alkyl, in formula I, R¹Is hydroxyalkyl or alkenyl, R²，R³，R⁴And R⁵As defined above in formula I.

N-oxides of the formula I, in which R is¹Is an alkyl group, with an excess of a carboxylic anhydride, preferably trifluoroacetic anhydride, in an inert solvent, preferably dichloromethane. The reaction is carried out at a temperature of about 5to 60 c, preferably about 25 c, for about 10 to 60 hours, preferably 48 hours. To obtain wherein R¹Mixtures of compounds of the formula I which are 6-hydroxyalkyl or 6-alkenyl are then isolated and purified by customary methods, preferably by chromatography.

By replacing R with other groups⁴And R⁵One or two of hydrogen of formula I, wherein R is¹，R²And R³Is as defined above, R⁴And R⁵Is hydrogen, may be converted to other compounds of formula I:

A. for example, compounds of formula I wherein R⁴Is acetyl which may be optionally in the presence of 4-dimethylaminopyridine by reaction with an acylating agent, preferably acetic anhydridePrepared by the following reaction. The reaction mixture is carried out at a temperature of 0 ℃ to 100 ℃ for about 4 hours. The diacetyl product is isolated by conventional means and dissolved in a protic solvent such as methanol and treated with sodium bicarbonate for about 1-24 hours. The monoacetylated product, the compound of formula I, obtained is isolated and purified by conventional methods.

B. For example, compounds of formula I wherein R⁴And R⁵Is methanesulfonyl and may be prepared by reaction with triethylamine and a sulfonylating agent, preferably methanesulfonyl chloride. The reaction is carried out at a temperature of about 0 c in an inert organic solvent, such as dichloromethane, for a period of about 5 minutes to 3 hours, preferably 30 minutes. The resulting bis-methylsulfonyl product, the compound of formula I, is isolated and purified by conventional methods.

C. For example, under alkaline (preferably sodium hydroxide) conditions, wherein R⁴Is methanesulfonyl and R⁵The compound of formula I that is hydrogen may be prepared from the bis-methanesulfonyl product described above in (B). The reaction is carried out in a protic organic solvent (e.g., methanol) at about room temperature for about 30 minutes to 3 hours, preferably 1 hour. The resulting mono-methanesulfonyl product, a compound of formula I, is isolated and purified by conventional methods.

D. For example, compounds of formula I wherein R⁴And R⁵Is hydrogen and may be prepared by reaction with phenyl isocyanate. The reaction is carried out in an inert organic solvent, preferably toluene, at reflux temperature for about 10 to 60 hours, preferably 48 hours. The resulting urea product, the compound of formula I, is isolated and purified by conventional means.

E. For example, compounds of formula I wherein R⁴Is 2- (dimethylamino) imino, R⁵Is hydrogen, can be prepared by reaction with a guanidine derivative, such as 1, 1-dimethylguanidine, and following the procedure described in scheme I.

If desired, isolation and purification of the compounds and intermediates described herein can be carried out by any suitable method of isolation or purification, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography or a combination of these procedures. Specific descriptions of suitable separation methods can be found in the preparations and examples. However, other equivalent separation methods may of course be used as well.

The compounds of formula I are basic and can therefore be converted into the corresponding acid addition salts.

The conversion reaction is accomplished by treatment with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and an organic acid such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Typically, the free base is dissolved in an inert organic solvent, such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, and the like, and the acid is added in a similar solvent. The temperature is maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or can be isolated from solution with a small amount of a polar solvent.

The acid addition salts of the compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric amount of a suitable base such as sodium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.

The compounds of formula I can be prepared as follows:

1. reacting a compound of the formulaWherein R is¹And R²Is as defined above and R⁴And R⁵Is hydrogen or lower alkyl; with a boronic acid derivative of formula (5), namely R³B(OH)₂Reaction of wherein R³As defined in formula I.

2. Additionally, a method of preparing a compound of formula I comprises:

reacting a compound of the formulaWherein R is¹And R²As defined in formula I, and R⁴And R⁵Is hydrogen or lower alkyl; with boron complexes of formula (7), i.e. R³B(OCH₃)₂Reaction of wherein R³As defined in formula I.

3. Additionally, a method of preparing a compound of formula I comprises:

reacting a compound of the formulaWherein R is¹And R²As defined in formula I, and R⁴And R⁵Is hydrogen or lower alkyl; with a compound of the formula (8)Wherein Y and n are as defined above.

4. Additionally, a method of preparing a compound of formula I comprises:

reacting a compound of the formulaWherein R is¹，R²And R³As defined in formula I; and formula NH₂C(:NH)NR⁴R⁵(formula (2)) wherein R is⁴And R⁵As defined in formula I.

5. Additionally, a method of preparing a compound of formula I comprises:

reacting a compound of the formulaWherein R is²And R³As defined in formula I; and formula NH₂C(:NH)NR⁴R⁵(formula (2)) wherein R is⁴And R⁵As defined in formula I.

6. Additionally, a method of preparing a compound of formula I comprises:

reacting a compound of the formulaWhereinR³As defined in formula I; and formula NH₂C(:NH)NR⁴R⁵(formula (2)) wherein R is³As defined in formula I.

7. Additionally, a method of preparing a compound of formula I comprises:

reacting a compound of formula I, wherein R¹Is chlorine:wherein R is²And R³As defined in formula I, R⁴And R⁵Is hydrogen or lower alkyl; with A) a reducing agent to give compounds of the formula I, in which R¹Is hydrogen; or B) HNR of the formula⁶R⁷Secondary amine of (wherein R is⁶And R⁷As defined in formula I) to give a compound of formula I, wherein R¹is-NR⁶R⁷。

8. Additionally, a method of preparing a compound of formula I comprises:

reacting a compound of the formula:wherein R is¹，R²And R³As defined in formula I; and formula HNR⁴R⁵Secondary amine of (wherein R is⁴And R⁵As defined in formula I) to give a compound of formula I, wherein R⁴And R⁵As defined in formula I.

9. In addition, compounds of formula I (wherein R is¹Is hydroxyalkyl or alkenyl) includes: reacting an N-oxide of a compound of formula I (wherein R is¹Is alkyl) with a carboxylic acid anhydride to give a compound of formula I.

10. Additionally, preparing the compound of formula I includes: reacting a compound of formula I with an oxidizing agent to obtain an N-oxide of the compound of formula I, or: reacting a compound of formula I with a strong acid to obtain a pharmaceutically acceptable salt of the compound of formula I.

The compounds of the invention are selective 5-HT_2BA receptor antagonist. For 5-HT_2BThe affinity of the receptor is demonstrated by using an in vitro binding assay which utilizes the used³H]-5HT radiolabeled cloned 5-HT_2BThe acceptor, as described in example 17 below. For 5-HT_2BThe selectivity of the receptor is determined by the presence of 5-HT_2AAnd 5-HT_2CCounter screening on the receptor (counter screening) was shown (see example 18 below for details). Antagonist performance was measured in rat fundic longitudinal muscle (see example 19 below for details).

Thus, the compounds of the present invention are useful in the treatment of those mediated by 5-HT_2BThe blocking of receptors is improved. Due to the fact that in 5-HT_2CAnd 5-HT_2BThe pharmacological similarity in ligand interactions at the receptors has been suggested as 5-HT_2CTherapeutic targets for receptor antagonists are also 5-HT_2BTarget bodies for receptor antagonists. In particular, several clinical studies have shown 5-HT_2BThe therapeutic effect of receptor antagonists in the prevention of migraine, since the phenomenon of 5-HT entry into the plasma is believed to be a contributing factor to migraine. In addition, non-selective 5-HT_2BReceptor agonists trigger migraine attacks in susceptible individuals, not selective 5-HT_2BReceptor antagonists are effective in preventing migraine attack [ Kalkman, Life Sciences, 54, 641-644(1994)]。

Clinical and experimental evidence support 5-HT_2CTherapeutic use of receptor antagonists in the treatment of anxiety disorders. 5-HT_2CReceptor agonist 1- (3-chlorophenyl) -piperazine (mCPP), when administered to human volunteers, will cause anxiety [ Charney et al (1987), psychopharmacogenogy, 92, 14-24]. MCPP also produces anxiogenic effects in rats in an increased X-maze model of Social Interaction (SI) and anxiety, these effects being mediated by non-selective 5-HT_2C/2AReceptor antagonists that block, but are not selectively 5-HT_2ABlockade by receptor antagonists [ Kennett et al (1989), Eur.J.Pharmacol., 164, 445-Asca 454 and Kennett (1993), supra]. Also, non-selective 5-HT_2C/2AReceptor antagonists themselves produce anxiolytic effects in SI and Geller Seifter conflict experimentsAccordingly, 5-HT is selected_2AReceptor antagonists do not have this effect. 5-HT_2CThis therapeutic target of a receptor antagonist is likewise 5-HT_2BTarget bodies for receptor antagonists.

Furthermore, when administered to panic sufferers or obsessive-compulsive disorder sufferers, mCPP will exacerbate the degree of panic and/or anxiety [ Charney et al (1987), supra, and Zohar et al (1987), Arch.Gen.Psychiat., 44, 946-]. Thus, current evidence supports selective 5-HT_2CUse of a receptor antagonist for the treatment of generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. 5-HT_2CThese therapeutic targets for receptor antagonists are likewise 5-HT_2BTarget bodies for receptor antagonists.

Anxiolytic activity can be determined experimentally by a well-established Crawley and Goodwin two-compartment exploratory model of the prior art (see, e.g., Kilfoil et al (1989), Neuropharmacology, 28(9), 901-905.) briefly, this method measures the extent to which a compound affects natural anxiety in mice in a new, intense region (see, for details, example 21, below).

Clinical and experimental evidence support selective 5-HT_2CTherapeutic effects of receptor antagonists in the treatment of chemical dependence. 5-HT_2CReceptor agonist mCPP induces craving for alcohol during alcohol withdrawal [ Benkelfat et al (1991), arch.gen.Psychiat.48, 383]. In contrast, non-selective 5-HT_2C/2AThe receptor antagonist ritanserin will reduce alcohol preference in rats (Meert et al, (1991), Drug Development Res.24, 235-]And optionally 5-HT_2AThe receptor antagonist ketanserin did not affect alcohol preference [ Kennett et al (1992), j.psychopharmacol., abstr.a26 ]]. Ritanserin also simultaneously reduces preference for cocaine and fentanyl in rat craving models [ Meert et al (1991), Drug Development Res.25, 39-53 and Meert et al (1991), Drug Development Res.25, 55-66]. Clinical studies have shown that ritanserin reduces chronic alcohol absorption [ Monti et al (1991), Lancet.337, 60]And can be used to de-addiction patients from other drugs of abuse [ Sadzot et al (1989), psychopharmacography, 98, 495-499]. Thus, current evidence supports selective 5-HT_2CUse of a receptor antagonist for the treatment of alcoholism and addiction to other drugs of abuse. 5-HT_2CThis therapeutic target of the receptor antagonist is likewise 5-HT_2BTarget bodies for receptor antagonists.

The relief effect of a compound during withdrawal from drugs of abuse can be determined experimentally in mice, i.e. the withdrawal anxiety test, an accepted assay [ Carboni et al (1988), Eur.J. Pharmacol, 151, 159-160 ]. This method utilizes the exploratory model described above to measure the extent to which the compound improves withdrawal symptoms that occur after long-term treatment with an addictive substance followed by a sudden cessation of treatment (see example 22 below for details).

Clinical evidence supports selective 5-HT_2CTherapeutic efficacy of receptor antagonists in the treatment of depression. For example, non-selective 5-HT_2C/2AReceptor antagonists have shown clinical efficacy in the treatment of depression [ Murphy (1978), brit.j.pharmacol., 5, 81S-85S; klieser et al, (1988), Pharmacopeshiat, 21, 391-; and Camara (1991), biol. psychiat., 29, 201A]. Furthermore, experimental results indicate that the mechanism by which conventional antidepressant drugs exert their therapeutic effects is via adaptive changes in the serotonin system (serotonergic system) [ Anderson (1983), Life Sci, 32, 1791-]. For example, chronic treatment with monoamine oxidase inhibitors will reduce mCPP-induced/5-HT in various paradigms_2CA functional response mediated. Similar effects are shown by selective 5-HT reuptake inhibitors. These findings indicate that treatment to increase extraneural 5-HT levels will result in 5-HT_2CDesensitization of receptor function (desensize), which in turn causes or contributes to antidepressant activity ([ Kennett (1993), supra]。5-HT_2CThis therapeutic target of the receptor antagonist is likewise 5-HT_2BTarget bodies for receptor antagonists.

