WO2000071131A1

WO2000071131A1 - Hexacyclic g-csf mimetics

Info

Publication number: WO2000071131A1
Application number: PCT/US2000/014857
Authority: WO
Inventors: Kevin J. Duffy; Juan I. Luengo
Original assignee: Smithkline Beecham Corporation
Priority date: 1999-05-26
Filing date: 2000-05-24
Publication date: 2000-11-30
Also published as: AU7253400A

Abstract

Invented are G-CSF mimetics. Also invented are selected hexacyclic compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds as G-CSF mimetics. Also invented are novel processes used in preparing these compounds.

Description

Hexacvclic G-CSF Mimetics

BACKGROUND OF THE INVENTION Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein secreted by macrophages, fibroblasts, and endothelial cells originally identified by its ability to stimulate the survival, proliferation, and differentiation in vitro of predominantly neutrophilic granulocytes from bone marrow progenitors. Nicola, N. A., Annu. Rev. Biochem. (1989) 58:45. The capacity of G-CSF to regulate in vivo granulopoiesis is supported by animal and clinical studies, which demonstrated a reversible rise in circulating neutrophil levels in response to administered recombinant G-CSF. Gabrilove, J. L. et al., N. Enel. J. Med. ( 1988) 318: 1414. G-CSF has pleiotropic effects on mature neutrophils, enhancing their survival and stimulating functional activation, including induction of neutrophil alkaline phosphatase (Sato. N. et al., J. Cell. Phvsiol. (1988) 37:272) and high affinity IgA F_c receptors (Weisbart, R. H., et al., Nature (Lond.) (1988) 332:647), priming for respiratory burst (Nathan, C. F. Blood (1989) 73:301) and increased chemotaxis (Wang, J.M., Blood (1988) 72: 1456). G-CSF effects have also been observed on hematopoietic cells that are not committed to the granulocyte lineage, for example, stimulation of the proliferation on monocytic differentiation in vitro of some myeloid leukemic cells (Geissler, K., J. Immunol. (1989) 143:140) and the proliferation in vitro of some multipotential hematopoietic precursors (Ferrero, D., Blood (1989) 73:402).

Administration of recombinant G-CSF to patients suffering from neutropenia due to various causes indicated that G-CSF is beneficial as an adjuvant in chemotherapy and in bone marrow transplantation (Morstyn, G., et al., Trends Pharmacol. Sci. JO, ( 1989) 154- 159). G-CSF activity is also associated with mobilization of hematopoietic stem cells from the marrow to the peripheral blood. (See review article, Good Review article Haylock et al., Blood 89:2233-2258, 1997). It would be desirable to provide compounds which allow for the treatment of neutropenia to enhance leukocyte production by acting as a G-CSF mimetics. As disclosed herein it has unexpectedly been discovered that certain hexacyclic compounds are effective as G-CSF mimetics. SUMMARY OF THE INVENTION

This invention relates to compounds of Formula (1):

wherein R ! and R^ are independently aryl, where aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NRHR 12, NR^R^, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, Cg-C^aryl, alkoxy, acyloxy, substituted Cg-Ci2^aryf trifluoro methyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C(O)ORl 1, -S(O)_nR¹³, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C - Cnaryl, substituted C6-Ci2^aryl> amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O)_nRl3, aryloxy, nitro, cyano, halogen and protected -OH, where

R 1 1 is hydrogen or alkyl, n is 0-2,

R !2 i_s hydrogen or alkyl and

Rl3 is hydrogen, cycloalkyl, Cg-C^aryl_' substituted cycloalkyl, substituted C6-Ci2^aryh alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORl 1, -S(O)_nRl2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, Cβ-C^aryl, substituted Cg-Cj 2^aryl and protected -OH, where R* 1, n, and R 12 are as described above;

R³, R⁴, R⁵ and R⁶ are independently hydrogen, C(O)NRl !R¹ , Np! 1R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, Cg-C^aryl- alkoxy, acyloxy, substituted C6-Ci2aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, - C(O)ORl 1, -S(O)_nR!3, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, Cβ-C^aryl, substituted Cg-C^aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O)_nRl3, aryloxy, nitro. cyano, halogen and protected - OH, where R ! 1, n, Rl2 and R 13 are as described above; X is O. S or NR^{1 1}, where R ! 1 is as described above; and Y is O or S; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

The present invention also relates to the discovery that the compounds of Formula (I) are active as G-CSF mimetics.

