A pharmaceutical composition containing the aforementioned inhibitors of osteoclastogenesis may also contain different divalent metal ions such as Mg, Ca or Zn. The composition consists of varying amounts of the above acidic amino acid/dicarboxylic acid derivatives and their pharmaceutically acceptable selected alkali/alkaline earth metal salts. The invention also provides a process for the preparation of the aforesaid compounds, useful for the inhibition of the osteoclast differentiation, maturation and activation. These compounds can also be used for developing effective drugs for the treatment of osteoporosis, osteoarthritis, bone metastasis and bone loss in other metabolic diseases of clinical importance.

1) The inhibitors of osteoclastogenesis also contain different divalent metal ions such as Mg, Ca or Zn, wherein all the symbols are the same meaning as hereinafter defined and non-toxic salts thereof as an active ingredient, 2) The composition consists of varying amounts of the above acidic 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,

3) The process for the preparation of the aforesaid compounds, useful for the inhibition of the osteoclast differentiation, maturation and activation.

4) These compounds can also be used for developing effective drugs for the treatment of osteoporosis, osteoarthritis, bone metastasis and bone loss in other metabolic diseases of clinical importance.

Background of the invention 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 osteoclastogenesis. Amino acid derivatives and calcium ion when used separately did not show any activity on inhibition of the osteoclastogenesis. 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) Alkaline earth metals such as Mg, Zn and Ca as their suitable salts Related arts A lot of information is available on the matrix metalloproteinases (MMP's) commonly used as MMP inhibitors for the treatment of osteoporosis (Nigel, R. A.

Beeley, Phillip, R. J. , Ansell, Andrew, J. P. , Dochert, 1994, Curr. Opin. Ther.

Patents. , 4,7-16). A cylinder shaped solid compound has been prepared from the atelocollagen solution, L-alanine solution and bone morphogenetic protein for treating bone loss and elevating bone deformities (Hiroo, Akhihiko, Rebecca, Wozney, Seeherman, 2003, WO Patent #2003066083). In another study glutamate and glutamate derivatives/analogs or their mixtures have been used for modulating the bone quality (Tadeusz, Jose Luis; Stefan, 2003, WO Patent # 2003043626).

Toshhiro (2003) invented a compound consisting of interacting trans-activators with glutamic acid, aspartic acid and rich carboxyl-terminal domain for estrogen receptor dependent activity (Toshihiro, 2002, WO Patent # 2003000730). Glutamic acid has been defined as an effective neuromediator and one of its derivatives is involved in osteoclast formation and bone resorption : The modification of glutamic acid action in bone could be used for bone remodeling (Hopital E. Herriot, Lyon Fr., 2002, Microscopy Research and technique, 58 (2), 70-76).

However, these inhibitors have various problems and efforts were made for the development of non-peptide inhibitors. For instance in the specification of EP 606046, several aryl-sulfonamide derivatives have been described. In another invention several aryl sulfonyl amino acid derivatives of the following specifications have been described (Sakaki, Kanazawa, Sugiura, Miyazaki, Oleo, 2002, US Patent, 6,403, 644) as MMP inhibitors: 1) N- [ [4- (Benzoylamino) phenyl] sulfonyl] glycine, 2) N- [ [3- (Benzoylamino) phenyl] sulfonyl] glycine, 3) N-[[2-(Benzoylamino) phenyl] sulfonyl] glycine, 4) N- [ [4- (Acetylamino) phenyl] sulfonyl] glycine, 5) N- [ [4- (Phenylacetylamino) phenyl] sulfonyl] glycine, 6) N-[[4-[(Phenylethylcarbonyl) amino] phenyl] sulfonyl] glycine, 7) N- [ [4- (Cinnamoylamino) phenyl] sulfonyl] glycine, 8) N- [ [4- (N-Phenylureido) phenyl] sulfonyl] glycine, 9) N- [ [4- (N-Phenylthioureido) phenyl] sulfonyl] glycine, 10) N-[[4-[(Benzyloxycarbonyl)amino]phenyl]sulfonyl] glycine, 11) N-[[4-[(Phenyloxymethylcarbonyl amino] phenyl] sulfonyl] glycine, 12) N-[[4-[(Benzyloxymethylcarbonyl)amino] phenyl] sulfonyl] glycine, 13) N-[[4-(4-Methoxybenzoylamino) phenyl] sulfonyl] glycine, 14) N- [ [4- (4-Fluorobenzoylamino) phenyl] sulfonyl] glycine,

15) N-[[4-(4-Nitrobenzoylamino) phenyl] sulfonyl] glycine, 16) N- [ [4- (3-Nitrobenzoylamino) phenyl] sulfonyl] glycine, 17) N-[[4-(2-Nitrobenzoylamino) phenyl] sulfonyl] glycine, 18) N-[[4-(4-Formylbenzoylamino)phenyl]sulfonyl] glycine, 19) N-[[4-(Benzoylamino) phenyl] sulfonyl]-D-alpha-phenylglycine, 20) N- [ [4- (Benzoylamino) phenyl] sulfonyl]-L-alpha-phenylglycine, 21) N-[[4-(4-Methylbenzoylamino) phenyl] sulfonyl]-D-alpha-phenylglycine, 22) N- [ [4- (Methylbenzoylamino) phenyl] sulfonyl]-L-alpha-phenylglycine, 23) N-[[4-(4-Methoxybenzoylamino) phenyl] sulfonyl]-D-alpha-phenylglycine, 24) N-[[4-(4-Methoxybenzoylamino) phenyl] sulfonyl]-L-alpha-phenylglycine, 25) N-[[4-(4-Fluorobenzoylamino) phenyl] sulfonyl]-D-alpha-phenylglycine, 26) N- [ [4- (4-Fluorobenzoylamino) phenyl] sulfonyl]-L-alpha-phenylglycine, 27) N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-D-alpha-phenylgl ycine, 28) N- [ [4- (4-Nitrobenzoylamino) phenyl] sulfonyl]-L-alpha-phenylglycine, 29) N- [ (4-Pivaloyloxyphenyl) sulfonyl]-D, L-alpha-phenylglycine, 30) N- [ (4-Pivaloyloxyphenyl) sulfonyl]-D, L-phenylalanine, 31) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl] glycine, 32) N-[[4-(2,4-Dichlorobenzoylamino) phenyl] sulfonyl]-D, L-alanine, 33) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]- beta-alanine, 34) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]-L-valine, 35) N-[[4-(2,4-Dichlorobenzoylamino) phenyl] sulfonyl]-D, L-valine, 36) N-[[4-(2,4-Dichlorobenzoylamino) phenyl] sulfonyl]-L-Ieucine, 37) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D, L-Ieucine, 38) N-[[4-(2,4-Dichlorobenzoylamino) phenyl] sulfonyl]-D, L-serine, 39) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]- L-phenylalanine, 40) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]- L-tyrosine, 41) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]-D, L-alanine methyl ester, 42) N-[[4-(2,4-Dichlorobenzoylamino) phenyl] sulfonyl]-L-valine methyl ester, 43) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]-D, L-valine methyl ester, . 44) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]-L-Ieucine methyl ester, 45) N- [ [4- (2, 4-Dichlorobenzoylamino) phenyl] sulfonyl]-D, L-serine methyl ester, 46) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-tyrosine methyl ester, 47) N- [ [4- (3-Nitrobenzoylamino) phenyl] sulfonyl]-L-aspartic acid,

