JPH06503814A - Substituted tricyclic compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention provides tricyclic compounds that inhibit the enzyme thymidylate synthase ("TS"). Pharmaceutical compositions containing these tricyclic compounds and all effects derived from inhibition of TS. and the use of these compounds for inhibiting TS, including. From TS inhibition The induced effects include cell growth of higher organisms and microorganisms such as yeast and fungi; and inhibition of proliferation. Such effects include antitumor activity. of the present invention Processes for the preparation of substituted tricyclic compounds are also disclosed.

A large group of antiproliferative drugs include antimetabolites. antifolat A special small group of antimetabolites known as es or antifols are , is an antimetabolite of the vitamin folic acid. Typically, antifolate s represents the chemical structure of folic acid, including its characteristic p-hendiylglutamate moiety. It closely resembles the construction. TS has long been an important target in the design of antitumor drugs. It is considered as an enzyme, and many folate analogs are synthesized, and their ability to inhibit TS Power was considered. For example, Br1xner et al., Folate Analo as Inhibitors of Thymidylate Syn this, J, Med, Chem, 30. 675 (1987); J, M ed, Chem, 29. 468 (1986); Jones et al.

Quinazoline Antifolates Inhibiting T hymidylateSynthase: Variation of the Am1no Ac1d, J, Med, Chem.

29.1114 et al., Quinazoline Antifolates [nhi biting Thymidylate 5ynthase: Variati on of theNloSubstituent, J, Med, Chem, 28. No. 468 (1985): and filed on November 6, 1989 See Copending U.S. Patent Serial No. 07/432,338. A novel group of molecules that does not resemble acids in structure, but unexpectedly inhibits the enzyme TS. Introducing the compound. The present invention also provides pharmaceutical compositions containing these substituted tricyclic compounds. , and the use of these compounds to inhibit TS. Induction from inhibition of TS The induced effects include cell growth and proliferation of higher organisms and microorganisms such as yeast and fungi. Inhibition or inclusion of Such effects include anti-tumor activity. The location of the present invention Processes for the preparation of substituted tricyclic compounds are also disclosed.

Detailed description of the invention The present invention has a chemical structural formula (Q) and is capable of inhibiting thymidylate synthase. Concerning antiproliferative tricyclic compounds that can: X and Y form a 5-membered ring or a 6-membered ring containing at least one nitrogen: Z is a hydrogen, halogen, carbon, oxygen or nitrogen atom: U is carbon or nitrogen atom: n is 0 or an integer I: ■ is a carbon or nitrogen atom: W is a carbon or nitrogen atom: A is in the l- or 2-position, is a nitrogen atom, a sulfur atom, or is substituted or is an unsubstituted alkylene group: Ar is an aryl group having one or more rings, or a heteroaryl group. Ri: And, B means that (i) the enzyme or the nitrogen atom, or both of them, are amino acids, 100- or -So bonded to a metal group, a heterocyclic group, or an alkyl group.

- group, or (ii) a substituted or unsubstituted alkyl group.

As used in the present invention, "capable of inhibiting thymidylate synthase" The expression "can" refers to a compound that has a TS inhibition constant, K, of about 10-'M or less. It means. Preferably, the compounds of the invention have a Ki value of less than about 10-'M. more preferably less than about 10-@M, and even more preferably less than about 10 -'M, most preferably in the range of about 10-'M to about 10-'M. Ru.

X and Y in the chemical structural formula (Q) are, for example, virol, imidazole, pyrazole , pyridine, pyrazine, pyrimidine, and pyridazine rings. A 5-membered ring or a 6-membered heterocyclic ring containing nitrogen atoms can be formed. preferred Alternatively, X and Y form the following ring: In the formula, P is hydrogen: methyl, ethyl, propyl, isopropyl, tert-butyl and the like: or R1 and R2 are independently hydrogen, Alkyl, amino, hydroxyl, or the like - NR’ R” It is an amino group.

2 in the chemical structural formula (Q) is a hydrogen atom; chloro, bromo, or fluoro Halogens such as: substituted or unsubstituted alkyl, alkyl, along with other suitable atoms. Kenyl, alkynyl, alkyl-oxy-alkylene, allyl, Benzyl, acetyl, carbamyl, carbalkoxy, cyano, phenylacetyl , aminoalkyl, etc.; with other suitable atoms; hydroxy, alkoxy, oxamide, oxamyl, acetoxy, phenylene Forming groups like noxy, phenylsulfamyl, phenylsulfonamide, etc. Oxygen atoms that may be: or with other suitable atoms, amino, nitro, acetate do, anilino, benzamide, formamide, hydrazino, hydroxamino, iso Cyano, nitramino, nitroso, oxamide, sulfamide, alkylamino Any group may be formed by a nitrogen atom. More preferably, Z is a hydrogen atom.

The integer n in the chemical structural formula (Q) can be 0 or 1, but is preferably 0. . In other words, as written above, the left-hand ring in the formula is either a 6-membered ring or a 7-membered ring. There is a difference.

U, V and W in formula (Q) are each independently a carbon or nitrogen atom. , together with (CH2)- and other suitable carbon atoms, as shown in the formula , for example, benzene, cyclohexene, pyridine, tetrahydropyridine, pyridine Dazine, pyrimidine, 1,2,3-triazine, cycloheptene, tetrahydro Forms a 6-membered ring, such as that of acepine, or a 7-membered ring.

In a more preferred embodiment, U is a carbon atom, ■ is also a carbon atom, and So, W is a nitrogen atom. Most preferably, U, V and W are as shown in the above structural formula. As shown, together with (CHz)- and one or more other atoms, it has the following structure: two forming a ring Generally, A in the above formula (Q) is U, -(CHt　), , v, w and in the 1- or 2-position of the ring formed by other suitable atoms cited above. be.

A, together with the appropriate atoms, forms a group such as a di- or tri-substituted amine. a nitrogen atom that can form a thio bond (-8-) with other suitable atoms; , thioalkylene, thioamide, etc.; or , for example, methylene, ethylene, n-propylene, isopropylene, n-butylene Substituted or unsubstituted amines such as n-, tert-butylene, n-hexylene, etc. It can be either a lekylene group. If A is sulfur, then W and V is carbon to produce a reasonably stable compound. You should be careful. Preferably, A is, for example, methylene, ethylene, n-propylene. Pyrene, isopropylene, n-butylene, tert-butylene, n-hexylene It is a substituted or unsubstituted alkylene group such as.

As shown above, Ar can be a multiple aryl with one or more rings. , or a heteroaryl group. Useful allyl rings Examples of groups include phenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, phenyl, These include enanthryl and anthryl. Examples of typical heteroaryl groups include Che Nyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, furyl, isothi Five-membered monocyclic rings such as azoyl, furazanyl, isoxasilyl, etc. Groups; such as pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc. 6-membered monocyclic ring group: and henzo (b) chenyl, naphtho (2,3-b ) chenyl, trianthrenyl, isobenzofuranyl, chromenyl, xanthenyl ru, phenoxathiinyl, intridinyl, isoindolyl, 3H-intolyl , indolyl, imidazolyl, purinyl, 4H-quinarinyl, isoquinolyl, Noryl, phthalazinyl, naphthyridinyl, xanthenyl, quinazolinyl, dinoly nil, pteridinyl, 4H-carbazolyl, carbazolyl, β-carbolinyl, Phenoxazinyl, acridinyl, perimidinyl, zenatronil, phthalazinyl polycyclics such as ole, isothiasilyl, phenothianidyl, phenoxazinyl, etc. There is a heteroaryl group. Preferably, Ar is phenyl or naphthyl. is a monocyclic or bicyclic aryl group.

The substituent B on the Ar group discussed above alone forms an ether bond (-0-). or with other suitable atoms, hydroxy, alkylenoxy, oxami Oxamyl, acetoxy, phenoxy, phenylsulfamyl, phenyl an oxygen atom capable of forming a group such as sulfonamide; or other suitable R1 and R2 are each independently an alkyl group or the like. There are amino NR'R'' groups, nitro, acetamide, anilino, benzamide, Formamide, hydrazino, hydroxamino, isocyano, nitroamino, nit a nitrogen atom capable of forming roso, oxamide, sulfamide, etc.; or , -CO-1 or -5O2- group.

Any one of the above divalent B groups can be alanine, arginine, subaragin, as Partic acid, cysteine, glutamine, glutamic acid, glycine, histidine, Isoleucine, leucine, lysine, methionine, phenylalanine, proline, Amino acids such as serine, threonine, tryptophan, tyrosine, and valine :Aryl group such as phenyl, naphthyl, etc.: chenyl, pyrrolyl , imidazolyl, pyrazolyl, isothiazolyl, pyriminyl, pyrazinyl, te Trahydroylazinyl, benzo(b)chenyl, naphtho(2,3,-b)chenyl ru, phoxathiinyl, imidazolyl, phthalazinyl, dinolinyl, carbolinyl , phenanthrolinyl, phenoxazinyl, etc., or methyl ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n It can be further bonded to an alkyl group such as -hexyl. lastly, B itself is methyl, ethyl, n-propyl, isopropyl, n-butyl, t It may be an alkyl group such as ert-butyl, n-hexyl, etc.

In a more preferred embodiment, B is aryl, or more preferably or 100- bonded to the heterocyclic group of phenyl or tetrahydroirasanyl. 1 or -5O2- group. B or if it contains an aryl group, The group can be unsubstituted or carry one or more of a wide variety of electron-donating and electron-withdrawing groups. Can be replaced. Typical substituents include halogen, hydroxy, alkyl, koxy, alkyl, hydroxyalkyl, fluoroalkyl, amino, -CN , -No2, carbalkoxy, carbamyl, carbonyl, carboxyldioxy , carboxy, amino acid carbonyl, amino acid sulfonyl, sulfamyl, sulfonyl phanylyl, sulfhydryl, sulfino, sulfinyl There's something called Lufonil. Most preferably B is unsubstituted or hydroxy group, methoxy, ethoxy, isopropoxy, tert-butoxy, chloroeth An alkoxy group such as It is a -SO2- group.

