SK52003A3 - Colchinol derivatives as angiogenesis inhibitors, method for their preparation and pharmaceutical composition comprising the same - Google Patents

Abstract

The invention related to colchinol derivatives of the formula (I): Wherein: R<1>, R<2> and R<3> are each independently hydroxy, phosphoryloxy (-OPO3H2), C1-4alkoxy or an in vivo hydrolysable ester of hydroxy, with the proviso that at least 2 of R<1>, R<2> and R<3> are C1-4alkoxy; A is -CO-, -C(O)O-, -CON(R<8>)- (wherein R<8> is hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl, aminoC1-3alkyl or hydroxyC1-3alkyl); a is an integer from 1 to 4 inclusive; R<a> and R<b> are independently selected from hydrogen, hydroxy and amino; B is -O-, -CO-, N(R<9>)CO-, -CON(R<9>)-, -N(R<9>)C(O)O-, -N(R<9>)CON(R<10>)-, -N(R<9>)SO2-, -SO2N(R<9>)- or a direct single blond (wherein R<9> and R<10> are independently selected from hydrogen, C1-4alkyl, C1-3alkoxyC1-3alkyl,aminoC1-3alkyl and hydroxyC1-3alkyl); b is O or an integer from 1 to 4 inclusive, (provided that when bis O, B is a single direct bond); D is carboxy, sulpho, tetrazolyl, imidazolyl, phosphoryloxy, hydroxy, amino, N-(C1-4alkyl)amino, N,N-di(C1-3alkyl)amino, or of the formula-Y<1>(CH2)0R<11> or -NHCH(R<12>)COOH;[wherein Y<1> is a direct single bond, -O-, -C(O)-, -N(R<13>)C(O)- or -C(O)N(R<13>)- (wherein R<13> is hydrogen, C1-4alkyl,C1-3alkoxyC2-3alkyl, aminoC2-3alkyl or hydroxyC2-3alkyl); e is O or an integer from 1 to 4 inclusive.

Description

Colchinol derivatives as angiogenesis inhibitors, process for their preparation and pharmaceutical composition containing them

Technical field

The present invention relates to vascular damaging agents, the use of the compounds of the present invention for the preparation of medicaments for obtaining an anti-angiogenic effect in warm-blooded animals, such as man, methods of preparing such compounds, pharmaceutical compositions containing these compounds as active ingredients, methods for treating disease states associated with angiogenesis and use of these compounds as medicaments.

BACKGROUND OF THE INVENTION

Normal angiogenesis plays an important role in various processes, including embryonic development, wound healing and various components of reproductive function in women. Undesirable or pathological angiogenesis has been associated with disease states such as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma (Fan et al., Trends Pharmacol. Sci. 16, 57-66 (1995); Folkman, Nature Medicine 1, 27-31 (1995)). The emergence of new vasculature through angiogenesis is a key pathological element of several diseases (Folkman, New England Journal of Medicine 333, 1757-1763 (1995)).

For example, in order to grow solid tumors, their own blood supply must be developed, on which the supply of oxygen and nutrients is critical; if this blood supply is mechanically cut off, necrotic death occurs in the case of a tumor. Neovascularization is also a clinical factor of skin lesions in psoriasis, invasive panus in the joints of patients with rheumatoid arthritis and patients with atherosclerotic plaque. Retinal neovascularization is pathological in the case of macular degeneration and diabetic retinopathy.

Reversal of neovascularization by damage to the emerging vascular endothelium is expected to have a significant therapeutic effect. The present invention is based on the discovery of tricyclic compounds that surprisingly specifically damage newly emerging vasculature without affecting the normal already established vascular endothelium of the patient, which is important in the treatment of angiogenesis-related conditions such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune disease, acute inflammation, endometriosis, uterine bleeding dysfunction, and ocular retinal vascular diseases.

The compounds of the present invention are colquinol derivatives. Colquinol derivatives, for example N-acetylcolquinol, are known. The antitumor effect has been reported in animal models (see, for example, J. Natl. Cancer Inst., 13, 379-392 (1952)). However, the effect studied was general impairment (bleeding, softening and necrosis) and therefore there is no indication of treatment of unwanted angiogenesis by destruction of neovasculature.

It is believed (although not limited to the scope of the present invention) that the use of the compounds of the present invention will damage newly formed vasculature, such as tumor vasculature, thereby effectively reversing the process of angiogenesis compared to known anti-angiogenic agents, which

less effective when the vasculature is already established.

SUMMARY OF THE INVENTION

According to a first aspect, the present invention provides a compound of formula I

where:

R ¹ , R ² and R ³ are independently hydroxyl, phosphoryloxy (-OPO 3 H 2), (C 1 -C 4) alkoxy or in vivo hydrolysable esterified hydroxyl, provided that at least two of R ¹ , R ² and R ³ is an alkoxy group having 1 to 4 carbon atoms;

A is -C0-, -C (0) 0-, -CON (R ⁸⁾ -, -SO2- or a group -SO 2 N (R ⁸⁾ - (wherein R ⁸ is H, alkyl of 1 up to 4 carbon atoms, alkoxyalkyl having 1 to 3 carbon atoms in the alkoxy moiety as well as in the alkyl moiety, 1 to 3 carbon atoms aminoalkyl or 1 to 3 carbon hydroxy groups);

a is an integer from 1 to 4 inclusive;

R ^a and R ^b are independently selected from the group consisting of hydrogen, hydroxyl and amino;

B is --O--, --CO--, --N (R @ ⁹ ) - CO--, --CON (R @ ⁹ ) -, --O (O) - O -, --N (R @ ⁹ ) -, - -N (R ⁹ ) C (O) O-, -N (R ⁹ ) CON (R ¹⁰ ) -, -N (R ⁹ ) SO ₂ -, -SO ₂ N (R ⁹ ) - or direct, single a bond (wherein R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, C 1 -C 3 alkyl, up to 3 carbon atoms and a hydroxyalkyl group containing 1 to 3 carbon atoms);

b is 0 or an integer from 1 to 4 inclusive, (provided that when b is 0, B is a single direct bond);

D is a carboxyl group, a sulfo group, a tetrazolyl group, an imidazolyl group, a phosphoryloxy group, a hydroxyl group, an amino group, an N- (alkyl) amino group having 1 to 4 carbon atoms, an N, N-di (alkyl) amino group having 1 to 3 in each alkyl moiety carbon atoms or a group of the formula Y ¹ - (CH 2) ⁿ R _c, or -NHCH (R ¹²⁾ COOH; [wherein Y ¹ is a direct single bond, -O-, -O (O) -, -N (R ¹³ ) -, -N (R ¹³ ) C (O) -, or -C (O) N (R ¹³ ) (wherein R ¹³ is hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, C 1 -C 3 alkyl, C 2 -C 3 aminoalkyl, or C 1-4 hydroxyalkyl 2 to 3 carbon atoms); c is 0 or an integer from 1 to 4 inclusive; R ¹¹ is a 5- to 6-membered saturated heterocyclic group (bonded via a carbon or nitrogen atom) containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or a 5- to 6-membered unsaturated or partially an unsaturated heteroaryl group (bonded via a carbon or nitrogen atom) containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the heterocyclic group or heteroaryl group may carry one or two substituents selected from a group consisting of:

oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, carbamoyl, N- (C 1 -C 5) carbamoyl C 1 -C 4 alkyl, N, N -di (alkyl) carbamoyl group containing from 1 to 4 carbon atoms in each alkyl moiety, hydroxy group containing from 1 to 4 carbon atoms, alkoxy group containing from 1 to 4 carbon atoms, cyanoalkyl group containing from 1 to 3 carbon atoms, carbamoylalkyl group containing in the alkyl portion of 1 to 3 carbon atoms, a carboxyalkyl group containing in the alkyl portion of 1 to 4 carbon atoms, an aminoalkyl group of 1 to 4 carbon atoms, an N- (alkyl) aminoalkyl group containing in each alkyl portion of 1 to 4 carbon atoms, N, N-di (alkyl) aminoalkyl having 1 to 4 carbon atoms in each alkyl moiety; containing from 1 to 4 carbon atoms in both the alkoxy moiety and the alkyl moiety, an alkylsulfonylalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety and a group R ¹⁴ (wherein R ¹⁴ is a 5- to 6-membered saturated heterocyclic group (bonded via carbon or nitrogen)) containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the heterocyclic group is optionally substituted with one or two substituents independently selected from the group consisting of:

oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkyl, and C 1 -C 4 alkyl. and an alkylsulfonylalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety);

R ¹² is an amino acid side chain;

R ⁵ is an alkoxy group having 1 to 4 carbon atoms;

R ⁴ and R ⁶ are independently selected from the group consisting of:

a hydrogen atom, a fluorine atom, a nitro group, an amino group, a C 1-4 alkyl group, a N, N-di (alkyl) amino group having 1-4 carbon atoms in each alkyl moiety, a hydroxyl group, a 1-alkoxy group up to 4 carbon atoms and an alkyl group containing 1 to 4 carbon atoms;

R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, or C 1 -C 3 hydroxyalkyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In a further aspect, the present invention relates to a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof.

As used herein, the term &quot; alkyl &quot; means both straight and branched chain alkyl. However, references to individual groups such as "propyl" are specific for the straight-chain version only, and references to individual branched alkyl groups such as "isopropyl" are specific for the branched chain versions only. An analogous rule applies to all other general terms.

R ¹² is an amino acid side chain. This includes side chains derived from natural and artificial amino acids and includes the possibility of attaching R ¹² to the -NH- group to form a ring, as is the case with proline amino acid. Includes α-amino acids, β-amino acids and γ-amino acids. In addition, the amino acids may be L-isomers or D-isomers, but preferably L-isomers. Preferred amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparaginine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, histidine, histidine, histidine, histidine, histidine, histidine, and ornithine. More preferably, the amino acids include glutamic acid, serine, threonine, arginine, glycine, alanine, β-alanine and lysine. Particularly preferred amino acids include glutamic acid, serine, tr'eonine, arginine, alanine and β-alanine. Particular values of R ¹² include hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylthioalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 thioalkyl, phenylalkyl (1-4C) alkyl (optionally substituted with hydroxyl), (1-4C) alkyl guanidinoalkyl, (1-4C) alkylcarboxyalkyl, (1-4C) carbamoylalkyl carbon atoms, aminoalkyl having 1 to 4 carbon atoms and imidazolylalkylová group having the alkyl moiety with 1 to 4 carbon atoms and R ¹² forming a pyrrolidinyl ring with the NH group. Preferred values for R ¹² include hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkylthioalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 thioalkyl, C1-C4 guanidinoalkyl, C1-C4 carboxyalkyl, C1-C4 carbamoylalkyl and C1-C4 aminoalkyl.

It is to be understood that if certain compounds of formula I as defined herein may exist in optically active or racemic forms because of the presence of one or more asymmetric carbon atoms, the present invention includes within its definition any such optically active forms which are active. in terms of vascular damage. The synthesis of optically active forms can be carried out by standard procedures known to those skilled in the art of organic chemistry, for example by synthesis from optically active starting materials or by resolution of racemic forms. Similarly, the above activity can be evaluated using conventional laboratory techniques described below.

Suitable meanings of the foregoing general groups include those set forth below. According to the present invention, it is understood that the compound of formula I or a salt thereof may be characterized by the phenomenon of tautomerism and that the representations of the formulas in this specification may represent only one tautomeric form. It is to be understood that the present invention encompasses all tautomeric forms having vascular damaging activity and is not limited to the single tautomeric form used to represent the formulas.

It is also to be understood that certain compounds of formula I and their salts may exist in solvated as well as unsolvated forms such as hydrated forms. It is also to be understood that the present invention encompasses all such solvated forms which are active in vascular damage.

The present invention relates to the compounds of formula I as defined hereinbefore and to their salts. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be used in the preparation of the compounds of formula I and their pharmaceutically acceptable salts. ^{For example, the} pharmaceutically acceptable salts of the present invention may include acid addition salts of the compounds of formula I as hereinbefore defined which are sufficiently basic to form salts. Such acid addition salts include, for example, salts with inorganic or organic acids providing pharmaceutically acceptable anions such as hydrohalides (especially hydrochloric acid and hydrobromic acid, of which hydrochloric acid is particularly preferred) or sulfuric or phosphoric acid, or trifluoroacetic acid, citric acid or maleic acid.

Suitable salts include hydrochlorides, hydrobromides, phosphates, sulfates, hydrogensulfates, alkylsulfonates, arylsulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates and tartrates. In addition, if the compounds of formula I are sufficiently acidic, pharmaceutically acceptable salts may be prepared with inorganic or organic bases which provide a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include, for example, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris ( 2-hydroxyethyl) amine.

Various forms of prodrugs are known to those skilled in the art. Examples of these prodrugs can be found, for example, in:

a) Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985, and Methods in Enzymology, Vol. 42, K. Widder et al. Eds. , Academic Press, 1985, p. 309-396;

b) A Textbook of Drug Design and Development, Krogsgaard-Larsen & H. Bundgaard Eds., Chapter 5, H. Bundgaard, Design and Application of Prodrugs, 1991, p. 113-191;

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8: 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e) N. Kakeya, et al., Chem. Pharm. Bul., 32, 692 (1984).