Clinical evidence supports 5-HT_2CReceptor antagonists inTherapeutic effects in the treatment of sleep disorders. When administered to human volunteers, 5-HT_2CReceptor agonist mCPP reduces total sleep time, sleep efficiency, Slow Wave Sleep (SWS) and rapid eye movement sleep [ Lawlor et al (1991), biol. psychiat, 29, 281-. In contrast, non-selective 5-HT_2C/2AThe receptor antagonist ritanserin increases SWS, shortens the latency to sleep onset and improves the quality of conscious sleep in healthy volunteers [ Idzikowski et al (1986), Brain res, 378, 164-; idzikowski et al (1987), Psychopharmacology, 93, 416-420; declerck et al (1987), curr. therap. res., 41, 427-; and Adam et al (1989), Psychopharmacology, 99, 219-221-]. Thus, 5-HT is given_2CReceptor stimulation and 5-HT_2COpposite effects of receptor antagonism, selective 5-HT_2CReceptor antagonists are of therapeutic value, inter alia, in the treatment of sleep disorders [ Kennett (1993), supra]。5-HT_2CThis therapeutic target of the receptor antagonist is likewise 5-HT_2BTarget bodies for receptor antagonists.

Clinical evidence supports 5-HT_2CTherapeutic effects of receptor antagonists in feeding disorders. Non-specific 5-HT_2C/2AReceptor antagonists have been shown to be enhanced in both appetite and body weight. Thus, there is some clinical evidence to support selective 5-HT_2CUse of a receptor antagonist in the treatment of anorexia nervosa. 5-HT_2CThis therapeutic target of the receptor antagonist is likewise 5-HT_2BTarget bodies for receptor antagonists.

Experimental evidence supports 5-HT_2CTherapeutic effect of receptor antagonists in the treatment of priapism. MCPP induces penile erection in rats, the effect of which can be non-selective 5-HT_2C/2AReceptor antagonists that block but are not selectively 5-HT_2AReceptor antagonist blockade [ Hoyer (1989), see: fozard J. (eds.) peripheral action of 5-HT, Oxford university Press, Oxford, 72-99]。5-HT_2CThis therapeutic target of the receptor antagonist is likewise 5-HT_2BTarget bodies for receptor antagonists.

Where the compounds of the present invention are used to treat the above conditions, administration of the active compounds and salts thereof described herein can be accomplished by any accepted mode of administration, including oral, parenteral and other systemic routes of administration. Any pharmaceutically acceptable mode of administration can be used, including solid, semi-solid or liquid dosage forms, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions and the like, preferably in unit dosage form suitable for single administration of the correct dosage, or in sustained or controlled release dosage form for prolonged administration of the compound at the intended rate. The compositions will typically include conventional pharmaceutical carriers or excipients and the active compound of formula I or a pharmaceutically acceptable salt thereof, and may additionally include other agents, pharmaceutical agents, carriers, adjuvants and the like.

The amount of active compound administered will, of course, depend on the subject being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician. However, effective dosages for oral, parenteral and other systemic routes of administration are in the range of 0.01-20 mg/kg/day, preferably 0.1-10 mg/kg/day. For a person with an average body weight of 70kg, this will be 0.7-1400 mg/day, or preferably 7-700 mg/day.

Without requiring unique practical experience but relying on personal expertise and the disclosure of this application, one skilled in the art of treating such diseases will be able to determine a therapeutically effective amount of a compound of formula I for a particular disease.

For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose derivatives, croscarmellose sodium, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like. The active compounds defined above may be formulated as suppositories by using, for example, polyalkylene glycols, acetylated triglycerides and the like as carriers. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving or dispersing, etc., the active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form a solution or suspension. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack publishing Co., Iston, Pa., 15 th edition, 1975. The composition or formulation to be administered will in any case contain an amount of the active compound sufficient to effectively alleviate the symptoms of the subject being treated.

Dosage forms or compositions may be prepared containing 0.25-95% of the active ingredient (a compound of formula I or a salt thereof) with the balance being non-toxic carriers.

For oral administration, pharmaceutically acceptable non-toxic compositions can be prepared by incorporating any of the commonly used excipients such as pharmaceutical grades of mannitol, lactose, cellulose derivatives, croscarmellose sodium, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate and the like. The composition is in the form of a solution, suspension, tablet, pill, capsule, powder, sustained release formulation, and the like. Such compositions may contain from 1% to 95% active ingredient, more preferably from 2 to 50%, most preferably from 5to 8%.

Parenteral administration is generally characterized by injection, subcutaneous, intramuscular, or intravenous. Injectable formulations can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. Also, if desired, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate and the like.

The parenteral routes of administration designed in recent years use an implantation method of delayed or sustained release systems so as to maintain a constant amount of dosage. See U.S. Pat. No.3,710,795.

The percentage of active compound contained in the parenteral composition depends primarily on its particular properties, as well as the activity of the compound and the needs of the subject. However, a percentage of active ingredient of 0.1-10% in solution would be useful and may be higher if the composition is subsequently diluted to a solids of the above percentage. Preferably, the composition will comprise 0.2-2% active ingredient in solution.

In using the compounds of the present invention to treat ocular conditions associated with abnormally high intraocular pressure, administration thereof may be effected by any pharmaceutically acceptable form of administration which is capable of providing sufficient local concentration to achieve the desired response. These include direct application to the eye by means of drops and controlled release inserts or implants, as well as systemic application as previously described.

Drops and solutions for direct application to the eye are typically sterile aqueous solutions containing 0.1 to 10%, most preferably 0.5to 1% of the active ingredient together with suitable buffers, stabilisers and preservatives. The total concentration of solute should be such that, if possible, the prepared solution is isotonic with tear fluid (although this is not absolutely necessary) and has an equivalent pH range of 6-8. Typical preservatives are phenylmercuric acetate, thimerosal, chlorobutanol, and benzalkonium chloride. Typical buffer systems and salts are based on, for example, citrate, borate or phosphate; suitable stabilizers include glycerol and polyethoxy ethers. Aqueous solutions are simply and ultimately prepared by dissolving the solute in an appropriate amount of water, adjusting the pH to about 6.8-8.0, making a final volume adjustment with additional water, and sterilizing the formulation using methods known to those skilled in the art.

The dosage level of the composition prepared will of course depend on the concentration of the drops, the condition of the subject being treated and the respective degree of response to the treatment. However, typical ophthalmic compositions can use 0.5% active ingredient solutions at a rate of about 2-10 drops/day/eye.

The compositions of the present invention may also be formulated for administration in any convenient manner similar to other topical compositions employed by mammals. These compositions can be presented in any of a number of conventional forms with the aid of a pharmaceutical carrier or vehicle. For such topical administration, pharmaceutically acceptable non-toxic formulations can take the form of semi-solids, liquids, or liquids, such as gels, emulsions, lotions, solutions, suspensions, ointments, powders, and the like. As an example, the active ingredient may be formulated into a gel by using ethanol, propylene glycol, propylene carbonate, polyethylene glycol, diisopropyl adipate, glycerol, water, and the like, with suitable gelling agents such as Carbomers, Klucels, and the like. If desired, the formulations may also contain minor amounts of non-toxic auxiliary substances, such as preservatives, antioxidants, pH buffers, surfactants, and the like. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack publishing Co., Iston, Pa., 16 th edition, 1980.

Preferably, the pharmaceutical composition is administered in a single unit dosage form suitable for continuous treatment or optionally (ad libitum) when remission is deliberately required. Representative pharmaceutical compositions containing compounds of formula I are described in examples 4-10.

The following preparations and examples are intended to illustrate the invention but not to limit the scope thereof.

Preparation 1

Preparation of the Compound of formula (3)

A. (3) Wherein R is ¹ Is tert-butyl and R ² Is hydrogen

Methyl 4, 4-dimethyl-3-oxopentanoate (15.82g) and guanidine carbonate (20.0g) were mixed in 80ml of ethanol, and the solution was refluxed for 16 hours. The reaction mixture was concentrated to 50ml by removing the solvent under reduced pressure, and 20ml of water was added. The remaining mixture was acidified with acetic acid to pH 5to obtain a white precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (12.6g), m.p.285-288 ℃ (dec.).

B. (3) Wherein R is ² Is hydrogen, changing R ¹

Similarly, methyl 4, 4-dimethyl-3-oxopentanoate was replaced with:

3-oxopentanoic acid ethyl ester;

4-methyl-3-oxopentanoic acid ethyl ester;

3-cyclobutyl-3-oxopropanoic acid ethyl ester;

3-cyclopentyl-3-oxopropanoic acid ethyl ester;

4-methyl-3-oxohexanoic acid ethyl ester;

ethyl 2-methyl-3-oxobutyrate;

3-oxo-4-phenylpentanoic acid ethyl ester;

3-cyclopropyl-3-oxopropanoic acid ethyl ester;

ethyl 2-fluoro-3-oxobutyrate;

2-aminocarbonylacetic acid ethyl ester;

4, 4, 4-trifluoro-3-oxobutanoic acid ethyl ester; and

3-phenyl-3-oxopropanoic acid ethyl ester; (in some syntheses, methyl esters are used instead of ethyl esters, both being equally effective): and following the procedure described above for preparation 1A, the following compound of formula (3) was prepared:

2-amino-6-ethyl-4-hydroxypyrimidine;

2-amino-4-hydroxy-6-isopropylpyrimidine, m.p.238-241 ℃;

2-amino-6-cyclobutyl-4-hydroxypyrimidine, m.p.253-254 ℃;

2-amino-6-cyclopentyl-4-hydroxypyrimidine, m.p.237-241 ℃ (dec.);

2-amino-6- (but-2-yl) -4-hydroxypyrimidine, m.p.195-198 ℃;

2-amino-5, 6-dimethyl-4-hydroxypyrimidine;

2-amino-6-benzyl-4-hydroxypyrimidine;

2-amino-6-cyclopropyl-4-hydroxypyrimidine;

2-amino-5-fluoro-4-hydroxy-6-methylpyrimidine;

2, 6-diamino-4-hydroxypyrimidine;

2-amino-4-hydroxy-6-trifluoromethylpyrimidine; and

2-amino-4-hydroxy-6-phenylpyrimidine.

C. Similarly, other compounds of formula (3) are prepared following the procedure of preparation 1A above, optionally replacing methyl 4, 4-dimethyl-3-oxopentanoate with other compounds of formula (1) and optionally replacing guanidine carbonate with other compounds of formula (2).

Preparation 2

Preparation of the Compound of formula (4)

A. (4) Wherein R is ¹ Is tert-butyl and R ² Is hydrogen

2-amino-4-hydroxy-6-tert-butylpyrimidine (8.35g) was dissolved in 50ml of phosphorus oxychloride, and the solution was refluxed for 2 hours. Excess phosphorus oxychloride was removed in vacuo and the residue was dissolved in 100ml ethanol. The solution was adjusted to pH 8 with ice-cold concentrated ammonium hydroxide and the solvent was removed under reduced pressure. The residue was filtered to give a white solid which was recrystallized from ethanol-water to give 2-amino-4-chloro-6-tert-butylpyrimidine (3.66g), m.p.87.7-88.9 ℃.

B. Similarly, the following compound of formula (4) was prepared following the procedure for preparation of 2A above, substituting the other compound of formula (3) for 2-amino-4-hydroxy-6-tert-butylpyrimidine:

2-amino-4-chloro-6-ethylpyrimidine;

2-amino-4-chloro-6-isopropylpyrimidine, m.p.94-97 ℃;

2-amino-4-chloro-6-cyclopropylmethylpyrimidine, m.p.116.5-120.0 ℃;

2-amino-4-chloro-6-cyclobutylpyrimidine, m.p.98-99 ℃;

2-amino-6- (but-2-yl) -4-chloropyrimidine, m.p.63-65 ℃;

2-amino-4-chloro-6-cyclopentylpyrimidine, m.p.101.5-103 ℃.