48) N- [ [3- (3-Nitrobenzoylamino) phenyl] sulfonyl]-L-aspartic acid, 49) N- [ [4- (3-Aminobenzoylamino) phenyl] sulfonyl]-L-aspartic acid, 50) N-[[3-(3-Aminobenzoylamino) phenyl] sulfonyl] -L-aspartic acid, 51) N-[[4-(Benzoylamino)phenyl]sulfonyl]-L-glutamic acid, 52) N-[[4-(4-Chlorobenzoylamino) phenyl] sulfonyl]-L-glutamic acid, 53) N-[[4-(4-Nitrobenzoylamino) phenyl] sulfonyl]-L-glutamic acid, 54) N-[[4-[2-(4-(1-Pyrrolidinyl)phenyl] butyryloxy] phenyl] sulfonyl]-D, L-3- morpholinoalanine ethyl ester, 55) N-[[4-[2-(4-(1-Nitrophenyl) butyryloxy] phenyl] sulfonyl]-D, L-3- morpholinoalanine ethyl ester, 56) N- [ [4- (2-Methoxy-2-phenylacetyloxy) phenyl] sulfonyl]-D, L-3- morpholinoalanine ethyl ester, 57) N-[[4-[[[1-(4-Nitrophenyl)cyclobutyl]carbonyl]oxy]phenyl]sul fonyl]-D, L-3- morpholinoalanine ethyl ester, 58)N-[[3-Methyl-4-[2-[4-(1-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-t- butoxycarbonyl-L-lysine, 59) N-[[4-(2-Phenylbutyryloxy) phenyl] sulfonyl] glycine, 60) N- [ [4- [2- [4- (I-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-D, L- phenylalanine, 61)N-[[4-[2-[4-(I-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-D, L-aspartic acid, 62) N-[[4-[[[1-(4-Nitrophenyl)cyclobutyl]carbonyl]oxy]phenyl]sul fonyl]-D, L- aspartic acid, 63) 1-[[4-[2-[4-(I-Pyrrolidinyl)phenyl] butyryloxy] phenyl] sulfonylamide]-I- cyclopropanecarboxylic acid, 64) N-[[4-[2-[4-(I-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-D, L-2- (2- furanyl) glycine, 65) N- [ [4- [2- [4- (I-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-D, L-2-(2-tri- enyl) glycine, 66) N-[[4-[2-[4-(I-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-L-valine, 67) N-[[4-[2-[4-(I-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-S- carboxymethyl-L-cysteine,

68) N-[[4-[2-Ethyl-2-(4-methoxyphenyl)butyryloxy]phenyl]sulfonyl ]-glycine, 69) N- [ [3-Methyl-4- [2- [4- (1-Pyrrolidinyl) phenyl] butyryloxy] phenyl] sulfonyl]-L- lysine, 70) N- [ [3Methyl-4- [2- [4- (I-pyrrolidinyl) phenyl] butylyloxy] phenyl] sulfonyl] amino] pentanoic acid, 71) N- [ [ (3-Methyl-4-pivaloyloxy) phenyl] sulfonyl]-beta-alanine.

Purpose of the invention Bone is a metabolically active and highly organized connective tissue. The main functions of the bones are provision of mechanical and structural support, maintaining blood calcium levels, supporting haematopoiesis and housing the important vital organs such as brain, spinal cord and heart. To accomplish these functions bone needs continuous remodeling. Bone contains two distinct cell types, the osteoblasts, essential for bone formation (synthesis); and the osteoclasts, essential for bone resorption (break down). Morphogenesis and remodeling of bone involves the synthesis of bone matrix by osteoblasts and coordinated resorption by osteoclasts. The co-ordination between the osteoblasts and osteoclasts is very crucial in maintaining bone horneostasis and structural integrity of the skeleton. Both these processes are influenced by several hormones and local factors generated within bone and bone marrow, resulting in a complex network of control mechanisms. An imbalance of osteoblast and osteoclast functions can result in skeletal abnormalities characterized by increased or decreased bone mass. This may leads to excessive bone loss that reflects the balance of bone formation and bone resorption. Bone destruction or resorption is carried out by haematopoietically derived osteoclasts.

Their number and activity is determined by cell lineage allocation, proliferation and differentiation of osteoclast precursors and the resorptive efficiency of mature osteoclasts. Important bone diseases such as osteoporosis, rheumatoid arthritis, Paget's disease of bone and bone metastasis of breast and prostate cancers are caused by increased osteoclast activity (Teitelbaum, 2000). In these disorders bone resorption exceeds bone formation resulting in decreased skeletal mass. This causes bones to become thin, fragile and susceptible to fracture. The consequences of osteoporotic bone fractures include chronic pain in bone, body deformity including height loss and muscle weakness. Therefore, to understand both pathogenesis and

suuuessiui (. reamiem 01 inese bone diseases mere is a need tor better understanding of biology of osteoclasts.

Osteoporosis is now a serious problem that imposes substantial limitations on the affected individuals. In human, 1 in 3 women and 1 in 12 men over 45 years are at risk of suffering painful and deforming fractures as a result of osteoporosis. More women die after hip fractures than from cancers of ovaries, cervix and uterus.

Osteoporosis occurs at a relatively earlier age in Indian males and females compared to western countries (Gupta, 1996). A variety of disadvantages are associated with current therapeutic agents used in osteoporosis and other metabolic bone disorders.

The side effects of current therapie include increase in the risk of breast and uterine cancers, upper gastrointestinal distress and induction of immune responses. Drugs that inhibit the formation or activity of osteoclasts and with no toxicity and harmful side effects will be valuable for treating osteoporosis and other bone diseases.

Bone resorption and loss of calcium from bone are complications associated with arthritis, many cancers and with bone metastases of breast and prostate tumors.

Because of lack of research into osteoporosis and related diseases, we don't know all the answers to treat these diseases. Progress in better understanding the pathogenesis and successful treatment of these diseases to date has targeted osteoclast.

Osteoclasts, the only cells capable of resorbing bone differentiate from the haemopoietic precursors of monocyte/macrophage lineage that also give rise to macrophages and dendritic cells (Miyamoto et al. 2001). Lineage choice and the differentiation process is guided by lineage restricted key regulatory molecules and transcription factors. Osteoclasts are large multinucleated cells. They are formed by the fusion of mononuclear cells of haemopoietic origin and not by mitosis, since DNA synthesis is not required. Osteoclast formation and bone resorption is regulated by many hormones, growth factors and immune cell-derived cytokines (Udagawa et al. 1995, Wani et al. 1999, Fox et al. 2000, Fuller et al. 2000). These factors act directly or indirectly via other cell types to influence osteoclast differentiation. The most important cell type influencing osteoclast formation is osteoblast, which promote this process by a contact-dependent mechanism. Recent advances revealed that two molecules, macrophage colony stimulating factor (M-CSF) and receptor activator of NF-KB ligand (RANKL) expressed by osteoblasts are essential and sufficient for the differentiation of haemopoietic cells to form osteoclasts (Tanaka et

al. 1993, Anderson et al., 1997, Wong et al. 1997, Lacey et al. 1998, Yasuda et al.

