SI9010607A - Pharmacologically active cns compounds - Google Patents

Abstract

Use of a phenyl pyrimidine deriv. of formula (I) or its salts for the mfr. of a medicament for treating CNS disorders or diseases is new: R1, R2 = H, halo, OH, alkyl, alkoxy, alkylthio, or NR'R''; R', R'' = H, alkyl, aryl or aralkyl; or NR'R'' = heterocyclyl opt. contg. a further heteroatom and opt. substd. by alkyl; R3 = H, alkyl (opt. substd. by halo), NH2, alkylamino, dialkylamino, CN, NO2, halo, carbamoyl, OH, COOH, alkoxy, alkylthio, alkylthioalkyl S(O)n-alkyl, di(alkoxy)alkyl, CRNOH, COR, CO2R or CH2X; R = H or alkyl; X = OH, alkoxy, aryloxy, aralkoxy, halo, CN, NR'R'', S(O)n-alkyl or SO2N(R)2; n = 1-2; R4-R8 = H, halo, alkyl, perhaloalkyl, CN, carbamoyl, COOH, COR, NO2, NH2, alkylsulphonylamino, alkoxy, S(O)n-alkyl or SO2N(R)2; or R4 + R5 or R5 + R6 = CH=CH-CH=CH or (CH2)4; and R7, R8 = H; one of the N on the pyrimidine ring is opt. N-alkylated or an N-oxide; alkyl = 1-6C; aryl = 6-10C. (I) are new provided that at least one of the R4-R8 is not H and when R1 = R2 = NH2 or R1 = OH and R2 = NH2, R3 = H or alkyl and R7 = H, then R4 and R5 are both halo.

Description

THE WELLCOME FOUNDATION LIMITED

Pharmacologically active CNS compounds

The present invention relates to a class of pyrimidine compounds useful for the treatment of diseases and disorders of the central nervous system (CNS = central nervous system), such as damage due to cerebral ischemia, to pharmaceutical preparations containing them, for their use in the treatment of such diseases and the procedures for preparing them.

Glutamate is an excitatory amino acid that acts as a neurotransmitter. Of course, when its extracellular concentration is satisfactorily high, glutamate acts as a potent neurotoxin that can kill neurons in the central nervous system. (Rothman & Oliney (1986) Prog. Brain Res., 63, 69). The neurotoxic effect of glutamate has been implicated in a number of disorders and conditions of the central nervous system, including cerebral ischemic injury, epilepsy and chronic degenerative disorders such as Alzheimer's disease, disorders of the motor system and Huntington's measles (Meldrum Clinical Science (1985) 68 113- 122). Furthermore, glutamate is implicated in other neurological disorders such as manic depression, depression, schizophrenia, high pressure neurological syndrome, chronic pain, trigeminal neuralgia and migraine.

In European patent application no. 21121 describes a group of 3,5-diamino-6- (substituted phenyl) -1,2,4-triazines that are active in the treatment of CNS disorders, e.g. in the treatment of epilepsy. One of the compounds described in this application, 3,5-diamino-6- (2,3dichlorophenyl) -1,2,4-triazine (lamotrigine), has been shown to inhibit the release of excitatory amino acids, glutamate and asparaginate, (Leach et al , New Anticonvulsant Drugs, Ed. Meldrum and Porter 165-177,1987).

The present inventors have discovered that a range of substituted pyrimidine compounds, as defined by Formula I, forms potent inhibitors of glutamate release; these compounds are

- 2 useful for the treatment of the aforementioned disorders and conditions of the central nervous system. Pyrimidine Compounds of Formula I are also asparaginate release inhibitors.

Thus, in a first aspect of the present invention, it is ensured the use of a compound of formula I or an acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of damage or disease of a mammalian CNS

wherein in formula I

R 1 and R _{2 are the} same or different and are selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, alkyl, alkylthio and the group NRH ¹¹ , where R ¹ and R ^{11 are the} same or different and selected from the group containing hydrogen , alkyl, aryl and arylalkyl or together with the nitrogen atom to which they are attached form a cyclic ring which is optionally substituted by one or more alkyl groups and optionally contains a further heteroatom;

R _{3 is} hydrogen, alkyl optionally substituted by one or more halo radicals, or is amino, alkylamino, dialkylamino, cyano, nitro, halo, carbamoyl, hydroxy, carboxy, alkoxy, alkylthio, alkylthioalkyl, S (O) _n alkyl, di (alkyloxy) alkyl, -C (R): NOH or -COR or -CO ₂ R, where R is hydrogen or alkyl or a group CH ₂ X, where X is hydroxy, alkoxy, aryloxy, arylalkyloxy, halo, cyano , -NRH ¹¹ , where R ¹ and R ¹¹ , as defined above, are S (O) alkyl, where n is 1 or 2, or SC 4 NRH ¹¹ ;

each of R ₄ to R _g is the same or different and each is selected from the group consisting of hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR, nitro, amino, alkylsulfonylamino, alkoxy, S (O) _n - alkyl, wherein n is 1 or 2, or SO ^ RH ¹¹ ; or R ₄ and R _s , or R _s and R _f> together are a group -CH = CH-CH = CH- or a group -CH ₂ -CH, -CH ₉ -CH ₂ -, in which case both R _? and R _$ is hydrogen;

and optionally one of the nitrogen atoms in the pyrimidine ring may be N alkylated or optionally N oxide;

wherein the preceding alkyl groups or portions of the alkyl-containing groups have 1 to 6 carbon atoms, and the aryl groups or aryl moieties of the aryl-containing groups have 6 to 10 carbon atoms.

Certain compounds of formula I are chiral, and it is clear that in these cases formula I comprises both a racemic mixture and the individual enantiomers of such compounds. It will also be clear that when one or more of R _{p is} R ₂ and R _{3 is} hydroxy, they may also exist in their tautomeric form.

A preferred class of compounds of formula I which are potent glutamate inhibitors are those in which one of R ₃ and R _{2 is} amino and the other is selected from the group consisting of amino, hydroxy, halo, morpholino, piperazinyl, N-alkyl- piperazinyl, N, N-dialkylamino, N-alkylamino or alkylthio;

R ₃ is alkyl, optionally substituted by one or more alkyl radicals, or alkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl or a CH ₂ X group, wherein X is hydroxy, phenoxy benzyloxy, alkoxy or alkylthio;

one of R ₄ and R _{5 is} halo and the other is selected from the group consisting of halo or hydrogen;

R _{6 is} halo, hydrogen, nitro or amino;

is R _? hydrogen, halo, cyano, alkylthio, SO ₂ NR ¹ R ¹¹ alkyl, nitro, amino or methanesulfonamido; and R _{g is} hydrogen or halo.

In the present invention, R1 is preferably hydroxy, amino, N-alkylamino, N, N-dialkylamino, morpholino, piperazinyl, N-alkylpiperazinyl;

R _{2 is} preferably chloro, amino, N, N-dialkylamino or piperidino;

R _{3 is} preferably hydrogen, alkyl, methoxymethyl, trifluoromethyl, benzyloxymethyl, phenoxymethyl or methylthiomethyl;

R ₄ to R _{g are} preferably selected from the group consisting of hydrogen and chloro. Preferably, the alkyl groups contain from 1 to 4 carbon atoms.

In formula I, as appropriate, at least one of R and R ₂ are amino, and the other is amino, piperazinyl or N-methylpiperazinyl, N-alkylamino, Ν, Ν-dialkylamino; and R _{3 is} hydrogen, methyl, trifluoromethyl or methoxymethyl.

An advantageous property of formula I is that two of R ₄ , R ₅ and R _{7 are} chloro, especially preferably all of R ₄ , R ₅ and R 7 being _? chloro. Such compounds are very potent inhibitors of glutamate release. Preferred examples of the group NR @ ¹¹ are amino, N-methylamino, N-ethylamino, Ν, Ν-dimethylamino, piperazinyl, N-methylpiperazinyl, piperidinyl, and morpholino.

A particularly preferred class of compounds within Formula I are those in which:

R _{x is} selected from the group consisting of amino, piperazinyl, N-methylpiperazinyl, N-morpholino, N, N-dimethylamino and N-ethylamino;

R _{2 is} amino;

R _{3 is} selected from the group consisting of trifluoromethyl, hydrogen, methyl, benzyloxymethyl, methoxymethyl and methylthiomethyl;

R _{4 is} chloro; and is at least one of R ₅ , R ₆ and R _? chloro and the residue is selected from the group consisting of hydrogen, chloro and nitro; and R _{g is} hydrogen;

are R ₄ and R _g both hydrogen, R ₅ and R _? both chloro and R _{6 is} selected from the group consisting of hydrogen, chloro and nitro.

The present invention also provides a subclass of compounds of Formula I which, while potent glutamate release inhibitors, show only poor (i.e., IC ₅₀ less than 20 µm) or insignificant inhibitory effects on the enzyme dehydrofolate reductase. Thus, in a preferred embodiment of the present invention are provided compounds of formula I, in which R to R _g are as hereinbefore defined, provided that when _R7 is halo, then

R _{3 is} hydrogen, perhaloalkyl, methyl or methoxymethyl and / or R _{6 is} nitro and / or R 1 is N-alkylpiperazinyl, morpholino, N, N-dimethylamino, piperazinyl or N-ethylamino;

or provided that when

R _{6 is} chloro, then it is

R _{4 is} halo and R _{3 is} hydrogen, perhaloalkyl, methoxymethyl, methyl or halo and / or R _{t is} N-methylpiperazinyl, piperazinyl, morpholino or N, N-dimethylamino or N-ethylamino.

The compounds of formula I can be used for the treatment and prophylaxis of acute and chronic disorders of the mammalian central nervous system. The acute condition comprises cerebral ischemia, which can be caused by a variety of causes including stroke, cardiac arrest, by-pass surgery, neonatal anoxia, and hypoglycemia; and also physical injury or trauma to the spinal cord or brain. Chronic neurodegenerative disorders that can be treated include Alzheimer's disease, Huntington's chorea, olivopontocerebral atrophy, disorders of the motor system. Other neurological conditions that can be treated with the compound of Formula I include depression, manic depression, schizophrenia, chronic pain, epilepsy, trigeminal neuralgia, and migraine.

In a further aspect, the present invention provides a method for treating or preventing disorders or diseases of a mammalian CNS, including a human, comprising administering to the mammal a non-toxic effective amount of a compound of formula I or an acid addition salt thereof.

The present invention particularly provides a method of treating a mammal that is predisposed to or has neurotoxic extracellular levels of central nervous system glutamate, comprising administering to the mammal a non-toxic effective amount of a compound of formula I or an acid addition salt thereof.

Certain phenylpyrimidines of the present invention are known to have antimalarial activity. See, e.g. Brit. J. Pharmacol. 6, 185-200 (1951); JACS, 73, 3763-70, (1951). Other phenylpyrimidines are known from Chem. Biol. Pteridines, 463-468, (1982) and Pharmacotherap. Budesinsky, p. 129-141 (1963), ed. Oldrich Hanc.

Certain compounds of the present invention are, however, novel and the present invention therefore provides a compound of formula I or an acid addition salt thereof, wherein R _t to R _{g are} as defined hereinbefore provided that at least one of R ₄ to R _{g is} different from and further provided that when R 1 and R ₂ are both amino or when R _{4 is} hydroxy and R _{2 is} amino and R _{3 is} alkyl or hydrogen and R _? hydrogen, then R ₄ and R ₅ are both halo.

Other novel compounds of the present invention are those wherein R _t to R ₃ and R _g are as hereinbefore defined and one of R ₄ or R _{5 is} different from hydrogen and R _? halo, alkyl, perhaloalkyl, cyano, nitro, amino, alkylthio, S (O) _n -alkyl or SOjNR ^ ¹¹ .

A third class of novel compounds of the present invention are those compounds of formula I wherein R _{1 is} morpholino, piperazinyl, N-alkylpiperazinyl, N, N-dialkylamino, N-alkylamino or alkylthio and are R ₂ to R _g as defined hereinbefore .

A fourth class of novel compounds of the present invention are those compounds of formula I wherein R ₄ and R _{2 are} as hereinbefore defined;

and R _{3 is} alkoxy, alkylthio or alkyl substituted by one or more halo radicals, or is a CH ₂ group X, wherein X is alkylthio, aryloxy, arylalkyloxy, alkyloxy or hydroxy;

R ₄ to R ₆ are the same or different and are each selected from the group consisting of hydrogen, halo, perhaloalkyl, nitro, amino or alkylthio;

is R _? halo, alkyl, perhaloalkyl, cyano, nitro, amino or a group SO ₂ N (R ^{is not} ) wherein R ^{111 is} alkyl; and R _{g is} hydrogen or halo.

The fifth class of novel compounds of the present invention are those compounds of formula I wherein R _t and R ₂ and R ₄ to R _{g are} as defined hereinbefore and R ^{3 is} alkoxy, aryloxy, arylalkyloxy or alkylthio.

Preferred new compounds of the present invention include the following, the numbers referring to the examples that appear later:

Example no.

1. 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine

2. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methoxymethylpyrimidine

3. 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine

4. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine

5. 2,4-Diamino-5- (4-nitro-2,3,5-trichlorophenyl) pyrimidine

6. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methylpyrimidine

7. 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine

8. 4-amino-2-N, N-dimethylamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine

9. 4-amino-2-morpholino-N-5- (2,3,5-trichlorophenyl) pyrimidine

10. 4-amino-2-N ₁ N-dimethylamino-5- (2,3,5-trichlorophenyl) pyrimidine

11. 4-amino-6-methyl-2- (4-methylpiperazin-1-yl); 5- (2,3,5-trichlorophenyl) pyrimidine

14. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine

15. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methylpyrimidine

16. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methoxymethylpyrimidine

25. 2,4-Diamino-5- (2,4-dichlorophenyl) -6-trifluoromethylpyrimidine

26. 6-Benzylosquimethyl-2,4-diamino-5- (2,4-dichlorophenyl) pyrimidine

27. 2-N-methylpiperazinyl-4-amino-5- (2,4-dichlorophenyl) pyrimidine

28. 2,4-Diamino-5- (2,5-dichlorophenyl) -6-trifluoromethylpyrimidine

29. 2,4-Diamino-5- (2,3,5-trichlorophenyl) pyrimidine

36. 4-amino-5- (3,5-dichlorophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) pyrimidine 58. 4-amino-2-N-ethylamino-5- (2,5 -dichlorophenyl) pyrimidine 79. 4-Amino-2-N-methylamino-5- (2,3,5-trichlorophenyl) pyrimidine or an acid addition salt thereof.

Suitable acid addition salts of the compounds of formula I include those formed with organic or inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, milky, pyro-grape, acetic, amber, oxal, fumaric, maleic, oxalocet, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, benzenesulfonic acid. These salts can be prepared by reaction of the compound in the form of the free base with the corresponding acid.

Although it is possible to administer compounds of formula I as a crude chemical, it is desirable to formulate them as a pharmaceutical formulation. The formulations of the present invention comprise a novel compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers for these substances and, optionally, other therapeutic ingredients. The carrier (s) must be acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to their recipient.

Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), rectal, and topical (including dermal, buccal, and sublingual) administration, although the preferred route may be dependent, e.g. from the condition and disorder of the patient. The formulations can be suitably formulated in the form of a dosage unit and can be prepared by any of the well-known methods of pharmacy. All processes involve the step of coupling a compound of formula I or a pharmaceutically acceptable acid addition salt (active ingredient) with a carrier to form one or more auxiliary ingredients. Generally, formulations are prepared by uniquely and homogeneously coupling the active ingredient to liquid carriers or finely divided solid carriers or both, and then, if necessary, forming the product into the desired formulation.

The tablet may be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing the active ingredient in such a free-flowing form, such as powder or granules, optionally mixed with a binder, an inert diluent, a lubricant, a surfactant or a dispersing agent, in some suitable machine. . Molded tablets can be prepared by molding a mixture of a powdered wetted compound with an inert liquid diluent in a suitable machine. The tablets can optionally be coated or measured and can be formulated to ensure a slow and controlled release of the active ingredient from them.

Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic to the intended patient's blood; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations can be formulated into a dosage unit or into multi-dose containers, e.g. sealed ampoules and vials, and can be stored in a lyophilized state that only requires the addition of a sterile liquid carrier, e.g. water for injection, just before use. Injectable solutions and suspensions may be prepared at any time from sterile powders, granules and tablets of the species previously described.

Formulations for rectal administration can be formulated as suppositories with conventional carriers such as cocoa butter or polyethylene glycol.

Formulations for topical oral administration, e.g. buccal or sublingual include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia or tragacanth and lozenges comprising the active ingredient in such a base as gelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those that contain an effective dose of the active ingredient as previously illustrated or a corresponding portion thereof.