2-amino-4-chloro-5, 6-dimethylpyrimidine;

2-amino-6-benzyl-4-chloropyrimidine;

2-amino-4-chloro-6-cyclopropylpyrimidine;

2-amino-4-chloro-5-fluoro-6-methylpyrimidine;

2, 6-diamino-4-chloropyrimidine;

2-amino-4-chloro-6-trifluoromethylpyrimidine; and

2-amino-4-chloro-6-phenylpyrimidine.

C. Similarly, the other compound of formula (4) was prepared following the procedure for preparation of 2A above, substituting 2-amino-4-hydroxy-6-tert-butylpyrimidine with the other compound of formula (3).

Preparation 3

Preparation of the Compound of formula (9)

A. (9) Wherein R is ³ Is 4, 7-difluoronaphthalen-1-yl and R ² Is hydrogen

1, 6-Difluoronaphthalene (0.164g, 1.0mmol) was dissolved in 1, 2-dichloroethane (5ml) and cooled to 0 ℃. Aluminum trichloride (0.264g, 2.0mmol) was added as a solid to the solution. Acetic anhydride (0.1ml, 1.0mmol) was slowly added to the solution over 20 minutes while maintaining the temperature at 0 ℃. The reaction was poured onto ice-cold 10% aqueous hydrochloric acid and extracted with dichloromethane (2X 10 ml). The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to give 1- (4, 7-difluoronaphthalen-1-yl) ethanone (ethanone) (0.165g, 80%) as an oil.

B. Similarly, with the formula R³In place of 1, 6-difluoronaphthalene, and following the procedure of preparation 3 above, other compounds of formula (9) were prepared.

Preparation 4

Preparation of Compound of formula (15)

A. (15) Wherein R is ¹ Is methyl and R ² Is hydrogen

S-methylisothiourea (22.26g, 160mmol) was added to a solution of sodium carbonate (16.9g, 160nmol) in water (50ml) and stirred at room temperature until S-methylisothiourea was completely dissolved. To the mixture was added one portion of ethyl acetoacetate (10.41g, 80 mmol). After stirring at room temperature for 60 hours, the reaction was neutralized with acetic acid and precipitated to give a white solid. The solid was collected, washed with water and dried in vacuo to give 4-hydroxy-6-methyl-2- (methylsulfanyl) pyrimidine (9.38g, 75%), m.p.218-221 ℃.

B. (15) Wherein R is ² Is hydrogen, changing R ¹

Similarly, the following compound of formula (15) was prepared using ethyl 4-methyl-3-oxopentanoate or methyl 4, 4-dimethyl-3-oxopentanoate instead of ethyl acetoacetate, and following the procedure described above for preparation of 4A:

4-hydroxy-6-isopropyl-2- (methylsulfanyl) pyrimidine; and

6-tert-butyl-4-hydroxy-2- (methylthio) pyrimidine.

C. (15) Wherein R is ² Is hydrogen, changing R ¹

Similarly, other compounds of formula (15) were prepared following the procedure of preparation 4A above, substituting the other compounds of formula (1) for ethyl acetoacetate.

Preparation 5

Preparation of the Compound of formula (16)

A. (16) preparation of wherein R ¹ Is methyl and R ² Is hydrogen

4-hydroxy-6-methyl-2- (methylthio) pyrimidine (9.20g, 59mmol) and phosphorus oxychloride (60ml) were combined and refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The resulting aqueous mixture was extracted with ethyl acetate; the organic layer was washed with saturated sodium bicarbonate solution, then with water, dried over magnesium sulfate, and dried under vacuum to give 4-chloro-6-methyl-2- (methylthio) pyrimidine (8.27g, 80%) m.p.37-38 ℃.

B. Similarly, 4-hydroxy-6-methyl-2- (methylthio) -pyrimidine was substituted with the other compound of formula (15), and the following compound of formula (16) was prepared following the procedure of 5A above:

4-chloro-6-isopropyl-2- (methylthio) pyrimidine, b.p.127-128 ℃ @ 0.5 torr; and

6-tert-butyl-4-chloro-2- (methylthio) pyrimidine, m.p.46-48 ℃.

C. Similarly, the other compound of formula (15) was used in place of 4-hydroxy-6-methyl-2 (methylthio) pyrimidine, and the other compound of formula (16) was prepared according to the procedure of 5A above.

Preparation 6

Preparation of the Compound of formula (17)

A. (17) Wherein R is ¹ Is isopropyl, R ² Is hydrogen and R ³ Iso-4-fluoro-1-naphthyl

A stirred solution of 1-bromo-4-fluoronaphthalene (4.95g) in 100ml of tetrahydrofuran was cooled to-80 ℃ and stirred, and 2.5M n-butyllithium (10ml) was added dropwise. The mixture was stirred for 30 minutes, then trimethoxyborane (3ml) was added and the mixture was stirred for 1 hour, then warmed to room temperature and the solvent was removed under reduced pressure. To the residue were added benzene (100ml), 4-chloro-6-isopropyl-2- (methylthio) pyrimidine (4.04g), tetrakis (triphenylphosphine) palladium (O) (500mg), and sodium carbonate (20ml, 2M), and heated under reflux (about 80 ℃ C. to 90 ℃ C.) for 14 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with 2% ethyl acetate/hexanes to give impure 4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2- (methylsulfanyl) pyrimidine (4.87g), which was used directly in the next reaction without further purification.

B. Similarly, 4-chloro-6-isopropyl-2- (methylthio) pyrimidine was substituted with the other compound of formula (16), and the following compound of formula (17) was prepared following the procedure of 5A above:

4- (4-fluoronaphthalen-1-yl) -6-methyl-2- (methylthio) pyrimidine, m.p.140-142 ℃; and

4- (4-fluoronaphthalen-1-yl) -6-methoxy-2- (methylsulfanyl) -pyrimidine,¹HNMR 8.19(2H，m)，7.65(3H，m)，7.25(1H，dd，J＝8，10Hz)，6.45(1H，s)，3.98(3H，s)，2.55(3H，s)。

C. similarly, 4-chloro-6-isopropyl-2- (methylthio) -pyrimidine was substituted with the other compound of formula (16), and the other compound of formula (17) was prepared according to the procedure of 6A above.

D. Another preparation of the formula (17), in which R ¹ Is aralkyl, from which R is ¹ Is an alkyl group of the formula (17) The compound of (a) is started,

to a solution of lithium diisopropylamide (1.2eq) in tetrahydrofuran (10ml) was added dropwise a solution of 4- (4-fluoronaphthalen-2-yl) -6-methyl-2- (methylthio) -pyrimidine (0.500g, 1.76mmol) in tetrahydrofuran (2ml) and cooled to-70 ℃. After stirring for 30 minutes, 1 part of benzyl bromide (0.251ml, 2.11mmol) was added to the solution. The solution was warmed to room temperature and diluted with ethyl acetate (50ml) and poured into water (50 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo, and the resulting oil was purified by column chromatography to give 4- (4-fluoronaphthalen-1-yl) -2-methylsulfanyl-6-phenethylpyrimidine (0.342g, 52%).

E. Similarly, with formula (16) (wherein R¹Is alkyl) substituted 4- (4-fluoronaphthalen-2-yl) -6-methyl 2- (methylthio) pyrimidine, and following the procedure of 6D above, the following compound of formula (17) was prepared:

4- (4-fluoronaphthalen-1-yl) -6- (2-hydroxyphenylethyl) -2- (methylsulfanyl) pyrimidine; and

4- (4-fluoronaphthalen-1-yl) -6- (3-hydroxypropyl) -2- (methylsulfanyl) pyrimidine.

F. Similarly, 4- (4-fluoronaphthalen-2-yl) -6-methyl-2- (methylthio) pyrimidine was substituted with other compound of formula (16), and the other compound of formula (17) was prepared according to the procedure of 6C above, wherein R is¹Is a lower alkyl group.

Preparation 7

Preparation of Compound of formula (18)

A. (18) Wherein R is ¹ Is isopropyl, R ² Is hydrogen, R ³ Is 4-fluoro-1-naphthyl

4- (4-fluoronaphthalen-1-yl) -2-methylsulfanyl-6-phenethyl-pyrimidine (0.342g, 0.914mmol) was dissolved in dichloromethane at room temperature. Meta-chloroperoxybenzoic acid (55-60%, 0.554g, 1.83mmol) was added in small portions. After 16 hours, the reaction mixture was washed with saturated aqueous sodium bisulfite solution. The organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, and concentrated in vacuo to give 4- (4-fluoronaphthalen-1-yl) -2-methylsulfonyl-6-phenethylpyrimidine as an oil (0.402g, 97%),¹HNMR 8.07(1H，m)，7.85(1H，m)，7.47(2H，m)，7.32(1H，s)，7.13(7H，m)，3.29(2H，m)，3.07(2H，m)。

B. similarly, 4- (4-fluoronaphthalen-1-yl) -2-methylsulfanyl-6-phenethylpyrimidine was substituted with the other compound of formula (17), and the following compound of formula (18) was prepared following the procedure of 7A above:

4- (4-fluoronaphthalen-1-yl) -6- (2-hydroxyphenylethyl) -2-methylsulfonyl-pyrimidine, m.p.88.1-90.0 ℃;

4- (4-fluoronaphthalen-1-yl) -6- (3-hydroxypropyl) -2-methylsulfonyl-pyrimidine,¹HNMR8.21(2H，m)，7.69(1H，dd，J＝5.3，8.2Hz)，7.68(1H，s)，7.61(2H，m)，7.24(1H，dd，J＝8，10Hz)，3.76(2H，t，J＝7.5Hz)，3.40(3H，s)，3.09(2H，t，J＝7.5Hz)，2.11(2H，m)；

4- (4-fluoronaphthalen-1-yl) -6-methoxy-2-methylsulfonyl-pyrimidine,¹HNMR8.20(2H, m), 7.64(3H, m), 7.25(1H, dd, J ═ 8, 10Hz), 7.15(1H, s), 4.20(3H, s), 3.39(3H, s); and

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2-methylsulfonyl-pyrimidine, m.p.96.1-97.1 ℃.

C. Similarly, 4- (4-fluoronaphthalen-1-yl) -2-methylsulfanyl-6-phenethylpyrimidine was substituted with the other compound of formula (17), and the other compound of formula (18) was prepared according to the procedure of 7A above.

Example 1

Preparation of Compounds of formula I

A. Preparation of I wherein R ¹ And R ² Is methyl, R ³ Is naphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

A stirred heterogeneous solution of 1-naphthylboronic acid (0.382g), 2-amino-4-chloro-5, 6-dimethylpyrimidine (0.350g), tetrakis (triphenylphosphine) palladium (0) (0.153g), ethanol (8ml), water (4ml), 1, 2-dimethoxyethane (8ml) and sodium carbonate (0.85g) was heated to reflux (ca. 80 ℃ to 90 ℃) for 14 hours. The solution was then cooled to room temperature, filtered and extracted with ethyl acetate. The solvent was removed under reduced pressure and the resulting yellow solid was recrystallized to give 2-amino-5, 6-dimethyl-4- (naphthalen-1-yl) -pyrimidine (0.213g), m.p.213.5-215.1 ℃.

B. Similarly, 2-amino-4-chloro-5, 6-dimethylpyrimidine optionally substituted with other compounds of formula (4), and 1-naphthylboronic acid optionally substituted with other compounds of formula (5), and following the procedure of 1A above, the following compounds of formula I were prepared.

