Method of inducing differentiation of dendritic cells

Description

FIELD OF INVENTION

The present invention relates to compound having general formula Z-OC (CR_n1R_n2)—CO-Z wherein Z=OH or NH₂and n1=n2=1 to 8, useful for modulation of immune response by differentiation of dendritic cells, containing novel class of amino acid/dicarboxylic acid derivatives of the general formula ZOC—CR₃R₄—CR₁R₂—COOH, ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH and ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH.

BACKGROUND AND PRIOR ART REFERENCES

Indian green mussels (Perna viridis) are the cheap source of proteins and considered as a delicacy. Extract prepared from green mussels by enzyme-acid hydrolysis process showed various biological activities. In our earlier patent (US patent application #20030044470) we have shown the inhibition of osteoclast differentiation and activation in the crude extract. In same continuation, attempts have been made to purify the active compound that showed inhibition of osteoclast differentiation and activation. The purification of the crude extract was done using HPLC, gel filtration and TLC methods. The purified compound was again checked for the above activity. The compound was characterized using NMR and LC-MS/MS techniques. This compound was synthesized and checked for the presence of the above biological activity. This patent in particular describes the synthesis of the compound and also its activity for inhibition of osteoclast formation.

Novel class of amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) along with calcium is for their activation to show inhibition of the dendritic cells. Amino acid derivatives and calcium ion when used separately did not show any activity on differentiation of dendritic cells. The following classes of compounds are identified

- (1) Natural acidic amino acids (Aspartic acid, Glutamic acid and their amides),
- (2) Unnatural amino acids, amides such as homoglutamic acid,
- (3) Dicarboxylic acids such as succinic acid, glutaric acid, and adipic acid
- (4) N-sulfonyl, C-sulfonyl/sulfate derivatives of the above acids
- (5) Alkali and alkaline earth metals such as Na, K, Mg, Zn and Ca as their suitable salts.

A number of molecules are known to induce the differentiation and maturation of dendritic cells from precursors. Some of the recent ones are listed below:

- 1. The most studied is differentiation of DCs with GM-CSF which is the conventional method to generate DCs from bone marrow. The DCs obtained in this manner are immature in nature.
- 2. Maturation of DCs is normally obtained by stimulating the immature DCs has been shown to □). Recently TNF-□ with Tumor Necrosis Factor-alpha (TNF-induce the differentiation of DCs from monocytes.
- 3. CD40 ligand (CD401) that is normally expressed on T cells also induces the maturation of DCs. An alternative for CD401 is the use of commercially available anti-CD40 monoclonal antibody.
- 4. Stimulation with the extracellular endotoxin, Lipopolysaccharide (LPS) from Escherichia coli is also a common method to mature DCs
- 5. Atrial natriuretic peptide (ANP) a cardiovascular hormone secreted mainly by the cardiac atria regulates the volume-pressure homeostasis. The action of ANP is mediated by its receptor, guanylyl cyclase-coupled receptor A (GC-A) and has recently been shown to induce the maturation of DCs by increasing cytokine secretion and increases in various cell surface molecule expression.
- 6. The imidazoquinoline compounds imiquimod and R-848 are low-molecular-weight anti-viral compounds that are immune response modifiers and induce the synthesis of interferon-alpha and other cytokines in a variety of cell types. These compounds have potent anti-viral and anti-tumor properties and have recently been shown to induce the activation of macrophages and splenocytes and induce the maturation of Dendritic cells.
- 7. Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand expands early hematopoietic progenitor and Dendritic cells (DCs) in humans and mice.
- 8. Prostaglandin E2, found at high concentrations under the skin has been shown to facilitate initiation of skin immune responses by promoting the migration and maturation of Langerhans cells, a DC subtype found under the epidermis and in the dermis of the skin.
- 9. Fermented mistletoe extract often used for adjuvant treatment of cancer patients, significantly stimulated the maturation of pre-differentiated immature DC, as evidenced by a heightened expression of CD83. Like the positive control TNF-alpha, the mistletoe extract significantly activated CD80 and CD86 as well as HLA class I and II molecules on these cells.
- 10. Lysophosphatidylcholine (LPC) is a major lipid component of oxidized low density lipoprotein with reported pro-inflammatory activities. It is now reported that LPC acts through G protein-coupled receptors on differentiating monocytes to generate mature dendritic cells with the ability to stimulate IL-2 and IFN-gamma production by allogeneic T lymphocytes.

OBJECTIVE OF INVENTION

The objective of the invention relates to compounds having general formula Z-OC (C R_n1R_n2)—CO-Z wherein Z=OH or NH₂and n1=n2=1 to 8 for induction of differentiation of dendritic cells containing novel class of amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) Compounds for induction of differentiation of dendritic cells containing novel class of amino acid/dicarboxylic acid derivatives of the general formula ZOC—CR₃R₄—CR₁R₂—COOH, ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH, ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH wherein Z=OH or NH₂; R₁, to R₈denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H. wherein all the symbols are the same meaning as hereinafter defined and non-toxic salts thereof as an active ingredient.

Another objective of the present invention relates to a method for modulation of immune response controlled by differentiating dendricts cells.

Another objective of the present invention relates to use of compound in vaccine formulation or in protection based studies to promote more efficient and faster presentation of the antigens to T-cell thereby initiative primary protective Th1 immune response and help in clearance in pathogens.

Another objective of the present invention relates to novel compound useful in vaccination, cancer therapy and other immunomodulatory regiments.

The further objective of the present invention relates to administration a pharmaceutical acceptable amount of a compound optionally with an additive, excipient, diluents or carrier for modulation of immune response.

SUMMARY OF THE INVENTION

This invention is related to compounds having general formula Z-OC (CR_n1R_n2)—CO-Z wherein Z=OH or NH₂and n1=n2=1 to 8 for induction of differentiation of dendritic cells containing novel class of amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides). More particularly, this invention is related to:

- 1) Compounds for induction of differentiation of dendritic cells containing novel class of amino acid/dicarboxylic acid derivatives of the general formula ZOC—CR₃R₄—CR₁R₂—COOH, ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH, ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH wherein Z=OH or NH₂; R₁, to R₈denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H.
  - wherein all the symbols are the same meaning as hereinafter defined and non-toxic salts thereof as an active ingredient,
- 2) The compounds inducing differentiation of dendritic cells also contain different divalent metal cations such as Mg, Ca and Zn,
  - wherein all the symbols are the same meaning as hereinafter defined and non-toxic salts thereof as an active ingredient,
- 3) The composition consists of varying amounts of the above amino acid/dicarboxylic acid derivatives and their pharmaceutically acceptable selected alkali/alkaline earth metal salts,
  - wherein all the symbols are the same meaning as hereinafter defined and non-toxic salts thereof as an active ingredient,
- 4) The process for the preparation of the aforesaid compounds, useful in inducing differentiation of dendritic cells.

DETAIL DESCRIPTION OF THE INVENTION

The present invention is relates to a compound of general formula Z-OC (C R_n1R_n2)—CO-Z wherein Z=OH or NH₂and n1=n2=1 to 8.

Yet another embodiments of a present invention relates to a compound having a structure as shown below and bearing general formula ZOC—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁, to R₄denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H
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Yet another embodiments of a present invention relates to a compound having a structure as shown below and bearing general formula ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁to R₆denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H
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Yet another embodiments of a present invention relates to a compound having a structure as shown below and bearing general formula ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁to R₈denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H
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Yet another embodiments of a present invention relates to a compound formula (Ia), wherein the compound is selected from the group consisting of:

- I. [L-Aspartic acid, N-Sulfonic acid],
- II. [2α,3-dicarboxy, propane-1-sulfonic acid],
- III. [2α,3-dicarboxy, propane-1-sulfate],
- IV. [1α,2-carboxy ethane sulfonic acid],
- V. [1α,2-carboxy ethane sulfate],
- VI. [D-aspartic acid, N-sulfonic acid],
- VII. [2β,3-carboxy,propane-1-sulfonic acid],
- VIII. [2β,3-carboxy,propane-1-sulfate],
- IX. [1β,2-carboxy ethane-1-sulfonic acid],
- X. [1β,2-carboxy ethane-1-sulfate],
- XI. [D-aspartic acid, 3α-sulfonic acid],
- XII. [D-aspartic acid, 3α-sulfate],
- XIII. [D-aspartic acid, 3β-sulfonic acid],
- XIV. [D-aspartic acid, 3β-sulfate],
- XV. [L-asparagine,N-sulfonic acid],
- XVI. [2α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVII. [2α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1α-carboxy, 2-carboxamido, ethane sulfonic acid],
- XIX. [1α-carboxy, 2-carboxamido, ethane sulfate],
- XX. [L-asparagine, 3α-sulfonic acid],
- XXI. [L-asparagine, 3α-sulfate],
- XXII. [L-asparagine, 3β-sulfonic acid],
- XXIII. [L-asparagine, 30-sulfate,
- XXIV. [D-asparagine, N-sulfonic acid],
- XXV. [2β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI. [2β-carboxy, 3-carboxamido, propane-1-sulfate],
- XXVII. [1β-carboxy, 2-carboxamido, ethane sulfonic acid],
- XXVIII. [1β-carboxy, 2-carboxamido, ethane sulfate],
- XXIX. [D-asparagine, 3α-sulfonic acid],
- XXX. [D-asparagine, 3α-sulfate],
- XXXI. [D-asparagine, 30-sulfonic acid],
- XXXII. [D-asparagine, 3β-sulfate],
- XXXIII. [L-glutamic acid, N-sulfonic acid],
- XXXIV. [2α,4-dicarboxy, butane-1-sulfonic acid],
- XXXV. [2α,4-dicarboxy, butane-1-sulfate],
- XXXVI. [1α,3-dicarboxy, propane sulfonic acid],
- XXXVII. [1α,3-dicarboxy, propane sulfate],
- XXXVIII. [1β,3-dicarboxy, propane sulfate],
- XXXIX. [1β,3-dicarboxy, propane sulfonic acid],

Yet another embodiment of a present invention relates to a compound formula (Ib) wherein the compound is selected from the group consisting of:

- I. [D-glutamic acid, N-sulfonic acid],
- II. 2β,4-dicarboxy, butane-1-sulfonic acid],
- III. [2β,4-dicarboxy, butane-1-sulfate],
- IV. [D-glutamic acid, 3α-sulfonic acid],
- V. [D-glutamic acid, 3α-sulfate],
- VI. [D-glutamic acid, 3β-sulfonic acid],
- VII. [D-glutamic acid, 3β-sulfate],
- VIII. [D-glutamic acid, 4α-sulfonic acid],
- IX. [D-glutamic acid, 4α-sulfate],
- X. [D-glutamic acid, 4β-sulfonic acid],
- XI. [D-glutamic acid, 3β-sulfate],
- XII. [L-glutamine, N-sulfonic acid],
- XIII. [2α-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XIV. [2α-carboxy, 4-carboxamido, butane-1-sulfate],
- XV. [1α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVI. [1α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVII. [1β-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XIX. [D-glutamine, N-sulfonic acid],
- XX. [2β-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXI. [2β-carboxy, 4-carboxamido, butane-1-sulfate],
- XXII. [D-glutamine, 3α-sulfonic acid],
- XXIII. [D-glutamine, 3α-sulfate],
- XXIV. [D-glutamine, 3-sulfonic acid],
- XXV. [D-glutamine, 30-sulfate],
- XXVI. [D-glutamine, 4α-sulfonic acid],
- XXVII. [D-glutamine, 4α-sulfate],
- XXVIII. [D-glutamine, 40-sulfonic acid],
- XXIX. [D-glutamine, 4β-sulfate],
- XXX. [L-homoglutamic acid, N-sulfonic acid],
- XXXI. [Pentane-2α,5-dicarboxy-1-sulfonic acid],
- XXXII. [Pentane-2α,5-dicarboxy-1-sulfate],
- XXXIII. [Butane-1α,4-dicarboxy-1-sulfonic acid],
- XXXIV. [Butane-1α,4-dicarboxy-1-sulfate],
- XXXV. [D-homoglutamic acid, N-sulfonic acid],
- XXXVI. [Pentane-2β,5-dicarboxy-1-sulfonic acid],
- XXXVII. [Pentane-2β,5-dicarboxy-1-sulfate],
- XXXVIII. [Butane-1β,4-dicarboxy-1-sulfonic acid],
- XXXIX. [Butane-1β,4-dicarboxy-1-sulfate],

Yet another embodiment of a present invention relates to a compound formula (Ic) wherein the compound is selected from the group consisting of

- I. [D-homoglutamic acid, 3α-sulfonic acid],
- II. [D-homoglutamic acid, 3α-sulfate],
- III. [D-homoglutamic acid, 30-sulfonic acid],
- IV. [D-homoglutamic acid, 3β-sulfate],
- V. [D-homoglutamic acid, 4α-sulfonic acid],
- VI. [D-homoglutamic acid, 4α-sulfate],
- VII. [D-homoglutamic acid, 4β-sulfonic acid],
- VIII. [D-homoglutamic acid, 40-sulfate],
- IX. [D-homoglutamic acid, 5α-sulfate],
- X. [D-homoglutamic acid, 5α-sulfate],
- XI. [D-homoglutamic acid, 50-sulfonic acid],
- XII. [D-homoglutamic acid, 5β-sulfate],
- XIII. [L-homoglutamine, N-sulfonic acid],
- XIV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid],
- XV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfate],
- XVI. [Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid],
- XVII. [Butane-1α-carboxy, 4-carboxamido-1-sulfate],
- XVIII. [D-homoglutamine, N-sulfonic acid],
- XIX. [Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid],
- XX. [Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid],
- XXI. [Butane-1β-carboxy, 4-carboxamido-1-sulfate],
- XXII. [D-homoglutamine, 3α-sulfonic acid],
- XXIII. [D-homoglutamine, 3α-sulfate],
- XXIV. [D-homoglutamine, 3β-sulfonic acid],
- XXV. [D-homoglutamine, 3β-sulfate],
- XXVI. [D-homoglutamine, 4α-sulfonic acid],
- XXVII. [D-homoglutamine, 4α-sulfate],
- XXVIII. [D-homoglutamine, 413-sulfonic acid],
- XXIX. [D-homoglutamine, 41-sulfate],
- XXX. [D-homoglutamine, 5α-sulfonic acid],
- XXXI. [D-homoglutamine, 5α-sulfate],
- XXXII. [D-homoglutamine, 5β-sulfonic acid] and
- XXXIII. [D-homoglutamine, 5β-sulfate].