It should be clear that the formulations of the invention may include, in addition to the ingredients specifically mentioned herein, other conventional agents of the art, depending on the type of formulation concerned, e.g. those suitable for oral administration may include flavoring agents.

Tablets or other formulations provided as individual units may contain an amount of a compound of formula I that is effective at such a dose or multiple product thereof, e.g. units containing 5 mg to 500 mg, usually about 10 mg to 250 mg.

The compounds of formula I are preferably used to treat CNS disorders or diseases by oral administration or injection (intraperitoneal or subcutaneous). The exact amount of compound administered to a patient is determined by the doctor. However, the dose used will depend on a number of factors including the age and gender of the patient, the exact disorder being treated and its severity. Thus, for example, when treating a patient with epilepsy, the dosage interval will likely be significantly lower than when treating a patient after a stroke to alleviate cerebral ischemic injury. Likewise, the route of administration is likely to vary with the condition and its severity.

The compounds of formula I can be administered orally or by injection at a dose of 0.1 to 30 mg / kg per day. The dosing interval for adults is generally 8 to 2400 mg / day and preferably 35 to 1050 mg / day. Because certain compounds of formula I are long acting, it may be appropriate to administer an initial dose of 70 to 2400 mg on the first day and then a lower dose of 20 to 1200 mg later in the day.

Examples of such long-acting compounds are:

2,4-diamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine;

4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine; and

4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine.

Long-acting compounds are appropriate in clinics because they are easier to handle. In a chronic situation, they can be given without infusion and there is a minimum of direct medical intervention; also, in acute conditions, the patient is encouraged by minimizing daily dosing. In contrast, short-acting compounds such as:

2.4-Diamino-5- (2,3,5-trichlorophenyl) -6-methoxymethylpyrimidine allow the clinician to control the pharmacological action of the compound with great precision, since such compounds will be rapidly eliminated from the central nervous system (CNS).

The compounds of the present invention can be prepared in a manner known in the art for analogous compounds (e.g., JACS vol 73 (1951) 3763-70).

The present invention also provides a process for the preparation of a compound of formula I or an acid addition salt thereof, comprising the reaction of a compound of formula II:

f? ₅ lo if, «3

II in which R ₃ to R _g , as defined hereinbefore, L is a leaving group and Y is cyano or carboxy, carbonyl or alkoxycarbonyl, with a compound or a salt thereof of formula III:

NH

H ₂ N - C - R ₁ IH in which R ₁ is as defined herein, and isolating the compound of formula I in the form of a free base or its acid addition salt, and optionally converting the base into its acid addition salt or to another acidic salt an addition salt, or to another compound of formula I, or an acid addition salt thereof.

It will be appreciated that certain compounds of formula III, e.g. in which R1 is hydroxy, exist in an appropriate tautomic form (eg as carbamide).

As examples of the internal conversion of compounds of formula I, when in the product of the above process one of R _{p is} R ₂ or R _{3 is} hydroxy, the compound may be halogenated, e.g. using a Wilsmeier-Haack reagent or phosphorus oxychloride (POC1 ₃ ) into the corresponding halo compound. This compound may be further converted to a compound of formula I in which Ri, R ₂ or R ₃ alkylthio by reaction with the appropriate alkylthiolate or to the appropriate amino compound of (R i, R ₂ or R ₃ is NR ¹¹⁾ by reaction with an appropriate an amino compound in some such suitable solvent as alkanol, e.g. ethanol, or converted to a compound in which R, R ₂ or R ₃ alkoxy, by reaction with the appropriate alkoxide.

If it is necessary to produce a compound of formula I in which one of R ₄ to R _{g is} nitro, this can be done from a suitable compound of formula I wherein one of R ₄ to R _{g is} hydrogen, using standard nitration conditions , e.g. sulfuric acid and potassium nitrate, and then further converted by standard reducing agent to the corresponding amino compound, e.g. using PtO ₂ , AcOH, H ₂ .

It will be appreciated that the amino or halo compounds can be further converted to R ₄ to R _g as defined herein by standard internal conversion, e.g. over diazonium salts. When R _{3 is} alkyl, it can be converted to a perhaloalkyl or halogenated alkyl group by reaction with the corresponding halogen or N-halosuccinimide (NXS) in some suitable solvent such as acetic acid.

Compounds containing R ₃ CH (OEt) ₂ may be converted to the corresponding aldehyde by hydrolysis with dilute acid (s) and then reduced to the corresponding alcohol by a standard reducing agent (eg NaBH ₄ sodium borohydride), or it is converted to the corresponding oxime (hydroxylamine hydrochloride in ethanol) which can then be converted to the corresponding cyano compound using e.g. of trifluoroacetic anhydride (TFAA) and then to the corresponding amido compound using concentrated sulfuric acid. Alternatively, the aldehyde can be oxidized with KMnO ₄ (potassium permanganate) to give the corresponding acid, which can again be reacted with alcohol to give the corresponding ester.

When in the product of the above process R _{3 is} a CH ₂ OR group, where R is alkyl or arylalkyl, the product can be converted to CH ₂ X by reaction with ΗΧ (X = halo) in e.g. acetic acid and this can be further converted to the corresponding cyano compound, e.g. by treatment with sodium cyanide and DMF or into fluoromethyl by treatment with e.g. cesium fluoride (CsF) or to a group CH? R ¹¹ by reaction with an appropriate amine. Alternatively, the CH ₂ OR group can be dealkylated to give the corresponding alcohol, e.g. with Me ₃ SiJ and fly is further converted to fluoromethyl with diethylamino sulfur trifluoride (DAST).

When R ₃ to R _g contain an alkylthio group, it can be oxidized to the corresponding sulfoxide and sulfolone using, e.g. MCPBA (metachloroperbenzoic acid).

It will be clear that we can perform other internal conversions, as required by those skilled in the art, using standard methodologies.

Examples of suitable leaving groups (L) include R ₁₄ alkoxy, halo, NR ^x R ⁿ , as defined herein, e.g. anilino, morpholino, Cb4 alkylamino, benzylamino or alkylthio. Preferably, in formula III, R is hydroxy, alkoxy, alkylthio or a group NR ¹¹ as defined herein. R4 is amino, alkylamino, dialkylamino, piperazinyl or N-methylpiperazinyl.

Preferably, the reaction of the compounds of formula I and II is carried out in a non-aqueous solvent, e.g. to some alkanol, e.g. ethanol at elevated temperatures (e.g., between 50 and 110 ° C) in a base, preferably an alkanoxide, preferably under reflux using sodium ethoxide as the base.

Alternatively, a compound of formula I or an acid addition salt thereof may also be prepared by reacting a compound of formula III with a compound of formula IV:

Oh

IV in which R ₃ to R _g and Y are as defined herein. The reaction is preferably carried out in a non-aqueous solvent, e.g. alkanols such as ethanol and at elevated temperatures, preferably under reflux.

The compounds of formula IV can be prepared by known techniques in the art (JACS, 1951, 73, 3763-3770).

The compounds of formula II can be prepared by known techniques in the art (JACS above), e.g. by reaction of a compound of formula IV with diazomethane or alkylorthoesters (JACS, 1952, 74, 1310-1313), or by condensation with an amine.

In Formula III, when R ^{1 is} piperazinyl or alkylpiperazinyl, they can be prepared by standard procedures, e.g. by reacting a known compound of formula II, wherein R ^{1 is} alkylthio with the corresponding amine, e.g. N-methylpiperazine. This reaction is preferably carried out at room temperature in water.

Compounds of formula I can also be prepared by reaction of a compound of formula V:

Oh

O in which Y and R ₃ are as previously defined and R ₁₀ and R _{n are} alkyl or together form a group (CR ₂ ) _n , wherein n is 2 to 4 and is RH or alkyl, with a compound of formula III. Most preferably, R1 is amino, piperazinyl or methylpiperazinyl. The preferred reaction is carried out in a non-aqueous solvent, e.g. ethanol under reflux using sodium ethoxide as a base.

The compounds of formula I may also be prepared from the corresponding dihydropyrimidine using standard conditions for dehydrogenation (e.g., JCS, 1956,1019).

Such dihydropyrimidine can be prepared by reacting a compound of formula II, wherein R ₃ to R _{g are} as defined and L is hydrogen, with a compound of formula III.

In the examples of the invention shown below, chemical and other abbreviations used are standard in the art and have the following meanings:

NaBH ₄ sodium borohydride CHCLj chloroform NaHCO ₃ sodium bicarbonate MgSO ₄ magnesium sulfate PBr ₃ phosphorus tribromide DMF dimethylformamide KCN potassium cyanide Et ₃ ° diethyl ether NaOEt sodium ethoxide EtOH ethanol ^ 04 sulfuric acid AcOH acetic acid MeOH methanol n ₂ nitrogen HC1 Hydrochloric acid NaOH sodium hydroxide SiO ₂ silica DMSO dimethylsulfoxide On sodium DME dimethoxyethane May methyl iodide (iodomethane) EtOAc ethyl acetate

ch ₂ ci ₂

Et ₃ N

MeNH ₂

NH ₄ OH

SOC1 ₂

THF:

NaH

CCL

DHFR

PtO ₂

NXS:

\

TFAA

CsF

Me ₃ SiJ

DAST

MCPBA

AIBN dichloromethane triethylamine methylamine ammonium hydroxide thionyl chloride tetrahydrofuran sodium hydride carbon tetrachloride dihydrofolate reductase platinum oxide (Adams catalyst)

N-halo-succinimide halogen trifluoroacetic anhydride cesium fluoride trimethylsilyliodide diethylamino sulfur trifluoride metachloroperbenzoic acid α, α′-azoisobutyronitrile (2,2′-azobis (2-methylpropionitrile)

Example 1

Preparation of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine

1. Preparation of N-methylpiperazinoformamidine hydroiodide

Thiocarbamide (10.8 g) was dissolved in acetone (250 ml) at 50 ° C. Iodomethane (10 ml) was added and the reaction was stirred at 50 ° C for 4 h. After cooling, the solution was diluted with ether (1 liter) and the methyl iodide salt filtered, washed with ether and dried in vacuo, 29.2 g, 113-115 ° C. The methyl iodide salt (5 g) was dissolved in water (30 ml) and N-methylpiperazine was added. The solution was stirred, purged with nitrogen at room temperature for 24 h. The solution was concentrated in vacuo, 4.98 g, mp 230-242 ° C.

2. Preparation of 2,3,5-trichlorobenzylalcohol

To a solution of 2,3,5-trichlorobenzylaldehyde (Aldrich, 50 g) in ethanol (1.0 L) at room temperature was added NaBH ₄ (7.00 g) and the resulting mixture was stirred for 3.5 h. The reaction is quenched with water and the solvent evaporated in vacuo before distribution of the residue between CHC1 ₃ and a saturated solution of NaHCO _third The organic phase was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to leave a white solid. 43.00 g, m.p. 90-93 ° C.

3. Preparation of 2,3,5-trichlorobenzyl bromide

To the solution of alcohol in benzene (400 ml) was added PBr ₃ (126.58 g) under nitrogen and the mixture was stirred at 55-60 ° C for 3.5 h. After cooling, the mixture is poured onto crushed ice (2 L) and the benzene layer precipitated. The aqueous phase was washed with benzene (x 3) and the combined benzene extracts washed with saturated NaHCO ₃ solution and water, dried over MgSO ₄ , filtered and the solvent was evaporated to leave a brownish, solidifying liquid, 37.53 g, m.p. 40-42 ° C.

4. Preparation of 2,3,5-trichlorophenylacetonitrile

The bromide was suspended in DMF (130 ml) / water (86.67 ml) at 0 ° C and KCN (12.99 g) was added portionwise. After stirring for 3 h at 30-35 ° C, the suspension was diluted with water and extracted with Et ₂ O. The combined ether extracts were washed with water, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo. Chromatography on silica gel eluting with hexane to 20% ether-hexane gave the desired product as a white solid, 18.52 g, m.p. 60-62 ° C.

5. Preparation of 2- (2,3,5-trichlorophenyl) -4,4,4-trifluoro-3-oxo-butyronitrile

To a solution of NaOEt (from 1.04 g Na) in EtOH (60 ml) at room temperature under nitrogen was added nitrile (8.40 g) and then ethyl trifluoroacetate (6.57 g) and the mixture was refluxed for 5 h. After cooling, the solvent was removed in vacuo and the residue dissolved in water. The aqueous phase was washed with Et ₂ O (discarded), acidified with H ₂ SO ₄ and extracted with Et ₂ O. The combined Et ₂ O extracts were washed with water, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to leave an oil. It is treated with light petroleum and the solid is filtered off and dried. The solid was azeotroped with toluene (x5), 4.89 g, m.p. Mp 160-163 ° C.

6. Preparation of 2- (2,3,5-trichlorophenyl) -4.4.4-trifluoro-3-methoxybut-2-enonitrile

To a solution of trifluoromethyl ketone in Et ₂ O (39.62 ml) at room temperature was added diazomethane (from 8.55 g Diazald-a) in Et ₂ O (79.62 ml) and the resulting mixture was allowed to stand at room temperature overnight. The excess of diazomethane was then removed in vacuo in AcOH and the residue was dissolved in Et ₂ O, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to leave a brownish oil, 5.20 g.

7. Preparation of 4-amino-2-4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl-6-trifluoro methyl-pyrimidine

To a solution of NaOEt (from 0.144 g Na) in EtOH (12.5 ml) was added N-methylpiperazinoformamidine hydroiodide (1.39 g). After stirring for 10 minutes at room temperature, a solution of the above intermediate (0.85 g) in EtOH (2.5 ml) was added and the resulting mixture was stirred at reflux for 4.5 h. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel, eluting with CHCl ₃ 4 4% MeOH / CHCl ₃ gave the desired product, which was treated with petroleum ether (boiling point 40-60 ° C) and dried in vacuo, 0.56 g, m.p. 127-129 ° C.

8. 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine methanesulfonate

The phenylpyrimidine base (9.6 g) was dissolved in absolute ethanol, cooled to 0 ° C and then methanesulfonic acid was added. After stirring at room temperature for 2 hours, the solution was evaporated to dryness and the residue was treated with Et ₂ O, filtered and dried in vacuo to leave a solid beige. This was dissolved in water (500 ml) and lyophilized to give a yellow-brown solid. The methanesulfonate salt can be further purified by treatment with tBuOH (30 ml), filtration, dissolution in water and repeated drying by lyophilization to give the title compound as a whitish solid.

8.33 g, m.p. 145-147 ° C.

Example 2

Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl-6-methoxymethyl pyrimidine

A. 2- (2,3,5-Trichlorophenyl) -4-methoxy-3-oxo-butyronitrile

A mixture of 2,3,5-trichlorophenylacetonitrile (11 g) and ethyl methoxyacetate (8.85 g) in dry DME (25) was added over 5 minutes to a stirred refluxed solution of sodium ethoxide (1.38 g sodium) in ethanol (25 ml). ml). After 4 h, the mixture was cooled on ice and acidified with acetic acid (about 6 ml), diluted with ice water (150 ml) and then extracted with dichloromethane (2 x 100 ml). The dichloromethane extract was washed with water, dried over MgSO ₄ and concentrated to give a yellow solid which was triturated with a little ether and filtered. 8.6 g, homogeneous based on TLC (19: 1 CH ₂ Cl: MeOH).

B. Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl-6-methoxy-methylpyrimidine

A suspension of crude acylacetonitrile (8.5 g) in ether (100 ml) was cooled on ice, treated with an excess of non-alcoholic diazomethane in ether (0.035 M). After one hour, TLC (19: 1 CH ₂ Cl ₂ : MeOH) indicated that there was no starting material. Concentrate this solution to give a brown waxy solid, which is used without further purification.

To a solution of sodium ethoxide (from 0.76 g of sodium) in ethanol (30 ml) was added guanidine hydrochloride (2.9 g). After 15 minutes, a solution of crude enol ether in ethanol (25 ml) was added and the mixture was refluxed with stirring for 4 h, cooled and concentrated. The residue was mixed with 2M NaOH (150 ml) and then the dark solid was filtered off, washed with water, air-dried and recrystallized from ethanol (150 ml). 5 g, m.p. 214-216 ° C, TLC (1: 9 MeOH: CHCl ₃ ) Rf about 0.35.

C. 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methoxymethylpyrimidine ethanesulfate

Ethanesulfonic acid (0.67 g) in ethanol (10 ml) was added dropwise to a mixed suspension of phenylpyrimidine (2 g) in ethanol (75 ml). After about 30 minutes, the solution becomes cloudy. The stirring was continued for a further 1.5 h and then the solvent was concentrated to 20 ml. Ether was added, the solid was filtered off and washed with Et ₂ O before drying in vacuo. 2.17 g, m.p. 265-268 ° C.

