SK6172000A3 - Use of macrolides for the treatment of cancer and macular degeneration - Google Patents

Abstract

A method for treating tumors and macular degeneration in a human or veterinary patient comprising administering a compound selected from the group consisting of (I), (II), (III), (IV), (V), (VI), (VII), and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound thereof.

Description

The present invention relates to novel uses of polysynthetic macrolides, more specifically anti-tumor activity and activity against macular degeneration. More particularly, the present invention relates to 6-O-substituted erythromycin derivatives and compositions containing such compounds used for the treatment of tumors and macular degeneration.

BACKGROUND OF THE INVENTION

Erythromycins A to D represented by formula (E),

Ervtiromycin A B

R ⁴ R ^b

-OH -CH ₃ -H -CH ₃

C -OH -H

D-H-H are known and potent antibacterial agents. However, over the past few years, publications have been published stating that erythromycin may have antitumor activities as well as other beneficial activities.

Hamada et al. reported that mice having tumor and treated orally with erythromycin doses of 1-10 mg / kg showed a 2 to 3-fold increase in survival times compared to control mice (Chemotherapy, 41, 59-69 (1995)). Mikasa et al. reported that long-term clarithromycin treatment ("clarithromycin") in patients with lung cancer prolongs survival times (Chemotherapy, 43, 288-296 (1997)). WO 95/28939 discloses that 14-membered to 15-membered macrolides, including clarithromycin and erythromycin B, have a potent, antitumor effect on small cell lung cancer cells and are therefore beneficial as practical therapeutic agents for this type of cancer. These cancers are the most difficult to treat surgically and chemotherapeutically.

Much research has been done and much has been spent to develop anticancer drugs. And some chemotherapeutic agents have been discovered. However, new anti-tumor agents and methods for inhibiting, modifying, or regulating tumor growth are still needed.

Angiogenesis is the process by which new, blood vessels attack tissue. This commonly occurs during the treatment of wounds, menstruation and embryo development. However, angiogenesis is extremely important in the development of some tumors. This process of generating new, capillary, blood vessels, also related to neovascularization, is an important part of the fibroproliferative process representing solid tumor growth and inflammation. There are many works on this topic eg. Philips et al. (Others, J. Cancer, 17, 549-588 (1976)) is a work suitable to address this problem.

Unlike angiogenesis in normal, physiological conditions, tumor-induced angiogenesis extends uncontrollably until the cancer kills the host or until the tumor is exterminated. Therefore, inhibition of the angiogenic process is expected to slow the growth of some solid tumors. Marshall and Hawkins reviewed clinical experience with angiogenic compounds in the treatment of both malignant and benign diseases (Breast Cancer Research and Treatment, 36, 253-261 (1995)).

The pathological growth of new, blood vessels is also the basis of most eye diseases that cause severe vision loss. These new vessels, which proliferate under the sensory retina, leak serum and blood, leading to a fibrotic response or disciform scars. Unless the affected eye is treated, choroidal neovascularization generally results in severe vision loss (from 50% to 90%). In addition, patients with a neovascular membrane in one eye are exposed to a high risk of a neovascular membrane in the other eye for 5 years. Therefore, patients with macular degeneration, prior to severe neovascularization and permanent scarring, should be treated with an anti-angiogenic agent.

Age-related macular degeneration (AMD) is the most common cause of vision loss in older Americans. Choroidal neovascularization associated with severe vision loss breaks out in 10-20% of patients with age-related macular degeneration. Current treatments for age-related macular degeneration are divided into four categories: subretinal surgery, laser surgery, radiation and pharmacological treatment. There is no suitable pharmacological treatment for choroidal neovascularization or age-related macular degeneration. Anti-angiogenic agents are among the latest compounds that can be used to pharmacologically treat macular degeneration. These anti-angiogenic drugs are useful in the treatment of the neovascular phase of the disease. Anti-angiogenic therapy mainly inhibits the growth of new vessels rather than stimulating regression of existing vessels. Therefore, there is a need to recognize agents that can prevent the emergence, growth or recurrence of these diseases.

The present invention provides novel utilities of polysynthetic 6-O-alkyl derivatives of erythromycin, particularly for the treatment of tumors and macular degeneration.

SUMMARY OF THE INVENTION

The present invention relates to the use of a pharmaceutical composition for the treatment of tumors and macular degeneration in a human or veterinary subject comprising administering to a patient a therapeutically effective amount of a compound selected from the group consisting of:

₃ (II).

ο

ch ₃ h ₃ c ^ ch ₃

(VI),

wherein R ^a is hydrogen or hydroxy;

R ^b is hydrogen or methyl;

R ^c is a hydrogen atom or a hydroxy protecting group;

X is -NR ¹ R ² wherein R ¹ and R ² are independently selected from the group consisting of (1) a hydrogen atom and (2) C 1 -C 3 -alkyl optionally substituted with a substituent selected from the group consisting of (a) aryl, ( b) substituted aryl, (c) heteroaryl and (d) substituted heteroaryl,

Y is hydrogen or hydroxyl;

or

X and Y are joined together to form a bond;

W is absent or is selected from the group consisting of -Ο-, -NH-, -NHCO-α-N = CH;

R ^w is selected from the group consisting of (1) a hydrogen atom, (2) C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl, (b) substituted aryl, (c) heteroaryl; (d) substituted heteroaryl, (e) hydroxy groups, (f) C 1 -C 6 -alkoxy groups, (g) NR 1 R ² , wherein R ¹ and R ² are as defined above, and (h) -CH 2 -MR ³ wherein the substituent M is selected from the group consisting of:

(i) -C (O) -NH- (ii) -NH-C (O) -, (iii) -NH-, (iv) -N =, (v) -N (CH ₃ ) -, (vi) ) -NH-C (O) -O-, (vii) -NH-C (O) -NH-, (viii) -OC (O) -NH-, (ix) -OC (O) -O-, (x) -O-, (xi) -S (O) _n -, wherein the index n is 0, 1 or 2, (xii) -0 (0) -O-, (xiii) -OC (O) - and (xiv) -C (O) -, and

R ³ is selected from the group consisting of:

(i) C 1 -C 6 -alkyl optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted aryl, (cc) heteroaryl, (dd) substituted heteroaryl, (ii) aryl, (iii) substituted aryl and (iii) iv) heteroaryl, (v) substituted heteroaryl and (vi) heterocycloalkyl, (3) C 3 -C 7 -cycloalkyl, (4) aryl, (5) substituted aryl, (6) heteroaryl and (7) substituted heteroaryl; R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -CO ² R ⁴ , wherein R ⁴ is selected from the group consisting of C 1 -C 3 -alkyl, aryl substituted with C 1 -C ₃ -alkyl and heteroaryl substituted with C 1 -C 3 -alkyl, (d) S (O) _n R ⁴ , wherein the index n is 0, 1 or 2 and the substituent R ⁴ is as defined above (e) NHC (O R ⁴ , wherein R ⁴ is as defined above, (f) NHClO ¹ NR ¹ R ² , wherein R ¹ and R ² are as defined above, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl;

(2) C ₂ -C 10 -alkyl;

(3) C 2 -C 10 -alkyl substituted by one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C 1 -C 3 -alkoxy, (d) C 1 -C 6 -alkoxy-C 1-6 -alkyl; C 1-6 alkoxy groups, (e) oxo groups, (Ο -ν ₃ , (g) -CHO, (h) O-SO ₂ - (substituted C 1 -C 6 -alkyl), (i) -NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are selected from the group consisting of (i) a hydrogen atom, (ii) C 1 -C 10 -alkyl, (iii) substituted C 1 -C 10 -alkyl, (iv) C 1 -C 10 -alkenyl, (v) substituted (C 1 -C 12 -alkenyl), (vi) C 1 -C 12 -alkynyl, (vii) substituted C 1 -C ₁₂ -alkynyl, (viii) aryl, (ix) C ₃ -C 8 -cycloalkyl, (x) substituted C ₃ -C 8 -alkyl; -cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) -C 1 -C 11 -alkyl substituted with aryl, (xv) -C 1 -C 10 -alkyl substituted with substituted aryl, (xvi) - C 1 -C 12 -alkyl substituted with heterocycloalkyl, (xvii) -C 1 -C 12 -alkyl substituted with substituted heterocycloalkyl, (xviii) -C 1 -C 8 -alkyl substituted with -C ₃ -C 8 -cycloalkyl, (xix) -C 1 -C 11 -alkyl substituted with -C ₃ -C ₈ -cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) - Heteroaryl-substituted C 1 -C 12 -alkyl and substituted-heteroaryl-substituted C 1 -C 12 -alkyl or R ⁵ and R ⁶ substituents are taken together with the atom to which they are attached to form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (aa) halogen, (bb) hydroxy, (cc) C 1 -C 3 -alkoxy, (dd) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy, ( ee) oxo groups, (ff) C 1 -C ₃ -alkyl, (gg) halo-C 1 -C 3 -alkyl and (hh) C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, (j) -CO ² R ⁴ , wherein the substituent R ⁴ is as defined above, (k) - (O) -NR'R ² , wherein R ¹ and R ² are as defined above, (1) = N-O-R ⁴ , wherein R ⁴ is as defined above, ( (m) -ON, (n) -OS ( O) _n -R ⁴ where n is 0, 1 or 2, wherein R ⁴ is as defined above, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C ₃ -C8-cycloalkyl, (t) substituted C 3 -C 8 -cycloalkyl, (u) C 1 -C 12 -alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) -NH-C (0) -R ⁴ , wherein R ⁴ is as defined above, (y) -NH-C (O) -R * R ² , wherein R ¹ and R ² are as defined above, (z) = N-NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are as defined above, (aa) = NR ³ , wherein R ³ is as defined above, (bb) = N-NH-C (O) -R ⁴ , wherein R ⁴ is as defined above, and (cc) = N-NH-C (O) -NR'R ² , wherein R ¹ and R ² are as defined above;

(4) C 3 -alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO 2 R ^4, wherein R ⁴ is as defined above, (d) -C (O) ^-R3 wherein R ³ is as defined above, (e) -C (O) -NR * R ² , wherein R ¹ and R ² are as defined above, (f) - (= N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C 3 -C 7 -cycloalkyl and (1) C ₁ -C 12 -alkyl substituted by heteroaryl, (5) C ₄ -C 10 -alkenyl, (6) C ₄ -C 10 -alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C 1 -C 3 -alkoxy, (c) oxo, (d) -CHO, (e) CO ² R ⁴ , wherein R is ⁴ is as defined above, (f) -C (O) -NR * R ² wherein R ¹ and R ² are as defined above, (g) -NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are as defined above, (h) = NOR ⁴ , wherein the substituents R ⁴ are as defined above, (>) -C = N, (j) -OS (O) _n -R ⁴ , wherein i ndex n is 0, 1 or 2 and R ⁴ is as defined above, (k) aryl, (1) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C 3 -C ₇ -cycloalkyl, (p) heteroaryl-substituted C 1 -C 11 -alkyl, (q) -NH-C (O) -R ⁴ , wherein R ⁴ is as defined above, (r) -NH-O ² -R'R ² , wherein R is ¹ and R ² are as defined above, (s) = N-NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are as defined above, (t) = NR ³ , wherein R ³ is as defined above, (u) = N -NH-C (O) -R ⁴ wherein R ⁴ is as defined above and (v) = Ν-ΝΗ-O (O) -ΝΠ <^ ² , wherein R ¹ and R ² are as defined above, (7) ) C 3 -C 10 -alkynyl and (8) C 3 -C 10 -alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl and (e) substituted heteroaryl,

The present invention also provides pharmaceutical compositions for treating tumors and macular degeneration in humans or veterinary subjects comprising a pharmaceutically acceptable carrier and a compound selected from the above formulas (I) to (VR) in combination with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

definitions

The terms used in the specification and the appended claims have the following specified meanings:

The term "C 1 -C 3 -alkyl", "C 1 -C 6 -alkyl" or "C 1 -C 6 -alkyl" as used herein refers to a saturated, branched or unbranched chain of hydrocarbon radicals having an alkyl group of 1 to 3, s Examples of C1-C3 alkyl radicals include methyl, ethyl, propyl and isopropyl. Examples of C 1 -C 6 -alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n -butyl, n -butyl, neopentyl, and N-hexyl. Examples of, but not limited to, C 1 -C 10 -alkyl radicals include all of the foregoing examples and e.g. n-heptyl, n-octyl, n-nonyl, n -decyl, n-undecyl and ndodecyl.