Yet another embodiment of a present invention relates to a compound Novel sulfonic acid/sulfate derivatives of the formulae ZOC—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁, to R₄denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H

- I. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=NHSO₃H is the same meaning as is before defined;
- II. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- III. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- IV. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=SO₃H is the same meaning as is before defined;
- V. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=OSO₃H is the same meaning as is before defined;
- VI. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=NHSO₃H is the same meaning as is before defined;
- VII. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- VIII. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- IX. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=SO₃H is the same meaning as is before defined;
- X. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=OSO₃H is the same meaning as is before defined;
- XI. A compound wherein Z=OH, R₁=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XII. A compound wherein Z=OH, R₁=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XIII. A compound wherein Z=OH, R₁=R₃=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XIV. A compound wherein Z=OH, R₁=R₃=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XV. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=NHSO₃H is the same meaning as is before defined;
- XVI. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- XVII. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=SO₃H is the same meaning as is wherein Z=NH₂, R₂=R₃=R₄=H, R₁=OSO₃H is the same meaning as is before defined;
- XIX. A compound wherein Z=NH₂, R₁=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XX. A compound wherein Z=NH₂, R=R₄=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXI. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXII. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=NHSO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- XXV. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=SO₃H is the same meaning as is before defined;
- XXVII. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=OSO₃H is the same meaning as is before defined;
- XXVIII. A compound wherein Z=NH₂, R=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XXIX. A compound wherein Z=NH₂, R₁=R₄=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXX. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXXI. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined.

Yet another embodiment of a present invention relates to a compound novel sulfonic acid/sulfate derivatives of the formulae ZOC—CR₅R(—CR₃R₄—CR₁R₂—COOH, wherein: Z=OH or NH₂, R₁, to R₆denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H

- I. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=NHSO₃H is the same meaning as is before defined;
- II. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- III. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- IV. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=SO₃H is the same meaning as is before defined;
- V. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=OSO₃H is the same meaning as is before defined;
- VI. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=OSO₃H is the same meaning as is before defined;
- VII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=SO₃H is the same meaning as is before defined;
- VIII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=NHSO₃H is the same meaning as is before defined;
- IX. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- X. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- XI. A compound wherein Z=OH, R₁=R₄=R₅=R₆=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XII. A compound wherein Z=OH, R₁=R₄=R₅=R₆=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XIII. A compound wherein Z=OH, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XIV. A compound wherein Z=OH, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XV. A compound wherein Z=OH, R=R₄=R₃=R₆=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XVI. A compound wherein Z=OH, R=R₄=R₃=R₆=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- XVII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined;
- XIX. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=NHSO₃H is the same meaning as is before defined;
- XX. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- XXI. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- XXII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=SO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=OSO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=OSO₃H is the same meaning as is before defined;
- XXV. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=SO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=NHSO₃H is the same meaning as is before defined;
- XXVII. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- XXVIII. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- XXIX. A compound wherein Z=NH₂, R=R₄=R₅=R₆=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XXX. A compound wherein Z=NH₂, R₁=R₄=R₅=R₆=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXXI. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXXII. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XXXIII. A compound, wherein Z=NH₂, R₁=R₄=R₃=R₆=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XXXIV. A compound wherein Z=NH₂, R=R₄=R₃=R₆=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- XXXV. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XXXVI. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined.

Yet another embodiment of a present invention relates to a compound Novel sulfonic acid/sulfate derivatives of the formulae ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH as claimed in claim 4, wherein: Z=OH or NH₂, R₁, to R₈denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H

- I. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=NHSO₃H is the same meaning as is before defined;
- II. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R=—CH₂SO₃H is the same meaning as is before defined;
- III. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- IV. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=SO₃H is the same meaning as is before defined;
- V. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=OSO₃H is the same meaning as is before defined;
- VI. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=NHSO₃H is the same meaning as is before defined;
- VII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- VIII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- IX. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=SO₃H is the same meaning as is before defined;
- X. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=OSO₃H is the same meaning as is before defined;
- XI. A compound wherein Z=OH, R₁=R₄=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XII. A compound wherein Z=OH, R₁=R₄=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XIII. A compound wherein Z=OH, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XIV. A compound wherein Z=OH, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XV. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₇=R₈=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XVI. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₇=R₈=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- XVII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₈=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₈=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined;
- XIX. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=SO₃H is the same meaning as is before defined;
- XX. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=OSO₃H is the same meaning as is before defined;
- XXI. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=SO₃H is the same meaning as is before defined;
- XXII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=OSO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=NHSO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- XXV. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=SO₃H is the same meaning as is before defined;
- XXVII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=OSO₃H is the same meaning as is before defined;
- XXVIII. A compound wherein Z-NH₂, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=NHSO₃H is the same meaning as is before defined;
- XXIX. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- XXX. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=R₇=IZ=H, R₂=SO₃H is the same meaning as is before defined;
- XXXI. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=OSO₃H is the same meaning as is before defined;
- XXXII. A compound wherein Z=NH₂, R₁=R₄=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XXXIII. A compound wherein Z=NH₂, R₁=R₄=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXXIV. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXXV. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XXXVI. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=R₇=R₈=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XXXVII. A compound wherein Z=NH₂, R=R₄=R₃=R₆=R₇=R₈=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- XXXVIII. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=R₇=R₈=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XXXIX. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=R₇=R₈=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined;
- XL. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=SO₃H is the same meaning as is before defined;
- XLI. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=OSO₃H is the same meaning as is before defined;
- XLII. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=SO₃H is the same meaning as is before defined;
- XLIII. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=OSO₃H is the same meaning as is before defined;

Yet another embodiment of a present invention relates to a compound wherein said compound is non-toxic salts selected from the group consisting of:

- I. [L-Aspartic acid, N-Sulfonic acid],
- II. [2α,3-dicarboxy, propane-1-sulfonic acid],
- III. [2α,3-dicarboxy, propane-1-sulfate],
- IV. [1α,2-carboxy ethane sulfonic acid],
- V. [1α,2-carboxy ethane sulfate],
- VI. [D-aspartic acid, N-sulfonic acid],
- VII. [2β,3-carboxy,propane-1-sulfonic acid],
- VIII. [2β,3-carboxy,propane-1-sulfate],
- IX. [1β,2-carboxy ethane-1-sulfonic acid],
- X. [1β,2-carboxy ethane-1-sulfate],
- XI. [D-aspartic acid, 3α-sulfonic acid],
- XII. [D-aspartic acid, 3α-sulfate],
- XIII. [D-aspartic acid, 3β-sulfonic acid],
- XIV. [D-aspartic acid, 3β-sulfate],
- XV. [L-asparagine, N-sulfonic acid],
- XVI. [2α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVII. [2α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1α-carboxy, 2-carboxamido, ethane sulfonic acid],
- XIX. [1α-carboxy, 2-carboxamido, ethane sulfate],
- XX. [L-asparagine, 3α-sulfonic acid],
- XXI. [L-asparagine, 3α-sulfate],
- XXII. [L-asparagine, 3β-sulfonic acid],
- XXIII. [L-asparagine, 3β-sulfate,
- XXIV. [D-asparagine, N-sulfonic acid],
- XXV. [2β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI. [2β-carboxy, 3-carboxamido, propane-1-sulfate],
- XXVII. [1β-carboxy, 2-carboxamido, ethane sulfonic acid],
- XXVIII. [1β-carboxy, 2-carboxamido, ethane sulfate],
- XXIX. [D-asparagine, 3α-sulfonic acid],
- XXX. [D-asparagine, 3α-sulfate],
- XXXI. [D-asparagine, 3β-sulfonic acid],
- XXXII. [D-asparagine, 3β-sulfate],
- XXXIII. [L-glutamic acid, N-sulfonic acid],
- XXXIV. [2α,4-dicarboxy, butane-1-sulfonic acid],
- XXXV. [2α,4-dicarboxy, butane-1-sulfate],
- XXXVI. [1α,3-dicarboxy, propane sulfonic acid],
- XXXVII. [1α,3-dicarboxy, propane sulfate],
- XXXVIII. [1β,3-dicarboxy, propane sulfate],
- XXXIX. [1β,3-dicarboxy, propane sulfonic acid],

Yet another embodiment of a present invention relates to a compound wherein said compound is non-toxic salts selected from the group consisting of:

- I. [D-glutamic acid, N-sulfonic acid],
- II. [2β,4-dicarboxy, butane-1-sulfonic acid],
- III. [2β,4-dicarboxy, butane-1-sulfate],
- IV. [D-glutamic acid, 3α-sulfonic acid],
- V. [D-glutamic acid, 3α-sulfate],
- VI. [D-glutamic acid, 31-sulfonic acid],
- VII. [D-glutamic acid, 31-sulfate],
- VIII. [D-glutamic acid, 4α-sulfonic acid],
- IX. [D-glutamic acid, 4α-sulfate],
- X. [D-glutamic acid, 4β-sulfonic acid],
- XI. [D-glutamic acid, 3β-sulfate],
- XII. [L-glutamine, N-sulfonic acid],
- XIII. [2α-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XIV. [2α-carboxy, 4-carboxamido, butane-1-sulfate],
- XV. [1α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVI. [1α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVII. [1β-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XIX. [D-glutamine, N-sulfonic acid],
- XX. [2β-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXI. [2β-carboxy, 4-carboxamido, butane-1-sulfate],
- XXII. [D-glutamine, 3α-sulfonic acid],
- XXIII. [D-glutamine, 3α-sulfate],
- XXIV. [D-glutamine, 3β-sulfonic acid],
- XXV. [D-glutamine, 3β-sulfate],
- XXVI. [D-glutamine, 4α-sulfonic acid],
- XXVII. [D-glutamine, 4α-sulfate],
- XXVIII. [D-glutamine, 40-sulfonic acid],
- XXIX. [D-glutamine, 40-sulfate],
- XXX. [L-homoglutamic acid, N-sulfonic acid],
- XXXI. [Pentane-2α,5-dicarboxy-1-sulfonic acid],
- XXXII. [Pentane-2α,5-dicarboxy-1-sulfate],
- XXXIII. [Butane-1α,4-dicarboxy-1-sulfonic acid],
- XXXIV. [Butane-1α,4-dicarboxy-1-sulfate],
- XXXV. [D-homoglutamic acid, N-sulfonic acid],
- XXXVI. [Pentane-2β,5-dicarboxy-1-sulfonic acid],
- XXXVII. [Pentane-2β,5-dicarboxy-1-sulfate],
- XXXVIII. [Butane-lp, 4-dicarboxy-1-sulfonic acid],
- XXXIX. [Butane-1β, 4-dicarboxy-1-sulfate],

Yet another embodiment of a present invention relates to a compound said compound is non-toxic salts selected from the group consisting of:

- I. [D-homoglutamic acid, 3α-sulfonic acid],
- II. [D-homoglutamic acid, 3α-sulfate],
- III. [D-homoglutamic acid, 3β-sulfonic acid],
- IV. [D-homoglutamic acid, 3β-sulfate],
- V. [D-homoglutamic acid, 4α-sulfonic acid],
- VI. [D-homoglutamic acid, 4α-sulfate],
- VII. [D-homoglutamic acid, 4β-sulfonic acid],
- VIII. [D-homoglutamic acid, 4β-sulfate],
- IX. [D-homoglutamic acid, 5α-sulfate],
- X. [D-homoglutamic acid, 5α-sulfate],
- XI. [D-homoglutamic acid, 5β-sulfonic acid],
- XII. [D-homoglutamic acid, 5β-sulfate],
- XIII. [L-homoglutamine, N-sulfonic acid],
- XIV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid],
- XV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfate],
- XVI. [Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid],
- XVII. [Butane-1α-carboxy, 4-carboxamido-1-sulfate],
- XVIII. [D-homoglutamine, N-sulfonic acid],
- XIX. [Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid],
- XX. [Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid],
- XXI. [Butane-1β-carboxy, 4-carboxamido-1-sulfate],
- XXII. [D-homoglutamine, 3α-sulfonic acid],
- XXIII. [D-homoglutamine, 3α-sulfate],
- XXIV. [D-homoglutamine, 3β-sulfonic acid],
- XXV. [D-homoglutamine, 3β-sulfate],
- XXVI. [D-homoglutamine, 4α-sulfonic acid],
- XXVII. [D-homoglutamine, 4α-sulfate],
- XXVIII. [D-homoglutamine, 4β-sulfonic acid],
- XXIX. [D-homoglutamine, 4β-sulfate],
- XXX. [D-homoglutamine, 5α-sulfonic acid],
- XXXI. [D-homoglutamine, 5α-sulfate],
- XXXII. [D-homoglutamine, 5β-sulfonic acid] and
- XXXIII. [D-homoglutamine, 5β-sulfate].