IT

Example 3

Synthesis of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine mesylate

1. Preparation of 2- (2,3,5-trichlorophenyl) -3-oxo-propionitrile sodium salt

To a solution of NaOEt (from 0.803 g sodium) in ice-cooled ethanol (55 ml), 2,3,5-trichlorophenyl acetonitrile was added under nitrogen (see Example 1.4). Ethylformate (5.1 ml) was added and the mixture was stirred at room temperature overnight. After stirring for the next 2.5 h at 50 ° C, the mixture was cooled and filtered. The filtrate was evaporated and the residue was treated with diethyl ether, filtered and dried (6.82 g).

2. Preparation of 2- (2,3,5-trichlorophenyl) -3-methoxy-acrylonitrile

The above solid was dissolved in DMF (36 ml) and methyl iodide (2 ml) added. The reaction vessel was closed and the mixture stirred at 40 ° C for 3 h. The solvent was then evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (MgSO ₄ ) ₂ and the solvent was evaporated to give a crude product of a reddish-brown color, which solidified under condition (5.04 g).

3. Preparation of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine

To a solution of NaOEt (0.21 g sodium) in ethanol (20 ml) was added N-methylpiperazinoformamidine hydroiodide (2.06 g) (see Example 1.1). After stirring for 10 minutes, the compound of Example 3.2 (1 g) was added to the mixture and stirred at reflux for 4 h. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated and the residue purified by chromatography on SiO ₂ , eluting with CHCl ₃ to 4% MeOH / CHCl ₃ to give the title compound as the free base. 0.89 g, m.p. Mp 162-164 ° C.

The free base (0.805 g) was dissolved in ethanol (35 ml) and cooled in an ice bath. Methanesulfonic acid (0.21 g) was added and the reaction was stirred at room temperature 2

h. The solvent was then evaporated and the residue treated with diethyl ether, filtered, dissolved in cold water and lyophilized. We obtain the title salt as a pale green solid. 0.98 g, m.p. Mp 143-146 ° C.

Example 4

Synthesis of 2,4-diamino-5-f2,3,5-trichlorophenyl) -6-trifluoromethyl pyrimidine

To a solution of NaOEt (from 0.88 g Na) in EtOH (82 ml) was added guanidine hydrochloride (2.98 g). The resulting white suspension was stirred at room temperature for 10 minutes. To this was added a solution of enol ether (Example 1.6) in ethanol (27 ml) and the resulting mixture was refluxed for 4.25 h. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 ₃ to 2% MeOH / CHCl ₃ gave the desired product, which was treated with Et ₂ O and dried in vacuo. 1.78 g, m.p. 226227 ° C.

Example 5

Preparation of 2,4-diamino-5- (4-nitro-2,3,5-trichlorophenyl) pyrimidine

The compound of Example 29 was dissolved in concentrated sulfuric acid (2.5 ml). Potassium nitrate (25.8 mg) was added and the solution stirred for 3 h. The solution was then poured onto ice and basified with ION NaOH. The product was extracted with ethyl acetate (x3), dried over MgSO ₄ , filtered and the solvent was evaporated. Chromatography on silica gel eluting with ethyl acetate gave the desired product. 40.7 mg, m.p. 293-295 ° C.

Example 6

Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) -6-methyl pyrimidine

1. Preparation of 2- (2,3,5-trichlorophenyl) -3-oxobutyronitrile

To a solution of NaOEt (from 0.68 g of sodium) in ethanol (20 ml) was added 2,3,5 trichlorophenylacetonitrile (5 g) and ethyl acetate (4.43 ml). The mixture was refluxed under nitrogen for 2.5 hours. The mixture was allowed to stand at room temperature overnight. The mixture was then concentrated and the residue dissolved in water. The aqueous phase was washed with ether, acidified with concentrated H ₂ SO ₄ and extracted with ether. The extracts were collected, dried (MgSO ₄ ) and evaporated. 2.59 g, m.p. 134-135 ° C.

2. Preparation of (2- (2,3,5-trichlorophenyl-3-methoxybut-2-enonitrile)

To a solution of ketone in ether (100 ml) at room temperature was added diazomethane (from 5.43 Diazald-a) in ether (50 ml) and the resulting mixture was allowed to stand at room temperature overnight. The ether is then distilled off to leave the desired product. 2,45 g.

3. Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) -6-methyl-pyrimidine

Guanidine hydrochloride (3.87 g) was added to a solution of sodium ethoxide (from 1.01 g sodium) in ethanol (80 ml). The resulting white suspension was stirred at room temperature for 10 minutes and then added to a solution of enol ether (Example 6.2) (5.60 g) in ethanol (20 ml). The resulting mixture was stirred at reflux for 8 h under nitrogen. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 ₃ to 2% MeOH / CHCl ₃ gave the desired product, which was treated with ether and dried in vacuo. Yield 1.70 g, m.p. 236-238 ° C.

Example 7

Preparation of 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine

To a solution of NaOEt (from 0.144 g Na) in EtOH (12.5 ml) was added morpholinoformamidine hydrobromide (1.08 g) (Lancaster Synthesis). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of enol ether (0.85 g) (Example 1.6) in EtOH (2.5 L) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHCl3 afforded the desired product, which was treated with petroleum ether (boiling point 40-60 ° C) and dried in vacuo. 0.47 g, m.p. 177-181 ° C.

Example 8

Preparation of 4-amino-2-fN, N-dimethylamino) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine

To a solution of NaOEt (from 0.144 g Na) in EtOH (12.5 ml) was added 1,1-dimethylguanidine sulfate (1.4 g) (Aldrich). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of 2- (2,3,5-trichlorophenyl) -4,4,4-trifluoro-3-methoxybut-222 enonitrile (see Example 1.6) (0.85) in EtOH (2.5 ml) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHCl ₃ gave the desired product. 0.61 g, m.p. 124-126 ° C.

Example 9

Synthesis of 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -pyrimidine

To a solution of NaOEt (from 0.21 g sodium) in ethanol (20 ml) was added morpholinoformamidine hydrobromide (1.6 g). After stirring for 10 minutes, the adduct of Example 3.2 (1 g) was added and the mixture was refluxed for 4 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated. The residue was purified by chromatography on SiO ₂ and elution with CHCl ₃ to give the desired product, 0.73 g, m.p. Mp 168-170 ° C.

Example 10

Synthesis of 4-amino-2- (N, N-dimethylaminol-5- (2,3,5-trichlorophenyl) -pyrimidine

To a solution of NaOEt (0.21 g sodium) in ethanol (20 ml) was added 1,1-dimethylguanidinesulfate (2.07 g). After stirring for 10 minutes, the adduct of Example 3.2 (1 g) was added and the mixture was refluxed for 4 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on SiO ₂ and elution with CHCl 3 to give the desired product, 0.69 g, m.p. 145-147 ° C.

Example 11

To a solution of NaOEt (0.16 g sodium) in ethanol (15 ml) was added N-methylpiperazinoformamidine hydroiodide (1.6 g). After stirring for 10 minutes, the enolniether of Example 6.2 (0.82 g) in ethanol (5 ml) was added to the solution and the mixture was refluxed for 5 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated. The residue was purified by chromatography on a SiO ₂ gel, eluting with CHC1 ₃ to 4% MeOH / CHCl ₃ to give the desired product. 0.31 g, m.p. Mp 156-159 ° C.

Example 12

Synthesis of 2,4-diamino-6-methyl-5- (2,3,5-trichloro-4-nitrophenyl) pyrimidine

2,4-Diamino-6-methyl-5- (2,3,5-trichlorophenyl) pyrimidine (0.152 g) (Example 6) was dissolved in concentrated sulfuric acid and then potassium nitrate (50 mg) was added. The solution was stirred at room temperature overnight and then poured onto ice and basified with 0.880 ammonia. The product was extracted into ethyl acetate, collected, dried (MgSO ₄ ) and evaporated. The residue was purified by chromatography on SiO ₂ gel, eluting with ETOAc to 8% MeOH / EtOAc to give the desired product. 0.13 g, m.p. 313-315 ° C.

Example 13

Synthesis of 4-amino-2- (N, N-dimethylamino) -6-methyl-5- (2,3,5-trichlorophenyl) -pyrimidine

To a solution of NaOEt (0.16 g sodium) in ethanol (15 ml) was added 1,1-dimethylguanidinesulfate (1.6 g). After stirring for 10 minutes, the enol ether of Example 6.2 (0.82 g) in ethanol (5 ml) was added and the mixture was refluxed for 5 hours. The mixture was allowed to stand at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on SiO ₂ gel, eluting with CHCl3 to give the desired product, 54 mg, m.p. Mp 151-153 ° C.

Example 14

Synthesis of 2,4-diamino-5- (2,3, -dichlorophenyl) -6-trifluoromethyl-pyrimidine

1. Preparation of 2,3-dichlorobenzylalcohol

To a solution of 2,3-dichlorobenzaldehyde (Aldrich, 50 g) in alcohol (800 ml) at room temperature was added NaBH ₄ (8.54 g) and the resulting mixture was stirred for 1.5 hours. The reaction was quenched with water and the solvent was evaporated in vacuo before partitioning the residue between CHCl ₃ and saturated NaHCO ₃ solution _{. The} organic phase was washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to leave a white solid, 48.38 g. , tal. 87-87.5 ° C.

2. Preparation of 2,3-dichlorobenzyl bromide

To the solution of alcohol in benzene (500 ml) under N _{2 was} added PBr ₃ (167.8 g) and the mixture was stirred at 55-60 ° C for 3.5 hours. After cooling, the mixture is poured onto crushed ice (21) and the benzene layer is decided. The aqueous phase was washed with benzene (x3), and the combined benzene extracts were washed with saturated NaHCO ₃ solution and water, dried over MgSO ₄ , filtered and the solvent was evaporated to leave a brownish liquid substance which was in contact with the liquid. 37.53 g, m.p. 31-32 ° C.

3. Preparation of 2,3-dichlorophenylacetonitrile

The bromide was suspended in DMSO (155 ml / water (105 ml) at 0 ° C and KCN (20.24 g) was added in parts. After stirring at 30-35 ° C for 2 hours, the suspension was diluted in water and extracted with Et ₂ O. The combined ether extracts were washed with water, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to leave a white solid, 27.52 g, mp 64-67 ° C.

4. Preparation of 2- (2,3-dichlorophenyl) -4,4,4-trifluoro-3-oxo-butyronitrile

To a solution of NaOEt (from 1.48 g Na) in EtOH (25 ml) at room temperature below N _{2 was} added nitrile (10.0 g) and then ethyltrifluoroacetate (9.3 g) and the mixture was refluxed for 5 hours. After cooling, the solvent was removed in vacuo and the residue dissolved in water. The aqueous phase was washed with Et ₂ O (discarded), acidified with H ₂ SO ₄ and extracted with Et ₂ O. The combined Et ₂ O extracts were washed with water, dried over MgSO ₄ , filtered and the solvent evaporated in vacuo to leave an oil. This is triturated with petroleum ether and the solid is filtered off and dried. 9.56 g, m.p. 74-75 ° C.

5. Preparation of 2- (2,3-dichlorophenyl) -4,4,4-trifluoro-3-methoxybut-2-enonitrile

To a solution of trifluoromethyl ketone in Et ₂ O (90 ml) at room temperature was added diazomethane (from 19.35 g Diazald-a) in Et ₂ O (180 ml) and the resulting mixture was allowed to stand at room temperature overnight. The excess diazomethane was then removed in vacuo in AcOH and the residue dissolved in Et ₂ O, dried over MgSO ₄ , filtered and the solvent evaporated in vacuo to leave a brownish solid, 6.44 g.

6. Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-trifluoromethyl-pyrimidine

To a solution of the above single ether in ethanol (33 ml) was added guanidine hydrochloride (1.92 g) and then a solution of NaOEt (from 540 mg Na) in EtOH (90 ml) and the resulting mixture was refluxed for 3 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 ₃ to 2% MeOHCHC1 ₃ gave the desired product, which was treated with Et ₂ O and dried in vacuo, 673 mg, m.p. 218-9 ° C.

7. 2,4-Diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine-methanesulfonate

To the free base suspension (100 mg) in ethanol was added methanesulfonic acid (30 mg) and the resulting clear solution was stirred at room temperature for 2 hours. The solution was evaporated to dryness and the resulting solid was triturated with ether, filtered and dried in vacuo, 107 mg, m.p. 253-256 ° C.

8.2,4-diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine hydrochloride

Ether hydrogen chloride was added to a solution of free base (150 mg) in methanol. After stirring, the solvent was evaporated to dryness and the resulting solid was triturated with ether, filtered and dried in vacuo, 160 mg, m.p. 233-236 ° C.

Example 15

Synthesis of 2,4-diamino-5- (2,3-dichlorophenyl) -6-methylpyrimidine

This compound was prepared in an analogous manner with the compound of Example 6 of 2,3dichloroacetonitrile, m.p. 245-247 ° C.

Example 16

Synthesis of 2,4-diamino-5- (2,3-dichlorophenyl) -4-methoxy-3-oxo-butyronitrile

1. Preparation of 2- (2,3-dichlorophenyl) -4-methoxy-3-oxo-butyronitrile

A mixture of ethylmethoxyacetate (8.85 g) and 2,3-dichlorophenylacetonitrile (Example 14.3) (9.3 g) dissolved in DME (20 ml) was added to a stirring reflux solution of NaOEt (from 1.38 g Na) in EtOH (25 ml). ) within 5 minutes. After 5 hours a precipitate appears (sodium salt of the product). The mixture was cooled and filtered, the filtrate was evaporated to dryness in vacuo and the residue was partitioned between ether and water (discarded ether phase). The aqueous residue was acidified with 2N H ₂ SO ₄ and extracted with ether (2x). The combined Et ₂ O extracts were washed with water, dried over MgSO ₄ , filtered and evaporated in vacuo to give a yellow solid (a). The sodium salt (above) was dissolved in water and the solution was extracted with ether and discarded. The aqueous solution was acidified with 2N H ₂ SO ₄ and extracted with ether. The ether extract was washed with water, dried over MgSO ₄ , filtered and evaporated in vacuo to give a white solid (b).

The above products (a) and (b) were combined to give a yield of 10.4 g, which was used without further purification. One stain using TLC (19: 1 CH ₂ C1 ₂ : MeOH) Rf0.35.

2. Preparation of 2- (2,3-dichlorophenyl) -3,4-dimethoxybut-2-enonitrile

Diazomethane (0.4-0.45 M) in ether was added portionwise to a mixed solution of the above nitrile (9.4 g) in ether. Strong foaming occurs initially and no further reaction is generated after further addition. The mixture was allowed to stir at room temperature for 3 hours and evaporated in vacuo in AcOH to give a single ether.

3. Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-methoxymethylpyrimidine

To a solution of NaOEt (from 0.92 g Na) in EtOH (40 ml) was added guanidine hydrochloride (3.44 g). A solution of enol ether (above) in EtOH (30 ml) was added from the mixture to reflux for about 3 hours. After cooling, the solvent was evaporated in vacuo and the residue was treated with 5N NaOH (about 50 ml). The red solid was filtered, dissolved in AcOH (about 20 ml), diluted with water (40 ml), treated with charcoal and filtered. The filtrate (yellow solution) was basified with 2N NaOH and the white precipitate was filtered, dried and recrystallized from EtOH, 4.39 g, m.p. 237-240 ° C.

Example 17

Preparation of 2,4-diamino-5- (1-naphthyl) pyrimidine

To a solution of NaOEt (from 1.45 g Na) in ethanol (60 ml) at room temperature below N _{2 was} added 1-naphthylacetonitrile (Aldrich, 10.02 g). After stirring for 10 minutes, ethylfor 27 miate (8.88 g) was added and the mixture was stirred at reflux for 5 hours. The mixture was cooled, the solvent was evaporated and the residue triturated with Et ₂ O before filtration and drying of the solid in vacuo (6.86 g).

The above was dissolved in DMF (45 ml), methyl iodide (5.4 g) was added and the reaction vessel was closed before stirring the contents at 40 ° C for 4 hours. The solvent was then removed in vacuo and the residue partitioned between EtOAc and water. The organic phase was washed with water, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to leave the crude product as a viscous reddish oil (5.4 g).