1998). The precise role of other cells, such as T lymphocytes in bone homeostasis is yet to be fully elucidated. It has recently been reported that activated T cells regulates osteoclast formation by some unknown mechanisms. T cells support osteoclast formation by RANKL-dependent and RANKL-independent mechanisms (Weitzmann et al. 2001). Cytokines produced by activated T cells, as well as by other cell types regulates osteoclastogenesis in physiological and pathological conditions. Recent discovery of RANKL has enabled us for the meticulous dissection of mechanisms by which various factors regulate osteoclastogenesis, and better understanding of both pathogenesis and successful treatment bone diseases.

In our preliminary studies, we have investigated the role of novel compounds on osteoclastogenesis induced by RANKL in the presence of M-CSF in stromal cell- free cultures of osteoclast precursors.

Natural products from plants and organisms have frequently been used as a source for development of effective drugs. There is an increased interest in analysis of natural products from marine organisms. Sea animals contain metabolites which can be used for treatment of many diseases.

The inventors have previously shown (US Patent &num 2003066083) that a novel extract (mussel hydrolysate) prepared from the Indian green mussel (Perna viridis) inhibits the osteoclast differentiation in murine haemopoietic precursors of monocyte/macrophage cell lineage. The extract also inhibits the bone resorbing activity of osteoclasts. There was approximately 80-90% inhibition of osteoclast formation and bone resorption in the presence of extract. More importantly, the extract is non-toxic to other cells and is useful to prepare a drug for the treatment of osteoporosis and other bone diseases.

In further investigation, at each stages of purification we found a significant inhibition of osteoclast formation and bone resorption (60-90%). We have purified some active components from extract and these active components significantly inhibit both osteoclast formation and bone resorption. These active compounds can be used in therapeutic settings to protect and cure the individuals against osteoporosis and other metabolic bone diseases.

The current known therapeutic agents have a variety of associated disadvantages.

The side effects of current therapies include an elevated risk of breast and uterine cancers, upper gastrointestinal distress and induction of immune responses (Watts' 1999). Our earlier US Patent (&num 2003066083) describes preparation of mussell hydrolysate from the Indian green mussel (Per na viridis) and its inhibition of the osteoclast differentiation in murine hemopoietic precursors of monocyte/niacrophage cell lineage. The extract also shows inhibition of the bone resorbing activity of osteoclasts.

The present inventors have found that a series of novel sulfonic acid/sulfate derivatives of acidic amino acids, aspartic acids, glutamic acid, homoglutamic acid and their related aliphatic dicarboxylic acids (Succinic acid, glutaric acid and adipic acid) have inhibitory activity against osteoclast formation and bone resorption.

These compounds are novel and non-toxic to other cells. The active compounds may play a vital role in inhibition of differentiation of osteoclast from hemopoietic precursors and can be used in therapeutic settings to protect and cure the individuals against osteoporosis and other metabolic bone diseases.

Summary of the invention This invention relates to a novel class of acidic amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) useful as inhibitors of osteoclastogenesis. The invention also provides methods of using the novel class of acidic amino acid/dicarboxylic acid derivatives of the general formula Z-OC-CRnlRn2-COOZ, wherein nl=n2= 1 to 8 and Z=OH or NH2 and its derivatives for inhibition of osteoclastogenesis. Derivative compounds prepared from this compounds may bear the general formula ZOC-CR7Rs-CRsR6-CR3R4- CRiR2-COOH, ZOC-CRsR6-CR3R4-CRR2-COOH or ZOC-CR3R4-CRlR2-COOH wherein Z=OH or NH2, Ri to R8 denotes H, NH2, SO3H, or OS03H, CH2-SO3H, CH2-OS03H, NHS03H.

Detailed description of the invention: The present invention is related to: A) Osteoclast inhibitors containing novel class of acidic amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) wherein

B) Osteoclast inhibitors containing novel class of acidic amino acid/dicarboxylic acid derivatives of the general formula Z-OC-CRn11An2-COOZ, wherein nl=n2= 1 to 8 and Z=OH or NH2. Derivative compounds prepared from this compounds may bear the general formula 4-CRIR2-COOH (Ia), ZOC-CRsR6-CR3R4-CRR2-COOH (Ib), ZOC-CR7R8-CR5R6-CR3R4-CR1R2-COOH (Ic) wherein Z=OH or NH2; Rl, to R8 denotes H, NH2, S03H, or OS03H, CH2-S03H, CH2-OS03H, NHSO3H consisting of the following class of compounds: 1. A compound in whichZ=OH, RI=NHS03H, R2=R3=R4=H is the same meaning as hereinbefore defined ; 2. A compound in whichZ=OH, Rl=NH2, R3=R4=H, R2=S03H is the same meaning as hereinbefore defined ; 3. A compound in which Z=OH, R1=NH2, R3=R4=H, R2=OSO3H is the same meaning as hereinbefore defined ; 4. A compound in which Z=OH, R1=NH2, R2=R4=H, R3=S03H is the same meaning as hereinbefore defined ; 5. A compound in whichZ=OH, RI=NH2, R2=R4=H, R3=OS03H is the same meaning as hereinbefore defined ; 6. A compound in which Z=OH, R1=NH2, R2=R3=H, R4=SO3H is the same meaning as hereinbefore defined ; 7. A compound in whichZ=OH, R1=NH2, R2=R3=H, R4=OSO3H is the same meaning as hereinbefore defined ; 8. A compound in which Z=OH, RI=R3=R4=H, R2=CH2S03H is the same meaning as hereinbefore defined; 9. A compound in which Z=OH, R1=R3=R4=H, R2=CH2OSO3H is the same meaning as hereinbefore defined ; 10. A compound in which Z=OH, R1=R3=R4=H, R2=SO3H is the same meaning as hereinbefore defined ; 11. A compound in which Z=OH, R1=R3=R4=H, R2=OSO3H is the same meaning as hereinbefore defined ; 12. A compound in which Z=OH, R2=NHS03H, RI=R3=R4=H is the same meaning as hereinbefore defined;.