The invention also is a method for treating neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound. The invention is also a method for treating bacterial and fungal infections in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound.

In a further aspect of the invention there is provided novel processes useful in preparing the presently invented G-CSF mimetics compounds. Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.

Also included in the present invention are methods of co-administering the presently invented G-CSF mimetics compounds with further active ingredients. DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention that act as G-CSF mimetics have the following Formula (1):

wherein R ! and R^ are independently aryl, where aryl is cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NRl 1 R12, NRI 1R 12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C^-C^aryl. alkoxy, acyloxy, substituted C6-C 2aryl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C(O)ORl 1, -S(O)_nRl³, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, Cg-

Ci 2aryl, substituted C6-Cj2aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O)_nRl³, aryloxy, nitro, cyano, halogen and protected -OH, where R ! 1 is hydrogen or alkyl, n is 0-2,

Rl2 is hydrogen or alkyl and

RI³ is hydrogen, cycloalkyl, ^- ^aτ l, substituted cycloalkyl, substituted 6~ i2aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORl 1, -S(O)_nRl2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen,

substituted Cg-Ci2^aryl ^and protected -OH, where RI 1, n, and Rl2 are as described above; R³, R⁴, R⁵ and R⁶ are independently hydrogen, C(O)NR R 1², NRI 1R 2, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-Ci2^aryl_' lk°xy> acyloxy, substituted C6-Cj2^aryl_' mino, N-acylamino, nitro, cyano, halogen, hydroxy, - C(O)ORl 1, -S(O)_nRl³, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, Cg-C^aryl, substituted Cβ-Cj^aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O)_nRl³, aryloxy, nitro, cyano, halogen and protected - OH, where Rl 1, n, Rl2 and R I are as described above; X is O, S or NRH , where RI 1 is as described above; and Y is O or S; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Preferred among the presently invented Fromula I compounds are those in which aryl is: C5-Ci2^aryl, optionally containing one or two heteroatoms and optionally substituted with one or more substituents selected from the group consisting of: -OCg-C^aryl, -(CH2)_mOH, Cg-C^aryl, Cι -C4alkyl,-OCι -C4alkyl, amino, nitro, cyano, methoxycarbonyl, N-acylamino, trifluoromethyl, C3. cycloalkyl, halogen, -(CH2)_pCOOH, -S(O)_nRl² and protected -OH, where m is 0- 4, p is 0-3, n is 0-2 and Rl2 is hydrogen or Ci _4alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Particularly preferred among the presently invented compounds are those in which R and R² are independently phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl or quinolyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, Cj-salkyl, trifluoromethyl, methoxycarbonyl, C3_7cycloalkyl and -O-C 1-4 alkyl;

R³, R⁴, R5 and R^ are independently hydrogen, -OCg-C^ryh Cg-C^ryl, C1-C4 alkyl, -OCj-C4alkyl, amino, nitro, cyano, N-acylamino, C3-7cycloalkyl, halogen, -S(O)_nRl2 or protected -OH, where m is 0-4, p is 0-3, n is 0-2 and Rl2 is hydrogen or C 1-4 alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. Particularly preferred among the presently invented compounds are those in which RI and R² are independently phenyl, furyl, thienyl or pyridyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, Cj_5alkyl, trifluoromethyl, methoxycarbonyl, C3_6cycloalkyl and -O-Cj. 3 alkyl;

R³, R⁴, R and R^ are independently hydrogen, halogen, C^alkyl, C3-. cycloalkyl or -O-Cj^alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

The most preferred compounds of the present invention are those in which RI and R² are independently phenyl, furyl or pyridyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, C\_ 5alkyl, trifluoromethyl, methoxycarbonyl and -O-Cj-3alkyl; and

R³, R⁴, R5 and R^ are independently hydrogen, trifluoromethyl, methoxycarbonyl, halogen or C^alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

By the term "protected hydroxy" or "protected -OH" as used herein, is meant the alcoholic or carboxylic-OH groups which can be protected by conventional blocking groups in the art as described in "Protective Groups In Organic Synthesis" by Theodora W. Greene, Wiley-Interscience, 1981, New York. By the term "C5-C12 aryl" ^{as use}d herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic C5-C12 optionally containing one or two heteroatoms.