To a solution of NaOEt (from 1.19 g Na) in ethanol (80 ml) was added guanidine hydrochloride (4.94 g). After stirring for a further 5 minutes, the above intermediate in ethanol was added and the resulting mixture was stirred at reflux for 3.5 hours. After cooling, the solvent was removed in vacuo and the residue partitioned between CHCl3 and water. The organic phase was washed with water, dried over MgSO ₄ , filtered and the solvent evaporated to leave a pale yellow solid. Chromatography on SiO ₂ eluting with up to 4% CHC1 ₃ in CHCl ₃ : MeOH and then recrystallization from ethanol gives this desired product as a white substance. 2.82 g, m.p. 171-3 ° C.

Example 18

Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-fluoromethyl-pyrimidine

1- 2,4-Diamino-5- (2,3-dichlorophenyl) -6- (diethoxymethyl) -pyrimidine

To a stirring reflux solution of NaOEt (from 1.38 g Na) in ethanol (25 ml) was added over a 5 minute period a mixture of ethyldiethoxyacetate (13.21 g; 75 mmol) and (Example 14.3) 2,3 dichlorophenylacetonitrile (9.3 g; 50 mmol) ) in dry dimethoxyethane (20 ml). After 4 hours, it was cooled and evaporated in vacuo. The residue was partitioned between water (100 ml) and ether (100 ml), the ether phase discarded and the aqueous residue acidified with IN H ₂ SO ₄ . Extraction with CH ₂ C1 ₂ gave acylacetonitrile (13.47 g), which was used without further purification.

A solution of diazomethane (about 3 g) in ether was added portionwise to a stirred solution of the above acylacetonitrile in ether (100 ml), which was cooled on ice. After 2 hours the solution was evaporated in vacuo to give the desired enol ether as an oil which was used without further purification.

To a solution of NaOEt (1.4 g sodium) in ethanol (50 ml) was added guanidine hydrochloride (4.8 g; 50 mmol). A solution of the above single ether in ethanol (20 ml) was added and the mixture was refluxed for 4 hours, cooled and concentrated in vacuo to give a dark purple solid which was filtered, dissolved in CH ₂ C1 ₂ , washed with water, dried over MgSO ₄ and evaporated in vacuo. The residue was triturated with ethanol (50 ml) and filtered to give the desired product (8.4 g), which was used without further purification (mp 214-217 ° C).

2. 2,4-Diamino-5- (2,3-dichlorophenyl) pyrimidine-6-carboxaldehyde

The mixture of the above acetal (7 g) and 0.4M HCl (150 ml) was refluxed with stirring for 1 hour, cooled on ice and neutralized with 2M NaOH. The mixture was filtered, washed with water and air-dried to give the desired product (6.2 g), which was used without further purification.

3.2.4-Diamino-5- (2,3-dichlorophenyl) -6-hydroxymethylpyrimidine

Sodium borohydride (110 mg; 3 mmol) was added to a stirred solution of the above aldehyde (2.8 g; 10 mmol) in a mixture of dimethoxyethane (15 ml) and ethanol (15 ml). After 30 minutes, the solution was treated with water (50 ml) and a few drops of acetic acid were added to destroy excess borohydride. It was extracted with dichloromethane (2 x 50 ml), washed with water and the extract was then dried over MgSO ₄ . Evaporation of the solvent in vacuo gave a pink solid, which was triturated with ether, filtered and dried (1.6 g). Recrystallization from methanol (50 ml) gave the desired product as fine colorless crystals 0.65 g, m.p. 173-6 ° C.

4.2.4-Diamino-5- (2,3-dichlorophenyl) -6-fluoromethylpyrimidine

To a stirred suspension of 2,4-diamino-5- (2,3-dichlorophenyl) -6-hydroxymethylpyrimidine (185 mg; 1 mmol) in dry dichloromethane (25 ml) was added under nitrogen at -70 ° C by dropwise addition of diethylamine sulfur trifluoride (263 μ \; 2 mmol). The mixture was allowed to warm to 0 ° C and maintained at this temperature for 4 hours. After cooling to -70 ° C, the mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane (2 x 50 ml), washed with saturated brine and dried (MgSO ₄ ). Concentration gave a colorless gum (0.2 g). Chromatography on silica gel, eluting with a mixture of 0.01: 1: 19 Et ₃ N: MeOH: CH ₂ Cl ₂ gave the desired product, which was triturated with CCl ₄ and dried in vacuo. 111 mg, m.p. 224-6 ° C.

Example 19

2,4-Diamino-5- (2,3-dichlorophenyl) -6-phenoxymethylpyrimidine

A mixture of 2,3-dichlorophenylacetonitrile (9.3 g) and ethylphenoxyacetate (13.5 g) in dry dimethoxyethane was added over 10 minutes to a stirred solution of NaOEt (from 1.38 g sodium) in ethanol (70 ml) at reflux. (50 ml). After stirring at reflux for 3 hours, the mixture was cooled, filtered and the solvents were evaporated in vacuo. The residue was dissolved in water, washed with ether (discarded), acidified with 2N hydrochloric acid and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO ₄ ) and evaporated in vacuo to leave a yellow-brown solid (8 g) which was used without further purification.

To a suspension of crude acylacetonitrile (8 g) in ether (150 ml) was added in part the excess solution of diazomethane in ether. After stirring for 1 hour at room temperature, the solution was concentrated in vacuo to give a single ether, which was used without further purification.

Guanidine hydrochloride (2.39 g) was added at room temperature to a solution of sodium ethoxide (0.63 g sodium) in ethanol (25 ml). After 15 minutes, a solution of the above enol ether in ethanol (25 ml) was added and the mixture was refluxed for 4 hours. After cooling, the solvent was evaporated in vacuo. The residue was suspended in 2N NaOH (75 ml), filtered, washed with water, air-dried and recrystallized from ethanol to give the desired product as a colorless solid. 3.82 g, m.p. 211-213 ° C.

Example 20

2,4-diamino-5-f2,3-dichlorophenyl) -6-methylthiomethylpyrimidine

A mixture of 2,3-dichlorophenylacetonitrile (9.3 g) and ethylmethylthioacetate (10.07 g) in dry dimethoxyethane (20) was added over 5 minutes to a stirred solution of NaOEt (from 1.38 g of sodium) in ethanol (25 ml). ml). After stirring for 5 hours at reflux, the mixture was cooled on ice, acidified with acetic acid (5 ml), poured into ice water and extracted with dichloromethane. The combined extracts were washed with water, dried (MgSO ₄ ) and concentrated to give a yellow oil which was used without further purification.

The crude acylacetonitrile was heated under N ₂ with triethylorthoformiate (40 ml) to 140-150 ° C for 4 hours and the material was distilled off at low boiling point. After cooling, the mixture was concentrated in vacuo to leave a dark oil (15.2 g). The oil was dissolved in ethanol (20 ml) and added to a mixture of guanidine hydrochloride (4.8 g) and sodium ethoxide (from 1.38 g sodium) in ethanol (50 ml). After stirring at reflux for 4 hours, the mixture was cooled and concentrated in vacuo. The residue was shaken with 5M NaOH to give a dark oil, which was extracted with dichloromethane, washed with water and dried (MgSOJ. Concentration in vacuo left a dark gum. The desired product was crystallized from ethanol (20 ml) as a light yellow brown solid. 0.57 g, mp 205-7 ° C.

Example 21A

Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) pyrimidine

a. 2- (2,3-Dichlorophenyl) -3-oxo-propionitrile

To a solution of NaOEt (from 3.63 g Na) in ethanol (500 ml) was added 2,3 dichlorophenylacetonitrile (Example 14.3) in ethanol (150 ml). Ethylformate (16.67 g) was then added and the mixture was stirred at 80 ° C for 45 minutes before further volumes of ethylformate (2.78 g) were added. After stirring at 80 ° C, the precipitate was filtered off and dried under vacuum for 1.5 hours. The solid was dissolved in water, filtered, acidified with concentrated hydrochloric acid and the precipitate filtered and dried in vacuo, 14.35 g, 45% yield.

b. A solution of the above product, ethylene glycol (9.19 g), and p-toluenesulfonic acid (8.9 g) in toluene (100 ml) was stirred at reflux with water collected in Dean and Stark traps. After cooling, the solution was washed with water, 1N NaOH and water before drying over MgSO ₄ . Evaporation of the solvent gave an oil (20.17 g) which was dissolved in EtOH (70 ml). After 1 hour, the cream precipitate was filtered off and dried in vacuo (10.44 g).

c. To a solution of NaOMe (5.1 g) in ethanol (75 ml) was added guanidine hydrochloride (8.2 g). After stirring for 30 minutes, NaCl was filtered, the above acetal was added and the mixture was stirred at reflux for 1 hour. The solvent was then concentrated and the product filtered off. Recrystallization from ethanol gave the product as a white solid, 7.67 g, 70% yield, m.p. 212.5-214 ° C.

The diamino pyrimidine (6.12 g) was dissolved in ethanol (250 ml), concentrated hydrochloric acid (2.07 ml) was added and the suspension was cooled vigorously for 2 hours. The precipitate was then filtered off and dried to give the hydrochloride salt, 5.52 g.

Example 21B

a. 2,3-Dichlorophenylacetic acid

The concentrated hydrochloric acid (100 ml) was poured onto crushed ice (150 ml), the solution was added to 2,3-dichlorophenylacetonitrile (30.6 g) and the mixture was refluxed for 3 hours. After cooling, the mixture was diluted with water (500 ml), extracted with EtOAc (600 ml) and the organic phase was washed with brine before drying over MgSO ₄ . Evaporation of the solvent left a white solid, 31.3 g.

b. Ethyl 2,3-dichlorophenyl acetate

To the acid suspension in ethanol (200 ml) was added concentrated H ₂ SO ₄ (1 ml) and the mixture was stirred at reflux for 3 hours. After cooling, the solvent was evaporated and the residue was treated with concentrated NH ₄ OH (3 ml) in water (50 ml). The organic phase was extracted into CE? C ?, dried over MgSO ₄ and the solvent evaporated to leave a clear liquid, 19.88 g.

c. Ethyl 2,3-dichlorophenyl acetate

Acetane anhydride (0.5 ml) was added to a mixture of ester, morpholine (40.7 g) and ethylorthoformate (69.24 g) and the resulting pale yellow solution was stirred at reflux for 3 hours. After cooling, the mixture was concentrated in vacuo. A white precipitate begins to form and is filtered off before concentrating the filtrate to give a brownish clear oil. The overnight condition in vacuo gave a yellow solid, 34.34 g.

d. 5- (2,3-Dichlorophenyl) isocytosine

Guanidine hydrochloride (26.6 g) suspended in sodium 2-methoxyethoxide (from 6.6 g Na) in 2-methoxyethanol (150 ml) was added to the above ester and the mixture was stirred at reflux overnight. After cooling, the mixture was concentrated in vacuo, diluted with water (100 ml) and then washed with Et ₂ O (200 ml). The aqueous phase was acidified with AcOH and the precipitate filtered and washed with EtOH and then with Et ₂ O before drying in vacuo, 13.48 g.

e. N ^1- (4-chloro-5- (2,3-dichlorophenyl) -2-pyrimidinyl-N-N-dimethylformamidine

To the mixture of the above isocytosine (14.4 g), in CH ₂ C1 ₂ (200 ml), a fresh Vilsmeier-Haack reagent (from 2.75 equivalents of SOCl ₂ and 2.58 equivalents of DMF) was added dropwise over 30 minutes and the mixture reflux for 6 hours. After cooling, slowly add IN NaOH (250 ml). The aqueous phase was washed with CH ₂ Cl ₂ and the combined organic extracts were washed with brine before drying over MgSO ₄ . Solvent evaporation and chromatography on SiO ₂ gel eluting with EtOAc gave 13.6 g, m.p. 113-115 ° C.

f. 2-amino-4-chloro-5- (2,3-dichlorophenyl) pyrimidine

To formamidine in EtOH (50 ml) was added ethanol MeNH ₂ (8 eq) in EtOH (50 ml) and the mixture was sealed in a Parr reaction vessel before stirring at room temperature for 5 h. The reaction mixture was then concentrated in vacuo, the residue was stirred with 1N NaOH (75 ml), filtered, washed with water and dried in vacuo, 11.2 g, m.p. 228-30 ° C.

Mr Rücker 2,4-Diamino-5- (2,3-dichlorophenyl) pyrimidine

To 2-amino-4-chloro-5- (2,3-dichlorophenyl) pyrimidine (6.73 g) was added ethanol ammonia (30 eq in 50 ml EtOH) and the mixture was sealed in a Parr reaction vessel and heated to 125 ° C 38 hours After cooling, the mixture was concentrated in vacuo and the residue was stirred with 1N NaOH (75 ml), filtered, washed with water and dried in vacuo, 6.14 g, m.p. Mp 208-211 ° C.

Example 22

Synthesis of 2,4-diamino-5- (2-chlorophenyl) -pyrimidine

This compound was prepared according to JACS (1951), 73, 3763-70, m.p. 225 ° C.

Example 23

Synthesis of 2,4-diamino-5-yl-chlorophenyl) -6-methyl-pyrimidine

This compound was prepared according to JACS (1951), 73, 3763-70, m.p. 125-8 ° C.

Example 24

Synthesis of 2,4-diamino-5-f2-chlorophenyl-6-ethylpyrimidine

Prepare as in Example 22 except that ethyl propionate replaces ethyl acetate, m.p. 197-8 ° C.

Example 25

Synthesis of 2,4-diamino-5- (2,4-dichlorophenyl) -6-trifluoromethyl-pyrimidine

This compound was prepared in an analogous manner as the compound of Example 14 from 2,4-dichlorophenylacetonitrile (Aldrich); mp: 220.5-221 ° C.

Example 26

Synthesis of 6-benzyloxymethyl-2,4-diamino-5- (2,4-dichlorophenylpyrimidine

This compound was prepared in an analogous manner as the compound of Example 16 from 2,4 dichlorophenyl acetate and ethylbenzyloxyacetate, 3.77 g, m.p. 171-172 ° C.

Example 27

2- (4-methylpiperazin-1-yl-4-amino-5- (2,4-dichlorophenyl) pyrimidine

A) Prepare a solution of 55.7 g (0.4 eq.) Of S-methylisothiocarbamide sulfate in 280 ml of water and heat gently on a steam bath with stirring. Then, 40 g (0.4 mol) of N-methyl-piperazine are slowly added to the solution by blowing the flask with nitrogen. The developed gases were collected in a few portions of a solution of 132 g of mercuric chloride in 400 ml of ethanol, which caused the developed methylmercaptan to precipitate as methyl mercuric chloride. When the addition of N-methylpiperazine is complete, the reaction is continued until methyl mercuric chloride has ceased to precipitate. The reaction mixture was then concentrated in vacuo and cooled strongly, causing it to crystallize N-methylN′-amidinopiperazine sulfate; we collect 50.79 g.

B) A mixture of 76.3 g (0.356 mol) of alpha-formyl-2,4-dichlorophenylacetonitrile, 63.7 g of isoamylalcohol, 0.36 g of p-toluenesulfonic acid, 895 ml of toluene and 10 drops of concentrated sulfuric acid is refluxed for 20 hours in the presence of Dean &

Stark traps to remove the water that forms in the reaction. An equal proportion of i-amylalcohol is then added and a few drops of sulfuric acid are added and the reaction is heated for a further 20 hours until the theoretical amount of water is collected. The solution is strongly cooled.

C) Dissolve 8.2 g of a large piece of sodium in 500 ml abs. ethanol and 50 g of N-methylN'-amidinopiperazine sulfate were added. The mixture was allowed to stir for 10 minutes. This was then added to solution B. The mixture was stirred at reflux for 6 hours, allowed to stand overnight and the solvent removed in vacuo. The residue is then extracted with dilute hydrochloric acid, which dissolves most of the residue. The solution is extracted three times with ether and then the aqueous fraction is neutralized, which precipitates the rubber which hardens overnight; weight 30 g. This substance was recrystallized from 50% ethanol using decolorizing charcoal. Very slow cooling was required to form crystals; m.p. 137 ° C.

Anal. calcd. for C ₁₅ H ₁₇ C1 ₂ N ₅

C, 53.27; H, 5.14; N, 20.21;

Found: C, 53.58; H, 5.14; N, 20.40.

Example 28

Synthesis of 2,4-diamino-5- (2,5-dichlorophenyl) -6-trifluoromethylpyrimidine

This compound was prepared in an analogous manner as the compound of Example 14 from 2,5 dichlorobenzyl alcohol (Lancaster Synthesis, 48.26 g) to give the title compound in a yield of 3.85 g, m.p. Mp 215-217 ° C.