13. A compound in which Z=OH, R2=H, R1=CH2SO3H is the same meaning as hereinbefore defined ;

14. A compound in whichZ=OH, R2=H, RI=CH2OSO3H is the same meaning as hereinbefore defined; 15. A compound in whichZ=OH, R2=H, R1=SO3H is the same meaning as hereinbefore defined; 16. A compound in whichZ=OH, R2=H, Rl=OS03H is the same meaning as hereinbefore defined; 17. A compound in which Z=OH, R2=NH2, R3=R4=H, R1=SO3H is the same meaning as hereinbefore defined; 18. A compound in which Z=OH, R2=NH2, R3=R4=H, R1=SO3H is the same meaning as hereinbefore defined; 19. A compound in which Z=OH, R2=NH2, R1=R4=H, R3=SO3H is the same meaning as hereinbefore defined; 20. A compound in whichZ=OH, R2=NH2, Rl=R4=H, R3=OS03H is the same meaning as hereinbefore defined; 21. A compound in which Z=OH, R2=NH2, Rl=R3=H, R4=S03H is the same meaning as hereinbefore defined ; 22. A compound in whichZ=OH, R2=NH2, Rl=R3=H, R4=OS03H is the same meaning as hereinbefore defined; 23. A compound in which Rl=NHS03H, R2=R3=R4=H is the same meaning as hereinbefore defined; 24. A compound in which Z=NH2, R1=H, R2=CH2S03H is the same meaning as hereinbefore defined; 25. A compound in which Z=NH2, R1=H, R2=CH2OSO3H is the same meaning as hereinbefore defined; 26. A compound in which Z=NH2, R1=H, R2=SO3H is the same meaning as hereinbefore defined; 27. A compound in whichZ=NH2, Rl=H, R2=OS03H is the same meaning as hereinbefore defined; 28. A compound in which Z=Rl=NH2, R2=R4=H, R2=S03H is the same meaning as hereinbefore defined; 29. A compound in whichZ=Rl=NH2, R2=R4=H, R3=OS03H is the same meaning as hereinbefore defined ;

30. A compound in which Z=Rl=NH2, R2=R4=H, R3=S03H is the same meaning as hereinbefore defined; 31. A compound in whichZ=Rl=NH2, R2=R4=H, R3=OS03H is the same meaning as hereinbefore defined; 32. A compound in whichZ=Rl=NH2, R2=R3=H, R4=S03H is the same meaning as hereinbefore defined; 33. A compound in whichZ=RI=NH2, R2=R3=H, R4=OS03H is the same meaning as hereinbefore defined; 34. A compound in which Z=NH2, R2=NHS03H, RI=R3=R4=H is the same meaning as hereinbefore defined; 35. A compound in which Z=NH2, R2 to R4=H, Rl=CH2S03H is the same meaning as hereinbefore defined; 36. A compound in which Z=NH2, R2 to R4=H, RI=CH2S03H is the same meaning as hereinbefore defined; 37. A compound in which Z=OH, R2 to R4=H, R1=SO3H is the same meaning as hereinbefore defined; 38. A compound in which Z=OH, R2 to R4=H, R1=OSO3H is the same meaning as hereinbefore defined; 39. A compound in whichZ=R2=NH2, R3=R4=H, R1=SO3H is the same meaning as hereinbefore defined; 40. A compound in whichZ=R2=NH2, R3=R4=H, RI=OS03H is the same meaning as hereinbefore defined; 41. A compound in whichZ=R2=NH2, R1=R4=H, R3=SO3H is the same meaning as hereinbefore defined; 42. A compound in whichZ=R2=NH2, R1=R4=H, R3=OS03H is the same meaning as hereinbefore defined; 43. A compound in whichZ=R2=NH2, RI=R3=H, R4=SO3H is the same meaning as hereinbefore defined; 44. A compound in whichZ=R2=NH2, R1=R3=H, R4=OS03H is the same meaning as hereinbefore defined; 45. A compound in which Z=OH, R1=NHSO3H, R2=R3=R4=R5=R6=H is the same meaning as hereinbefore defined ;

46. A compound in which Z=OH, Ri, R3 to R6=H, R2=CH2S03H is the same meaning as hereinbefore defined ; 47. A compound in which Z=OH, Rl, R3 to R6=H, R2=CH2OSO3H is the same meaning as hereinbefore defined ; 48. A compound in which Z=OH, Rl,, R3 to R6=H, R2=S03H is the same meaning as hereinbefore defined ; 49. A compound in which Z=OH, Ri, R3 to R6=H, R2=OS03H is the same meaning as hereinbefore defined; 50. A compound in which Z=OH, R2 to R6=H, R1=OSO3H is the same meaning as hereinbefore defined; 51. A compound in which Z=OH, R2 to R6=H, RI=S03H is the same meaning as hereinbefore defined; 52. A compound in which Z=OH, Rl=NH2, R3 to R6=H, R2=S03H is the same meaning as hereinbefore defined; 53. A compound in which Z=OH, R1=NH2, R3 to R6=H, R2=OS03H is the same meaning as hereinbefore defined; 54. A compound in which Z=OH, RI=NH2, R2=H, R4 to R6=H, R3=S03H is the same meaning as hereinbefore defined; 55. A compound in which Z=OH, Rl=NH2, R2=H, R4 to R6=H, R3=OS03H is the same meaning as hereinbefore defined; 56. A compound in which Z=OH, R1=NH2, R2=R3=R5=R6=H, R4=S03H is the same meaning as hereinbefore defined; 57. A compound in which Z=OH, R1=NH2, R2=R3=R5=R6=H, R4=OSO3H is the same meaning as hereinbefore defined; 58. A compound in which Z=OH, R1=NH2, R2=R3=R4=R6=H, R5=SO3H is the same meaning as hereinbefore defined; 59. A compound in which Z=OH, R1=NH2, R2=R3=R4=R6=H, R5=OSO3H is the same meaning as hereinbefore defined ; 60. A compound in which Z=OH, Rl=NH2, R2 to R5=H, R6=SO3H is the same meaning as hereinbefore defined ; 61. A compound in which Z=OH, RI=NH2, R2 to Rs=H, R6=OSO3H is the same meaning as hereinbefore defined ;

62. A compound in which Z=OH, R2=NHSO3H, R1, R3 to R6=H is the same meaning as hereinbefore defined ; 63. A compound in which Z=OH, R2 to R6=H, R1=CH2SO3H is the same meaning as hereinbefore defined; 64. A compound in which Z=OH, R2 to R6=H, R1=CH2OSO3H is the same meaning as hereinbefore defined; 65. A compound in which Z=OH, R2=NH2, R3 to R6 H, R1=SO3H is the same meaning as hereinbefore defined; 66. A compound in which Z=OH, R2=NH2, R3 to R6 H, Rl=OS03H is the same meaning as hereinbefore. defined ; 67. A compound in which Z=OH, R2=NH2, Rl, R4 to R6 H, R3=S03H is the same meaning as hereinbefore defined ; 68. A compound in which Z=OH, R2=NH2, Rl, R4 to R6 H, R3=OS03H is the same meaning as hereinbefore defined; 69. A compound in which Z=OH, R2=NH2, R1=R3=R5=R6=H, R4=SO3H is the same meaning as hereinbefore defined; 70. A compound in which Z=OH, R2=NH2, Rl=R3=R5=R6=H, R4=OS03H is the same meaning as hereinbefore defined; 71. A compound in which Z=OH, R2=NH2, R1=R3-R4-R6=H, R5=SO3H is the same meaning as hereinbefore defined; 72. A compound in which Z=OH, R2=NH2, R1=R3=R4=R6=H, R5=OSO3H is the same meaning as hereinbefore defined; 73. A compound in which Z=OH, R2=NH2, Rl=R3=R4=Rs=H, R6=S03H is the same meaning as hereinbefore defined; 74. A compound in which Z=OH, R2=NH2, Rl=R3=R4=R5=H, R6=OS03H is the same meaning as hereinbefore defined; 75. A compound in which Z=NH2, RI=NHS03H, R2 to R6=H is the same meaning as hereinbefore defined; 76. A compound in which Z=Rl=NH2, R3 to R6 =H, R2=S03H is the same meaning as hereinbefore defined ; 77. A compound in which Z=R, =NH2, R3 to R6 =H, R2=OS03H is the same meaning as hereinbefore defined;