More preferred structures for -Ar-B include:

In addition to substituent B as defined above, Ar in formula (Q) can contain one or more broadly It can also be substituted with various electron-donating and electron-withdrawing groups. Typical substituents include , halogen, hydroxy, alkoxy, alkyl, hydroxyalkyl, full Oroalkyl, amino, -'CN.

N　O　　　, carbalkoxy, carbamyl, carbonyl, carboxyldioxy cy, carboxy, amino acid carbonyl, amino acid sulfonyl, sulfamyl, Sulfanilyl, sulfhydryl, sulfino, sulfinyl, sulfo, sulfonyl Examples include honamide and sulfonyl. Preferably, these further substituents are , -CN, fluoroalkyl, and sulfonyl .

According to the present invention, particularly preferred compounds capable of inhibiting thymidate synthase are provided. In the preferred group of compounds, X and Y in formula (Q) form the following ring: Completing: In the formula, P is lower alkyl such as methyl group, amino group, or hydrogen; U is carbon: n is zero: V is carbon: W is nitrogen; A is methylene and -Ar-B is selected from the group consisting of: Examples of particularly preferred compounds include where P is hydrogen and -Ar-B is In the formula, P is an amino group, -Ar-B is P in the formula or an amino group, -Ar- B is the formula in which P is an amino group, -Ar-B is the formula in which P is an amino group, and -A r-B, or in the formula, P is a methyl group and -Ar-B is CM -CM CM -C M In the formula, it is an amino group, -Ar-B or CH-C)l CH-CM In the formula, -NHCH3 is -Ar-B, in the formula P is an amino group, - Ar-B is an amino group in which P is an amino group, and -Ar-B is an amino group in which P is an amino group. -Ar-B includes compounds that fall under the above group.

In another particularly preferred embodiment of the present invention, in structural formula (Q) X and Y form the following ring: P in this ring is a group consisting of -NH, and methyl. selected: U is carbon; n is zero; V is carbon; W is nitrogen. Yes; A is methylene: and -Ar-B, In an even more preferred group of compounds according to the invention, structural formula (Q) X and Y in form the following ring In this ring, P is selected from the group consisting of -NHOH and NHNH2. Bare; U is carbon: n is zero: V is carbon: W is nitrogen: A is methylene: and -Ar-B or Still more particularly capable of inhibiting thymidylate synthase according to the present invention In preferred compounds, X and Y in structural formula (Q) form the following ring: : U is carbon; n is zero; V is carbon; A is divalent sulfur , and -Ar-B, the present invention prepares the compounds of the present invention consisting of the following steps. Also related to the manufacturing process: (1) A, Ar and B are defined as above, and D is a substitutable group. In the compound of formula B-Ar-A-D, the X-precursor and the Y-precursor are ring-closed to each other. A chemical that forms a 5- or 6-membered heterocyclic ring containing at least one nitrogen atom when Reacting with a compound of structural formula (I) 5 A substituted compound having the following structural formula is formed.

(2) The X precursor and the X precursor are ring-closed to each other and contain at least one nitrogen atom. A 5-membered ring or a 6-membered heterocyclic ring is formed.

A substitutable group can be any group that can be substituted under the reaction conditions used. , typically a halogen such as fluoro, chloro, or bromo; sulfonyloquine, trifluoromethanesulfonyloxy, toluene-p-su Substituted groups such as sulfonyloxy or 4-promobenzenesulfonyloxy sulfonyloxy group, aldedo: or the like. Halogeno is more preferable substitution possible bromo is particularly preferred.

The first step in reacting B-Br-A-D with the compound of structural formula (I) is to It can be done in a drug. Typically, when an organic solvent is used, dimethyl Formamide, dimethylacetamide, dimethylsulfoxide, or tetrohyde An aprotic solvent, such as Dorofuran, is used. Particularly preferred organic solvents include , dimethylformamide and dimethylacetamide.

Typically, the first step is to use a weak base that does not itself react with one of the reactants. carried out in the presence of For example, useful bases include cyisopropylethylamine, Dimethyl-5eC-butylamine, N-methyl-N-ethylaniline, N,N- a batter base such as a substituted amine such as dimethylaniline, and sodium carbonate; A weak inorganic base such as potassium carbonate and/or calcium carbonate Ru. The reaction temperature for the first step can vary from about room temperature to about 100°C. or preferably in the range of about 65°C to about 85°C.

The X-precursor and the X-precursor are ring-closed to each other to form a 5-membered compound containing at least one nitrogen atom. The second step to form a ring or 6-membered ring is HC(OCH=　)! /H Cji’, CNB r, CHs C (OCH3) * /HCt7 or tin-like It is carried out in the presence of a ring-closing reagent such as a combination of metal and acetic acid. Most preferably, The ring-closing reagent HC(OCH,)s/HCI, or CNBr.

Reactions include methanol, ethanol, butanol, acetonitrile, and mixtures thereof. It can be carried out in the presence of an organic solvent such as . For example, if the ring-closing reagent is CNBr If so, a mixture of methanol and acetonitrile can be used for operation. deer And the ring-closing reagent is HC(OCHs)s/HCI! In contrast, when Typically, the starting material is converted to HC(OCH,)3 without the addition of further solvents. dissolves in itself and then a relatively small amount of HCI! Start the ring closure step by adding let

The temperatures used for the ring closure step range from slightly below room temperature to about 70°C. °C, but more preferably from about 20°C to about 60'C.

X-precursor, Y-precursor, U, V and W are substituted in substitution step (1) or ring-closing step. Before or after step (2), or during: (a) protected by a protecting group; (b) contains one or more of the protecting groups present or one or more chemical groups to be removed; It should be noted that this may occur.

Suitable protecting groups for ring nitrogens such as U, V, or W include, for example, sodium hydroxide. Pivalo can be removed by hydrolysis with a base such as thorium. methyl group, acids such as hydrochloric acid, and bases such as lithium hydroxide. tert-butyroxycarbonyl, which can be removed by water lysis or a fluoride such as tetra-n-butylammonium fluoride 2-(trimethyl (rusilyl)ethoxymethyl group.

A suitable group for the hydroxy group is, for example, a base such as sodium hydroxide. such as acetyl or hendiyl groups, which can be removed by hydrolysis of It is an esterification group. Alternatively, other groups present in the starting material are When it does not contain a kenyl or alkynyl group, for example, the protecting group is by hydrogenation in the presence of a catalyst such as palladium or Raney nickel. α-aryl alkyl, such as the Hensyl group, which can be removed by It may be.

A suitable protecting group for the mercapto group is, for example, a base such as sodium hydroxide. An esterified group such as an acetyl group that can be removed by hydrolysis with Ru.

Suitable protecting groups for amino groups are, for example, inorganic acids such as nitric acid, sulfuric acid or hydrochloric acid. or by basic hydrolysis with sodium hydroxide. Alkyl groups such as acetyl groups (CH, Co-) can be removed by It may be a rubonyl group. Another protecting group for the amino group is methoxycarbonyl , or an alkoxycarbonyl group such as tert-butoxycarbonyl group be. These groups can be modified by treatment with organic acids such as trifluoroacetic acid. Can be removed. Alternatively, the protecting group is borontris (trifluoro acetate) or hydrogen gas in the presence of mature palladium. benzyloxycarbonyl, which can be removed by treatment with It's fine.

Suitable protecting groups for primary amino groups are, for example, nitric acid, sulfuric acid, or hydrochloric acid. Alkyl carboxylic acids, such as acetyl, which can be removed by treatment with inorganic acids alkyl amines such as 3-dimethylaminopropylamine, Fluids can be removed by treatment with drazine or ammonia. It is a taloyl group.

A suitable group for the carboxy group is hydrolysis with a base such as sodium hydroxide. an esterified group, such as a methyl or ethyl group, which can be removed by It may be. Another useful protecting group is the tert-butyl group, trifluoro It can be removed by treatment with an organic acid such as acetic acid.

More preferred protecting groups include esterification groups, α-aryl groups, alkyl Carbonyl group, substituted or unsubstituted alkoxycarbonyl group, phthaloyl group, baloyloxomethyl group, or methoxymethyl, or 2-(trimethylsilyl) There are methyloxyether-type groups such as (l)-ethoxymethyl.

A special aspect of the invention is to synthesize thymidylate synthase from a starting compound of structural formula (1). The present invention relates to a process for making substituted tricyclic compounds capable of inhibiting. Formation of structural formula (I) The compound has the structure of structural formula (II): In the formula, Ac is a protecting group for CH, Co-. Prepare starting compounds for this group The process may consist of the following steps: (1) Selectively protect the amine compound of structural formula ■: form the corresponding acetamide. ; and (2) nitration of the corresponding acetamide to form a compound of structural formula (II) form.

In the first step, a protecting group is added to the compound of structural formula ■ to form the corresponding structural formula Forming the acetamide of (ii) involves converting the amine compound of structural formula (III) into treatment with a suitable acid anhydride such as acetic anhydride in the presence of an organic solvent such as carried out by. Addition of protecting groups can be carried out at temperatures below or above room temperature. It can happen at any time.

However, typically the addition of protecting groups occurs at temperatures between about -10° and 15°C. , most preferably occurring between about -10C and -5C.

The acetamide formed by selectively protecting the amine compound is The second step is (1) a mixture of nitric acid and sulfuric acid: (2) nitric acid, sulfuric acid, and vinegar. or (3) many known nitrification tests, such as a mixture of nitric acid and acetic anhydride. This can be done in the presence of one or more drugs. More preferably, the nitrating reagent is nitric acid. and sulfuric acid. The nitrification step can be carried out over a wide range of temperatures. is typically carried out at temperatures of -10°C and +10°C, more preferably at temperatures of about It is carried out between -10°C and 5°C.