Examples of such prodrugs can be used to prepare in vivo cleavable esters of compounds of Formula I. In vivo cleavable esters of compounds of Formula I containing a carboxyl group are, for example, pharmaceutically acceptable esters that cleave in the human or animal body to give the parent acid. Suitable pharmaceutically acceptable esters include, for example: alkoxymethyl esters having 1 to 6 carbon atoms in the alkoxy moiety, for example methoxymethyl esters; alkanoyloxymethyl esters having 1 to 6 carbon atoms in the alkanoyl moiety, for example pivaloyloxymethyl esters; phthalidyl esters; cycloalkoxycarbonyloxyalkyl esters having 3 to 8 carbon atoms in the cycloalkoxy moiety and 1 to 6 carbon atoms in the alkyl moiety, for example, 1-cyclohexylcarbonyloxyethyl ester; 1,3-dioxolan-2-ylmethyl esters, for example 5-methyl-1,3-dioxolan-2-ylmethyl ester; and alkoxycarbonyloxyethyl esters having 1 to 6 carbon atoms in the alkoxy moiety, for example, 1-methoxycarbonyloxyethyl ester; and may be formed at any carboxyl group of the compounds of the present invention.

Suitable values for R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹³ or for various substituents on D or R ¹⁴ include:

for a halogen atom: a fluorine atom, a chlorine atom, a bromine atom and an iodine atom;

for (1-4C) alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;

for N- (1-4C) alkyl: methylamino, ethylamino, propylamino, isopropylamino and butylamino;

for N, N-di (alkyl) amino having 1 to 4 carbon atoms in each alkyl moiety: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino;

for (C 2 -C 4) alkanoyl: acetyl and propionyl;

for (1-4C) alkoxy: methoxy and ethoxy;

for a cyanoalkyl group having 1 to 4 carbon atoms: a kya11 nomethyl group and a 2-cyanoethyl group;

for N- (alkyl) carbamoyl having 1 to 4 carbon atoms in the alkyl moiety: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl;

for N, N-di (alkyl) carbamoyl having 1 to 4 carbon atoms in each alkyl moiety: N, N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N, N-diethylcarbamoyl;

for (1-4C) alkylsulfonylalkyl: methylsulfonylmethyl and ethylsulfonylmethyl;

for (1-4C) hydroxyalkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl as appropriate;

for alkoxyalkyl having 1 to 4 carbon atoms in both the alkoxy moiety and the alkyl moiety: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl, as appropriate;

for (1-4C) aminoalkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl as appropriate;

for N- (alkyl) aminoalkyl having 1 to 4 carbon atoms in each alkyl moiety: methylaminomethyl, ethyls, nomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl as appropriate;

for N, N-di (alkyl) aminoalkyl having 1 to 4 carbon atoms in each alkyl moiety: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl,

2-dimethylaminoethyl and 3-dimethylaminopropyl as appropriate;

for a carboxyalkyl group having from 1 to 4 carbon atoms in the alkyl moiety: carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl and 4-carboxybutyl;

for a carbamoylalkyl group having 1 to 4 carbon atoms in the alkyl moiety: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl;

for alkoxyalkyl having 1 to 4 carbon atoms in both the alkoxy moiety and the alkyl moiety: methoxymethyl, ethoxyethyl, methoxyethyl and methoxypropyl.

Carbamoyl means -CONH2.

Piperazino means piperazin-1-yl.

Examples of five or six membered saturated heterocyclic groups are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.

Examples of five- or six-membered unsaturated or partially unsaturated heteroaryl groups are imidazolyl, imidazolinyl, pyridyl, pyrrolyl, furyl, triazolyl, pyrazinyl, pyrazolinyl, pyrimidinyl, pyridazinyl, isoxazolyl, isoxazolyl, isoxazolyl thiazolyl and thienyl.

Preferably at least two of R ¹ , R ² and R ³ are methoxy.

Preferably, R ¹ , R ² and R ^{3 are} all C 1 -C 4 alkoxy.

Most preferably, R ^1, R ² and R ³ all methoxy.

Preferably, R ⁸ is a hydrogen atom, a methyl group, an ethyl group, a 2-methoxyethyl group, a 2-aminoethyl group or a 2-hydroxyethyl group.

More preferably, R ⁸ is hydrogen, 2-aminoethyl or 2-hydroxyethyl, and most preferably R ⁸ is hydrogen.

Preferably A is a group -C0-, -C (0) 0- or-CON (R ⁸⁾ -. Most preferably, A is -C (O) O-.

Preferably, α is 1, 2 or 3, and most preferably α is 2 or 3.

Preferably R ^a and R ^b are hydrogen atoms.

Preferably, B is -N (R ⁹ ) CO-, -CON (R ⁹ ), -0 (O) O-, -N (R ⁹ ) -, -N (R ⁹ ) C (O) O-, -N (R ⁹ ) CON (R ¹⁰ ) - or a single direct bond.

Most preferably B is -C0-, -N (R ⁹⁾ -CO- or a single direct bond.

Even more preferably, the B group is -CO- or a single direct bond.

Most preferably, B is -CO-. In another aspect, B is a single direct bond.

Preferably, R ⁹ and R ^{10 are} independently selected from the group consisting of hydrogen, methyl, ethyl, 2-methoxyethyl, 2-aminoethyl and 2-hydroxyethyl.

More preferably, R ⁹ and R ^{10 are} independently selected from the group consisting of hydrogen, 2-aminoethyl and 2-hydroxyethyl.

Most preferably, R ⁹ and R ^{10 are} hydrogen.

Preferably, b is 0, 1 or 2, more preferably b is 0 or 1, and most preferably b is 0.

Preferably, R ^{11 is a} five-membered or six-membered saturated heterocyclic ring containing 1 or 2 ring heteroatoms selected from nitrogen and oxygen.

Most preferably, R ^{11 is a} six membered saturated heterocyclic ring containing 1 or 2 ring heteroatoms selected from nitrogen and oxygen.

Further preferably, R ¹¹ contains at least one ring nitrogen atom.

Further preferably R ^{11 is} piperazinyl, morpholinyl or piperidyl, each of which is bonded via a ring carbon atom or a ring nitrogen atom and each ring is optionally substituted with one or two substituents already mentioned for R ¹¹ .

Further preferably, R ^{11 is} attached via a ring nitrogen atom.

Most preferably, R ^{11 is} piperazino or morpholino, each ring optionally substituted with one or two substituents already mentioned for R ¹¹ .

The saturated heterocyclic ring may be substituted at the ring carbon atom or ring nitrogen atom provided that this does not result in quaternization.

Preferred substituents for the saturated heterocyclic rings in R ¹¹ are C 1-4 alkyl, C 2-4 alkanoyl, C 1-4 carbamoyl, C 1-3 cyanoalkyl, C 1 alkyl hydroxyalkyl C 3 to C 3, a carboxyalkyl group having 1 to 3 carbon atoms in the alkyl moiety, and an aminoalkyl group having from 1 to 3 carbon atoms.

More preferred substituents for the saturated heterocyclic rings in R ¹¹ are C 1 -C 3 alkyl, C 2 -C 3 alkanoyl, carbamoyl, and C 2 -C 3 hydroxyalkyl.

Even more preferred substituents for the saturated heterocyclic rings in R ¹¹ are methyl, acetyl, carbamoyl, and 2-hydroxyethyl.

Most preferred substituents for saturated heterocyclic rings are methyl, acetyl, and carbamoyl.

Preferably, the saturated heterocyclic ring in R ^{11 is} unsubstituted or substituted with one substituent.

When the saturated heterocyclic ring in R ¹¹ is morpholino, preferably it is unsubstituted. If the saturated heterocyclic ring in R ^{11 is a} piperazino group, it is preferably unsubstituted or substituted with one substituent on the ring nitrogen atom.

Y ¹ is preferably -CONH- or -NHCO-.

Preferably it is at 0, 1 or 2.

More preferably, c is 0.

Preferred meanings of R ¹¹ include morpholino, 4-methylpiperazin-1-yl and 4-acetylpiperazin-1-yl.

R ¹⁴ is preferably morpholino or piperazin-1-yl, each optionally substituted with one or two substituents selected from the group consisting of alkyl having 1 to 3 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 3 carbon atoms 3 carbon atoms and an alkoxyalkyl group containing 1 to 3 carbon atoms in both the alkoxy moiety and the alkyl moiety.

More preferably, R ¹⁴ is morpholino or piperazin-l-yl, unsubstituted or substituted by methyl.

D is preferably a carboxyl group, a phosphoryloxy group, a hydroxyl group, an amino group, a N- (alkyl) amino group having 1 to 4 carbon atoms, an N, N-di (alkyl) amino group having 1 to 4 carbon atoms in each alkyl moiety, or a group of the formula -Y ¹ (CH 2) ⁿ R _c / wherein Y ^1, c and R ¹¹ are as hereinabove defined.

More preferably D is carboxy, phosphoryloxy, hydroxy, amino or a group of the formula Y ¹ - (CH ₂₎ c R ^11, wherein Y ^1, c and R ¹¹ are as hereinabove defined.

More preferably, D is phosphoryloxy, amino or of the formula Y ¹ - (CH ₂₎ c R ¹¹ / wherein Y ^1, c and R ¹¹ are as hereinabove defined.

More preferably D is phosphoryloxy, amino or of the formula Y ¹ - (CH 2) c R ^V, wherein Y ¹ and c are as hereinabove defined and R ¹¹ is morpholino, imidazolyl, or piperazinyl, wherein the heterocyclic group is carry one or more substituents as defined herein.

Even more preferably, D is phosphoryloxy, amino, or -Y ¹ - (CH ₂ ) _c ^{-R 11} wherein Y ¹ and c are as defined herein, and R ¹¹ is morpholino, imidazolyl, 4-methylpiperazine-1- or 4-acetylpiperazin-1-yl.

More preferably D is phosphoryloxy, amino or of the formula Y ¹ - (CH 2) c R ^11, wherein Y ¹ is a direct single bond, and c is 0 and R ¹¹ is morpholino, imidazol-yl, 4-methylpiperazin-l- or 4-acetylpiperazin-1-yl.

R ⁵ is preferably methoxy.

R ⁴ and R ⁶ are preferably independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 3 alkoxy and C 1 -C 3 alkyl. 1 to 3 carbon atoms.

More preferably, at least one of R ⁴ and R ⁶ is hydrogen. Most preferably, R ⁴ and R ^{6 are} both hydrogen.

R ⁷ is preferably a hydrogen atom or a methyl group. Most preferably, R ⁷ is hydrogen.

A preferred class of compounds are those compounds of formula I wherein:

R ¹ , R ^2, and R ³ are all C 1 -C 4 alkoxy;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms and alkyl of 1 to 3 carbon atoms;

R ⁵ is methoxy;

A is -CO-, -C (O) O-, or -COH-;

a is 1, 2 or 3;

B is -CO-, -NHCO-, -CONH-, -O (O) O-, -NH-, -NHC (O) O-, -NHCONH or a single direct bond;

b is 0, 1 or 2;

D is a carboxyl group, a sulfo group, a phosphoryloxy group, a hydroxyl group, an amino group, an N- (alkyl) amino group containing from 1 to 4 carbon atoms, an N, N-di (alkyl) amino group containing from 1 to 4 carbon atoms in each alkyl moiety; of formula -Y ¹ (CH ₂ ) c R ¹¹ (wherein Y ¹ is -NHCO- or -CONH-; c is 1 or 2; R ¹¹ is a 5- to 6-membered saturated heterocyclic group (bonded via a nitrogen atom) containing 1 or 2 ring heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclic group may carry one or two substituents selected from the group consisting of C 1-4 alkyl, C 2-4 alkanoyl, carbamoyl, cyanoalkyl a group having 1 to 3 carbon atoms in the alkyl moiety, a hydroxy group having 1 to 3 carbon atoms, a carboxyalkyl group containing having 1 to 3 carbon atoms in the alkyl moiety and 1 to 3 carbon aminoalkyl groups);

R ⁷ is hydrogen;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class are compounds of formula I wherein:

R ¹ , R ² and R ³ are all methoxy;

R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, hydroxyl, methoxy and methyl;

R ⁵ is methoxy;

A is -CO-, -C (O) O-, or -CONK-;

a is 2 or 3;

B is -CO-, -NHCO-, -CONH- or a direct single bond;

b is 0 or 1;

D is a carboxyl group, a phosphoryloxy group, a hydroxyl group, an amino group, a N- (alkyl) amino group having 1 to 4 carbon atoms, an N, N-di (alkyl) amino group having 1 to 4 carbon atoms in each alkyl moiety, or a group. all of I of the formula -Y ¹ (CH ₂ ) c R ¹¹ (wherein Y ¹ is -NHC (O) -or -C (O) NH-; c is 1 or 2; R ¹¹ is piperazinyl, morpholinyl or a piperidyl group, each of which is attached via a ring nitrogen atom and each ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, C 2-4 alkanoyl, carbamoyl a cyanoalkyl group having 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a carboxyalkyl group having 1 to 3 carbon atoms in the alkyl portion, and an aminoalkyl group having 1 to 3 carbon atoms);