2-amino-6-cyclopentyl-4- (naphthalen-1-yl) -pyrimidine, m.p.146.8-147.4 ℃;

2-amino-6- (but-2-yl) -4- (naphthalen-1-yl) -pyrimidine, m.p.109.6-110.8 ℃;

2-amino-6- (2-methylpropyl) -4- (naphthalen-1-yl) -pyrimidine hydrobromide, m.p.147.0-151.5 ℃;

2-amino-6- (tert-butyl) -4- (naphthalen-1-yl) -pyrimidine, m.p.161.0-161.3 ℃;

2-amino-6-benzyl-4- (naphthalen-1-yl) -pyrimidine, m.p.147.9-148.2 ℃;

2-amino-6-cyclobutyl-4- (naphthalen-1-yl) -pyrimidine, m.p.147-148 ℃;

2-amino-6-cyclopropyl-4- (naphthalen-1-yl) -pyrimidine, m.p.182.8-184.0 ℃;

2-amino-4- (naphthalen-1-yl) -6-n-propylpyrimidine, m.p.119.5-120.5 ℃;

2-amino-6-isopropyl-4- (naphthalen-1-yl) -pyrimidine, m.p.124-126 ℃;

2-amino-5-fluoro-6-methyl-4- (naphthalen-1-yl) -pyrimidine, m.p.155-157 ℃;

2-amino-6-ethyl-4- (naphthalen-1-yl) -pyrimidine hydrochloride, m.p.157-160 ℃;

2, 6-diamino-4- (naphthalen-1-yl) -pyrimidine hydrochloride, m.p. > 290 ℃;

2-amino-6-trifluoromethyl-4- (naphthalen-1-yl) -pyrimidine, m.p.152-154 ℃;

2-amino-4- (naphthalen-1-yl) -6-phenylpyrimidine hydrochloride, m.p.232-236 ℃;

2-amino-4- (3-fluorophenyl) -6-methylpyrimidine, m.p.140.6-141.4 ℃;

2-amino-4- (3-methoxyphenyl) -6-methylpyrimidine, m.p.125.8-129.6 ℃;

2-amino-6-methyl-4- (3-nitrophenyl) -pyrimidine, m.p.198.5-199.6 ℃;

2-amino-4- (3-chloro-4-fluorophenyl) -6-methylpyrimidine, m.p.163.8-165.5 ℃;

2-amino-4- (3, 5-dichlorophenyl) -6-methylpyrimidine, m.p.187.0-187.9 ℃;

2-amino-6-methyl-4- (3-trifluoromethylphenyl) -pyrimidine, m.p.122.0-122.8 ℃;

2-amino-6-methyl-4- (naphthalen-1-yl) -pyrimidine hydrochloride, m.p.226 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (3, 3, 3-trifluoropropyl) -pyrimidine hydrochloride, m.p.152-155 ℃;

2-amino-4- (5-fluoronaphthalen-1-yl) -6-isopropylpyrimidine, m.p.86-88 ℃;

2-amino-4- (2-fluoronaphthalen-1-yl) -6-isopropylpyrimidine hydrochloride, m.p.205-206 ℃;

2-amino-4- (2-fluoronaphthalen-1-yl) -6-methoxypyrimidine hydrochloride, m.p.189-190 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-methoxypyrimidine hydrochloride salt, m.p. > 280 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (2, 2, 2-trifluoroethoxy) -pyrimidine hydrochloride, m.p.206.1-208 ℃;

2-amino-6-tert-butyl-4- (2-fluoronaphthalen-1-yl) -pyrimidine hydrochloride, m.p.230-233 ℃;

2-amino-4- (2-fluoronaphthalen-1-yl) -6-methylpyrimidine, m.p.149-150 ℃;

2-amino-4- (2-methylnaphthalen-1-yl) -6-isopropylpyrimidine hydrochloride, m.p.193-194 ℃;

2-amino-4- (6-methylacenaphthen-5-yl) -6-methyl-pyrimidine, m.p.198-199 ℃;

2-amino-6-cyclopropyl-4- (1H-indol-4-yl) -pyrimidine hydrochloride, m.p. > 280 ℃;

2-amino-6-tert-butyl-4- (1H-indol-4-yl) -pyrimidine, m.p.171-173 ℃;

2-amino-4- (8-hydroxymethylnaphthalen-1-yl) -6-methyl-pyrimidine, m.p.206-208 ℃;

2-amino-4- (1H-indol-7-yl) -6-isopropylpyrimidine, m.p.143-145 ℃;

2-amino-4- (4-amino-5-chloro-2-methoxyphenyl) -6-isopropylpyrimidine hydrochloride, m.p.187.1-190.6 ℃;

2-amino-6-cyclobutyl-4- (1H-indol-4-yl) -pyrimidine, m.p.225-226 ℃;

2-amino-6- (3-methylbutyl) -4- (naphthalen-1-yl) -pyrimidine hydrochloride, m.p.151.5-153 ℃; and

2-amino-4- (4-amino-5-chloro-2-methoxyphenyl) -6-methylpyrimidine, m.p.183-184 ℃.

C. Similarly, 2-amino-4-chloro-5, 6-dimethylpyrimidine optionally substituted with other compounds of formula (4), and 1-naphthylboronic acid optionally substituted with other compounds of formula (5), and the other compounds of formula I were prepared according to the procedure of 1A above.

Example 2

Another process for the preparation of the compounds of formula I

A. Preparation of I wherein R ¹ Is n-propyl, R ² Is hydrogen, R ³ Is 4-fluoronaphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

To a solution of 1-bromo-4-fluoronaphthalene (0.5g) in 10ml of tetrahydrofuran was added dropwise n-butyllithium (1.6M, 1.53ml) at-78 ℃ under a nitrogen atmosphere. The solution was stirred for 5 minutes, then trimethoxyborane (0.33ml) was added dropwise. The solution was warmed to room temperature and the solvent was removed under reduced pressure to give the compound of formula (7), dimethoxy- (4 fluoronaphthalen-1-yl) borane, as a solid.

The solid was dissolved in 5ml of benzene and 2-amino-4-chloro-6-n-propylpyrimidine (0.381g), tetrakis (triphenylphosphine) palladium (0) (0.100g) and 6ml of 2M aqueous sodium carbonate solution were added. The heterogeneous solution was heated to reflux (about 80-90 ℃) for 1 hour, then the solution was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue chromatographed on silica gel, eluting with a hexane/ethyl acetate mixture to give 2-amino-4- (4-fluoronaphthalen-1-yl) -6-n-propylpyrimidine (0.110g), m.p.136.9-137.4 ℃.

B. Similarly, optionally substituting 1-bromo-4-fluoronaphthalene with other compounds of formula (6), and optionally substituting 2-amino-4-chloro-6-n-propylpyrimidine with other compounds of formula (4), and following the procedure of 2A above, the following compounds of formula I are prepared:

2-amino-4- (4-chloronaphthalen-1-yl) -6- (2-methylpropyl) pyrimidine hydrochloride, m.p.198.2-199.8 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (2-methylpropyl) -pyrimidine hydrochloride, m.p.191.3-193.0 ℃;

2-amino-4- (4-chloronaphthalen-1-yl) -6-ethylpyrimidine, m.p.142.7-143.2 ℃;

2-amino-4- (4-methylnaphthalen-1-yl) -6-isopropylpyrimidine, m.p.143.9-145.0 ℃;

2-amino-6- (tert-butyl) -4- (4-fluoronaphthalen-1-yl) -pyrimidine hydrochloride, m.p.193-194 ℃;

2-amino-4- (4, 5-dimethylnaphthalen-1-yl) -6-methylpyrimidine, m.p.194-195 ℃;

2-amino-4- (4, 5-difluoronaphthalen-1-yl) -6-isopropyl-pyrimidine, m.p.123-124 ℃;

2-amino-4- (4-chloronaphthalen-1-yl) -6-isopropylpyrimidine hydrochloride, m.p.183.2-185.6 ℃;

2-amino-6-cyclopropyl-4- (4-fluoronaphthalen-1-yl) -pyrimidine, m.p.150.7-151.5 ℃;

2-amino-6-cyclopropylmethyl-4- (4-fluoronaphthalen-1-yl) -pyrimidine hydrochloride, m.p.128.4-129.4 ℃;

2-amino-6-cyclobutyl-4- (4-fluoronaphthalen-1-yl) -pyrimidine hydrochloride, m.p.168-171 ℃;

2-amino-4- (4, 5-difluoronaphthalen-1-yl) -6-methylpyrimidine, m.p.200 ℃;

2-amino-4- (1H, 3H-benzo [ de ] isochroman-6-yl) -6-methylpyrimidine, m.p.216-218 ℃;

2-amino-4- (acenaphthen-5-yl) -6-isopropylpyrimidine, m.p.167-168 ℃;

2-amino-6-methyl-4- (phenanthren-9-yl) -pyrimidine, m.p.191.3-191.8 ℃;

2-amino-4- (4-methylnaphthalen-1-yl) -6-methylpyrimidine, m.p.175.2-176.6 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine hydrochloride, m.p.156-158 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine maleate, m.p.155-157 ℃;

2-amino-6-ethyl-4- (2-methyl-4-fluoronaphthalen-1-yl) -pyrimidine, m.p.121-122 ℃;

2-amino-4- (acenaphthen-5-yl) -6-methylpyrimidine, m.p.211-213 ℃;

2-amino-4- (isoquinolin-4-yl) -6-methylpyrimidine, m.p.212.0-213.5 ℃;

2-amino-4- (quinolin-8-yl) -6-methylpyrimidine, m.p.194.8-195.5 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -pyrimidine, m.p.203.4-204.1 ℃;

2-amino-6-ethyl-4- (4-fluoronaphthalen-1-yl) -pyrimidine hydrochloride, m.p.198-199 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-methylpyrimidine hydrochloride, m.p.238.3-238.6 ℃; and

2-amino-4- (2-methylnaphthalen-1-yl) -6-methylpyrimidine hydrochloride, m.p.216.6-219.4 ℃.

C. Similarly, 1-bromo-4-fluoronaphthalene is optionally substituted with other compounds of formula (6), and 2-amino-4-chloro-6-n-propylpyrimidine is optionally substituted with other compounds of formula (4), and the other compounds of formula I are prepared following the procedure of 2A above.

Example 3

Another process for the preparation of the compounds of formula I

A. Preparation of I wherein R ¹ Is methyl, R ² Is hydrogen, R ³ Is 6-methoxy-3, 4-dihydro-2H- Quinolin-1-yl, R ⁴ And R ⁵ Is hydrogen

A flask containing 6-methoxy-1, 2, 3, 4-tetrahydro-quinoline (1.33g), 2-amino-4-chloro-6-methylpyrimidine (1.00g), sulfuric acid (0.6g), and 100ml of water was heated in a steam bath for 2 hours. The solution was then cooled to room temperature and treated with ammonium hydroxide until the solution was basic (pH 8-9). The resulting solid, which precipitated out of solution, was collected by filtration and recrystallized from ethanol to give 2-amino-4- (6-methoxy-3, 4, -dihydro-2H-quinolin-1-yl) -6-methylpyrimidine (0.93g), m.p.175.2-175.9 ℃.

B. Similarly, optionally substituting 6-methoxy-1, 2, 3, 4-tetrahydroquinoline with other compounds of formula (8), and optionally substituting 2-amino-4-chloro-6-methylpyrimidine with other compounds of formula (4), and following the procedure of 3A above, the following compounds of formula I are prepared:

2-amino-4- (6-fluoro-3, 4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, m.p.156-157 ℃;

2-amino-6-chloro-4- (3, 4-dihydro-2H-quinolin-1-yl) -pyrimidine hydrochloride, m.p. > 180 ℃ (dec);

2, 6-diamino-4- (3, 4-dihydro-2H-quinolin-1-yl) -pyrimidine dihydrochloride, m.p.196-197 ℃;

6- (3, 4-dihydro-2H-quinolin-1-yl) -9H-purin-2-ylamine, m.p.203.5-204.0 ℃;

2-amino-4- (2-methyl-3, 4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, m.p.141-144 ℃;

2-amino-4- (6-methoxy-3, 4-dihydro-2H-quinolin-1-yl) -6-trifluoromethylpyrimidine, m.p.175.6-177.5 ℃;

2-amino-4- (3, 4-dihydro-2H-quinolin-1-yl) -6-ethylpyrimidine, m.p.141.4-142.1 ℃;

2-amino-6-methyl-4- (6-methyl-3, 4-dihydro-2H-quinolin-1-yl) -pyrimidine, m.p.170.6-171.4 ℃;

2-amino-4- (3, 4-dihydro-2H-quinolin-1-yl) -6-trifluoromethylpyrimidine, m.p.162-164 ℃;

2-amino-4- (6-fluoro-2-methyl-3, 4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, m.p.154.9-155.6 ℃;

4- (3, 4-dihydro-2H-quinolin-1-yl) -2- (methylamino) -pyrimidine;

[2- (3, 4-dihydro-2H-quinolin-1-yl) -pyrimidin-4-yl ] methylamine;

2-amino-6-methyl-4- (2, 3, 4, 5-tetrahydro-benzo [ b ] azepin-1-yl) -pyrimidine, m.p.182.6-184.2 ℃;

2-amino-4- (2, 3-dihydro-benzo [1, 4] oxazin-4-yl) -6-methylpyrimidine, m.p.177.7-178.5 ℃;

2-amino-4- (2-methyl-2, 3-dihydro-indol-1-yl) -6-methylpyrimidine, m.p.182.9-183.4 ℃;

2-amino-4- (3, 4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine hydrochloride, m.p.261.5-262.3 ℃; and

2-amino-4- (3, 4-dihydro-1H-isoquinolin-2-yl) -6-methylpyrimidine, m.p.142.2-143.3 ℃.

