HU203100B - Process for producing quinoline-carboxylic acids substituted with heterocyclic group - Google Patents

Abstract

Fused pyridine derivs. of formula (I) and their pharmaceutically acceptable acid addn. salts are new. Y = 1-3C alkyl (opt. substd. by OH, F or Cl), vinyl, cyclopropyl, o,p-difluorophenyl or p-fluorophenyl, A = CH, CF, CCl, COMe or N; or A + Y = C-Z-CH2-C(R3) or C-Z-CH2-C(CH2)-; Z = O or CH2; R3 = H, 1-3C alkyl, fluoromethyl or chloromethyl, R1 = OH, 1-6C alkoxy, NH2, 1-6C alkylamino or OM; M = pharmaceutically acceptable cation; R2 = a gp. of formula (a)-(m); Q = O, S or NH; each H = H, CH2NHR4, NHR4 or 1-6C alkylsulphonyl; x = 1-2; R4 = H or 1-6C alkyl; R5 = H, 1-5C alkyl, OH, NH2, mono- or di-(1-4C alkyl)amino, 1-4C aminoalkyl, 1-4C alkylamono-(1-4C)alkyl, phenylamino, pyridylamino or (H2N)2C=N; either: (1) p = 1; and m = 1-2; or (2) p = 2; and m = 1; n = 0-1.

Description

The present invention relates to a process for the preparation of 1-substituted-6-fluoro-7-heterocyclic-1,4-dihydroquinoline (or dihydronaphthyridine) -4-on-carboxylic acids, their prodrug derivatives and pharmaceutically acceptable acid addition or base salts thereof. These compounds have antibacterial activity.

Several US patents disclose the antibacterial activity of 1-substituted-6-fluoro (or 6,8-difluoro) -7-heterocyclic-1,4-dihydro-4-quinolone carboxylic acids. In the compounds of U.S. Patent 4,146,719, the 7-position substituent is a cyclic amine derivative such as piperazinyl or pyrrolidinyl; a 1-imidazolyl group is attached to the 7-position of the compounds disclosed in U.S. Patent 4,530,930, the 7-position of the compounds disclosed in U.S. Patent 4,636,506 is a 6-quinolyl group, and In the compounds of U.S. Patent No. 382,892, substituent 7 is a cyclic amine derivative such as pyrrolidinyl or piperidinyl.

A saturated bicyclic (bicyclic) moiety as a 7 substituent on the quinolone backbone is disclosed in Japanese Patent Application Publication No. 59204194, which discloses a 7-diazabicycloalkane substitution.

The 7-position substituent of the compounds of the present invention is a bicyclic ring having one ring saturated and the other ring unsaturated.

The present invention relates to a process of formula (I) wherein

A is a methyl group or a fluoromethyl group, and

Y is C 1-4 alkyl, C 3-5 cycloalkyl, halophenyl, C 1-4 alkylamino or halo (C 1-4) alkyl, and

R ² (p), (c) or (k) wherein Q is sulfur or-NH-,

R ^{5 is} hydroxy, amino, C 1-4 alkyl, pyridylamino, phenylamino, di- (C 1-4) alkylamino, C 1-4 alkylamino, or (NH) ^ -CA- group, or

A is nitrogen,

Y is C 3-5 cycloalkyl and

^R2 (c) a group of formula or

A and, taken together, form a group of formula (a) wherein

R ^{3 is C} 1-4 alkyl, and

R ² (p) or (c) a group of formula wherein Q is S ^and R amino group, l, 4-dihydro-4-quinolone-3-carboxylic acids and their pharmaceutically acceptable salts.

Preferred are compounds of formula I according to the invention wherein

Y is ethyl, 2-fluoroethyl, cyclopropyl copoly, p-fluorophenyl, and wherein

A is a methine group.

Particularly preferred compounds of the present invention are:

7- [5- (2-amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - l-ethyl-6-fluoro-l, 4-dihydro-4-oxo- quinoline-3-carboxylic acid,

7- [5- (2-Amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7- [5- (2-methyl-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl) -4-Oxo-quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [5- (2- (3-pyridyl) -amino-4,5,6) , 7-tetrahydro-thiazolo [5,4-c] pyridyl)] - quinoline-3-carboxylic acid,

-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid, 1-cyclopropyl -6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid, 7- [6- (2-Amino-5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidyl)] - 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3 carboxylic acid,

1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] -1,8-naphthyridine-3 Carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-7-oxo-10- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] -7H-pyrido [13.3- de] -1,4-benzoxazine-64-carboxylic acid,

6-Fluoro-1-methylamino-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid, 6-Fluoro-1- (4-fluoro-phenyl) -1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline- 3-carboxylic acid, and

6-Fluoro-1- (2-fluoro-ethyl) -1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline- 3-Carboxylic acid and its pharmaceutically acceptable acid addition or base salts.

The compounds of the present invention may be formulated into an antibacterial pharmaceutical composition comprising an amount of a compound of formula (Γ) necessary to produce an antibacterial activity, in association with a pharmaceutically acceptable carrier. Preferred and particularly preferred are the compositions comprising the compounds of formula (I) as hereinbefore preferred or particularly preferred.

The compounds of the present invention and pharmaceutical compositions containing them can be used to treat bacterial infections and diseases by administering to a subject suffering from a bacterial infection an amount of a compound of formula (I) required to produce an antibacterial effect.

As used herein and in the claims, "halogen" means fluorine, chlorine, bromine or iodine. Alkyl groups may be straight or branched. The R ^s substituent may be pyridyl

2-pyridyl, 3-pyridyl or 4-pyridyl, and preferably 3-pyridyl.

Compounds of formula (I) may be prepared by reacting a compound of formula (Π) wherein R ¹ , Y and A are as defined above, and

L is a leaving group, reacting a compound of formula R ² H wherein R ² is as defined above with an amine.

The leaving group at L can be halogen or C 1-3 alkylsulfonyl. Suitable leaving groups include fluorine-23

EN 203 100 Β atom, chlorine atom, methylsulfonyl group and ethylsulfonyl group.

When the R ² group contains an amino group or an alkylamino group, they may be protected to render them substantially neutral under the reaction conditions. Examples of suitable protecting groups include:

groups derived from carboxylic acids, such as formyl acetyl or trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, tert-butoxycarbonyl, β, β, β-trichloroethoxycarbonyl, or β-iodoethoxycarbonyl;

aryloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or phenoxycarbonyl;

silyl groups such as trimethylsilyl; trityl; tetrahydropyranyl group; vinyloxy-carbonyl; o-nitrophenyl sulfenyl group; diphenylphosphinyl group; p-toluenesulfonyl or benzyl.

After the reaction, the protecting group is cleaved by methods known to those skilled in the art. For example, the ethoxycarbonyl group may be removed by hydrolysis with an acid or base, and the trityl group may be removed by hydrogenolysis. The reaction of the compound of formula (II) with the amine R ² H as described above may be carried out in the presence or absence of a solvent, preferably at elevated temperature, for a period of time necessary to complete the reaction. Suitable solvents for the reaction are inert solvents such as acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, picoline and water. Mixtures of solvents may also be used. The reaction temperature is conveniently from about 20 ° C to about 150 ° C.

The reaction may be carried out in the presence of an acid acceptor such as an alkali metal or alkaline earth metal carbonate or bicarbonate or a tertiary amine such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine or picoline. It can be carried out.

The starting compounds of the formula II and the compounds of the formula R ² H are known or may be prepared from known starting materials by the conventional methods known per se.

5,6,7,8-naphthyridines

5,6,7,8-Tetrahydro-1,6-naphthyridine (ΙΠ) can be prepared by 4-aminopyridine according to the method of Paudler and Kress (J. Chem. Comm., 1967, 3). benzene and fuming sulfuric acid in a mixture of glycerol. The resulting 1,6-naphthyridine is reacted with benzyl bromide to give the quaternized salt at position 6, the reduction of which with sodium borohydride leads to N-benzyl-tetrahydronaphthyridine. This intermediate is debenzylated with hydrogen in the presence of palladium on charcoal to give compound (III).

43,6,7-Tetrafiidro-tia2olo [5,4-pyridin

Formula (XXVIII) wherein R ³ is as defined above for compounds of Formula (I)

4,5,6,7-Tetrahydrothiazolo [5,4-c] pyridines can be prepared by the following methods.

R ⁵ is amino, di-C 1-4 alkylamino, C 1-4 alkylamino, phenylamino, pyridylamino or (H ₂ N) _2; Compounds of formula (XXVIII) containing guanidino group C = N can be prepared by first reacting methyl vinyl ketone with phthalimide and brominating the product to give 1-bromo-4-phthalimido-2-butanone. This ketone is reacted with a thiourea of the general formula where R ^s is as defined above to give a thiazole derivative of the general formula XXIX where Phth is a phthalimido group. This thiazole derivative (XXIX) is deprotected and the resulting compound is ring-linked with formaldehyde. In this way, the desired thiazolopyridine is obtained.

^R5 is appropriate alkyl compound of formula (XXVIII) in which 1-4 carbon atoms may be prepared from the corresponding R ⁵ C (S) NH _2, wherein

R ^s is as defined at the beginning of this paragraph, thioamides (XXX) wherein R ⁶ is reacted with a nitrogen-protecting group such as acetyl, α-bromo ketones. The protecting group is then cleaved to give the desired thiazolopyridines. In the case when R ^s is a substituted amino group, and substituted alkylamino containing 1-4 carbon atoms or alkyl of 1-4 carbon atoms and a C1-4 alkyl group, then the leading front of the thiazole ring cyclization of the amino protecting group is a preferred acyl group. After ring closure, the acyl group may be cleaved under acidic or basic conditions.

Wherein ^R5 is hydroxyl group-containing compound (XXVIII) can be prepared cyclized to the N-acetyl-3-thiocyanato-4-piperidone under acid conditions.

Tetrahydropyrido-pirirrúdinek

Formula (XXXV) wherein

X, m and p for 2-amino-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine as defined above for the compounds of formula (I) may be prepared from 4-piperidone having a nitrogen atom in a form protected by a suitable nitrogen protecting group such as acetyl. Thus, the N-protected 4-piperidone is reacted with methoxybis-dimethylamino-methane CH ₃ OCH [N (CH ₃ ) ₂ ] ₂ and the resulting enamine is reacted with the amidine H ₂ NC (NH) NH ₂ .

Salts of the compounds of formula I with pharmaceutically acceptable bases are salts with metals or amines. Suitable metals for use as cations are, for example, alkali metals, such as sodium and potassium, and alkaline earth metals, such as magnesium and calcium. Suitable amines for salt formation include N, N-dibenzylethylenediamine, chloro-procaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

HU 203 100 Β

The pharmaceutically acceptable acid addition salts of the compounds of formula (I) are prepared by treating a solution or suspension of the free base form of the compound of formula (I) in a chemical amount of about 1 equivalent of a pharmaceutically acceptable organic or inorganic acid. Suitable such acids are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, lactic acid, p-toluenesulfonic acid, gluconic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid and methanesulfonic acid. Acid addition salts may be advantageous for certain physical properties, such as their solubility in polar solvents, and in particular water.

The compounds of formula I may exist in unsolvated or solvated forms, including hydrated forms. The antimicrobial activity of the compounds of formula I is generally not affected by the degree of solvation.

The compounds of formula (I) and their pharmaceutically acceptable acid addition and base salts can be used in a broad spectrum of treatment of bacterial infections.

The compounds of the present invention may be administered alone, but will generally be administered in the presence of a pharmaceutical carrier selected according to the route of administration selected and usual pharmaceutical practice, such as oral administration of the active ingredient in the form of tablets containing certain excipients such as starch or lactose. they may also be administered in the form of capsules in which the active ingredient is present either alone or in association with excipients. Solutions and suspensions which may contain coloring and flavoring agents are also suitable for oral administration. When treating animals with these compounds, the active compounds are preferably mixed with the animal feed or drinking water at a concentration of 5 to 5,000 ppm, and preferably 25,500 ppm. In addition, these agents may be administered parenterally (bypassing the gastrointestinal tract), for example, by intramuscular (intramuscular), intravenous (intravenous) or subcutaneous (subcutaneous) injection. For parenteral administration, the most preferred dosage form is a sterile aqueous solution which may contain additional solutes, for example, sodium chloride or glucose, to make the solution isotonic.

When treated with animals, the compounds may be administered intramuscularly or subcutaneously daily at a dose of from about 0.1 mg to 50 mg, and preferably from 0.2 mg to 10 mg, in a single daily dose or in up to three divided doses.

The invention further relates to a process for the preparation of a pharmaceutical composition comprising, as an active ingredient, an amount of a compound of formula (I) required to produce an antibacterial effect, in association with a pharmaceutically acceptable diluent or carrier.

The compounds of the present invention may be administered orally or parenterally to humans for the treatment of bacterial infections, at dosages of from about 0.1 mg to 50 mg per day and per kilogram of body weight and preferably from 0.5 mg to 5 mg per day. administered in a single dose or in up to three divided doses. For intramuscular or intravenous administration, the dosage will vary from about 0.1 mg to about 20 mg per kg body weight per day, and preferably from about 0.5 mg to about 5 mg. Although intramuscular administration may be accomplished by a single daily dose or by up to three divided doses, intravenous administration may also be by drip infusion. The above dosages may necessarily be varied depending upon the body weight and condition of the individual being treated and the route of administration chosen, as known to those skilled in the art.

The antibacterial activity of the compounds of the present invention can be demonstrated by assaying by the Steer replication method. This assay is an in vitro assay for antimicrobial activity, described by E. Steers et al., Antibiotics and Chemotherapy, 9,307 (1959).

The invention is further illustrated by the following non-limiting examples. Temperatures are given in degrees Celsius.

Example 1

the step

7-l5- (2-Amino-4 ^, 6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-3- tínolin carboxylic acid

To a solution of 2-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (0.75 g, 4.83 mmol) in dimethylsulfoxide (75 mL) was added 1.28 g (4.83 mmol). 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and the mixture was heated at 80 ° C overnight. The dimethylsulfoxide is then distilled off and the residue is triturated with isopropanol. The solid product was filtered off, washed with diethyl ether and dried under nitrogen. This gave 1.81 g (4.52 mmol, 94%) of the title compound as a yellow solid, mp 245-250 ° C (dec.).

1 H NMR (DMSO-d 6) δ 8.57 (s, 1H),

7.86 (d, J = 13 Hz, 1H), 7.54 (d, J = 8 Hz, 1H),

6.82 (bs, 2H), 4.40 (bs, 2H), 3.76 (m, 1H), 3.70 (m,

2H), 2.62 (bs, 2H), 1.30 (bd, J = 6Hz, 2H), 1.13 (bs, 2H).

Step b)

7- [5- (2-Amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo- ldnolin-3-carboxylic acid sodium salt

1.60 g (4.00 mmol) of 7- (2-amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl) -1-cyclopropyl-6-fluoro-1,4- Dihydro-4-oxo-quinoline-3-carboxylic acid is suspended in 150 ml of water, 4.0 ml of 1 N sodium hydroxide solution (4.00 mmol) are added and the mixture is stirred vigorously for half an hour. The resulting solution was filtered and freeze-dried. This gave 1.496 g (3.54 mmol, 89%) of the title compound as a yellow solid, mp 230-250 ° C (dec.). 1 H NMR (D ₂ O) δ 8.40 (s, 1H), 7.85 (d,

J = 13 Hz, 1H), 7.54 (d, J = 7 Hz, 1H), 4.32 (bs,

2H), 3.64 (bs, 2H), 3.49 (bs, 1H), 2.51 (bs, 2H),

1.18 (bd, J = 7Hz, 2H), 0.96 (bs, 2H).

-4Ί

HU 203 100 Β

Example 2

7- [5- (2-Amino-45,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - l-ethyl-6-fluoro-l, 4-dihydro-4-oxo-quinoline To a solution of 3-carboxylic acid mg (0.322 mmol) in 2-amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine in 10 mL of dimethyl sulfoxide was added 83 mg (0.327 mmol) of 1-ethyl-6 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and the mixture was heated at 80 ° C for 18 hours. It is then distilled off with dimethyl sulfoxide and the residue is triturated with n-butanol. The solids were filtered off, washed with n-butanol then diethyl ether and dried under reduced pressure. Trituration with n-propanol gave the title compound as a yellow solid (95 mg, 0.24 mmol, 74%), mp 235-240 ° C (dec).

1 H NMR (DMSO-d 6) δ 8.91 (s, 1H),

7.92 (d, J = 13 Hz, 1H), 7.17 (d, J = 8 Hz, 1H),

6.84 (bs, 2H), 4.56 (bq, 2H), 4.40 (bs, 2H), 3.67 (m, 2H), 2.62 (bs, 2H), 1.36 (t , J = 7Hz, 3H).

Example 3

7- [5- (2-Amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid

54.2 mg (0.349 mmol) of 2-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine and 90.0 mg (0.318 mmol) of 1-cyclopropyl-6,7,8- A mixture of trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 4 ml of dimethylsulfoxide was heated at 80 ° C for 18 hours. The solvent was evaporated under reduced pressure and the residue was triturated with isopropanol to give the title compound as a yellow solid (81.9 mg, 0.20 mmol, 63%), m.p.

Example 4

7- [5- (2-Amino-45,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - 6-fluoro-1- (4-fluoro-phenyl) -], 4-dihydro -4-oxoquinoline-3-carboxylic acid

53.5 mg (0.344 mmol) of 2-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine and 100 mg (0.313 mmol) of 6,7-difluoro-1- (4 (fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 6 ml of dimethylsulfoxide was heated at 80 ° C for 96 hours. The solvent was then distilled off under reduced pressure and the residue was triturated with isopropanol and diisopropyl ether. The resulting solid was subjected to column chromatography eluting with chloroform: methanol: concentrated aqueous ammonium hydroxide (79: 20: 1) to give 53.1 mg (0.12 mmol, 39%) of a yellow solid. %) to give the title compound, m.p. 236-237 ° C.

Example 5

10- [5- (2-Amino-45,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)) - 9-fluoro-25, dihydro-3-methyl-7-oxo-7H-pyrido [ 123-deJ-1,4-benzoxazine-6-carboxylic acid

133.3 mg (0.858 mmol) of 2-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridyl)] and 219.4 mg (0.78 mmol) of 9,10-difluoro- A mixture of 23-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid in 10 ml of dimethylsulfoxide was heated at 80 ° C for 48 hours. Triethylamine (0.109 mL, 0.78 mmol) was then added and the mixture was heated at 80 ° C for a further 18 hours. A further 0.109 mL (0.78 mmol) of triethylamine was added and the reaction mixture was heated at 80 ° C for a further 72 hours. The solvent was then distilled off under reduced pressure and the residue was washed several times with isopropanol. The crude product was chromatographed on silica gel eluting with chloroform / methanol / concentrated aqueous ammonium hydroxide (79:20: 1). This gives the title compound as a solid, m.p. 228 'C (dec).

1 H NMR (DMSO-d 6) δ 8.96 (s, 1H),

7.61 (d, J = 13 Hz, 1H), 6.80 (m, 2H), 4.92 (m,

1 H), 4.6 (bd, J = 10 Hz, 1 H), 4.39 (bd, J = 10 Hz,

1H), 4.33 (bs, 1H), 3.55 (m, 2H), 2.63 (bs, 2H),

1.47 (d, J = 7Hz, 3H).

Example 6 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [5- (2- (3-pyridyl) amino-45,6,7-tetrahydro-thiazolof 5,4-c). ] pyridyl)] - quinoline-3-carboxylic acid

2- (3-Pyridyl) amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine (0.270 g, 1.16 mmol) and triethylamine (0.162 mL, 1.16 mmol). To a solution of dimethylsulfoxide (1 mL) was added 0.307 g (1.16 mmol) of 1-cyclic opropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and the reaction mixture was stirred for 24 hours at 80 '. C is maintained. The insolubles were then filtered off and the filtrate was evaporated under reduced pressure. This gave 0.305 g (0.64 mmol, 55% yield) of the title compound as an off-white solid, mp 160 ° C (dec).

1 H NMR (DMSO-d 6) δ 8.65 (d, J = 3)

Hz, 1H), 8.56 (s, 1H), 8.07 (m, 2H), 7.85 (d, J = 13

Hz, 1H), 7.55 (d, J = 7Hz, 1H), 7.24 (dd, J = 8,

Hz, 1H), 4.51 (bs, 2H), 3.74 (m, 3H), 2.77 (vbs,

2H), 1.27 (bd, J = 6Hz, 2H), 1.11 (bs, 2H).

Example 7

7- [5- (2-Phenylamino-45,6,7-tetrahydro-thiazolo [5,4-c] pyridyl) Jl-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxoquinoline -3-carboxylic acid

To a solution of 0.281 g (1.21 mmol) of 2-phenylamino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine in 15 mL of dimethyl sulfoxide is added 0.259 g (0.979 mmol) of 1-cyclopropyl. -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and the mixture was heated at 80 ° C overnight. The dimethylsulfoxide is then distilled off and the residue is triturated with isopropanol. The solid product is filtered off, washed with diethyl ether and dried. This gave 0.309 g (0.65 mmol, 66%) of the title compound as a yellow powder which decomposed above 200 ° C.

1 H NMR (DMSO-d 6) δ 8.62 (s, 1H),

7.93 (d, J = 13 Hz, 1H), 7.60 (m, 3H), 7.28 (m,

2H), 6.91 (m, 1H), 4.56 (bs, 2H), 3.80 (bs, 3H),

2.81 (bs, 2H), 1.32 (bd, J = 6Hz, 2H), 1.17 (bs,

2 H).

Example 8 Preparation of l-cyclopropyl-6-fluoro-1,4-dίhidro-7- [5- (2-dimethylamino-4 aιnino · _r 5, 6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] -4-oxoquinoline-3-carboxylic acid

128.5 mg (0.702 mmol) of 2-dimethylamino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine and 0.10 ml (0.7 mmol) of tri5

To a mixture of 100 Β ethylamine in 15 mL of dimethyl sulfoxide was added 0.185 g (0.702 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and Keep at 80 ° C for 48 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was triturated with diisopropyl ether and isopropanol. This gave 286 mg (0.67 mmol, 95% yield) of the title compound as a brown solid, m.p. 190-191 ° C (dec.). 1 H-Nuclear Magnetic Resonance Spectrum (DMSO-cL), δ 8.60 (s, 1H),

7.88 (d, J = 13 Hz, 1H), 7.56 (d, J = 7 Hz, 1H),

4.49 (bs, 2H), 3.73 (m, 3H), 3.00 (s, 6H), 2.71 (bs,

2H), 1.31 (bd, J = 6Hz, 2H), 1.16 (bs, 2H).

Example 9

-Cyclopropyl-7- [5- (2-ethylamino-4 H, 6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - 6-fluoro-1,4-dihydro-4-oxo-quinoline -3-carboxylic acid

To a solution of 2-ethylamino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (0.100 g, 0.546 mmol) in dimethyl sulfoxide (8 mL) was added 1-cyclopropyl-6 (0.115 g, 0.436 mmol). 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and the mixture was heated at 80 ° C overnight. The resulting light yellow precipitate was filtered off, washed with isopropanol and diethyl ether and dried. This gave 93.5 mg (0.22 mmol, 50% yield) of the title compound as a light yellow powder, m.p. 280-287 ° C (dec). 1 H NMR (DMSO-d 6) δ 8.60 (s, 1H),

7.90 (d, J = 13 Hz, 1H), 7.57 (d, J = 8 Hz, 1H),

7.43 (t, J = 5Hz, 1H), 4.44 (bs, 2H), 3.77 (m, 3H),

3/20 (m, 2H), 2.67 (bs, 2H), 1.30 (bd, J = 6Hz,

2H), 1.13 (m, 5H).

Example 10 1-Cyclopropyl-6-fluoro-7- [5- (2-guanidino-4,6,6-tetrahydro-thiazolo [5,4-c] pyridyl)] -], 4-dihydro-4-oxo quinoline-3-carboxylic acid

111.7 mg (0.566 mmol) of 2-guanidino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine, 149.5 mg (0.566 mmol) of 1-cyclopropyl-6,7-difluoro- A mixture of 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 0.095 mL (0.68 mmol) of triethylamine in 10 mL of dimethyl sulfoxide was heated at 80 for 24 h. The solvent was then distilled off under reduced pressure and the resulting solid was washed well with isopropanol. This gave 195 mg (0.44 mmol, 78%) of the title compound as a solid, m.p. 259-270 ° C (dec).

1 H-Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ ), δ 8.60 (s, 1H),

7.88 (d, J = 13 Hz, 1H), 7.57 (d, J = 7 Hz, 1H),

7.00 (bs, 4H), 4.49 (bs, 2H), 3.75 (m, 3H), 2.72 (bs,

2H), 1.29 (bd, J = 6Hz, 2H), 1.14 (bs, 2H).

Example 11 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- [5- (2-methyl-4,6,6-tetrahydro-thiazole [5,4-c] pyridyl) -1-4-oxo-quinoline -3-carboxylic acid

To a solution of 2-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (0.243 g, 1.57 mmol) in dimethylsulfoxide (15 mL) was added 1-cyclopropyl (0.412 g, 1.55 mmol). -6,7-Difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 0.22 mL (1.6 mmol) of triethylamine and the mixture was heated at 80 for 72 h. The dimethyl sulfoxide was then distilled off and the residue was chromatographed on silica gel, eluting with chloroform: methanol: concentrated aqueous ammonium hydroxide (89: 10: 1). This gave 250 mg (0.63 mmol, 40%) of the title compound as a yellow solid, m.p. 253-255 ° C. 1 H NMR (DMSO-d 6) δ 8.62 (s, 1H),

7.93 (d, J = 13 Hz, 1H), 7.60 (d, J = 8 Hz, 1H),

4.67 (bs, 2H), 3.79 (m, 3H), 2.90 (m, 2H), 1.30 (bd,

J = 6Hz, 2H), 1.16 (bs, 2H).

Example 12

-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-16- (5,6,7,8-tetrahydro-1,6-naphthyridine)] quinoline-3-carboxylic acid

600 mg (4.48 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine and 506 mg (2 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo- Quinoline-3-carboxylic acid in pyridine (5 mL) was heated at 95 ° C for 3 h. The mixture was cooled, and the precipitate was filtered off and washed first with a little chilled chloroform and then with diethyl ether. After drying, 333 mg (0.9 mmol, 45%) of the title compound are obtained as a solid, m.p. 235-236 ° C.

Example 13 1-Cyclopropyl-6-fluoro-1,4-dihydro-7- [5- (2-hydroxy-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - 4 lanolin-oxo-3-carboxylic acid

108.8 mg (0.65 mmol) of 2-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine and 171.6 mg (0.65 mmol) of 1-cyclopropyl-6,7- A mixture of difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 10 ml of dimethyl sulfoxide was heated at 80 ° C for 48 hours. The reaction mixture was cooled, the insolubles were filtered off, and the filtrate was evaporated under reduced pressure. This gave a yellow solid which was washed with diisopropyl ether, triturated with isopropanol and washed several times with methanol. This gave 70.5 mg (0.18 mmol, 28%) of the title compound as a yellow solid, m.p. 231 C (dec).

1 H NMR (DMSO-d 6) delta 8.65 (s, 1H),

7.94 (d, J = 13 Hz, 1H), 7.60 (d, J = 7 Hz 1H),

4.30 (s, 2H), 3.82 (bs, 1H), 3.76 (m, 2H), 2.55 (m,

2H), 1.35 (d, J = 6Hz, 2H), 1.20 (bs, 2H).

Example 14

7- [6- (2-amino-5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidin-7-yl)] l-cyclopropyl-6-fluoro-l, 4 dihydro-4 oxo-quinoline-3-carboxylic acid

24.3 mg (0.161 mmol) of 2-amino-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine and 34 mg (0.129 mmol) of 1-cyclopropyl-6,7-difluoro-1, A mixture of 4-dihydro-4-oxo-quinoline-3-carboxylic acid in 3 ml of dimethylsulfoxide was heated at 80 ° C for 16 hours. The resulting white precipitate was filtered off and washed first with isopropanol and then with diethyl ether. This gave 39.3 mg (0.1 mmol, 62%) of the title compound as a white solid, m.p. 295-305 (dec). 1 H NMR (DMSO-d 6) delta 8.69 (s, 1H),

8/20 (s, 1H), 7.98 (d, J = 13 Hz, 1H), 7.65 (d, J = 7

Hz, 1H), 6.54 (s, 2H), 4.48 (s, 2H), 3.86 (m, 1H),

3.78 (m, 2H), 2.86 (m, 2H), 1.35 (bd, J = 5 Hz,

2H), 1.20 (bs, 2H).

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HU 203 100 Β

Example 75 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - indoline-3-carboxylic acid

2.5 g (18.6 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine;

A mixture of 2.5 g (9.4 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 25 ml of pyridine was heated at 85 ° C for 3 hours. The precipitate was filtered off and washed with chloroform. The crude product was recrystallized from dimethylformamide to give 1.9 g (5.0 mmol, 53%) of the title compound as a solid.

Example 16 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - 1,8-naphthyridine -3-carboxylic acid

402 mg (3 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine and 282 mg (1 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- A mixture of 1,8-naphthyridine-3-carboxylic acid in 5 ml of pyridine was heated at 80 ° C for 5 hours. The reaction mixture was cooled and the precipitate was filtered off and washed extensively with chloroform and diethyl ether. The filtrate was washed with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The solid residue was slurried in diethyl ether and the solid was filtered off and purified by column chromatography (eluent: chloroform: methanol = 99: 1). This gives an off-white solid. This product was recrystallized from acetonitrile to give 110 mg (0.29 mmol, 29%) of the title compound, m.p.

Example 17

9-Fluoro-23-dihydro-3-methyl-7-oxo-10- [6- (5,6,73-tetrahydro-1,6-naphthyridine)] - 7H-pyrido [1,2,3-d, e ] -l, 4-benwxazin-6-carboxylic acid

402 mg (3 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine and 281 mg (1 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H- A mixture of pyrido [1,2,3-d, e] -1,4-benzoxazine-6-carboxylic acid in 5 ml of dimethyl sulfoxide was heated at 80 for 18 hours. The reaction mixture was poured into water and the precipitate was filtered off. The filtrate is extracted twice with chloroform, the combined organic phases are dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue was combined with the precipitate collected after pouring into water and the combined crude product was purified by column chromatography eluting with chloroform followed by 99: 1 chloroform: methanol. The material thus obtained was recrystallized from the minimum amount of chloroform to give 21 mg (0.05 mmol, 5%) of the title compound, m.p. 254-255 ° C.

Example 18

6-Fluoro-1,4-dihydro-1-methyl-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid

295 mg (1.75 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride, 239 mg (1 mmol) of 6,7-difluoro-1,4-dihydro-1-methyl-4- A mixture of oxoquinoline-3-carboxylic acid and 533 mg (3.5 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene in 5 ml of pyridine was heated at 80 ° C for 1 hour. The reaction mixture is cooled, the precipitate is filtered off, washed with chloroform and diethyl ether and dried. The product was recrystallized once from isopropanol and then once from dimethylsulfoxide to give 75 mg (0.21 mmol, 21%) of the title compound, m.p.

Example 79

6-Fluoro-1,4-dihydro-1-methylamino-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthalane)] - quinoline-3-carboxylic acid

268 mg (2 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine and 254 mg (1 mmol) of 6,7-difluoro-1,4-dihydro-1-methylamino-4-oxo- A solution of quinoline-3-carboxylic acid in 3 ml of pyridine was heated at 80 ° C for 18 hours. The reaction mixture is cooled, the precipitate is filtered off, washed thoroughly with chloroform and diethyl ether and recrystallized from dimethylsulfoxide. Yield: 280 mg (0.76 mmol, 76% yield) of the title compound, m.p.

Example 20

6-Fluoro-1- (4-fluoro-phenyl) -1,4-dihydro-4-oxo-7- [6- (5,6,7,8-telrahydro-1,6-naphthyridine)] - quinoline- 3-carboxylic acid

268 mg (2 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine and 319 mg (1 mmol) of 6,7-difluoro-1- (4-fluorophenyl) -1,4-dihydro- A solution of 4-oxoquinoline-3-cartilic acid in 3 ml of pyridine was first heated at 80 ° C for 4 hours and then at 60 ° C for a further 16 hours. The precipitate is then filtered off and washed with chloroform. The filtrate was diluted with chloroform and washed with water followed by 1N hydrochloric acid. The combined aqueous washings were treated with sodium bicarbonate and shaken with chloroform. The combined organic layers were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting off-white solid was combined with the precipitate filtered off and recrystallized from ethyl acetate. This gave 110 mg (0.25 mmol, 25%) of the title compound, mp 254-255 ° C.

Example 21 1-Ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7, 3-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid

300 mg (2.24 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine and 300 mg (1.25 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro- A mixture of 4-oxoquinoline-3-carboxylic acid in 5 ml of pyridine was heated at 80 ° C for 90 hours. The reaction mixture was then diluted with chloroform (100 mL) and the solution was washed with water. The organic layer was evaporated under reduced pressure and the solid residue was triturated with diethyl ether. The solid thus obtained was dissolved in chloroform (100 ml) and the solution was extracted with 1N hydrochloric acid. The aqueous layer was then adjusted to pH 7 with saturated aqueous sodium bicarbonate solution, and the precipitate was filtered off and recrystallized from ethyl acetate. This gave 65 mg (0.17 mmol, 14%) of the title compound, mp 224-225 ° C.

Example 22

6-Fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (6- (5,6,7,8-tetrahydro-1,6-ruththyridine)] - quinoline- 3-carboxylic acid

300 mg (2.24 mmol) of 5,6,7,8-tetrahydro-1,6-naphthyridine and 325 mg (1.2 mmol) of 6,7-difluoro-1- (2-fluoro-ethyl) -1, A mixture of 4-dihydro-4-oxo-quinoline-3-carboxylic acid in 3 ml of pyridine was heated at 90 ° C for 18 hours.

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HU 203 100 Β

The precipitate was filtered off and triturated first with twice hot ethyl acetate and then hot isopropanol. The resulting solid was recrystallized from dimethylformamide to give 50 mg (0.13 mmol, 11%) of the title compound as a solid, m.p.

The following examples illustrate the preparation of starting materials.

Example 23

the step

6.7- Ethofluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

10.0 g (39.5 mmol) of ethyl 6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 25.1 g (197.5 mmol) of 1-bromo A mixture of 2-fluoroethane and 10.9 g (79 mmol) of potassium carbonate in 200 ml of dimethylformamide was heated at 90 ° C for 20 hours. The reaction mixture was then poured into 1.51 cold water and the precipitated copious precipitate was filtered off and washed with cold water. The crude product was recrystallized from ethyl acetate to give 8.22 g (27.5 mmol, yield: 70%) of the title compound as a light brown needle, m.p. 178180C.

b) spleen

6.7-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid

7.74 g (25.9 mmol) of 6,7-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester and 300 ml of 1 N aqueous hydrochloric acid was refluxed for 2 hours. The reaction mixture is cooled, the precipitate is filtered off, washed with water and dried under reduced pressure. This afforded 6.07 g (22.4 mmol, 86%) of the title compound as a white solid, m.p. 249-251 ° C.

1 H NMR (DMSO-d 6), δ 9.05 (s, 1H),

8.35 (m, 2H), 5.03 (m, 1H), 4.93 (m, 2H), 4.75 (m,

IH).

Example 24

the step

6.7-Difluoro-1,4-dihydro-1-methyl-4-oxo-quinoline-3-carboxylic acid ethyl ester

Ethyl ester of 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (10.0 g, 39.5 mmol), methyl iodide (56 g, 395 mmol) and 10.9 g (79 mmol) of potassium carbonate in dimethylformamide was heated at 90 ° C for 20 hours. The reaction mixture was cooled and poured into 1.5 L of cold water. The precipitate was filtered off, washed with cold water and recrystallized from ethyl acetate. In this way it is in the form of a white needle-like substance

6.60 g (24.7 mmol, 63%) of the title compound are obtained, m.p. 210-212 ° C.

Step b)

6,7-Difluoro-1,4-dihydro-1-methyl-4-oxo-quinoline-3-carboxylic acid

A mixture of 6,7-difluoro-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester (7.24 g, 27.1 mmol) and 300 mL of 1 N hydrochloric acid was heated to reflux for 2 hours. . The precipitate was filtered off, washed with water and dried under reduced pressure. This gave 5.78 g (24.2 mmol, 89%) of the title compound as a white solid, m.p. 284-287 ° C. 1 H NMR (CF ₃ COOD), δ 9.42 (s, 1H),

8.5 (apparent t, J = 7Hz, 1H), 8.19 (dd, J = 8,

Hz, 1H), 4.5 (s, 3H).

Example 25

the step

2-Chloro-4,5-difluorobenzoyl chloride

A mixture of 2-chloro-4,5-difluorobenzoic acid (19.2 g, 0.1 mol) and thionyl chloride (50 ml) was heated to reflux for 3 hours. The excess thionyl chloride is then distilled off and the residue is dissolved in dichloromethane. This solvent was distilled off under reduced pressure and the procedure was repeated once with dichloromethane and then once with benzene. The resulting material (19 g, 0.09 mol, 90% yield) was used without further purification.

Step b)

Ethyl 2- (2-chloro-4A-difluorobenzoyl) -acetic acid ethyl ester (199 mmol) was dissolved in tetrahydrofuran (500 mL) and cooled to -70 ° C. Then, 112.5 ml of a 1.6 M solution of n-butyllithium in hexane (isomer mixture) (180 mmol) was added, and the reaction mixture was allowed to warm to -10 ° C and then added.

112.5 ml of a solution of n-butyllithium of the same quality as above. The resulting milky white mixture was cooled to -70 ° C and a solution of 19 g (90 mmol) of 2-chloro-4,5-difluorobenzoyl chloride in 200 ml of tetrahydrofuran was added. The mixture was allowed to warm to room temperature and stirred for a further 2 hours and poured into 750 ml of 2N hydrochloric acid. The aqueous portion was extracted with diethyl ether, the combined organic portions were dried and the solvent was distilled off. This gave 20.6 g (78.6 mmol, 87%) of the title compound as a light amber oil which was used without further purification.

step c)

2- (2-Chloro-4,5-difluoro-benzoyl) -3-ethoxy-2-propenoic acid ethyl ester g (76 mmol) 2- (2-chloro-4,5-difluoro-benzoyl) -acetic acid A mixture of ethyl ester, triethyl ortho-formic acid (17.0 g, 115 mmol) and acetic anhydride (19.5 g, 191 mmol) was heated to reflux for 3 hours. The excess solvent was then distilled off under reduced pressure and the crude title compound thus obtained was used without purification.

Step d)

Ethyl 2- (2-chloro-4 3-difluorobenzoyl) -3- (4-fluoroanitino) -2-propenoic acid

A mixture of 2- (2-chloro-4,5-difluorobenzoyl) -3-ethoxy-2-propionic acid ethyl ester obtained in step c) above and 250 ml of isopropanol was cooled to 0 ° C, and 9.33 was added. g of 4-fluoroaniline (84.0 mmol) was allowed to warm to room temperature and stirred for 18 hours. The precipitate was filtered off and washed with diisopropyl ether. 11.0 g (28.7 mmol) of the title compound are obtained. The filtrate was distilled off under reduced pressure and the residue was subjected to column chromatography using chloroform as eluent. The product thus obtained was purified by recrystallization from a mixture of diethyl ether and hexane (isomer mixture) to give an additional 10.2 g (26.6 mmol) of the title compound.

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HU 203 100 Β was obtained. Thus step c) above and the present

Step d: Yield: 73%.

1 H NMR (CDCl ₃ ), δ 12.7 and 11.3 (bd,

1H), 8.6 and 8.5 (d, 1H), 7.2 (m, 6H), 4.0 (m, 2H),

1.1 and 0.9 (t, 3H).

step e)

6.7-Difluoro-1- (4-fluoro-phenyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl and 2-ter

11.0 g (28.7 mmol) of ethyl 2- (2-chloro-4,5-difluorobenzoyl) -3- (4-fluoroanilino) -2-propenoic acid are dissolved in 200 ml of dimethoxyethane, and cooling the solution to 0 ° C. Sodium hydride (50% suspension in mineral oil, 34.5 mmol) (1.65 g) was added portionwise and the mixture was refluxed for 3 hours. The reaction mixture was poured into 2 L of water and the title compound was filtered off. 8.96 g (25.8 mmol, 90% yield) of product are obtained.

1 H NMR (DMSO-d 6) δ 8.5 (s, 1H), 8.1 (dd, J = 6.7 Hz, 1H), 7.7 (m, 2H), 7.5 (m, 2H),

7.0 (dd, J = 5, 8 Hz, 1H), 4.2 (q, J = 5 Hz, 2H),

1.3 (t, J = 5Hz, 3H).

Step f)

6.7-Difluoro-1- (4-fluoro-phenyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

To a mixture of ethyl ethyl ester (14.5 g, 42 mmol) 6,7-difluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 300 ml acetic acid was added 100 ml. 1N HCl and the mixture was heated at 100 ° C for 4 hours. The reaction mixture was cooled, and the precipitate was filtered off and washed with water and diethyl ether. This gave 11.5 g (36.0 mmol, 86%) of the title compound as a solid, m.p. 252256C.

1 H NMR (DMSO-d 6) δ 8.8 (s, 1H), 8.3 (dd, J = 6.7 Hz, 1H), 7.8 (m, 2H), δ , 6 (m, 2H),

7.2 (dd, J = 5, 8 Hz, 1H).

Example 26

the step

4- (N-Phthalimido) -2-butanone g (0.61 mol) of phthalate and 15.3 ml of a 40% solution of Triton B (trimethylbenzylammonium hydroxide) in 40% (350 ml) in 350 ml After suspension in ethyl acetate, methyl vinyl ketone (51 mL, 0.61 mol) was added. Ethyl acetate (75 mL) was added to facilitate the mixing of the heterogeneous mixture and refluxed for 50 minutes. The solvent was evaporated under reduced pressure and the resulting light brown solid was recrystallized from ethanol. This gave the title compound (76.48 g, 0.35 mol, yield: 58%) as an off-white solid, m.p.

1 H NMR (CDCl ₃ ) delta 7.8 (m, 2H), 7.7 (m, 2H), 3.94 (t, J = 7Hz, 2H), 2.86 (t , J = 7 Hz,

2H), 2.18 (s, 3H).

Step b) 1-Bromo-4- (N-phthalimido) -2-butanone

4- (N-Phthalimido) -2-butanone (70.0 g, 0.322 mol) was dissolved in a mixture of dichloromethane (525 mL) and methanol (425 mL). A solution of 16.5 ml (0.322 mol) of bromine in 100 ml of methanol is added dropwise over 2 hours, and the mixture is stirred overnight. An additional 4 ml (0.078 mol) of bromine were then added, and the starting material was no longer detectable by TLC 1 hour later. The solvent was distilled off under reduced pressure and the resulting yellow solid was triturated with diethyl ether and dried under nitrogen. This gave the title compound as a white solid, 54.84 g (0.185 mol, yield: 58%), m.p. 88-90 ° C.

1 H NMR (CDCl ₃ ) delta 7.82 (m, 2H), 7.72 (m, 2H), 4.01 (t, J = 8 Hz, 2H), 3.93 (s) , 2H), 3.12 (t, J = 8 Hz, 2H).

step c)

2-Amino-4- [2- (N-phthalimido) ethyl] thiazole hydrochloride 50.0 g (0.169 mol) of 1-bromo-4- (N-phthalimido) -2-butanone and 25.71 g of To a mixture of thiourea (0.338 mol) in 1000 ml of n-propanol was added 100 ml of concentrated hydrochloric acid and the mixture was refluxed for 1.5 hours. After cooling, the precipitate formed is filtered off, washed with n-propanol and diethyl ether and air-dried. This gave 37.51 g (0.121 mol, yield: 72%) of the title compound as a foamy white solid, m.p. 230-240 ° C (dec.).

1 H NMR (DMSO-d 6) δ 9.08 (bs, 2H), 7.84 (m, 4H), 6.53 (s, 1H), 3.84 (t, J = 6). Hz, 2H), 2.83 (t, J = 6 Hz, 2H).

Step d)

2-Amino-4- [2- (N-phthalimido) ethyl] thiazole

A mixture of 31.40 g (0.101 mol) of 2-amino-4- [2- (N-phthalimido) ethyl] thiazole hydrochloride in 300 ml of water was heated to 80 ° C and the insolubles were filtered off. The filtrate was adjusted to pH 13 with saturated aqueous potassium carbonate solution, and the precipitated solid was filtered, washed with diethyl ether and air dried. This gave 26.34 g (96.4 mmol, 95% yield) of the title compound as a light brown solid, m.p. 190-194 ° C.

1 H-Nuclear Magnetic Resonance Spectrum (CDCl ^, δ D), delta 7.75 (m, 2H), 7.66 (m, 2H), 6.07 (s, 1H), 3.90 (t, J = 7 Hz, 2H), 2.84 (t, J = 7 Hz, 2H).

step e)

2-Amino-4- (2-aminoethyl) thiazole 4.00 g (14.6 mmol) of 2-amino-4- [2- (N-phthalimido) ethyl] thiazole are added in 200 ml of 0.2 molar methanolic hydrazine solution and the mixture is heated until homogeneous, which takes half an hour. The mixture was stirred at room temperature for a further 2 hours and then the solvent was distilled off under reduced pressure. The resulting white solid was purified by column chromatography using a 89: 10: 1 mixture of chloroform, methanol and concentrated aqueous ammonium hydroxide as eluant. This gave 1.82 g (12.7 mmol, 87%) of the title compound as a white solid, m.p. 69-71 ° C. 1 H NMR (DMSO-d 6), δ 6.79 (s, 2H),

6.10 (s, 1H), 2.73 (t, J = 6Hz, 2H), 2.45 (t, J = 6Hz, 2H), 2.2 (vbs, H).

Step f)

2-Amino-4 5,6,7-tetrahydro-thiazolo [5,4-c] pyridine 1.57 g (11.0 mmol) of 2-amino-4- (2-aminoethyl) -thiazole

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HU 203 100 Β

To a solution of 120 mL of methanol was added 0.15 mL (2.6 mmol) of acetic acid and 0.89 mL of 37% aqueous formaldehyde solution (11 mmol). After 10 minutes, the solvent was distilled off under reduced pressure and the residue was subjected to column chromatography eluting with 95: 4: 1 chloroform: methanol: concentrated aqueous ammonium hydroxide. This gave 1.547 g (10.0 mmol, 91%) of the title compound as a white solid, m.p. 169-173 ° C.

1 H-Nuclear Magnetic Resonance Spectrum (DMSO-cL), δ 6.64 (s, 2H),

3.59 (s, 2H), 2.87 (t, J = 6Hz, 2H), 2.33 (bt, 2H).

Example 27

the step

5-Acetyl-2-amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine

To a solution of thiourea (756 mg, 9.9 mmol) in anhydrous ethanol (13.5 mL) at 60 ° C was slowly added 3.0 g (9.9 mmol) of N-acetyl-3-bromo-4-piperidone hydrobromido. the reaction mixture was stirred at 40 ° C for 1 hour, then the ethanol was distilled off at normal pressure and the residue was heated to 160-170 ° C for 20 minutes. The mixture was cooled, dissolved in water and neutralized with saturated aqueous sodium bicarbonate. The neutral mixture was extracted three times with chloroform, the combined organic extracts were dried over sodium sulfate, the desiccant was filtered off and the filtrate was evaporated. The resulting oil was purified by flash chromatography (eluent: chloroform: methanol = 9: 1). This gave 200 mg (1.0 mmol, 10%) of the title compound as a solid.

1 H NMR (D ₂ O), δ 4.54 and 4.50 (bs, 2H),

3.8 (m, 2H), 2.64 and 2.56 (m, 2H), 1.20 and 1.15 (s,

3H).

Step b)

2-Amino-4 J, 6,7-tetrahydro-thiazolo [5,4-c] pyridine

5-Acetyl-2-amino-tetrahydro-thiazolo [5,4-c] pyridine (110 mg, 0.51 mmol) was dissolved in ethanol (1 mL) and sodium hydroxide (15.4 mg, 0.38 mmol) in ethanol (1 mL) was added. The resulting solution was heated at 100 ° C for 16 hours and then added

Sodium hydroxide (25.6 mg, 0.64 mmol) was added and the mixture was refluxed for an additional 16 hours. Solid ammonium chloride was added, the insolubles were filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, dried over sodium sulfate and the solvent was distilled off. This gave 67.4 mg (0.43 mmol, 84%) of the title compound as a yellow solid which was used without further purification.

Example 28

the step

2- (3-Pyridyl) amino-4- [2- (N-phthalimido-ethyl] -tiaz0l

A mixture of 3.07 g (10.3 mmol) of 1-bromo-4- (N-phthalimido) -2-butanone and 1.59 g (10.3 mmol) of N- (3-pyridyl) thiourea in 100 ml of acetone was added. Boil for 26 hours. The precipitate was filtered off, washed with acetone and dried, and the resulting greenish-yellow solid was purified by column chromatography using chloroform: methanol: concentrated aqueous ammonium hydroxide (89: 10: 1) as eluent. This gave 1.9 g (5.2 mmol, 50%) of the title compound.

1 H-Nuclear Magnetic Resonance Spectrum (DMSO-cL), δ 8.6 (d, J = 3)

Hz, 1H), 8.0 (m, 2H), 7.8 (m, 4H), 7.1 (dd, J = 8,

Hz, 1H), 6.6 (s, 1H), 3.87 (t, J = 7Hz, 2H), 2.9 (t, J = 7Hz, 2H).

Step b)

2- (3-Pyridyl) amino-4- (2-aminoethyl) thiazole

A mixture of 1.88 g (5.1 mmol) of 2- (3-pyridyl) amino-4- [2- (N-phthalimido) ethyl] thiazole and 16.4 mmol hydrazine in 55 mL of methanol was stirred at room temperature for 20 hours. stirred. The insolubles were then filtered off and the filtrate was evaporated. This gives 1.61 g of an oil which is the title compound and is contaminated with a by-product derived from phthalimide. This crude product was used in the next step without further purification.

Partial 1 H-Nuclear magnetic resonance spectrum (DMSO-cL), δ 8.7 (d, J = 2 Hz, 1H), 8.1 (m, 2H), 7.3 (dd, J = 8.5)

Hz, 1H), 6.56 (s, 1H), 2.9 (t, J = 7Hz, 2H), 2.7 (t,

J = 7 Hz, 2H).

step c)

2- (3-Pyridyl) amino-43,6,7-tetrahydro-thiazolo [5,4-pyridin

2- (3-Pyridyl) amino-4- (2-aminoethyl) thiazole (0.50 g) obtained in step b) and acetic acid (0.19 ml, 3.3 mmol) were dissolved in methanol (23 ml). , and 0.19 ml of a 37% aqueous formaldehyde solution (2.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then an additional 0.02 ml of 37% aqueous formaldehyde solution (0.25 mmol) was added. After a further 2 hours, the insolubles were filtered off, the filtrate was evaporated under reduced pressure, and the residue was dissolved in an aqueous base. The aqueous mixture was extracted with dichloromethane, the organic portions were dried over sodium sulfate and the solvent was distilled off. This gave 310 mg (1.3 mmol, 57%) of the title compound.

1 H NMR (CDCl ₃ ) delta 8.56 (d, J = 2 Hz,

1H), 8.26 (m, 1H), 8.00 (m, 1H), 7.27 (dd, J = 8,

Hz, 1H), 3.93 (m, 2H), 3.20 (t, J = 6 Hz, 2H),

2.71 (m, 2H).

Example 29

the step

2-Phenyl-4- [2- (N-phthalimido) ethyl] thiazole

To a mixture of 4.00 g (13.5 mmol) of 1-bromo-4- (N-phthalimido) -2-butanone and 4.19 g (27.0 mmol) of phenylthiourea in 80 ml of n-propanol is added 8 ml of concentrated hydrochloric acid and refluxed for 4 hours. After cooling, the precipitate was filtered off and washed first with n-propanol and then with diethyl ether and air-dried. 3.5 g of a light orange solid are obtained. This product was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution, the aqueous portion was extracted twice with ethyl acetate, and the combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The oily solid residue was crystallized from diethyl ether to give 1.72 g

-1019

100% (4.9 mmol, 36% yield) of a yellow solid were obtained.

1 H NMR (CDCl 3, delta 7.80 (m, 2H), 7.70 (m, 2H), 7.28 (m, 5H), 7.02 (m, 1H), 6.30 (s, 1H), 4.04 (t, J = 7Hz, 2H), 3.03 (t, J = 7Hz, 2H).

Step b)

2-Phenylamino-4- (2-aminoethyl) -thiazole To a solution of 2M-phenylamino-4- [2- (N, 1.49 g, 4.26 mmol) in 2M methanolic hydrazine (64 mL) was added. phthalimido) ethyl] thiazole and the mixture was heated for 3 hours. The solvent was distilled off under reduced pressure and the solid residue was purified by column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonium hydroxide 89: 10: 1). Trituration with diethyl ether gave 0.306 g (1.40 mmol, 33%) of the title compound as a white solid.

1 H NMR (CDCl 3, delta 7.32 (m, 5H), 7.04 (m, 1H), 626 (s, 1H), 3.07 (t, J = 7Hz, 2H), δ , 77 (t, J = 7Hz, 2H).

step c)

2-Phenylamino-4H, 6,7-tetrahydro-thiazolo [5,4-c] pyridine 0.30 g (1.37 mmol) 2-phenylamino-4- (2-aminoethyl) thiazole To a solution of 15 ml of methanol was added 0.02 ml (0.35 mmol) of acetic acid and 0.11 ml of a 37% aqueous formaldehyde solution (1.37 mmol). After 20 minutes, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, then with water and finally with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This gave 0.31 g (1.34 mmol, 98%) of a glassy solid which was used without further purification. 1 H NMR (DMSO-d 6, delta 10.0 (m, 1H),

7.60 (m, 2H), 7.28 (m, 2H), 6.92 (m, 1H), 3.74 and 3.65 (bs, 2H), 2.98 (m, 2H), 2 , 65 and 2.54 (bs, 2H).

Example 30

the step

2-Dimethylamino-4- [2- (N-phthalimido) ethyl] thiazole 10.21 g (34.46 mmol) of 1-bromo-4- (N-phthalimido) -2-butanone and 3.59 A mixture of N, N-dimethylthiourea (g, 34.5 mmol) in acetone (345 mL) was refluxed for 48 hours. The precipitate was filtered off to give 9.33 g (31 mmol, 90% yield) of the title compound as a white solid.

1 H NMR (DMSO-d 6, delta 7.83 (m, 4H), 6.70 (s, 1H), 3.88 (t, J = 6Hz, 2H), 3.21 (s) , 6H), 2.92 (t, J = 5 Hz, 2H).

Step b)

To a solution of 2-dimethylamino-4- (2-aminoethyl) -thiazole in 30 mmol of hydrazine in 100 ml of methanol was added 3.0 g (9.96 mmol) of 2-dimethylamino-4- [2- (N- phthalimido) ethyl] thiazole and the mixture was stirred at room temperature for 16 hours. The white precipitate was filtered off and the filtrate was evaporated. This gives 2.9 g of the title compound which is contaminated by a by-product of a phthalimide derivative by Ή-NMR spectroscopy. The crude product thus obtained is used without further purification.

1 H NMR (DMSO-d 6, delta 8.03 (m, 2H),

7.77 (m, 2H), 6.38 (s, 1H), 3.00 (s, 6H), 2.91 (t,

J = 6 Hz, 2H), 2.64 (t, J = 6 Hz, 2H).

step c)

2-Dimethylamino-4.beta, 6,7-tetrahydro-thiazolo [5,4-c] pyridine

1.7 g of 2-dimethylamino-4- (2-aminoethyl) -thiazole obtained in the same manner as in b) above, 0.78 ml of a 37% aqueous formaldehyde solution (9.6 mmol). and 0.15 mL (2.6 mmol) of acetic acid in 100 mL of methanol was stirred at room temperature for 2.5 hours. An additional 0.15 mL (1.8 mmol) of formaldehyde was then added and the reaction stirred for an additional 16 hours. The insolubles were then filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (eluent: chloroform / methanol / concentrated aqueous ammonium hydroxide 89:10: 1). This gave 1.04 g (5.7 mmol) of the title compound as a white solid.

1 H NMR (CDCl 3, delta 3.84 (bs, 2H), 3.11 (t, J = 8Hz, 2H), 3.04 (s, 6H), 2.59 (m, 2H) ), 1.68 (bs, 1H).

Example 31

the step

2- (ethylamino) -4- [2- (N-ftátimido) ethyl] thiazole

A mixture of 2.50 g (8.44 mmol) of 1-bromo-4- (N-phthalimido) -2-butanone and 0.88 g (8.44 mmol) of N-ethylthiourea in 85 ml of acetone was heated at reflux for 16 hours. . The precipitate was filtered off, washed with acetone and dried. The light yellow solid thus obtained was partitioned between ethyl acetate and a saturated aqueous potassium carbonate solution. The organic layer was separated, dried over sodium sulfate and the solvent was distilled off under reduced pressure. This afforded 2.03 g (5.31 mmol, 63%) of the title compound as a yellow oil which was used without further purification.

1 H NMR (CDCl 3, delta 7.82 (m, 2H), 7.70 (m, 2H), 6.13 (s, 1H), 3.98 (t, J = 7Hz, 2H), 3.20 (m, 2H), 2.92 (t, J = 7Hz, 2H), 1.24 (t, J = 7Hz,

3H).

Step b)

2-Ethyl-4- (2-aminoethyl) thiazole

A mixture of 2.03 g (5.31 mmol) of 2-ethylamino-4- [2- (N-phthalimido) ethyl] thiazole and 15.9 mmol of hydrazine in 80 mL of methanol is stirred for 2 hours at 50 ° C. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonium hydroxide 89: 10: 1). This afforded 0.63 g (3.68 mmol, 69%) of the title compound as a yellow solid.

1 H NMR (DMSO-d 6) delta 7.32 (bs, 1H),

6.10 (s, 1H), 3.12 (m, 2H), 2.72 (t, J = 7Hz, 2H),

2.45 (t, J = Hz, 2H, 1.10 (t, J = 7Hz, 3H).

-1 121

HU 203 100 Β

step c)

2-Ethylamino-4f, 6,7-tetrahydro-thiazolo [5,4-c] pyridine

To a solution of 2-ethylamino-4- (2-aminoethyl) thiazole (0.20 g, 1.17 mmol) and acetic acid (0.02 mL, 0.35 mmol) in methanol (15 mL) was added 0.095 mL (37%). aqueous formaldehyde solution (1.17 mmol). After stirring for a quarter hour at room temperature, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonium hydroxide 89: 10: 1). This afforded 0.105 g (0.57 mmol, 49%) of the title compound as a yellow solid.

1 H NMR (DMSO-d 6, delta 7.22 (bt, J = 5

Hz, 1H), 3.61 (s, 2H), 3.17 (m, 2H), 2.88 (t, J = 6

Hz, 2H), 2.37 (m, 2H), 1.12 (t, J = 7 Hz, 3H).

Example 32

the step

5-Acetyl-2-guanidino-4,6,6-telhydro-thiazolo [5,4-c] pyridine

To a suspension of aminoiminomethylthiourea (4.735 g, 40 mmol) in ethanol (40 mL) at 70 ° C was added N-acetyl-3-bromo-4-piperidone hydrobromide (12.09 g, 40 mmol). After the addition, the reaction mixture was stirred for 48 hours at 40 ° C. 1.6 g (40 mmol) of sodium hydroxide are then added and the mixture is stirred for an additional 72 hours at 40 ° C. The solvent was distilled off and the crude oil was purified by column chromatography (eluent: chloroform / methanol / concentrated aqueous ammonium hydroxide 89:10: 1). This gave 822 mg (3.4 mmol, 9%) of the title compound.

1 H NMR (DMSO-d 6, delta 6.84 (bs, 4H),

4.50 and 4.46 (bs, 2H), 3.72 (m, 2H), 2.63 and 2.51 (bs, 2H), 2.11 and 2.06 (s, 3H).

Step b)

_{2-guanidino-4-r} 5,6,7-tetrahydro-thiazolo [5,4-c] pyridine

To a mixture of 232.4 mg (0.971 mmol) of 5-acetyl-2-guanidino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine and 7 ml of ethanol was added 1.98 ml of a 1.46 molar solution, aqueous sodium hydroxide solution (2.9 mmol). After 72 hours at 81 ° C, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: chloroform / methanol / concentrated aqueous ammonium hydroxide 89: 10: 1). 129.9 mg (0.66 mmol, 68%) of the title compound are obtained in the form of an oil.

1 H NMR (DMSO-d 6, delta 6.75 (bs, 5H),

3.64 (bs, 2H), 2.93 (bs, 2H), 2.43 (bs, 2H).

Example 33

the step

5-Acetyl-2-methyl-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridine

To a mixture of 5.0 g (16.6 mmol) of N-acetyl-3-bromo-4-piperidone hydrobromide in 160 mL of acetone is added 2.31 mL (33.1 mmol) of triethylamine and 1.24 g (16.6 mmol) of thioacetamide. The reaction mixture was refluxed for 24 hours, then cooled and the precipitated solid filtered off. The yellow solid thus obtained is filtered off. The resulting yellow solid was purified by column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonium hydroxide (89: 10: 1)). This gave 995 mg (5.1 mmol, 31%) of the title compound as a yellow oil.

1 H NMR (DMSO-d 6, delta 4.68 and 4.64 (bs, 2H), 3.74 (m, 2H), 2.82 and 2.69 (m, 2H), 2.13 and 2.09 (s, 3H).

Step b)

2-Methyl-4 ', 6,7-tetrahydro-thiazolo [5,4-c] pyridine

5-Acetyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (990.4 mg, 5.05 mmol) was dissolved in ethanol (23 mL) and 0.12 g (3 mmol) was added. sodium hydroxide

3.3 ml of water. The resulting solution was heated at 50 ° C for 40 hours, then additional sodium hydroxide (1.01 g, 25 mmol) was added and the mixture refluxed for an additional 32 hours. The ethanol is then distilled off under reduced pressure and the aqueous residue is extracted three times with dichloromethane. The aqueous portion was triturated with potassium sulfate and the salts were washed with methanol. The combined organic extracts were evaporated under reduced pressure and the residual yellow oil was purified by column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonium hydroxide 89: 10: 1). This gave 311 mg (2.0 mmol, 40%) of the title compound as a yellowish solid.

1 H-Nuclear Magnetic Resonance Spectrum (DMSO-r6, delta 3.83 (s, 2H),

2.97 (t, J = 6Hz, 2H), 2.60 (m, 5H).

Example 34

4,5,6,7-Tetrahydro-thiazolo [5,4-c] pyridin-2 (11) -one

A mixture of 5.54 g (72.8 mmol) of ammonium thiocyanate and 450 mL of water was heated to 80 ° C and 20.0 g (66.2 mmol) of N-acetyl-3-bromo-4-piperidone was added dropwise over 3 hours. hydrobromide in 200 ml water. After stirring for 16 hours at 80 ° C, 6 ml of concentrated (12M) hydrochloric acid (93mmol) was added to the crude solution of N-acetyl-3-thiocyanato-4-piperidone and the mixture was refluxed for 2 hours. . The reaction mixture is then freeze-dried, then the residue is dissolved in methanol and the insolubles are filtered off. The filtered precipitate was purified by column chromatography (eluent: chloroform / methanol / concentrated aqueous ammonium hydroxide 89: 10: 1). This gave 0.60 g (3.8 mmol, 6%) of the title compound as a white solid, m.p. 208 DEG C. (dec.).

1 H NMR (DMSO-d 6) delta 3.40 (m, 2H),

3.30 (vbs, 1H), 2.89 (t, J = 6Hz, 2H), 2.20 (m,

2 H).

Example 35

the step

2 - [(dimethylamino) methylene] -l-triphenylmethyl-4-piperidone

To 1.75 ml of methoxybis (dimethylamino) methane was added 0.239 g (0.70 mmol) of 1-triphenylmethyl-4-piperidone and the mixture was stirred for 16 hours at 50 ° C. The volatiles were then reduced to 1223

The residue was triturated with 100 Β of each other, and the resulting yellow solid was triturated with diethyl ether and air-dried. This gave 0.179 g (0.45 mmol, 64%) of the title compound as a light yellow solid.

1 H NMR (CDCl ₃ ) δ 7.56-7.15 (m,

16H), 3.33 (bs, 2H), 2.91 (s, 6H), 2.6-2.5 (m, 4H).

Step b)

2-Amino-5,6,7,8-tetrahydro-6-triphenyl-methyl-pyrido [4,3-d] pyrimidine

2 - [(Dimethylamino) methylene] -1-triphenylmethyl-4-piperidone (0.172 g, 0.434 mmol) was dissolved in ethyl acetate (4 mL), and guanidine carbonate (47 mg, 0.260 mmol) was added and the reaction mixture was stirred at room temperature. Boil for 16 hours. The solvent was distilled off under reduced pressure and the residue was purified by flash chromatography (eluent: ethyl acetate / hexane 3: 1). This gave 83 mg (0.21 mmol, 48%) of the title compound as a yellow oil.

1 H NMR (DMSO-d 6) δ 7.90 (s, 1H),

7.46 (bd, J = 8 Hz, 6H), 7.35 (t, J = 7 Hz, 6H),

7.22 (t, J = 7Hz, 3H), 6.36 (bs, 2H), 3.15 (bs, 2H),

2.83 (bs, 2H), 2.45 (bs, 2H).

step c)

2-Amino-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine mg (0.20 mmol) 2-amino-5,6,7,8-tetrahydro-6-triphenylmethyl- pyrido [4,3-d] pyrimidine is mixed with 0.5 ml water and 0.5 ml acetic acid and heated on a water bath for 5 minutes. Acetone was then added to give a homogeneous mixture. The solvents were evaporated and the oily residue was purified by flash chromatography eluting with chloroform: methanol: concentrated aqueous ammonium hydroxide (89: 10: 1). 24.3 mg (0.16 mmol, 80%) of the title compound are obtained. 1 H NMR (CD ₃ OD) δ 7.98 (s, 1H), 3.80 (s, 2H), 3.12 (t, J = 6Hz, 2H), 2.71 (t , J = 6 Hz,

2 H).

Example 36

the step

1,6-Naphthyridine

For ice-cold "sulfo-mix" [a mixture of nitrobenzene and fuming sulfuric acid, see W.P. Utermohlen, J. Org. Chem., 8, 544 (1943)], glycerol (138.15 g, 1.5 mol) was added dropwise and the mixture was added.

56.46 g (0.6 mol) of 4-aminopyridine are added and 225 ml of water are added dropwise rapidly. The latter addition causes the reaction temperature to rise to 80 ° C. The reaction mixture was then stirred until a homogeneous solution was obtained and then heated at 135 ° C for 48 hours. The mixture was allowed to cool, poured into ice-water (11) and adjusted to pH 13 by addition of granular sodium hydroxide. The resulting thick precipitate was filtered off and the filtrate was extracted twice with 21 dichloromethane. The combined organic extracts are dried over sodium sulfate, the desiccant is filtered off and the solvent is distilled off. The crude product thus obtained was purified by column chromatography (eluent: dichloromethane: methanol = 98: 2). This gave 13.7 g (0.11 mol, yield: 18%) of the title compound as an amber oil which crystallized on standing.

Step b)

6-Benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine

A mixture of 13.7 g (105 mmol) of 1,6-naphthyridine and 36.05 g (210 mmol) of benzyl bromide in 200 ml of acetonitrile is refluxed until 1,6-naphthyridine can no longer be detected by thin layer chromatography. The solvent was distilled off under reduced pressure, and the residue was washed several times with diethyl ether and dissolved in 700 ml of methanol. Water (250 mL) was added to the solution, and the mixture was cooled to 0 ° C and sodium borohydride (20.8 g, 550 mmol) was added portionwise. As a result, vigorous gas evolution is observed and the temperature of the mixture increases slightly. The reaction mixture was then allowed to warm to room temperature and stirred for 18 hours. The solvent was distilled off under reduced pressure and the residue was partitioned between 750 ml water and 300 ml dichloromethane. The aqueous layer was extracted with dichloromethane (2 x 300 mL), and the combined organic layers were washed once with water and once with saturated brine. The organic layer was distilled off and the residual dark amber foam was purified by column chromatography (dichloromethane: methanol = 99: 1). 12.1 g (54 mmol, 51%) of the title compound are obtained.

step c)

5,6,7,8-Tetrahdiro-1,6-naphthyridine

6-Benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine (5.0 g, 22.3 mmol) was dissolved in acetic acid (150 mL) and 10% palladium on carbon (2.5 g) was added and The mixture was hydrogenated for 18 hours in a Parr hydrogenator at 55 ° C and 2.8 x 10 ⁵ H 2. The catalyst is then filtered off with a layer of Super-Cel filtration aid and the solvent is distilled off from the filtrate. The resulting amber oil was dissolved in 6N sodium hydroxide solution and extracted with toluene (2 x 50 mL) and dichloromethane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. This gave 2.8 g (21 mmol, 94%) of the title compound as a light amber oil.

Claims (8)

A process for the preparation of a compound of formula I wherein: A is a methyl group or a fluoromethyl group, and Y is C 1-4 alkyl, C 3-5 cycloalkyl, halophenyl, C 1-4 alkylamino or halo (C 1-4) alkyl, and R ^{2 is} (o), (c) or (k), wherein Q is sulfur or -NH-, R ^{5 is} hydroxy, amino, C 1-4 alkyl, pi 13 -1 325 EN 203 100-Cidylamino, phenylamino, di- (C 1-4) alkylamino, C 1-4 alkylamino, or (NH 1) ₂ -C = N-, or A is a nitrogen atom, Y is C 3-5 cycloalkyl and ^R2 (c) a group of formula or A and Y together form a group of formula (a) wherein R ^{3 is C} 1-4 alkyl, and R ² (p) or (c) a group of formula wherein Q is S and R ^and the amino group of compounds and pharmaceutically acceptable salts thereof, wherein formula (II) wherein Y and Meaning above, and L is a leaving group, reacting a compound of formula R ² H wherein R ² is as defined above with an amine and optionally converting the resulting free compound to a salt thereof. A process for the preparation of a compound of formula (I) according to claim 1, wherein A is a methine group, wherein appropriate starting components are used. 3. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6, wherein R * is 6- (5,6,7,8-tetrahydro-1,6-naphthyridin) yl, characterized in that appropriate starting components are used. A process for the preparation of a compound of formula I according to claim 1 wherein κ is 5- (2-R ^5- substituted-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl) alkyl, wherein ^R5 is as defined in claim 1, characterized in that corresponding starting components are used. A process for the preparation of a compound of formula (I) according to claim 4, wherein ^R5 is amino or 3-pyridylamino group, characterized by using suitable starting components. The process of claim 1, 7- [5- (2-amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] - 1-ethyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 7- [5- (2-Amino-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl)] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7- [5- (2-methyl-4,5,6,7-tetrahydro-thiazolo [5,4-c] pyridyl) -4-Oxo-quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [5- (2- (3-pyridyl) -amino-4,5,6) , 7-Tetrahydro-thiazolo [5,4-c] pyridyl) -quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6) , 7,8-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid, 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - 1,8-naphthyridine-3 carboxylic acid, 7- [6- (2-Amino-5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidyl)] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo quinoline-3-carboxylic acid, 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid, 9-Fluoro-2,3-dihydro-3-methyl-7-oxo-10- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - 7H-pyrido [1,2- 3-de] -1,4-benzoxazine-6-carboxylic acid, 6-Fluoro-1-methylamino-1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline-3-carboxylic acid, 6-Fluoro-1- (4-fluoro-phenyl) -1,4-dihydro-4-oxo-7- [6- (5,6,7,8-tetrahydro-1,6-naphthyridine)] - quinoline- 3-carboxylic acid, and 6-fluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- [6- (5,6,7, 8-Tetrahydro-1,6-naphthyridine) -quinoline-3-carboxylic acid and their pharmaceutically acceptable salts, characterized in that appropriate starting materials are used.