Example 29

Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) pyrimidine

Guanidine hydrochloride (3.20 g) was added to a solution of sodium ethoxide (from 848 mg sodium) in ethanol (52 ml). The resulting white suspension was stirred at room temperature for 10 minutes. The enol ether of Example 3.2 (4.40 g) was added and the resulting mixture was stirred under reflux for 3.5 hours. After cooling, the suspension was filtered and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHC1 ₃ to 3% MeOH-CHCl ₃ gave the desired product, which was triturated with ether and dried in vacuo. Yield = 2.01 g, m.p. 246-249 ° C.

Example 30

Synthesis of 4-amino-5- (3-bromophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) -pyrimidine

To a solution of NaOEt (from 0.92 g of sodium) in ethanol (75 ml) was added

3-bromophenylacetonitrile (aldrich, 7.85 g) and ethyl acetate (3.52 g). The mixture was refluxed for 6 hours. After cooling, the mixture was concentrated and the residue dissolved in water. The aqueous phase was washed with ether, acidified with 2N HCl and extracted with ether. The extracts were collected, dried (MgSO ₄ ) and boiling point, 3.8 g, m.p. 97-103 ° C.

The resulting ketone (3.7 g), ethylene glycol (5 ml) and p-toluenesulfonic acid (100 mg) were refluxed in toluene (100 ml) in a Dean & Stark apparatus for 3.5 hours. The mixture was cooled, concentrated and water was added to the residue. The product was extracted with ether and the extracts were collected, dried (MgSO ₄ ) and evaporated, 4.03 g, m.p. 68-71 ° C.

To a solution of NaOEt (0.28 g sodium) in ethanol (30 ml) was added N-methylpiperazinoformamidine hydroiodide (2.7 g). After stirring for 10 minutes, ketal (1.41 g) was added and the mixture was refluxed for 4 hours. After cooling, the suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography on a SiO ₂ gel, eluting with 10% MeOH / CHCl2 to give the desired product, 0.48 g, m.p. 120-122 ° C.

Example 31

Synthesis of 2,4-diamino-5- (1-naphthyl) -6-trifluoromethylpyrimidine

This compound was prepared in an analogous manner as the compound of Example 14 from 1-naphthylacetonitrile (Aldrich, 10 g) to give the title compound in a yield of 0.69 g, m.p. 224-226 ° C.

Example 32

Preparation of 2-amino-5- (2,4-dichlorophneyl) -4,6-dichloropyrimidine

1. Ethyl-2,4-dichlorophenyl acetate

2,4-Dichlorophenylacetonitrile (27.9 g, 150 mmol) was suspended in 2N NaOH (400 ml) and the mixture was refluxed for 4 hours. The cooled reaction mixture was extracted with ether (2 x 200 mL), acidified to pH 3 and the solid filtered off and dried (22 g, 70%).

The product (20 g) was dissolved in EtOH (300 ml) and concentrated H ₂ SO ₄ (5 ml) was carefully added. The mixture was refluxed for 7 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue was partitioned between CH ₂ Cl ₂ and water (30 ml each). The organic layer was extracted with saturated NaHCO ₃ solution (200 ml), washed with water (100 ml), dried and evaporated in vacuo to give ethyl-2,4dichlorophenyl acetate as an oil (22.2 g, 89.5%).

2. Diethyl-2,4-dichlorophenylmalonate

Sodium (1.86 g, 0.081M) was added portionwise into abs. ethanol (150 ml) with stirring. After all the sodium was dissolved, a solution of ethyl 2,4-dichlorophenyl acetate (20 g) in diethyl carbonate (40 ml) was added dropwise. The reaction mixture was heated until EtOH was distilled off. The rate of addition is controlled to be equal to the rate of distillation. After the addition is complete, the reaction mixture is heated and distilled for a further 4 hours. The cooled reaction mixture was partitioned between water (300 ml) and EtOAc (300 ml) and the organic layer was dried and evaporated in vacuo to give a yellow oil (21 g, 85%).

3. 2-amino-5- (2,4-dichlorophenyl) -4,6-dihydroxypyrimidine

Sodium (4.52 g, 0.196 M) was added portionwise to ethanol (150 ml). After all the sodium was dissolved, guanidine hydrochloride (12.44 g, 0.13M) was added followed by diethyl-2,4-dichlorophenylmalonate (20 g, 0.0655M). The mixture was refluxed for 6 hours, the EtOH was separated under reduced pressure and the residue was partitioned between 2N NaOH (400 ml) and EtOAc (400 ml). The aqueous layer was acidified with concentrated hydrochloric acid upon cooling, and the precipitated material was filtered and dried (11 g, 62%).

4. 2-amino-5- (2,4-dichlorophenyl) -4,6-dichloropyrimidine

A mixture of 2-amino-5- (2,4-dichlorophenyl) -4,6-dihydroxypyrimidine (10 g), phosphoryl chloride (100 ml) and dimethylaniline (1.5 ml) was refluxed for 6 hours. The cooled reaction mixture was carefully added to the crushed ice and the insoluble solid filtered off and washed with 2N HCl and then with water. The solid was resuspended in water, neutralized (0.88 NH ₄ OH) under cooling, and the mixture was left overnight at room temperature. The insoluble material was filtered, dried and purified by flash column chromatography to give the title compound (2.5 g, 22%), m.p. 211-213 ° C. Microanalysis:

Calc .:

Found:

C, 38.83; H, 1.6; N, 13.59; C, 38.59; H, 1.53; N, 13.40.

Example 33

Synthesis of 2,4-diamino-6-chloro-5- (2,4-dichlorophenyl) pyrimidine

Mixture of 2-amino-4-chloro-5- (2,4-dichlorophenyl) -4-6-dichloropyrimidine (0.5 g) (Example 32), ammonia-saturated EtOH (20 ml) and copper powder (0.05 g) was heated in an autoclave at 180 ° C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.12 g, 25%), m.p. 219 ° C. Microanalysis:

Calcd: C, 40.82; H, 2.55; N, 19.05;

Found: C, 41.27; H, 2.46; N, 18.74.

Example 34

Synthesis of 2-amino-4-chloro-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine

Mixture of 2-amino-5- (2,4-dichlorophenyl) -4,6-dichloropyrimidine (0.5 g) (Example 32), THF (15 ml), methanethiol sodium salts (0.113 g), copper powder (0 , 05 g) and tris [2- (2methoxyethoxy) ethyl] amine (0.1 g) were heated in an autoclave at 180 ° C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.262 g, 52%), m.p. 201-202 ° C (softens to 196 ° C). Microanalysis:

Calc .:

Found:

C, 41.19; H, 2.50; N, 13.10; C, 41.10; H, 2.52; N, 12.77.

Example 35

Synthesis of 2,4-diamino-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine

Mixture of 2-amino-4-chloro-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine (0.5 g) (Example 32), ammonia-saturated EtOH (20 ml), copper powder (0 , 05 g) and tris- [2- (2methoxyethoxy) ethyl] amine (0.01 g) were heated in an autoclave at 180 ° C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.11 g, 23.5%), m.p. 191-192 ° C. Microanalysis:

Calcd for 0.2 hydrate: C, 43.33; H, 3.41; N, 18.38;

Found: C, 43.37; H, 3.23; N, 18.33.

Example 36

4-amino-5- (3,5-dichlorophenyl) -6-methyl-2-4-methylpiperazin-1-yl) -pyrimidine

a. 3,5-dichlorophenylacetonitrile

A mixture of 3,5-dichlorobenzyl alcohol (Aldrich, 25 g), thionyl chloride (100 ml) and DMF (0.5 ml) was stirred and refluxed for 4 hours. After cooling, the mixture was concentrated in vacuo, the residue collected in ether, washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO ₄ ) and concentrated in vacuo to give 3,5-dichlorobenzoyl chloride as a light yellow solid, which was used without further purification, 28 mg, m.p. 3236 ° C.

To a strongly stirred solution of 3,5-dichlorobenzyl chloride (28 g) in dichloromethane (150 ml) was added a mixture of KCN (27.5 g) and tetrabutylammonium bisulfate (2.38 g) in water (110 ml). After stirring at room temperature for 22 hours, the mixture was diluted with dichloromethane, the organic phase was washed with water and concentrated in vacuo to leave an oil. Filtration through silica with toluene and then concentration and trituration with hexane give the desired product as a colorless solid. 15.8 g, m.p. 31-32 ° C.

b. 4-amino-5- (3,5-dichlorophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) pyrimidine

A mixture of 3,5-dichlorophenylacetonitrile (9.3 g) and ethyl acetate (3.3 g) in dry dimethoxyethane (10) was added over 5 minutes to a stirred solution of NaOEt (0.69 g sodium) in ethanol (25 ml). ml). After stirring at reflux for 4 hours, the mixture was cooled on ice, acidified with acetic acid, poured into cold water and extracted with dichloromethane. The combined extracts were washed with water and concentrated to give an oil. Trituration with hexane gave 2- (3,5-dichlorophenyl) -3-oxobutyronitrile as a colorless solid (4.15 g).

To a solution of acylacetonitrile (4.1 g) in ether (100 ml) was added in part the excess solution of diazomethane in ether. After stirring for 2 hours at room temperature, the solution was concentrated in vacuo to give a single ether.

To a stirred solution of NaOEt (0.72 g of sodium) in ethanol (25 ml) was added N-methylpiperazinoformamidine hydroiodide (7.29 g). After 10 minutes, a solution of the above enol ether in ethanol (25 ml) was added and the mixture was then stirred and refluxed for 4.5 hours. After cooling, the solvent was evaporated in vacuo and the residue was shaken with 2N NaOH (50 ml). The material was filtered off, washed with water, dried in air and chromatographed (silica; 1: 9 MeOH: CHCl ₃ ) to give the desired product as a colorless solid, 1.6 g, m.p. Mp 164-166 ° C.

Example 37

Preparation of 2,4-diamino-5- (2,5-dichlorophenyl) -6-methylpyrimidine

This compound was prepared in an analogous manner as the compound of Example 6 from 2,5 dichlorobenzyl alcohol (Lancaster Synthesis). Tal. 226-228 ° C:

TLC (SiO ₂ : CHCl ₃ / MeOH, 9: 1) Rf = 0.24.

Example 38

Preparation of 2,4-diamino-5- (3,4-dichlorophenyl) -6-trifluoromethylpyrimidine

This compound was prepared in an analogous manner as the compound of Example 4 from 3,4dichloroacetonitrile (Aldrich), m.p. 252-254.5 ° C: TLC (SiO ₂ ; methanol / chloroform, 1: 9) Rf = 0.38.

Example 39

Preparation of 2,4-diamino-5- (2,3-dichlorophenyl-4-nitrophenyl) -pyrimidine

This compound was prepared in an analogous manner as the compound of Example 5 from 2,4-diamino-5 (2,3-dichlorophenyl) pyrimidine (Example 21). The reaction gave a mixture of 4-nitro and 5-nitro derivatives, from which the title compound was separated by column chromatography (SiO ₂ , EtOAc), mp. 237-9 ° C. 2,4-diamino-5- (2,3-dichloro-5-nitrophenyl) pyrimidine is also separated in this way, m.p. 264-6 ° C.

Example 40

Preparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6- (diethoxymethyl) pyrimidine

This compound was prepared in a manner analogous to 2,4-diamino-5- (2,3-dichlorophenyl) -6diethoxymethyl) pyrimidine (Example 18,1) from 2,4-dichlorophenylacetonitrile, m.p. 225 ° C.

Example 41

Preparation of 2,4-diamino-5- (3,5-dichlorophenyl) -6-methylpyrimidine

This compound was prepared in an analogous manner with the compound of Example 6 from 3,5 dichlorophenylacetonitrile (Aldrich), m.p. 242-244 ° C.

Example 42

Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine-N-oxide

This compound was prepared from the compound of Example 14 by reaction with MCPBA in CHCl ₃ at room temperature. Tal. 275-278 ° C.

Example 43

Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-tribromomethylpyrimidine

This compound was prepared from the compound of Example 15 by reaction with excess bromine and sodium acetate in acetic acid at reflux. The title compound was separated from the mixture of compounds of Example 75 by column chromatography, m.p. 210 ° C (dec).

Example 44

Preparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-methoxymethylpyrimidine

This compound was prepared in an analogous manner to Example 2 from 2,4-dichlorophenylacetonitrile, m.p. 183-185 ° C. One stain on TLC.

Example 45

Preparation of 2,4-diamino-5- (2,6-dichlorophenyl) -6-methylpyrimidine

This compound was prepared in an analogous manner to Example 6 from 2,6-dichlorophenylacetonitrile (Aldrich), m.p. 250 ° C.

Example 46

Preparation of 2,4-diamino-5- (2,4-dichlorophenyl) -pyrimidine-6-carboxaldehyde

This compound was prepared from the compound of Example 40 in an analogous manner as the compound of Example 18.2, m.p. above 350 ° C.

Example 47

Preparation of 2,4-diamino-5- (2,3-dichloro-4-nitrophenyl) -6-methylpyrimidine

This compound was prepared from the compound of Example 15 in an analogous manner as the compound of Example 39, m.p. above 265 ° C. This reaction also yields 2,4-diamino-5- (2,3dichloro-5-nitrophenyl) -6-methylpyrimidine.

Example 48

Preparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-hydroxyiminomethylpyrimidine

This compound was prepared from the compound of Example 46 by reaction with hydroxylamine hydrochloride in ethanol, m.p. 260-5 ° C.

Example 49

Preparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-hydroxymethylpyrimidine

This compound was prepared from the compound of Example 46 in an analogous manner as the compound of Example 18.3, m.p. Mp 169-171 ° C.

Example 50

Preparation of 2,4-diamino-5- (2,3,4-trichlorophenyl) -6-methylpyrimidine

This compound was prepared from the compound of Example 47 by reduction to an amine (PtO ₂ , H ₂ , AcOH), by the formation of a diazonium salt (NaNO ₂ , H ₂ SO ₄ ) and by reaction with CuCl (as for Example 57). Sublimates to 275 ° C. Homogeneous on TLC (methanol / chloroform, 1: 9) Rf = 0.36.

Example 51

2,4-Diamino-5- (2,6-dichlorophenyl) -6-methoxymethyl-pyrimidine

This compound was prepared in an analogous manner as the compound of Example 2 from 2,6dichlorophenylacetonitrile (Aldrich), m.p. 204-207 ° C.

Example 52

Preparation of 2,4-diamino-5- (2,3,5-trichlorophenyl) -6-trichloromethyl-pyrimidine

This compound was prepared from the compound of Example 6 by reaction with NCS in AcOH at 100 ° C (AIBN as catalyst), m.p. 226-227 ° C.

Example 53

2,4-Diamino-5- (2,4-dichlorophenyl) -6-fluoromethylpyrimidine

1. 2,4-Diamino-6-bromomethyl-5- (2,4-dichlorophenyl) pyrimidine

2.4-Diamino-6-benzyloxymethyl-5- (2,4-dichlorophenyl) pyrimidine (Example 25) (6.5 g) was dissolved in 47% hydrochloric acid in acetic acid (75 ml) and the mixture was stirred and heated to 100 ° C for 6 hours. At room temperature overnight, the dihydrobromide salt was filtered off, washed with ether and dried in vacuo, 6 g. To a stirred solution of the dihydrobromide salt (0.43 g) in dimethylsulfoxide (4 ml) was added dropwise a solution of sodium bicarbonate (0.84 g) in water (10 ml). After 30 minutes the precipitate was filtered off, washed with water, then with ether and dried in vacuo, 0.26 g, mp. above 270 ° C (decomposition).

2.2.4- Diamino-5- (2,4-dichlorophenyl) -6-fluoromethylpyrimidine

To a solution of 2,4-diamino-6-bromomethyl-5- (2,4-dichlorophenyl) pyrimidine (1.04 g) in tetramethylenesulfone (4.5 ml) was added cesium fluoride (1 g). The mixture was stirred and heated at 100 ° C for 4 hours, cooled, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed (silica; 19: 1: 0.1 dichloromethane / methanol / triethylamine) to give the title compound, which was recrystallized from ethanol. 0.19 g, m.p. 210-211 ° C.

Example 54

Preparation of 2,4-diamino-5- [2-chloro-5- (N, N-dimethylsulfamoyl) phenyl] -6-methylpyrimidine

1.2.4- Diamino-5- (2-chloro-5-nitrophneyl) -6-methylpyrimidine

To a solution of 2,4-diamino-5- (2-chlorophenyl) -6-methylpyrimidine (11.84 g) (Example 22) in concentrated H ₂ SO ₄ (100 ml) was added potassium nitrate (5.1 g). After stirring at room temperature for 90 minutes, the solution was poured onto ice and basified with 10N NaOH. The product was extracted with ethyl acetate, collected, dried (MgSO ₄ ) and evaporated, 13.9 g, 23624G ° C.