R ⁷ is hydrogen;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class of compounds are those of Formula II

MeO

MeO

l · · H H |

NH-A- _{(CH2), and} -B- _{(CH2) b-D}

IIθ (II) wherein a, b, A, B and D are the same as defined herein;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class of compounds are those compounds of formula (II) wherein:

A is -CO-, -C (O) O-, or -CONH-;

a is 2 or 3;

B is -CO-, -NHCO-, -CONH- or a single direct bond;

I b is 0 or 1;

D is a carboxyl group, a phosphoryloxy group, a hydroxyl group, an amino group, a C 1-4 alkyl group, an N, N-di (alkyl) amino group having 1-4 carbon atoms in each alkyl moiety, or a group of the formula -Y ¹ (CH 2) _c R ¹¹ (wherein Y ¹ is -NHC (O) - or -C (O) NH-; c is 1 or 2; R ¹¹ is piperazinyl, morpholinyl or piperidyl, each of they are bonded via a nitrogen atom and each ring is optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, C 2-4 alkanoyl, carbamoyl, cyanoalkyl 1 of the alkyl moiety 1 (C 3-C 3), (C hydroxy-C hydroxy) hydroxyalkyl, (C až-C kar) carboxyalkyl, and (Calkyl-C amino) alkyl; and 1 to 3 carbon atoms);

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class of compounds are those compounds of formula (II) wherein:

A is -CO-, -C (O) O-, or -CONH-;

a is 2 or 3;

B is -CO-, -NHCO-, -CONH or a single direct bond;

b is 0 or 1;

D is phosphoryloxy, carboxyl, amino or imidazolyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class of compounds are compounds of the general formula

of formula II, where: A is a group -CO-, -C (O) O-, or -CONH-; and is 2 or 3; B is a group ba; -CO-, -NHCO- or a single direct bond b is 0 or 1;

D is phosphoryloxy, amino or imidazolyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. .

Another preferred class of compounds of the present invention are those of Formula III

where:

R ¹ , R ² and R ³ are independently hydroxyl, phosphoryloxy (-OPO 3 H 2), C 1 -C 4 alkoxy or in vivo hydrolysable esterified hydroxyl, provided that at least two of R ¹ , R ² and R ³ is C 1 -C 4 alkoxy;

A is -C0-, -C (0) 0-, -CON (R ⁸⁾ -, -SO2- or a group -SO 2 N (R ⁸⁾ - (wherein R ⁸ is H, alkyl of 1 1-4 carbon atoms, alkoxyalkyl having 1 to 3 carbon atoms in the alkoxy moiety and 2 to 3 carbon atoms in the alkyl moiety, 2 to 3 carbon atoms aminoalkyl or 2 to 3 carbon atoms hydroxyalkyl);

a is an integer from 1 to 4 inclusive;

R ^a and R ^b are independently selected from the group consisting of hydrogen, hydroxyl and amino;

B is -0-, -C0- group, -N ^(R9) CO-, -CON (R ⁹⁾ -, -C (0) 0-, -N (R ⁹⁾ -, R -N (R ⁹ ) C (O) O-, -N (R ⁹ ) CON (R ¹⁰ ) -, -N (R ⁹ ) SO ₂ -, -SO ₂ N (R ⁹ ) - or single a direct bond (wherein R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, and C 2 -C 3 alkyl moiety , an aminoalkyl group having 2 to 3 carbon atoms and a hydroxyalkyl group having 2 to 3 carbon atoms);

b is 0 or an integer from 1 to 4 inclusive;

D is a 5- to 6-membered saturated heterocyclic group bonded via a carbon or nitrogen atom containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen and nitrogen, wherein the heterocyclic group may carry one or two substituents selected from the group consisting of forms:

oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, carbamoyl, N- (C 1 -C 4 alkyl) carbamoyl, N, N- a di (alkyl) carbamoyl group having from 1 to 4 carbon atoms in each alkyl moiety, a hydroxyalkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms _,; (C 1 -C 3) -alkyl cyanoalkyl, (C 1 -C 3) -carbamcylalkyl, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkyl, N- (alkyl) ) aminoalkyl group containing 1 to 4 carbon atoms in each alkyl moiety, N, N-di (alkyl) aminoalkyl group containing 1 to 4 carbon atoms in each alkyl moiety, alkoxyalkyl group containing 1 to 4 carbon atoms in both the alkoxy moiety and the alkyl moiety , an alkylsulfonylalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety and a group R ¹⁴ (wherein R ¹⁴ is a 5- to 6-membered saturated heterocyclic group bonded via a carbon or nitrogen atom containing 1 or 2 ring heteroatoms independently selected from the group consisting of an oxygen atom and a nitrogen atom, wherein the heterocyclic group is hydrogen the pin is optionally substituted with one or two substituents selected from the group consisting of;

oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkyl and C 1 -C 4 alkyl; and an alkylsulfonylalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety;

R ⁵ is an alkoxy group having 1 to 4 carbon atoms;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, halogen, nitro, amino, N- (alkyl) amino containing 1 to 4 carbon atoms, N, N-di (alkyl) amino containing in each (C časti-C alky) alkyl moiety, hydroxyl, (C alko-C alko) alkoxy and (C až-C alkyl) alkyl;

R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, or C 1 -C 3 hydroxyalkyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class of compounds are those compounds of formula III wherein:

R ¹ , R ^2, and R ³ are all C 1 -C 4 alkoxy;

R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms and alkyl of 1 to 3 carbon atoms;

R ⁵ is methoxy;

A is -CO-, -O (O) O-, or -CONH-;

a is 1, 2 or 3;

B is -CO-, -NHCO-, -CONH, -C (O) O-, -NH-, -NHC (O) O-, -NHCONH or a direct single bond;

b is 0, 1 or 2;

D is piperazinyl or morpholinyl or piperidyl, each optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, C 2-4 alkanoyl, carbamoyl, cyanoalkyl a C 1-3 alkyl group, a C 1-3 hydroxyalkyl group, a C 1-3 alkyl carboxyalkyl group, and a C 1-3 alkyl aminoalkyl group;

R ⁷ is hydrogen;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class of compounds are those compounds of formula III wherein:

R ¹ , R ² and R ³ are all methoxy;

R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, hydroxyl, methoxy and methyl;

R ⁵ is methoxy;

A is -CO-, -C (O) O-, or -CONH-;

a is 2 or 3;

B is -00-, -NHCO-, -CONH, or a single direct bond;

b is 0 or 1;

D is piperazino or morpholino, each ring optionally substituted with one or two substituents selected from the group consisting of methyl, ethyl, acetyl, propionyl, carbamyl and 2-hydroxyethyl;

R ⁷ is hydrogen;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, the present invention relates to compounds of formula IV

wherein a, b, A, B and D are as defined hereinbefore for compounds of Formula III;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another advantageous class of compounds are compounds of of formula IV, where: A is -CO-, -C (O) O- or - • CONH-; and is 2 or 3; B is -CO-, -NHCO-, -CONH- or one-

direct bond;

b is 0 or 1;

D is piperazino or morpholino wherein each ring is optionally substituted with one or two substituents selected from the group consisting of methyl, ethyl, acetyl, propionyl, carbamoyl, and 2-hydroxyethyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class are compounds of formula IV wherein:

A is a group -00-, -C (O) O- or -CONH-; and is a 2 or 3; B is a -C0-, -NHCO- -CONH or one

spiritual bond;

b is 0 or 1;

D is morpholino, 4-methylpiperazin-1-yl or

4-acetylpiperazin-1-yl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another preferred class are compounds of formula IV,

A is -CO-, -C (O) O-, or -CONH-;

a is 2 or 3;

B is -CO- or a single direct bond;

I b is 0;

D is morpholino, 4-methylpiperazin-1-yl or

4-acetylpiperazin-1-yl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Particularly preferred compounds of the present invention include:

N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl] -2- [2-aminoacetylamino] acetamide;

Disodium 4-oxo-4 - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] amino] butylphosphate;

N- (N- [2- (imidazol-1-yl) ethyl] carbamoyl} -5 (S) -3,9,10,11-terramethoxy-β, 7-dihydro-5 H -dibenzo [a, c] cycloheptene 5-Ylamine, α - {N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamoyloxy} ethyl disodium phosphate ;

and pharmaceutically acceptable salts, solvates or prodrugs thereof.

Other particularly preferred compounds of the present invention are:

2-morpholinoethyl N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydroc-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate;

3- (1-methylpiperazin-4-yl) propyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate;

N- [(5S) -3,9,9,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] 29

cycloheptene-5-yl] -2- (2-amino-acetylamino) acetamide;

2- (1-acetylpiperazin-4-yl) ethyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate;

N - [(5S) -3,9,10,11-tetramethoxy-6-7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] -4- (1-methylpiperazine-4- yl) -4-oxobutan-l-amide;

Disodium 4-oxo-4 - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl] amino] butyl phosphate;

N- {N- [2- (imidazol-1-yl) ethyl] carbamoyl} -5 (S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-ylamine;

3- (1-Acetylpiperazin-4-yl) propyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate;

Disodium N-1 - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamoyloxy] ethyl phosphate;

4-morpholino-4-oxobutyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate; and

4- (1-methylpiperazin-4-yl) -4-oxobutyl-N - [(5S) -3,9,10,11-terramethoxy-6,7-dihydro-5H-dibenzo [a, c] cycloheptene -5-yl) carbamar;

and pharmaceutically acceptable salts, solvates or prodrugs thereof.

Synthesis of compounds of formula I

The compounds of formula (I) may be prepared by a number of methods generally described in the next section of the present invention and in more detail in the following examples. Processes for the preparation of the novel compounds of formula (I) are presented as a further feature of the present invention and are described below. The necessary starting materials can be obtained by methods customary in the field of organic chemistry. The preparation of these starting materials is described in the accompanying examples, which, however, do not limit the scope of the present invention in any way.

Alternatively, the necessary starting materials can be obtained by methods analogous to those illustrated and well known to those skilled in the art of organic chemistry.

Thus, according to another aspect of the present invention, compounds of formula I may be prepared by deprotection of compounds of formula I in which at least one functional group is protected. For example, amino, hydroxyl, carboxyl or phosphoryloxy groups may be protected during the reaction process used to prepare a compound of formula (I).

Protecting groups may generally be selected from any of the groups described for this purpose in the literature or groups known to those skilled in the chemical art as suitable for protecting the respective groups and may be introduced by conventional methods.

Protecting groups may be removed by any of the appropriate methods described in the literature or by methods known to those skilled in the art of organic chemistry as suitable for removal of the appropriate protecting groups, such groups being selected so as to have as little effect on the groups anywhere in the removal. molecule.

Suitable hydroxyl protecting groups include, for example, arylmethyl (especially benzyl), trialkylsilyl having 1 to 4 carbon atoms in each alkyl moiety (especially trimethylsilyl or tert-butyldimethylsilyl), aryldialkylsilyl having 1 to 4 alkyl moieties carbon atoms (especially dimethylphenylsilyl), diarylalkylsilyl group containing 1 to 4 carbon atoms in the alkyl moiety (especially tert-butyldiphenylsilyl group), alkyl group containing 1 to 4 carbon atoms (especially methyl), aalkenyl group containing 2 to 4 carbon atoms ( especially an allyl group), an alkoxymethyl group having 1 to 4 carbon atoms in the alkoxy moiety (especially a methoxymethyl group) or a tetrahydropyranyl group (especially a tetrahydropyran-2-yl group). The conditions for removal of said protecting groups will necessarily vary depending on the choice of protecting group. Thus, for example, an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium on activated carbon. Alternatively, a trialkylsilyl or aryldialkylsilyl group, such as a tert-butyldimethylsilyl or dimethylphenylsilyl group, may be removed, for example, by reaction with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, or an alkali metal fluoride or ammonium fluoride. is sodium fluoride or preferably tetrabutylammonium fluoride. Alternatively, the alkyl group may be removed, for example, by reaction with an alkali metal alkyl sulfide containing from 1 to 4 carbon atoms in the alkyl moiety, such as sodium thioethoxide, or, for example, by reaction with an alkali metal diaryl phosphide such as lithium diphenylphosphide. is boron tribromide. Alternatively, the alkoxymethyl group containing 1-4 carbon atoms in the alkoxy moiety or the tetrahydropyranyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid.

Alternatively, a suitable protecting group for a hydroxyl group is, for example, an acyl group, for example an alkanoyl group containing 2 to 4 carbon atoms (especially an acetyl group) or an aroyl group (especially a benzoyl group). The conditions for removal of said protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl group or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide.

A suitable protecting group for an amino, imino or N- (alkyl) amino group is, for example, an acyl group, for example a C 2-4 alkanoyl group (especially acetyl group), an alkoxycarbonyl group. containing in the alkoxy moiety 1-4 carbon atoms (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl (especially benzyloxycarbonyl) or aroyl (especially benzoyl). The conditions for removal of said protecting groups will necessarily vary with the choice of the particular protecting group. Thus, for example, an acyl group such as an alkanoyl group, an alkoxycarbonyl group or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group can be removed, for example, by reaction with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group such as benzyloxycarbonyl can be removed, for example a catalyst such as palladium on carbon.

A suitable protecting group for a carboxyl group is, for example, an esterifying group, for example an alkyl group having 1 to 4 carbon atoms (such as a methyl or ethyl group), which can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide; or, for example, a tert-butyl group can be removed, for example, by reaction with a suitable acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or trifluoroacetic acid.

References can be found in J. March, Advanced Organic Chemistry, 4 ^th Ed., John Wiley & Sons, 1992, as a general guide for reaction conditions and reagents, and in T. Greene et al., Protective Groups in Organic Synthesis, 2 ^nd Ed. ., John Wiley & Sons 1991, as a general guide to protecting groups.

In the following description of the process, unless otherwise stated, the symbols R ¹ to R ⁷ , A, B, D, R ^a , R ^b , and b have the meanings already described in connection with formulas I and II.

A compound of formula I or a compound of formula I wherein at least one functional group is protected may be prepared using the following methods:

a) a compound of formula X

is reacted with a compound of formula XI

L ¹ -A- [CH (R ^a )] and B- [CHR ^b )] bD (XI) wherein L ¹ is a leaving group; or

b) converting one compound of formula I into another compound of formula I; or

c) when a phosphoryloxy group is desired, the corresponding hydroxy compound reacts with phosphoramidite;

all functional groups being optionally protected;

and then, if necessary:

i) converting a compound of formula I to another compound of formula I;

(ii) any protecting groups are removed;

iii) preparing a pharmaceutically acceptable salt, solvate or prodrug.

The reaction between a compound of formula X and a compound of formula L ¹ -A- [CH (R ^a )] _and -B- [CHR ^b )] b -D is usually carried out using standard acylation or sulfonylation conditions. L ¹ is usually a halogen atom, for example a chlorine or bromine atom, a hydroxyl group, a mesyloxy group, a tosyloxy group or an "activated hydroxyl group". The exact conditions depend mainly on the character of A.

For example, when A is -CO-, L ¹ may be a hydroxyl group and the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. Alternatively, a base, for example an organic base such as triethylamine, may be used. Suitable solvents include usually aprotic solvents, for example dimethylformamide, or chlorinated solvents, for example trichloromethane or dichloromethane. The temperature is usually in the range of -30 ° C to 60 ° C, often close to room temperature.

When A is -C (O) O-, L ¹ is usually an "activated hydroxyl group". This is a group that acts as a leaving group in the same way as a hydroxyl group, but is more labile. May occur in situ. An example of an activated hydroxyl group is a 4-nitrophenoxy group which may be formed by reacting a hydroxyl group (HO- [CH (R ^a )] and B- [CH (R ^b )] b ^- D) with 4-nitrophenyl chloroformate. This reaction is usually carried out in an organic solvent such as dichloromethane, acetonitrile or tetrahydrofuran at a temperature of -20 ° C to the boiling point of the solvent. In addition, an organic base such as N-methylmorpholine may conveniently be present. Alternatively, the compound of formula X can be reacted with 4-nitrophenylchloroformate and the resulting intermediate reacted with HO- [CH (R ^a )] and B- [CH (R ^b )] b -D using similar conditions to those described above for the reaction of the compound of formula X with a compound of formula L ² - [CH (R ^a )] and B- [CH (R ^b )] b ^- D, wherein L ² is 4-nitrophenoxy.

When A is -CON (R ⁸ ) -, L ¹ is preferably halogen, especially chlorine. Alternatively, when A is -CONH-, the compound of formula X may be reacted with an isocyanate of formula ON- [CH (R ^a )] and B- [CH (R ^b )] bD. These reactions are usually carried out in the presence of a base, in particular an organic base such as triethylamine, pyridine or N-methylmorpholine, in a solvent such as an ethereal solvent such as tetrahydrofuran, or, in a chlorinated solvent such as dichloromethane at -20 ° C to at the boiling point of the solvent. Alternatively, the compound of formula X can be reacted with 4-nitrophenylchloroformate and the resulting intermediate is reacted with a compound of formula R ¹⁷ -NH 2 using similar conditions to those described above for the reaction of a compound of formula I with a compound of formula L ² - [CH (R ^a ) ] aB- [CH (R ^b )] _b -D, wherein L ² is 4-nitrophenoxy.

When A is -SO 2 - or -SO 2 N (R ⁸ ) -, L ¹ is preferably a halogen atom, for example a chlorine atom. The reaction is usually carried out in the presence of a base such as dimethylaniline in a chlorinated solvent such as trichloromethane at a temperature of -20 ° C to 60 ° C, more preferably pyridine, at a temperature in the range of -20 ° C to 60 ° C.

A compound of formula I may be prepared from another compound of formula I by chemical modification. Examples of chemical modifications include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, phosphorylation, aromatic h-allogeneation and condensation reactions. These reactions can be used to introduce new substituents or to modify existing substituents. Alternatively, existing substituents in the compounds of formula I may be modified, for example, by oxidation, reduction, elimination reactions, hydrolysis or cleavage reactions, to give compounds of formula I.

For example, compounds of formula I containing an amino group may be acylated on an amino group by reaction with, for example, an acyl halide or anhydride in the presence of a base, for example a tertiary amine base, for example in a solvent such as a hydrocarbon solvent, for example dichloromethane. 120 ° C, usually at or near room temperature.

In another general conversion example of the interconversion process, the amino group of the compound of formula I may be sulfonylated by reaction with, for example, an alkyl or arylsulfonyl chloride or an alkyl or arylsulfonic acid anhydride in the presence of a base such as a tertiary amine base such as triethylamine such as a solvent such as hydrocarbon a solvent such as dichloromethane at a temperature in the range of -30 ° C to 120 ° C, usually at or near room temperature.

In another general example, a compound of formula I containing a hydroxyl group can be converted to a hydroxyl group. the corresponding dihydrogen phosphate ester by reaction with, for example, di-tert-butyldiisopropylphosphoramidite or di-tert-butyldiethylphosphoramidite in the presence of a suitable catalyst, for example tetrazole. As the solvent, an ether solvent such as tetrahydrofuran can be used. The reaction is usually carried out at a temperature of -40 ° C to 40 ° C, usually at or near room temperature, followed by reaction with an oxidizing agent, for example 3-chloroperoxybenzoic acid, at a temperature of -78 ° C to 40 ° C, preferably at - 40 ° C to 10 ° C. This resulting intermediate phosphate is reacted with an acid, for example trifluoroacetic acid, in a solvent such as a chlorinated solvent, for example dichloromethane, at a temperature of -30 ° C to 40 ° C, usually at a temperature near 0 ° C to give a compound of formula I containing dihydrogenfosfátester.

In another general example, an amide-containing compound of formula I can be hydrolyzed by reaction with, for example, an acid such as hydrochloric acid in a solvent such as an alcohol such as methanol at elevated temperature, usually at the boiling point of the reaction mixture.

In another general example, an alkoxy group can be converted to the corresponding alcohol by reaction with boron tribromide in a solvent such as a chlorinated solvent such as dichloromethane at a low temperature such as about -78 ° C.

In another general example, a compound of formula (I) may be alkylated by reaction with a suitable alkylating agent such as an alkyl halide, an alkyltholuenesulfonate, an alkyl methanesulfonate, or an alkyl triflate. The alkylation reaction may be carried out in the presence of a base, for example an inorganic base such as a carbonate such as cesium carbonate or potassium carbonate, a hydride such as sodium hydride, or an alkoxide such as potassium tert-butoxide, in a suitable solvent such as an aprotic solvent. for example dimethylformamide, or an ether solvent such as tetrahydrofuran at -10 ° C to 80 ° C.

In another example, an unsubstituted ring nitrogen atom in a saturated heterocyclic ring may be acylated using similar reaction conditions to those described above for the acylation of the amino group.

Synthesis of intermediates

The compound of formula X may be known or may be prepared according to the methods described in International Patent Application No. PCT / GB 98/01977.

The compound of formula (XI) may be known or may be prepared by methods known to those skilled in the art. For example, when A is -C (O) O- and L ¹ is 4-nitrophenyloxy, a compound of formula XI can be prepared by reacting a compound of formula

HO- [CH (R ⁷ )] and B- [CH (R ⁷ )] b D with 4-nitrophenyl chloroformate in the presence of a base, preferably an organic base such as triethylamine in an inert organic solvent such as dichloromethane. The reaction is usually carried out at a temperature of -30 ° C to 60 ° C, most commonly at room temperature.

The acid addition salts of the compounds of formula I are prepared in a known manner by reacting a solution or suspension of the compound of formula I in the free base form with about one equivalent of a pharmaceutically acceptable acid. Salts of compounds of formula I derived from inorganic or organic bases are prepared in a conventional manner by reacting a solution or suspension of a compound of formula I in the free acid form with about one equivalent of a pharmaceutically acceptable organic or inorganic base. Alternatively, both acid addition salts and base-derived salts can be prepared by reacting the parent compound with a suitable ion exchange resin in a conventional manner. Conventional concentration and recrystallization techniques can be used to isolate salts.

The compounds of the present invention are capable of destroying the vasculature that has emerged as a tumor vasculature, while the original normal vasculature remains intact. The necessary identification methods for compounds that selectively and preferably efficiently damage the emerging vasculature are a subject of the present invention. The ability of compounds to act in this manner is tested, for example, using one or more of the following methods:

(a) Activity against tumor vasculature as measured by radiolabel

This assay demonstrates the ability of the compounds to selectively damage tumor vasculature.

Subcutaneous CaNT tumors are induced by injection of 0.05 ml of a suspension of crude tumor cells (approximately 10 ⁶ cells) under the skin covering the back of the back of mice aged 12-16 weeks. Animals are selected for the test after about 3 to 4 weeks when their tumors reach a geometric diameter of 5.5 to 6.5 mm. Compounds are dissolved in sterile saline and injected intra39 peritoneally in a volume of 0.1 ml per 10 g body weight. Tumor perfusion is measured 6 hours after intraperitoneal administration in tumor, kidney, liver, skin, muscles, intestines and brain by the ⁸⁶ RbCl extraction technique (Sapirsten, Amer. J. Physiol. 193, 161-168 (1958)). One minute after intravenous injection of ⁸⁶ RbCl is used to calculate the relative blood flow as a proportion of cardiac output (Hill and Denekamp, Brit. J. Radiol. 55, 905-913 (1982)). Five animals are used in the control and treatment groups. expressed as a percentage of blood flow in the corresponding tissues for animals treated with the vehicle.

(b) Activity against tumor vasculature as measured by a fluorescent dye

This assay demonstrates the ability of the compounds to damage the vasculature of tumors.

The functional volume of the tumor vasculature in mice bearing CaNT tumors is measured using a Hoechst 33342 fluorescent dye according to the procedure described by Smith et al., Brit. J. Cancer 57: 247-253 (1988). Five animals are used in the control and treatment groups. The fluorescent dye is dissolved in saline at 6.25 mg / ml and injected intravenously at 10 mg / kg 24 hours after intraperitoneal drug administration. After 1 minute, the animals are sacrificed and the tumors are removed and frozen; 10 μιη sections are cut off at three different levels and UV λ is observed.

radiation using an Olympus microscope equipped with epifluorescence. The vessels are identified using their fluorescent lines and the vessel volume is quantified using a point system based on the procedure described in Chakley, J. Natl. Cancer Inst. 4, 47-53 (1943). All ratings were based on a calculation of at least 100 fields from the cut off sections at three different levels.

The ability of the compounds to bind mammalian tubulin preparations can be assessed using a variety of methods available in the literature, such as the following temperature-induced tubulin polymerization by turbidity in the absence and presence of the compound (e.g., O. Boye et al., Med. Chem. Res. 1, 142-150). (1991)).

Activity of N- (3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl) acetamide, (V. Fernholz, Justus Liebigs Ann., 568, 63-72 (1950)), against tumor vasculature is measured using the fluorescent dye method described above. This compound reduces the vessel wash volume by 88% relative to control when administered at 50 mg / kg intraperitoneally. The IC 50 value for this compound in the tubulin polymerization assay was 58 μιτιοί (O. Boye et al., Med. Chem. Res. 1, 142-150 (1991)).

(c) HUVEC test

Using this assay, the effect of the compounds on the adhesion of HUVEC to a plastic culture vessel was determined.