The term "C 1 -C 6 -alkoxy" as used herein refers to a C 1 -C 6 -alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Examples of the C 1 -C 6 -alkoxy group include, but are not limited to, methoxy group, ethoxy group, propoxy group, isopropoxy group, n -butoxy group, tert -butoxy group, iso -pentoxy group, and n-hexoxy group.

The term "C 1 -C 11 -alkenyl" refers to a monovalent group having at least one carbon double bond obtained from a hydrocarbon moiety containing 2-12 carbon atoms by removing one hydrogen atom. Alkenyl includes e.g. ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "C 1 -C ₁₂ -alkynyl" as used herein refers to a monovalent group having at least one carbon-carbon triple bond derived from a hydrocarbon containing 2-12 carbon atoms by removing one hydrogen atom. Representative alkynyl groups include e.g. ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term "alkylene" refers to a divalent group obtained from a branched or unbranched, saturated, hydrocarbon chain by removal of two hydrogen atoms, e.g. methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.

The term "C 1 -C 3 -alkylamino" as used herein refers to one or two of the above-defined C 1 -C 3 -alkyl groups attached to the parent molecular moiety through a nitrogen atom. Examples of the C 1 -C 3 -alkylamino group include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, and propylamino groups.

The term "oxo" refers to groups wherein two hydrogen atoms on one carbon atom in the above alkyl group are replaced by one oxygen atom (namely, a carbonyl group).

The term "aryl" as used herein refers to a monocyclic or bicyclic, carbocyclic, ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Aryl groups (including bicyclic, aryl groups) may be unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of lower alkyl, substituted lower alkyl, cycloalkyl, alkenyl, alkoxy, alkanoyl, haloalkyl, alkoxy, thioalkoxy, amino groups, alkylamino groups, dialkylamino groups, acylamino groups, cyano groups, hydroxy groups, hydroxyalkyl, halogen, mercapto groups, nitro groups, carboxaldehyde, carboxy groups, alkoxycarbonyl and carboxamide In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "C 3 -C 12 -cycloalkyl" refers to a monovalent group obtained from a monocyclic or bicyclic, saturated, carbocyclic ring by the removal of one hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl and bicyclo [2.2.2] octyl.

The term "halo" or "halogen" as used herein refers to an atom selected from the group consisting of fluorine, chlorine, bromine and iodine.

The term "alkylamino" refers to a group having the structure -NHR ', wherein R is alkyl as defined above. Examples of the alkylamino group include a methylamino group, an ethylamino group, an iso-propylamino group, and the like.

The term "dialkylamino" refers to a group having the structure -NR'R, wherein R 'and R' are independently selected from alkyl as defined above. Optionally, R 'and R' are joined together to form - (C 1-6 -) wherein the index k is a number ranging from 2 to 6. Examples of a dialkylamino group include dimethylamino, diethylaminocarbonyl, methylethylamino, piperidino, and the like.

The term "haloalkyl" refers to an alkyl group as defined above having one, two or three halogen atoms attached to each other. Examples of such a group include chloromethyl, bromomethyl, trifluoromethyl, and the like.

The term "alkoxycarbonyl" refers to an ester group; namely an alkoxy group attached to the parent molecular moiety through a carbonyl group. Examples include methoxycarbonyl, ethoxycarbonyl, and the like.

The term "thioalkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom.

The term "carboxaldehyde" as used herein refers to a group of formula -CHO.

The term "carboxy," as used herein, refers to a group of the formula -CO ₂ H.

The term "carboxamide" as used herein refers to a group of formula CONHR'R, wherein R 'and R' are independently selected from the group consisting of hydrogen or alkyl, or R 'and R are optionally joined together to form - (CH ₂ ) k -, wherein the index k takes values from 2 to 6.

The term "heteroaryl" as used herein refers to a cyclic, aromatic radical having from 5 to 10 ring atoms of which one ring atom is selected from sulfur, oxygen and nitrogen; none, one or two ring atoms are other heteroatoms independently selected from sulfur, oxygen and nitrogen; and increasing ring atoms are carbon, a radical that is linked to the remainder of the molecule via any ring atoms, such as e.g. pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

The term "heterocycloalkyl", as used herein, refers to non-aromatic partially unsaturated or fully saturated 3 to 10-membered ring systems that contain single rings of 3 to 8 atoms and bicyclic or tricyclic, ring systems, which may include aromatic six-membered aryl groups or heteroaryl rings fused to a non-aromatic ring. These heterocycloalkyl rings contain ring systems having 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen may be quatized.

Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl and tetrahydrofuryl.

The term "heteroarylalkyl" as used herein refers to a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, wherein the alkylene group has 1 to 4 carbon atoms.

The term "hydroxy position protecting group" as used herein refers to an easily removable group known in the art to protect a hydroxyl group against undesired reactions during the syntheses and which is selectively removable. The use of hydroxy protecting groups is well known in the art, as well as protecting groups against adverse reactions during syntheses, and many such groups can be found e.g. in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2 ^nd edition, John Wiley &amp; Sons, New York (1991). Examples of hydroxy protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as methoxymethyl and esters including acetylbenzoyl, and the like.

The term "protected hydroxy position" refers to a protecting group as defined above, which is used to protect the hydroxy position, including e.g. benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

The term "substituted aryl" as used herein refers to an aryl group, as defined herein, substituted independently by substituting one, two, or three hydrogen atoms with Cl, Br, F, I, OH, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -alkyl. C 6 -alkoxy, C 1 -C 6 -alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any substituent may be aryl, heteroaryl or heterocycloalkyl. Substituted aryl groups also include tetrafluorophenyl and pentafluorophenyl.

The term "substituted heterocycloalkyl" as used herein refers to a heterocycloalkyl group as defined herein substituted by independently replacing one, two, or three hydrogen atoms with a group of e.g. Cl, Br, F, I, OH, -CN, C 1 -C 3 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any substituent may be aryl, heteroaryl or heterocycloalkyl.

Many asymmetric centers may exist in the compounds of the present invention.

Without those places where otherwise noted, the present invention contemplates various stereoisomers and mixtures thereof. Thus, whenever a bond is represented by a wavy line, it is believed that a mixture of stereo-oriented or individual isomers of specified or unspecified orientation may be present.