Amine compounds of structural formula (I[I) are themselves susceptible to several different reaction schemes. It can be prepared by

In one embodiment, the amine compound of structural formula (I[I) has a suitable number of carbon atoms. A 6-membered ring formed by U, V and W, or a 7-membered ring that combines a hydrogen atom and a hydrogen atom Reducing a compound corresponding to an amine that has one or more unsaturated sites in the ring. It is prepared by In this embodiment, the reduction is performed under a wide variety of reduction conditions. Can be carried out preferably in water, or methanol, ethanol In organic solvents such as , tetrahydrofuran, acetic acid, etc. or at least 1 atmosphere, more preferably from about 1 psi to about 50 psi. The force is carried out in the presence of hydrogen gas. Platinum oxide (Ishikawa et al., Chem, Phar m, Bull,, 37. 2103 (1989), and reference This reference is incorporated herein by reference. ) are also used.

In the most preferred embodiment, the amine corresponding to one or more sites of unsaturation is The compound has the following structural formula: and treatment with hydrogen gas and a platinum oxide catalyst in an organic solvent such as glacial acetic acid. will be reduced by

Alternatively, in another more preferred embodiment, an amine compound of structural formula (III) The things are: (1) Structuring (■): The unsubstituted compound is nitrated to form a nitrated compound having the following structural formula: : (2) Reducing the nitro compound to form an amine of structural formula (II[).

The reaction conditions for nitration step (1) are typically those for common nitration reactions. The response is as described above. But more preferably the nitration step is carried out in the presence of nitric acid at a temperature between about -10 and about 20°C. . A particularly preferred nitration step using these conditions is described by Amlt et al. J, Chem, Soc.

Perkins n, 57 (1976), and in the present invention, the cited text Incorporated by donation.

The reaction conditions used for reduction step (2) vary widely, but are typically contains one or more of the following = (a) treatment with 5nC1, in the presence of hydrochloric acid; (b) treatment with zinc in the presence of acetic acid; (c) treatment with benzene and Treatment with Fe”(Co)+2 in tanol: (d) of palladium on mature wood. treatment with hydrogen gas in the presence of: (e) oxidized white in an organic solvent, such as glacial acetic acid; treating with hydrogen gas in the presence of a gold catalyst; and (f) in the presence of a reducing catalyst. Then, treat it with hydrazine. However, more preferably, reducing step (2) using an alcohol as a solvent, e.g. methanol, in the presence of a charcoal catalyst. In this process, hydrogen gas is used as a reducing agent.

Most preferably, the compound of structure (IV) has the following structural formula: In the formula, Ac is an acetyl (CHsC0-) group, which is a protecting group, and removed between step and reduction step. Removal of this protecting group from the amino group Removal of protecting groups can be accomplished by the general methods described above. Yo More preferably, the acetyl group is, for example, water, an alcohol such as ethanol, or or in a mixture of water and alcohol, in an inorganic acid such as hydrochloric acid, at the boiling point of the solvent. removed by treatment.

As mentioned above, when the X-precursor and the Y-precursor are ring-closed with each other, at least one It is a group that forms a 5-membered or 6-membered heterocyclic ring containing a nitrogen atom. more preferable In some embodiments, the compound In , the X-precursor is -NH-Ac and the Y-precursor is -N02 group. Ru. In this embodiment, the -NH-Ac and -NO□ groups can be used in several alternative ways. can be ring-closed to each other using one of the methods (A), two of which are , and (B) below.

In process (A), the compound is treated sequentially as follows: (1) For example, by treating with an inorganic acid such as hydrochloric acid, which is a deprotecting base, the NH-Ac group is removed. converting into a free amino group; (2) A reducing agent, e.g. hydrazine, in the presence of a reducing catalyst such as Raney nickel. and (3) HC(OCR,'), CH2C(OCR,), or by treatment with a ring-closing reagent such as CNBr to form a ring with the following structure: Ru: In the formula, P is an alkyl group such as a methyl group, an amino group, and hydrogen. Method (A) In this case, P is determined by the ring-closing reagent selected. For example, ring-closing reagent or H If C(OCH3)3, P is hydrogen; the ring-closing reagent is CH,C(OCH,> 3, P is a methyl group, and if the ring-closing reagent is CNBr, P is an amino group. It is.

In alternative method (B), the -NH-Ac group is used as the X-precursor and the -NO7 group is used as the Y-precursor. - Direct treatment of compounds contained as precursors with metals such as tin and zinc in the presence of acetic acid do.

In the resulting ring-closed compound, P is methyl. many other known Either method (A) or method (B) is useful, as is the ring closure method. However, the ring-closing method (B) is preferable.

Another aspect of the present invention is to provide an amount of the present invention that is effective to inhibit thymidylic acid. a pharmaceutically acceptable diluent or carrier in combination with at least one compound A pharmaceutical composition comprising: The composition preferably comprises an effective amount of of the compound of the invention.

Substituted tricyclic compounds of the present invention that can be used in the pharmaceutical compositions of the present invention include those mentioned above. Includes all of the compounds listed above, as well as pharmaceutically acceptable salts of these compounds. It will be done.

Pharmaceutically acceptable acid addition salts of compounds of the invention containing a basic group are well known in the art. strong or moderate oxidation, as appropriate, in the presence of a basic amine by methods known in the art. It is often formed with strong organic or inorganic acids. Representative acid addition salts included in the present invention Examples include maleate, fumarate, lactate, oxalate, methanesulfone ethanesulfonate, benzenesulfonate, talcrate, cytol hydrochloride, hydrobromide, sulfate, phosphate, and nitrate salts. Pharmaceutically acceptable compounds of the invention having acidic groups Addition salts of bases are prepared by known methods, and the bases include, for example, hydroxylated salts. Like calcium, sodium hydroxide, potassium hydroxide, and calcium hydroxide non-toxic alkali metals, alkaline earth metal hydroxides, and ammonium hydroxide : and triethylamine, butylamine, piperazine, and tri(hydro Non-toxic organic bases such as (oxymethyl) methylamine are included.

As mentioned above, the compounds of the present invention have properties that can be expressed in the form of anti-tumor activity. It has some anti-proliferative activity.

The compounds of the present invention are active per se or in vivo.

may be prodrugs that are converted into active compounds in According to the present invention A preferred compound is a murine leukemia cell line that can be grown in cell culture. It is active in inhibiting the growth of the L1210 cell line. Such a method of the present invention The compound is a Gram-negative bacterium that can be grown in culture. It is also active in inhibiting the growth of bacteria such as Erichia coli .

Substituted tricyclic compounds according to the present invention, as well as pharmaceutically acceptable salts thereof, include: Incorporation into convenient dosage forms such as capsules, tablets, or injectable formulations Can be done. Solid or liquid pharmaceutically acceptable carriers can be used. solid carrier The body contains starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, and tar. gelatin, agar, pectin, acacia, magnesium stearate, There is alic acid. Liquid carriers include cabbage, peanut oil, olive oil, and salt. Contains water and water. Similarly, the carrier or diluent may include glyceryl monoester. Alate, or glyceryl distearate, alone or with a wax. Any intermixing materials may be included. liquid carrier or used When used, the formulations include tablets, elixirs, emulsifiers, soft gelatin capsules, Sterile liquids (e.g. solutions), such as in ampoules, or aqueous or non-aqueous Can be in suspension form.

The pharmaceutical formulation is mixed, granulated and, if necessary, compressed for tablet form. or by mixing, filling, and dissolving the ingredients as appropriate for oral, parenteral, or topical administration. Preferred formulations for topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural and rectal administration according to the routine techniques of pharmaceutical formulation chemists, including steps such as giving Made.

The compositions of the invention further include antimitotic agents (e.g., himblastine), Killing agents (e.g., cysuplatin, carpoplatin, and cyclophosphamide) ), DHFR inhibitors (e.g., methotrexate, piritrequine, or rimetrexate), antimetabolites (e.g. 5-fluorouracil, and cytocytolytic arabinosides), intercalating antibiotics (e.g. adriamycin), enzymes (e.g. asparaginase), topoisomerase inhibitors (e.g. etopocide), or biological response modifiers. one or more anti-tumor agents, such as feron (e.g., interferon); May contain other compounds.

The compositions of the present invention also have antibacterial, antifungal, antiviral, antixorosis, and anticoccyx properties. One or more other compounds may be included, including a diuretic agent. Typical antibacterial agents include , for example, sulfamethoxazole, sulfadiazine, sulfameter, or sulfonamides like sulfatoxin, trimethoprim, bromode HFR inhibitors such as diabrim or trimetrexate; penicillin Class; Cephalosporins Diaminoglycosides: Bacteriostatic protein synthesis inhibitors; Quinolo carboxylic acids, and their Fuyuzermanthiazolo analogues. Ru.

Another aspect of the invention is that tricyclic compounds according to the invention inhibit thymidylate synthase. administration to an animal host, such as a mammal or bird, in an amount effective to The therapeutic process of inhibiting thymidylate synthase comprising: Compounds of the invention The product is particularly useful for the treatment of mammalian hosts, such as human hosts, and for the treatment of avian hosts. It is for use.

Any of the substituted tricyclic compounds described above, or a pharmaceutically acceptable salt thereof, It can be used in the therapeutic process of the present invention. The compounds of the invention are as described above. The present invention may be prepared in the form of a pharmaceutically acceptable composition containing a diluent or carrier as described above. can be administered during the course of treatment. The dose of the compound is more preferably includes pharmaceutical dosage units containing an effective amount of an active compound. An effective amount is one or more Administration of the above pharmaceutical dosage unit inhibits TS and induces seedling-raising effects therefrom. This is a sufficient amount. A typical daily dose for an animal host is: The amount of active compound per animal host body surface area is approximately 5,000 μm.

The selected dose is based on the need for therapy mediated by thymidylate synthase inhibition. when administered, topically (e.g. ointment or cream), orally, rectally (e.g. (e.g., suppositories), intravaginal, intranasal, or intrabronchial administration by parenteral injection or infusion. by any known method of administration, including intraocularly, intraocularly, or intraocularly. can be administered to a mammal, eg, a human patient.