Yet another embodiment of a present invention relates to a compound said compound is selected from the group consisting of aspartic acid, asparagine and corresponding de-amino analogs:

- I. [L-Aspartic acid, N-Sulfonic acid],
- II. [2α,3-dicarboxy, propane-1-sulfonic acid],
- III. [2α,3-dicarboxy, propane-1-sulfate],
- IV. [1α,2-carboxy ethane sulfonic acid],
- V. [1α,2-carboxy ethane sulfate],
- VI. [D-aspartic acid, N-sulfonic acid],
- VII. [2β,3-carboxy, propane-1-sulfonic acid],
- VIII. [2β,3-carboxy, propane-1-sulfate],
- IX. [1β,2-carboxy ethane-1-sulfonic acid],
- X. [1β,2-carboxy ethane-1-sulfate],
- XI. [D-aspartic acid, 3α-sulfonic acid],
- XII. [D-aspartic acid, 3α-sulfate],
- XIII. [D-aspartic acid, 3β-sulfonic acid],
- XIV. [D-aspartic acid, 3β-sulfate],
- XV. [L-asparagine, N-sulfonic acid],
- XVI. [2α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVII. [2α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1α-carboxy, 2-carboxamido, ethane sulfonic acid],
- XIX. [1α-carboxy, 2-carboxamido, ethane sulfate],
- XX. [L-asparagine, 3α-sulfonic acid],
- XXI. [L-asparagine, 3α-sulfate],
- XXII. [L-asparagine, 30-sulfonic acid],
- XXIII. [L-asparagine, 3β-sulfate,
- XXIV. [D-asparagine, N-sulfonic acid],
- XXV. [2β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI. [2β-carboxy, 3-carboxamido, propane-1-sulfate],
- XXVII. [1β-carboxy, 2-carboxamido, ethane sulfonic acid],
- XXVIII. [1β-carboxy, 2-carboxamido, ethane sulfate],
- XXIX. [D-asparagine, 3α-sulfonic acid],
- XXX. [D-asparagine, 3α-sulfate],
- XXXI. [D-asparagine, 3β-sulfonic acid],
- XXXII. [D-asparagine, 3β-sulfate],

Yet another embodiment of a present invention relates to a compound said compound is selected from the group consisting of glutamic acid, glutamine and corresponding de-amino analogs:

- I. [L-glutamic acid, N-sulfonic acid],
- II. [2α,4-dicarboxy, butane-1-sulfonic acid],
- III. [2α,4-dicarboxy, butane-1-sulfate],
- IV. [1α,3-dicarboxy, propane sulfonic acid],
- V. [1α,3-dicarboxy, propane sulfate],
- VI. [1β,3-dicarboxy, propane sulfate],
- VII. [1β,3-dicarboxy, propane sulfonic acid],
- VIII. [D-glutamic acid, N-sulfonic acid],
- IX. [2β,4-dicarboxy, butane-1-sulfonic acid],
- X. [2β,4-dicarboxy, butane-1-sulfate],
- XI. [D-glutamic acid, 3α-sulfonic acid],
- XII. [D-glutamic acid, 3α-sulfate],
- XIII. [D-glutamic acid, 313-sulfonic acid],
- XIV. [D-glutamic acid, 313-sulfate],
- XV. [D-glutamic acid, 4α-sulfonic acid],
- XVI. [D-glutamic acid, 4α-sulfate],
- XVII. [D-glutamic acid, 40-sulfonic acid],
- XVIII. [D-glutamic acid, 3β-sulfate],
- XIX. [L-glutamine, N-sulfonic acid],
- XX. [2α-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXI. [2α-carboxy, 4-carboxamido, butane-1-sulfate],
- XXII. [1α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXIII. [1α-carboxy, 3-carboxamido, propane-1-sulfate],
- XXIV. [1α-carboxy, 3-carboxamido, propane-1-sulfate],
- XXV. [1β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI. [D-glutamine, N-sulfonic acid],
- XXVII. [2β-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXVIII. [2β-carboxy, 4-carboxamido, butane-1-sulfate],
- XXIX. [D-glutamine, 3α-sulfonic acid],
- XXX. [D-glutamine, 3α-sulfate],
- XXXI. [D-glutamine, 3β-sulfonic acid],
- XXXII. [D-glutamine, 3β-sulfate],
- XXXIII. [D-glutamine, 4α-sulfonic acid],
- XXXIV. [D-glutamine, 4α-sulfate],
- XXXV. [D-glutamine, 40-sulfonic acid],
- XXXVI. [D-glutamine, 4β-sulfate],
- XXXVII. [L-homoglutamic acid, N-sulfonic acid],
- XXXVIII. [Pentane-2α,5-dicarboxy-1-sulfonic acid],
- XXXIX. [Pentane-2α,5-dicarboxy-1-sulfate],
- XL. [Butane-i a, 4-dicarboxy-1-sulfonic acid],
- XLI. [Butane-1α,4-dicarboxy-1-sulfate],

Yet another embodiment of a present invention relates to a compound wherein said compound is selected from the group consisting of homoglutamic acid, homoglutamine and corresponding de-amino analogs:

- I. [D-homoglutamic acid, N-sulfonic acid],
- II. [Pentane-2β,5-dicarboxy-1-sulfonic acid],
- III. [Pentane-2β,5-dicarboxy-1-sulfate],
- IV. [Butane-1β, 4-dicarboxy-1-sulfonic acid],
- V. [Butane-1β,4-dicarboxy-1-sulfate],
- VI. [D-homoglutamic acid, 3α-sulfonic acid],
- VII. [D-homoglutamic acid, 3α-sulfate],
- VIII. [D-homoglutamic acid, 3β-sulfonic acid],
- IX. [D-homoglutamic acid, 3β-sulfate],
- X. [D-homoglutamic acid, 4α-sulfonic acid],
- XI. [D-homoglutamic acid, 4α-sulfate],
- XII. [D-homoglutamic acid, 4β-sulfonic acid],
- XIII. [D-homoglutamic acid, 4β-sulfate],
- XIV. [D-homoglutamic acid, 5α-sulfate],
- XV. [D-homoglutamic acid, 5α-sulfate],
- XVI. [D-homoglutamic acid, 50-sulfonic acid],
- XVII. [D-homoglutamic acid, 5-sulfate],
- XVIII. [L-homoglutamine, N-sulfonic acid],
- XIX. [Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid],
- XX. [Pentane-2α-carboxy, 5-carboxamido-1-sulfate],
- XXI. [Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid],
- XXII. [Butane-1α-carboxy, 4-carboxamido-1-sulfate],
- XXIII. [D-homoglutamine, N-sulfonic acid],
- XXIV. [Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid],
- XXV. [Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid],
- XXVI. [Butane-1β-carboxy, 4-carboxamido-1-sulfate],
- XXVII. [D-homoglutamine, 3α-sulfonic acid],
- XXVIII. [D-homoglutamine, 3α-sulfate],
- XXIX. [D-homoglutamine, 3β-sulfonic acid],
- XXX. [D-homoglutamine, 3β-sulfate],
- XXXI. [D-homoglutamine, 4α-sulfonic acid],
- XXXII. [D-homoglutamine, 4α-sulfate],
- XXXIII. [D-homoglutamine, 4β-sulfonic acid],
- XXXIV. [D-homoglutamine, 4β-sulfate],
- XXXV. [D-homoglutamine, 5α-sulfonic acid],
- XXXVI. [D-homoglutamine, 5α-sulfate],
- XXXVII. [D-homoglutamine, 5β-sulfonic acid] and
- XXXVIII. [D-homoglutamine, 5β-sulfate].

Still another embodiment of the present invention relates to a process for preparing L-glutamyl N-sulfonic acid from glutamic acid mono tertiary butyl ester comprising the steps of:

- a) adding L-glutamyl acid mono tertiary butyl ester portion wise to a solution of SO₂Cl₂in dry CH₂Cl₂at 0° C.) and Et₃N (3 eq.) to obtain a solution,
- b) stirring the solution for a time period in the range of 5 to 10 hrs at room temperature unless thin layer chromatography (TLC) shows complete consumption of starting material and evaporating the solvent present in TLC and crude is drying in vaccum,
- c) adding water to dried crude and stirring the slurry for a time period in the range of 0.5 to 3 hr,
- d) adding 45 ml CH₂Cl₂and 3 equivalent of TFA at 0° C. to the solution and stirring for 24 hrs
- e) evaporating the solvent and drying in vacuum to obtain the product L-glutamyl, N-sulfonic acid.

A further embodiment of the present invention relates to for preparing L-glutamyl, N-sulfonic acid from glutamyl acid di tertiary butyl ester comprising the steps of:

- a. adding L-aspartic acid di tertiary butyl ester portion wise to a solution of SO₂Cl₂in dry CH₂Cl₂at 0° C.) and Et₃N (3 eq.) to obtain a solution,
- b. stirring the solution for a time period in the range of 5 to 10 hrs at room temperature unless thin layer chromatography shows complete consumption of starting material evaporating the solvent present in TLC and crude is drying in vaccum,
- c. adding water to dried crude and stirring the slurry for a time period in the range of 0.5 to 3 hr,
- d. adding 45 ml CH₂Cl₂and 3 equivalent of TFA at 0° C. to the solution and stirring for 24 hrs
- e. evaporating the solvent and drying in vacuum to obtain the product L-aspartyl, N-sulfonic acid.

A further embodiment of the present invention relates to a process for preparing L-Aspartyl, N-sulfonic acid from L-aspartic acid di tertiary butyl ester comprising the steps of:

- a. adding L-aspartic acid di tertiary butyl ester portion wise to a solution of SO₂CI₂in dry CH₂Cl₂at 0° C.) and Et₃N (3 eq.) to obtain a solution,
- b. stirring the solution for a time period in the range of 5 to 10 hrs at room temperature unless thin layer chromatography shows complete consumption of starting material evaporating the solvent and drying the crude in vacuum,
- c. adding water to dried crude and stirring the slurry for a time period in the range of 0.5 to 3 hr,
- d. adding 45 ml CH₂Cl₂and 3 equivalent of TFA at 0° C. to the solution and stirring for 24 hrs
- e. evaporating the solvent and drying in vacuum to obtain the product L-aspartyl, N-sulfonic acid.

A Further another embodiment of the present invention relates to process for preparing L-Homoglutamyl, N-sulfonic acid from L-Homoglutamic acid di tertiary butyl ester comprising the steps of:

- a. adding L-Homoglutamic acid di tertiary butyl ester portion-wise to a solution of SO₂CI₂in dry CH₂Cl₂at 0° C. and Et₃N,
- b. stirring the solution for 8 hrs at r. t. till TLC showed complete consumption of starting material evaporating the solvent and drying the crude in vacuum,
- c. adding water to it to obtain a slurry which is stirred for 1 hr,
- d. adding to the slurry 45 ml CH₂Cl₂followed by 3 eq of TFA at 0° C. and stirring the resulting solution for 24 hrs,
- e. evaporating and drying the solution in vacuum to obtain the product L-homoglutamyl, N-sulfonic acid.

A further embodiment of the present invention relates to use of a composition comprising general formula Z-OC (CR_n1R_n2)—CO-Z wherein Z=OH or NH₂and n1=n2=1 to 8 together with an additive, excipient, diluents or carrier for modulation of immune response by differentiation of dendritic cells, by administration a pharmaceutical acceptable amount to a subject need thereof.

Yet another embodiment of the present invention relates to use wherein said compound useful in vaccine formulation to prevent more efficient and faster presentation of antigens to T-cells thereby initiate primary protective Th1 immune response and help in the clearance of the pathogen.

Yet another embodiment of the present invention relates to use wherein said compound having a structure as herein and bearing general formula ZOC—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁, to R₄denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H
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Yet another embodiment of the present invention relates to use, wherein said compound having a structure as herein and bearing general formula ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁to R₆denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H
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Yet another embodiment of the present invention relates to use, wherein said compound having structure as herein and bearing general formula ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁to R₈denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H
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Yet another embodiment of the present invention relates to use, wherein said compound in non-toxic to monocytes.

Yet another embodiment of the present invention relates to use, wherein said compound in non-toxic to macrophages.

Yet another embodiment of the present invention relates to use, wherein additives are different divalent metal cations such as Mg, Ca and Zn.

Yet another embodiment of the present invention relates to use, wherein additives are amino acid/dicarboxylic acid derivatives and their pharmaceutically acceptable selected alkali/alkaline earth metal salts.

Yet another embodiment of the present invention relates to use, wherein the compound is selected from the group consisting of:

- I [L-Aspartic acid, N-Sulfonic acid],
- II [2α,3-dicarboxy, propane-1-sulfonic acid],
- III [2α,3-dicarboxy, propane-1-sulfate],
- IV [1α,2-carboxy ethane sulfonic acid],
- V [1α,2-carboxy ethane sulfate],
- VI [D-aspartic acid, N-sulfonic acid],
- VII [2β,3-carboxy,propane-1-sulfonic acid],
- VIII [2β,3-carboxy,propane-1-sulfate],
- IX [1β,2-carboxy ethane-1-sulfonic acid],
- X [1β,2-carboxy ethane-1-sulfate],
- XI [D-aspartic acid, 3α-sulfonic acid],
- XII [D-aspartic acid, 3α-sulfate],
- XIII [D-aspartic acid, 30-sulfonic acid],
- XIV [D-aspartic acid, 30-sulfate],
- XV [L-asparagine,N-sulfonic acid],
- XVI [2α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVII [2α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII [1α-carboxy, 2-carboxamido, ethane sulfonic acid],
- XIX [1α-carboxy, 2-carboxamido, ethane sulfate],
- XX [L-asparagine, 3α-sulfonic acid],
- XXI [L-asparagine, 3α-sulfate],
- XXII [L-asparagine, 3β-sulfonic acid],
- XXIII [L-asparagine, 30-sulfate,
- XXIV [D-asparagine, N-sulfonic acid],
- XXV [2β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI [2β-carboxy, 3-carboxamido, propane-1-sulfate],
- XXVII [1β-carboxy, 2-carboxamido, ethane sulfonic acid],
- XXVIII [1β-carboxy, 2-carboxamido, ethane sulfate],
- XXIX [D-asparagine, 3α-sulfonic acid],
- XXX [D-asparagine, 3α-sulfate],
- XXXI [D-asparagine, 3β-sulfonic acid],
- XXXII [D-asparagine, 30-sulfate],
- XXXIII [L-glutamic acid, N-sulfonic acid],
- XXXIV [2α,4-dicarboxy, butane-1-sulfonic acid],
- XXXV [2α,4-dicarboxy, butane-1-sulfate],
- XXXVI [1α,3-dicarboxy, propane sulfonic acid],
- XXVII [1α,3-dicarboxy, propane sulfate],
- XXVIII [1β,3-dicarboxy, propane sulfate],
- XXXIX [1β,3-dicarboxy, propane sulfonic acid],

Yet another embodiment of the present invention relates to use, wherein the compound is selected from the group consisting of:

- I. [D-glutamic acid, N-sulfonic acid],
- II. 2β,4-dicarboxy, butane-1-sulfonic acid],
- III. [2β,4-dicarboxy, butane-1-sulfate],
- IV. [D-glutamic acid, 3α-sulfonic acid],
- V. [D-glutamic acid, 3α-sulfate],
- VI. [D-glutamic acid, 3β-sulfonic acid],
- VII. [D-glutamic acid, 3β-sulfate],
- VIII. [D-glutamic acid, 4α-sulfonic acid],
- IX. [D-glutamic acid, 4α-sulfate],
- X. [D-glutamic acid, 4β-sulfonic acid],
- XI. [D-glutamic acid, 3β-sulfate],
- XII. [L-glutamine, N-sulfonic acid],
- XIII. [2α-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XIV. [2α-carboxy, 4-carboxamido, butane-1-sulfate],
- XV. [1α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVI. [1α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVII. [1β-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XIX. [D-glutamine, N-sulfonic acid],
- XX. [2β-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXI. [2β-carboxy, 4-carboxamido, butane-1-sulfate],
- XXII. [D-glutamine, 3α-sulfonic acid],
- XXIII. [D-glutamine, 3α-sulfate],
- XXIV. [D-glutamine, 30-sulfonic acid],
- XXV. [D-glutamine, 3β-sulfate],
- XXVI. [D-glutamine, 4α-sulfonic acid],
- XXVII. [D-glutamine, 4α-sulfate],
- XXVIII. [D-glutamine, 4β-sulfonic acid],
- XXIX. [D-glutamine, 4β-sulfate],
- XXX. [L-homoglutamic acid, N-sulfonic acid],
- XXXI. [Pentane-2α,5-dicarboxy-1-sulfonic acid],
- XXXII. [Pentane-2α,5-dicarboxy-1-sulfate],
- XXXIII. [Butane-1α,4-dicarboxy-1-sulfonic acid],
- XXXIV. [Butane-1α,4-dicarboxy-1-sulfate],
- XXXV. [D-homoglutamic acid, N-sulfonic acid],
- XXXVI. [Pentane-2β,5-dicarboxy-1-sulfonic acid],
- XXXVII. [Pentane-2β,5-dicarboxy-1-sulfate],
- XXXVIII. [Butane-1β,4-dicarboxy-1-sulfonic acid],
- XXXIX. [Butane-1β,4-dicarboxy-1-sulfate],

Yet another embodiment of the present invention relates to use, wherein the compound is selected from the group consisting of

- I. [D-homoglutamic acid, 3α-sulfonic acid],
- II. [D-homoglutamic acid, 3α-sulfate],
- III. [D-homoglutamic acid, 30-sulfonic acid],
- IV. [D-homoglutamic acid, 313-sulfate],
- V. [D-homoglutamic acid, 4α-sulfonic acid],
- VI. [D-homoglutamic acid, 4α-sulfate],
- VII. [D-homoglutamic acid, 413-sulfonic acid],
- VIII. [D-homoglutamic acid, 413-sulfate],
- IX. [D-homoglutamic acid, 5α-sulfate],
- X. [D-homoglutamic acid, 5α-sulfate],
- XI. [D-homoglutamic acid, 51-sulfonic acid],
- XII. [D-homoglutamic acid, 5β-sulfate],
- XIII. [L-homoglutamine, N-sulfonic acid],
- XIV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid],
- XV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfate],
- XVI. [Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid],
- XVII. [Butane-1 α-carboxy, 4-carboxamido-1-sulfate],
- XVIII. [D-homoglutamine, N-sulfonic acid],
- XIX. [Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid],
- XX. [Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid],
- XXI. [Butane-1β-carboxy, 4-carboxamido-1-sulfate],
- XXII. [D-homoglutamine, 3α-sulfonic acid],
- XXIII. [D-homoglutamine, 3α-sulfate],
- XXIV. [D-homoglutamine, 3β-sulfonic acid],
- XXV. [D-homoglutamine, 3β-sulfate],
- XXVI. [D-homoglutamine, 4α-sulfonic acid],
- XXVII. [D-homoglutamine, 4α-sulfate],
- XVIII. [D-homoglutamine, 4β-sulfonic acid],
- XXIX. [D-homoglutamine, 4β-sulfate],
- XXX. [D-homoglutamine, 5α-sulfonic acid],
- XXXI. [D-homoglutamine, 5α-sulfate],
- XXXII. [D-homoglutamine, 5β-sulfonic acid] and
- XXIII. [D-homoglutamine, 5β-sulfate].

Yet another embodiment of the present invention relates to use, wherein novel sulfonic acid/sulfate derivatives of the formulae ZOC—CR₃R₄—CR₁R₂—COOH wherein: Z=OH or NH₂, R₁, to R₄denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H

- I. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=NHSO₃H is the same meaning as is before defined;
- II. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- III. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- IV. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=SO₃H is the same meaning as is before defined;
- V. A compound wherein Z=OH, R₂=R₃=R₄=H, R₁=OSO₃H is the same meaning as is before defined;
- VI. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=NHSO₃H is the same meaning as is before defined;
- VII. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- VIII. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- IX. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=SO₃H is the same meaning as is before defined;
- X. A compound wherein Z=OH, R₁=R₃=R₄=H, R₂=OSO₃H is the same meaning as is before defined;
- XI. A compound wherein Z=OH, R₁=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XII. A compound wherein Z=OH, R₁=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XIII. A compound wherein Z=OH, R₁=R₃=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XIV. A compound wherein Z=OH, R₁=R₃=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XV. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=NHSO₃H is the same meaning as is before defined;
- XVI. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- XVII. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=SO₃H is the same meaning as is before defined;
- XIX. A compound wherein Z=NH₂, R₂=R₃=R₄=H, R₁=OSO₃H is the same meaning as is before defined;
- XX. A compound wherein Z=NH₂, R₁=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XXI. A compound wherein Z=NH₂, R₁=R₄=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXII. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=NHSO₃H is the same meaning as is before defined;
- XXV. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- XXVII. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=SO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=NH₂, R₁=R₃=R₄=H, R₂=OSO₃H is the same meaning as is before defined;
- XXIX. A compound wherein Z=NH₂, R₁=R₄=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XXX. A compound wherein Z=NH₂, R₁=R₄=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXXI. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXII. A compound wherein Z=NH₂, R₁=R₃=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined.

Yet another embodiment of the present invention relates to use, wherein novel sulfonic acid/sulfate derivatives of the formulae ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH, wherein: Z=OH or NH₂, R₁, to R₆denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H

- I. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=NHSO₃H is the same meaning as is before defined;
- II. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- III. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- IV. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=SO₃H is the same meaning as is before defined;
- V. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=H, R₁=OSO₃H is the same meaning as is before defined;
- VI. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=OSO₃H is the same meaning as is before defined;
- VII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=SO₃H is the same meaning as is before defined;
- VIII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=NHSO₃H is the same meaning as is before defined;
- IX. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- X. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- XI. A compound wherein Z=OH, R₁=R₄=R₅=R₆=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XII. A compound wherein Z=OH, R₁=R=R₅=R₆=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined; XIII. A compound wherein Z=OH, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XIV. A compound wherein Z=OH, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XV. A compound wherein Z=OH, R₁=R₄=R₃=R₆=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XVI. A compound wherein Z=OH, R₁=R₄=R₃=R₆=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- XVII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined;
- XIX. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=NHSO₃H is the same meaning as is before defined;
- XX. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- XXI. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- XXII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=SO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=H, R₁=OSO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=OSO₃H is the same meaning as is before defined;
- XXV. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=SO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=NHSO₃H is the same meaning as is before defined;
- XXVII. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- XXIX. A compound wherein Z=NH₂, R₁=R₄=R₅=R₆=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XXX. A compound wherein Z=NH₂, R₁=R₄=R₅=R₆=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXXI. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXXII. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₁=R₄=R₃=&=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- XXXV. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined.

Yet another embodiment of the present invention relates to use, wherein novel sulfonic acid/sulfate derivatives of the formulae ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH, wherein: Z=OH or NH₂, R₁, to R₈denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H

- I. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=NHSO₃H is the same meaning as is before defined;
- II. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R=—CH₂SO₃H is the same meaning as is before defined;
- III. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- IV. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=SO₃H is the same meaning as is before defined;
- V. A compound wherein Z=OH, R₂=R₃=R₄=R₅=R₆=R₇=R=H, R₁=OSO₃H is the same meaning as is before defined;
- VI. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=NHSO₃H is the same meaning as is before defined;
- VII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- VIII. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=CH₂OSO₃H is the same meaning as is before defined;
- IX. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=SO₃H is the same meaning as is before defined;
- X. A compound wherein Z=OH, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=OSO₃H is the same meaning as is before defined;
- XI. A compound wherein Z=OH, R₁=R₄=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XII. A compound wherein Z=OH, R₁=R₄=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XIII. A compound wherein Z=OH, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XIV. A compound wherein Z=OH, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XV. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₇=R₈=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XVI. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₇=R₈=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- XVII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₈=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₈=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined;
- XIX. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=SO₃H is the same meaning as is before defined;
- XX. A compound wherein Z=OH, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=OSO₃H is the same meaning as is before defined;
- XXI. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=SO₃H is the same meaning as is before defined;
- XXII. A compound wherein Z=OH, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=OSO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=NHSO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=CH_{2 SO}₃H is the same meaning as is before defined;
- XXV. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R(=R₇=R₈=H, R₁=CH₂OSO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=SO₃H is the same meaning as is before defined;
- XXVII. A compound wherein Z=NH₂, R₂=R₃=R₄=R₅=R₆=R₇=R₈=H, R₁=OSO₃H is the same meaning as is before defined;
- XVIII. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=NHSO₃H is the same meaning as is before defined;
- XXIX. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=CH₂SO₃H is the same meaning as is before defined;
- XXX. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=SO₃H is the same meaning as is before defined;
- XXXI. A compound wherein Z=NH₂, R₁=R₃=R₄=R₅=R₆=R₇=R₈=H, R₂=OSO₃H is the same meaning as is before defined;
- XXXII. A compound wherein Z=NH₂, R₁=R₄=R₅=R₆=R₇=R₉=H, R₂=NH₂, R₃=SO₃H is the same meaning as is before defined;
- XXIII. A compound wherein Z=NH₂, R₁=R=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₃=OSO₃H is the same meaning as is before defined;
- XXIV. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=SO₃H is the same meaning as is before defined;
- XXV. A compound wherein Z=NH₂, R₁=R₃=R₅=R₆=R₇=R₈=H, R₂=NH₂, R₄=OSO₃H is the same meaning as is before defined;
- XXVI. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=R₇=F8=H, R₂=NH₂, R₅=SO₃H is the same meaning as is before defined;
- XVII. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=R₇=R₈=H, R₂=NH₂, R₅=OSO₃H is the same meaning as is before defined;
- VIII. A compound wherein Z=NH₂, R₁=R₃=R₅=F4=R₇=R₈=H, R₂=NH₂, R₆=SO₃H is the same meaning as is before defined;
- XXIX. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=R₇=R₈=H, R₂=NH₂, R₆=OSO₃H is the same meaning as is before defined;
- XL. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=SO₃H is the same meaning as is before defined;
- XLI. A compound wherein Z=NH₂, R₁=R₄=R₃=R₆=R₅=R₈=H, R₂=NH₂, R₇=OSO₃H is the same meaning as is before defined;
- XLII. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=SO₃H is the same meaning as is before defined;
- XLIII. A compound wherein Z=NH₂, R₁=R₃=R₅=R₄=R₇=R₆=H, R₂=NH₂, R₈=OSO₃H is the same meaning as is before defined;

Yet another embodiment of the present invention relates to use, wherein said compound is non-toxic salts selected from the group consisting of:

- I [L-Aspartic acid, N-Sulfonic acid],
- II [2α,3-dicarboxy, propane-1-sulfonic acid],
- III [2α,3-dicarboxy, propane-1-sulfate],
- IV [1α,2-carboxy ethane sulfonic acid],
- V [1α,2-carboxy ethane sulfate],
- VI [D-aspartic acid, N-sulfonic acid],
- VII [2β,3-carboxy,propane-1-sulfonic acid],
- VIII [2β,3-carboxy,propane-1-sulfate],
- IX [1β,2-carboxy ethane-1-sulfonic acid],
- X [1β,2-carboxy ethane-1-sulfate],
- XI [D-aspartic acid, 3α-sulfonic acid],
- XII [D-aspartic acid, 3α-sulfate],
- XIII [D-aspartic acid, 3β-sulfonic acid],
- XIV [D-aspartic acid, 3β-sulfate],
- XV [L-asparagine,N-sulfonic acid],
- XVI [2α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVII [2α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII [1α-carboxy, 2-carboxamido, ethane sulfonic acid],
- XIX [1α-carboxy, 2-carboxamido, ethane sulfate],
- XX [L-asparagine, 3α-sulfonic acid],
- XXI [L-asparagine, 3α-sulfate],
- XXII [L-asparagine, 3β-sulfonic acid],
- XXIII [L-asparagine, 3β-sulfate,
- XXIV [D-asparagine, N-sulfonic acid],
- XXV [2β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI [2β-carboxy, 3-carboxamido, propane-1-sulfate],
- XXVII [1β-carboxy, 2-carboxamido, ethane sulfonic acid],
- XXVIII [1β-carboxy, 2-carboxamido, ethane sulfate],
- XXIX [D-asparagine, 3α-sulfonic acid],
- XXX [D-asparagine, 3α-sulfate],
- XXXI [D-asparagine, 3β-sulfonic acid],
- XXXII [D-asparagine, 30-sulfate],
- XXXIII [L-glutamic acid, N-sulfonic acid],
- XXXIV [2α,4-dicarboxy, butane-1-sulfonic acid],
- XXXV [2α,4-dicarboxy, butane-1-sulfate],
- XXXVI [1α,3-dicarboxy, propane sulfonic acid],
- XXVII [1α,3-dicarboxy, propane sulfate],
- XXVIII [1β,3-dicarboxy, propane sulfate],
- XXXIX [1β,3-dicarboxy, propane sulfonic acid],

Yet another embodiment of the present invention relates to use, wherein said compound is non-toxic salts selected from the group consisting of:

- I. [D-glutamic acid, N-sulfonic acid),
- II. [2β,4-dicarboxy, butane-1-sulfonic acid],
- III. [2β,4-dicarboxy, butane-1-sulfate],
- IV. [D-glutamic acid, 3α-sulfonic acid],
- V. [D-glutamic acid, 3α-sulfate],
- VI. [D-glutamic acid, 3β-sulfonic acid],
- VII. [D-glutamic acid, 3β-sulfate],
- VIII. [D-glutamic acid, 4α-sulfonic acid],
- IX. [D-glutamic acid, 4α-sulfate],
- X. [D-glutamic acid, 4β-sulfonic acid],
- XI. [D-glutamic acid, 3β-sulfate],
- XII. [L-glutamine, N-sulfonic acid],
- XIII. [2α-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XIV. [2α-carboxy, 4-carboxamido, butane-1-sulfate],
- XV. [1α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVI. [1α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVII. [1β-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XIX. [D-glutamine, N-sulfonic acid],
- XX. [2β-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXI. [2β-carboxy, 4-carboxamido, butane-1-sulfate],
- XXII. [D-glutamine, 3α-sulfonic acid],
- XXIII. [D-glutamine, 3α-sulfate],
- XXIV. [D-glutamine, 30-sulfonic acid],
- XXV. [D-glutamine, 31-sulfate],
- XXVI. [D-glutamine, 4α-sulfonic acid],
- XXVII. [D-glutamine, 4α-sulfate],
- XXVIII. [D-glutamine, 40-sulfonic acid],
- XXIX. [D-glutamine, 41-sulfate],
- XXX. [L-homoglutamic acid, N-sulfonic acid],
- XXXI. [Pentane-2α,5-dicarboxy-1-sulfonic acid],
- XXXII. [Pentane-2α,5-dicarboxy-1-sulfate],
- XXXIII. [Butane-1α,4-dicarboxy-1-sulfonic acid],
- XXXIV. [Butane-1α,4-dicarboxy-1-sulfate],
- XXXV. [D-homoglutamic acid, N-sulfonic acid],
- XXXVI. [Pentane-2β,5-dicarboxy-1-sulfonic acid],
- XXXVII. [Pentane-2β,5-dicarboxy-1-sulfate], 1 (XXXVIII. [Butane-1β,4-dicarboxy-1-sulfonic acid],
- XXXIX. [Butane-1β,4-dicarboxy-1-sulfate],

Yet another embodiment of the present invention relates to use, wherein said compound is non-toxic salts selected from the group consisting of:

- I. [D-homoglutamic acid, 3α-sulfonic acid],
- II. [D-homoglutamic acid, 3α-sulfate],
- III. [D-homoglutamic acid, 3β-sulfonic acid],
- IV. [D-homoglutamic acid, 3β-sulfate],
- V. [D-homoglutamic acid, 4α-sulfonic acid],
- VI. [D-homoglutamic acid, 4α-sulfate],
- VII. [D-homoglutamic acid, 4β-sulfonic acid],
- VIII. [D-homoglutamic acid, 4β-sulfate],
- IX. [D-homoglutamic acid, 5α-sulfate],
- X. [D-homoglutamic acid, 5α-sulfate],
- XI. [D-homoglutamic acid, 5β-sulfonic acid],
- XII. [D-homoglutamic acid, 513-sulfate],
- XIII. [L-homoglutamine, N-sulfonic acid],
- XIV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid],
- XV. [Pentane-2α-carboxy, 5-carboxamido-1-sulfate],
- XVI. [Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid],
- XVII. [Butane-1α-carboxy, 4-carboxamido-1-sulfate],
- XVIII. [D-homoglutamine, N-sulfonic acid],
- XIX. [Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid],
- XX. [Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid],
- XXI. [Butane-1β-carboxy, 4-carboxamido-1-sulfate],
- XXII. [D-homoglutamine, 3α-sulfonic acid],
- XXIII. [D-homoglutamine, 3α-sulfate],
- XXIV. [D-homoglutamine, 3β-sulfonic acid],
- XXV. [D-homoglutamine, 3β-sulfate],
- XXVI. [D-homoglutamine, 4α-sulfonic acid],
- XXVII. [D-homoglutamine, 4α-sulfate],
- XVIII. [D-homoglutamine, 40-sulfonic acid],
- XXIX. [D-homoglutamine, 4β-sulfate],
- XXX. [D-homoglutamine, 5α-sulfonic acid],
- XXXI. [D-homoglutamine, 5α-sulfate],
- XXXII. [D-homoglutamine, 513-sulfonic acid] and
- XXIII. [D-homoglutamine, 5β-sulfate].

Yet another embodiment of the present invention relates to use, wherein said compound is selected from the group consisting of aspartic acid, asparagine and corresponding de-amino analogs:

- I. [L-Aspartic acid, N-Sulfonic acid],
- II. [2α,3-dicarboxy, propane-1-sulfonic acid],
- III. [2α,3-dicarboxy, propane-1-sulfate],
- IV. [1α,2-carboxy ethane sulfonic acid],
- V. [1α,2-carboxy ethane sulfate],
- VI. [D-aspartic acid, N-sulfonic acid],
- VII. [2β,3-carboxy,propane-1-sulfonic acid],
- VIII. [2β,3-carboxy,propane-1-sulfate],
- IX. [1β,2-carboxy ethane-1-sulfonic acid],
- X. [1β,2-carboxy ethane-1-sulfate],
- XI. [D-aspartic acid, 3α-sulfonic acid],
- XII. [D-aspartic acid, 3α-sulfate],
- XIII. [D-aspartic acid, 3β-sulfonic acid],
- XIV. [D-aspartic acid, 3β-sulfate],
- XV. [L-asparagine,N-sulfonic acid],
- XVI. [2α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XVII. [2α-carboxy, 3-carboxamido, propane-1-sulfate],
- XVIII. [1α-carboxy, 2-carboxamido, ethane sulfonic acid],
- XIX. [1α-carboxy, 2-carboxamido, ethane sulfate],
- XX. [L-asparagine, 3α-sulfonic acid],
- XXI. [L-asparagine, 3α-sulfate],
- XXII. [L-asparagine, 313-sulfonic acid],
- XXIII. [L-asparagine, 3β-sulfate,
- XXIV. [D-asparagine, N-sulfonic acid],
- XXV. [2β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI. [2β-carboxy, 3-carboxamido, propane-1-sulfate],
- XXVII. [1β-carboxy, 2-carboxamido, ethane sulfonic acid],
- XVIII. [1β-carboxy, 2-carboxamido, ethane sulfate],
- XXIX. [D-asparagine, 3α-sulfonic acid],
- XXX. [D-asparagine, 3α-sulfate],
- XXXI. [D-asparagine, 3β-sulfonic acid],
- XXXII. [D-asparagine, 3β-sulfate],

Yet another embodiment of the present invention relates to use, wherein said compound is selected from the group consisting of glutamic acid, glutamine and corresponding de-amino analogs:

- I. [L-glutamic acid, N-sulfonic acid],
- II. [2α,4-dicarboxy, butane-1-sulfonic acid],
- III. [2α,4-dicarboxy, butane-1-sulfate],
- IV. [1α,3-dicarboxy, propane sulfonic acid],
- V. [1α,3-dicarboxy, propane sulfate],
- VI. [1β,3-dicarboxy, propane sulfate],
- VII. [1β,3-dicarboxy, propane sulfonic acid],
- VIII. [D-glutamic acid, N-sulfonic acid],
- IX. [2β,4-dicarboxy, butane-1-sulfonic acid],
- X. [2β,4-dicarboxy, butane-1-sulfate],
- XI. [D-glutamic acid, 3α-sulfonic acid],
- XII. [D-glutamic acid, 3α-sulfate],
- XIII. [D-glutamic acid, 30-sulfonic acid],
- XIV. [D-glutamic acid, 3β-sulfate],
- XV. [D-glutamic acid, 4α-sulfonic acid],
- XVI. [D-glutamic acid, 4α-sulfate],
- XVII. [D-glutamic acid, 4β-sulfonic acid],
- XVIII. [D-glutamic acid, 3β-sulfate],
- XIX. [L-glutamine, N-sulfonic acid],
- XX. [2α-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXI. [2α-carboxy, 4-carboxamido, butane-1-sulfate],
- XXII. [1α-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXIII. [1α-carboxy, 3-carboxamido, propane-1-sulfate],
- XXIV. [1β-carboxy, 3-carboxamido, propane-1-sulfate],
- XXV. [1β-carboxy, 3-carboxamido, propane-1-sulfonic acid],
- XXVI. [D-glutamine, N-sulfonic acid],
- XXVII. [2β-carboxy, 4-carboxamido, butane-1-sulfonic acid],
- XXVIII. [2β-carboxy, 4-carboxamido, butane-1-sulfate],
- XXIX. [D-glutamine, 3α-sulfonic acid],
- XXX. [D-glutamine, 3α-sulfate],
- XXXI. [D-glutamine, 3β-sulfonic acid],
- XXXII. [D-glutamine, 3β-sulfate],
- XXXIII. [D-glutamine, 4α-sulfonic acid],
- XXXIV. [D-glutamine, 4α-sulfate],
- XXXV. [D-glutamine, 40-sulfonic acid],
- XXXVI. [D-glutamine, 4β-sulfate],
- XXXVII. [L-homoglutamic acid, N-sulfonic acid],
- XXXVIII. [Pentane-2α,5-dicarboxy-1-sulfonic acid],
- XXXIX. [Pentane-2α,5-dicarboxy-1-sulfate],
- XL. [Butane-1α,4-dicarboxy-1-sulfonic acid],
- XLI. [Butane-1α,4-dicarboxy-1-sulfate],

Yet another embodiment of the present invention relates to use, wherein said compound is selected from the group consisting of homoglutamic acid, homoglutamine and corresponding de-amino analogs:

- I. [D-homoglutamic acid, N-sulfonic acid],
- II. [Pentane-2β,5-dicarboxy-1-sulfonic acid],
- III. [Pentane-2β,5-dicarboxy-1-sulfate],
- IV. [Butane-1β,4-dicarboxy-1-sulfonic acid],
- V. [Butane-1β,4-dicarboxy-1-sulfate],
- VI. [D-homoglutamic acid, 3α-sulfonic acid],
- VII. [D-homoglutamic acid, 3α-sulfate],
- VIII. [D-homoglutamic acid, 3β-sulfonic acid],
- IX. [D-homoglutamic acid, 3β-sulfate],
- X. [D-homoglutamic acid, 4α-sulfonic acid],
- XI. [D-homoglutamic acid, 4α-sulfate],
- XII. [D-homoglutamic acid, 4β-sulfonic acid],
- XIII. [D-homoglutamic acid, 4β-sulfate],
- XIV. [D-homoglutamic acid, 5α-sulfate],
- XV. [D-homoglutamic acid, 5α-sulfate],
- XVI. [D-homoglutamic acid, 5β-sulfonic acid],
- VII. [D-homoglutamic acid, 5β-sulfate],
- XVIII. [L-homoglutamine, N-sulfonic acid],
- XIX. [Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid],
- XX. [Pentane-2α-carboxy, 5-carboxamido-1-sulfate],
- XXI. [Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid],
- IXII. [Butane-1α-carboxy, 4-carboxamido-1-sulfate],
- XXIII. [D-homoglutamine, N-sulfonic acid],
- XXIV. [Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid],
- XXV. [Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid],
- XXVI. [Butane-1β-carboxy, 4-carboxamido-1-sulfate],
- XXVII. [D-homoglutamine, 3α-sulfonic acid],
- XXVIII. [D-homoglutamine, 3α-sulfate],
- XXIX. [D-homoglutamine, 3β-sulfonic acid],
- XXX. [D-homoglutamine, 3β-sulfate],
- XXXI. [D-homoglutamine, 4α-sulfonic acid],
- XXXII. [D-homoglutamine, 4α-sulfate],
- XXXIII. [D-homoglutamine, 4β-sulfonic acid],
- XXXIV. [D-homoglutamine, 4β-sulfate],
- XXXV. [D-homoglutamine, 5α-sulfonic acid],
- XXXVI. [D-homoglutamine, 5α-sulfate],
- XXXVII. [D-homoglutamine, 513-sulfonic acid] and
- XXXVIII. [D-homoglutamine, 5β-sulfate].

Still another embodiment of a present invention relates to a compound incubation of BM leukocyte precursors with different concentrations of the synthetic compound increases the cell surface densities of CD11c, CD80, CD54 and CD11c to various levels with maximum up regulation at 200 mM.

Still further another embodiment of a present invention relates to a compound it gives the fold increase in the levels of molecules of cells stimulated with either 15 ng/ml of GM-CSF or 200 mM of the synthetic compound at 48 h of incubation.

Yet another embodiment of a present invention relates to a compound wherein the viability of the cultures is more than 99% at the end of the incubation period at this concentration of the synthetic compound.

Yet another embodiment of a present invention relates to a compound useful for inhibition of mononuclear TRAP- positive osteoclasts.

Yet another embodiment of a present invention relates to a compound useful for inhibition of fusion of mononuclear cells into multinuclear osteoclasts.

Yet another embodiment of a present invention relates to a compound useful for inhibition of bone resorption.

Yet another embodiment of a present invention relates to a compound has non-toxic to monocytes.

Yet another embodiment of a present invention relates to a compound has non-toxic to macrophages.

Further embodiment of a present invention relates to a method for inhibition of osteoclast formation comprising the step of administering a pharmaceutically acceptable amount of a compound to a subject in need thereof optionally with an additive, excipient, diluent or carrier.

Yet another embodiment of a present invention relates to a method wherein dosage the compound is 5 to 10 mg/kg body weight.

Yet another embodiment of a present invention relates to a method wherein the period of administration is 25-30 days.

Further embodiment of a present invention relates to a method for inhibition of mononuclear TRAP-positive osteoclasts comprising the step of administering a pharmaceutically acceptable amount of a compound subject in need thereof optionally with an additive, excipient, diluent or carrier.

Yet another embodiment of a present invention relates to a method wherein dosage of the compound is 5 to 10 mg/kg body weight.

Yet another embodiment of a present invention relates to a method wherein the period of administration is 25-30 days.

Further embodiment of a present invention relates to a method for inhibition of multinuclear TRAP-positive osteoclasts comprising the step of administering a pharmaceutically acceptable amount of a compound to a subject in need thereof optionally with an additive, excipient, diluent or carrier.

Yet another embodiment of a present invention relates to a method wherein the dosage of the compound is 5 to 10 mg/kg body weight.

Yet another embodiment of a present invention relates to a method wherein the period of administration is 5 to 30 days.

Still further embodiment of a present invention relates to a method for modulation of immune response controlled by differentiation of dendricts cells comprising the step of administration a pharmaceutical acceptable amount of a compound to a subject in need thereof optionally with an additive, excipient, diluents or carrier.

Yet another embodiment of a present invention relates to a compound useful to induce differentiation of dendritic cells and modulation of immune response controlled by dendritic cell.