The term "pharmaceutically acceptable salt" as used herein refers to those salts which, within the scope of reasonable medical judgment, are suitable for use in contact with human or lower animal tissues without toxic action, irritation, allergic reactions, and the like. and are proportional to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art e.g. Berge, S. M., et al., Describes pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. Salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reaction of the free base reacted with a suitable organic acid. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino group salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, orthophosphoric acid, sulfuric acid or perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid , citric acid, succinic acid or malonic acid, or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecylsulfate, ethanesulfonate, glucerate, fumarate, fumarate, fumarate, fumarate, fumarate, , hexanoate, hydrogen iodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pamoate, pectinate, pectinate, , pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, ptoluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include the following cations sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium ion, quaternary ammonium ion, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and arylsulfonate.

The term "pharmaceutically acceptable ester" as used herein refers to esters that hydrolyze in vivo and include those esters that readily tear off in the human body and leave the parent compound or salt thereof. Suitable ester groups include e.g. groups obtained from pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each part of the alkyl or alkenyl moiety preferably has no more than 6 carbon atoms. Examples of individual esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates.

The term "pharmaceutically acceptable prodrug" as used herein refers to those prodrugs of the compounds of the present invention which, to the extent of reasonable medical judgment, are suitable for use in contact with human and lower animal tissues without causing toxicity, irritation, allergic reactions, etc., proportional to the reasonable benefit / risk ratio and effective for their intended use, as well as forms of zwitterion, where possible, of the compounds of the present invention. The term "prodrug" refers to compounds that are rapidly transformable in vivo to obtain the parent compound of the above formula e.g. hydrolysis in the blood. Complete information can be found in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol 14 of the A.C.S. Syria Syria and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference.

Pharmaceutical preparations

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carriers" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulated or excipient of any type. Examples of substances that can be administered as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powder crushed traganth; malt; gelatin; talc; excipients such as cocoa butter and suppositories of wax; oils, such as peanut oil, cottonseed oil; saffron oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffering solutions as well as other non-toxic, compatible lubricants such as sodium lauryl sulphate and magnesium stearate as well as coloring agents, disintegrating agents, coating agents, sweeteners, flavor enhancers and fragrance release agents, protective compositions, antioxidant preparations may also be present in the compositions, at the discretion of the inventor. The pharmaceutical compositions of this invention may be administered to humans and other animals orally, rectally, parenterally, intracisterially, intravaginally, intraperitoneally, topically (by dusting, ointments, drops), buccally, or as oral or nasal sprays.

Dosages in liquid form for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, dosages in liquid form may contain inert diluents commonly used in the art e.g. such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cotton, peanut, corn, germ, olive, olive, oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. Compared to inert diluents, oral preparations may also include adjuvants, such as detergents, emulsifiers and suspending agents, sweeteners, flavorants and fragrance release agents.

injectable preparations e.g. sterile injectable aqueous or oleaginous suspensions may be formulated according to techniques known in the art using suitable detergents or dispersing and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally-acceptable diluent or solvent such as e.g. solution in 1,3-butanediol. Suitable vehicles and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, solid oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations may be sterilized e.g. by filtration through a bacterial-retaining filter or by inserting a sterilizing agent in the form of sterile, solid preparations which can be dissolved or dispersed in sterile water or other sterile injectable compositions prior to use.

To prolong the effect of the drug, it is often desirable to delay the absorption of the drug upon subcutaneous intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous substances with poor water solubility. The rate of absorption of the drug then depends on its dissolution rate, which may depend on crystalline size and crystalline form. Alternatively, slower absorption of the parenterally administered form of the drug is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable, depot forms are made by forming microencapsulated drug matrices in biodegradable polymers such as polyactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the type of individual polymers used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by retaining the drug in liposomes or microemulsions that are compatible with body tissues.

Formulations for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of this invention with suitable, non-irritating excipients or carriers such as cocoa butter, polyethyl ethylene glycols or suppositories of wax that are solid at room temperature but liquid at temperature of the body and therefore melt in the rectum or vaginal cavity to release the active compound.

Dosages in solid form for oral administration include capsules, tablets, pills, powders, and granules. In such dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and orthosilicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gelatin; c) wetting agents such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic, certain silicates and calcium carbonate, e) solution inhibitors such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) detergents such as cetyl alcohol and glycerol monostearate, h) adsorbents such as kaolin and bentonite kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent.

Solid formulations of a similar type may also be employed as fillers in lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Dosages in solid form, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulations art. Dosages in solid form may optionally contain a opacifying agent, and may also be free of such formulations that release only or preferably the active ingredients in a particular part of the intestinal tract, or be delayed to some extent. Examples of embedded compositions that can be used include polymeric substances and waxes.

The active compounds may also be in microencapsulated form with one or more of the above-mentioned excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the art of pharmaceutical formulations. In such dosage forms, the active compound may be admixed with at least one inert diluent such as starch, lactose or sucrose. Such dosage forms may also contain, as is normal practice, other substances other than inert diluents, e.g. tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent. They may optionally contain a opacifying agent and may also be free of such agents which release only or preferably the active ingredients in a certain part of the intestinal tract, possibly to some extent delayed. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of the invention further include ointments, pastes, creams, liquid forms for external use, gels, dusts, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as desired. Ophthalmic formulations, ear drops, eye ointments, dusting powders and solutions are also contemplated within the scope of the present invention.

Ointments, pastes, creams and gels may contain, in addition to the active compound of the invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, orthosilicic acid, talc, oxide zinc or mixtures thereof.

The powders and sprays may contain, in addition to the active compound of the invention, excipients such as lactose, talc, orthosilicic acid, aluminum hydroxide, calcium silicate and polyamide 22 powder or mixtures thereof. Sprays may further contain conventional propellants such as chlorofluorocarbons.

In addition, transdermal patches have the advantage of providing accurate delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may be used to increase the flow of the compound through the skin. The rate of increase can be controlled by either controlling membrane permeation or dispersing the compound in a polymer matrix or gel.

In the present invention, bacterial infections are treated or prevented, in patients such as humans or lower mammals, by administering a therapeutically effective amount of a compound of the invention to the patient in such amounts and at such time as is necessary to achieve the desired result. By "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of a compound of the invention to treat bacterial infections in a reasonable benefit / risk ratio applicable to any medical treatment. However, it is clear that the total daily use of the compounds and compositions of the present invention depends on the judgment of the attending physician after reasonable medical judgment. The specific, therapeutically effective dose level for any individual patient will depend on various factors including the disease being treated and the severity of the disease; the activity of the specific compound used; use of a specific formulation; the age, body weight, general health, sex and lifestyle of the patient; the time of administration, the method of administration and the rate of excretion of the specific compound used; duration of treatment; drugs used in combination or in association with the specific compound used; and similar factors well known in medical practice.