78. A compound in which Z=Rl=NH2, R2=H, R3 to R6=H, R3=SO3H is the same meaning as hereinbefore defined ; 79. A compound in which Z=Ri=NH2, R2=H, Rs to R6 =H, R3=OS03H is the same meaning as hereinbefore defined ; 80. A compound in which Z=R1=NH2, R2=R3=R5=R6 =H, R4=SO3H is the same meaning as hereinbefore defined; 81. A compound in which Z=Rl=NH2, R2=R3=Rs=R6 =H, R4=OS03H is the same meaning as hereinbefore defined ; 82. A compound in which Z=Rl=NH2, R2=R3=R4=R6=H, R5=S03H is the same meaning as hereinbefore defined ; 83. A compound in which Z=R1=NH2, R2=R3=R4=R6=H, R5=OSO3H is the same meaning as hereinbefore defined ; 84. A compound in which Z=Rl =NH2, R2 to R5=H, R6=SO3H is the same meaning as hereinbefore defined; 85. A compound in which Z=R1=NH2, R2 to R5=H, R6=OS03H is the same meaning as hereinbefore defined; 86. A compound in whichZ=NH2, R1, R3 to R6=H, R2=CH2SO3H is the same meaning as hereinbefore defined; 87. A compound in which Z=NH2, R1, R3 to R6=H, R2=CH2OSO3H is the same meaning as hereinbefore defined; 88. A compound in which Z=NH2, Rl, R3 to R6=H, R2=S03H is the same meaning as hereinbefore defined; 89. A compound in which Z=NH2, Ri, R3 to R6=H, R2=OS03H is the same meaning as hereinbefore defined ; 90. A compound in which Z=NH2, R2 to R6=H, R1=OSO3H is the same meaning as hereinbefore defined; 91. A compound in which Z=NH2, R2 to R6=H, RI=S03H is the same meaning as hereinbefore defined; 92. A compound in whichZ=NH2, R2=NHS03H ; Rl=H, R3 to R6=H is the same meaning as hereinbefore defined; 93. A compound in which Z=NH2, R2 to R6=H, Rl=CH2S03H is the same meaning as hereinbefore defined;

94. A compound in which Z=NH2, R2 to R6=H, R1=CH2OSO3H is the same meaning as hereinbefore defined; 95. A compound in which Z=NH2, R2=NH2, R3 to R6=H, R1=S03H is the same meaning as hereinbefore defined ; 96. A compound in which Z=NH2, R2=NH2, R3 to R6=H, R1=OSO3H is the same meaning as hereinbefore defined; 97. A compound in which Z=NH2, R2=NH2, Ri, R4 to R6 H, R3=S03H is the same meaning as hereinbefore defined; 98. A compound in which Z=R2=NH2, R1, R4 to R6 H, R3=OS03H is the same meaning as hereinbefore defined ; 99. A compound in which Z=R2=NH2, Rl=R3=R5=R6=H, R4=S03H is the same meaning as hereinbefore defined; 100. A compound in which Z=R2=NH2, R1=R3=R5=R6=H, R4=OS03H is the same meaning as hereinbefore defined; 101. A compound in which Z=R2==MH2, Rt=R3=R4=R6=H, Rs=S03H is the same meaning as hereinbefore defined ; 102. A compound in which Z=R2=NH2, Rl=R3=R4=R6=H, Rs=OS03H is the same meaning as hereinbefore defined; 103. A compound in which Z=R2=NH2, Rt=R3=R4=R5=H, R6=S03H is the same meaning as hereinbefore defined; 104. A compound in which Z=R2=NH2, Rl=R3=R4=R5=H, R6=OS03H is the same meaning as hereinbefore defined ; 105 A compound in which Z=OH, R1=NHSO3H, R2 to R8=H is the same meaning as hereinbefore defined ; 106 A compound in which Z=OH, Rl, R3 to R8=H, R2=CH2SO3H is the same meaning as hereinbefore defined; 107. A compound in which Z=OH, Rl, R3 to R8=H, R2=CH2OSO3H is the same meaning as hereinbefore defined ; 108. A compound in which Z=OH, R1, R3 to R8=H, R2=S03H is the same meaning as hereinbefore defined; 109. A compound in which Z=OH, Ri, R3 to Rs=H, R2=OS03H is the same meaning as hereinbefore defined;

110. A compound in which Z=OH, R1=NH2, R3 to Rg=H, R2=S03H is the same meaning as hereinbefore defined ; 111. A compound in which Z=OH, R1=NH2, R3 to R8=H, R2=OS03H is the same meaning as hereinbefore defined ; 112. A compound in which Z=OH, Rl=NH2, R2=H, R4 to Rg=H, R3=S03H is the same meaning as hereinbefore defined ; 113. A compound in which Z=OH, Ri=NH2, R2=H, R4 to R8=H, R3=OS03H is the same meaning as hereinbefore defined ; 114. A compound in which Z=OH, R1=NH2, R2=R3=H, R5 to R8=H, R4=S03H is the same meaning as hereinbefore defined ; 115. A compound in which Z=OH, Rl=NH2, R2=R3=H, Rs to Rg=H, R4=OS03H is the same meaning as hereinbefore defined ; 116. A compound in which Z=OH, R1=NH2, R2=R3=R4=H, R6 to R8=H, Rs=S03H is the same meaning as hereinbefore defined; 117. A compound in which Z=OH, Ri=NH2, R2=R3=R4=H, Re to R8=H, R5=OS03H is the same meaning as hereinbefore defined; 118. A compound in which Z=OH, Rl=NH2, R2=R5=H, R7=R8=H, R6=SO3H is the same meaning as hereinbefore defined; 119. A compound in which Z=OH, RI=NH2, R2=R5=H, R7=RS=H, R6=OS03H is the same meaning as hereinbefore defined ; 120. A compound in which Z=OH, Rl=NH2, R2 to R6=H, R8=H, R7=S03H is the same meaning as is before defined; 121. A compound in which Z=OH, R1=NH2, R2 to R6=H, Rg=H, R7=OS03H is the same meaning as hereinbefore defined; 122. A compound in which Z=OH, R1=NH2, R2 to R7 =H, R8=SO3H is the same meaning as hereinbefore defined; 123. A compound in which Z=OH, R1=NH2, R2 to R7=H, R8=OS03H is the same meaning as hereinbefore defined; 124. A compound in which Z=OH, R2=NHS03H, RI, R3 to R8=H is the same meaning as hereinbefore defined ; 125. A compound in which Z=OH, R2 to Rg=H, Rl=CH2S03H is the same meaning as hereinbefore defined;