Yet another embodiment of a present invention relates to a compound useful in vaccine formulation to prevent more efficicent and faster presentation of antigens to T-cells thereby initiate primary protective Th1 immune response and help in the clearance of the pathogen.

The compounds for differentiation of dendritic cells also contained different divalent metal ions such as Mg, Ca and Zn. The composition consisted of varying amounts of the above acid amino acid/dicarboxylic acid derivatives and their pharmaceutically acceptable salts. Non toxic salts of the present invention are contained all pharmaceutically acceptable salts, for example, general salts, acid addition salt, hydrate salts.

The compounds of the formulae (Ia), (Ib) and (Ic) of the present invention may be converted into the corresponding salts. Non toxic and water soluble salts are preferable. Suitable salts for example are as follows:

- Salts of alkaline earth metals (Mg, Ca etc)
- Ammonium Salts
- Salts of pharmaceutically acceptable organic amines (tetramethyl ammonium, triethyl amine, methyl amine, cyclopentyl amine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl) amine, lysine, arginine, N-methyl glucamine, etc.
  
  a) a process for the preparation of sulfonic acid/sulfate derivatives of the formula (Ia) (Ib) (Ic) and non-toxic salts thereof:
  
  b) a process for the preparation of sulfonic acid/sulfate derivatives of the formula and non-toxic salts thereof:
  
  c) a process for the preparation of sulfonic acid/sulfate derivatives of the formula and non-toxic salts thereof:
  
  d) In the compound of the present invention of the formula (Ia) wherein the compound is selected from the group consisting of aspartic acid, asparagine and corresponding de-amino analogs:
  
  e) In the compound of the present invention of the formula (Ib) wherein the compound is selected from the group consisting of glutamic acid, glutamine and corresponding de-amino analogs:
  
  f) In the compound of the present invention of the formula (Ic) wherein the compound is selected from the group consisting of homoglutamic acid, homoglutamine and corresponding de-amino analogs:

Among the various Antigen Presenting Cells (APCs) of the immune system, Dendritic Cells (DCs) constitute the most potent APCs and act as a bridge between the innate and the acquired arm of the immune system. This is largely attributed to the ability of DCs to take-up pico- to femtomoles of antigen and to stimulate primary naïve quiescent T cells, thereby initiating a primary immune response. DCs exist in various states of activation that translates into distinct functions. For example, DCs arising from the Bone Marrow (BM) are essentially immature DCs. These DCs exhibit low levels of T cell costimulatory molecules such as CD80, CD86, CD40 & CD54 and also low levels of surface MHC class I and class II molecules. Further, these DCs express a range of phagocytic, endocytic and scavenger receptors and owing to the above features are thus programmed for antigen capture and uptake. Upon contact , bacterial endotoxins (e.g.Flwith various inflammatory stimuli such as, TNF-LPS), CD40 ligand (CD401), CpG containing bacterial DNA, double stranded viruses and certain (but not all) antigens, DCs undergo a process of maturation, wherein they now upregulate their surface levels of costimulatory molecules and MHC-peptide complexes (now exported to the cell surface following degradation and loading onto MHC trimers) and are thus programmed for antigen presentation and T lymphocyte stimulation. The transformation from the immature to the mature stage is a tightly regulated process often requiring T cell help. During maturation these DCs also secrete a range of cytokines such as and low levels of IL-10.□, IL-12, IFN-□TNF-Owing to secretion of pro-inflammatory cytokines, DCs are thought to drive pro-inflammatory or Th1 responses and help in the clearance of the pathogen. Therefore, factors/molecules that increase the population of immature DCs in the immune system offer added advantage for the host's fight against infectious pathogens. In this context efforts have been focused on finding and generating ways to increase the DC numbers in the immune system. These have included the use of recombinant DCs or even pathogens that have been transformed to express Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), the growth factor that is conventionally used to generate DCs in vitro.

A number of studies have identified pathogen and host products such as proteins that induce the maturation of different DC subsets. Owing to their fully mature status these DCs are more programmed for antigen presentation and T cell stimulation and have reduced capacity to capture antigens of pathogens. Immature DCs that are de novo differentiated from precursors offer better advantage than mature DCs because of their ability to scavenge pathogens followed by their uptake and processing and subsequent presentation to T lymphocytes. Our observation on the ability of ‘the molecule’ to induce differentiation of Dendritic Cells from mouse bone marrow leukocyte precursors, therefore, assumes paramount importance and is a significant step towards modulation of immune responses controlled by DCs. As the DCs differentiated by ‘the molecule’ are immature in nature and resemble very closely to the DCs differentiated by GM-CSF they will be efficient not only at antigen capture but also be effective T cell stimulators.

Among the many applications, the two most important ones would include the use of ‘the molecule’ in vaccine formulations or in protection based studies that would promote more efficient and faster presentation of the antigens to T cells thereby initiate primary protective Th1 immune responses and help in the clearance of the pathogen. Further, ‘the molecule’ offers a cheap alternative to GM-CSF for commercial purposes to generate DCs in vitro for research based studies.

Basically, immuno-supression is a common clinical feature in many infectious diseases. This immuno-supression cripples the ability of the immune systems to get rid of the infectious agents eventuating in the death of the host. It has been found that the host recovering from disease after chaemotherapy shows a significant improvement of antigen-specific immune functions. Despite the urgency of the need, and immuno-potentiator which can be of human use remains awaited. The cumulative incidence of the diseases obviates the need for a drug(s) that restores the immune response of the affected individual to a normal level.

In response to any invasion by a pathogen, the complex multicellular organisms have evolved a defense mechanism to make their internal environment more hostile to invaders. All immune systems have one feature in common: they respond to infection by switching from a resting to an active state. The innate response limits the infection and activates Antigen Presenting Cells (APCs) to trigger adaptive immunity, which increases specificity and generates memory. Consequently, the immune responses that occur during an encounter with antigens-be it infectious agents or allergens are primarily characterized by the plasticity of their nature and magnitude. This feature provides an important advantage that permits the immune system to tailor its defense strategy to particular groups of antigens. Interactions between APCs such as Dendritic cells (DCs) and macrophages and the different subsets of T cells (CD4+ and CD8+) in the T cell rich areas of the lymph nodes and spleen, amplify the consequent immune responses. Following this interaction, T helper (Th) cell precursors then differentiate into effectors. that secrete either pro-inflammatory or suppressor/regulatory cytokines such as Interferon (IFN)-□E Tumor Necrosis Factor (TNF)-□, and Interleukin (IL)-1, or IL-4, IL-10 and Transforming Growth Factor (TGF)-□, respectively.

Among the most potent of the APCs are the macrophages and different subsets of DCs, that together virtually regulate the antigen capture and presentation of the innate arm of the immune system. DCs are professional APCs that are continuously produced by the stem cells in the hematopoeitic tissues. DCs exist at various states of activation that are primarily classified as immature (iDCs) and mature (mDCs). iDCs are programmed for antigen capture, which upon contact with various stimuli, such as bacterial products, CD40 ligand, (TNF)-□, and certain antigens undergo a process of maturation wherein they now become programmed for antigen presentation and T-cell stimulation. Consequently, agents that promote the maturation of iDCs play a vital role in shaping the early immune responses elicited during an infection. Along with macrophages, that constitute the all important phagocytic component of the innate immune system DCs activate the effector cells such as the various subsets of T-cells, Natural Killer (NK) cells and NK-T cells by secreting a profile of cytokines that would eventually prime these effector cells to carryout their functions. These range from stimulating the adaptive arm of the immune system for the generation of antibody mediated responses, to stimulation of the cytotoxic activity by the CD8⁺ T-cells against the infected cells/tissues. The invention may provide a novel compound that will be useful in vaccination, cancer therapy and other immunomodulatory regiments.

The preferable specific compounds of the formulae (Ia), (Ib) and (Ic) are the derivatives of aspartic acid, asparagine and corresponding de-amino analogs (Table 1), glutamic acid, glutamine and corresponding de-amino analogs (Table 2) and homoglutamic acid, homoglutamine and corresponding de-amino analogs (Table 3) and non toxic salts thereof and example compounds.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1, or Plate A, represents surface level of CD 80.

FIG. 2, or Plate B, represents surface level of CD 54.

FIG. 3, or Plate C, represents surface level of CD I Ic.

FIG. 4, or Plate D, represents surface level of CD H-2D (MHC class 1).

BRIEF DESCRIPTION OF THE ACCOMPANYING PLATES

Plate I. Compound I Induces Differentiation of Dendritic Cells from BALB/c Mouse Bone Marrow

Enriched leukocyte precursors from 4 to 6 weeks old mice were stimulated with varying concentrations of compound as given in example-3 for 48 h. Cells were stained for the surface levels of indicated markers. Plates A-D represent surface levels of CD80, CD54, CD11c and H-2D (MHC class 1), respectively. Results obtained with Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) are also shown for comparison. Panels a to d in each Plate shows the surface levels of indicated markers on cells stimulated with 15 ng/ml of GM-CSF, 10 μg/ml, 5 μg /ml and I jig /ml of compound 1, respectively. The Green line represents staining of stimulated cells while the black line depicts staining of unstimulated cells.

Differentiation of Dendritic Cells

The fine suspension obtained above was transferred into a 50 ml sterile centrifuge tube and centrifuged for 10 minutes at 1200 rpm. After removing the supernatant, RBC lysis buffer was added, mixed thoroughly and incubated for 3-5 minutes at room temperature. The pellets were washed using HBSS wash buffer and then centrifuged again for 10 minutes at 1200 rpm. This process was repeated for one more time. The pellet was dissolved in 2 ml HBSS and passed through a pre-separation filter (Miltenyi Biotech # 130-041-407) to remove unwanted tissue etc. Microbeads (I-A, CD45R and CD90) were added to this clear solution and incubated for one hour at 4° C. with shaking to eliminate other lymphocytes and macrophages and MHC positive cells. This suspension was then finally passed through a MACS (Magnetic Activated Cell Sorting) column to get essentially and predominately leukocyte precursors. The cell pellet was suspended in complete medium (RPMI 1640, 10% Foetal Calf Serum, Sodium pyruvate (1 mM) and 2-Mercaptoethanol (50 mM). About 2.5-3×10⁶leukocyte precursors were plated in each well of a 24 well culture plate in 1 ml culture volume. Cells were stimulated with either 15 ng per ml of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) or 50 micro gram per ml of the compound (neutralized with 1 M Tris HCl to achieve a pH of 7.0). The plate was incubated for 48 hours at 37° C. in a CO₂incubator.

Evaluation of Cell Surface Marker Expression

In order to evaluate the upregulation of various cell surface markers associated with Dendritic cells, flow cytometry on the cells stimulated with GM-CSF or the compound was carried out using fluorescent labeled antibodies to various molecules (CD11c, I-A^d, CD80, CD86, H2-D^d, CD54, CD40).

List of Tables

TABLE 1

1. L-Aspartic acid, N-Sulfonic acid Z = OH, R₁= NHSO₃H, R₂= R₃= R₄= H2. L-Aspartic acid, 2β-sulfonic acid Z = OH, R₁NH₂, R₃= R₄= H, R₂= SO₃H3. L-Aspartic acid, 2β-sulfate Z = OH, R₁= NH₂, R₃= R₄= H, R₂= OSO₃H4. L-aspartic acid, 3α-sulfonic acid Z = OH, R₁NH₂, R₂= R₄= H, R₃= SO₃H5. L-aspartic acid, 3α-sulfate Z = OH, R₁= NH₂, R₂= R₃= H, R₃= OSO₃H6. L-aspartic acid, 3β-sulfonic acid Z = OH, R₁= NH₂, R₂= R₃= H, R₄= SO₃H7. L-aspartic acid, 3β-sulfate Z = OH, R₁NH₂, R₂= R₃= H, R₄= OSO₃H8. 2α, 3-dicarboxy, propane-1-sulfonic acid Z = OH, R₁= R₃= R₄=H,R₂= CH₂SO₃H9. 2α,3 -dicarboxy, propane-1-sulfate Z = OH, R₁R₃= R₄= H, R₂= CH₂OSO₃H10. 1α,2-carboxy ethane sulfonic acid Z = OH, R₁= R₃= R₄=H, R₂= SO₃H11. 1α,2-carboxy ethane sulfate Z = OH, R₁= R₃= R₄=H, R₂= OSO₃H12. D-aspartic acid, N-sulfonic acid Z = OH, R₂= NHSO₃H, R₁= R₃= R₄=H13. 2β,3-carboxy,propane-1-sulfonic acid Z = OH, R₂= H, R₁= CH₂SO₃H14. 2β,3 -carboxy,propane-1-sulfate Z = OH, R₂= H, R₁CH₂OSO₃H15. 1β,2-carboxy ethane-1-sulfonic acid Z = OH, R₂= H, R₁= SO₃H16. 1β,2-carboxy ethane-1-sulfate Z = OH, R₂= H, R₁= OSO₃H17. D-aspartic acid, 2α-sulfonic acid Z = OH, R₂= NH₂, R₃= R₄= H, R₁= SO₃H18. D-aspartic acid, 2α-sulfonic acid Z = OH, R₂= NH₂, R₃= R₄= H, R₁= SO₃H19. D-Aspartic acid, 3α-sulfonic acid Z = OH, R₂= NH₂, R₁= R₄= H, R₃= SO₃H20. D-Aspartic acid, 3α-sulfate Z = OH, R₂= NH₂, R₁= R₄= H, R₃= OSO₃H21. D-Aspartic acid, 3β-sulfonic acid Z = OH, R₂= NH₂, R₁= R₃= H, R₄= SO₃H22. D-aspartic acid, 3β-sulfate Z = OH, R₂= NH₂, R₁= R₃= H, R₄= OSO₃H23. L-asparagine,N-sulfonic acid Z = NH₂, R₁= NHSO₃H, R₂= R₃= R₄= H24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid Z = NH₂, R₁= H,R₂= CH₂SO₃H25. 2α-carboxy, 3-carboxamido, propane-1-sulfate Z = NH₂, R₁= H,R₂= CH₂OSO₃H26. 1α-carboxy, 2-carboxamido, ethane sulfonic acid Z = NH₂, R₁= H, R₂= SO₃H27. 1α-carboxy, 2-carboxamido, ethane sulfateZ = NH₂, R₁= H, R₂= OSO₃H28. L-asparagine, 2β-sulfonic acid Z = R₁= NH₂, R₂= R₄= H, R₂= SO₃H29. L-asparagine, 2β-sulfateZ = R₁= NH₂, R₂= R₄= H, R₃= OSO₃H30. L-asparagine, 3β-sulfonic acid Z = R₁NH₂, R₂= R₄= H, R₃= SO₃H31. L-asparagine, 3α-sulfateZ = R₁= NH₂, R₂= R₄= H, R₃= OSO₃H32. L-asparagine, 3β-sulfonic acid Z = R₁= NH₂, R₂= R₃= H, R₄= SO₃H33. L-asparagine, 3β-sulfateZ = R₁= NH₂, R₂= R₃= H, R₄= OSO₃H34. D-asparagine, N-sulfonic acid Z = NH₂, R₂= NHSO₃H, R₁= R₃= R₄= H35. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acidZ = NH₂, R₂to R₄= H,R₁= CH₂SO₃H36. 2β-carboxy, 3-carboxamido, propane-1-sulfateZ = NH₂, R₂toR₄= H,R₁= CH₂SO₃H37. 1β-carboxy, 2-carboxamido, ethane sulfonic acid]Z = OH, R₂to R₁= H,R₁= SO₃H38. 1β-carboxy, 2-carboxamido, ethane sulfate Z = OH, R₂to R₄= H, R₁= OSO₃H39. D-asparagine, 2α-sulfonic acid Z = R₂= NH₂, R₃= R₄= H, R₁= SO₃H40. D-asparagine, 2α-sulfateZ = R₂= NH₂, R₃= R₄= H, R₁= OSO₃H41. D-asparagine, 3α-sulfonic acid Z = R₂= NH₂, R₁= R₄= H, R₃= SO₃H42. D-asparagine, 3α-sulfateZ = R₂= NH₂, R₁= R₁= H, R₃= OSO₃H43. D-asparagine, 3β-sulfonic acid Z = R₂= NH₂, R₁= R₃= H, R₄= SO₃H44. D-asparagine, 3β-sulfateZ = R₂= NH₂, R₁R₃= H, R₄= OSO₃H