The total daily dose of the compounds of the invention administered to a human or other mammal in single or divided doses may be in an amount of, for example, from 0.01 to 200 mg / kg body weight, or more preferably 10 to 100 mg / kg body weight. Single dosages of preparations may contain such amounts or fractions thereof to form a daily dosage. Generally, the treatment regimens of the present invention comprise administering to a patient in need of such treatment from about 10 mg to about 2000 mg of the compounds (s) of the present invention per day in single or divided doses.

In the present invention, a compound selected from the group of compounds having formulas (I) - (V) is used to treat tumors and macular degeneration. Preferably, the compound is selected from the group of compounds having the formulas:

Compound of Formula (I): R ^a = OH, X = NHMe, Y = H, R ^c = H;

Compound of Formula (I): R ¹ = OH, X = β 2, Y = H, R ^c = formyl; Compound of Formula (I): R ^a = OH, X and Y = are joined together to form a bond, R ^c = H;

Compound of Formula (I): R ^a = OH, X = ββ2, Y = OH, R ^c = H;

Compound of Formula (I): R ^a = OH, X = NMe (benzyl), Y = H, R ^c = H; Compound of Formula (II);

Compound of Formula (R): R = -CH 2 CH = CH 2

Compound of formula (III). R = -CH 2 CH = N-O- (benzyl);

Compound of Formula (III): R = -CH 3; (clarithromycin)

Compound of Formula (IV);

Compound of Formula (V): R ^a = OH, R ^b = H; and

Compound of Formula (V): R ^a = OH, R ^b = CH 3.

In a preferred pharmaceutical formulation of the invention, the compound is selected from the group of compounds of formulas (I) - (V). In a more preferred pharmaceutical composition, the compound is selected from the group of compounds in the above section.

The present invention will be better understood in conjunction with the following examples which illustrate methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention, which is fully defined in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Anti-angiogenic in vitro activity of selected macrolides

Representative compounds of the present invention were tested in vitro for the ability to induce giant cells in a peritoneal macrophage culture of mice. Since the anti-angiogenic activity of macrolides correlates with their ability to induce giant cells in the culture of peritoneal 24 macrophages in mice. In vitro macrolide activity was determined according to the method described by E.Kita et al. , Nat. Immun., 12, 326-338 (1993). The numbers indicate the minimum concentration of the analytical sample necessary to induce giant cells. The data presented in Table 1 below show that the compounds were effective in inducing giant cells and therefore these compounds have anti-angiogenic activity.

Table 1

In vitro activity of selected compounds * in the induction of giant cells

in Compound number Minimum concentration for induction (μΜ) 1 2.0 2 1.0 3 2.5 4 1.0 5 3.5 6 2.0 7 5.0 8 2.0 11 1.0 12 2.0

the compounds are listed in Table II below

Table 2

Labeling and source of selected macrolides tested in vitro or in vivo as described below

Number compound Indication or method of preparation 1 Compound of Formula (I): R ^a = OH, X = NHMe, Y = H, R ^c = H; Freiberg, U.S. Pat. Patent 3,725,385 (1973) 2 Compound of Formula (I): R ^a = OH, X = β 2, Y = H, R ^c = formyl; Tanadier et al., J. Org. Chem. 39, 2495 (1974). 3 Compound of Formula (I): R ^a = OH, X and Y = are joined together to form a bond, R ^c = H; Jones and Rowley, J. Org. Chem., 33, 665 (1968). 4 Compound of Formula (I): R ^a = OH, X = ββ2, Y = OH, R ^C = H; Compound of Formula (II); Jones et al., Antimicrob. Agents Chemother., 123 (1970) 5 Compound of Formula (I): R ^a = OH, X = NMe (benzyl), Y = H, R ^c = H; Freiberg, U.S. Patent 3,681,325, issued 1.8.1972 6 Compound of Formula (II); Kurath et al. (Experientia, 27, 362, 1971) 7 Compound of Formula (III): R = -CH ₂ CH = CH 2 Or et al. U.S. Pat. No. 08 / 841,038 filed April 29, 1997 8 Compound of Formula (III): R = -CH ₂ CH = NO- (benzyl); Or et al. U.S. Pat. No. 08 / 841,038 filed April 29, 1997 9 Compound of Formula (III): R = -CH ₃ (clarithromycin) Abbott Laboratories 10 Compound of Formula (IV); Hardy et al., Antimicrob. Agents Chemother. 32, 1710-1719 (1988). 11 Compound of Formula (V): R ^a = OH, R ^b = H; McAlpine et al., 30 ^{, h} Intl. Conf. Antibiot. Agents. Chemother., Atlanta, USA, 1990, Abst. 810 12 Compound of Formula (V): R ^a = OH, R ^b = CH ₃ . McAlpine et al., 30 ^{, h} Intl. Conf. Antibiot. Agents. Chemother., Atlanta, USA, 1990, Abst. 810

Example 2

Anti-angiogenic in vivo activity of selected macrolides

The anti-angiogenic properties of macrolides were tested in vivo in a mouse corneal model. In this model, neovascularization is induced by a bFGF-containing pellet implanted into the cornea. Macrolide was administered orally, QD, from day 0 (pellet implantation day) until day 5. On day 6, mice were perfused with saline and ink. The eyes were removed, fixed, and the cornea was removed and mounted on a microscope slide. Microvessel density was determined by an image analysis system and the anti-angiogenic effect of the test compounds was also estimated.

procedures

Pellet preparation

The pellets were prepared containing a mixture of three substances: 1) Hydron ™ (polyhydroxyethyl methacrylate), a slow-release polymer; 2) Sucralfate ™ to stabilize and slow down the released, basic fibroblast growth factor? (BFGF); and 3) bFGF of a potent anti-angiogenic, growth factor. The mixture, after rapid evaporation and resuspension to a small volume, was coated onto a sterile, polyamide, mesh knit. After drying, pellets having approximately the same sizes of 0.4 x 0.4 x 0.2 mm were obtained by separating the fibers of the mesh knitted fabric. Each pellet contained approximately 100 ng of the optimally determined dose of bFGF.