The substituted tricyclic compounds according to the invention furthermore have antibacterial, antiparasitic and antiviral effects. It has no anticoccidial, antipsoriasal, antiprotozoal, anticoccidial, or antifungal effect. may be further characterized by producing one or more anti-proliferative effects. You can do something like that. The compound exhibits antitumor activity in the animal host harboring the tumor. Particularly useful in producing sex.

Compounds of the invention are antagonists of the folic acid cofactor and therefore have one or more Other forms of folate-dependent enzymes may also be affected. Other leaves that may be affected Examples of acid-dependent enzyme systems include 5. lO-Methylenetetrahydrofolate, Redac tase, serine, hydroxymethyltransferase, and glycine amine There is also ribotide transformylase.

The following examples illustrate the invention, but the scope and spirit of the invention is thereby understood. It is not subject to any restrictions.

Example The structures of all compounds of this invention have been determined by proton magnetic resonance spectroscopy, infrared spectroscopy, Ctroscopy, trace element analysis and, in certain cases, mass spectrometry - confirmed.

Proton magnetic resonance spectra were obtained using a General Electric QE-300 spectrometer. The measurement was carried out using a motor operated at a magnetic strength of 300 MH2. The chemical shift is C DCf, the peak of CHCls is at 7.26 ppm, D, DMS For O, the standard was set to 1-ppm so that the peak of DMSO was at 2°49 ppm. It was described as m(δ). The standard and peak multiplicity were expressed as follows. S, Thing let, d, doublet, dd, doublet of doublet, t, triplet, brs, wide singlet, brd, wide doublet, br, wide signal, and m, multibullet.

Mass spectra were obtained using a VO2070E-HF high-resolution mass spectrometer. Measured using the direct insertion method at an ionization voltage of 70 eV and an ion source temperature of 200°C. . Infrared absorption spectra were measured using a Perkinco Lumar 457 spectrometer. It was measured by Trace element analysis is expressed as ±0.496 of the theoretical value for each element. The results were as follows.

N-N-dimethylformamide (rl) MFJ) is activated (250°) 3-person Dry over molecular sieves and prepare N,N-dimeracetamide (rDMAl) ( Aldrich Goldberg class) also dried out similarly. Tetrahydrofuran (rTHF) ) was distilled from sodium benzophenone ketyl under nitrogen. It's called "ether" The word "U" means diethyl ether. The word "vetrol" has a boiling point of 36-53 Means petroleum ether at °C.

For flash chromatography, use silica gel 60 (Merck AR) 9385) This was done using If the trachyhedra are insoluble in the eluent of choice, they can be dissolved in a more polar solvent. Oak, Merck Art 7734 silica was added. The slurry is sprinkled with silica. Evaporate until dry in a rotary evaporator with the addition of coarsely ground glass to prevent did. The coated silica was packed into a column. Thin layer chromatography (rTL CJ) is a pre-coated silica 60Fts<(Merck AR) 5719). I did it on the sheet. The extract was added to anhydrous N at S O4 or M g S04. It was dried. Melting points were determined using a Meltenbu apparatus and were uncorrected.

Example 1 Preparation of compounds 2 and 3 Compounds 2 and 3 were prepared according to the reaction scheme described below.

Preparation of compound 2 6-nitrotetrahydroquinoline N- obtained by acylation of tetrahydroquinoline (acetic anhydride, pyridine) Acyltetrahydroquinolines were prepared by Amlt et al., J. Chem., So. c, nitration and protection as described in Perkins Il, 57 (1976). Perform group removal.

'HNMR (CDC173') 67.86-7.90 (2H, m), 6.36 (lH, d, J=9.6Hz).

4.75 (IH, brs), 3.41 (2H, t, J=5.6Hz), 2. 79 (2H, t, J=6.3Hz).

and 1.91-1.99 (2H, m).

Preparation of compound 3 6-acyltetrahydroquinoline 2-Nitrotetrahydroquinoline 2 (29, OOg.

0.16 mol) in 200 ml of methanol and 10% palladium on charcoal (3, 00 g) into a Parr hydrogenator and shaken with 35 psi hydrogen for 1.5 hours. did. The mixture was filtered through diatomaceous earth sold under the trade name Celite, concentrated, and filtered. Purified by rush chromatography (50%-7596EtOAc/hexane) 15.79 g (0.11 mol 68%) of a tan solid was obtained. melting point 75-80°C, 'HNMR (CDC1g) 66.40 (3H, m), 3. 23 (2H, t, J = 5.4Hz), 2.69 (2H, t + J = = e, 5 Hz), and 1.89-1.92 (2H, m). IR(KBr)3400.3 360, 3900, 880, 810゜6-amitutetrahydroxylin - another person Method 6-Aminoquinoline (1,00 g, 6.93 mmol) in 20 ml of rice vinegar, Pt0z (0.06g, 0.30mmol) and Ishikawa et al,,chem,Pharm,Bull,.

37.2103 (+989) and shaking at 45 psi for 2 hours. Mixed The mixture was filtered through diatomaceous earth sold under the trade name Celite, and salted with 6N NaOH. Made basic and extracted with CH2C12 (2X 100ml). Wash the organic layer with water, Dry over anhydrous Na*SOa and concentrate to 0.62 g (4,18 mmo I, 6 0%) of a gray solid was obtained.

Example 3: Preparation of compounds 5 and 6 Preparation of compound 6 In 6-acylamino-7-nitrotetrahydroquinoline compound 5, compound 3 is The primary amino group was selectively protected as acetamide (acetic anhydride, pyridine, -10℃).

Compound 5 (3,72g) to 989iH, So, of 30-.

19.55mmo 1) was dissolved at -10°C. , 30m7.20.22mmo1). Meanwhile, the temperature rose to 5°C. Ta. This mixture was poured into 400 ml of water, neutralized with 6N NaOH, and ethyl acetate. tate (3 x 500 mj'). The 'HNMR of this crude product is compound 6. and the 5-nitro isomer in a 2.5:l mixture. The extract is anhydrous Na After drying over SO4 and concentration, flash chromatography (65% Et OAc/hexane) to give a dark red solid (10,97 mmol, 5696) 2.58 g of Compound 6 was obtained. Melting point 150-155°C1C11HN ( CDC1,) δ9.80 (IH, brs), 8°22 (LH, s), 7.2 2 (LH, s), 4. t.

(IH, brs), 3.32 (2H, t, J=5.5H2), 2.82 (2 H, t, J26.4Hz), 2゜22 (3H,s), and 1.91-1.9 5 (2H.

m). IR (KBr) 3410.3320.2930°+650.1580,8 50° high-resolution mass spectrometry, accurate calculation of C++H+-NiOs The mass is M”+!235.0957. Actual value 235.0950° Compound 13 ~16 and compounds 7(d) and 7(e) were prepared according to the following reaction scheme.

Preparation of compound 13 Di-4-(p-)luenesulfonyl)phenyl carbonate Diphenyl carbonate (50.16 g, 0.2 3 mmol), toluenesulfonyl chloride (90.04 g, 0.47 m ol) and FeCl! s (1.12g, 0.Omol) was added to 12 It was heated to 0°C and the HCl1 generated was captured through a water trap. after 2 hours When the mixture was cooled to 23°C, a light beige precipitate formed. Filter out the solids Wash with MeOH to obtain 87.61 g of crude compound 13 (0°) 7 mol, 72% ) was obtained. Melting point 149-160°C0IHNMR (CDC1,) δ7.98 ( 2H, d, J=8.7Hz), 7.82 (2H, d, J=8.3Hz), 7. 40 (2H, m), 7.24-7.32 (2H, m), and 2. 40 (3 H,s).

Preparation of compound 14 4-(p-1-luenesulfonyl)phenol compound 13 (87.61g, 0 ．． 17mo1. ) in 150EtOH/150ml 15N KOH. Heated to 80°C for 1 hour. Pour the mixture into 500ml MeOH and NHCj? When I neutralized it with KCI! A precipitate was formed. Filter the salt and filtrate with CH Dissolved in zClt, washed with water, dried over anhydrous Na2S04, concentrated and purified. A non-white solid was obtained. Yield: 69.65 g (0.28 mol, 82%). Melting point 1 43-144℃, 'HNMR (CDCI!,) δ7.76 (4H, d, J=8 ．． 6Hz), 7.27 (2H, d, J=8.4Hz), 6°90 (2H, d , J=8.8Hz), 6.47 (IH.

brs), and 2.38 (3H, s), IR (KBr) 3325, 1900 ．．　1200. 830. 800°C + sHI*Os The calculated analysis value of S is C, 62,89, H, 4°87, S, 12.91. Actual value C, 62, 90°H ,4,91,S,12. 93° Preparation of compound 15 4-(p-)luenesulfonyl)phenylbenzoate Compound 14 (7゜64g, 3 0.77 mmol) was dissolved in benzoyl chloride (0.77 mmol) at 23°C. , 20 t/, 36.18 mmol). After 1 hour, the mixture was converted into CH Diluted with Cf$, washed with water, dried over anhydrous NatSO4, and concentrated. light beige The yellow solid was azeotroped with toluene to yield 9.22 g of product (26.26 mmol .

8596) and used without purification. Melting point 192-198°C,'HN MR (CDC7,) δ8.17 (2H, m), 8.01 (2H, d, J=8. 8Hz).

7.83 (2H, d, J=8.3Hz), 7.66 (IH, m), 7.52 (2H, t, J=7.7Hz), 7°30-7.37 (4H, m), and 2 ．． 41 (3H.

S). IR(KBr)1745,1200.1045゜820.730,700 ゜ Preparation of compound 16 4-(p-1 luenesulfonyl)phenyl methyl ether Compound 14 (20.13g, 81.07mmo 1), Kt Cow (16 , 61 g, 120.18 mmol) and CHs I (6,20 rJ, 99. Reflux 58 mmol of the mixture in 500 mj7 of acetone for 4 hours. I set it.