HUVECs are plated on 12-well culture plates coated with 0.2% gelatin at a concentration of 3 x 10 ⁴ cells per well in 1 ml TCS medium. After 24 hours, when the cells reach a conficiency of about 30%, the compound is dosed for 40 minutes at 37 ° C in an atmosphere of 5% carbon dioxide. After this incubation, the drug-containing medium is pipetted and the cells are gently washed with 2 ml HBSS (Hank's Balanced Salt Solution from Life Technologies Ltd., Paisley, UK; Catalog # 24020-083) to remove separate cells. The wash solution is then removed and the adherent cells are trypsinized using 1 x 300 μ 300 of Trypsin-EDTA solution (Life Technologies Ltd., Paisley, UK; Catalog # 43500-019) at room temperature for 2 minutes. The trypsinized cells are then made up to 1 ml with TCS biological medium, then centrifuged at 2000 rpm for 2 minutes. The cell pellet is then resuspended in a volume of 50 μΐ TCS of the biological medium. The total number of cells is obtained by counting the cells on a hemocytometer. The amount of detached cells is calculated by comparing the number of cells remaining attached after treatment in untreated control wells.

(d) Hras5 necrosis model

NIH 3T3 fibroblasts transfected with Harvey ras, stem 5, (Hras5 cells) are maintained in a continuous passage in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS) and 1% glutamine at 37 ° C in a humidified incubator filled with 7.5% carbon dioxide and 92.6% oxygen. Cells are implanted subcutaneously in the left flank of male nude mice (8-10 weeks of age) in an inoculum of 2 x 10 ⁵ cells / mouse. Tumors are measured using calipers and mice are randomized into groups of 2-4 mice between days 9-14 after implantation. Mice are administered compounds either intravenously or intraperitoneally once on the day of distribution and sorted 24 hours after administration. The compounds are dissolved in 20% hydroxypropyl-3-cyclodextrin in saline at pH 7 and administered in a volume of 0.1 ml per 10 g body weight. Tumors are removed, weighed and placed in buffered formalin. The area of necrosis for individual tumors is evaluated from the haematoxylin / eosin-stained film according to pathology and is evaluated from 0 (meaning no significant change) to 10 (meaning 91 to 100% necrosis). The activity of the compounds of Examples 5 and 7 (described in the next section of the present invention) against tumor vasculature was measured using a fluorescent dye method as described above. The compound of Example 1 was rated 6.0 at 100 mg / kg and the compound of Example 4 was rated 3.2 at 50 mg / kg.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a pharmaceutically acceptable excipient or carrier.

The composition may be in a form suitable for oral administration, for example, as a tablet or capsule, for nasal administration or for administration by inhalation, for example, as a powder or solution, for parenteral injection (including intravenous, subcutaneous, intramuscular and intravascular injection or infusion) e.g. a sterile solution, suspension or emulsion for topical administration, for example, as an ointment or cream, or for rectal administration, for example, in the form of a suppository. In general, said compositions may be prepared in a conventional manner using conventional additives.

The compositions of the present invention are preferably present in unit dosage form. The compounds will normally be administered to warm-blooded animals in a unit dose in an amount of 5 to 5000 mg per square meter of body surface area of the animal, i. j. about 0.1 to 100 mg / kg. A unit dose in an amount of, for example, 1 to 100 mg / kg, preferably 1 to 50 mg / kg is contemplated, and this dose will normally provide a therapeutically effective dose. A unit dosage form such as a tablet or capsule will usually contain, for example, 1 to 250 mg of the active ingredient.

As mentioned above, the size of the dose required for the therapeutic or prophylactic treatment of a particular disease will necessarily be varied depending upon the host ¹ patient, route of administration and the severity of the disease being treated. Preferably, a daily dose in the range of 1 to 50 mg / kg is used. However, the daily dose will necessarily vary depending on the subject being treated, the particular mode of administration, and the severity of the disease being treated. Thus, the optimum dose can be determined by the physician treating the particular patient.

According to another aspect of the present invention, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as hereinbefore defined, for use in a method of treating a human or animal by therapy.

Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for use as a medicament, preferably a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use as a medicament providing vasculature damaging effect in warm blooded patients. to live in the eyes like a man. ¹

Thus, in a further aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for use in producing a vasculature damaging effect in warm-blooded animals such as man.

In another aspect, the present invention provides a method of obtaining a vasculature damaging effect in a warm-blooded animal, such as a human, in need thereof, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, such as already defined, to this animal.

In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, preferably in the form of a pharmaceutical composition which, when administered in divided dose procedures, provides a greater antitumor effect than when administered as a single dose.

The anti-tumor effect of the method of treatment of the present invention includes, but is not limited to, inhibiting tumor growth, delaying tumor growth, tumor regression, tumor reduction, prolonged tumor regrowth time at treatment termination, slowing disease progression. It is expected that when the method of the present invention is administered to a warm-blooded animal such as a human in need of cancer treatment comprising a solid tumor, said method of treatment will provide an effect that can be measured by, for example, one or more of the following parameters: responses, disease progression time, and survival rate.

According to another aspect, the present invention provides a method of producing a vascular damaging effect in a warm-blooded animal, such as a human, comprising administering to said animal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof in divided doses, preferably in the form of a pharmaceutical composition. .

In another aspect, the present invention provides a method of treating a cancer comprising a solid tumor in a warm-blooded animal, such as a human, comprising administering to said animal in divided doses an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. .

According to another aspect, the present invention provides a medicament comprising two or more dose portions of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, preferably in the form of a pharmaceutical composition that together provide up to a full daily dose for administering divided doses for use in a method of treatment. human or animal.

In another aspect, the present invention provides a kit comprising one or more dose portions of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, preferably in the form of a pharmaceutical composition that together provide up to a full daily dose for administration in divided doses.

According to another aspect, the present invention provides a kit comprising:

(a) one or more portions of doses of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which together provide up to a full daily dose, in unit dosage forms for single dose administration; and

b) a container for holding said dosage forms.

According to another aspect, the present invention provides a kit comprising:

(a) one or more dose portions of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that together provide up to a full daily dose, together with a pharmaceutically acceptable excipient or carrier, in unit dosage forms; and

b) a container for holding said dosage forms.

In another aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for administration in divided doses for use in providing a vascular damaging effect in warm-blooded animals such as man.

According to another aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for administration in divided dose form for use in providing an antitumor effect in warm-blooded animals such as man.

The term divided doses means that the total dose to be administered to a warm-blooded animal, such as a human, at any time of the day (e.g., once every 24 hours from midnight to midnight) is divided into two or more parts of the total dose. administered over a period of time between each part greater than 0 hours to 10 hours, preferably 1 hour to 6 hours, more preferably 2 hours to 4 hours. Parts of the total daily dose may be the same or unequal.

Preferably, the total daily dose is divided into two portions, which may be the same or unequal.

For example, the time intervals between doses may be selected from:

I ₍ about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours and about 6 hours.

The time intervals between doses may be any number of minutes (including less than) from 0 minutes to 600 minutes, preferably 45 to 375 minutes inclusive. If more than two doses are administered, the time intervals between them may be the same or unequal.

Preferably, two doses are administered wherein the time interval between them is greater than or equal to about 1 hour and less than or equal to about 6 hours.

More preferably, two doses are administered at a time interval greater than or equal to about 2 hours and less than about 5 hours.

Even more preferably, two doses are administered at a time interval greater than or equal to about 2 hours and less than or equal to about 4 hours.

More preferably, the total daily dose is divided into two portions, which may be the same or unequal, at a time interval between doses greater than or equal to about 2 hours and less than or equal to about 4 hours.

More preferably, the total daily dose is divided into two portions, which may be the same, at a time interval between doses greater than or equal to about 2 hours and less than or equal to about hours.

For the avoidance of doubt, the term &quot; approximately &quot; in describing time periods means a given time of plus-minus 15 minutes, e.g., about 1 hour means 45 to 75 minutes, about

1.5 hours means 75 minutes to 105 minutes. Elsewhere, the term "roughly common meaning" is given in dictionaries.

The anti-angiogenic treatment, as defined above, may be used in a single treatment or may involve one or more other substances and / or treatments in addition to the compound of the present invention. Such concomitant treatment may be by simultaneous, sequential or separate administration of the individual components of the treatment. . In the field of therapeutic oncology, it is common practice to use a combination of different forms of treatment to treat each cancer patient. In therapeutic oncology, the other ingredients may be concurrent treatments, in addition to the anti-angiogenic treatment already defined, the following procedures: surgery, radiotherapy or chemotherapy. This chemotherapy may include the following categories of therapeutic agents:

(i) other antiangiogenic agents that work by different mechanisms from those already defined (for example linomide, inhibitors of integrin _α ν β _3, angiostatin, endostatin, razoxin, thalidomide), including receptor tyrosine kinase inhibitors (rtkit) vascular endothelial growth factor (VEGF; see, for example, those described in International Patent Applications Nos. WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354, the contents of which are incorporated herein by reference);

(ii) cytostatic agents such as anti-estrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, iodoxyphene), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandamide namide, antiandrogen namide (e.g. bicalutamide, cyproterone acetate), LHRH agonists and antagonists (eg goserelin acetate, luprolide), testosterone inhibitors, 5α-dihydroreductase (eg finasteride), anti-invasive agents (eg metalloproteinase inhibitors such as marimastat, and inhibitors of urinary plasminogen activator function and urokinogen activator function) factor (such as growth factors include, for example, epidermal growth factor (EGF), platelet-derived growth factor, and hepatocyte growth factor (such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and inhi serine / threonine kinase inhibitors);

(iii) biological response modifiers (e.g., interferon);

(iv) antibodies (e.g., edrecolomab); and (v) antiproliferative / antineoplastic drugs and combinations thereof as used in therapeutic oncology such as antimetabolites (e.g., antifolates, such as methotrexate, fluoropyrimidines such as 5-fluorouracil, purine and adenosine analogs, arabinoside cytosine); antitumor antibiotics (for example anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mitramycin); platinum derivatives (e.g. cisplatin, carboplatin); alkylating agents (e.g. nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example, vinca alkaloids such as vincristine, and taxoids such as taxol, taxotere); enzymes (e.g., asparaginase); thymidylate synthase inhibitors (e.g. raltitrexed); topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan).

As already mentioned, the compounds defined according to the present invention are of interest in their vascular damaging effect. These compounds of the present invention are expected to be useful in the prophylaxis and treatment of a wide range of diseases in which undesirable angiogenesis occurs, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute inflammation, endometriosis, dysfunction and maternal bleeding. ocular diseases with retinal vascular proliferation. In particular, it is expected that the compounds of the present invention will preferably retard the growth of primary and recurrent solid tumors, for example, the colon, breast, prostate, lung and skin.

In addition to their use in medical medicine, the compounds of formula I and their pharmaceutically acceptable salts, solvates and prodrugs will also be useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems to evaluate the effects of vascular damaging agents in laboratory animals such as cats, dogs , rabbits, monkeys, rats and mice as part of research into new therapeutic agents.

It is understood that whenever the term "ether" is used in the specification, it means that it is diethyl ether.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be illustrated by the following non-limiting examples, in which, unless stated otherwise: (i) the evaporation is carried out using a rotary evaporator under vacuum and treatment is carried out after removal of residual solids such as drying reagents, by filtration;

(ii) the operations are carried out at room temperature, that is, at a temperature in the range of 18 ° C to 25 ° C and under an atmosphere of an inert gas such as argon or nitrogen;

(iii) yields are given for illustration only and are not necessarily the maximum yields that can be achieved;

(iv) the structures of the target products of formula I were confirmed by nuclear (usually proton) magnetic resonance (NMR) and mass spectroscopy techniques; proton magnetic resonance chemical shift values were measured on a δ scale and peak multiplicities were described as follows: s, singlet; d, doublet; t, triplet; m, multiplet; w, broad; q, quadruplet, quin, quintet;

(v) intermediates are generally not fully characterized and purity was tested by thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), infrared spectroscopy (IR) and NMR analysis;

abbreviations:

4-Dimethylaminopyridine DMAP

1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EDCI

Dimethyl sulfoxide DMSO

Trifluoroacetic acid TFA

Example 1

N - [(5S) -3,9,10,11-Tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] -2- (2-aminoacetylamino) acetamide

A solution of 0.9 g (0.64 mmol) of N - ((5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] - 2- [2- (butoxycarbonylamino) acetylamino] acetamide in 6 ml of dichloromethane is treated with 6 ml of trifluoroacetic acid for 0.5 hour at room temperature, after evaporation to dryness, the residue is neutralized to pH 6.5 with solid sodium bicarbonate and purified on silica gel reversed phase with a gradient of 30 to 40% methanol / ammonium carbonate buffer (2 g / l, pH 7) The appropriate fractions were evaporated to dryness and triturated in ether to give the title compound.

Yield: 65%.

¹ H-NMR (DMSO-d 6): 1.88-2.21 (m, 3H); 2.58 partially covered by pi51

Com DMSO (m, 1H); 3.10 (s, 2H); 3.46 (s, 3H); 3.79 (with, 3H); 3.82 (s, 3H); 3.83 (s, 3H); 3.84 (s, 3H); 4.47 to 4.5 8 (m, 1H); 6.77 (with, 1H); 6.87 (dd, IH); 6. 91 (d, 1 H); 7.25 (d, 1H); 8.06 (M, 1H); 8.41 (d, IH); MS-ESI: 444 [M + H] ^&lt; ^{+ &gt};; | Elemental analysis Found C, 59.14 6.44 N 9.08 C23H29N3O6. 1.2 _H2O C, 59.39; 6, 80 N 9.03.

The starting material is prepared as follows:

A solution of 0.329 g (1.36 mmol) of (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-ylamine (Collect. Czech. Chem. Commun 64 (2), 217-228 (1999)), 0.230 g (1.2 mmol) EDCI,

0.025 g (0.2 mmol) of DMAP and 0.189 g (1.2 mmol) of 2- [2- (tert-butoxycarbonylamino) acetylamino] acetic acid in dichloromethane were stirred under argon overnight. The resulting precipitate was filtered off and washed with ether to give N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl ] -2- [2- (butoxycarbonylamino) acetylamino] acetamide as a white solid.

Yield: 65%.

¹ H-NMR (DMSO-d 6): 1.33 (s, 9H) ; 1.94-2.24 (m, 3H); 2.97-3.08 (M, 1H); 3.35 (s, 3H); 3.56 (T, 3H); 3.71-3.77 (M, 1H); 3.75 (with, 3H); 3.78 (s, 3H); 3.80 (with, 3H); 4.48-4.59 (M, 1H); 6.79 (with, 1H); 6.87 (dd, IH); 6.93 (D, 1H); 7.14 (t, 1H); 7.25 (d, 1H);

8.17 (t, IH); 8.21 (d, IH);

MS-ESI: 544 [M + H] &lt; ^{+ &gt};.

Example 2

Disodium 4-Oxo-4 - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-ylamino] butyl phosphate

A solution of 0.529 g (0.892 mmol) of N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl] -4- [di ( tert-butoxy) phosphoryloxy] butanamide in a mixture of 5 ml of 12 N hydrochloric acid and 25 ml of dioxane was stirred under argon for 4 hours. After evaporation of dioxane, the pH is adjusted to 7.2 with 2 N sodium hydroxide solution and the residue is purified on HP20SS resin eluting with a 0 to 40% methanol / water gradient to give the title compound after freeze-drying.

Yield: 75%.

1 H-NMR (DMSO-d 6): 1.71-2.36 (m, 7H); 2.58 partially overlapped with DMSO peak (m, 1H); 3.49 (s, 3H); 3.78-3.85 (m, 11H); 5.20 (dd,

1H); 5.00 (s, 1 H); 6.77 (s, 1 H); 6.88 (dd, IH); 6.91 (d, IH);

6.26 (d, IH).

The starting material is prepared as follows:

N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] -4- [di (tert-butoxy) phosphoryloxy] ] butanamide is prepared using a method similar to that described in Example 1, by reacting (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-ylamine with 4- [di (tert-butoxy) phosphoryloxy] butanoic acid. .

Yield: 89%.

^X H-NMR (DMSO-d₆): 1.40 (s, 18 H); 1.80 (t, 2 H); 1.82-1.94 (m, IH);

2.00-2.20 (M, 2H); 2.23-2.33 (M, 2H); 2,52- -2.58 (M, 1H); 3.48 (with, 3H); 3.78 (with, 3H); 3.80 -3.85 (M, 8H); 4,50- • 4.59 (M, 1H); 6.78 (with, 1H); 6.89 (Dd, 1H); 6, 90 (D, 1H); 7.26 (D, 1H); 8.42

(d, 1 H).

Example 3

N- (N- [2- (Imidazol-1-yl) ethyl] carbamoyl} -5 (S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cycloheptene 5-ylamine

A solution of 0.263 g (0.8 mmol) of (5S) -3,9,10,11-tetramethoxy-6,7.-dihydro-5H-dibenzo [a, c] cyclohepten-5-ylamine, 0.177 g (0.88) mmol) of 4-nitrophenyl chloroformate and 0.123 ml (0.88 mmol) of triethylamine in dichloromethane are stirred under argon for 1 hour. Add 0.145 mL (1.2 mmol) of 2- (imidazol-1-yl) ethylamine. After stirring for 2 hours, the mixture is evaporated to dryness and the residue is purified on reverse phase silica gel, eluting with a gradient of 40 to 60% methanol / ammonium carbonate buffer (2 g / l, pH 7) and evaporated and triturated in ether. to give the title compound.

Yield: 52%.

^X H-NMR (DMSO-d₆): 1.66 to 1, 77 (m, 1 H); 1.97 -2.10 (M, 1H); 2.13-2.25 (m, 1 H); 2.53 partly covered with peak DMSO (M, 1H); 3.12-3.32 (m, 2H); 3.47 (s, 3H); 3 77 (s, 3H); 3.79 (s, 3H); 3.83 (s, 1 H); 3.94 (t, 3H); 4.32-4.42 (m, 1 H); 5.97 (T, 1H); 6.63 (d, IH); 6.77 (s, 1H); 6.83-6.92 (m, 3H); 7.11 (with, 1H); 7.24 (d, IH); 7.54 (s, 1H); MS-ESI: 481 [M + H] ^&lt; ^{+ &gt};; Elemental analysis Found: C, 64.68 H 6.89 N, 11.55 C26H32N4O5 Calculated C 64, 98 H 6.71 N, 11.66

Example 4

Disodium 2- {N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [f], c] cyclohepten-5-yl] carbamoyloxyjetyl phosphate

A solution of 0.576 g (0.85 mmol) of 2- [di (benzyloxy) phosphoryloxy] ethyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] 1-cyclopent-5-yl] carbamate dissolved in a mixture of 10 ml of methanol and 5 ml of ethyl acetate was hydrogenated for 4 hours in the presence of 0.165 g of 10% palladium on carbon. After filtration through diatomaceous earth and evaporation, the residue is purified on HP20SS resin, eluting with a gradient of 0 to 80% methanol / distilled water. The pH of the corresponding fractions is adjusted to 8 with 2 N sodium hydroxide solution after evaporation of the methanol. After freeze-drying, the title compound is obtained as a white solid.

Yield: 83%.

¹ H-NMR (DMSO-d ₆ + TEA-d): 1.85-1.97 (m, 1H); 1.98-2.09 (m, IH);

2.13 -2.27 (m, 1H); 2.42-2.52 (m, 1H); 3.48 (s, 3H); 3 79 (WITH, 3H); 3.80 (s, 3H); 3.84 (s, 3H); 3.98 (m, 2 H); 4.03 to 4, 18 (M, 2H); 4.04-4.17 (M, 2H); 4.24 to 435 (m, 1 H); 6.77 (s, 1H) T 6.89 (Dd, 1H); 6.96 (D, 1H); 7.27 (d, IH) r

MS-ESI: 498 [M + H] &lt; ^{+ &gt};.

The starting material is prepared as follows:

1.01 g (5.04 mmol) of 4-nitrophenyl chloroformate are added to a solution of 1.62 g (5.09 mmol) of 2- [di (benzyloxy) phosphoryloxy] ethanol and 0.7 ml under argon at 0 ° C. (5 mmol) of triethylamine in 20 ml of dichloromethane. The mixture was stirred for 30 minutes at room temperature, evaporated and purified by flash chromatography eluting with petroleum ether / ethyl acetate (40:60) to give 2- [di (benzyloxy) phosphoryloxy] ethyl 4-nitrophenyl carbonate.

Yield: 45%.

1 H-NMR (CDCl ₃ ): 4.21-4.30 (m, 2H); 4.41 (m, 2 H); 5.01-5.15 (m,

4H); 7.29-7.42 (m, 12H); 8.25 (d, 2 H).

A solution of 0.329 g (1 mmol) of (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-ylamine and 0.633 g (1.3 mmol) 2- [di (benzyloxy) phosphoryloxy] ethyl 4-nitrophenyl carbonate in 8 ml acetonitrile was heated at 65 ° C under argon for 8 hours. After evaporation to dryness, the residue is purified by flash chromatography eluting with a gradient of 50 to% ethyl acetate / petroleum ether to give 2- [di (benzyloxy) phosphoryloxy] ethyl-N- [(5S) -3,9,10,11]. tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl) carbamate.

Yield: 85%.

^X H-NMR (DMSO-d): 1.81-1.93 (m, 1H); 1.94-2.06 (m, 1H); .2,06-2,20

(M, 1H); 2.40-2.52 (m, 1 H) ; 3 . 43 (s, 3H); 3.73 (s, 3H); 3.77 (s, 3H); 3.82 (s, 3H); 4.11 (M, 4H) ; 4.20-4.33 (m, 4H); 5.02 (d, 4H); 6.7 (s, 1H); 6, 86 (Dd, 1H) ; 6.93 (d, IH); 7.25 (d, 1 H), 7.35 (s, 10H); 7.99 (D, lH)

Example 5

2-Morpholinoethyl N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-ylcarbamate

A solution of 0.263 g (0.8 mmol) of (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-ylamine (Collect. Czech. Chem. Commun 64 (2), 217-228 (1999)), 0.177 g (0.88 mmol) of 4-nitrophenyl chloroformate and 0.123 ml (0.88 mmol) of triethylamine in 5 ml of acetonitrile were stirred under argon at room temperature for 2 hours. . To this solution was added 0.145 mL (1.2 mmol) of 4- (2-hydroxyethyl) morpholine dissolved in 2 mL of acetonitrile. Stir the mixture overnight at 60 ° C. After evaporation to dryness, the residue is purified by flash chromatography eluting with ethanol / dichloromethane (4: 96) to give the title compound.

Yield: 64%.

¹ H-NMR spectrum (DMSO-d 6 + AcOH-d ₄ ): 1.82-2.31 (m, 3H); 2.44 (m,

4H); 2.49 (m, 2 H); 2.57 partially overlaid with DMSO peak (m, 1H); 3.47 (s, 3H); 3.56 (m, 4H); 3.78 (s, 3H); 3.79 (s, 3H); 3.83 (s, 3H); 4.03 (m, 2 H); 4.17-4.33 (m, IH); 6.76 (s, 1 H); 6.88 (dd,

1H); 6.93 (d, IH); 7.26 (d, IH); 7.86 (d, IH);

MS-ESI: 487 [M + H] ^&lt; ^{+ &gt};;

Elemental analysis: C 26 H 34 N 2 O 7, 0.3 H2O

Found C 63.38 H 7.04 Calculated C 63.48 H 7.09

N 5.74 N 5.69

Example 6

3- (1-Methylpiperazin-4-yl) propyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate

Using a similar procedure to that described in Example 5, (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-ylamine is reacted with 4- ( 3-hydroxypropyl) -1-methylpiperazine to give the title compound.

Yield: 40%.

¹ H-NMR (DMSO-d6): 1.62-2.44 (m, 20H); 2.54 partially covered peak DMSO (m, 1 H); 3.46 (s, 3H); 3.77 (with, 3H); 3.78 (s, 3H); 3.82 ( s, 3H); 6.78 (s, 1 H); 6.89 (dd, 1H); 6, 93 (D, 1H); 7.27

(d, 1 H); 7.80 (d, IH);

MS-ESI: 514 [M + H] ^&lt; ^{+ &gt};;

Elemental analysis for C28H39N3O6

Found C 65.42 H 7.54 Calculated C 65.48 H 7.65

N, 8.18

Example 7

2- (1-Acetylpiperazin-4-yl) ethyl-N - [(5S) -3,9,9,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5- yl] carbamate

A solution of 0.255 g (0.525 mmol) of 2- (piperazin-4-yl) ethyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cycloheptene -5-yl] carbamate, 0.038 mL (0.53 mmol) of acetyl chloride and 0.073 mL (0.525 mmol) of triethylamine in 10 mL of dichloromethane were stirred at room temperature under argon for 2 h. After evaporation to dryness, the residue was purified by flash chromatography eluting with dichloromethane / ethanol (93: 7) to give the title compound.

Yield: 90%.

¹ H-NMR (DMSO-d 6): 1.81-2.32 (m, 3H); 1.97 (s, 3H); 2.33 (M, 2H); 2.40 (m, 2 H); 2.47 partially covered with peak DMSO (m, 2H); 2.58 partially covered with DMSO peak (m, 1H); 3.38 (M, 4H); 3.46 (with, 3H); 3.77 (m, 3H); 3.80 (s, 3H); 3.82 (s, 3H); 3.92-4.10 (M, 2H); 4.20-430 (m, IH); 6.77 (s, 1 H); 6.88 (Dd, 1H); 6, 92 (D,

1H); 7.25 (d, IH); 7.87 (d, IH);

MS-ESI: 528 (M + H ⁺⁾ ;

Elemental analysis: Found C 63.21 H 7.30 N 7.86

C28H37N3O7 Calculated C 63.52 H 7.08 N 7.94

The starting material is prepared as follows:

2- (1-tert-Butoxycarbonylpiperazin-4-yl) ethyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5- yl] carbamate was prepared using a similar procedure to that described in Example 1 except that 2- [1- (tert-butoxycarbonyl) -piperazin-4-yl] ethanol was used.

Yield: 75%.

¹ H-NMR (DMSO-d ₆ ): 1.78-1.94 (m, 1H); 1.95-2.07 (m, IH); 2.10-2.23 (m, IH); 2.30 (m, 4H); 2.38-2.53 (m, 3H); 2.65 (t, 2 H); 3.46 (s, 3H); 3.77 (s, 3H); 3.78 (s, 3H); 3.82 (s, 3H); 3.99 (t, 2 H);

4.20-4.32 (m, IH); 6.77 (s, 1 H); 6.88 (dd, IH); 6.92 (d, IH);

7.25 (d, IH); 7.86 (d, IH).

0.617 g (1.05 mmol) of 2- (1-tert-Butoxycarbonylpiperazin-4-yl) ethyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [α, c] -cyclohepten-5-yl] carbamate in 10 mL of dichloromethane is treated with 5 mL of trifluoroacetic acid for 1 hour at room temperature. After evaporation to dryness, the residue is neutralized to pH 8 with sodium hydroxide solution and purified by reversed-phase silica gel chromatography eluting with a gradient of 30 to 40% methanol / ammonium carbonate buffer (2 g / l, pH 7), and 2- (piperazin-4-yl) ethyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl was obtained ] carbamate.

Yield: 60%.

¹ H-NMR (DMSO-d 6): 1.39 (s, 9H); 1.81-1.94 (m, IH); 1.95-2.07 (m,

1H); 2.09-2.27 (m, IH); 2.34 (m, 4H); 2.52-2.64 (m, IH); 3.28 (m, 2 H); 3.36 (s, 3H); 3.46 (s, 3H); 3.77 (s, 3H); 3.82 (s, 3H);

3.94-4.09 (m, 2 H); 4.20-430 (m, IH); 6.77 (s, 1 H); 6.87 (dd,

1H); 6.92 (d, IH); 7.25 (d, IH); 7.86 (d, IH).

Example 8

N - [(5S) -3,9,10,11-Tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl] -4- (1-methylpiperazin-4-yl) ) -4-oxobutan-l-amide,

A solution of 0.356 g (1.78 mmol) of 4- (1-methylpiperazin-4-yl) -4-oxobutanoic acid, 0.367 g (1.78 mmol) of EDCI and 0.05 g (0.41 mmol) of DMA? in 30 ml of dichloromethane was stirred for 35 minutes under argon. 0.45 g (1.37 mmol) of (5S) -3, 9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c) cyclohepten-5-ylamine is then added and the mixture is stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by flash chromatography eluting with dichloromethane / ethanol (95: 5) to give the title compound as a white solid after evaporation and trituration in pentane.

Yield: 60%.

¹ H-NMR (DMSO-d ₆ ): 1.85-1, 96 (n 3H); 2.22 (t, 2 H); 2.26 (t, 2H); 3.35-3.46 (m, 4H); 3.46

3H); 3.84 (s, 3H); 4.44-4.56

1H); 6.98 (d, IH); 7.25 (d, IH); 8.40 (d, IH);

1H) ; 2.01-2.15 (m, 1 H); 2.16 (with, ; 233-2.42 m 1H); 2.47-2.53 (M, (with, 3H); 3.79 (s, 3H); 3.82 (with, m. 1H), 6.79 (s, 1 H); 6,8 6 (Dd,

MS-ESI: 512 [M + H] ^&lt; ^{+ &gt};;

Elemental analysis for C28H37N3O6

Found C 65.51 H 7.40 N 8.19

H, 7.29; N, 8.21

Example 9

3- (1-Acetylpiperazin-4-yl) propyl N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-ylcarbamate

A solution of 0.329 g (1 mmol) of (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-ylamine and 0.456 g (13 mmol)

3- (4-Acetylpiperazino) propyl 4-nitrophenyl carbonate in 8 ml of acetonitrile was heated to 70 ° C under argon for 6 hours. After evaporation to dryness, the residue is purified by flash chromatography eluting with dichloromethane / ethanol (93: 7) to give the title compound.

Yield: 80%.

1 H-NMR (DMSO-d ₆ ): 1.62-2.51 (m, 12H); 1.97 (s, 3H); 3.32-3.44 (m,

4H); 3.46 (s, 3H); 3.77 (s, 3H); 3.78 (s, 3H); 3.82 (s, 3H); 3.87-4.01 (m, 2 H); 4.19-4.31 (m, IH); 6.77 (s, 1 H); 6.88 (dd, IH); 6.92 (d, IH); 7.25 (d, IH); 7.80 (d, 1H);

MS-ESI: 542 [M + H] ^&lt; ^{+ &gt};;

Elemental Analysis Found C, 63.48; H, 7.25; N, 7.72

C29H39N3O7, 0.4 H2O Calculated C 63.46 H 7.31 N 7.66

The starting material is prepared as follows:

0.733 g (3.63 mmol) of 4-nitrophenyl chloroformate is added to a solution of 0.645 g (3.46 mmol) of 3- (4-acetylpiperazin-1-yl) propanol (Synthesis, 1997, 643-648) and 0.51 ml ( 3.36 mmol) of triethylamine in ml of dichloromethane at 0 ° C under argon. The mixture was stirred for 1 hour at room temperature, evaporated to dryness and purified by flash chromatography eluting with dichloromethane / ethanol (95: 5) to give 3- (4-acetylpiperazino) propyl 4-nitrophenyl carbonate.

¹ H-NMR (CDCl ₃ ): 1.96 (m, 2H); 2.09 (s. 3H); 2.39-2.48 (m, 4H); 2.51 (t, 2 H); 3.47 (t, 3 H); 3.63 (t, 2 H); 3.68-3.78 (m, 2H); 4.38 (t, 2 H); 7.39 (d, 2 H); 8.29 (d, 2 H).

Example 10

4-morpholino-4-oxobutyl-N - [(5S) -3,9,10, ll-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c]-5-yl] carbamate

NO.

The compound is described in Example 9, but substituting 3- (4-acetylpiperazino) propyl-4-nitrophenyl carbonate for 4-morpholino-4-oxobutyl-463.

-nitrofenylkarbonátom.

Yield: 55%.

¹ H-NMR (DMSO-d 6): 1.71-1.81 (m, 2H); 1.82-1.94 (m, IH); 1.95-2.07

(s, 1 H); 2.11 -2.24 (with, 1H) ; 2 34 (t T 2H); 2.46 (M, 1H); 3.31-3.44 (M, 4H); 3.45 (with, 3H); 3.52 (M, 4H); 3.77 (with, 3H); 3.78 (s, 3H); 3, 82 (with, 3H); 3.86 -3.98 (M, (2H); 4,20 · -4.32 (M, 1H); 6.77 (with, 1H); 6, 88 (Dd, 1H); 6, 92 (d (1H); 7.25 (D, 1H);

7.80 (d, IH);

MS-ESI: 529 [M + H] ^&lt; ^{+ &gt};;

Elemental Analysis Found C, 62.81; H, 6.95; N, 5.27

C28H36N2O8, 0.3 H ₂ 0 Calculated C 62 H 6 98, N 91 5.25

The starting material was prepared in a similar manner to that described in Example 9, but starting from 4-morpholino-4-oxobutyl-4-nitrophenyl carbonate.

Yield: 92%.

¹ H-NMR (CDCl 3): 2.15 (m, 2H); 2.50 (t, 2 H); 3.46-3.53 (m, 2H);

I

3.51-3.75 (m, 6H); 3.38 (t, 2 H); 7.33 (d, 2 H); 8.29 (d, 2 H).

Example 11

4- (1-Methylpiperazin-4-yl) -4-oxobutyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5 -ylcarbamate

NO.

The title compound was prepared using a similar procedure to that described in Example 9, but substituting 3- (4-acetylpiperazino) propyl 4-nitrophenyl carbonate for 4- (methylpiperazin-1-yl) -4-oxobutyl-4-nitrophenyl carbonate .

Yield: 65%.

1 H-NMR (DMSO-d 6): 1.75 (m, 2H); 1.81-2.07 (m, 2 H); 2.08-2.40 (m, 7 H); 2.15 (s. 3H); 2.50-2.60 (m, 1H); 3.22-3.56 (m, 4H); 3.45 (s, 3H); 3.77 (s, 3H); 3.78 (s, 3H); 3.82 (s, 3H); 3.82-3.99 (m, 2H); 4.12-4.32 (m, IH); 6.76 (s, 1 H); 6.87 (dd, IH); 6.92 (d, IH); 7.25 (d, IH); 7.80 (d, IH);

MS-ESI: 542 [M + H] ^&lt; ^{+ &gt};;

Elemental analysis for C 29 H 39 N ₃ O 7, 0.4 H ₂ O

Found C 63.38 H 7.58 Calculated C 63.46 H 7.31

N, 64 N, 7.66

The starting material was prepared according to the procedure described in Example 9, from 4- (4-methylpiperazin-1-yl) -4-oxobutanol.

Yield: 65%.

¹ H-NMR (CDCl 3): 2.08-2.19 (m, 2H); 2.32 (s, 3H); 2.35-2.46 (m, 4H); 2.49 (t, 2 H); 3.51 (t, 2 H); 2.66 (t, 2 H); 4.38 (t, 2 H); 7.39 (d, 2 H); 8.29 (d, 2 H).

Claims (17)

PATENT CLAIMS T '£ 200 $ A compound of formula I wherein: R ^1, R ² and R ³ are each independently hydroxy, phosphoryloxy (-OPO ₃ H _2), one alkoxy group having ¹ to 4 carbon atoms, or an in vivo hydrolysable ester of hydroxy, with the proviso that at least two of R ¹ R ² and R ³ are C 1 -C 4 alkoxy; A is -C0-, a group -0 (0) 0- group, -C0N (R ⁸⁾ -, a group of -S0 ₂ -, or -SO ₂ N (R ⁸⁾ - wherein R ⁸ is H, C (C 1 -C 4) group, (C 1 -C 3) alkoxyalkyl, (C 1 -C 3) alkoxyalkyl, (C 1 -C 3) alkyl or (C 1 -C 3) hydroxyalkyl group; a is an integer from 1 to 4 inclusive; R ^a and R ^b are independently selected from the group consisting of hydrogen, hydroxyl and amino; B is -0-, -C0- group, -N (R ⁹⁾ C0-, -C0N group (R ⁹⁾ -, a group -0 (0) 0-, -N (R ⁹⁾ -, R -N (R ⁹ ) C (O) O-, -N (R ⁹ ) CON (R ¹⁰ ) -, -N (Ŕ ⁹ ) SO ₂ -, -SO ₂ N (R ⁹ ) - or direct a single bond wherein R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxyalkyl, C 1-3 alkyl, and C 1-4 aminoalkyl 1 to 3 carbon atoms and a hydroxyalkyl group containing 1 to 3 carbon atoms; b is 0 or an integer from 1 to 4 inclusive, provided that when b is 0, B is a single direct bond; D is a carboxyl group, a sulfo group, a tetrazolyl group, an imidazolyl group, a phosphoryloxy group, a hydroxyl group, an amino group, an N- (alkyl) amino group having 1 to 4 carbon atoms, an N, N-di (alkyl) amino group having 1-3 groups in each alkyl moiety carbon atoms or a group of the formula -Y ¹ - (CH ₂ ) c R ¹¹ or -NHCH (R ¹² ) COOH; wherein Y ¹ is a direct single bond, -O-, -C (O) -, -N (R ¹³ ) -, -N (R ¹³ ) C (O) -, or -C (O) N (R ¹³ ) -, wherein R ¹³ is a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 3 alkoxyalkyl group and a C 3 -C 3 alkyl group, and a C 3 -C 3 aminoalkyl group or a hydroxyalkyl group having 2 to 3 carbon atoms; c is 0 or an integer from 1 to 4 inclusive; R ¹ is a 5- to 6-membered saturated heterocyclic group bonded via a carbon or nitrogen atom containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or a 5- to 6-membered unsaturated or partially unsaturated heteroaryl group attached through a carbon atom or a nitrogen atom containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, wherein the heterocyclic group or heteroaryl group may carry one or two substituents selected from the group consisting of: oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, carbamoyl, N- (C 1 -C 4 alkyl) carbamoyl, N, N- a di (alkyl) carbamoyl group having 1 to 4 carbon atoms in each alkyl moiety, a hydroxyalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyanoalkyl group having 1 to 3 carbon atoms in the alkyl moiety, a carbamoylalkyl group having 1 to 3 carbon atoms in the alkyl moiety, a carboxyalkyl having 1 to 4 carbon atoms in the alkyl moiety, 1 to 4 carbon atoms aminoalkyl, ¹ N- (alkyl) aminoalkyl having 1 to 4 carbon atoms in each alkyl moiety, N, N-di (alkyl) aminoalkyl group containing 1 to 4 carbon atoms in each alkyl moiety, alkoxyalkyl group C 1-4 alkyl, C 1-4 alkylsulfonylalkyl, and R ¹⁴ where R ¹⁴ is a 5- to 6-membered saturated heterocyclic group bonded via a carbon atom or a nitrogen atom containing an alkyl group containing from 1 to 4 carbon atoms in both the alkoxy moiety and the alkyl moiety. 1 or 2 ring heteroatoms independently of one another. is selected from the group consisting of oxygen, sulfur and nitrogen, wherein the heterocyclic group is optionally substituted with one or two substituents independently selected from the group consisting of:. ₍ i. 1 oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkyl, and C 1 -C 4 alkyl 4 carbon atoms and an alkylsulfonylalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety; R ¹² is an amino acid side chain; R ⁵ is an alkoxy group having 1 to 4 carbon atoms; R ⁴ and R ⁶ are independently selected from the group consisting of: hydrogen, fluorine, nitro, amino, N- (C 1-4 alkyl) amino, N, N-di (alkyl) amino containing each alkyl moiety having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group containing from 1 to 4 carbon atoms, and an alkyl group containing from 1 to 4 carbon atoms; R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, or C 1 -C 3 hydroxyalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof. A compound according to claim 1, wherein R ¹ , R ² and R ³ are all methoxy; or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound of claim 1, wherein R ¹ , R ^2, and R ³ are all C 1 -C 4 alkoxy; R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms and alkyl of 1 to 3 carbon atoms; R ⁵ is methoxy; A is -CO-, -C (O) O-, or -CONH-; a is 1, 2 or 3; B is -CO-, -NHCO-, -CONH-, -C (O) O-, -NH-, -NHC (O) O-, -NHCONH or a single direct bond; b is 0, 1 or 2; ^{! 1} I D is a carboxyl group, a sulfo group, a phosphoryloxy group, a hydroxyl group, an amino group, a N- (alkyl) amino group having 1 to 4 carbon atoms, a N, N-di (alkyl) amino group having 1 to 4 carbon atoms in each alkyl moiety, or a group -Y ¹ (CH ₂ ) c R ¹¹ / wherein Y ¹ is -NHC (O) - or -C (O) NH-; c is 1 or 2; R ¹¹ is a 5- to 6-membered saturated heterocyclic group bonded via a nitrogen atom containing 1 or 2 ring heteroatoms independently selected from an oxygen atom and a nitrogen atom, wherein the heterocyclic group may carry one or two substituents selected from the group consisting of: (1-4C) alkyl, (2-4C) alkanoyl, carbamoyl, (1-3C) cyanoalkyl, (1-3C) hydroxyalkyl, (1-4C) carboxyalkyl 3 carbon atoms and an aminoalkyl group containing 1 to 3 atoms . Carbon; '' i _t · R ⁷ is hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound of claim 1, wherein 12 3 R, R and R are all methoxy; R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, hydroxyl, methoxy and methyl; R ⁵ is methoxy; A is -CO-, -C (O) O-, or -CONH-; 11a is 2 or 3; B is -CO-, -NHCO-, -CONH- or a direct single bond; b is 0 or 1; D is a carboxyl group, a phosphoryloxy group, a hydroxyl group, an amino group, a C 1-4 alkyl group, a N, N-di (alkyl) amino group having 1-4 carbon atoms in each alkyl moiety, or a group of the formula -Y ¹ (CH ₂ ) _c R ^u wherein Y ¹ is -NHC (O) - or -C (O) NH-; c is 1 or 2; R ¹¹ is piperazinyl, morpholinyl or piperidyl, each of which is attached via a ring nitrogen atom and each ring is optionally substituted with one or two substituents selected from the group consisting of: alkyl having 1 to 4 carbon atoms, alkanoyl having 2 to 4 carbon atoms, a carbamoyl group, a cyanoalkyl group having the ^alkyl: 1 to 3 of the atoms. carbon, a (C1-C3) hydroxyalkyl group, a (C1-C3) carboxyalkyl group and a (C1-C3) aminoalkyl group; R ⁷ is hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof. A compound of formula II wherein a, b, A, B and D are as defined herein in claim 1; or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound of claim 5, wherein A is -CO-, -C (O) O-, or -COH-; a is 2 or 3; B is -CO-, -NHCO-, -CONH- or a single direct bond; b is 0 or 1; D is a carboxyl group, a phosphoryloxy group, a hydroxyl group. pina, amino, N- (C 1-4 alkyl) amino, N, N-di (alkyl) amino containing 1 to 4 carbon atoms in each alkyl moiety, or -Y ¹ (CH ₂ ) c R ¹¹ / wherein Y ¹ is -NHC (O) - or -C (O) NH-; c is 1 or 2; R ¹¹ is piperazinyl, morpholinyl or piperidyl, each of which is attached via a nitrogen atom and each ring is optionally substituted with one or two substituents selected from the group consisting of: (1-4C) alkyl, (2-4C) alkanoyl, (carb72) amoyl, (C1-C3) cyanoalkyl, (1-3C) hydroxyalkyl, (C1-C4) carboxyalkyl up to 3 carbon atoms and an aminoalkyl group containing 1 to 3 carbon atoms; or a pharmaceutically acceptable salt, solvate or prodrug thereof. A compound of formula III wherein: R ¹ , R ² and R ³ are independently hydroxyl, phosphoryloxy (-OPO ₃ H ₂ ), (C 1 -C 4) alkoxy or in vivo hydrolysable esterified hydroxy group, provided that at least two of R ¹ groups R ² and R ³ are C 1 -C 4 alkoxy; A is -C0-, -C (0) 0-, -CON (R ⁸⁾ -, a group of -S0 ₂ -, or -SO ₂ N (R ⁸⁾ - wherein R ⁸ is H, C (1-4C) alkoxy, (1-3C) alkoxyalkyl, (2-3C) alkyl, (2-3C) aminoalkyl, or (2-3C) hydroxyalkyl; a is an integer from 1 to 4 inclusive; R ^a and R ^b are independently selected from the group consisting of hydrogen, hydroxyl and amino; B is -0-, -C0- group, -N ^(R9) CO-, -CON (R ⁹⁾ -, -C (0) 0-, -N (R ⁹⁾ -, R -N (R ⁹ ) C (O) O-, -N (R ⁹ ) CON (R ¹⁰ ) -, -N (R ⁹ ) SO ₂ -, -SO ₂ N (R ⁹ ) - or single a direct bond wherein R 1 and R ¹⁰ are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, and C 2 -C 3 alkyl moieties a (C 2 -C 3) aminoalkyl group and a (C 2 -C 3) hydroxyalkyl group; I b is 0 or an integer from 1 to 4 inclusive; D is a 5- to 6-membered saturated heterocyclic group bonded via a carbon or nitrogen atom containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen and nitrogen, wherein the heterocyclic group may carry one or two substituents selected from the group consisting of forms: oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, carbamoyl, N- (C 1 -C 4 alkyl) carbamoyl, N, N- a di (alkyl) carbamoyl group having 1 to 4 carbon atoms in each alkyl moiety, a hydroxy group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyanoalkyl group having 1 to 3 carbon atoms in the alkyl moiety, a carbamoylalkyl group containing (C 1 -C 3) alkyl, (C 1 -C 4) carboxyalkyl, (C 1 -C 4) aminoalkyl, (C 1 -C 4) aminoalkyl, N, N-di (alkyl) aminoalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety, alkoxyalkyl group C 1-4 alkoxy, C 1-4 alkylsulfonylalkyl, and R ¹⁴ where R ¹⁴ is a 5- to 6-membered saturated heterocyclic group (bonded via a carbon or nitrogen atom) containing 1 or 2 ring heteroatoms independently selected from the group consisting of oxygen and nitrogen, wherein the heterocyclic group is optionally substituted with one or two substituents selected from the group consisting of: oxo, hydroxyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkyl, and C 1 -C 4 alkyl; and an alkylsulfonylalkyl group containing from 1 to 4 carbon atoms in each alkyl moiety; R ⁵ is an alkoxy group having 1 to 4 carbon atoms; R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, halogen, nitro, amino, N- (C 1-4 alkyl) amino, N, N-di- (alkyl) amino containing each alkyl moiety having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group containing from 1 to 4 carbon atoms, and an alkyl group containing from 1 to 4 carbon atoms; R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, or C 1 -C 3 hydroxyalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof. A compound according to claim 7, wherein R ¹ , R ^2, and R ³ are all C 1 -C 4 alkoxy; R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms and alkyl of 1 to 3 carbon atoms; R ⁵ is methoxy; A is -CO-, -C (O) O-, or -CONH-; a is 1, 2 or 3; B is -CO-, -NHCO-, -CONH-, -O (O) O-, -NH-, -NHC (O) O-, -NHCONH, or a direct single bond; b is 0, 1 or 2; D is piperazinyl or morpholinyl or piperidyl, each optionally substituted with one or two substituents selected from the group consisting of C 1-4 alkyl, C 2-4 alkanoyl, carbamoyl, cyanoalkyl a C 1-3 alkyl group, a C 1-3 hydroxyalkyl group, a C 1-3 alkyl carboxyalkyl group, and a C 1-3 alkyl aminoalkyl group; R ⁷ is hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound of claim 7, wherein R ¹ , R ² and R ³ are all methoxy; R ⁴ and R ⁶ are independently selected from the group consisting of hydrogen, hydroxyl, methoxy and methyl; R ⁵ is methoxy; A is -CO-, -C (O) O-, or -CONH-; a is 2 or 3; B is -CO-, -NHCO-, -CONH or a single direct bond; b is 0 or 1; D is piperazino or morpholino, each ring optionally substituted with one or two substituents selected from the group consisting of methyl, ethyl, acetyl, propionyl, carbamoyl and 2-hydroxyethyl; R ⁷ is hydrogen; or a pharmaceutically acceptable salt, solvate or prodrug thereof. A compound of formula IV wherein a, b, A, B and D are as defined herein in claim 7; or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound of claim 10, wherein Ά is -CO-, -C (O) O-, or -CONH-; a is 2, or 3; B is -CO-, -NHCO-, -CONH- or a single direct bond; b is 0 or 1; D is piperazino or morpholino wherein each ring is optionally substituted with one or two substituents selected from the group consisting of methyl, ethyl, acetyl, propionyl, carbamoyl, and 2-hydroxyethyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof. The compound of claim 10, wherein A is -CO-, -C (O) O-, or -CONH-; a is 2 or 3; B is -CO-, -NHCO-, -CONH- or a single bond; b is 0 or 1; D is morpholino, 4-methylpiperazin-1-yl or 4-acetylpiperazin-1-yl; or a pharmaceutically acceptable salt, solvate or prodrug thereof. 13. A compound selected from the group consisting of: N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] 78 -cyclohepten-5-yl] -2- (2-aminoacetylamino) acetamide; Disodium 4-oxo-4 - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl] amino] butyl phosphate; N- {N- [2- (imidazol-l-yl) ethyl] carbamoyl} - (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, d] cycloheptene 5-ylamine; Disodium 2- {N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamoyloxy} ethyl phosphate; 2-morpholinoethyl N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl] carbamate; 3- (1-Methylpiperazin-4-yl) propyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate; N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5 H -dibenzo [a, c] cyclohepten-5-yl] -2- (2-aminoacetylamino) acetamide; 2- (1-acetylpiperazin-4-yl) ethyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate; N - ((5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] -4- (1-methylpiperazin-4-yl) ) -4-oxobutan-l-amino Disodium 4-oxo-4 - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] amino] butylphosphate; N- (N- [2- (imidazol-1-yl) ethyl] carbamoyl} - (5S) -3,9,10,11-tetramethoxy-6,7-dihydro-57H-dibenzo [a, c] cyclohepten- 5-ylamine; 3- (1-acetylpiperazin-4-yl) propyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate; Disodium N-1 - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamoyloxy] ethyl phosphate; 4-morpholino-4-oxobutyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo [a, c] cyclohepten-5-yl] carbamate; and 4- (1-methylpiperazin-4-yl) -4-oxobutyl-N - [(5S) -3,9,10,11-tetramethoxy-6,7-dihydro-57H-dibenzo [a, c] cyclohepten-5 -yl) carbamate; or a pharmaceutically acceptable salt, solvate or prodrug thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a pharmaceutically acceptable carrier. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the preparation of a medicament for use in obtaining a blood-damaging effect in warm-blooded animals. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the preparation of a medicament for administration in divided dose form for use in producing a vascular damaging effect in warm-blooded animals. 17. A process for preparing a compound of formula I or a compound of formula I, wherein at least one functional group is protected, wherein R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ^7, R ^s, R ^9, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , A, B, D, a, b and c are as defined in claim 1, characterized in that it comprises: a) reacting a compound of formula X (X) with a compound of formula XI L ¹ -A- [CH (R ^a )] and B- [CHR ^b )] b ^- D (XI) wherein L ¹ is a leaving group; or b) converting one compound of formula I into another compound of formula I; c) if a phosphoryloxy group is desired, reacting the corresponding hydroxy compound with phosphoramidite; wherein any functional group is optionally protected; and then, if necessary: i) converting a compound of formula I to another compound of formula I; (ii) removal of any protecting groups; iii) preparing a pharmaceutically acceptable salt, solvate or prodrug.