2.2.4- Diamino-5- (5-amino-2-chlorophenyl) -6-methylpyrimidine

A solution of 2,4-diamino-5- (2-chloro-5-nitrophenyl) -6-methylpyrimidine (13.9 g) in acetic acid was reduced under a hydrogen atmosphere in the presence of PtO ₂ (0.28 g). The mixture was filtered through hyflo and the filtrate was concentrated. The residue was neutralized with saturated NaHCO ₃ solution and the product was extracted with ethyl acetate, collected, dried (MgSO ₄ ) and evaporated. Chromatography on SiO ₂ gel eluting with CHC1 ₃ to 40% MeOH / CHCl3 gave the desired product, 6 g, m.p. 117-121 ° C.

3. 2,4-Diamino-5- (2-chloro-5-N.N-dimethylsulfamoylphenyl) -6-methylpyrimidine

2.4-Diamino-5- (5-amino-2-chlorophenyl) -6-methylpyrimidine (0.25 g) was dissolved in water (0.8 ml) and concentrated HCl (0.5 ml). A solution of sodium nitrite (0.07 g) in water (0.5 ml) was added to a strongly cooled solution (below 10 ° C). After stirring at room temperature for 2 hours, the solution was cooled to 5 ° C. Copper chloride (0.05 g) and 5.14M SO ₂ in acetic acid (0.97 ml) were added and the reaction was stirred at 5 ° C overnight. The mixture was filtered and washed with water to give sulfonyl chloride, 0.23 g.

The sulfonyl chloride (0.16 g) was dissolved in THF (2 ml) and aqueous dimethylamine (2 ml) was added. After stirring overnight, the solution was diluted with water, extracted with ethyl acetate, collected, dried (MgSO ₄ ) and evaporated. Chromatography on SiO ₂ gel eluting with 2% MeOH / CHCL gave the desired product, 0.047 g m.p. 283-285 ° C.

Example 55

Preparation of 2,4-diamino- (3,5-dichlorophenyl) -6-methoxymethylpyrimidine

This compound was prepared in an analogous manner as the compound of Example 2 from 3,5 dichlorophenylacetonitrile, m.p. Mp 228-230 ° C.

Example 56

Preparation of 2,4-diamino-5- (2,3-dichlorophenyl) -6-hydroxypyrimidine

1. Ethyl-2-cyano-2- (2,3-dichlorophenyl) acetate

Sodium (1.2 g) was added portionwise to ethanol (50 ml). After dissolving sodium, a solution of 2,4-dichlorophenylacetonitrile (9.4 g) in diethyl carbonate (25 ml) was added dropwise. The reaction mixture was heated until it was distilled off with EtOH. The rate of addition is controlled to be equal to the rate of distillation. After the addition is complete, the reaction mixture is heated and distilled for another 4 hours. The cooled reaction mixture was partitioned between water and EtOAc (300 ml each). The organic layer was dried and evaporated in vacuo and the residue was purified by flash column chromatography to give the title product. (5 g, 39%).

2,2,4-diamino-5- (2,3-dichlorophenyl) -6-hydroxypyrimidine

Sodium (1.2 g, 0.52 mol) was added portionwise into abs. ethanol (50 ml) with stirring. After dissolving sodium, guanidine hydrochloride (3.69 g, 0.039 mol) was added followed by ethyl 2cyano-2- (2,3-dichlorophenyl) acetate (5 g, 0.0195 mol). The mixture was refluxed for 8 hours, the EtOH was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was extracted with 2N NaOH and the extract was neutralized with 2N HCl upon cooling. The precipitated material was filtered off and dried to give the title compound. (0.22 g, mp 275 ° C). (breakup). Microanalysis:

Anal. calcd. by 0.25 hydrate:

C, 43.56; H, 3.09; N, 20.33;

C, 43.76; H, 3.09; N, 20.03.

Example 57

Synthesis of 2,4-diamino-5- (2,4-trichlorophenyl) -6-methylpyrimidine

a. Preparation of 2- (2,4-dichlorophenyl) -3-oxo-butyronitrile

A solution of 2,4-dichlorophenylacetonitrile (30.0 g, 161 mmol) (Aldrich) in dry ethyl acetate (36 ml) was added dropwise to an ethanolic sodium ethoxide solution prepared in situ from metallic sodium (4.90 g, 213 mmol). and dry ethanol (60 ml). The reaction mixture was refluxed for 2 hours, allowed to stand at room temperature overnight and the ethanol was evaporated. The resulting yellow substance was dissolved in water and the resulting solution was extracted twice with ether. The aqueous layer was cooled strongly and acidified with hydrochloric acid. The crude product was extracted with ether to give 23.31 g of a white solid.

b. Preparation of 2,4-diamino-5- (2,4-dichlorophenyl) -6-methylpyrimidine

A solution of crude 2- (2,4-dichlorophenyl) -3-oxo-butyronitrile (23.24 g) in dry toluene (400 ml) was refluxed with ethylene glycol (280 ml) and p-toluenesulfonic acid (8.00 g, 42 mmol) ) 4 hours using Dean & Stark traps. After vigorous cooling, the organic phase was washed with saturated NaHCO ₃ , dried over MgSO ₄ , and the solvent was evaporated to leave a solid (24.0 g). Finely ground guanidine hydrochloride (19.1 g, 200 mmol) was added to an ethanolic sodium ethoxide solution prepared in situ from metallic sodium (5.0 g, 218 mmol) in dry ethanol (500 ml). A solution of ketal (25.0 g, 92 mmol) in dry ethanol (10 ml) was added to the guanidine solution. The mixture was refluxed for 2 hours and allowed to stand at room temperature overnight. The ethanol was evaporated and the crude product was recrystallized from hot acetone to give 17.23 g of product, m.p. 222-222.5 ° C.

c. Preparation of 2,4-diamino-5- (2,4-dichloro-5-nitrophenyl) -6-methylpyrimidine

Fine ground potassium nitrate (6.5 g, 64 mol) was added to a solution of 2,4-diamino-5- (2,4 dichlorophenyl) -6-methylpyrimidine (17.23 g, 64 mmol) in concentrated sulfuric acid (150 ml). . The mixture was stirred at room temperature for 90 minutes. The reaction mixture was then added to sodium bicarbonate and ice. The product was extracted with ethyl acetate. After ethyl acetate was determined, a yellow solid (30.86 g) was obtained. A portion of this crude product (7.0 g) was passed through a silica column for flash chromatography and eluted with ethyl acetate to give the pure product (4.81 g).

d. Preparation of 2,4-diamino-5- (5-amino-2,4-dichlorophenyl) -6-methylpyrimidine

2,4-Diamino-5- (2,4-dichloro-5-nitrophenyl) -6-methylpyrimidine (4.80 g, 15 mmol) was dissolved in glacial acetic acid (18 ml). This solution and 10 mg of Adams catalyst were stirred under a hydrogen atmosphere at room temperature for 4 hours. The catalyst was filtered off and the acetic acid was evaporated. The resulting colorless liquid was dissolved in ethyl acetate and washed three times with water. Evaporation of ethyl acetate gave a white solid (2.64 g, 9 mmol).

e. Preparation of 2,4-diamino-5- (2A5-trichlorophenyl) -6-methylpyrimidine

2,4-Diamino-5- (5-amino-2,4-dichlorophenyl) -6-methylpyrimidine (1.95 g, 7 mmol) was dissolved in a mixture of concentrated hydrochloric acid (3.6 ml) and water (6 ml). . The temperature is lowered to 10 ° C. A strongly cooled aqueous solution (3.6 ml) of sodium nitrite (0.50 g, 7 mmol) was added dropwise while maintaining the temperature at 10 ° C. This mixture was stirred at room temperature for 2 hours, then cooled strongly before being added dropwise to a cold solution of copper chloride (1.7 g, 17 mmol) in concentrated hydrochloric acid (50 ml). The precipitate is grayed out, which is filtered off and dried. The crude product (2.30 g) was dissolved in ethyl acetate and washed twice with ammonium hydroxide solution and once with brine. Evaporation of ethyl acetate gave a whitish substance (2.04 g). Recrystallization from 10% methanol in chloroform gave the pure product (0.55 g, 2 mmol), m.p. 262 ° C (decomposition).

Example 58

Synthesis of 4-amino-2- (ethylamino) -5- (2,3,5-trichlorophenyl) pyrimidine

Ethylguanidine sulfate (1 g) (Aldrich) was added to a solution of NaOEt (0.1 g of sodium in ethanol (10 ml). After stirring for 10 minutes, enol ether (Example 3.2) (0.486 g) was added and the mixture was refluxed for 4 hours The mixture was allowed to stand at room temperature overnight and then filtered, the filtrate was concentrated, the residue was purified by chromatography on SiO ₂ gel, eluting with CHCl3 to give the desired product, 0.11 g, mp 149-152 ^O C.

Example 59

2,4-Diamino-5- (2,4-dichlorophenyl) -6-cyanomethyl-pyrimidine

This compound was obtained from 2,4-diamino-5- (2,4-dichlorophenyl) -6-bromomethyl-pyrimidine (Example 53) by reaction with sodium cyanide in DMF at room temperature. Tal. 249251 ° C.

Example 60

2,4-diamino-5- (2,4-dichlorophenyl) -6-dimethylaminomethyl-pyrimidine

This compound was obtained from 2,4-diamino-5- (2,4-dichlorophenyl) -6-bromomethyl-pyrimidine (Example 53) by reaction with dimethylamine in ethanol at room temperature. Tal. 170172 ° C.

Example 61

2,4-diamino-5- (2,4-dichlorophenyl) -6-cyano-pyrimidine

This compound is obtained from the compound of Example 48 by reaction with trifluoroacetic anhydride in pyrimidine. Tal. 249 ° C.

Example 62

2.4-diamino-5- (2-chloro-4-fluorophenyl) -6-methylpyrimidine

This compound was obtained in the same manner as the compound of Example 15 from 2-chloro-4fluorophenylacetonitrile obtained from 2-chloro-4-fluorotoluene (Aldrich). Tal. 238 ° C.

Example 63

2,4-Diamino-5- (3,4-dichlorophenyl) -6-methoxymethyl pyrimidine

This compound was obtained in an analogous manner as the compound of Example 2 from 3,4-dichlorophenylacetonitrile (Aldrich). Tal. 204-206 ° C.

Example 64

2,4-Diamino-5- (2,3-dichlorophenyl) -6-ethyl pyrimidine

This compound was obtained in an analogous manner as the compound of Example 15 from ethyl propionate. Tal. Mp 228-230 ° C.

Example 65

2,4-Diamino-5- (2,4-difluorophenyl) -6-methyl pyrimidine

This compound was obtained in an analogous manner as the compound of Example 6 from 2,4difluorophenylacetonitrile (Aldrich). Tal. 291-296 ° C.

Example 66

2,4-Diamino-5- (2-naphthyl-6-methylpyrimidine

This compound was obtained in an analogous manner as the compound of Example 6 from 2-naphthylacetonitrile (Aldrich). Tal. Mp 221-222 ° C.

Example 67

2,4-Diamino-5- (1-naphthyl) -6-methylpyrimidine

This compound was obtained in an analogous manner as the compound of Example 6 from 1-naphthylacetonitrile (Aldrich). Tal. 224-225 ° C.

Example 68

2-hydroxy-4-amino-5- (2,3-dichlorophenyl) pyrimidine

This compound is obtained from the compound of Example 21 by reaction with sodium nitrite in IN H ₂ SO ₄ at reflux to give a mixture of the title compound and the compound of Example 21B.d. The title compound was separated by column chromatography. Tal. Mp 330-334 ° C.

Example 69

2-amino-4-ethoxy-5- (2,4-dichlorophenyl) -6-methylthiopyrimidine

This compound is obtained from the compound of Example 32.4 by reaction with the methanethiol sodium salt in ethanol. Tal. 123-124 ° C.

Example 70

2.4-diamino-5-f2,3,5-trichlorophenyl) -6-hydroxymethylpyrimidine

This compound is obtained from the compound of Example 2 by reaction with trimethylsilyl iodide in sulfolane at 80 ° C. Tal. 101-105 ° C.

Example 71

2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-fluoromethylpyrimidine

This compound was obtained in an analogous manner as the compound of Example 18 from 2,4-diamino-5 (2,3,5, -trichlorophenyl) -6-hydroxymethylpyrimidine. Tal. Mp 215-217 ° C.

Example 72

2,4-Diamino-5- (2,4-dichlorophenyl) -6-carbamoylpyrimidine

This compound is obtained from the compound of Example 61 by reaction with concentrated sulfuric acid at room temperature. Tal. 298-299 ° C.

Example 73

2,4-Diamino-5- (2,4-dichlorophenyl) pyrimidine-6-carboxylic acid

This compound is obtained from the compound of Example 46 by reaction with potassium permanganate. Tal. 227 ° C.

Example 74

Ethyl-2,4-diamino-5- (2,4-dichlorophenyl) pyrimidine-6-carboxylate

This compound was obtained from the compound of Example 73 by refluxing in ethanol in the presence of concentrated sulfuric acid. Tal. 177.5 ° C.

Example 75

2,4-Diamino-5- (2,3-dichlorophenyl) -6-dibromomethylpyrimidine

This compound is obtained from the compound of Example 15 by reaction with two equivalents of NBS in CC1 ₄ and AIBN as the initiator. The title compound was separated from the mixture with the compound of Example 43 by column chromatography. Tal. 270 ° C (decomposition).

Example 76

2-dimethylamino-4-amino-5- (2,4-dichlorophenyl) pyrimidine

This compound was obtained in an analogous manner as the compound of Example 10 from 2,4-dichlorophenylacetonitrile (Aldrich). Tal. 151 ° C.

Example 77

2-dimethylamino-4-amino-5- (3,4-dichlorophenyl) -6-methylpyrimidine

This compound was obtained in an analogous manner as the compound of Example 13 from 3,4-dichlorophenylacetonitrile.

Example 78

2-N-Piperidyl-4-amino-5- (2,4-dichlorophenyl) pyrimidine

This compound was obtained in an analogous manner as the compound of Example 76 from

1- piperidinecarboxamidine sulfate (Bader). Tal. 169 ° C.

Example 79

2-methylamino-4-amino-5- (2,3,5-trichlorophenyl) pyrimidine

This compound was obtained in an analogous manner as the compound of Example 58 from 1-methyl-guanidine hydrochloride (Aldrich). Tal. 155M57C.

Example 80

2.4-diamino-5- (2-chloro-5-bromophenyl) -6-methylpyrimidine

This compound was obtained in an analogous manner as the compound of Example 54 by reaction of the diazonium salt with copper bromide. Tal. 212 ° -216 ° C.

Example 81

2,4-Diamino-5- (2-chloro-5-iodophenyl) -6-methylpyrimidine

This compound was obtained in a similar manner to the compound of Example 54 by reaction of the diazonium salt with potassium iodide. Tal. 232 ° -234 ° C.

Example 82

2.4-diamino-5- (2-chloro-5-cyanophenyl) -6-methylpyrimidine

This compound was obtained in a similar manner to the compound of Example 54 by reaction of the diazonium salt with copper cyanide. Tal. 239 ° -241 ° C.

Example 83

2.4-diamino-5- (2-chloro-5-fluorophenyl) -6-methylpyrimidine

This compound was obtained in a similar manner to the compound of Example 54 using a diazonium tetrafluoroborate salt. Tal. 195 ° -197 ° C.

Example 84

2,4-Diamino-5- (2-chloro-5-methylthiophenyl) -6-methylpyrimidine

This compound was obtained in a similar manner to the compound of Example 54 by reaction of the diazonium salt with methanethiol in the presence of powdered copper. Tal. 194 ° -198 ° C.

Example 85

2-amino-4,6-di- (methylthio) -5- (2,4-dichlorophenyl) pyrimidine

This compound is obtained from the compound of Example 32.4 by reaction with the methanethiol sodium salt in methanol in the presence of tris [2- (2-methoxyethoxy) ethyl] amine and copper powder. Tal. 164 ° -165 ° C.

Example 86

2.4-diamino-5- (2-chloro-5-methanesulfonylaminophenyl) -6-methylpyrimidine

This compound was obtained from 2,4-diamino-5- (2-chloro-5-aminophenyl) -6-methylpyrimidine from Example 54 by reaction with methanesulfonyl chloride in pyrimidine. Melting point: 234 ° -240 ° C.

Example 87

2,4-Diamino-5- (2,3-dichlorophenyl-1-methylpyrimidimidioiodide

This compound is obtained from the compound of Example 21 and methyl iodide. M.p .: 280 ° -284 ° C.

Example 88

2-amino-4-methylamino-5- (2,3-dichlorophenyl) pyrimidine

This compound was obtained in an analogous manner as the compound of Example 21B.g by reaction with methylamine in ethanol. Melting point: 233 ° -237 ° C.