(To complete the reaction, ■, 00-CH,I (16°00mmo 1) An addition was necessary. ) This mixture is mixed with diatomaceous earth, which is commercially available under the name Celite. Filter and concentrate. The yellowish white solid is CHCl! , dissolve in water, wash with water, then brine and dried over anhydrous NaxSO4. Reduce the volume and transfer the compound to hexane Trituration and filtration yielded compound 16 as 119.53 g of white solid (92%). Ta. 'HNMR (CD (1,) 67.85 (2H.

d, J=8.9Hz), 7.79 (2H, d, J=8°3Hz), 7.27 (2H, d, J=8.4Hz), 6°95 (2H, d, J=8.9Hz), 3 ．． 83 (3H.

s), and 2.38 (3H, s).

Preparation of compound 7(d) 4-(4-benzoyloxyphenyl)sulfonylbenzyl bromide 15 (4-(p-)luenesulfonyl)phenylbenzo to (ltl' CCl4) ate (7,43 g, 21.08 mmol) and N-promosuccinimide (3,7 Refrack the suspension of 6 g, 21° 13 mm 1) under a 200 W light. Heat until simmering. After 1 hour, the IHNMR of the sample showed the desired yield of approximately 5396. It showed product, 30% dibromide and 17% starting material. Cool this mixture , CH2Ct;, washed with water, dried (anhydrous N a2 S O4), and concentrated. 8.36 g of a yellow-white solid (approximately 4.35 g of 7(d), 48%) was obtained. this life The product was used without purification. 'HNMRCCDC12) δ8.19 (2H , m), 7.90-8.05 (4H, m), 7°70 (IH, m), 7.5 0-7.56 (4H, m).

7.39 (2H, m), and 4,49 (2H, S').

Preparation of compound 7(e) 4-(4-methoxyphenyl)sulfonylbenzyl bromide Compound 16 was brominated as described for compound 7(d) to give 6496 Compound 7(e) was obtained with a yield of .

The product was used without purification. 'HNMR (CDCf,) 67.86 ( 4H, m), 7.48 (2H, s, J=8.4Hz), 6.95 (2H, d , J=8.9Hz), 4.44 (2H, s), and 3.83 (3H, s).

Example 5: Preparation of compounds 8(a)-8(e) Preparation of compound 8(a) 6-acylamino-7-nitro-N-(4-(N,N(1-tert-butylcarbon) ruboxamil)piperazinylsulfamoylbenzyl]-tetrahydroquinoline Compound 6 (0,277 g, 1.18 mmol) and bromide 7 (a) (0, A solution of 56 g, 1.35 mmol) dissolved in 10 ml of DMA was added to dry CaC. Heated to 80°C with O5 (0°184g, 1.84mmol) for 6 hours. child The mixture was diluted in ethyl acetate, washed twice with water, and dried over anhydrous NazSO4. and concentrated. Flash chromatography (50% EtOA'C/Hex) 0.403g (0.7g) of compound 8(a) as a purple solid 0 mmol, 60%) was obtained. Melting point: 190-195°C. 'HNMR (CD Cf) s) δ9゜95 (IH, brs), 8.29 (IH, s), 7.71 ( 2H, d, J=8.3Hz), 7.39 (2H, d.

J=8.2Hz), 7.12 (IH, S), 4.57 (2H, s), 3.50 (4H, m), 3.40 (2H.

m), 2.98 (4H, m), 2.90 (2H, m).

2.22 (3H, s), 2°04 (2H, m), and 1°40 (9H, s ). IR (KBr) 1680, 1510゜1330゜ High-resolution mass spectrometry, accurate calculated mass of CztH3sNeO□S M”　573.2257゜Actual value 573.2257゜ Preparation of compound 8(b) 6-acylamino-7-nitro-N-(4-(phenylsulfonyl)benzylco) Tetrahydroxyphosphorus compound 6 (0,402g, 1.17mmol), broma Ide 7 (b) (0,765 g, 2.46 mmol) and diisopropylethyl A solution of amine (0.44d, 2.53 mmol) dissolved in 4-DMF was diluted with 70 Heated to °C for 5 hours. 8(a) and purification as described for 0.8(a). 5 Obtained 77 g (7396) of 8(b) as a red-orange solid. Melting point 202-20 5℃. 'HNMR (CDCI!s) 69. 90 (IH, brs), 8.　 28 (IH, S), 7. 89-7. 95 (4H, m), 7°50~7.　 52 (3H, m), 7. 35 (2H, d, J=8.2Hz), 7. 0 7 (IH, s), 4. 52 (2H, s), 3. 36 (2H, m), 2 ．． 87 (2H.

m), 2.22 (3H, s), and 2. 04 (2H.

m). High-resolution mass spectrometry, accurate measurement of C2, H,, N, Os, S Calculated mass M”465.1358゜Actual value 465.1373゜ Preparation of compound 8(c) 6-acylamino-7-nitro-N-(6-tert-butyldiphenylcylo (oxymethyl)-2-naphthobenzylcotetrahydroxyphosphorus Compound 8(c) is derived from compounds 6 and 7(c) as described for compound 8(b). It was obtained in this way with a yield of 91%. 'HNMR (CDCf!) δ9.90 (IH.

s), 8.28 (IH, s), 7.70-7.82 (8H, m), 7.63 (IH, s), 7.35-7.43 (7H, m), 7.30 (IH, s), 4.91 (2H.

s), 4.65 (2H, s), 3.45 (2H, m).

2.90 (2H, m), 2.22 (3H, S), 2.05 (2H, m) , and 1. +1 (9H, s). IR (pure product) 3360, 1,680. ! , 080 (wide), 880°820.700° High resolution mass spectrometry ,C3! Accurate calculation mass of H41N304Si M”643°2866°actual Measured value 643.2822° Preparation of compound 8(d) 6-acylamino-7-nitro-N-(4-(1”-benzoyloxyphenyl) sulfonyl)benzylco-tetrahydroquinoline Compound 8(d) is derived from compounds 6 and 7(d) as described for compound 8(b). It was obtained in a yield of 57%. Melting point 174-178゜IHNMR (CD(u s) δ9.95 (IH, s), 8.29 (IH, s), 8°16 (2H, d, J=8.3Hz), 8.01 (2H.

d, J=8.7H2), 7.92 (2H, d, J=8°3Hz), 7.65 (IH, m), 7.51 (2H.

m), 7.37 (4H, dd, J=8.6.2.1Hz), 7.12 (IH , s), 4.54 (2H, s).

3.36 (2H, m), 2.88 (2H, m), 2.22 (3H, s), and 2. 04 (2H9m) o I R (KBr) 3360.1730.1 670,1570°1150.880,830,810,700. high resolution mass Spectrometry, C,, H,, N, 07 S exact calculation mass M” 58 5.1570° Actual value 585.1567° Preparation of compound 8(e) 6-acylamino-7-nitro N-(4-(4-methoxyphenylsulfony) )-benzyl]tetrohydroquinoline Compound 8(e) can be prepared from 6 and 7(e) as described for 8(b). Obtained with a yield of 2%. Melting point 168-171″C,’HNMR (CDCI!! ) δ8゜30 (IH, s), 7.86 (4H, d, J=8.9Hz), 7. 33 (2H, d, J=8.4Hz), 7°08 (IH, s), 6.96 ( 2H, d, J = 8.9Hz), 4.52 (2H, s), 3.83 (3H, s ).

3.37 (2H, m), 2.87 (2H, m), 2.22 (3H, s), and 2. 01 (2H, m).

C2SH2SN 10s S i (D calculation analysis value + IC, 0,59, H.

5.09. N, 8.48° Actual value C, 60, 51, H.

5.12. N, 8.37° Example 5: Preparation of compounds 9(f)-9(j) and compounds 1O(f)-10(j) Compounds 9(f) to 9(j) and 10(f) to 1O(j) were prepared according to the reaction scheme below. It was prepared by

Preparation of compounds 9(f)-9(j) 6-amitsutsunitro-N-(4-(N,N-piperazinylsulfamoyl) Benzylco-tetrahydroquinoline, 6-amino-N-(4(phenylsulfony) (6- Hydroxymethyl)-2-naphthobenzylcotetrahydroxyline, 6-amitsu -2nitro-N-C4-(4--hydroxyphenylsulfonyl)-benzyl cotetrahydroxyline and 6-amitsutunitro-N-C4-(4=-metho Regarding compound 9(f) The procedure described below is typical. Suspended in 3N HCl2 (12rnl) Compound 8 (a) (0,4036 g, 0.70 mmol) was heated to 60°C for 5 minutes. ．． Heated for 5 hours. Pour the mixture into 100++t' saturated N a HCOz, Extracted four times with ethyl acetate, dried over anhydrous N a S OA and concentrated. . By flash chromatography (10% EtOH/CHCl!s) Purification yielded 0.215 g of compound 9(f) as a purple solid (0.50 mmol I, 71% ) was obtained. Melting point 194-196°C0'HNMR (CDC12) δ7. 71 (2H, d, J=8.2Hz), 7.42 (2H, d.

J=8.1Hz), 7.06 (IH, s), 6.52 (IH, s), 5.67 (2H, brs), 4.50 (2H, S), 3.31 (2H, t, J=5. 7Hz).

2.95-2.99 (4H, m), 2.90-2.93 (4H, m), 2.8 0 (2H, t, J=6.0Hz).

and 2.01-2.03 (2H, m). IR(KBr)3460.3420, 1240° high-resolution mass spectrometry, accurate measurement of C2°H2□N, O, S Calculated mass M'431.1627° Actual value 431. +626゜9 (g):' HNMR (CDCj’s) δ7°88~7.94 (4H, m), 7.50~ 7.54 (3H.

m), 7.38 (2H, d, J=8.3Hz), 7.02 (IH, s), 6 ．． 50 (IH, s), 5. 65 (2H, brs), 4. 46 (2H, s), 3. 25~3゜27 (2H, m), 2.75~2.77 (2H, m ).

and 1.90-2.04 (2H, m).

9 (h): 'HNMRCCDC1g) 67, 79 (3H, m), 7. 68 (IH, s), 7.39-7°48 (2H, m), 7. 25 (I H,s), 6. 51 (IH, s), 5.63 (2H, brs), 4.85 ( 2H, d, J=5.9Hz), 4.58 (2H, s).