By the term "C6-C 2 aryl" as used herein, unless otherwise defined, is meant phenyl, naphthyl, 3,4-methylenedioxyphenyI, pyridyl, or biphenyl. By the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: hydroxyalkyl, alkoxy, acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH2)_gC(O)ORl 1, -S(O)_nR 2, nitro, cyano, halogen, trifluoromethyl and protected -OH, where g is 0-6, R¹1 is hydrogen or alkyl, n is 0-2, and Rl2 is hydrogen or alkyl. By the term "alkoxy" as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH3)2CH3.

The term "cycloalkyl" as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12. Examples of cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.

By the term "acyloxy" as used herein is meant -OC(O)alkyl where alkyl is as described herein. Examples of acyloxy substituents as used herein include: - OC(O)CH₃, -OC(O)CH(CH₃)₂ and -OC(O)(CH₂)3CH₃.

By the term "N-acylamino" as used herein is meant -N(H)C(O)alkyl, where alkyl is as described herein. Examples of N-acylamino substituents as used herein include: -N(H)C(O)CH₃, -N(H)C(O)CH(CH₃)₂ and -N(H)C(O)(CH₂)3CH₃.

By the term "aryloxy" as used herein is meant -OCg-C^^l where Cg- Ci2^aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N- acylamino, hydroxy, -(CH2)_gC(O)ORl 1, -S(O)_nRl2, nitro, cyano, halogen and protected -OH, where g is 0-6, Rl 1 is hydrogen or alkyl, n is 0-2 and Rl2 is hydrogen or alkyl. Examples of aryloxy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.

By the term "heteroatom" as used herein is meant oxygen, nitrogen or sulfur.

By the term "halogen" as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride. By the term "alkyl" and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having C1 -C12 carbon atoms. Examples of alkyl substituents as used herein include: -CH3, -CH₂-CH₃, -CH₂-CH₂-CH3, -CH(CH₃)₂, -C(CH₃)₃, -(CH₂)3-CH₃, -CH₂-CH(CH₃)₂ and -CH(CH₃)-CH₂-CH₃, -CH=CH₂. By the term "treating" and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy. By the phrase "mobilizing peripheral blood stem cells" as used herein is meant the mobilization of hematopoietic stem cells from the marrow to the peripheral blood.

All publications, including but not limited to patents and patent applications, cited in this specificaiton are herein incorporated by reference as if each individual publicaiton were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Compounds of Formula (1) are included in the pharmaceutical compositions of the invention and used in the methods of the invention. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. By the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a G-CSF mimetic compound, as described herein, and a further active ingredient or ingredients, such as antibacterial agents, antifungal agents as well as agents known to treat neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compounds may be administered orally. The novel compounds of Formula (I) are prepared as shown in Scheme I below provided that the R\ X and Y substituents do not include any such substituents that render inoperative the Scheme I process. The compounds of Foumula (2) are prepared by methods analogous to the Schemes and Examples used to prepare the Formula (I) compounds in International Application PCT/US97/08864, Published on November 27, 1997 as WO 97/44033. The reagents used herein are commercially available or are readily made by those skilled in the art from commercially available materials.

Scheme (I) Preparation of Compounds of Formula ( 1 )

Compounds of Formula (2)

(2)

wherein Rl, R², R3, R4 R5 _and R^ and X are as described in Formula (I) above, are reacted with phosgene or thiophosgene or an appropriate phosgene or thiophosgene equivalent such as bistrichloromethyl carbonate, disuccinidimoyl carbonate, carbonyl diimidazole or thiocarbonyl diimidazole in an appropriate solvent, preferably pyridine or 1 ,2-dichloroethane, to afford hexacyclic compounds of Foumula (1),

wherein Rl, R², R³, R4_? R5₅

d in Formula (1) above; or a mixture comprising a compound of Formula (1) and a compound of Formula (3)

wherein Rl, R², R³, R⁴, R5₍ R6 y _and X are as described in Formula (1) above. The mixtures of compounds of Formulas (1) and (3) are readily separated by chromatography.