TABLE 2

1. L-glutamic acid, N-sulfonic acid Z = OH, R₁= NHSO₃H,

R₂= R₃= R₄= R₅= R₆= H

2. 2α, 4-dicarboxy, butane-1-sulfonic acid Z = OH, R₁, R₃to R₆= H,

R₂= CH₂SO₃H

3. 2α, 4-dicarboxy, butane-1-sulfate Z = OH, R₁, R₃to R₆= H, R₂= CH₂OSO₃H

4. 1α, 3-dicarboxy, propane sulfonic acid Z = OH, R₁, R₃to R₆= H, R₂= SO₃H

5. 1α, 3-dicarboxy, propane sulfate Z = OH, R₁, R₃to R₆= H, R₂= OSO₃H

6. 1β, 3-dicarboxy, propane sulfate Z = OH, R₂to R₆= H, R₁= OSO₃H

7. 1β, 3-dicarboxy, propane sulfonic acid Z = OH, R₂to R₆= H; R₁= SO₃H

8. L-glutamic acid, 2β-sulfonic acid Z = OH, R₁= NH₂, R₃to R₆= H, R₂= SO₃H

9. L-glutamic acid, 2β-sulfateZ = OH, R₁= NH₂, R₃to R₆= H, R₂= OSO₃H

10. L-glutamic acid, 3α-sulfonic acid Z = OH, R₁= NH₂, R₂= H, R₄to R₆= H,

R₃= SO₃H

11. L-glutamic acid, 3α-sulfate Z = OH, R₁= NH₂, R₂= H, R₄to R₄= H, R₃= OSO₃H

12. L-glutamic acid, 3β-sulfonic acid Z = OH, R₁= NH₂, R₂= R₃= R₅= R₄= H,

R₄= SO₃H

13. L-glutamic acid, 3α-sulfate Z = OH, R₁= NH₂, R₂= R₃= R₅= R₄= H, R₄= OSO₃H

14. L-glutamic acid, 4α-sulfonic acid Z = OH, R₁= NH₂, R₂= R₃= R₄= R₆= H,

R₅= SO₃H

15. L-glutamic acid, 4α-sulfate Z = OH, R₁= NH₂, R₂= R₃= R₃= R₄= H, R₅= OSO₃H

16. L-glutamic acid, 4β-sulfonic acid Z = OH, R₁NH₂, R₂to R₅= H, R₆= SO₃H

17. L-glutamic acid, 4β-sulfate Z = OH, R₁= NH₂, R₂to R₅= H, R₄= OSO₃H

18. D-glutamic acid, N-sulfonic acidZ = OH, R₂= NHSO₃H, R₁, R₃to R₆= H

19. 2β, 4-dicarboxy, butane-1-sulfonic acid Z = OH, R₂to R₆= H, R₁= CH₂SO₃H

20. 2β, 4-dicarboxy, butane-1-sulfate Z = OH, R₂to R₆= H, R₁= CH₂OSO₃H

21. D-glutamic acid, 2α-sulfonic acid Z = OH, R₂= NH₂, R₃to R₆H, R₁= SO₃H

22. D-glutamic acid, 2α-sulfate Z = OH, R₂= NH₂, R₃to R₄= 3 H, R₁= = OSO₃H

23. D-glutamic acid, 3α-sulfonic acid Z = OH, R₂= NH₂, R₁, R₄to R₆= H,

R₃= SO₃H

24. D-glutamic acid, 3α-sulfate Z = OH, R₂= NH₂, R₁, R₄to R₆H, R₃= OSO₃H

25. D-glutamic acid, 3β-sulfonic acid Z = OH, R₂= NH₂, R₁= R₃= R₅= R₆= H,

R₄= SO₃H

26. D-glutamic acid, 3β-sulfate Z = OH, R₂= NH₂, R₁= R₃= R₅= R₄= H, R₄= OSO₃H

27. D-glutamic acid, 4α-sulfonic acid Z = OH, R₂= NH₂, R₁= R₃= R₄= R₄= H,

R₅= SO₃H

28. D-glutamic acid, 4α-sulfate Z = OH, R₂= NH₂, R₁= R₃R₄= R₆= H, R₅= OSO₃H

29. D-glutamic acid, 4β-sulfonic acid Z = OH, R₂= NH₂, R₁= R₃= R₄= R₅= H,

R₆= SO₃H

30. D-glutamic acid, 4β-sulfate Z = OH, R₂= NH₂, R₁= R₃= R₄= R₅= R₅= H,

R₆= OSO₃H

31. L-glutamine, N-sulfonic acid Z = NH₂, R₁NHSO₃H, R₂to R₆= H

32. L-glutamine, 2β-sulfonic acid Z = R₁NH₂, R₃to R₆= H, R₂= SO₃H

33. L-glutamine, 2β-sulfate Z = R₁= NH₂, R₃to R₆= H, R₂= OSO₃H

34. L-glutamine, 3α-sulfonic acid Z = R₁= NH₂, R₂= H, R₃to R₆= H, R₃= SO₃H

35. L-glutamine, 3α-sulfateZ = R₁= NH₂, R₂= H, R₃to R₄= H, R₃= OSO₃H

36. L-glutamine, 3β-sulfonic acid Z = R₁= NH₂, R₂= R₃= R₅= R₆= H, R₄= SO₃H

37. L-glutamine, 3β-sulfate Z = R₁NH₂, R₂= R₃= R₅= R₆= H, R₄= OSO₃H

38. L-glutamine, 4α-sulfonic acid Z = R₁= NH₂, R₂= R₃= R₄= = R₆= H, R₅= SO₃H

39. L-glutamine, 4α-sulfate Z = R₁= NH₂, R₂= R₃= R₄= R₄= H, R₅= OSO₃H

40. L-glutamine, 4β-sulfonic acid Z = R₁= NH₂, R₂to R₅= H, R₆= SO₃H

41. L-glutamine, 4β-sulfate Z = R₁= NH₂, R₂to R₅= H, R₄= OSO₃H

42. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid Z = NH₂, R₁, R₃to

R₆= H, R₂= CH₂SO₃H

43. 2α-carboxy, 4-carboxamido, butane-1-sulfate Z = NH₂, R₁, R₃to R₆= H,

R₂= CH₂OSO₃H

44. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid

Z = NH₂, R₁, R₃to R₆= H, R₂= SO₃H

45. 1α-carboxy, 3-carboxamido, propane-1-sulfateZ = NH₂, R₁, R₃to R₆= H,

R₂= OSO₃H

46. 1β-carboxy, 3-carboxamido, propane-1-sulfateZ = NH₂, R₂to R₆= H,

R₁= OSO₃H

47. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acidZ = NH₂, R₂to R₄= H,

R₁= SO₃H

48. D-glutamine, N-sulfonic acidZ = NH₂, R₂= NHSO₃H; R₁= H, R₃to R₆= H

49. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acidZ NH₂, R₂to R₆= H,

R₁= CH₂SO₃H

50. 2β-carboxy, 4-carboxamido, butane-1-sulfateZ = NH₂, R₂to R₆= H,

R₁= CH₂OSO₃H

51. D-glutamine, 2α-sulfonic acid Z = NH₂, R₂= NH₂, R₃to R₄= H, R₁= SO₃H

52. D-glutamine, 2α-sulfate Z = NH₂, R₂= NH₂, R₃to R₆= H, R₁= OSO₃H

53. D-glutamine, 3α-sulfonic acid Z = NH₂, R₂= NH₂, R₁, R₄to R₆H, R₃= SO₃H

54. D-glutamine, 3α-sulfate Z = R₂= NH₂, R₁, R₄to R₆H, R₃= OSO₃H

55. D-glutamine, 3β-sulfonic acid Z = R₂= NH₂, R₁= R₃= R₅= R₆= H, R₄= SO₃H

56. D-glutamine, 3β-sulfate Z = R₂= NH₂, R₁= R₃= R₅= R₆= H, R₄= OSO₃H

57. D-glutamine, 4α-sulfonic acid Z = R₂= NH₂, R₁= R₃= R₄= R₄= H, R₅= SO₃H

58. D-glutamine, 4α-sulfate Z = R₂= NH₂, R₁= R₃= 1(4 = R₆= H, R₅= OSO₃H

59. D-glutamine, 4β-sulfonic acid Z = R₂= NH₂, R₁= R₃= R₄= R₅= H, R₄= SO₃H

60. D-glutamine, 4β-sulfate Z = R₂= NH₂, R₁= R₃= R₄= R₅= H, R₆= OSO₃H

TABLE 3

1. L-homoglutamic acid, N-sulfonic acid Z = OH, R₁= NHSO₃H, R₂to R₈= H

2. Pentane-2α, 5-dicarboxy-1-sulfonic acid Z = OH, R₁, R₃to R₈= H,

R₂= CH₂SO₃H

3. Pentane-2α, 5-dicarboxy-1-sulfate Z = OH, R₁, R₃to R₈= H, R₂= CH₂OSO₃H

4. Butane-1α, 4-dicarboxy-1-sulfonic acid Z = OH, R₁, R₃to R₈= H, R₂= SO₃H

5. Butane-1α, 4-dicarboxy-l-sulfate Z = OH, R₁, R₃to R₈= H, R₂= OSO₃H

6. L-homoglutamic acid, 2β-sulfonic acid Z = OH, R₁= NH₂, R₃to R₈= H,

R₂= SO₃H

7. L-homoglutamic acid, 2β-sulfate Z = OH, R₁= NH₂, R₃to R₄= H, R₂= OSO₃H

8. L-homoglutamic acid, 3α-sulfonic acid Z = OH, R₁= NH₂, R₂= H, R₄to R₈H,

R₃= SO₃H

9. L-homoglutamic acid, 3α-sulfate Z = OH, R₁= NH₂, R₂= H, R₄to R₈H,

R₃= OSO₃H

10. L-homoglutamic acid, 3β-sulfonic acid Z = OH, R₁= NH₂, R₂= R₃= H, R₅to

R₈= H, R₄= SO₃H

11. L-homoglutamic acid, 3β-sulfate Z = OH, R₁= NH₂, R₂= R₃= H, R₅to R₄= H,

R₄= OSO₃H

12. L-homoglutamic acid, 4α-sulfonic acid Z = OH, R₁= NH₂, R₂= R₃= R₄= H, R₆

to R₈= H, R₅= SO₃H

13. L-homoglutamic acid, 4α-sulfate Z = OH, R₁= NH₂, R₂= R₃= R₄= H, R₆to

R₈= H, R₅= OSO₃H

14. L-homoglutamic acid, 4β-sulfonic acid Z = OH, R₁= NH₂, R₂= R₅= H,

R₇= R₈= H, R₆= SO₃H

15. L-homoglutamic acid, 4β-sulfate Z = OH, R₁= NH₂, R₂= R₅= H, R₇= R₈= H,

R₆= OSO₃H

16. L-homoglutamic acid, 5α-sulfonic acid Z = OH, R₁= NH₂, R₂to R₆= H, R₈

= H, R₇= SO₃H

17. L-homoglutamic acid, 5α-sulfate Z = OH, R₁= NH₂, R₂to R₆= H, R₈= H,

R₇= OSO₃H

18. L-homoglutamic acid, 5β-sulfonic acid Z = OH, R₁= NH₂, R₂to R₇= H,

R₈= SO₃H

19. L-homoglutamic acid, 5β-sulfate Z = OH, R₁= NH₂, R₂to R₇= H, R₈= OSO₃H

20. D-homoglutamic acid, N-sulfonic acid Z = OH, R₂= NHSO₃H, R₁, R₃to

R₈= H

21. Pentane-2β, 5-dicarboxy-1-sulfonic acid Z = OH, R₂to R₈= H,

R₁= CH₂SO₃H

22. Pentane-2β, 5-dicarboxy-1-sulfate Z = OH, R₂to R₈= H, R₁= CH₂OSO₃H

23. Butane-1β, 4-dicarboxy-1-sulfonic acid Z = OH, R₂to R₈= H, R₁= SO₃H

24. Butane-1β, 4-dicarboxy-1-sulfate Z = OH, R₂to R₈= H, R₁= OSO₃H

25. D-homoglutamic acid, 2α-sulfonic acid Z = OH, R₂= NH₂, R₃to R₈= H,

R₁= SO₃H

26. D-homoglutamic acid, 2α-sulfate Z = OH, R₂= NH₂, R₃to R₈= H, R₁= OSO₃H

27. D-homoglutamic acid, 3α-sulfonic acid Z = OH, R₂= NH₂, R₁, R₄to R₈H,

R₃= SO₃H

28. D-homoglutamic acid, 3α-sulfate Z = OH, R₂= NH₂, R₁, R₄to R₈H,

R₃= OSO₃H

29. D-homoglutamic acid, 3β-sulfonic acid Z = OH, R₂= NH₂, R₁= R₃= H, R₅to

R₈= H, R₄= SO₃H

30. D-homoglutamic acid, 3β-sulfate Z = OH, R₂= NH₂, R₁= R₃= H, R₅to R₈= H,

R₄= OSO₃H

31. D-homoglutamic acid, 4α-sulfonic acid Z = OH, R₂= NH₂, R₁= R₃= R₆= H, R₆

to R₈= H, R₅= SO₃H

32. D-homoglutamic acid, 4α-sulfate Z = OH, R₂= NH₂, R₁= R₃= R₄= H, R₆to

R₈= H, R₅= OSO₃H

33. D-homoglutamic acid, 4β-sulfonic acid Z = OH, R₂= NH₂, R₁= H, R₃to R₅= H,

R₇= R₈= H, R₆= SO₃H

34. D-homoglutamic acid, 4β-sulfate Z = OH, R₂= NH₂, R₁= H, R₃to R₅= H,

R₇= R₈= H, R₆= OSO₃H

35. D-homoglutamic acid, 5α-sulfonic acid Z = OH, R₂= NH₂, R₁= R₈= H, R₃to

R₆= H, R₇= SO₃H

36. D-homoglutamic acid, 5α-sulfate Z = OH, R₂= NH₂, R₁= R₈= H, R₃to R₆= H,

R₇= OSO₃H

37. D-homoglutamic acid, 5β-sulfonic acid Z = OH, R₂= NH₂, R₁= H, R₃to R₇= H,

R₈= SO₃H

38. D-homoglutamic acid, 5β-sulfate Z = OH, R₂= NH₂, R₁= H, R₃to R₇= H,

R₈= OSO₃H

39. L-homoglutamine, N-sulfonic acid Z = NH₂, R₁= NHSO₃H, R₂to R₈= H

40. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid Z = NH₂, R₁and R₃to

R₈= H, R₂= CH₂SO₃H

41. Pentane-2α-carboxy, 5-carboxamido-1-sulfate Z = NH₂, R₁and R₃to R₈= H,

R₂= CH₂OSO₃H

42. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid Z = NH₂, R₁and R₃to

R₈= H, R₂= SO₃H

43. Butane-1α-carboxy, 4-carboxamido-1-sulfate Z = NH₂, R₁and R₃to R₈= H,

R₂= OSO₃H

44. L-homoglutamine, 2β-sulfonic acid Z = R₁= NH₂, R₃to R₈= H, R₂= SO₃H

45. L-homoglutamine, 2β-sulfate Z = R₁= NH₂, R₃to R₈= H, R₂= OSO₃H

46. L-homoglutamine, 3α-sulfonic acid Z = R₁= NH₂, R₂= H, R₄to R₈= H,

R₃= SO₃H

47. L-homoglutamine, 3α-sulfateZ = R₁= NH₂, R₂= H, R₄to R₈= H, R₄= OSO₃H

48. L-homoglutamine, 3β-sulfonic acid Z = R₁= NH₂, R₂= R₃= H, R₅to R₈= H,

R₄= SO₃H

49. L-homoglutamine, 3β-sulfate Z = R₁= NH₂, R₂= R₃= H, R₅to R₈= H,

R₄= OSO₃H

50. L-homoglutamine, 4α-sulfonic acid Z = R₁= NH₂, R₂= R₃= R₄= H, R₆to R₈= H,

R₅= SO₃H

51. L-homoglutamine, 4α-sulfate Z = R₁= NH₂, R₂= R₃= R₄= H, R₆to R₈= H,

R₅= OSO₃H

52. L-homoglutamine, 4β-sulfonic acid Z = R₁= NH₂, R₂= R₅= H, R₇= R₈= H,

R₆= SO₃H

53. L-homoglutamine, 4β-sulfate Z = R₁= NH₂, R₂= R₅= H, R₇= R₈= H, R₆= OSO₃H

54. L-homoglutamine, 5α-sulfonic acid Z = R₁= NH₂, R₂to R₆= H, R₈= H,

R₇= SO₃H

55. L-homoglutamine, 5α-sulfate Z = R₁= NH₂, R₂to R₆= H, R₈= H, R₇= OSO₃H

56. L-homoglutamine, 5β-sulfonic acid Z = R₁= NH₂, R₂to R₇= H, R₈= SO₃H

57. L-homoglutamine, 5β-sulfate Z = R₁= NH₂, R₂to R₇= H, R₈= OSO₃H

58. D-homoglutamine, N-sulfonic acid Z = NH₂, R₂= NHSO₃H, R₁and R₃to

R₈= H

59. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid Z = NH₂, R₂to R₈= H,

R₁= CH₂SO₃H

60. Pentane-2β-carboxy, 5-carboxamido-1-sulfate Z = NH₂, R₂to R₈= H,

R₁= CH₂OSO₃H

61. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid Z = NH₂, R₂to R₈= H,

R₁= SO₃H

62. Butane-1β-carboxy, 4-carboxamido-1-sulfate ZNH₂, R₂to R₈= H,

R₁= OSO₃H

63. D-homoglutamine, 2α-sulfonic acid Z = R₂= NH₂, R₃to R₈H, R₁= SO₃H

64. D-homoglutamine, 2α-sulfate ZR₂= NH₂, R₃to R₈H, R₁= OSO₃H

65. D-homoglutamine, 3α-sulfonic acid Z = R₂= NH₂, R₁, R₄to R₈H, R₃= SO₃H

66. D-homoglutamine, 3α-sulfate Z = R₂= NH₂, R₁, R₄to R₈H, R₃= OSO₃H

67. D-homoglutamine, 3β-sulfonic acid Z = R₂= NH₂, R₁= R₃= H, R₅to R₈= H,

R₄= SO₃H

68. D-homoglutamine, 3β-sulfate Z = R₂= NH₂, R₁= R₃= H, R₅to R₈= H,

R₄= OSO₃H

69. D-homoglutamine, 4α-sulfonic acid Z = R₂= NH₂, R₁= R₃= R₄= H, R₆to R₈= H,

R₅= SO₃H

70. D-homoglutamine, 4α-sulfate Z = R₂= NH₂, R₁= R₃= R₄= H, R₆to R₈= H,

R₅= OSO₃H

71. D-homoglutamine, 4β-sulfonic acid Z = R₂= NH₂, R₁= H, R₃to R₅= H,

R₇= R₈= H, R₆= SO₃H

72. D-homoglutamine, 4β-sulfate Z = R₂= NH₂, R₁= H, R₃to R₅= H, R₇= R₈= H,

R₆= OSO₃H

73. D-homoglutamine, 5α-sulfonic acid Z = R₂= NH₂, R₁= R₈= H, R₃to R₆= H,

R₇= SO₃H

74. D-homoglutamine, 5α-sulfate Z = R₂= NH₂, R₁= R₈= H, R₃to R₆= H,

R₇= OSO₃H

75. D-homoglutamine, 5β-sulfonic acid Z = R₂= NH₂, R₁= H, R₃to R₇= H,

R₈= SO₃H

76. D-homoglutamine, 5β-sulfate Z = R₂= NH₂, R₁= H, R₃to R₇= H, R₈= OSO₃H

EXAMPLES

The following reference example and examples illustrate the present invention but do not limit the present invention.

The solvents in the parenthesis show the developing and eluting solvents and the ratios of the solvent used are by volume in the chromatographic separation or TLC.

The solvents in the parenthesis in NMR show the solvents used in measurement.

Reference Example 1

L-glutamyl, N-Sulfonic Acid from Glutamic Acid Mono Tertiary Butyl Ester

Glutamic acid monotertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂CI₂(2 eq.) in dry CH₂Cl₂at 0° C. followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 226.0049 confirmed the structure of the product L-glutamyl, N-sulfonic acid (calculated for C5H8NO7S; 226.0026).

Reference Example 2

L-glutamyl, N-sulfonic Acid from Glutamic Acid Di Tertiary Butyl Ester

Glutamic acid ditertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂Cl₂(2 eq.) in dry CH₂Cl₂at 0° C. followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 226.0049 confirmed the structure of the product L-glutamyl, N-sulfonic acid (calculated for C5H8NO7S; 226.0026).

Reference Example 3

L-Aspartyl, N-sulfonic Acid from L-aspartic Acid Di Tertiary Butyl Ester

L-aspartic acid di tertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂CI₂(2 eq.) in dry CH₂Cl₂at 0° C. followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 211.9885 confirmed the structure of the product L-aspartyl, N-sulfonic acid (calculated for C4H6NO7S; 211.9870).

Reference Example 4

L-Homoglutamyl, N-sulfonic Acid from L-Homoglutamic Acid Di Tertiary Butyl Ester

L-Homoglutamic acid di tertiary butyl ester (1 eq.) was added portion-wise to a solution of SO₂CI₂(2 eq.) in dry CH₂Cl₂at 0° C. followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showed complete consumption of starting material. Solvent was evaporated and the crude was dried in vacuum. 3 ml water was added to it and the slurry was stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂followed by 3 eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24 hrs. The solvent was evaporated and dried in vacuum. The pseudo molecular ion, [M−H]⁻ at 240.0169 confirmed the structure of the product L-Homoglutamyl, N-sulfonic acid (calculated for C₆H₁₀N₀₇S; 240.0182).

Reference Example 5

The calcium salt of L-glutamyl-N-sulphonic acid was prepared by adding 1 M equivalent of CaCl₂solution and incubated at temperature ranging from 30±5° C. The resulting complex was freeze-dried. The freeze-dried compound was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for dendritic celll differentiation (Table A).

TABLE AStimulation of BM precursors with the synthetic compounddifferentiates cells with DC specific markersFold increase in Relative MFI over unstimulated controlSurface markersViabilityGroupCD80CD54H-2D^dCD11c% of Viable cellsGM-CSF3.34.02.05.0180Compound2.54.03.02.0150

Table-A gives the fold increase in the levels of some of the molecules of cells stimulated with either 15 ng/ml of GM-CSF or 50 micro gram per ml of the synthetic compound at 48 h of incubation over unstimulated controls. The viability of the cultures was more then 99% at the end of the incubation period at this concentration of the synthetic compound. The data suggests that ‘the compound’ induces the differentiation of DCs from BM precursors.

Reference Example 6

The L-glutamyl-N-sulphonic acid prepared as described in Examples I & 2 was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for dendritic cell differentiation (Table B).

Reference Example 7

The calcium salt of L-glutamic acid was prepared by adding 1 M equivalent of CaCl2 solution and incubated at temperature ranging from 30±5° C. The resulting complex was freeze-dried. The freeze-dried compound was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for dendritic cell differentiation (Table B).

Reference Example 8

The L-glutamic acid was reconstituted in sterilized distilled water and assessed in a ose-dependent manner for dendritic cell differentiation (Table B).

TABLE BStimulation of BM precursors with the synthetic compounddifferentiates cells with DC specific markersFold increase in Relative MFI over unstimulated controlSurface markersViabilityGroupCD80CD54H-2D^dCD11c% of Viable cellsGM-CSF3.34.02.05.0180Example 61.52.01.21.0115Example 71.01.0N.D.1.090Example 81.00.9N.D.1.195

Reference Example 9

Isolation of Bone Marrow

For each set of experiment a group of 4 BALB/c mice were sacrificed by transferring the animals in a chloroform chamber. The hind limbs of the mouse were removed carefully and placed in a Petri dish with HBSS (Hanks Balanced Saline Solution) wash buffer. The tibias and femurs were cleared of all surrounding and attached tissues. This was followed by chipping the ends of bones. The bone marrow was flushed out by injecting HBSS solution into the bone with the help of a hypodermal syringe (No. 26 gauge). The bone marrow was finally made into a fine suspension by syringing in and out of the fluid several times using an 18 gauge syringe needle.

Reference Example 10

TABLE AEffect of compound 1 (L-glutamyl-N-sulphonic acid, Ca salt)on osteoclast formationNumber of TRAP-positivemultinuclear cells/wellCultureof 96 well plate% in-conditions(Mean ± SEM)hibitionM-CSF0—M-CSF + RANKL138.00 ± 9.37—M-CSF + RANKL + compound 1109.67 ± 9.7921.01(0.5 μg/ml)M-CSF + RANKL + compound 1 52.17 ± 6.4262.19(1.5 μg/ml)M-CSF + RANKL + compound 1 14.67 ± 1.9889.36(3.0 μg/ml)M-CSF + RANKL + compound 1 2.83 ± 1.0597.94(5.0 μg/ml)

Culture of murine bone marrow cells in the presence of M-CSF and RANKL induces the formation of osteoclasts, which were detected as TRAP-positive cells. A dose dependent inhibition in the number of osteoclast cells generated as observed with increasing dose of compound 1. Values given are the mean±SD of five separate experiments.

Reference Example 11

The calcium salt of L-glutamic acid was prepared by adding 1 M equivalent of CaCl₂solution and incubated at temperature ranging from 30±5° C. The resulting complex was freeze-dried. The freeze-dried compound was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table B).

TABLE BEffect of L-glutamic acid, calcium salt on osteoclast formationNumber of TRAP-positivemultinuclear cells/wellCultureof 96 well plate% in-conditions(Mean ± SEM)hibitionM-CSF0—M-CSF + RANKL158.33 ± 12.00—M-CSF + RANKL + compound 2167.17 ± 7.95 0(0.5 μg/ml)M-CSF + RANKL + compound 2152.83 ± 10.473.47(1.5 μg/ml)M-CSF + RANKL + compound 2130.50 ± 13.5717.37(3.0 μg/ml)M-CSF + RANKL + compound 2119.50 ± 10.0024.52(5.0 μg/ml)