126. A compound in which Z=OH, R2 to Rs=H, R1=CH2OSO3H is the same meaning as hereinbefore defined ; 127. A compound in which Z=OH, R2 to Rs=H, R1=SO3H is the same meaning as hereinbefore defined; 128. A compound in which Z=OH, R2 to Rs=H, Rl=OS03H is the same meaning as hereinbefore defined ; 129. A compound in which Z=OH, R2=NH2, R3 to R8=H, R1=SO3H is the same meaning as hereinbefore defined; 130. A compound in which Z=OH, R2=NH2, R3 to Rg=H, R1=OSO3H is the same meaning as hereinbefore defined; 131. A compound in which Z=OH, R2=NH2, R1, R4 to R8=H, R3=S03H is the same meaning as hereinbefore defined ; 132. A compound in which Z=OH, R2=NH2, R1, R4 to Rg=H, R3=OS03H is the same meaning as hereinbefore defined; 133. A compound in which Z=OH, R2=NH2, R1=R3=H, R5 to R8=H, R4=S03H is the same meaning as hereinbefore defined; 134. A compound in which Z=OH, R2=NH2, Rl=R3=H, Rs to R8=H, R4=OS03H is the same meaning as hereinbefore defined; 135. A compound in which Z=OH, R2=NH2 R1=R3=R4=H, R6 to R8=H, R5=SO3H is the same meaning as is before defined ; 136. A compound in which Z=OH, R2=NH2, R1=R3=R4=H, R6 to R8=H, Rs=OSQ3H is the same meaning as hereinbefore defined ; 137. A compound in which Z=OH,. R2=NH2, R1=H, R3 to R5=H, R7=R8=H, R6=SO3H is the same meaning as hereinbefore defined; 138. A compound in which Z=OH, R2=NH2, R1=H, R3 to R5=H, R7=Rg=H, R6=OS03H is the same meaning as hereinbefore defined; 139. A compound in which Z=OH, R2=NH2, R1=R8=H, R3 to R6=H, R7=SO3H is the same meaning as hereinbefore defined ; 140. A compound in which Z=OH, R2=NH2, Rl=Rs=H, R3 to R6=H, R7=OSO3H is the same meaning as hereinbefore defined ; 141. A compound in which Z=OH, R2=NH2, R1=H, R3 to R7=H, R8=SO3H is the same meaning as hereinbefore defined;

142. A compound in which Z=OH, R2=NH2, RI=H, R3. to R7=H, Rs=OS03H is the same meaning as hereinbefore defined; 143. A compound in which Z=NH2, Ri=NHS03H, R2 to R8=H is the same meaning as hereinbefore defined; 144. A compound in which Z=NH2, R1 and R3 to R8=H, R2=CH2SO3H is the same meaning as hereinbefore defined ; 145. A compound in which Z=NH2, R1 and R3 to R8=H, R2=CH2OSO3H is the same meaning as hereinbefore defined; 146. A compound in which Z=NH2, R1 and R3 to R8=H, R2=S03H is the same meaning as hereinbefore defined; 147. A compound in which Z=NH2, Rl and R3 to R8=H, R2=OS03H is the same meaning as hereinbefore defined; 148. A compound in which Z=R1=NH2, R3 to R8=H, R2=S03H is the same meaning as hereinbefore defined; 149. A compound in which Z=R, =NH2, R3 to R8=H, R2=OSO3H is the same meaning as hereinbefore defined; 150. A compound in which Z=R1=NH2, R2=H, R4 to R8=H, R3=S03H is the same meaning as hereinbefore defined ; 151. A compound in which Z =R1=NH2, R2=H, R4 to Rg=H, R3=OS03H is the same meaning as hereinbefore defined ; 152. A compound in which Z=R1=NH2, R2=R3=H, R5 to R8=H, R4=SO3H is the same meaning as hereinbefore defined ; 153. A compound in which Z=RI=NH2, R2=R3=H, Rs to Rg=H, R4=OS03H is the same meaning as hereinbefore defined; 154. A compound in which Z=Rj=NH2, R2=R3=R-4=H, R6 to R8=H, R5=S03H is the same meaning as hereinbefore defined; 155. A compound in which Z=R1=NH2, R2=R3=R4=H, R6 to Rg=H, R5=OS03H is the same meaning as hereinbefore defined; 156. A compound in which Z=R1=NH2, R2=R5=H, R7=R8=H, R6=SO3H is the same meaning as hereinbefore defined; 157. A compound in which Z=R1=NH2, R2=R5=H, R7=R8=H, R6=OSO3H is the same meaning as hereinbefore defined;

158. A compound in which Z=Rt=NH2, R2 to R6=H, R8=H, R7=SO3H is the same meaning as hereinbefore defined ; 159. A compound in which Z=RI=NH2, R2 to R6=H, R8=H, R7=OS03H is the same meaning as hereinbefore defined ; 160. A compound in which Z=R1=NH2, R2 to R7=H, R8=S03H is the same meaning as hereinbefore defined ; 161. A compound in which Z=RI=NH2, R2 to R7=H, R8=OS03H is the same meaning as hereinbefore defined; 162. A compound in which Z=NH2, R2=NHS03H, Rl and R3 to R8=H is the same meaning as hereinbefore defined; 163. A compound in which Z=NH2, R2 to R8=H, Rl=CH2S03H is the same meaning as hereinbefore defined ; 164. A compound in which Z=NH2, R2 to R8=H, Rl=CH2OS03H is the same meaning as hereinbefore defined ; 165. A compound in which Z=NH2, Rz to Rg=H, R1=SO3H is the same meaning as hereinbefore defined ; 166. A compound in which Z=NH2, R2 to Rs=H, R1=OSO3H is the same meaning as hereinbefore defined ; 167. A compound in which Z=R2=NH2, R3 to R8=H, R1=SO3H is the same meaning as hereinbefore defined ; 168. A compound in which Z=R2=NH2, R3 to Rg=H, R1=OSO3H is the same meaning as hereinbefore defined; 169. A compound in which Z=R2=NH2, R1, R4 to R8=H, R3=S03H is the same meaning as hereinbefore defined ; 170. A compound in which Z=R2=NH2, R1, R4 to R8=H, R3=OS03H is the same meaning as hereinbefore defined; 171. A compound in which Z=R2=NH2, R1=R3=H, Rs to R8=H, R4=S03H is the same meaning as hereinbefore defined; 172. A compound in which Z=R2=NH2, Rl=R3=H, R5 to R8=H, R4=OS03H is the same meaning as hereinbefore defined; 173. A compound in which Z=R2=NH2, R1=R3=R4=H, R6 to R8=H, R5=SO3H is the same meaning as hereinbefore defined;

174. A compound in which Z=R2=NH2, Rl=R3=R4=H, R6 is the same meaning as hereinbefore defined ; 175. A compound in which Z=R2=NH2, Rl=H, R3 to R5=H, R7=Rg=H, R6=S03H is the same meaning as hereinbefore defined; 176. A compound in which Z--R2=NH2, Rí=H, R3 to R5=H, R7=R8=H, R6=OS03H is the same meaning as hereinbefore defined; 177. A compound in which Z=R2=NH2, R1=R8=H, R3 to R6=H, R7=S03H is the same meaning as hereinbefore defined ; 178. A compound in which Z=R2=NH2, RI=R8=H, R3 to R6=H, R7=OS03H is the same meaning as hereinbefore defined; 179. A compound in which Z=R2=NH2, Ri=H, R3 to R7=H, R8=S03H is the same meaning as hereinbefore defined; 180. A compound in which Z=R2=NH2, R1=H, R3 to R7=H, R8=OSO3H is the same meaning as hereinbefore defined.