3, 33 (2H, t, J=5.7Hz), 2. 79 (2H, t, J = 6.3Hz), 2.04 (2H, m), and 1.71 (IH, t, J =6.0Hz). IR(KBr)3480.3320,2910.　1560゜ 880.810° High resolution mass spectrometry, CtIHz, N-Q, The exact calculated mass of M”363.1583゜actual value 343.1574゜ 9 (i): Melting point 200-250°C, 'HNMR (CDCI!,) 67.8 0 to 7.86 (4H, m), 7°37 (2H, d, J=8.2Hz), 7. 01 (IH.

s), 6.90 (28, d, J=8.7Hz), 6.50 (IH, s), 5 ．． 66 (2H, brs), 4.46 (2H, s), 3.28 (2H, t, H =5.7Hz).

2.77 (2H, t, J=6.2Hz), and 1.99 (2H, m). IR (KBr)3460.　3380.　2940. 1570. 1150. 8 80. 840°C2□HxINs Os　S accurate calculation mass M”439. 1202° Actual value 439.1213° 9(j): Melting point 141-143°C, 'HNMRCCDC12') δ7. 8 6 (4H, d, J=8.9Hz), 7. 35 (2H, d, J=8.3 Hz), 7°03 (IH, s), 6. 96 (2H, d, J=8.9Hz ), 6. 50 (IH, s), 5. 65 (2H.

brs), 4. 45 (2H, s), 3. 83 (3H.

s), 3. 26 (2H, t, J=5.8Hz), 2. 77 (2H, m ), 1. 98 (2H, m). IR (KBr) 3400.　1500.　 1250. 1150°1100, 860. 800° Preparation of compounds 10(f) to 10(J) 6.7-Diamitsu N-(4-(N,N-piperazinylsulfamoyl)benzi Ruco-tetrahydroquinoline, 6,7-diamituN-(4-(phenylsulfonate) benzylco-tetrahydroquinoline, 6,7-diamitu-N-((6-hydroxy (Droxymethyl)-2-naphthobenzylcotetrahydroxyline, 6,7-dia Mitsu N-(4-1'-hydroxyphenylsulfonyl)-benzylcotetrahy Droxyline, and 6,7-diamitu N-(4-4-methoxyphenyls (ruhonyl) benzylcotetrahydroxyline.

The following procedure described for compound 10(f) is representative. Compound 9 (f ) (0,215g, 0.50mmol) of 6mlMeOH/2rILITHF The solution was added to reflux in the presence of a catalytic amount of Raney Ni/HtO. It was heated and treated with anhydrous hydrazine (1,00ml, 31.54mmol). 1 After an hour (during which time the color disappears, the mixture is commercially available under the trade name Celite) Filtered through diatomaceous earth, concentrated, and azeotroped with CH, CN/benzene to give 0.158 g. Compound 10(a) (0.39 mmol, 79%) was obtained. diami in all cases The sample was used immediately for the cyclization reaction. 'HNMR (CDCf1　') 67.69 (2H , d, J=8.2Hz), 7.44 (2H, d.

J=8.2Hz), 6.44 (IH, s), 5.85 (IH, s), 4.42 (2H, s), 3.24 (2H.

m), 2.97 (4H, m), 2.93 (4H, m).

2, 70 (2H, m), and 1.98 (2H, m>.

Example 6: Preparation of compounds 11 and 12(f) to 12(j) of the invention Preparation of compound 11 6-Tuimidazole-N-(4-(N,N-piperazinylsulfamoyl)- Benzylcotetrahydroxylin 2ml HC of diamine compound 10 (f) (0,084g, 0.21mmol) (OCHs)3 solution was treated with -drops of concentrated HCl at 23°C to form a precipitate. I met. The mixture was stirred for 1 h and poured into saturated N a HCOs solution (20 mt’). , extracted with 50 mt' of CHCls. The organic layer was dried with anhydrous Na2SO4, Concentrate and flash chromatography (1,596NH,/13.596E Purification by tOH/85% CHCf gave compound 11 as a yellow-orange solid (0,032 g, 0.08 mmol, 38%). 'HNMR (acetone-aS) δ8. 01 (IH.

s), 7.76 (IH, s), 7.70 (2H, d, J=8.IHz), 7 ．． 56 (2H, d, J=8.1Hz), 7.20 (IH, s), 6.52 (IH, s).

4.62 (2H, s), 3.45 (2H, t, J=5°7Hz), 2.92 (2H, t, J=6.1Hz), 2°84 (4H, brs), 2.81 ( 4H, brs), and 2.04 (2H, m). High resolution mass spectrometry -, C+tHtsN　s　M”411.1729゜Accurate calculation mass of O2S Measured value 411.1719° compound! Preparation of 2(f)-12(j) 6.7-(2-aminoimidazole)-N-(4-(N,N-piperazinyl sulfur) famoyl)-benzyl)tetrahydroquinoline, 6,7-(2-aminoimida sol)-N-(4-(phenylsulfonyl)benzyl)tetrahydroquinolite 6.7-(2-aminoimidazole)-N-((6-hydroxymethyl)- 2-naphthobenzylcotetrohydroxyline, 6,7-(2-aminoimidazo )-N-(4-(4--Hydroxyphenylsulfonyl)benzylcotetrophy) Droxyline, and 6.7-(2-aminoimidazole)-N-(4-(4'- Methoxyphenylsulfonyl)benzyl)tetrahydroquinoline.

The following procedure described for 12(i) is representative. Diamine compound 10 (i) (1,59 mmol) of 6rdCH,CN/2ml MeOH solution was added to 70″ 5, OM CNBr/CHs CN solution (0.5yd, 2°5mm ol). After 2 hours, the mixture was reduced to 0. 5N HCI! diluted with ethyl Extracted twice with acetate.

The aqueous layer was neutralized with 6N NaOH, saturated with NaCl and twice with ethyl acetate. Extracted. The organic layer was dried over anhydrous NagSOl and concentrated to a brown solid. . Flash chromatography (5% to IO% EtOH/CH2CI!t ) to obtain 0.173 g (0.40 mmol, 25%) of compound 12(i). Obtained as a light brown solid. Melting point 230-245°C. 'HNMR (DMSO-d, ) δ7.86 (3H, m), 7.75 (2H, d.

J=8.7Hz), 7.43 (2H, d, J=8.2Hz), 6.91 (3 H, m), 6.16 (IH, s).

4.53 (2H, s), 3.35 (2H, m), 2.80 (2H, m) , and 1.90 (2H, m). IR (KBr) 3400 (width), 1660 ．． 1280° high-resolution mass spectrometry, accuracy of C2424N40s S The calculated mass M”434.1412° Actual value 434°1401° Mouth CNMR (DMSO-ds) δ162.3,149°5.144.8,14 1.5, 140.7, 130.7° 129.7, 129.2, 127.5, 12 7.4, 127.2, 120.3, 118.0.116.2. Ill, 5,93 ．． 3, 54.7, 49.9 and 29.3°12 (f):'HNMR (CDCf , ) δ7.65 (2H, d, J=8.3Hz), 7.48 (2H, d.

J=8. 2Hz), 6. 93 (IH, s), 6. 10 (IH, s), 4 ．． 52 (2H, s), 3. 43 (2H.

t, J=5. 5Hz), 3. 29 (4H, m), 3. 04 (4H, m ), 2. 92 (2H, t, J=6.5Hz), and 2. 17 (2H, m). IR (KBr) 3420.1610° high resolution mass spectrometry, Accurate calculated mass of C,,H,,N,O,S M″″426.1833゜Actual measurement value 4 27.1940° 12 (g): 'HNMR (CDC1,) δ7.92 (2H, d, J = 8.3H z), 7.83 (2H, d.

J=8.3Hz), 7.47-7.55 (3H, m).

7.39 (2H, m), 6.89 (IH, s), 6.23 (IH, s), 4.44 (2H, s), 3.32 (2H, m), 2. 85 (2H, m) , and 2. 01 (2H.

m), IR (film) 1630.1290.1150°820° High resolution mass Spectrometry, exact calculated mass of C2, H22N402S M”418. 1463° Actual value 418.1467° 12 (h): 'HNMR (DMSOds) δ7゜71~7.84 (4H , m), 7.41 (2H, m).

6.68 (IH, s), 6.30 (IH, s), 5.74 (2H, brs ), 4.62 (2H, s), 4.54 (28, s), 3.32 (2H, m) , 2.77 (2H.

m), and 1.93 (2H, m). IR (KBr) 3440.1720゜high minute Resolution mass spectrometry, accurate calculation mass of C22H2□N40 M”3 58.1793° Actual value 358.1814° t2(j): Melting point 217-228°C, 'HNMR (DMSO-d,) δ7. 84 (4H, d, J=8.9Hz), 7. 46 (2H, d, J=8. 3Hz), 7°o9 (2H, d, J=8.9Hz), 6. 66 (IH .

s), 6. 10 (IH, s), 5. 74 (2H.

brs), 4. 45 (2H, s), 3. 80 (3H.

s), 3. 1 5-3. 26 (2H, m), 2. 74 (2H, m), and I, 83 (2H, m). IR (KBr) 3400, 2950. 165 0.　1600. 1400° + 140.1100, 830, 800° high resolution Spectrometry, exact calculation mass of C24H24N40x S M″″448 ．． 1569° Actual value 448.1559° Example 7: Preparation of compound I7 6.7-(2-methylimidazole)-N-(4-(4'-methoxyphenyls) sulfonyl)benzylco-tetrahydroquinoline.

Compound 17 was prepared by the following reaction.

A solution of compound 8 (e) (0,1131 g, 0.228 mmol) in glacial acetic acid Treated with Sn’ (0,1443 g, 1.216 mmo 1) and refluxed at night. I went to The mixture was filtered through diatomaceous earth, commercially available under the trade name Celite, and saturated. It was neutralized with N a HCOs solution and extracted twice with ethyl acetate. combined oil The layer was dried over anhydrous Na2SO4, concentrated and flash chromatographed. (1096MeOH/CH2Cl2) to give 0.0724g (0,162 mmol, 71%) of compound 17 was obtained as a pale yellow solid. Melting point 162-16 5°C (decomposition).