Pellet implantation

Approximately 8 week old CF-1 albino mice were used in this observation. Under anesthesia and using a dissecting microscope, an intrastromal microtube was formed on a 0.7 mm temporal limbus. Individual pellets were applied to the corneal surface and placed in a pouch. Control animals were not treated with drugs. The antibiotic ointment was applied to the eyes implanted in the pellet immediately after surgery. The eyes were examined after surgery

therapy

Treatment was started on day 0 after recovery of the mice from anesthesia. In three experiments, the compounds were administered orally, 4 times a day to a group of three mice per dose. Doses were from 25 to 200 mg / kg / day for 6 days. Compound 8 was tested at 100 mg / kg / day, Compound 9 at 25 to 200 mg / kg / day, and Compound 10 at 100 mg / kg / day. Control groups contained three mice per experiment. For control toxicity measurements, in two experiments, taxol was administered intraperitoneally 4 times daily to a group of three mice per dose containing 10 mg / kg / day for 6 days.

Examination of neovascularization

On the sixth day after surgery, mice under deep anesthesia were perfused first by intracardial injection of 25 ml saline followed by a 1:30 tube. The eyes were enucleated overnight and fixed with 10% formaldehyde. After fixation, the corneas were dissected and mounted on a microscope slide. Microvessel density was measured by image analysis using the Image-Pro Plus software program. Microvessel density was measured in absolute units and is expressed as ± mean standard error (n = 6).

The results

Taxol-treated animals had positive signs of toxicity. No macroscopic signs of toxicity were observed in mice treated with macrolide. Compounds 8, 9, 10 administered at 100 mg / kg / day reduced angiogenesis in the mouse corneal model by 50%, as expected from reduced microvessel density in treated animals.

Claims (6)