C. Preparation of I wherein R ¹ Is chlorine, R ² Is hydrogen, R ³ Is 3.4-dihydro-2H-quinolin-1-yl, R ⁴ and R ⁵ Is hydrogen

1, 2, 3, 4-tetrahydroquinoline (2.66g, 20mmol) and 2-amino-4, 6-dichloropyrimidine (3.30g, 20mmol) were dissolved in 10ml of N, N-Dimethylformamide (DMF), and the whole solution was heated to 70-90 ℃ for 24 hours. DMF is removed in vacuo and the residue is refluxed with ethyl acetate to give 4.0g of a solid; the solid was chromatographed on silica gel eluting with dichloromethane to give 2-amino-6-chloro-4- (3, 4-dihydro-2H-quinolin-1-yl) -pyrimidine (400mg), m.p.167.1-167.5 ℃; 2-amino-6-chloro-4- (3, 4-dihydro-2H-quinolin-1-yl) -pyrimidine hydrochloride, m.p.179 ℃ (dec.).

D. Similarly, other compounds of formula I are prepared by optionally substituting 6-methoxy-1, 2, 3, 4-tetrahydroquinoline with other compounds of formula (8), and optionally substituting 2-amino-4-chloro-6-methylpyrimidine with other compounds of formula (4), and following the procedure of example 3A or 3C above.

Example 4

Another process for the preparation of the compounds of formula I

A. Preparation of I wherein R ¹ Is N, N-diethylamino, R ² Is hydrogen, R ³ Is 3, 4-dihydro- 2H-quinolin-1-yl, R ⁴ And R ⁵ Is hydrogen

Excess diethylamine was added to a solution of 2-amino-6-chloro-4- (1, 2, 3, 4-tetrahydroquinolin-1-yl) -pyrimidine (250mg) in 5ml of ethylene glycol. The mixture was heated at 100 ℃ for 2 days. The crude product was purified by chromatography to give 300mg of solid. The solid was treated with hydrochloric acid-ethanol to give 2-amino-6-diethylamino-4- (3, 4-dihydro-2H-quinolin-1-yl) -pyrimidine hydrochloride, m.p.167-170 ℃.

B. Similarly, optionally with the formula HNR⁶R⁷And optionally with other compounds of formula I (wherein R is¹Is chloro) substituted 2-amino-6-chloro-4- (1, 2, 3, 4-tetrahydroquinolin-1-yl) -pyrimidine, and the other compounds of formula I, wherein R is R¹is-NR⁶R⁷。

Example 5

Another process for the preparation of the compounds of formula I

A. Preparation of I wherein R ¹ Is methyl, R ² Is hydrogen, R ³ Is 1H-indol-4-yl, R ⁴ And R ⁵ Is hydrogen

4-acetylindole (0.101g) was refluxed in 5ml of ethyl acetate. Sodium hydride (0.20g, 60% oil dispersion) was added to the refluxing solution in portions until complete consumption of the starting material was indicated by thin layer chromatography. The reaction mixture was quenched with water and acidified to pH 3. The ethyl acetate layer was dried (magnesium sulfate) and concentrated to give the crude product. The crude material was chromatographed on silica gel eluting with a 4: 1 mixture of hexane/ethyl acetate to give 1- (1H-indol-4-yl) -1, 3-butanedione (0.104g), a compound of formula (11), m.p.104-105 ℃.

B. 1- (1H-indol-4-yl) -1, 3-butanedione (0.096g) was mixed with guanidine carbonate (0.070g), and the mixture was heated to 150 ℃ for 3 hours. Additional guanidine carbonate (0.070g) was added and the mixture was heated for an additional 2 hours. The reaction mixture was heated with ethyl acetate, filtered, and the ethyl acetate layer was concentrated to give a solid (0.090 g). Flash chromatography on silica gel eluting with a 1: 1 hexane/ethyl acetate mixture gave 2-amino-4- (1H-indol-4-yl) -6-methylpyrimidine (0.029g), m.p.242-243.5 ℃.

C. Similarly, the compound 2-amino-5- (6-methyl-naphthalen-1-yl) -pyrimidin-2-ylamino) -pentanoic acid was prepared m.p.264-266 ℃ following the procedure of example 5A and 5B, above substituting 1-acetylnaphthalene for 4-acetylindole and 1-arginine for guanidine carbonate in step B.

D. Similarly, the compound 2-amino-6-methyl-4- (naphthalen-1-yl) -pyrimidine hydrochloride was prepared by substituting 1-acetylnaphthalene for 4-acetylindole in step 5A above and following the procedure of examples 5A and 5B.

E. Similarly, the compound 2-amino-4- (3-chlorophenyl) -6-methylpyrimidine was prepared m.p.131.6-132.3 ℃ following the procedure of example 5B above, substituting 1- (3-chlorophenyl) -1, 3-butanedione for 1- (1H-indol-4-yl) -1, 3-butanedione.

F. Preparation of I wherein R ¹ Is methyl, R ² Is hydrogen, R ³ Is 2, 3-dihydro-1, 4-benzodioxyl Heterocyclohexen-5-yl (benzodioxin-5-yl), R ⁴ And R ⁵ Is hydrogen

1- (2, 3-dihydro-1, 4-benzodioxin-5-yl) -ethanone (1.2g) was dissolved in 20ml of ethyl acetate, and sodium hydride (0.33g, 60% oil dispersion) was added. The reaction mixture was heated to 80 ℃ and held overnight, quenched with water, and neutralized with carbon dioxide to give 1- (2, 3-dihydro-1, 4-benzodioxin-5-yl) butane-1, 3-dione (0.37g) as an oil.

1- (2, 3-dihydro-1, 4-benzodioxin-5-yl) -butane-1, 3-dione (0.37g) was mixed with guanidine carbonate (0.22g), and the mixture was heated to 135 ℃ for 1 hour. The black product was dissolved in dichloromethane, filtered, and concentrated. The residue was chromatographed on silica gel eluting with a 3: 2 mixture of ethyl acetate/hexane to give a solid (0.16g) which was treated with hydrochloric acid-ethanol to give 2-amino-4- (2, 3-dihydro-1, 4-benzodioxin-5-yl) -6-methylpyrimidine hydrochloride (0.125g), m.p.240-242 ℃.

G. Preparation of I wherein R ¹ And R ² Is hydrogen, R ³ Is 1-methylindol-3-yl, R ⁴ And R ⁵ Is hydrogen

3-acetyl-1-methylindole (0.870g) was dissolved in 3ml of anhydrous ethanol. To this solution was added a solution of tert-butoxybis (dimethylamino) methane (Bredereck's reagent) (0.960g) in 3ml ethanol at reflux temperature. The solution was refluxed for 2 days and the solvent was removed at room temperature under vacuum. The residue was triturated with a 7: 3 mixture of hexane/ethyl acetate to give a solid (0.094 g).

This solid was mixed with guanidine carbonate (0.037g) and the mixture was heated to 120 ℃ for 14 hours the reaction mixture was dissolved in hot anhydrous ethanol, filtered and recrystallized to give 2-amino-4- (1-methylindol-3-yl) pyrimidine (0.039g) as a white crystalline solid. The crystalline solid was treated with hydrochloric acid-ethanol and recrystallized from ethanol to give 2-amino-4- (1-methylindol-3-yl) -pyrimidine hydrochloride (0.0098g), m.p.274-276 ℃.

H. Preparation of I wherein R ¹ Is isopropyl, R ² Is hydrogen, R ³ Is 4, 7-difluoronaphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

1- (4, 7-Difluoronaphthalen-1-yl) -ethanone (0.150g, 0.72mmol) was dissolved in dry dioxane (1ml) and cooled to 0 ℃. Sodium hydride (0.145g, 3.6mmol, 60 wt.% dispersion) was added and the reaction mixture was stirred at room temperature for 1 hour. Ethyl isobutyrate (1.0ml, 7.2mmol) was added in one portion and the solution was heated under reflux for 15 minutes. After cooling to room temperature, the reaction mixture was poured into 10% aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was dried over sodium sulfate and purified by column chromatography to give 1- (4, 7-difluoronaphthalen-1-yl) -4-methylpentane-1, 3-dione (0.120g, 72%).

I. 1- (4, 7-Difluoronaphthalen-1-yl) -4-methylpentane-1, 3-dione (0.114g, 0.5mmol) was combined with guanidine carbonate (0.180g, 0.5mmol) and then heated to 150 ℃ for 6 hours. The reaction was cooled to room temperature and purified directly by column chromatography to give 2-amino-4- (4, 7-difluoronaphthalen-1-yl) -6-isopropylpyrimidine (0.052g, 34%) m.p.103-105 ℃.

J. Similarly, 1- (4, 6-difluoronaphthalen-1-yl) -ethanone, 1- (4, 8-difluoronaphthalen-1-yl) -ethanone, 1- (4-methoxynaphthalen-1-yl) -ethanone, or 1- (1-methyl-1H-indol-4-yl) -ethanone is substituted for 1- (4, 7-difluoronaphthalen-1-yl) ethanone in step 5H, and optionally 4, 4-dimethyl-3-oxopentanoate or 4, 4-dimethyl-3-oxopentanoate, or ethyl-2-fluoroisobutyrate for ethyl isobutyrate, substituted guanidinium salt for guanidine in step 5I, and following the procedure of examples 5H and 5I, the following compounds were prepared:

2-amino-4- (4, 6-difluoronaphthalen-1-yl) -6-isopropyl-pyrimidine hydrochloride, m.p.136-138 ℃;

2-amino-4- (4, 8-difluoronaphthalen-1-yl) -6-isopropyl-pyrimidine hydrochloride, m.p.216-219 ℃;

2-amino-4- (4-methoxynaphthalen-1-yl) -6-isopropylpyrimidine hydrochloride, m.p.196-197 ℃;

2-amino-6-tert-butyl-4- (4-methoxynaphthalen-1-yl) -pyrimidine hydrochloride, m.p.219-220.5 ℃;

2-amino-4- (1H-indol-4-yl) -6-isopropylpyrimidine hydrochloride, m.p.211-212 ℃;

2-amino-4- (1-methyl-1H-indol-4-yl) -6-isopropyl-pyrimidine, m.p.128-130 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine, m.p.135.5-137.0 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine hydrochloride, m.p.186.6-187.8 ℃;

4- (4-fluoronaphthalen-1-yl) -6- (1-fluoro-1-methylethyl) -2-methylaminopyrimidine, m.p.149-151 ℃;

2-amino-4- (4-methoxynaphthalen-1-yl) -6-methylpyrimidine hydrochloride, m.p.247.0-249.5 ℃;

2-amino-6-ethyl-4- (4-methoxynaphthalen-1-yl) -pyrimidine hydrochloride, m.p.218.5-218.9 ℃; and

2-amino-4- (4, 6-difluoronaphthalen-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine hydrochloride, m.p.129.6-131.3 ℃.

Example 6

Another process for the preparation of the compounds of formula I

A. Preparation of I wherein R ¹ Is chlorine, R ² Is hydrogen, R ³ Is naphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

2-amino-6-hydroxy-4- (naphthalen-1-yl) -pyrimidine (900mg) was added to a solution of chlorosulfonic acid (0.05ml) in 2.5ml of phosphorus oxychloride and the mixture was stirred at 95 ℃ for 6 hours. The mixture was poured onto ice, neutralized with potassium carbonate, and extracted with ethyl hydrochloride. The crude product (70mg) was purified by silica gel chromatography eluting with dichloromethane and treated with acetic acid-ethanol to give 2-amino-6-chloro-4- (naphthalen-1-yl) -pyrimidine hydrochloride (25mg), m.p.248-250 ℃.

B. Preparation of I wherein R ¹ And R ² Is hydrogen, R ³ Is naphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

2-amino-6-chloro-4- (naphthalen-1-yl) -pyrimidine (170mg) was dissolved in 10ml methanol at 0 ℃. To this solution was added 10% palladium on activated charcoal (70mg) and about 1ml of 20% sodium hydroxide, and the mixture was hydrogenated (1 atm) for 1 hour to give 2-amino-4- (naphthalen-1-yl) -pyrimidine (80mg) as a solid, and the solid was treated with hydrochloric acid-ethanol to give 2-amino-4- (naphthalen-1-yl) -pyrimidine hydrochloride (25mg), m.p.181-184 ℃.

Example 7

Another process for the preparation of the compounds of formula I

A. Preparation of I wherein R ¹ Is methoxy, R ² Is hydrogen, R ³ Is naphthalen-1-yl, R ⁴ And R5 Is that Hydrogen

A solution of 1-acetylnaphthalene (33g) in carbon disulfide (15g) was added over 15 minutes to a 12 ℃ solution containing 195ml of 1M potassium tert-butoxide (in 400ml of diethyl ether). The reaction mixture was warmed to room temperature and cooled to 10-12 ℃ and then methyl iodide (55.0g) was added dropwise over 45 minutes. The reaction mixture was adjusted to room temperature for 16 hours, filtered and concentrated. The residue was recrystallized from 125ml of methanol to give 3, 3- (bis-methylsulfanyl) - (1-naphthalen-1-yl) -prop-2-en-1-one (20.1g), m.p.73-79 ℃.

B. 3, 3- (bis-methylsulfanyl) - (1-naphthalen-1-yl) -prop-2-en-1-one (1.28g) was added to 10ml of a solution of sodium hydride (640mg, 60% oil dispersion) and guanidine carbonate (630g) in methanol. The reaction mixture was refluxed for 6 hours, poured into ethyl acetate and washed with saturated sodium bicarbonate, water and brine. The organic layer was dried over potassium carbonate and concentrated to about 5ml to give a crystalline solid of 2-amino-6-methoxy-4- (naphthalen-1-yl) -pyrimidine, m.p.159.6-159.8 ℃. The crystalline solid was treated with hydrochloric acid-ethanol to give 2-amino-6-methoxy-4- (naphthalen-1-yl) -pyrimidine hydrochloride (300mg), m.p.184-185 ℃.

C. Similarly, the following compound of formula I was prepared by substituting the corresponding alcohol (ethylene glycol, isopropyl alcohol, ethanol) for the methanol solution, and following the procedure of example 7B above:

2-amino-6- (2-hydroxyethoxy) -4- (naphthalen-1-yl) -pyrimidine hydrochloride, m.p.199-201 ℃;

2-amino-6-isopropyloxy-4- (naphthalen-1-yl) -pyrimidine hydrochloride, m.p.165-167 ℃; and

2-amino-6-ethoxy-4- (naphthalen-1-yl) -pyrimidine hydrochloride, m.p.194-195 ℃.

D. Preparation of I wherein R ¹ Is methylthio, R ² Is hydrogen, R ³ Is naphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

3, 3- (bis-methylsulfanyl) - (1-naphthalen-1-yl) -prop-2-en-1-one (1.13g) was added to a mixture of sodium hydride (0.38g, 60% oil dispersion) and guanidine carbonate (0.40g) in 10ml of N, N-Dimethylformamide (DMF) at room temperature. After 1 hour, the mixture was heated to 150 ℃ for 5 hours. Work-up after extraction gave the crude product which was chromatographed on silica gel eluting with a 6: 1 hexane/ethyl acetate mixture to give 2-amino-4-methylsulfanyl-6- (1-naphthyl) -pyrimidine (140 mg). Treatment of the free base with hydrochloric acid-ethanol gave 2-amino-6-methylsulfanyl-4- (naphthalen-1-yl) -pyrimidine hydrochloride (80mg), m.p.255-259 ℃ (dec.).

Example 8

Another process for the preparation of the compounds of formula I

A. Preparation of I wherein R ¹ Is isopropyl, R ² Is hydrogen, R ³ Is 4-fluoronaphthalen-1-yl, R ⁴ Is a Radical and R ⁵ Is hydrogen

4- (4-Fluoronaphthalen-1-yl) -6-isopropyl-2-methylsulfonylpyrimidine (0.100g, 0.29mmol) was added to a solution of ethylamine (0.33ml, 5.8mmol) in ethanol (1 ml). The reaction vessel was placed in a sonication bath at a bath temperature of 45 ℃ for 6 hours. The ethanol was removed in vacuo, leaving a viscous oil. The oil was crystallized from ethanol and water to give 2-ethylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine (49%), m.p.77-78 ℃.

B. Similarly, with the formula NHR⁴R⁵Other amine substitution ofEthylamine, and optionally substituting 4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2-methylsulfonylpyrimidine with other compounds of formula (18), and following the procedure of example 8A above, the following compound of formula I is prepared:

4- (4-fluoronaphthalen-1-yl) -2-hydrazino-6-isopropyl-pyrimidine hydrochloride, m.p.141-145 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2- (piperazin-1-yl) -pyrimidine fumarate, m.p.196.1-196.6 ℃;

2- (2-methoxyethylamino) -4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine, m.p.87.1-87.7 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2-n-propylaminopyrimidine, m.p.99.6-99.9 ℃;

2-allylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine, m.p.92.8-93.4 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2- (piperidin-1-yl) -pyrimidine, m.p.70-72 ℃;

2-benzylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropyl-pyrimidine, m.p.73-74 ℃;

2-cyclopropylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine, m.p.100.1-100.8 ℃;

2- (2-hydroxyethylamino) -4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine hydrochloride, m.p.70-71 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2-morpholinopyrimidine, m.p.81-83 ℃;

2-butylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropyl-pyrimidine, m.p.87-88 ℃;

2-butylamino-4- (4-fluoronaphthalen-1-yl) -6-methylpyrimidine hydrochloride, m.p.137-139 ℃;

2-dimethylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropyl-pyrimidine, m.p.41-42 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2-methylamino-pyrimidine, m.p.115-116 ℃;

4- (4-fluoronaphthalen-1-yl) -6- (2-hydroxy-2-phenylethyl) -2-methylaminopyrimidine, m.p.138.1-139.2 ℃;

4- (4-fluoronaphthalen-1-yl) -6-phenethyl-2-methylaminopyrimidine hydrochloride, m.p.130.7-131.2 ℃;

4- (4-fluoronaphthalen-1-yl) -2-isopropylamino-6-methoxypyrimidine hydrochloride, m.p.191.3-191.6 ℃;

2- (dimethylamino) ethylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine hydrochloride, m.p.176.5 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2- (methylamino) ethylamino-pyrimidine hydrochloride, m.p.152-153 ℃;

4- (4-fluoronaphthalen-1-yl) -6- (2-hydroxypropyl) -2- (methylamino) -ethylamino-pyrimidine hydrochloride, m.p.125-130 ℃;

2- (2-hydroxyethyl) amino-4- (4-fluoronaphthalen-1-yl) -6-methoxypyrimidine hydrochloride, m.p.191.3-191.6 ℃;

6-tert-butyl-4- (4-fluoronaphthalen-1-yl) -2-methylamino-pyrimidine, m.p.129.4-130.0 ℃;

2-benzylamino-6-tert-butyl-4- (4-fluoronaphthalen-1-yl) -pyrimidine, m.p.106.2-106.9 ℃;

6-tert-butyl-4- (4-fluoronaphthalen-1-yl) -2-isopropylamino-pyrimidine hydrobromide, m.p.196.5-197.2 ℃;

6-tert-butyl-4- (4-fluoronaphthalen-1-yl) -2- (2-methoxy-ethyl) amino-pyrimidine hydrochloride, m.p.114.5-117.8 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2- (pyridin-4-yl) methylamino-pyrimidine, m.p.149.1-149.5 ℃;

2- (2-amino) ethylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropyl-pyrimidine fumarate, m.p.172.4-172.6 ℃;

4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2- (4-methoxy-phenyl) methylamino-pyrimidine hydrochloride, m.p.65-67 ℃;

4- (4-fluoronaphthalen-1-yl) -2- (tetrahydro-2-furanyl) methyl-amino-6-isopropyl-pyrimidine, m.p.72.7-73.8 ℃;

4- (4-fluoronaphthalen-1-yl) -2- (2-hydroxy) ethylamino-6-isopropyl-pyrimidine maleate, m.p.101.9-104.1 ℃;

4- (4-fluoronaphthalen-1-yl) -2- (2-hydroxyethoxy) ethylamino-6-isopropyl-pyrimidine hydrobromide, m.p.115.3-116.7 ℃;

2- (1, 3-dihydroxypropan-2-yl) amino-4- (4-fluoronaphthalen-1-yl) -6-isopropyl-pyrimidine maleate, m.p.125.3-126.6 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6- (2-methoxy) ethyl-pyrimidine maleate, m.p.94-100 ℃; and

2-amino-4- (4-fluoronaphthalen-1-yl) -6-phenethylpyrimidine maleate, m.p.145-146 ℃.

C. Similarly, optionally with the formula NHR⁴R⁵And optionally substituting 4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2-methylsulfonylpyrimidine with the other compound of formula (18), and following the procedure of example 8A above, the other compound of formula I is prepared.

Example 9

Preparation of N-oxides of the Compounds of formula I

A. Preparation of N-oxides of compounds of formula I, wherein R ¹ Is methyl, R ² Is hydrogen, R ³ Is naphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

2-amino-6-methyl-4- (naphthalen-1-yl) -pyrimidine (0.28g) was dissolved in 15ml of chloroform at 0 ℃. Meta-chloroperbenzoic acid (0.54g) was added to the solution in portions over 5 minutes. After the addition was complete, the solution was heated to 40 ℃ for 30 minutes. The solution was washed with 10% aqueous sodium thiosulfate, 1M sodium hydroxide, and water. The chloroform layer was dried (sodium sulfate) and concentrated; the solid residue was recrystallized from ethanol-diethyl ether to give 2-amino-6-methyl-4- (naphthalen-1-yl) -pyrimidine-1-N-oxide (0.07g), m.p.228.7-229.5 ℃.

B. Similarly, 2-amino-6-methyl-6- (naphthalen-1-yl) pyrimidine was substituted with other compounds of formula I, and the procedure of example 9A above was followed to prepare the following N-oxides of compounds of formula I:

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-3-N-oxide, m.p.188-189 ℃;

2-amino-6-tert-butyl-4- (4-fluoronaphthalen-1-yl) -pyrimidine-3-N-oxide, m.p.188.6-190.9 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-1-N-oxide hydrochloride, m.p.207-208 ℃;

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-1-N-oxide, m.p.153-155 ℃;

2-acetylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-1-N-oxide,¹HNMR (200MHz), J1.39(d, 6H), 2.51(s, 3H), 3.81(m, 1H), 7.21-7.27(m, 2H), 7.62-7.68(m, 3H), 8.10-8.23(m, 1H), 8.38-8.41(m, 1H); and

4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-2-methylamino-1-N-oxide, m.p.181-182.5 ℃.

C. Similarly, other oxides of the compound of formula I were prepared following the procedure of example 9A above, substituting 2-amino-6-methyl-4- (naphthalen-1-yl) pyrimidine with other compounds of formula I.

Example 10

Preparation of a compound of formula I, wherein R ¹ Is hydroxyalkyl or alkenyl

A. Preparation of formula I wherein R ¹ Is 1-hydroxy-1-methylethyl or isopropenyl, R ² Is a hydrogen atom, and is, R ³ is 4-fluoronaphthalen-1-yl, R ⁴ And R ⁵ Is hydrogen

Trifluoroacetic anhydride (0.211ml, 1.50mmol) was added to a solution of 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-3-N-oxide (0.148g, 0.498mmol) in dichloromethane (5ml) at room temperature. The mixture was stirred at room temperature for 48 hours, and then poured into a 1N aqueous solution of sodium hydroxide. The organic layer was separated, concentrated in vacuo and purified using preparative thin layer chromatography to give 2-amino-4- (4-fluoronaphthalen-1-yl) -6- (1-hydroxy-1-methylethyl) -pyrimidine (0.043g, 29%) m.p.181-184 ℃; and 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropenylpyrimidine (0.051g, 36%), m.p.138-140 ℃.