C) The osteoclast inhibitors 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, arginin, N-methyl glucamin, etc. d) In the compound of the present invention of the formulae (Ia), (Ib) and (Ic) the following non toxic derivatives thereof are preferable: 1. L-Aspartic acid, N-Sulfonic acid 2. L-Aspartic acid, 2p-sulfonic acid 3. L-Aspartic acid, 2p-sulfate

4. L-aspartic acid, 3a-sulfonic acid 5. L-aspartic acid, 3a-sulfate 6. L-aspartic acid, 3ß-sulfonic acid 7. L-aspartic acid, 3) 3-sulfate 8.2a, 3-dicarboxy, propane-1-sulfonic acid 9.2a, 3-dicarboxy, propane-1-sulfate 10. la, 2-carboxy ethane sulfonic acid 11. la, 2-carboxy ethane sulfate 12. D-aspartic acid, N-sulfonic acid 13. 2 (3, 3-carboxy, propane-1-sulfonic acid 14. 2ß,3-carboxy,propane-1-sulfate 15. lp, 2-carboxy ethane-1-sulfonic acid 16. lp, 2-carboxy ethane-1-sulfate 17. D-aspartic acid, 2a-sulfonic acid 18. D-aspartic acid, 2a-sulfonic acid 19. D-Aspartic acid, 3a-sulfonic acid 20. D-Aspartic acid, 3a-sulfate 21. D-Aspartic acid, 3ß-sulfonic acid 22. D-aspartic acid, 3ß-sulfate 23. L-asparagine, N-sulfonic acid 24.2a-carboxy, 3-carboxamido, propane-1-sulfonic acid 25. 2a-carboxy, 3-carboxamido, propane-1-sulfate 26. la-carboxy, 2-carboxamido, ethane sulfonic acid 27. la-carboxy, 2-carboxamido, ethane sulfate 28. L-asparagine, 2ß-sulfonic acid 29.-asparagine, 2 (3-sulfate 30. L-asparagine, 3a-sulfonic acid 31. L-asparagine, 3a-sulfate 32. L-asparagine, 3ß-sulfonic acid 33. L-asparagine, 3ß-sulfate 34. D-asparagine, N-sulfonic acid 35. 2p-carboxy, 3-carboxamido, propane-1-sulfonic acid 36. 2 (3-carboxy, 3-carboxamido, propane-1-sulfate

37. lß-carboxy, 2-carboxamido, ethane sulfonic acid] 38. 1ß-carboxy, 2-carboxamido, ethane sulfate 39. D-asparagine, 2a-sulfonic acid 40. D-asparagine, 2a-sulfate 41. D-asparagine, 3a-sulfonic acid 42. D-asparagine, 3a-sulfate 43. D-asparagine, 3p-sulfonic acid 44. D-asparagine, 3 (3-sulfate 45. L-glutamic acid, N-sulfonic acid 46.2a, 4-dicarboxy, butane-1-sulfonic acid 47. 2a, 4-dicarboxy, butane-1-sulfate 48. la, 3-dicarboxy, propane sulfonic acid 49. la, 3-dicarboxy, propane sulfate 50. 1ß, 3-dicarboxy, propane sulfate 51. 1ß, 3-dicarboxy, propane sulfonic acid 52. L-glutamic acid, 2p-sulfonic acid 53. L-glutamic acid, 2 (3-sulfate 54. L-glutamic acid, 3a-sulfonic acid 55. L-glutamic acid, 3a-sulfate 56. L-glutamic acid, 3p-sulfonic acid 57. L-glutamic acid, 3 (3-sulfate 58. L-glutamic acid, 4a-sulfonic acid 59. L-glutamic acid, 4a-sulfate 60. L-glutamic acid, 4ß-sulfonic acid 61. L-glutamic acid, 4 (3-sulfate 62. D-glutamic acid, N-sulfonic acid 63. 2p, 4-dicarboxy, butane-1-sulfonic acid 64. 2p, 4-dicarboxy, butane-1-sulfate 65. D-glutamic acid, 2a-sulfonic acid 66. D-glutamic acid, 2a-sulfate 67. D-glutamic acid, 3a-sulfonic acid 68. D-glutamic acid, 3a-sulfate 69. D-glutamic acid, 3ß-sulfonic acid

70. D-glutamic acid, 3p-sulfate 71. D-glutamic acid, 4a-sulfonic acid 72. D-glutamic acid, 4a-sulfate 73. D-glutamic acid, 4ß-sulfonic acid 74. D-glutamic acid, 4p-sulfate 75. L-glutamine, N-sulfonic acid 76. L-glutamine, 2p-sulfonic acid 77. L-glutamine, 2ß-sulfate 78. L-glutamine, 3a-sulfonic acid 79. L-glutamine, 3a-sulfate 80. L-glutamine, 3p-sulfonic acid 81. L-glutamine, 3p-sulfate 82. L-glutamine, 4a-sulfonic acid 83. L-glutamine, 4a-sulfate 84. L-glutamine, 4ß-sulfonic acid 85. L-glutamine, 43-sulfate 86.2a-carboxy, 4-carboxamido, butane-1-sulfonic acid 87.2a-carboxy, 4-carboxamido, butane-l-sulfate 88. la-carboxy, 3-carboxamido, propane-1-sulfonic acid 89. la-carboxy, 3-carboxamido, propane-1-sulfate 90. 1ß-carboxy, 3-carboxamido, propane-1-sulfate 91. 1ß-carboxy, 3-carboxamido, propane-1-sulfonic acid 92. D-glutamine, N-sulfonic acid 93. 2ß-carboxy, 4-carboxamido, butane-1-sulfinc acid 94. 2ß-carboxy, 4-carboxamido, butane-1-sulfate 95. D-glutamine, 2a-sulfonic acid 96. D-glutamine, 2a-sulfate 97. D-glutamine, 3α-sulfonic acid 98. D-glutamine, 3a-sulfate 99. D-glutamine, 3p-sulfonic acid 100. D-glutamine, 3ß-sulfate 101. D-glutamine, 4a-sulfonic acid 102. D-glutamine, 4a-sulfate