Example 89

2-amino-4-dimethylamino-5- (2,3-dichlorophenyl) pyrimidine chlorohydrate

This compound was obtained in an analogous manner as the compound of Example 21B.g by reaction with dimethylamine in ethanol and subsequent conversion to the hydrochloride salt. Melting point: 295 ° 300 ° C.

Example 90

2-amino-4-chloro-5- (2,4-dichlorophenyl) pyrimidine

This compound was obtained in an analogous manner as the compound of Example 21B.f from 5- (2,4-dichlorophenyl) isocytosine. M.p .: 215 ° -216 ° C.

Example 91

2-amino-4-methylamino-5- (2,4-dichlorophenyl) pyrimidine

This compound is obtained from the compound of Example 90 by reaction with methylamine in ethanol. M.p .: 189 ° -190 ° C.

Example 92

2-amino-4-dimethylamino-5- (2,4-dichlorophenyl) pyrimidine hydrochloride

This compound is obtained from the compound of Example 90 by reaction with dimethylamine in ethanol with subsequent conversion to the hydrochloride salt. M.p .: 297 ° -301 ° C.

Example 93

2-amino-4-piperidino-5- (2,4-dichlorophenyl) pyrimidine hydrochloride

This compound is obtained from the compound of Example 90 by reaction with piperidine in ethanol and subsequent conversion to the hydrochloride salt. M.p .: 303 ° C (dec).

Among the compounds of formula (I), the preferred pyrimidines of the preceding examples are 1,2,3,4,14 and 16 together with their salts (especially pharmaceutically acceptable salts); these bases have the following corresponding two-dimensional structures.

Example 1

Example 2

Example 3

CI

Example 4

CI

Example 14

Table Ή NMR data (δ)

EXAMPLE NO. SOLVENT BELONGING 1 CDC1 ₃ 7.56 (d, 1H), 7.18 (d, 1H), 4.65-4.50 (br.s, 2H), 3.88 (t, 4H), 2.5 (t, 4H), 2.36 (s, 3H) 2 DMSO-dg * 3.06 (s, 3H, -0Me), 3.8 (d, 1H, J12.5Hz, -CH ₂ 0Me), 3.9 (d, 1H, J12.5Hz, -CH ₂ 0Me), 5.98 (br.s _f 2H , -NH ₂ ), 6.1 (br.s, 2H, -NH, 7.32 (d, 1H, J2.5Hz, 6'-H), 7.78 (d, 1H, J2.5Hz, 4'-H) 3 DMSO-dg 7.8 (d, 1H), 7.65 (s, 1H), 7.36 (d, 1H), 6.33-6.23 (brs, 2H), 3.68 (t, 4H), 2.32 (t, 4H), 2.2 (s, 3H) 4 DMSO-dg 6.40 (s, 2H), 6.55 (s, 2H), 7.35 (s, 1H), 7.80 (s, 1H) 5 DMSO-dg 8.6 (s, 1H), 7.49 (s, 1H), 6.4-6.3 (br.s 6.25-6.15 (br.s, 2H) 6 DMSO-dg 1.70 (s, 3H), 5.75 (s, 2H), 5.90 (s, 2H), 7.30 (s, 1H), 7.75 (s, 1H) 7 cdci ₃ 7.55 (d, 1H), 7.18 (d, 1H), 4.75-4.58 (br.s, 2H), 3.9-3.7 (m, 8H) 8 cdci ₃ 7.55 (d, 1H), 7.18 (d, 1H) 4_.56-4.50 (br.s, 2H), 3.2 (s, 6H)

DMSO-dg 7.79 (d, 1H), 7.67 (s, 1H), 7.36 (d, 1H), 6.47-6.27 (br.s, 2H), 3.72-3.57 (m, 8H) DMSO-dg 7.78 (d, 1H), 7.64 (s, 1H), 7.35 (d, 1H), 3.08 (s, 6H) cdci ₃ 7.51 (d, 1H), 7.17 (d, 1H), 4.40-4.22 (br.s, 2H), 3.82 (t _f 4H), 2.48 (t, 4H), 2.34 (s, 3H), 2.0 (s. 3H) DMSO-dg 8.28 (s, 1H), 6.18-6.04 (br.d, 4H), 2.1 (s, 3H) cdci ₃ 7.51 (d, 1H), 7.18 (d, 1H), 4.36-4.22 (br.s, 2H), 3.16 (s, 6H), 2.0 (s, 3H) DMSO dg 6.10 (s, 2H), 6.45 (s, 2H), 7.15 (d, 1H), 7.30 (t, 1H), 7.55 (d, 1H) DMSO-dg 1.70 (s, 3H), -5.60 (s, 2H), 5.80 (s, 2H), 7.15 (d, 1H), 7.30 (t, 1H), 7.55 (d; 1H) DMSO-dg 3.04 (s, 3H, -0Me), 3.76 (d, 1H, J12Hz, -CH ₂ 0Me) 3.85 (d, 1H, J12Hz _t -0CH ₂ 0Me), 5.84 (br.s, 2H, -NH ₂ ). 6.05 (br. _S , 2H, -NH ₂ ) _I 7.22 (dd, 1H, J7.5,1.5Hz, 6'-H), 7.38 (dd, 1H, J7.5Hz, 5'-H), 7.6 ( dd, 1H, J7.5, 1.5Hz, 4'-H) DMSO-dg 7.3-8.0 (m, 8H), 6.0-6.1 (br.s, 2H), 5.2-5.4 (No.s, 2H) DMSO-dg 4.75 (2xdd, 2H, J47.15Hz, -CH ₂ F), 5.95 (br.s, 2H, -NH ₂ ), 6.15 (br.s, 2H, -NH ₂ ), 7.25 (dd, 1H, J7. 5, 1.0Hz, 6'-H), 7.39

(dd, 1H, 07.5Hz), 7.64 (dd, 1H, 07.5, 1.0Hz)

DMSO-dg 4.43 (d, 1H, JllHz), 4.53 (d, 1H, JllHz),

5.95 (br.s, 2H), 6.12 (br.s, 2H),

6.7 (m, 2H), 6.85 (dd, 1H, J 7 Hz),

7.1-7.4 (m, 4H), 7.55 (dd, 1H, 07.1Hz).

DMSO-dg 4.4 (d, 1H, 012Hz, -CH ₂ OPh), 4.52 (d, 1H,

012Hz, -CH ₂ 0Ph), 5.92 (br.s, 2H, -NH ₂ ), 6.12 (br.s, 2H, -NH ₂ ), 6.69 (dd, 1H, 07.5, 1.0Hz, 6'-H) , 6.85 (dd, 1H, 07.5Hz, 5'-H), 7.10-7.35 (m, 5H, -OPh), 7.55 (dd, 1H, 07.5, 1.0Hz, 4'-H)

DMSO-dg 7.52 (s, 1H), 7.15-7.75 (τη, 3H),

6.02 (Nos, 4H, 2x-NH ₂ )

DMSO-dg 6.07 (s, 2H), 6.25 (s, 2H), 7.25 (d, 1H),

7.45 (d, 1H), 7.63 (s, 1H)

DMSO-dg 3.88 (d, 1H, 011Hz), 4.0 (d, 1H, 011Hz),

4.3 (s, 2H), 5.9 (br.s, 2H), 6.1 (br.s, 2H), 7.05-7.2 (m, 2H), 7.2-7.35 (m, 4H), 7.4 (dd, 1H, 08 , 2.5Hz), 7.62 (d, 1H, 02.5Hz)

DMSO-dg 6.25 (s, 2H), 6.50 (s, 2H), 7.30 (s, 1H),

7.40 (d, 1H), 7.50 (d, 1H)

DMSO-dg 5.85 (s, 2H), 6.1 (s, 2H), 7.25 (s, 1H),

7.45 (s, 1H), 7.7 (s, 1H)

CDC1 ₃ 7.53-7.12 (m, 4H), 4.48-4.30 (br.s, 2H),

3.81 (t, 4H), 2.46 (t, 4H), 2.33 (s, 3H), 2.03 (s, 3H)

CDCl _{3 3} 7.38 (d, 1H), 7.2 (dd, 1H), 7.08 (d ·, 1H),

8.2 (No.s, 2H)

DMSO-dg 7.7 (d, 1H), 7.48 (dd, 1H), 7.29 (d, 1H),

6.45 (no.s, 2H), 6.2 (no.s, 2H)

CDCl _{3 3} 7.5 (d, 1H), 7.35 (dd, 1H), 7.18 (d, 1H),

5.25 (br.s, 2H), 2.44 (s, 3H)

CDCl _{3 3} 7.52 (d, 1H), 7.32 (dd, 1H), 7.21 (d, 1H),

5.08 (br.s, 2H), 4.66 (br.s, 2H), 2.42 (s, 3H)

DMSO-d 1.9 (s, 3H, 6-CH _3), 2.2 (s, 3H, N-Me);

2.25-2.40 (m, 4H, -N N-), 3.55-3.75 (m, 4H, -N N-), 5.85 (2H, br.s, -NH ₂ ), 7.2 (d, 2H, J1.5Hz , 2 ', 6'-H), 7.52tdd, 1H, J1.5Hz, 4'-H)

DMSO-dg 7.53 (dd, 1H), 7.45 (dd, 1H), 7.35 (d, 1H),

7.24 (br.s, 1H), 3.35 (br.s, 2H), 3.96 (br.s, 2H)

DMSO-dg 1.8 (s, 3H), 5.8 (s, 2H), 5.95 (s, 2H),

7.53 (s, 1H), 7.92 (s, 1H)

DMSO-dg 7.78 (d, 1H), 7.59 (s, 1H), 7.36 (d, 1H),

6.60-6.47 (br.t, 1H), 6.25-6.03 (br.s, 2H), 3.25 (q, 2H), l.l (t, 3H)

The preceding table uses abbreviations as follows: s = singlet, d = doublet; dd = doublet doublet; t = triplet; q = quadriplet; m = multiplet; br.s = wide singlet; br.t = wide triplet.

Pharmacological activity

Inhibition of glutamate release and inhibition of rat DHFR

The compounds of formula (I) are tested for their effect on the release of veratrin-induced glutamate from rat brain slices according to the protocol described in Epilepis 27 (5): 490-497,1986. The protocol for inhibiting DHFR activity was a modification of the one shown in Biochemical Pharmacology Vol. 20 p. 561-574,1971.

The results are given in Table 1, with IC _{50 being the} concentration of a compound that causes 50% inhibition of (a) the release of glutamate induced by veratrin and (b) the activity of the DHFR enzyme.

TABLE 1

The compound of Example no. IC _5O (^ 0 glutamate release (P95 limit) ICsof / iM) DHFR liver rats (P95 borders) 1 1.18 (0.50-2.60) > 100 2 0.56 (0.23-1.37) 33 (27.00-40.00) 3 2.15 (0.90-5.10) > 100 4 0.33 (0.196-0.566) > 30 <100 5 3.50 (1.10-10.40) approx. 100 6 0.70 (0.40-1.50) 0.51 (0.36-0.73) 7 <10,00 > 10,0 8 <10,00 > 10,0 9 <10,00 > 100.00 10 <10,00 > 100.00 11 4.80 (2.30-10.20) > 100.00 12 <10,00 > 100.00 13 <10 > 100.00

3.1 (2.1-4.6) > 100.00 2.7 (1.0-7.2) 8.7 (5.2-14.7) 3.2 (1.7-6.1) > 100 2.4 (1.00-5.80) 4.9 (3.90-6.20) <10,00 approx. 100 2.6 (0.80-8.50) > 100.00 4.2 (1.20-15.30) 17.50 (9.80-31.40) 11.5 (4.80-27.60) 16.01 (12.05-21.282) 2.80 (0.80-9.80) 23,800 (9.00-61.00) 8.70 (2.60-29.10) 20,940 (9.00-61.00) 2.10 (Oj90-4,80) 15.10 (11.00-20.70) 4.10 (1.10-15.50) > 100.00 approx. 3.00 CIO, 00 approx. 10,00 > 100.00 4.6 (1.60-13.30) 46.10 (14.30-148.90) 1.57 (0.954-2.62) 0.53 (0.348-0.812)

Toxicological example

The compound of Example 1 was administered intravenously to groups of Six males and 6 Wistar rats once daily with dosage levels up to 15 mg / kg / day. The dose of the undetected effect was 2.5 mg / kg / day.

The compound of Example 2 was tested in both rats and dogs. In rats, the dose of the observed effect was 2.5 mg / kg / day and no effect of the dose was observed in dogs at 14 mg / kg / day.

An example of a pharmaceutical formulation

A: TABLET

INGREDIENT

Compound of Example 1 150 mg)

Lactose 200 mg)

Corn starch 50 mg)

Polyvinylpyrrolidone 4 mg)

Magnesium stearate 4 mg)) = content per tablet.

The product is mixed with lactose and starch and granulated with a solution of polyvinylpyrrolidone in water. The obtained granules were dried, mixed with magnesium stearate and pressed to give tablets.

B: INJECTION (I)

The salt of the compound of formula I is dissolved in sterile water for injection.

FORMULATION FOR INTRAVENOUS INJECTION (II)

Active ingredient 0.20 g

Sterile pyrogen free phosphate buffer (pH 9.0) up to 10 ml

The compound of Example 1 was dissolved as a salt in most of the phosphate buffer at 3540 ° C, then made up to volume and filtered through a sterile micro64 filter into 10 ml sterile glass vials (Type 1), sealed and sealed.

In the following cases, the active compound may be any compound of formula (I) or a pharmaceutically acceptable salt thereof.

C: CAPSUL FORMULATIONS

Capsule Formulation A

Formulation A can be prepared by mixing the ingredients and filling the two-part hard gelatin capsules r the resulting mixture.

mg / capsule (a) Active ingredient (b) Lactose B.P.

(c) Sodium starch glycolate (d) Magnesium stearate

250

143

420

Capsule Formulation B mg / capsule (a) Active ingredient (b) Macrogel 4000 BP

250

350

600

The capsules can be prepared by melting Macrogel 4000 BP, dispersing the active ingredient in solution, and filling two-part hard gelatin capsules.

Capsule B formulation (controlled release capsule)

(a) Active ingredient me / capsule 250 (b) Microcrystalline cellulose 125 (c) Lactose BP 125 (d) Ethylcellulose 13 513

The controlled release capsule formulation can be prepared by injection of mixed ingredients (a) to (c) using a syringe, then spheronization and drying of the extrudate. The dried granules were coated with ethylcellulose (d) as a controlled release membrane and filled into two-part hard gelatin capsules.

Syrup formulation

Active ingredient 0.2500 g

Sorbitol solution 1,5000 g

Glycerol 1,0000 g

Sodium benzoate 0.0050 g

Aroma 0.0125 ml

Purified water q.s. to 5,0 ml

Dissolve the sodium benzoate in a portion of the purified water and add the sorbitol solution. The active ingredient is added and dissolved. The resulting solution was mixed with glycerol and then made up to volume with purified water.

Mg / spark plug formulation

Active ingredient (63 μιη) * 250

Hard Fat, BP (Witepsol H15 - Dynamit Nobel) 1770

2020 * Use the active ingredient as a powder containing at least 90% of particles 63 μιη in diameter or smaller.

Dissolve one-fifth of Witepsol H15 in a frying pan at a maximum of 45 ° C. The active ingredient was siphoned through a 200 gm sieve and added to the molten base while stirring using Siverson equipped with a chopping head until a smooth dispersion was obtained. Continue to maintain the mixture at 45 ° C while adding the remaining Witepsol H15 to the suspension, which was stirred to ensure a homogeneous mixture. The whole suspension was then passed through a stainless steel sieve of 250 μτη and allowed to cool to 40 ° C with continuous stirring. At 38-40 ° C, aliquots of 2.02 g of the mixture are filled into suitable plastic molds and allowed to cool to room temperature.