Use of a compound selected from the group consisting of: (ΙΠ), (IV), (VI), (VII), wherein R * is hydrogen or hydroxy; R ^b is hydrogen or methyl; R ^c is a hydrogen atom or a hydroxy protecting group; X is -NR'R ² wherein R ¹ and R ² are independently selected from the group consisting of (1) a hydrogen atom and (2) C 1 -C 3 -alkyl optionally substituted with a substituent selected from the group consisting of (a) aryl, ( b) substituted aryl, (c) heteroaryl and (d) substituted heteroaryl, Y is hydrogen or hydroxyl; or X and Y are joined together to form a bond; W is absent or is selected from the group consisting of -Ο-, -NH-, NH-CO- and -N = CH; R ^w is selected from the group consisting of (1) a hydrogen atom, (2) C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl. (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) hydroxy groups, (f) C 1 -C 6 -alkoxy groups, (g) NR ¹ R ² , wherein R ¹ and R ² are as defined above above and (h) -CH 2 -MR ³ wherein M is selected from the group consisting of: (i) -C (O) -NH-> (ii) -NH-C (O) -, (iii) -NH-, (iv) -N =, (v) -N (CH ₃ ) -, (vi) -NH-C (O) -O- (vii) -NH-C (O) -NH-, (viii) -OC (O) -NH-, (ix) -OC (O) -O-, (x) -O-, (xi) - S (0) _n ', where index n is 0, 1 or 2, (xii) -C (O) -O-, (xiii) -OC (O) - and (xiv) -C (O) -> and R ³ is selected from the group consisting of: (i) C 1 -C 6 -alkyl optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted aryl, (cc) heteroaryl, (dd) substituted heteroaryl, (ii) aryl, (iii) substituted aryl and (iii) iv) heteroaryl, (v) substituted heteroaryl and (vi) heterocycloalkyl, (3) C 3 -C 7 -cycloalkyl, (4) aryl, (5) substituted aryl, (6) heteroaryl and (7) substituted heteroaryl; R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -CO ² R ⁴ , wherein R ⁴ is selected from the group consisting of C 1 -C 3 - alkyl, aryl substituted with C 1 -C 3 -alkyl and heteroaryl substituted with C 1 -C 3 -alkyl, (d) S (O) n R ⁴ , wherein the index n is 0, 1 or 2 and R ⁴ is as defined above (e) NHC (O) R ⁴ wherein R ⁴ is as defined above, (f) NHC (O) NR 1 R ² , wherein R ¹ and R ² are as defined above, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl; (2) C ₂ -C 10 -alkyl; Second (2) C 2 -C 10 -alkyl; (3) C 2 -C 10 -alkyl substituted with one or more substituents selected from the group consisting of (a) halogen. (b) hydroxy groups, (c) C 1 -C 3 -alkoxy groups, (d) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy groups, (e) oxo groups, (f) -N 5, (g) -CHO, (h) O-SO 2 - (substituted C 1 -C 6 -alkyl), (i) -NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are selected from the group consisting of (i) a hydrogen atom, (ii) C 1 -C 11 -alkyl, (iii) substituted C-Cl2-alkyl, (iv) Ci-Cu-alkenyl, (v) substituted Cl-Cn-alkenyl, (vi) C _r C 12 alkynyl, (vii) substituted C Cu alkynyl, (viii) aryl, (ix) C ₃ -C 8 -cycloalkyl, (x) substituted C 3 -C -cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) -C (Xv) -C 1 -C 12 -alkyl substituted with aryl, (xv) -C 1 -C 12 -alkyl substituted with substituted aryl, (xvii) -C 1 -C 12 -alkyl substituted with heterocycloalkyl, (xviii) -Ci -C12-alkyl substituted with -C3-C8-cycloalkyl, (xix) —C1-C12-alkyl substituted with substituted -C3-C8cycloalkyl, ( (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) -C 1 -C 11 -alkyl substituted with heteroaryl and (xxiii) -C 1 -C 10 -alkyl substituted with substituted heteroaryl or R ⁵ and R ⁶ are taken together with the atom to which they are attached linked to form a 3-10-membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (aa) halogen, (bb) hydroxy, (cc) C 1 -C 3 -alkoxy, (dd) _{Cl-C3-alkoxy-Ci-C3-alkoxy,} (ee) oxo, (ff) a C -C ₃ -alkyl, (gg) halo-C | -C ₃ -alkyl and (hh) a C ₃ -C -alkoxy-C 1 -C ₃ -alkyl, (j) -CO ² R ⁴ , wherein the substituent R ⁴ is as defined above, (k) -Q 0j-NR'R ² , wherein the substituents R ¹ and R ² are as defined above, (1) = N-O-R ⁴ wherein R ⁴ is as defined above, (m) -ON, (n) -OS (O) n -R ⁴ , wherein R ⁴ is as defined above, and n is 0, 1, or 2, (o) aryl, (p) substituted aryl, (q) h eteroarylu, (r) substituted heteroaryl, (s) C ₃ -C -cycloalkyl, (t) substituted C ₃ -C -cycloalkyl, (u) Ci-Cn-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, , (x) -NH-C (0) -R ^4, wherein R ⁴ is as previously defined, (s) -ΝΗ-ΟίΟ) ^^ ^2, wherein the substituents R and R ² are as previously defined, (z) = N-NR ⁵ R ⁶ wherein R ⁵ and R ⁶ are as defined above, (aa) = NR ³ wherein R ³ is as defined above, (bb) = N-NH-C (O) -R ⁴ wherein: R ⁴ is as defined above and (cc) = Ν-ΝΗ-Ο (Ο) -ΝΚ ² , wherein R 1 and R ² are as defined above (4) C 1 -alkenyl substituted with a moiety selected from the group consisting of (a) halogen (b) -CHO, (c) -CO ² R ⁴ wherein R ⁴ is as defined above, (d) -C (O) -R ³ wherein R ³ is as defined above, (e) -CfO 3 -NR '; R ^2, the substituents R ¹ and R ² are as defined above, (f) -C = N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C7-cycloalkyl and (1) heteroaryl-substituted C1-C8-alkyl, (5) C4-C10-alkenyl, (6) C4-C10- alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) a C 1 -C ₃ -alkoxy group, (c) an oxo group, (d) -CHO, (e) CO ² R ⁴ , wherein R ⁴ is as defined above, (f) -C10O-NR'R ² wherein R ¹ and R ² are as defined above, (g) -NR ⁵ R ^C , wherein R ⁵ and R ⁶ are as defined above, (h) = NOR ⁴ , wherein the substituents R ⁴ are as defined above. (i) -ON, (j) -OS (O) _n -R ⁴ , wherein n is 0, 1 or 2 and R ⁴ is as defined above, (k) aryl, (1) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C 3 -C 7 -cycloalkyl, (P) C 1 -C 6 -alkyl substituted with heteroaryl, (q) -NH-C (O) -R ⁴ , wherein R ⁴ is as defined above, (r) -NH-C 1 R ³ -R ¹ R ² , wherein the substituents R ¹ and R ² are as defined above, (s) = N-NR ⁵ R ⁶ , wherein the substituents R ⁵ and R ⁶ are as defined above, (t) = NR ³ wherein R ³ is as defined above, (u) = N-NH-C (O) -R ⁴ wherein R ⁴ is as defined above, and (v) = N-NH-C (O) -NR ¹ R ² , wherein R ¹ and R ² are as defined above, (7) C 3 -C 10 -alkynyl and (8) C 3 -C 10 -alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl, Use according to claim 2, wherein the compound is selected from the group of compounds having the formulas: Compound of Formula (I): R 1 = OH, X = NHMe, Y = H, R ^e = H; Compound of Formula (I): R 1 = OH, X = β 2, Y = H, R ^c = formyl; Compound of Formula (I): R 1 = OH, X and Y = are taken together to form a bond, R ^c = H; Compound of Formula (I): R 1 = OH, X = NMe 2, Y = OH, R ^c = H; Compound of Formula (I): R 1 = OH, X = NMe (benzyl), Y = H, R ^c = H; Compound of Formula (Π); Compound of Formula (III): R = -CH 2 CH = CH 2 Compound of Formula (ΠΙ): R = -CH 2 CH = N-O- (benzyl); Compound of Formula (III): R = -CH 3; (clarithromycin) Compound of Formula (IV); Compound of Formula (V): R ^a = OH, R ^b = H; and Compound of Formula (V): R 1 = OH, R ^b = CH 3. (3) C 2 -C 10 -alkyl substituted by one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C 1 -C 3 -alkoxy, (d) C 1 -C 3 -alkoxy-C 1 -C 3 - alkoxy groups, (e) oxo groups, (f) -n (g) -CHO, (h) O-SO 2 - (substituted C 1 -C 6 -alkyl), (i) -NR ⁵ R ⁶ , wherein the substituents R ⁵ and R ⁶ are selected from the group consisting of (f) (i) a hydrogen atom, (ii) C 1 -C 12 -alkyl, (iii) substituted C 1 -C 12 -alkyl, (iv) C 1 -C 12 -alkenyl, (v) substituted C 1 -C 12 -alkenyl, (vi) C 1 -C 12 -alkynyl, (vii) substituted C 1 -C 12 -alkynyl, (viii) aryl, (ix) C ₃ -C 8 -cycloalkyl, (x) substituted C ₃ -C 8 -cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) -C1-Cn-alkyl substituted with aryl, (xv) -C1-C12-alkyl substituted with substituted aryl, (xvi) -C1-Cn- heterocycloalkyl substituted alkyl, (xvii) -C 1 -C 12 -alkyl substituted heterocycloalkyl substituted, (xviii) -C 1 -C n-alkyl substituted with -C 1 -C 8 -cycloalkyl, (xix) -C 1 -C 6 -alkyl substituted with substituted -C 3 -C 8 cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) -C 1 -C 8 -alkyl substituted with heteroaryl, and (xxiii) ) C] -Ci2-alkyl substituted with substituted heteroaryl, or R ^a substituents, and R ⁶ are taken together with the atom to which they are attached to form a 3-10 membered heterocycloalkyl ring, optionally substituted by one or more substituents independently selected from a group consisting of (aa) halogen, (bb) hydroxy, i (cc) C 1 -C 3 -alkoxy groups, (dd) C 1 -C 3 -alkoxy-C 1 -C 3 -alkoxy groups, (ee) oxo groups, (ff) C 1 -C 3 -alkyl, (gg) halogen-C 1 -C 3 - alkyl and (hh) C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, (j) -CO ² R ⁴ , wherein the substituent R ⁴ is as defined above, (k) -C (O) -NR ¹ R ² , wherein the substituents R ¹ and R ² are as defined above, (1) = N-O-R ⁴ , wherein R ⁴ is as defined above, (m) -C = N, (n) -OS (O) _n -R ⁴ , wherein R is ⁴ is as defined above and index a is 0, 1 or 2, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C 3 -C 8 -cycloalkyl, (t) substituted C 5 -C 6 -cycloalkyl, (u) heteroaryl-substituted C 1 -C 12 -alkyl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) -NH-C (O) -R ⁴ , wherein R ⁴ is as defined above, ( y) -NH-C 1 -C 6 -R'R ² wherein R ¹ and R ² are as defined above, (z) = N-NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are as defined above, (aa) = NR wherein R is def as defined above, (bb) = N-NH-C (O) -R ⁴ wherein R ⁴ is as defined above and (cc) = N-NH-C (O) -NR ¹ R ² wherein R ¹ and R ² is as defined above (4) C 3 -alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO ² R ⁴ , wherein R ⁴ is as defined above, (d) -C ( O) -R ³ , wherein R ³ is as defined above, (e) -C (O) -NR ¹ R ² , wherein R ¹ and R ² are as defined above, (f) -C 1 N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C 3 -C 7 -cycloalkyl and (1) heteroaryl substituted C 1 -C 12 -alkyl, (5) C 4 -C 10 -alkenyl, (6) ) C 4 -C 10 -alkenyl substituted by one or more substituents selected from the group consisting of (a) halogen, (b) C 1 -C 3 -alkoxy, (c) oxo, (d) -CHO, (e) CO ² R ⁴ , wherein: R ⁴ is as defined above, (f) -C (O) -NR ¹ R ² , wherein R ¹ and R ² are as defined above, ( g) -NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are as defined above, (h) = NOR ⁴ , wherein R ⁴ are as defined above, (i) -C = N, (j) -OS (O) _n- R ⁴ , wherein the index n is 0, 1 or 2 and the substituent R ⁴ is as defined above, (k) aryl, (1) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl,, (o) C 3 - 7 -cycloalkyl, (p) Ci-Cn-alkyl substituted with heteroaryl, (q) -NH-C (O) -R ^4, wherein R ⁴ is as previously defined, (r) -NH-R a R ^QOÍ-2, wherein R ¹ and R ² are as defined above, (s) = N-NR ³ R ⁶ , wherein R ⁵ and R ⁶ are as defined above, (t) = NR ³ , wherein R ³ is as defined above, (u) ) = N-NH-C (O) -R ⁴ , wherein R ⁴ is as defined above, and (v) = Ν-ΝΗ-O (O) -ί ⁴ , wherein R ¹ and R ² are as defined above , (7) a C3-Cio-alkynyl, and (8) C ₃ -Cio-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl, in a pharmaceutically acceptable carrier. for the preparation of a medicament for the treatment of tumors and mucosal degeneration in humans or veterinary subjects. Use according to claim 1, wherein the compound is selected from the group of compounds having the formula (D- (V)). 4. A pharmaceutical composition for the treatment of tumors and macular degeneration in humans or veterinary subjects, comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of: (D, (II)). απ). (IV). ₃ (VI). (VII) wherein R ^a is hydrogen or hydroxy; R ^b is hydrogen or methyl; R ^c is a hydrogen atom or a hydroxy protecting group; X is -NR'R ² wherein R ¹ and R ² are independently selected from the group consisting of (1) a hydrogen atom and (2) C 1 -C 3 -alkyl optionally substituted with a substituent selected from the group consisting of (a) aryl, ( b) substituted aryl, (c) heteroaryl and (d) substituted heteroaryl, Y is hydrogen or hydroxyl; or X and Y are joined together to form a bond; W is absent or is selected from the group consisting of -Ο-, -NH-, -NH-CO- and -N = CH; R ^w is selected from the group consisting of (1) a hydrogen atom, (2) C 1 -C 6 -alkyl optionally substituted with one or more substituents selected from the group consisting of (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl; (e) hydroxy groups; (f) C1-C6 alkoxy groups; ² wherein R ¹ and R ² are as defined above and (h) -CH ₂ -MR ³ wherein M is selected from the group consisting of: (i) -C (O) -NH-, (ii) -NH-C (O) -, (iii) -NH-, (iv) -N =, (v) -N (CH ₃ ) -, ( vi) -NH-C (O) -O-, (vii) -NH-C (O) -NH-, (viii) -OC (O) -NH-, (ix) -OC (O) -O- , (x) -o-, (xi) -S (O) _n -, wherein the index n is 0, 1 or 2, (xii) -C (O) -O-, (xiii) -OC (O) - and (xiv) -C (O) -, (aa) aryl, (cc) heteroaryl, R ³ is selected from the group consisting of: (i) C 1 -C 6 -alkyl optionally substituted with a substituent selected from the group consisting of (bb) substituted aryl, (dd) substituted heteroaryl, (ii) aryl, (iii) substituted aryl, and (iv) heteroaryl, (v) substituted heteroaryl and (vi) heterocycloalkyl, (3) C 3 -C 7 -cycloalkyl, (4) aryl, (5) substituted aryl, (6) heteroaryl and (7) substituted heteroaryl; R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) (b) (c) -CO ² R ⁴ , wherein R ⁴ is selected from the group consisting of C 1 -C 3 -alkyl, aryl substituted C 1 -C 3 -alkyl and heteroaryl substituted with C 1 -C 3 -alkyl, (d) S (O) _n R ⁴ , wherein the index n is 0, 1 or 2 and the substituent R ⁴ is as defined above (e) NHC (O) R ⁴ wherein R ⁴ is as defined above, (f) NHClO ¹ NR ¹ R ^{2 3} , wherein R ¹ and R ² are as defined above, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl ; Pharmaceutical preparation according to claim 4, characterized in that the compound is selected from the group of compounds having formulas (I) - (V). Pharmaceutical preparation according to claim 5, characterized in that the compound is selected from the group of compounds having the formulas: Compound of Formula (I): R ^a = OH, X = NHMe, Y = H, R ^c = H; Compound of Formula (I): R ^a = OH, X = β 2, Y = H, R ^c = formyl; Compound of Formula (I): R ^a = OH, X and Y = are joined together to form a bond, R ^c = H; Compound of Formula (I): R ^a = OH, X = ββ2, Y = OH, R ^c = H; Compound of Formula (I): R ^a = OH, X = NMe (benzyl), Y = H, R ^c = H; Compound of Formula (II); Compound of Formula (R): R = -CH 2 CH = CH 2 Compound of Formula (III): R = -CH 2 CH = N-O- (benzyl); Compound of Formula (III): R = -CH 3; (clarithromycin) Compound of Formula (IV); Compound of Formula (V): R ^a = OH, R ^b = H; and Compound of Formula (V): R ^a = OH, R ^b = CH 3.