Ct*H21N　s　Os　S　(D Accurate mass calculation 447.1616゜Actual measurement Value 447.1586°IR (KBr) 3400°1590.1250.1140 ．． 'HNMR (CDC1,) δ7.84 (4H, m), 7.38 (2H, d , J=8.3Hz), 7.16 (IH, s), 6°96 (2H, d, J=8 ．． 9Hz), 6.33 (IH.

s), 4.49 (2H, s), 3.83 (3H, s).

3.38 (2H, m), 2.92 (2H, m), 2.47 (3H, s), and and 2.04 (2H, m).

Example 8: Determination of inhibition constant for 5.10-methylene-tetrahydroforate fixed The thymidylate synthase inhibition constant was determined by the following method. All analysis was carried out at 25°C, and three different thymidylate synthases (rTsJ) were added. It started by (1) Esquelikya Colli TS (rETsJ), ( 2) Candida TS obtained from bacteria (rCTSJ) and (3) human (7) TS (rHTs).

TS follows ordered bimolecular kinetics (Daron, H.

Hand Au1l, J, L,, J, Biol, Chem, 253.　940～ 9451 (1978)), and dUMP (2'-deoxyurin) used in these reactions. The concentration of lysine-5'-monophosphate) was close to saturation; The analysis was close to that of a single substrate. All reaction mixtures were supplemented with 50mM Tris. Containing pH 7.8 (final pH of reaction is 7.6), 10 mM DTT (dithiosin) Retol), 1mM EDTA (ethylenediaminetetraacetic acid , 25mM MgClx, 15mM H,Co (formaldehyde), and Contained 25 μM dUMP. In the analysis of human TS, 100 μg/rnl BSA (bovine serum albumin) was added to the reaction. THF (tetrahydro) rate) ranged from 5 to 150 μM (5.6.6.10.13.16. 8 concentrations of 25.5o and 150 μM). In each experiment, the standard curve without inhibitor was Created. Three curves with inhibitor added were then measured at different concentrations. Become The concentration was as low as possible, and if possible, 1/2 to 2 times the concentration (Cle 1and, W, W,.

Biochim, Biophys, Acta67. 173-187 (196 3)). These analyzes were conducted using DHF (dihydrophore) (mM extinction coefficient 6. 4) can be followed with a spectrophotometer at 340 μm (Wahba, A, J, and Fr1edkin, M., J., Biol.

Chem, 236. Pct 1-PCl3 (1961)), 5th place of dUMP The separation of tritium from the cl dUMP) (Lomax, M, 1S, and Greenb erg, G, R,,J.

Biol, Chem, 242. 109-113 (1967)). tritium Charcoal was used to remove unreacted dUMP from the separation reaction mixture, resulting in The progress of the reaction was determined by measuring the amount of water. The inhibition constant is the apparent value for the inhibitor concentration. However, the apparent V. , determined by plotting the reciprocal of 1 (CIel and, W, W,, The Enzymes, 2. 1-65 (1970)).

The results obtained are shown in Table 1.

Table 1 Emi Z Rin m * Yu Example 9: Test tube test Cell growth in the presence of the compounds in question was evaluated using three cell lines. ( 1) L1210 murine leukemia (ATCCCCCL 219), (2) CCRF-C EM, human lymphoblastic leukemia lineage of T cell origin (ATCCCCCL 119), and (3) a thymidine kinase-deficient human adenocarcinoma line (GCs/MTK). . Both strains were grown in RPM1 1640 medium supplemented with 5% heat-inactivated fetal bovine serum. Maintained without antibiotics.

IC,, values are 501 U/ml penicillin and 50 m 1500 each grown in growth medium supplemented with ci/− streptomycin. (L1210), 4000 (CCRE CEM) or 10.000 (GC , /M　TK) containing 150 μ! was determined in microcultures. Growth takes 3 days (L1210) or 5 days (CCRF-CEM and GCI/M TK), Initial cell inoculation was followed by continuous contact with various concentrations of each test compound added for 4 hours. Measured under. For measurements, Mosmann, T. J., Immunol, Met. h,, 65. MTT-tetrazolium ring element analysis of 55-63 (1983) , A11ey etat, CancerRes, 48.589-601 (1988) with modifications. Derivatives that are insoluble in water are dissolved in DMSO. and diluted to a final concentration of 0.3% solvent in cell culture.

The results obtained with this procedure are summarized in Table 2 below.

Table 2 12(f)-MachiOm,-02,052,2,)S.

12+1)-NH2Q-Q-1222>s.

1F-C:H30w5xODCH, 2-8El-04-1 Specific implementation of the present invention Although the invention has been described in detail with reference to examples, those skilled in the art will understand that the invention Various changes and modifications may be made without departing from the spirit and scope of the invention. It is clear. Therefore, the scope of the claims and equivalents to which it is attached On the premise that is intended to include.

Display of L incident Substituted tricyclic compounds Ageron Pharmaceuticals Incoholated: -′-・ 5-Date of amendment order Enino B, Supplementary jE L s11100 number 7, correction target Description, claims, and abstract translation 8- Contents of amendment as attached International search report with translation of the description, claims, and abstract (no changes to the contents) international search report Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number C07D471104 1 02 8829-4C1168829-4C 1198829-4C I

Claims (1)