Claims (36)

A process for the preparation of a compound of formula I or an acid salt thereof: Patent claims R R R R R '2' 8 R. wherein in formula I R 1 and R _{2 are the} same or different and are selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, alkyl, alkylthio and the group NR ^ ¹¹ , wherein R ¹ and R ^{11 are the} same or different and selected from the group consisting of hydrogen, alkyl, aryl and arylalkyl or together with the nitrogen atom to which they are attached form a cyclic ring which is optionally substituted by one or more alkyl groups and optionally contains a further heteroatom; R ₃ is hydrogen, alkyl optionally substituted by one or more halo radicals, or is amino, alkylamino, dialkylamino, cyano, nitro, halo, carbamoyl, hydroxy, carboxy, alkoxy, alkylthio, alkylthioalkyl, S (O) _n alkyl, di (alkoxy) alkyl, -C (R): NOH or -COR or -CO ₂ R, where R is hydrogen or alkyl, or a CH ₂ group X, where X is hydroxy, alkoxy, aryloxy, arylalkyloxy, halo , cyano, -NR ^ ¹¹ , where R ¹ and R ¹¹ , as defined above, are S (O) n-alkyl, where n is 1 or 2, or SO 2 N (R ^m ) 2; wherein R ^{111 is} selected from hydrogen and alkyl; each of R4 to Rg is the same or different and each is selected from the group consisting of hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR, nitro, amino, alkylsulfonylamino, alkoxy, S (O) n-alkyl, where n is 1 or 2 or SO2N (R ^and ) 2; or are R ₄ and R ₅ or R. and R ₆ together a group -CH = CH-CH = CH- or a group -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, in which case both are R _? and R _{8 is} hydrogen; and optionally one of the nitrogen atoms in the pyrimidine ring may be N-alkylated or optionally N-oxide; wherein the preceding alkyl groups or portions of the alkyl-containing groups have from 1 to 6 carbon atoms, and the aryl groups or aryl moieties of the aryl-containing groups have 6 or 10 carbon atoms, provided that when at least one of R ₄ to R _g different from hydrogen, 'and further provided that when R ₁ and R ₂ are both amino or when R _{t is} hydroxy and R _{2 is} amino and R _{3 is} alkyl or hydrogen and R _? hydrogen, then R ₄ and R ₅ are both halo; characterized in that it comprises the reaction of a compound of formula II: in which R ₃ to R _g , as defined hereinbefore, L is a leaving group and Y is cyano or carboxy, carbonyl or alkoxycarbonyl, with a compound of formula III: NH h ₂ n - C - r ₁ m in which R 1 is as defined herein, and isolation of a compound of formula I as the free base or its acid addition salt and, optionally, conversion of the base into its acid addition salt or other compound of formula I or its acid addition salt. A process for the preparation of a compound of formula I as defined in claim 1, characterized in that it comprises the reaction of a compound of formula V: wherein Y and R _{3 are} as hereinbefore defined and R _{1 ()} and R _{n are} alkyl, or selectively form a group (CR ₂ ) _n , wherein n is 2 to 4 and is RH or alkyl, with a compound of formula III : NH H ₂ N - C - R ₁ III wherein R _{t is} as hereinbefore defined, and isolating the compound of formula I as the free base or its acid addition salt, and optionally converting the base to its acid addition salt or other acid addition salt, or to another compound of formula I, or an acid addition salt thereof. A process according to claim 1 or 2, characterized in that R 1 to R ₆ and R _{g are} as defined in claim 1 and R 2 is _? halo, alkyl, perhaloalkyl, cyano, nitro, amino, alkylthio, S (O) _n- alkyl, where n is 1 or 2, SO ₂ N (R ^U1 ) ₂ , wherein R ^{111 is} hydrogen or alkyl. A process according to claim 1 or 2, characterized in that R 1 is morpholino, piperazinyl, N-alkylpiperazinyl, N, N-dialkylamino, N-alkylamino or alkylthio and R ₂ to R _g are as defined in claim 1. Process according to claim 1 or 2, characterized in that R 1 and R _{2 are} as defined in claim 1 and R _{3 is} alkoxy, alkylthio or alkyl which is substituted by one or more halo radicals or is a CH ₂ X group , wherein X is alkylthio, aryloxy, arylalkoxy, alkyloxy or hydroxy; R ₄ to R ₆ are the same or different and are each selected from the group consisting of hydrogen, halo, perhaloalkyl, cyano, nitro, amino or alkylthio; is R _? halo, alkyl, perhaloalkyl, cyano, nitro, amino or a group SO ₂ N (R ^{U 1} ) ₂ wherein R ^{111 is} alkyl; and R _{g is} hydrogen or halo. Process according to claim 1 or 2, characterized in that R ₁ and R ₂ and R ₄ to R _{g are} as defined in claim 1 and R _{3 is} alkoxy, aryloxy, arylalkyloxy or alkylthio. 7. A process according to claim 1 or 2, characterized in that 4-amino-2- (4methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine or an acid addition salt thereof is produced. 7C A process according to claim 1 or 2, characterized in that 2,4-diamino-5 (2,3,5-trichloro-phenyl) -6-methoxymethylpyrimidine or an acid addition salt thereof is produced. A process according to claim 1 or 2, characterized in that 4-amino-2- (4methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -pyrimidine or an acid addition salt thereof is produced. A process according to claim 1 or 2, characterized in that 2,4-diamino-5 (2,3,5-trichloro-phenyl) -6-trifluoromethylpyrimidine or an acid addition salt thereof is produced. Process according to claim 1 or 2, characterized in that any of the following compounds are produced: 2,4-Diamino-5- (4-nitro-2,3,5-trichlorophenyl) pyrimidine 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methylpyrimidine 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine 4-amino-2-N, N-dimethylamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine 4-amino-2-morpholino-N-5- (2,3,5-trichlorophenyl) pyrimidine 4-amino-2-N, N-dimethylamino-5- (2,3,5-trichlorophenyl) pyrimidine 4-amino-6-methyl-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine 2,4-diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methylpyrimidine 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methoxymethylpyrimidine 2,4-diamino-5- (2,4-dichlorophenyl) -6-trifluoromethylpyrimidine 6-Benzylosquimethyl-2,4-diamino-5- (2,4-dichlorophenyl) pyrimidine 2-N-methylpiperazinyl-4-amino-5- (2,4-dichlorophenyl) pyrimidine 2.4-diamino-5- (2,5-dichlorophenyl) -6-trifluoromethylpyrimidine 2,4-Diamino-5- (2,3,5-trichlorophenyl) pyrimidine 4-amino-5- (3,5-dichlorophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) pyrimidine 4-amino-2-N-ethylamino-5- (2,3,5-trichlorophenyl) pyrimidine 4-Amino-2-N-methylamino-5- (2,3,5-trichlorophenyl) pyrimidine or an acid addition salt thereof. A process according to any one of claims 1 to 11, characterized in that it is carried out at elevated temperature in a non-aqueous solvent. Method according to any one of claims 1 to 11, characterized in that it is carried out under reflux. Process according to claim 12, characterized in that the solvent is alkanol. Process according to claim 12 or 14, characterized in that the solvent is ethanol. A process for the production of a pharmaceutical formulation comprising mixing a compound of formula I as defined in any one of claims 1, 3 to 11 with a pharmaceutically acceptable ingredient. Use of a compound of formula I or an acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of CNS disorders or diseases in a mammal, characterized in that R 1 and R _{2 are the} same or different and are selected from the group consisting of hydrogen, halo, hydroxy, alkoxy, alkyl, alkylthio and the group NR ^ ¹¹ , wherein R ¹ and R ^{11 are the} same or different and selected from the group consisting of hydrogen, alkyl, aryl and arylalkyl or together with the nitrogen atom to which they are attached form a cyclic ring which is optionally substituted by one or more alkyl groups and optionally contains a further heteroatom; R _{3 is} hydrogen, alkyl optionally substituted by one or more halo radicals, or is amino, alkylamino, dialkylamino, cyano, nitro, halo, carbamoyl, hydroxy, carboxy, alkoxy, alkylthio, alkylthioalkyl, S (O) _n alkyl, di (alkoxy) alkyl, -C (R): NOH or -COR or -CO ₂ R, where R is hydrogen or alkyl, or a CH ₂ group X, where X is hydroxy, alkoxy, aryloxy, arylalkyloxy, halo, cyano, -NR'R ^n, where R ¹ and R ¹¹ are as defined above, S (O) n-alkyl where n is 1 or 2, or SO 2 N (R ^III) 2; wherein R ^{111 is} selected from hydrogen and alkyl; each of R ₄ to R _g is the same or different and is each selected from the group consisting of hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR, nitro, amino, alkylsulfonylamino, alkoxy, S (O) _n - alkyl wherein n is 1 or 2 or SO _{2 is} N (R ^1U ) ₂ ; or are R ₄ and R ₅ or R ₅ and R ₆ together a group -CH = CH-CH = CH- or a group -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, in which case both are R _? and R _{g is} hydrogen; and optionally one of the nitrogen atoms in the pyrimidine ring may be N-alkylated or optionally N-oxide; wherein the preceding alkyl groups or portions of the alkyl-containing groups have from 1 to 6 carbon atoms, and the aryl groups or aryl moieties of the aryl-containing groups have 6 or 10 carbon atoms. Use of a compound according to claim 17, wherein one of R 1 and R _{2 is} amino and the other is selected from the group consisting of amino, hydroxy, halo, morpholino, piperazinyl, N-alkylpiperazinyl, Ν, Ν-dialkylamino- N-alkylamino or alkylthio; R _{3 is} alkyl which is optionally substituted by one or more halo radicals, or alkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl or a CH ₂ X group, wherein X is hydroxy, phenoxy, benzyloxy, alkoxy or alkylthio; one of R ₄ and R _{5 is} halo and the other is selected from halo or hydrogen; R _{6 is} halo, hydrogen, nitro or amino; is R _? hydrogen, halo, cyano, alkylthio, SO ₂ N (R ^1U ) ₂ , alkyl, nitro, amino or methanesulfonamido; and R _{g is} hydrogen or halo. Use of a compound according to claim 17 or 18, wherein R _{t is} hydroxy, amino, N-alkylamino, N, N-dialkylamino, morpholino, piperazinyl, N-alkylpiperazinyl. Use of a compound according to any one of claims 17 to 19, wherein R _{2 is} chloro, amino, N, N-dialkylamino or piperidino. Use of a compound according to any one of claims 17 to 20, wherein R _{3 is} hydrogen, alkyl, methoxymethyl, trifluoromethyl, benzyloxymethyl, phenoxymethyl or methylthiomethyl. Use of a compound according to claim 17 or 18, characterized in that one of R, and R _{2 is} amino and the other is amino, piperazinyl, or N-methylpiperazinyl, N-alkylamino, Ν, ial dialkylamino, and R ₃ is hydrogen, methyl , trifluoromethyl or methoxymethyl. .73. Use of a compound according to claim 17, wherein R _{t is} selected from the group consisting of amino, piperazinyl, N-methylpiperazinyl, N-morpholino, N, N-dimethylamino and N-ethylamino; R _{2 is} amino; R _{3 is} selected from the group consisting of trifluoromethyl, hydrogen, methyl, benzyloxymethyl, methoxymethyl and methylthiomethyl; R _{4 is} chloro; and is at least one of R _s , R ₆ and R _? chloro and remain selected from the group consisting of hydrogen, chloro and nitro; and R _{g is} hydrogen or R ₄ and R _g are both hydrogen, R _s and R _? both chloro and R _{g is} selected from the group consisting of hydrogen, chloro and nitro. Use of a compound of formula I or an acid addition salt thereof as defined in claim 17 in the manufacture of a medicament for treating or preventing CNS mammalian disorders or diseases, characterized in that R 1 to R _{g are} as defined in claim 17, provided that when R _{7 is} halo, then R _{3 is} hydrogen, perhaloalkyl, methyl or methoxymethyl and / or R _{6 is} nitro and / or R 1 is N-alkylpiperazinyl, morpholino, N, N-dimethylamino, piperazinyl or N-ethylamino; or provided that when R _{6 is} chloro, then R _{4 is} halo and R _{3 is} hydrogen, perhaloalkyl, methoxymethyl, methyl or halo and / or R _{x is} N-methylpiperazinyl, piperazinyl, morpholino or N, N-dimethylamino or N-ethylamino. Use of a compound or an acid addition salt of formula I as defined in claim 1, provided that when at least one of R ₄ to R _{g is} different from hydrogen, and further provided that when R _t and R ₂ both amino, or when R _{t is} hydroxy and R _{2 is} amino and R _{3 is} alkyl or hydrogen and R _? hydrogen, then R ₄ and R ₅ are both halo, for the manufacture of a medicament for treating or preventing CNS mammalian disorders or diseases. 26. Use of a compound or an acid addition salt of formula I, wherein R _(the R ₆ and R _g are as defined in claim 17, and _R? Is halo, alkyl, perhaloalil, cyano, nitro, amino, alkylthio, S (O ) _n- alkyl or SO ₂ N (R ^H1 ) ₂ for the manufacture of a medicament for the treatment or prevention of CNS mammalian disorders or diseases. Use of a compound or an acid addition salt thereof of formula I wherein R ₍ to R _{g are} as defined in claim 17 and R _{1 is} morpholino, piperazinyl, N-alkylpiperazinyl, N, Ν-dialkylamino, N-alkylamino or alkylthio, for the manufacture of a medicament for the treatment or prevention of CNS mammalian disorders or diseases. Use of a compound or an acid addition salt thereof of formula I, wherein R ₁ and R _{2 are} as defined in claim 17 and R _{3 is} alkoxy, alkylthio or alkyl substituted with one or more halo radicals, or is a group CH ₂ X, wherein X is alkylthio, aryloxy, arylalkyloxy, alkyloxy or hydroxy; R ₄ to R ₆ are the same or different and are each selected from the group consisting of hydrogen, halo, perhaloalkyl, cyano, nitro, amino or alkylthio; is R _? halo, alkyl, perhaloalkyl, cyano, nitro, amino or a group SO ₂ N (R ^1U ) ₂ wherein R ^{111 is} alkyl; and R _{g is} hydrogen or halo for the manufacture of a medicament for treating or preventing CNS mammalian disorders or diseases. 29. Use of a compound or an acid addition salt thereof of formula I wherein R _{p is} R ₂ , R ₄ , R ₅ , R ₆ , R _? and R ₈ as defined in claim 17, and R _{3 is} alkoxy, aryloxy, arylalkyloxy or alkylthio, for the manufacture of a medicament for treating or preventing CNS mammalian disorders or diseases. 30. Use of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) -6-trifluoromethyl-pyrimidine or its acid addition salt for the manufacture of a medicament for the treatment or prevention of disorders or mammalian CNS diseases. 31. Use of 2,4-diamino-5- (2,3,5-trichlorophneyl) -6-methoxymethyl pyrimidine or its acid addition salt for the manufacture of a medicament for the treatment or prevention of CNS mammalian disorders or diseases. 32. Use of 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine or its acid addition salt for the manufacture of a medicament for the treatment or prevention of mammalian CNS disorders or diseases. 33. Use of 2,4-diamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine or its acid addition salt for the manufacture of a medicament for the treatment or prevention of a CNS mammalian disorder or disease. 34. Use of one of the following compounds: 2,4-Diamino-5- (4-nitro-2,3,5-trichlorophenyl) pyrimidine 2,4-Diamino-5- (2,3,5-trichlorophenyl) -6-methylpyrimidine 4-amino-2-N-morpholino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine 4-amino-2-N, N-dimethylamino-5- (2,3,5-trichlorophenyl) -6-trifluoromethylpyrimidine 4-amino-2-morpholino-N-5- (2,3,5-trichlorophenyl) pyrimidine 4-amino-2-N, N-dimethylamino-5- (2,3,5-trichlorophenyl) pyrimidine 4-amino-6-methyl-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine 2,4-Diamino-5- (2,3-dichlorophenyl) -6-trifluoromethylpyrimidine 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methylpyrimidine 2,4-Diamino-5- (2,3-dichlorophenyl) -6-methoxymethylpyrimidine 2,4-diamino-5- (2,4-dichlorophenyl) -6-trifluoromethylpyrimidine 6-Benzyloxymethyl-2,4-diamino-5- (2,4-dichlorophenyl) pyrimidine 2-N-methylpiperazinyl-4-amino-5- (2,4-dichlorophenyl) pyrimidine 2,4-Diamino-5- (2,5-dichlorophenyl) -6-trifluoromethylpyrimidine 2,4-Diamino-5- (2,3,5-trichlorophenyl) pyrimidine 4-amino-5- (3,5-dichlorophenyl) -6-methyl-2- (4-methylpiperazin-1-yl) pyrimidine 4-amino-2-N-ethylamino-5- (2,3,5-trichlorophenyl) pyrimidine 4-Amino-2-N-methylamino-5- (2,3,5-trichlorophenyl) pyrimidine or an acid addition salt thereof for the manufacture of a medicament for treating or preventing CNS disorders or diseases in a mammal. A process according to claim 1, characterized in that 2,4-diamino-5- (2,3dichlorophenyl) -6-fluoromethyl-pyrimidine is prepared. 36. Use of 2,4, -diamino-5- (2,3-dichlorophenyl) -6-fluoromethyl-pyrimidine for the manufacture of a medicament for treating or preventing CNS disorders or diseases in a mammal.