Pharmaceutically acceptable salts, hydrates and solvates are formed when appropriate by methods well known to those of skill in the art.

Because the pharmaceutically active compounds of the present invention are active as G-CSF mimetics they exhibit therapeutic utility in treating bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production.

In determining potency as G-CSF mimetic, the following assays were employed: Luciferase Assay

Compounds of the present invention are tested for potency as G-CSF mimetics in a Luciferase assay such as described in Lamb, et al., Nucleic Acids Research 23: 3283-3289 (1995) and Seidel, et al., Proc. Natl. Acad. Sci.. USA 92: 3041-3045 (1995) by substituting NFS60 cells for the HepG2 cells utilized therein. The NFS60 cells (Holmes, et al., Proc. Natl. Acad. Sci. USA 82: 6687-6691 (1985)) were substituted for the HepG2 cells in the Lamb assay because the NSF60 cells express endogenous G-CSF receptors closely matching the pattern of STAT (signal transducers and activators of transcription) activation observed in primary murine and human bone marrow cells.

Preferably, the compounds of present invention are tested for potency as G- CSF mimetics in a CFU-G assay, an example of which is described in King AG, Talmadge J., Badger AM, Pelus LM. Regulation of colony stimulating activity production from bone marrow stromal cells by the hematoregulatory peptide, HP-5. Exp. Hematol. 20:223-228. 1992.

The pharmaceutically active compounds within the scope of this invention are useful as G-CSF mimetics in mammals, including humans, in need thereof. The present invention therefor provides a method of treating bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production, which comprises administering a compound of Formula (1):

wherein Rl and R² are independently aryl, where aryl is cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NRl 1R 2, NRI 1R 12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl,

trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C(O)ORl 1, -S(O)_nRl³, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C - Ci2-ιryl, substituted Cg-C^aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl , -S(O)_nRl³, aryloxy, nitro, cyano, halogen and protected -OH, where Rl 1 is hydrogen or alkyl, n is 0-2,

Rl2 is hydrogen or alkyl and

Rl³ is hydrogen, cycloalkyl, ^-C^ τyl, substituted cycloalkyl, substituted 6" l2^aryl_> ^alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORH, -S(O)_nRl2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen,

"d protected -OH, where Rl 1, n, and R 12 are as described above; R³, R⁴, R⁵ and R⁶ are independently hydrogen, C(O)NRl 1R 12, NRI ! R ^{1 2}, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, Cg-C^ f alkoxy, acyloxy, substituted Cg-C^aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, - C(O)ORl 1, -S(O)_nRl3, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-Ci2aryl, substituted Cg-C^ryl_* ^amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O)_nRl3, aryloxy, nitro, cyano, halogen and protected - OH, where Rl 1, n, Rl2 and R I are as described above; X is O, S or NRl l, where Rl 1 is as described above; and Y is O or S; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof in a quantity effective to enhance leukocyte production. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as G-CSF mimetics. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral. The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension. The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingreidents, as appropriate, to give the desired oral or parenteral products. Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of a G-CSF mimetics, the selected dose is administered preferably from 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg, preferably 0.1 to 350 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular G-CSF mimetics in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

The method of this invention of inducing G-CSF mimetic activity in mammals, including humans, comprises administering to a subject in need of such activity an effective amount of of a presently invented G-CSF mimetic compound. The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use as a G-CSF mimetic.

The invention also provides for the use of a compound of Formula ( 1 ) in the manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula ( 1 ) in the manufacture of a medicament for use in enhancing leukocyte production. The invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use in treating bacterial and fungal infections.

The invention also provides for a pharmaceutical composition for use as a G- CSF mimetic which comprises a compound of Formula (1) and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of neutropenia which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in enhancing leukocyte production which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in treating bacterial infections which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides for a pharmaceutical composition for use in treating fungal infections which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.

The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula (I) into association with the pharmaceutically acceptable carrier or diluent.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production, or compounds known to have utility when used in combination with a G-CSF mimetic. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Experimental Details

Example 1 - Capsule Composition

An oral dosage form for administering a presently invented agonist of the G- CSF receptor is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.

Table I

INGREDIENTS AMOUNTS

Compound of Foumula ( 1 ) 25 mg

Lactose 55 mg

Talc 16 mg

Magnesium Stearate 4 mg

Example 2 - Injectable Parenteral Composition

An injectable form for administering a presently invented agonist of the G- CSF receptor is produced by stirring 1.5% by weight of a Compound of Foumula (1) in 10% by volume propylene glycol in water.

Example 3 - Tablet Composition

The sucrose, calcium sulfate dihydrate and a presently invented agonist of the G-CSF receptor, as shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet

Table II

INGREDIENTS AMOUNTS

Compound of Foumula ( 1 ) 20 mg calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg

While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved

Claims

What is claimed is:

1. A compound of the Formula (1):

wherein Rl and R2 are independently aryl, where aryl is cyclic or polycyclic aromatic C3-Cj2_> optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NRl 1 R 12, NRI 1 R 12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C -Ci 2aryl, alkoxy, acyloxy, substituted C -Ci 2 ryl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C(O)ORl 1, -S(O)_nRl³, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C5-

Ci2aryl, substituted C6-Ci2^aryl> ^amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O)_nRl³, aryloxy, nitro, cyano, halogen and protected -OH, where Rl 1 is hydrogen or alkyl, n is 0-2,

R 2 is hydrogen or alkyl and

Rl is hydrogen, cycloalkyl, C6-Ci2^aryl> substituted cycloalkyl, substituted 6" i2^aryh alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORl 1 , -S(O)_nRl2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, Cβ-C^ ry , substituted C6-Ci2^aryl ^and protected -OH, where Rl 1 , n, and Rl2 are as described above; R³, R⁴, R⁵ and R⁶ are independently hydrogen, C(O)NRl 1R ¹², NR¹ 1R 12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, Cg-Ci2^aryl_' ^alkoxy, acyloxy, substituted Cg-C^aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, - C(O)ORl 1, -S(O)_nRl³, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C -Ci 2 ryl, substituted C -C^aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O)_nRl3, aryloxy, nitro, cyano, halogen and protected - OH, where R l 1, n, Rl2 and R I³ are as described above; X is O, S or NRU , where Rl 1 is as described above; and

Y is O or S; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

2. A compound of claim 1 in which aryl is: C5-Ci2 ^ryf optionally containing one or two heteroatoms and optionally substituted with one or more substituents selected from the group consisting of: -OCg-Ci2 ^ryl> -(CH2)_mOH, Cg-C^-iryl, Cj-C4alkyl,-OCι-C4alkyl, amino, nitro, cyano, methoxycarbonyl, N- acylamino, trifluoromethyl, C3_7cycloalkyl, halogen, -(CH2)_pCOOH, -S(O)_nRl2 and protected -OH, where m is 0-4, p is 0-3, n is 0-2 and Rl2 is hydrogen or Cj. 4alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1.

4. A pharmaceutical composition for use in enhancing leukocyte production which comprises a compound of Claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition for use in treating bacterial infections which comprises a compound of Claim 1 and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition for use in treating fungal infections which comprises a compound of Claim 1 and a pharmaceutically acceptable carrier.

7. A method of enhancing leukocyte production in a subject which comprises administering to the subject a therapeutically effective amount of a compound of Claim 1.

8. A method of treating neutropenia in a subject which comprises administering to the subject a therapeutically effective amount of a compound of Claim 1.

9. A process for the preparation of a compound of Formula ( 1 ) as described in Claim 1, which comprises reacting a compound of Foumula 2

wherein Rl, R2, R3, 4_? R5 R6 _and X are as described in claim 1, are reacted in the presence of a solvent, followed by isolation; and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

10. A compound of Formula ( 1) for use as an active therapeutic substance.

11. Use of a compound of Formula ( 1 ) in the manufacture of a medicament for use in therapy.

12. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the Formula ( 1 ) as described in claim 1 and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which process comprises bringing the compound of the Formula (1) into association with the pharmaceutically acceptable carrier or diluent.