B. Similarly, 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidin-3-N-oxide was substituted with the other N-oxide of the compound of formula I, following the procedure of example 10A above, wherein R was prepared¹Other compounds of formula I that are hydroxyalkyl or alkenyl.

Example 11

Preparation of Compounds of formula I from other Compounds of formula I

A. Preparation of a compound of formula I, wherein R ⁴ Is acetyl, R ⁵ Is hydrogen

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine (0.5g) was dissolved in acetic anhydride (10ml), and 4-dimethylaminopyridine (0.125g) was added. The reaction mixture was stirred at room temperature overnight, then heated at 75-80 ℃ for a total of 4 hours and evaporated to dryness in vacuo. The residue was partitioned between water and ethyl acetate, then dried over magnesium sulfate. The diacetyl compound was isolated as an oil by evaporation and dissolved in methanol (20 ml). Solutions ofTreated with saturated sodium bicarbonate solution (2ml) and stirred overnight. The monoacetyl derivative obtained is isolated by evaporation to dryness and dried thoroughly under vacuum. The residue was dissolved in boiling hexane and the supernatant decanted off to separate it from a small amount of insoluble residue, which was then crystallized to give 2-acetylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine, m.p.115.4-116.7 ℃. B.Preparation of a compound of formula I, wherein R ⁴ Is phenylaminocarbonyl, R ⁵ Is hydrogen

2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine (288.3mg) was dissolved in benzene (50ml) and phenyl isocyanate (119.1mg) was added. The reaction mixture was heated to reflux for 48 hours and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with 80: 20 hexanes: ethyl acetate, to give 4- (4-fluoronaphthalen-1-yl) -6-isopropyl-2-phenylureidopyrimidine (49.1mg, m.p.117-178).

Example 12

This example describes a process for the preparation of representative oral pharmaceutical formulations containing an active compound of formula I (e.g., 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine). The amount of each tablet of ingredients, mgs active compound 200 lactose, spray dried 148 magnesium stearate 2

The above ingredients were mixed and introduced into hard shell gelatin capsules.

Other compounds of formula I, such as those prepared according to examples 1-10, may be used as active compounds in the preparation of the oral formulations of this example.

Example 13

This example describes a process for the preparation of another representative oral pharmaceutical formulation containing an active compound of formula I (e.g., 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine). The amount of each tablet of the ingredients, mgs active compound 400 corn starch 50 lactose 145 magnesium stearate 5

The above ingredients were thoroughly mixed and pressed into individual scored tablets.

Other compounds of formula I, such as those prepared according to examples 1-10, may be used as active compounds in preparing oral formulations of this example.

Example 14

This example describes a process for the preparation of another representative pharmaceutical formulation containing an active compound of formula I (e.g., 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine).

The prepared oral suspension had the following composition: ingredient active Compound 1.0g fumaric acid 0.5g sodium chloride 2.0g methyl p-hydroxybenzoate 0.1g granulated sugar 25.5g sorbitol (70% solution) 12.85g Veegum K (Vanderbilt Co.) 1.0g flavouring 0.035ml colouring agent 0.5mg distilled water q.s. to 100ml

Other compounds of formula I, such as those prepared according to examples 1-10, may be used as active compounds in the preparation of the oral formulations of this example.

Example 15

This example describes the preparation of a representative oral pharmaceutical formulation containing an active compound of formula I (e.g., 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine).

The prepared injectable formulation buffered to pH4 had the following composition: component active Compound 0.2g sodium acetate buffer (0.4M) 2.0ml HCI (1N) q.s.q.to pH4 water (distilled, sterile) q.s.to 20ml

Other compounds of formula I, such as those prepared according to examples 1-10, may be used as active compounds in the preparation of injectable formulations of this example.

Example 16

This example describes the preparation of a representative topical pharmaceutical formulation containing an active compound of formula I (e.g., 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine). Ingredient gram active compound 0.2-10Span 602 Tween 602 mineral oil 5 petrolatum 10 methyl paraben 0.15 ethyl paraben 0.05BHA (butylated hydroxyanisole) 0.01 water appropriate to 100

All the above components, except water, were combined and heated to 60 ℃ with stirring. Then, sufficient water at 60 ℃ was added under vigorous stirring to emulsify the ingredients, and then an appropriate amount of water was added to 100 g.

Other compounds of formula I, such as those prepared according to examples 1-10, may be used as active compounds in the preparation of the topical formulations of this example.

Example 17

This example describes the preparation of a representative pharmaceutical formulation containing an active compound of formula I (e.g., 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine).

Suppositories were prepared in a total weight of 2.5g, with the following composition: component active compound 500mgWitepsol H-15^*Balance (^*Triglycerides of saturated vegetable fatty acids; products of Riches-Nelson, inc., New York, n.y.)

Other compounds of formula I, such as those prepared according to examples 1-10, may be used as active compounds in preparing the suppository formulations of this example.

Example 18

Cloned rat 5-HT_2BReceptor binding assays

The following describes the use of the used [2 ]³H]-5HT radiolabeled cloned 5-HT_2BIn vitro binding assays with receptors.

Expression of cloned 5-HT_2BMouse NIH3T3 fibroblasts of the recipient were maintained at 95/5% O₂/CO₂Dulbecco's modified Eagle's Medium containing 10% fetal bovine serum and 250. mu.g/ml G418 under an atmosphere. Cells were harvested by using a 2mM solution of EDTA in phosphate buffered saline (no calcium/magnesium) and centrifuged (500 g). The cell pellet was disrupted in homogenization buffer (Tris, 50 mM; Na) by using a Polytron P10 disruptor (5 stops, 5 seconds)₂EDTA, 5mM) and then homogenized by using a Sorvall/Dupont RC5C centrifuge equipped with a rotor of SS34 at 19,500rpmCentrifugation (30,000-48,000g, 15 min) was performed. The precipitate was homogenized in homogenization buffer (5 steps, 5 seconds) and the homogenization solution was then centrifuged (30,000-. The pellet was homogenized (5 steps, 5 seconds) in resuspension buffer (Tris, 50 mM; EDTA, 0.5mM) and the homogenate was centrifuged (30,000-. The pellet was homogenized (5 steps, 5 seconds) in a small volume of resuspension buffer to give approximately 1.5X 10⁸Cells/ml. The membrane was divided into 1ml aliquots and stored at-70 ℃.

The membranes were thawed at room temperature and then assayed in assay buffer (CaCl)₂ξ2H₂O, 4.5 mM; tris, 50 mM; 0.1% ascorbic acid). Specific binding rate is 1.5X 10 per assay tube⁶At least 90% of the total binding rate per cell. The membrane is homogenized (5 th stop, 5 seconds), and then a homogenizing solution is added to the solution containing [2 ]³H]5HT(2×10^-10M), test Compound (1X 10)^-10-1×10^-4M) and assay buffer (appropriated amount to 500 μ λ). The assay mixture was incubated at 40 ℃ for 2 hours and then filtered on a 0.1% polyethyleneimine pretreated glass fiber filter pad using a Brandel cell harvester. The assay tubes were washed with cold assay buffer and then dried by blowing air over the filter for 10 seconds. The radioactivity retained on the filter was determined by liquid scintillation counting. For each compound tested, the concentration that produced 50% inhibition of binding (IC) was determined by using an iterative curve fitting technique₅₀)。

Following the procedure of example 17, the compounds of the invention were found to be active against 5-HT_2BThe receptor has an affinity.

Example 19

5-HT_2A 5-HT_2B 5-HT_2CReceptor binding methods

The following describes the receptor binding method in which p-5-HT is treated_2BThe receptor has high affinityLigand pair of (5-HT)_2AAnd 5-HT_2CCounter-screening was performed to demonstrate selectivity.

5-HT_2AThe term "for a receptor³H]Ketanserin in the human cortex, in the expression of cloned human 5-HT_2ACos-7 cell neutralization of receptors in expressing rat 5-HT_2AThe receptor was labeled in NIH-3T3 cells. For competitive binding studies, the ligand concentration was approximately 0.1 nM. For saturation binding studies, the concentration of radioligand was 0.01nM to 2.0 nM. The assay was carried out in 0.5ml of assay buffer (pH7.4, 4 ℃) containing 50mM Tris-HCl, 4mM calcium chloride and 0.1% ascorbic acid. Nonspecific binding rates were defined using 10mM unlabeled ketanserin. After incubation at 32 ℃ for 60 minutes, the membranes were collected on filters that had been treated with 0.1% polyethyleneimine and the bound radioactivity was determined.

As mentioned above, human 5-HT_2BThe receptor is labeled in the Cos-7 cell, except that the radioligand is³H]5-HT and assay buffer contained 10mM pargyline and 0.1% ascorbic acid. For competitive binding studies, the radioligand concentration is about 0.4nM, while for saturation binding studies, the concentration is³H]The concentration of 5-HT was 0.05-8 nM. The non-specific binding rate is defined by 10mM 5-HT. Incubate at 4 ℃ for 120 minutes.

5-HT_2CThe receptor is in the choroid plexus, expressing human 5-HT_2CCos-7 cell neutralization of receptors in expressing rat 5-HT_2CThe receptor is labeled in NIH-3T 3. The assay is in accordance with the protocol for 5-HT_2AThe method described for the receptor, except that the radioligand is³H]Mesulergine (mesulergine). The radioligand concentration was approximately 0.2nM for competition studies and 0.1-18nM for saturation binding studies. Nonspecific binding was defined using 10. mu.M unlabeled mesulerge.

Analysis of competitive radioligand binding data using four-parameter logistic equations and iterative curve fitting techniques to obtain IC₅₀And an estimate of Hill slope. The Kd values determined from the saturation binding assay were then usedInhibition dissociation constants (Ki) were calculated.

Following the procedure of example 18, the compounds of the invention were found to be active against 5-HT_2BThe receptor has an affinity.

Example 20

Based on 5-HT_2BFunctional analysis of recipient tissue

In vitro functional assays are described below, characterizing the 5-HT receptor (putative 5-HT) in rat gastropycnemius_2B)。

Rat gastric fundus was determined as described by Baxter et al (1994), Brit.J.Pharmacol., 112, 323-331. Several longitudinal muscles were obtained from the fundus of male Sprague Dawley rats. The mucosa was removed and the muscle strips were suspended in oxidized Tyrode solution at a static tension of 1 g. The temperature was maintained at 37 ℃ and the experiment was carried out in the presence of pargyline (100. mu.M).

To test the effect of the antagonist, concentration-response curves were plotted in the presence or absence of the putative antagonist. A Shild curve is plotted to determine the affinity of the antagonist. To test for stimulants, the effect of test compounds alone on the split tissue strips was quantified.

When tested by this method, the compounds of the invention were found to be at 5-HT_2BAn antagonist at the receptor.

Example 21

Analysis of anxiolytic behaviour

An in vivo method for measuring anxiolytic activity is described below, which is performed by measuring the extent to which a drug affects the natural anxiety of a mouse when the mouse is in a new, intense light-irradiated environment.

18-20g of primary male C5BI/6J mice used in the experiment were kept in groups of 10 mice in a sound, temperature and humidity controlled room. Food and water are available ad libitum. The mice were kept in a cycle of 12 hours light and 12 hours dark with lights on at 6:00a.m. and off at 6:00p.m. All experiments were started at least 7 days after arrival.

An automated device for detecting changes in probing (exploration) was purchased from Omni-Techlectronics Columbus Ohio and is similar to Crawley and Goodwin (1980), as described in the Kilfoil et al article cited above. In brief, a chamber (44 × 21 × 21cm) made of a plexiglas cassette was divided into two chambers by a black plexiglas partition. The partition separating the two chambers contained a 13 x 5cm opening through which the mouse could easily pass. The black chamber has bright side walls and a white floor. A fluorescent tube (40 watts) placed over the chamber provides the only illumination. The Digiscananimal Activity Monitor System RXYZCM16(Omni-Tech Electronics) recorded the exploratory Activity of the mice in the laboratory.

Mice had 60 minutes to acclimate to the experiment prior to study. After the mouse received an intraperitoneal (i.p.) injection of the test compound or vehicle, it was returned to its cage for a post-treatment period of 15 minutes. The mice were then placed in the center of the light chamber and monitored for 10 minutes.