[Claims] 1. Chemical structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula: X and Y form a 5- or 6-membered heterocycle containing at least one nitrogen; Z is hydrogen, is a halogen, carbon, oxygen or nitrogen atom; U is a carbon or nitrogen atom; n is 0 or an integer 1; V is a carbon or nitrogen atom; W is a carbon or nitrogen atom A is a nitrogen atom, a sulfuric acid atom, or a substituted or unsubstituted alkylene group in the 1st or 2nd position; Ar is an allyl or hetero group having one or more rings; and B is (i) an oxygen or nitrogen atom, or a -CO- or -SO2- group; is attached to an amino acid, an allyl group, a heterocyclic group, or an alkyl group, or (ii) is a substituted or unsubstituted alkyl group, and if A If it is yellow, it is a thymidylic acid salt with the condition that both V and W are carbon atoms. Compounds that have the ability to inhibit intase. 2. If the compound has a thymidylate synthase inhibition rate of less than or equal to about 10-4M A compound according to claim 1, having the number K1. 3. A compound according to claim 1, having a K1 value of less than or equal to about 10-8 M. thing. 4. A compound according to claim 1, having a K1 value of less than or equal to about 10-9M. thing. 5. X and Y are pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrrole The compound according to claim 1, which forms a heterocycle selected from the group consisting of rimidine and pyridazine rings. 6. The compound according to claim 1, wherein X and Y form a ring: ▲Numerical formula, chemical formula, table, etc.▼, in which P is a lower alkyl group, an amino group, or hydrogen. 7. 2. A compound according to claim 1, wherein Z is hydrogen. 8. 2. A compound according to claim 1, wherein n is 0. 9. The compound according to claim 1, wherein A is a substituted or unsubstituted alkylene group. 10. The compound according to claim 1, wherein Ar is phenyl or naphthyl group. 11. B is an -SO2- group bonded to an amino acid, an allyl group or an alkyl group; The compound according to claim 1. 12. X and Y form a ring in which P is a lower alkyl group, an amino group, or hydrogen; 0; V is carbon; W is nitrogen; A is methylene; and Ar-B is: ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲Mathical formulas, chemical formulas, tables, etc. etc. ▼ where R is hydrogen or alkyl such as methyl; and ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ where T is hydrogen or -CN. A compound according to item 1 of the claimed scope. 13. 13. The compound according to claim 12, wherein P is hydrogen and Ar-B is ▲a mathematical formula, a chemical formula, a table, etc.▼. 14. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 15. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 16. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 17. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 18. 13. The compound according to claim 12, wherein P is -CH3, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 19. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 20. 13. The compound according to claim 12, wherein P is -NHCH3, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 21. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 22. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B is ▲a numerical formula, a chemical formula, a table, etc.▼. 23. 13. The compound according to claim 12, wherein P is -NH2, and Ar-B has a mathematical formula, a chemical formula, a table, etc., and T in the formula is hydrogen or a -CN group. 24. X and Y form a ring: ▲Mathematical formula, chemical formula, table, etc.▼, where P is selected from the group consisting of -NH2 and methyl; U is carbon; n is 0; V is is carbon; W is nitrogen; A is methylene; and The compound according to claim 1, wherein Ar-B is ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 25. X and Y form a ring: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and P in the formula is selected from the group consisting of -NHOH and -NHNH2; U is a carbon n is 0; V is carbon; W is nitrogen; A is methylene; and -Ar-B is ▲a mathematical formula, a chemical formula, a table, etc.▼. 26. X and Y form a ring: ▲There are mathematical formulas, chemical formulas, tables, etc.▼; U is carbon; n is 0; V is carbon; W is carbon; A is divalent The compound according to claim 1, wherein Ar-B is sulfur; 27. Chemical structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, X and Y form a 5- or 6-membered heterocycle containing at least one nitrogen atom; Z is hydrogen, halogen, is a carbon, oxygen or nitrogen atom; U is a carbon or nitrogen atom; n is 0 or an integer 1; V is a carbon or nitrogen atom; W is a carbon or nitrogen atom; A is 1 or 2 is a nitrogen atom, a sulfuric acid atom, or a substituted or unsubstituted alkylene group; Ar is an allyl or hetero group having one or more rings; is a loallyl group; B is (i) an oxygen or nitrogen group bonded to an amino acid, an allyl group, or an alkyl group; an elementary atom or a -CO- or -SO2- group, or (ii) a substituted or unsubstituted alkyl group, with the condition that if A is sulfur, then V and W are both carbon atoms. a Next step: (1) A compound of formula B-Ar-A-D in which D is a substitutable group is Chemical structural formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ However, in the formula, the X-precursor and the Y-precursor have at least one nitrogen during cyclization. (2) X - cyclization of the precursor and the Y-precursor to form a 5-carbon compound containing at least one nitrogen atom; or form a 6-membered heterocycle, and one or more of the the process may contain chemical groups or groups that are a) protected by a protecting group, or b) have one or more protecting groups that are now missing; A method for producing a compound capable of inhibiting thymidylate synthase. 28, Thimidylate Synthase Inhibition Constant K of less than or equal to about 10-4 Claim 27, which is a compound capable of inhibiting midylate synthase. Manufacturing method described. 29. 28. The method according to claim 27, wherein X and Y form a heterocycle selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine and pyridazine rings. 30. 28. The manufacturing method according to claim 27, wherein X and Y form a ring: ▲Numerical formula, chemical formula, table, etc.▼, in which P is a lower alkyl group, an amino group, or hydrogen. 31. 28. The method of claim 27, wherein Z is hydrogen. 32. 28. The manufacturing method according to claim 27, wherein n=0. 33. 28. The method according to claim 27, wherein A is a substituted or unsubstituted alkylene group. 34. 28. The method of claim 27, wherein Ar is a phenyl or naphthyl group. 35. 28. The method of claim 27, wherein B is an -SO2 group bonded to an amino acid, an allyl group, or an alkyl group. 36. Ar-B has: ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲Mathematical formulas There are , chemical formulas, tables, etc. ▼; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R is hydrogen or alkyl such as methyl; , tables, etc. ▼ However, the manufacturing method according to claim 27, wherein T is selected from the group consisting of hydrogen or -CN. 37. A compound of chemical structural formula I has chemical structural formula (II): ▲ Numerical formula, chemical formula, table, etc. It has ▼(II), in the formula Ac is a CH3CO-protecting group, and (1) the chemical structure is The amine compound of Formula III is selectively protected to form the corresponding acetamide. 31. The method of claim 30, wherein the compound of chemical structure (II) is formed by chemical treatment. 38. U is a carbon atom, n is 0, V is a carbon atom, and W is a nitrogen atom. 38. The manufacturing method according to claim 37, wherein the element is an elementary atom. 39. The amine of chemical structural formula (III) has the chemical structural formula: ▲ Numerical formula, chemical formula, table, etc. The method according to claim 38, having ▼. 40. The amine of chemical structure (III) corresponds to an amine having one or more sites of unsaturation in a 6- or 7-membered ring formed by U, V, and W combined with an appropriate number of carbon and hydrogen atoms. The claimed compound is produced by reducing the compound The manufacturing method according to item 37. 41. The manufacturing method according to claim 40, wherein the compound corresponding to an amine having one or more unsaturated sites has the following chemical structural formula: ▲ Numerical formula, chemical formula, table, etc. ▼. 42. The amine of chemical structural formula (III) is obtained by nitrifying the unsubstituted compound of (1) chemical structural formula (IV): ▲Mathematical formula, chemical formula, table, etc.▼ Forming a nitric acid compound having the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼; and (2) forming an amine of chemical structural formula (III) by reducing the nitric acid compound, described in claim 37 the method of. 43. A compound of chemical structural formula (IV) has chemical structural formula: ▲ Numerical formula, chemical formula, table, etc. 43. The manufacturing method according to claim 42, wherein ▼ is the formula, and Ac is a CH3CO-protecting group that disappears during the nitrification step and the reduction step. 44. After step (1), the compound ▲Mathematical formula, chemical formula, table, etc.▼ is processed by (1) a deprotecting agent that converts the -NH-Ac group into a free amino acid, (2) a reduction that converts the -NO2 group into an amino group. (3) Chemical structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and P is alkyl, amino, or hydrogen. 28. The manufacturing method according to claim 27, wherein the manufacturing method is processed by: 45. 45. The manufacturing method according to claim 44, wherein the cyclizing agent is HC(OCH3)2 or CNBr. 46. After step (I), the compound ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ is treated with metal tin in the presence of acetic acid to have a chemical structural formula: ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ and the formula The compound according to claim 27, which forms a ring in which P is a methyl group. thing. 47. Chemical structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, if A is sulfur, then V and W are both carbon atoms, and X and Y are at least one nitrogen atom. forming a 5- or 6-membered heterocycle containing; Z is hydrogen, halogen, carbon, oxygen or nitrogen atom; U is carbon or nitrogen atom; n is 0 or an integer 1; V is carbon or a nitrogen atom; W is a carbon or nitrogen atom; A is a nitrogen atom, a sulfur atom, or a substituted or unsubstituted alkylene group in the 1 or 2 position; Ar is one or more is an allyl or heteroallyl group; and B is (i) an oxygen or nitrogen group bonded to an amino acid, an allyl group, or an alkyl group; or (ii) a substituted or unsubstituted alkyl group, combined with an effective amount of the compound to inhibit thymidylate synthase. A pharmaceutical composition comprising a diluent or carrier. 48. 48. The composition of claim 47, wherein the compound has a thymidylate synthase inhibition constant K1 of less than or equal to about 10-4M. 49. 48. The composition according to claim 47, wherein X and Y form a heterocycle selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine and pyridazine rings. 50. 48. The composition according to claim 47, wherein X and Y form a ring: ▲Numerical formula, chemical formula, table, etc.▼, in which P is a lower alkyl group, an amino group, or hydrogen. 51. 48. The composition of claim 47, wherein Z is hydrogen. 52. 48. The composition of claim 47, wherein n is 0. 53. 48. The set according to claim 47, wherein A is a substituted or unsubstituted alkylene group. A product. 54. 48. The composition of claim 47, wherein Ar is phenyl or naphthyl. 55. 48. The composition of claim 47, wherein B is an -SO2 group bonded to an amino acid, an allyl group, or an alkyl group. 56. X and Y form a ring: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, in which P is a lower alkyl group, an amino group, or hydrogen; Z is hydrogen; U is carbon; n is 0; V is carbon; W is nitrogen; A is methylene; and Ar-B is ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲Mathematical formulas, chemical formulas, Tables, etc. ▼ provided that R is hydrogen or an alkyl group such as methyl; and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Provided that T is hydrogen or -CN, selected from the group, Claims The composition according to item 47. 57. 48. The composition of claim 47, wherein the amount is a therapeutically effective amount. 58. The composition of claim 47 in a formulation selected from the group consisting of formulations suitable for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraotic and rectal administration. thing. 59. 48. The composition of claim 47, comprising other compounds, at least one of which is an anti-tumor agent. 60. Other compounds may consist of mitotic inhibitors, alkylating agents, DHFR inhibitors, antimetabolites, insertional antibiotics, enzymes, topoisomerase inhibitors or biological response modifiers. 60. The composition of claim 59, wherein the composition is selected from the group consisting of: 61. Antibacterial agents, antibacterial agents, antiparasitic agents, antiviral agents, antipsoriatic agents, antiprotozoal agents, or 48. The composition of claim 47, further comprising at least one other compound, wherein is an anticoccidial agent. 62. Chemical structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula: X and Y form a 5- or 6-membered heterocycle containing at least one nitrogen atom; Z is hydrogen, halogen, carbon , is an oxygen or nitrogen atom; U is carbon or nitrogen; n is 0 or an integer 1; V is a carbon or nitrogen atom; W is a carbon or nitrogen atom; A is in the 1st or 2nd position nitrogen atom, sulfur atom, or substituted or unsubstituted atom. alkylene group; Ar is allyl or hetero with one or more rings; is an allyl group; and B is (i) an oxygen or is a nitrogen atom or a -CO- or -SO2- group, or (ii) a substituted or unsubstituted atom; thymidylate synthase, comprising administering to a vertebrate host an effective amount of the compound to inhibit thymidylate synthase, with the condition that if A is sulfur, then V and W are both carbon atoms. A treatment method to suppress this. 63. Thimidylate synthase inhibition constant K1 of less than or equal to about 10-4. Claim 62, which is a compound capable of inhibiting midylate synthase. Treatment methods listed. 64. 63. The method of treatment according to claim 62, wherein X and Y form a heterocycle selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine and pyridazine rings. 65. 63. The method of treatment according to claim 62, wherein X and Y form a ring: ▲Numerical formula, chemical formula, table, etc.▼, in which P is a lower alkyl group, an amino group, or hydrogen. 66. 63. The method of claim 62, wherein Z is hydrogen. 67. 63. The method of treatment according to claim 62, wherein n is 0. 68. The method according to claim 62, wherein A is a substituted or unsubstituted alkylene group. Treatment method. 69. 63. The method of claim 62, wherein Ar is phenyl or naphthyl. 70. B is an -SO2- group bonded to an amino acid, an allyl group or an alkyl group; 63. The method of treatment according to claim 62. 71. Ar-B has: ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲ There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼; ▲There are mathematical formulas, chemical formulas, tables, etc.▼ However, R is hydrogen or alkyl such as methyl, and ▲Mathematical formulas, chemical formulas , tables, etc. ▼ The method of treatment according to claim 62, wherein T is selected from the group consisting of hydrogen or -CN. 72. Claim 62, wherein the compound is a formulation selected from the group consisting of formulations suitable for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural and rectal administration. Treatment methods described. 73. 63. The method of treatment of claim 62, wherein the dose of the compound is about 5,000 mg/m2 of body surface area of the vertebrate host. 74. 63. The method of treatment of claim 62, wherein the vertebrate host is a mammal. 75. 75. The method of treatment according to claim 74, wherein the vertebrate is a human. 76. 63. A method of treatment according to claim 62, wherein the vertebrate host is a bird. 77. 63. A method of treatment according to claim 62, wherein the compound is further characterized as producing an anti-proliferative effect. 78. 63. The compound of claim 62, wherein prior to said method of treatment, the vertebrate host harbors proliferating cells and is further characterized such that the compound produces an anti-tumor effect. 79. The compound is capable of producing an effect selected from the group consisting of antibacterial, antibacterial, antipsoriatic, antiviral, antiprotozoal, antiparasitic and anticoccidial effects. 63. A method of treatment according to claim 62, further characterized in that: