FI103277B - A process for the preparation of therapeutically useful pyrrolo and thieno [3,2-c] naphthyridine derivatives - Google Patents

Description

2 103277

Process for the preparation of therapeutically useful pyrrolo and thieno [3,2-c] naphthyridine derivatives

Separated from patent application 933756.

The present invention relates to processes for the preparation of pyrrolo and thieno [3,2-c] naphthyridine derivatives and their salts, which can be used in pharmaceutical compositions containing said compounds as active ingredients.

In particular, the novel compounds are inhibitors of the action of biological oxygen-containing free radicals such as, for example, the hyperoxide anion O2 'or the hydroxyl radical; it is known that when these inevitable free radicals in humans and animals are formed to be rapidly removed by normal physiological mechanisms, they attack and destroy cellular components such as nucleic acids, proteins, or walls. Injured tissues 20 are very diverse and many authors regard free radicals as a source of many degenerative diseases ranging from inflammatory and autoimmune diseases to respiratory failure and ischemia of the heart, brain or bowel; they are also involved in the degeneration phenomena associated with aging.

Compounds prepared by the process of the invention correspond to formula I,

30 / U

• ^ OH I

Wherein R2 is a lower alkoxy group or a group -N (C1-6 alkyl) 2, A is S where R is nothing, or A is N wherein R is H or C1-6 alkyl, which may be substituted with phenyl, R 2 is hydrogen, halogen, -N (C 1-6 alkyl) 2 or NZLZ 2 where Z 1f Z 2 and N together form a piperazine ring optionally substituted on its nitrogen atom with C 1-8 alkyl, benzyl or diphenylmethyl, or are acid or base salts of such compounds.

The alkyl and alkoxyl groups may be linear or branched or may form a ring, especially a cyclopentyl or cyclohexyl ring.

Preferred halogens are F and Cl.

Of the compounds of formula I, compounds corresponding to formula Ia V-V

5 / y- OH

Wherein R and Rj are the same groups as in Formula I, and particularly where Z2Z, N is located at the 8-position, ortho to the N atom. Of the latter compounds, those in which COR-1 further has an ester group are preferred.

The compounds of formula I can be prepared from appropriately substituted naphthyridines using methods known in the art.

In one method, a compound of formula

35 II

Wherein A, R, Rx and R2 have the same meaning as in formula I and Z represents an alkoxycarbonyl group, is cyclized by a Dieckmann reaction to give a compound of formula I-10.

According to another method, compounds corresponding to formulas III and IV

X

IV and R-A-CH3COR-, III

| wherein the symbols A, R, Ra and R2 have the same meaning as in formula I, X represents a Cl atom and Z represents an alkoxycarbonyl group, heating in the presence of phenol to form a compound of formula I.

To prepare substituted pyrroles of Formula I wherein A is an N atom, the amine of Formula IIIa, wherein R and R 1 have the same meaning as in Formula I, is reacted with a compound of Formula I. IVa,

J> i J

35 r 2 IVa • € 4 103277 wherein X represents a Cl or Br atom, R 5 represents a C 1-3 alkyl group, to provide a compound of formula V, 5 R N-CH 3 -COR 10 where R, R 11f and R 5 and B are similar to formulas IIIa and IVa, the latter compound being cyclized by the Dieckmann reaction by reacting with an organic or inorganic base such as 15 (C 2 H 5) 3 N, C 2 H 5 ONa, t-C 4 H 9 ONa, NaH or KOH in anhydrous solvent such as alcohol, ether (such as dioxane) or dimethylformamide, preferably at a temperature of 0-80 ° C.

When in the compound of formula I desired to be obtained, R is other than H, it is possible to substitute the pyrrole nitrogen of the corresponding compound of formula I wherein R is H by reacting it with a halide RX of a strong base such as NaH in a polar aprotic solvent or in a medium consisting of two phases in the presence of a phase transfer catalyst.

To provide thiophene compounds of formula I wherein A is an S atom, a substituted compound of formula HS-CH2CO3- [amine RNHCH3 -COR1 (formula IIIa) of si-30] is reacted with a compound of formula IV.

In order to provide compounds of formula I wherein Rx is a group NZ1Z2, it is possible to react the HNZ3Z2 amine with the corresponding ester under conditions conventional for the preparation of secondary or tertiary amides; however, it is preferred to allow the amide of formula III (RNHCH2-CONZ1Z2) to react 'directly with a compound of formula IV.

Coupled pyridines of Formula 5 — Nili

IV, prepared from amines I

by conventional methods such as those described in J. Med. Chem. 22, 816-823 (1979), through the corresponding hydroxylated derivatives of formula IV wherein X represents an OH group, for example, to give a compound wherein X represents a Cl atom by reaction with POCl3.

Compounds of Formula VIII, 15

OH

| VI11

Ro ^

20 L

wherein Z represents an ethoxycarbonyl or cyano group, may be prepared according to the following reaction scheme: H 5 CO 2 S-CO 2 CO 2

. 25 BHK2 ♦ 5 2 SC - C_ UI) ^ J1L> VIII

Rj 1 Rj 1

The first step is generally carried out in the absence of solvent, while the cyclization is carried out in a solvent having a very high boiling point, in Dowtherm R or in diphenyl ether.

• ·

Certain substituted compounds of formula V, which are derivatives of compounds of formula VIII, are described in EP-A-0 205 362 and 0 346 208. 35 Others may be prepared by similar procedures. One * 6,103,277 methods for preparing amino ketones of formula III are described in particular in Tetrahedron Letters 25 (1984) 2977-2980; aminoesters are known 1 compounds.

The compounds of Formula I may be used in compositions containing as active ingredient at least one compound of Formula I, or a salt thereof, with a pharmaceutically acceptable acid. Such compositions may: 10 contains a carrier which is conventionally i.

used orally, rectally or by intravenous or intramuscular injection of the formulation of the administrable pharmaceutical compositions.

* '

For oral administration in the form of tablets, gelatine capsules or granules, or even syrups, the unit dose is 5 to 200 mg, depending on the potency of the compound, i = n the nature of the disease being treated and the condition of the patient.

In the case of parenteral administration, water-soluble salts of the compounds of the formula I are preferably used (20 or, if not available, in composition i; products known as solubilising additives are added; the unit dose is then 1 to 30 mg per volume: = 1-5 cm 3).

i: The pharmaceutical compositions described above are administered to a human or animal for prophylactic or curative purposes to reduce or prevent the toxic effects of the presence of oxygen-containing free radicals and to treat the diseases resulting therefrom. The latter target various living organisms, and the compositions of the invention can be used to treat the effects of IZ, rheumatic diseases such as arthritis, lung diseases, cardiovascular diseases such as arteriosclerosis s or ischaemia, eye diseases such as cataracts, or even brain damage. (Including Alzheimer's disease - 35). For many of the potential therapeutic uses of these compounds, reference may be made to recent works and articles, in particular: Free Radicals in Molecular Biology, Aging and Disease, published by 5 Raven Press, New York, and the CRC Handbook of Free Radicals and Antioxidants in Biomedicine, published by CRC Press, Boca Raton, Florida, USA.

However, the therapeutic use of the compounds of formula I should not be limited to said indications; the compounds may be used for prophylactic or curative purposes in any situation where excess oxygen-containing free radicals may interfere with the normal physiological state.

The effect of the compounds of formula I on biological, oxygen-containing free radicals has been demonstrated in vitro and in vivo.

Their effect on the production of malonidial dehyde during the degradation of the endoperoxides resulting from the oxidation of polyunsaturated fatty acids contained in cell wall phospholipids in the presence of 20 iron salts has been studied in vitro. A conventional method such as that described in, for example, CRC Handbook of Methods for Oxygen Radical Research, CRC Press, Boca Raton, Florida, United States 1985, pp. 203-207 was used.

In vivo, these compounds were shown to inhibit the toxic effects of potassium cyanide in mice and to reduce the hyperglycemia of alloxan administration in mice.

In fact, it is generally recognized that cellular and neurological disorders during KCN-30 poisoning are the result not only of an increase in intracellular calcium but also of oxidation of the lipid walls of the brain cells, and in particular J. Med. Chem. 33: 1145-1151 (1990) 103277 and Arzneim. Forsch., Drug Research 39 (1989) 445-450, to demonstrate antioxidant activity in the brain.

It is further known that administration of an alloxan to an animal results in hyperglycemia due to the destruction of pancreatic beta cells caused by oxygen-containing radicals whose formation is triggered by the presence of alloxane, and has been demonstrated, in particular in Biochem. Pharmacol. 34: 3601-3603 (1985) and Fundamental Clinical

Pharmacology 3: 323-328 (1989) that several oxygen-containing free radical scavengers inhibit this hyperglycemia.

In the malonic aldehyde assay, the 50% inhibitory concentration (IC50) for the compounds of the invention is generally 0.1 to 10 μπιο1 / 1. In potassium cyanide 15, the effective dose 50 (ED 50) is about 2-30 mg / kg (intravenously) in mice, whereas in the alloxan test it is 0.1 to 10 mg / kg (intravenous) in mice.

The following are examples of the invention and, in some cases, a detailed process for their preparation.

Example 1

Ethyl 1H-8-chloro-3-hydroxypyrrolo [3,2-c] [1,5] naphthyridine-2-carboxylate (A = N, N in the pyridyl ring)

9-position and R 2 = c 1 which at 8-position R = H, R 2 = OC 2 H 5), 25 a) Ethyl (6-chloro-3-ethoxycarbonyl-1,5-naphthyridin-4-yl-2-amino) acetate to 4,6-dichloro-3-ethoxycarbonyl-1,5-naphthyridine (5.1 g) dissolved in ethanol (140 ml), and to the hydrochloride salt of glycine ethyl ester (2.65 g) are added 30 drops of triethylamine (5 ml). , 2 ml).

After the addition is complete, the reaction mixture is kept at reflux for 2 hours and then evaporated to dryness, the residue dissolved in dichloromethane and the organic phase washed with water and then dried. 1 f «9 103277

After removal of the solvent, the product is recrystallized from ethanol. Sp. 140 ° C (46% yield).

• b) To a solution of potassium t-butoxide (1.37 g) dissolved in t-butanol (25 ml) is added dropwise a solution of naphthyridine (3.84 g) dissolved in toluene (45 ml) under a small stream of nitrogen. and dimethylformamide (40 mL). The solution is stirred at room temperature overnight and then the reaction mixture is poured into a mixture of water and ice (150 ml). After neutralizing the aqueous phase, the expected product precipitates. Sp. 250 ° C (59% yield).

Examples of naphthyridine derivatives are listed in Table 1. _,,

Table 1 \ H / C0R1

15R

r2 ^ njT T

Pre- R? R Rl sp. (° c) character ^ Λ. Salt 20 2 K, β-Η (Ο, Β,), B OC, B, 92% X (CFjCOOH) 3 Oi "00.81 110 25 4 '» -Ow, CH1C'B1 190 • -O ** 11. »5 H OCjBj> 250 3 0 6 1« -06 "ϊ CB» °° 1η · 135 f 7 'H 150 8 1 i.iQ {e «, e, 1j H OCjHj 90 9 C« 1 OC, B, 220 35 10 '.-0 «» ^, », H OC, H, 230 11 1 CB, OC, H, 170 (CBjCOOR) 12 - B-Cl CB, N (C, H,), 231 10 103277 0 ("2 character (salt) 5 13 8 -N (C, n,), CH, N (C 1 H 1) 1B 8 14 '.-> 0.0.3 CB> 120 15 7-Cl H OC, H, > 250 10 16 H CHi 175 17 7-Cl HN (C, B7), 225 15 18 «7-Cl CH] N (C, H7) j 150

An example of a thienonaphthyridine derivative is shown in Table 2.

Table 2 _ .CORj ^ € ö ".

30 R1 R2 Sp.

• i «1- ¢ 1.

· _ Sign 0C, Hs | - {k, c- (Ok-I> 250 19 12 <jL.

Claims (3)

103277 A process for the preparation of therapeutically useful pyrrolo and thieno [3,2-c] naphthyridine derivatives of the formula (I), or salts thereof with an acid or a base thereof, wherein: in the formula R 2 is a lower alkoxy group or a group -N (C 1-6 alkyl) 2, A is S where R is nothing, or A is N where R is H or C 1-6 alkyl which may be substituted by phenyl, R 2 is hydrogen, halogen, -N (C 1 -C 4 alkyl) 2 or NZ 3 Z; wherein Z 1, Z 2 and N together form a piperazine ring optionally substituted on its nitrogen atom with C 1-8 alkyl, benzyl or diphenylmethyl, known wherein (a) a compound of formula II wherein R, Rx and R2 have the same meaning as above and Z is an alkoxycarbonyl group is cyclized by the Dieckmann reaction to form a compound of formula (I). -35 compounds, or 1 103277 b) compounds of formulas III and IV X! 5 Ϊ: 5151 / Ζ IV and R-A-CHaCORj. In which formulas, A, R, Rx and R2 have the same meaning as above, X is Cl and Z is an alkoxycarbonyl group, is heated in the presence of phenol to form a compound of formula (I). Process for the preparation of compounds of formula 15 (I) or salts thereof according to claim 1, characterized in that a compound according to formula - Ia R COR '1 - ^ 1 / V 2 in the formula, the symbols R and Rx have the same meaning as in claim 1 and Z2 and Z2 together with the nitrogen atom to which they are attached form a piperazine ring which may be substituted on its nitrogen atom by C1-6 alkyl, benzyl or diphenylmethyl 1 ~ 30 in style. Process according to claim 1 or 2, characterized in that a compound of the formula I is prepared wherein Rx is -O-C2H5. 103277