A general improvement in exploratory activity was found in the illuminated areas. The increase in exploratory activity is reflected by increased latency (time for the mouse to enter the dark chamber when first placed in the center of the illuminated area), increased round-trip activity, increased or unchanged locomotor activity (number of grid-crossing lines), and decreased residence time in the dark chamber.

The compounds of the invention improve anxiolytic behaviour when tested by this method.

Example 22

Analysis of extrications from anxiety

An in vivo method for determining an improvement in symptoms caused after weaning from an addictive substance by measuring the extent to which the drug affects anxiety that occurs after long term treatment of a mouse with an addictive substance and then discontinuing treatment is described below.

Primary male BKW mice (25-30g) were housed in groups of 10 in a room with controlled sound, temperature and humidity. Food and water are available ad libitum. The mice were kept under 12-hour light cycle and 12-hour dark cycle with lights on at 6:00a.m. and off at 6:00p.m. All experiments were started at least 7 days after arrival.

The extent of anxiety was determined by a two-chamber exploratory model of Crawley and Goodwin (see example 14). Anxiolytic activity was found to be a general increase in activity in the illuminated areas. The increase in exploratory activity is reflected by increased latency (time for the mouse to enter the dark chamber when first placed in the center of the illuminated area), increased or unchanged locomotor activity (number of crossing grid lines), increased number of cockings and decreased residence time in the dark chamber.

The increase in activity was detected in the illuminated area by treating the mice with ethanol (8.0% w/v in drinking water), nicotine (0.1mg/kg, i.p., twice daily) or cocaine (1.0mg/kg, i.p., twice daily) for 14 days. Anxiolytic effects were assessed at 1, 3,7 and 14 days after the start of the drug regimen. The treatment was stopped suddenly and then the activity was investigated in the illuminated area at 8, 24 and 48 hours. Vehicle or test compounds are administered by intraperitoneal injection during withdrawal. The response is expressed as a reduction in inhibition of anxiety behavior after cessation of ethanol, cocaine, or nicotine treatment.

When tested by this method, the compounds of the invention show an improvement in symptoms caused by weaning from addictive substances.

Claims (20)

1. A compound of formula I:wherein the compound is 5-HT_2BA receptor antagonist, and wherein:

R¹is hydrogen, C₁-C₁₂-alkyl, hydroxy-C₁-C₁₂-alkyl radical, C₁-C₆-alkoxy-C₁-C₁₂Alkyl, phenyl, C₃-C₈-cycloalkyl radical, C₃-C₈-cycloalkyl-C₁-C₆-alkyl radical, C₂-C₁₂-alkenyl radical, C₁-C₆Thioalkyl, halogen, fluoro-C₁-C₁₂Alkyl, phenyl-C optionally substituted by hydroxy₁-C₆-an alkyl group; -NR⁶R⁷or-O (CH)₂)_nR⁹Wherein

n is 1, 2 or 3; and

R⁹is hydrogen, C substituted by halogen or hydroxy₁-C₆-an alkyl group;

R²is hydrogen, C₁-C₆-alkyl or halogen;

R³is phenyl, naphthalene, acenaphthenyl, phenanthrene, quinoline, isoquinoline, dihydroquinoline, indole, 2, 3-dihydroindole, 2, 3, 4, 5-tetrahydro-1H-benzo [ b ] b]Azepines, 3, 4-dihydro-2H-benzo [1, 4]]Oxazines, 1H, 3H-benzo [ de ]]Isochroman, 6, 7,8, 9-tetrahydro-5-oxa-9-benzocycloheptane, 2, 3-dihydro-1, 4-benzodioxan, optionally substituted by C₁-C₆Alkyl, amino, C₁-C₆Alkoxy, nitro, C₁-C₆-fluoroalkyl and halogen substitution;

R⁴is hydrogen, C₁-C₆Alkyl, phenyl-C₁-C₆-alkyl, optionally substituted by C₁-C₆-alkyl radical, C₁-C₆-alkoxy and hydroxy substitution; hydroxy-C₁-C₆Alkyl, C (O) -C₁-C₆-alkyl or- (CH)₂)_mNR⁶R⁷(ii) a Wherein

m is an integer of 1 to 6; and

R⁶and R⁷Is hydrogen or C₁-C₆-an alkyl group; and

R⁵is hydrogen or C₁-C₆-an alkyl group; the precondition is that:

(i) when R is³Is naphthyl, indol-1-yl or 2, 3-indolin-1-yl, and R²，R⁴And R⁵When all are hydrogen, R¹Is not methyl;

(ii) when R is³When it is phenyl or naphthyl, R¹Is not-NR⁶R⁷；

(iii) When R is³When it is phenyl, R²Is not C₁-C₆-alkoxy, and R¹And R²Is not a halogen; and

(iv) when R is³Is phenyl and R¹When is hydrogen, R²Is not methyl; or a pharmaceutically acceptable salt or N-oxide thereof.

2. The compound of claim 1, wherein R⁴And R⁵Is hydrogen or C₁-C₆-an alkyl group.

3. The compound of claim 2, wherein R¹Is C₁-C₆-alkyl, fluoro-C₁-C₁₂-alkyl, or hydroxy-C₁-C₁₂-alkyl, and R³Is 1-naphthyl, optionally substituted by C₁-C₆-alkyl radical, C₁-C₆Alkoxy, nitro, C₁-C₆-fluoroalkyl and halogen substitution;

or a pharmaceutically acceptable salt or N-oxide thereof.

4. The compound of claim 3, wherein R¹Is methyl, R²，R⁴And R⁵Is hydrogen, and R³Is 2-methylnaphthalen-1-yl, i.e. 2-amino-4- (2-methylnaphthalen-1-yl) -6-methylpyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

5. The compound of claim 3, wherein R¹Is isopropyl, R²，R⁴And R⁵Is hydrogen, and R³Is 4-fluoronaphthalen-1-yl, i.e. 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

6. The compound of claim 5, wherein the N-oxide is in the 1-position, i.e., 2-amino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine-1-N-oxide.

7. The compound of claim 3, wherein R¹Is 1-fluoro-1-methylethyl, R²，R⁴And R⁵Is hydrogen, and R³Is 4-fluoronaphthalen-1-yl, i.e. 2-amino-4- (4-fluoronaphthalen-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

8. The compound of claim 3, wherein R¹Is 1-hydroxy-1-methylethyl, R²，R⁴And R⁵Is hydrogen, and R³Is 4-fluoronaphthalen-1-yl, i.e. 2-amino-4- (4-fluoronaphthalen-1-yl) -6- (1-hydroxy-1-methylethyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

9. The compound of claim 3, wherein R¹Is 1-fluoro-1-methylethyl, R²，R⁴And R⁵Is hydrogen, and R³Is 4, 6-difluoronaphthalen-1-yl, i.e. 2-amino-4- (4, 6-difluoronaphthalen-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

10. The compound of claim 3, wherein R¹Is isopropyl, R²And R⁴Is hydrogen, R⁵Is methyl, and R³Is 4-fluoronaphthalen-1-yl, i.e. 2-methylamino-4- (4-fluoronaphthalen-1-yl) -6-isopropylpyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

11. The compound of claim 3, wherein R¹Is 2-methylpropyl, R²，R⁴And R⁵Is hydrogen, and R³Is 4-fluoronaphthalen-1-yl, i.e. 2-amino-4- (4-fluoronaphthalen-1-yl) -6- (2-methylpropyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

12. The compound of claim 3, wherein R¹Is tert-butyl, R²，R⁴And R⁵Is hydrogen, and R³Is 4-fluoronaphthalen-1-yl, i.e. 2-amino-6- (tert-butyl) -4- (4-fluoronaphthalen-1-yl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

13. The compound of claim 2, wherein R¹Is C₁-C₆-alkyl and R³Is optionally substituted indole, or a pharmaceutically acceptable salt or N-oxide thereof.

14. The compound of claim 13, wherein R¹Is methyl, R²，R⁴And R⁵Is hydrogen, and R³Is indol-4-yl, i.e. 2-amino-4- (1H-indol-4-yl) -6-methylpyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14 in admixture with one or more pharmaceutically acceptable non-toxic carriers.

16. A process for preparing a compound of formula I:wherein:

R¹is hydrogen, C₁-C₁₂-alkyl, hydroxy-C₁-C₁₂-alkyl radical, C₁-C₆-alkoxy-C₁-C₁₂Alkyl, phenyl, C₃-C₈-cycloalkyl radical, C₃-C₈-cycloalkyl-C₁-C₆-alkyl radical, C₂-C₁₂-alkenyl radical, C₁-C₆Thioalkyl, halogen, fluoro-C₁-C₁₂Alkyl, phenyl-C optionally substituted by hydroxy₁-C₆-an alkyl group; -NR⁶R⁷or-O (CH)₂)_nR⁹Wherein

n is 1, 2 or 3; and

R⁹is hydrogen, C substituted by halogen or hydroxy₁-C₆-alkyl radical；

R²Is hydrogen, C₁-C₆-alkyl or halogen;

R³is phenyl, naphthalene, acenaphthenyl, phenanthrene, quinoline, isoquinoline, dihydroquinoline, indole, 2, 3-dihydroindole, 2, 3, 4, 5-tetrahydro-1H-benzo [ b ] b]Azepines, 3, 4-dihydro-2H-benzo [1, 4]]Oxazines, 1H, 3H-benzo [ de ]]Isochroman, 6, 7,8, 9-tetrahydro-5-oxa-9-benzocycloheptane, 2, 3-dihydro-1, 4-benzodioxan, optionally substituted by C₁-C₆Alkyl, amino, C₁-C₆Alkoxy, nitro, C₁-C₆-fluoroalkyl and halogen substitution;

R⁴is hydrogen, C₁-C₆Alkyl, phenyl-C₁-C₆-alkyl, optionally substituted by C₁-C₆-alkyl radical, C₁-C₆-alkoxy and hydroxy substitution; hydroxy-C₁-C₆Alkyl, C (O) -C₁-C₆-alkyl or- (CH)₂)_mNR⁶R⁷(ii) a Wherein

m is an integer of 1 to 6; and

R⁶and R⁷Is hydrogen or C₁-C₆-an alkyl group; and

R⁵is hydrogen or C₁-C₆-an alkyl group; the precondition is that:

(i) when R is³Is naphthyl, indol-1-yl or 2, 3-indolin-1-yl, and R²，R⁴And R⁵When all are hydrogen, R¹Is not methyl;

(ii) when R is³When it is phenyl or naphthyl, R¹Is not-NR⁶R⁷；

(iii) When R is³When it is phenyl, R²Is not C₁-C₆-alkoxy, and R¹And R²Is not a halogen; and

(iv) when R is³Is phenyl and R¹When is H, R²Is not methyl; or a pharmaceutically acceptable salt or N-oxide thereof; the process comprising reacting a compound of formula (4)With a boronic acid derivative of the general formula (5), namely R³B(OR¹¹)₂Reacting to form a compound of formula I, wherein R¹，R²And R³As defined in formula I, R⁴And R⁵Is hydrogen or C₁-C₆-alkyl and R¹¹Is H or methyl; or a compound of the formula (6)And general formula NHR⁴R⁵To form a compound of the general formula I, wherein R¹，R²，R³，R⁴And R⁵As defined in formula I.

17. The method of claim 16, further comprising reacting the compound of formula I with an oxidizing agent to obtain an N-oxide of the compound of formula I.

18. The method of claim 16, further comprising reacting the compound of formula I with a strong acid to provide a pharmaceutically acceptable salt of the compound of formula I.

19. The method of claim 17, further comprising reacting an N-oxide of a compound of formula I wherein R is¹Is C₁-C₁₂Alkyl, with carboxylic anhydride to give compounds of the formula I, in which R¹Is hydroxy-C₁-C₁₂-alkyl or C₂-C₁₂-an alkenyl group; optionally, the compound of formula I is subsequently reacted with a strong acid to provide a pharmaceutically acceptable salt of the compound of formula I.

20. The use of a compound as claimed in any of claims 1 to 14 for the preparation of a medicament for the treatment of a disease state selected from the group consisting of: generalized anxiety disorder, panic disorder, obsessive compulsive disorder, alcoholism, depression, migraine, hypertension, sleep disorders, anorexia nervosa and priapism.