103. D-glutamine, 4ß-sulfonic acid 104. D-glutamine, 4ß-sulfate 105. L-homoglutamic acid, N-sulfonic acid 106. Pentane-2a, 5-dicarboxy-1-sulfonic acid 107. Pentane-2a, 5-dicarboxy-1-sulfate 108. Butane-la, 4-dicarboxy-1-sulfonic acid 109. Butane-la, 4-dicarboxy-1-sulfate 110. L-homoglutamic acid, 2 (3-sulfonic acid 111. L-homoglutamic acid, 2ß-sulfate 112. L-homoglutamic acid, 3a-sulfonic acid 113. L-homoglutamic acid, 3a-sulfate 114. L-homoglutamic acid, 3p-sulfonic acid 115. L-homoglutamic acid, 3ß-sulfate 116. L-homoglutamic acid, 4a-sulfonic acid 117. L-homoglutamic acid, 4a-sulfate 118. L-homoglutamic acid, 4p-sulfonic acid 119. L-homoglutamic acid, 4 (3-sulfate 120. L-homoglutamic acid, 5a-sulfonic acid 121. L-homoglutamic acid, 5a-sulfate 122. L-homoglutamic acid, 5ß-sulfonic acid 123. L-homoglutamic acid, 5p-sulfate 124. D-homoglutamic acid, N-sulfonic acid 125. Pentane-2 (3, 5-dicarboxy-1-sulfonic acid 126. Pentane-2p, 5-dicarboxy-1-sulfate 127. Butane-1ß, 4-dicarboxy-1-sulfonic acid 128. Butane-1ß, 4-dicarboxy-1-sulfate 129. D-homoglutamic acid, 2a-sulfonic acid 130. D-homoglutamic acid, 2a-sulfate 131. D-homoglutamic acid, 3a-sulfonic acid 132. D-homoglutamic acid, 3a-sulfate 133. D-homoglutamic acid, 3ß-sulfonic acid 134. D-homoglutamic acid, 3 (3-sulfate 135. D-homoglutamic acid, 4a-sulfonic acid

136. D-homoglutamic acid, 4a-sulfate 137. D-homoglutamic acid, 4ß-sulfonic acid 138. D-homoglutamic acid, 4 (3-sulfate 139. D-homoglutamic acid, 5a-sulfonic acid 140. D-homoglutamic acid, 5a-sulfate 141. D-homoglutamic acid, 5p-sulfonic acid 142. D-homoglutamic acid, 5 (3-sulfate 143. L-homoglutamine, N-sulfonic acid 144. Pentane-2a-carboxy, 5-carboxamido-1-sulfonic acid 145. Pentane-2a-carboxy, 5-carboxamido-1-sulfate 146. Butane-1 a-carboxy, 4-carboxamido-1-sulfonic acid 147. Butane-1 a-carboxy, 4-carboxamido-1-sulfate 148. L-homoglutamine, 2p-sulfonic acid 149. L-homoglutamine, 2ß-sulfate 150. L-homoglutamine, 3a-sulfonic acid 151. L-homoglutamine, 3a-sulfate 152. L-homoglutamine, 3ß-sulfonic acid 153. L-homoglutamine, 3p-sulfate 154. L-homoglutamine, 4a-sulfonic acid 155. L-homoglutamine, 4a-sulfate 156. L-homoglutamine, 4ß-sulfonic acid 157. L-homoglutamine, 4 (3-sulfate 158. L-homoglutamine, 5a-sulfonic acid 159. L-homoglutamine, 5a-sulfate 160. L-homoglutamine, 5ß-sulfonic acid 161. L-homoglutamine, 5i-sulfate 162. D-homoglutamine, N-sulfonic acid 163. Pentane-2ß-carboxy, 5-carboxamido-1-sulfonic acid 164. Pentane-2ß-carboxy, 5-carboxamido-1-sulfate 165. Butane-l ß-carboxy, 4-carboxamido-1-sulfonic acid 166. Butane-1 ß-carboxy, 4-carboxamido-1-sulfate 167. D-homoglutamine, 2a-sulfonic acid 168. D-homoglutamine, 2a-sulfate

169. D-homoglutamine, 3a-sulfonic acid 170. D-homoglutamine, 3a-sulfate 171. D-homoglutamine, 3ß-sulfonic acid 172. D-homoglutamine, 3p-sulfate 173. D-homoglutamine, 4a-sulfonic acid 174. D-homoglutamine, 4a-sulfate 175. D-homoglutamine, 4p-sulfonic acid 176. D-homoglutamine, 4p-sulfate 177. D-homoglutamine, 5a-sulfonic acid 178. D-homoglutamine, 5a-sulfate 179. D-homoglutamine, 5ß-sulfonic acid 180. D-homoglutamine, 5ß-sulfate e) a process for the preparation of sulfonic acid/sulfate derivatives of the formula (Ia) and non-toxic salts thereof : 1. A compound wherein Z=OH, Rl=NHS03H, R2=R3=R4=H ; 2. A compound wherein Z=OH, R1=NH2, R3=R4=H, R2=SO3H ; 3. A compound in which Z=OH, R1=NH2, R3=R4=H, R2=OSO3H ; 4. A compound in which Z=OH, R1=NH2, R2=R4=H, R3=S03H; 5. A compound in whichZ=OH, RI=NH2, R2=R4=H, R3=OS03H ; 6. A compound in which Z=OH, R1=NH2, R2=R3=H, R4=SO3H ; 7. A compound in whichZ=OH, Rl=NH2, R2=R3=H, R4=OS03H ; 8. A compound in which Z=OH, RI=R3=R4=H, R2=CH2SO3H ; 9. A compound in which Z=OH, R1=R3=R4=H, R2=CH2OSO3H ; 10. A compound in which Z=OH, R1=R3=R4=H, R2=S03H ; 11. A compound in which Z=OH, R1=R3=R4=H, R2=OS03H ; 12. A compound in which Z=OH, R2=NHS03H, R1=R3=R4=H ; 13. A compound in which Z=OH, R2=H, R1=CH2SO3H ; 14. A compound in whichZ=OH, R2=H, R1=CH2OSO3H ; 15. A compound in whichZ=OH, R2=H, R1=SO3H ; 16. A compound in whichZ=OH, R2=H, R1=OSO3H ; 17. A compound in which Z=OH, R2=NH2, R3=R4=H, Rl=S03H ; 18. A compound in which Z=OH, R2=NH2, R3=R4=H, R1=SO3H ;

19. A compound in which Z=OH, R2=NH2, R1=R4=H, R3=SO3H ; 20. A compound wherein Z=OH, R2=NH2, R1=R4=H, R3=OS03H ; 21. A compound wherein Z=OH, R2=NH2, R1=R3=H, R4=SO3H ; 22. A compound wherein Z=OH, R2=NH2, RI=R3=H, R4=OS03H ; 23. A compound wherein R1=NHSO3H, R2=R3=R4=H; 24. A compound wherein Z=NH2, R1=H, R2=CH2SO3H ; 25. A compound wherein Z=NH2, R1=H, R2=CH2OSO3H ; 26. A compound wherein Z=NH2, R1=H, R2=SO3H ; 27. A compound wherein Z=NH2, R1=H, R2=OS03H ; 28. A compound wherein Z=R1=NH2, R2=R4=H, R2=SO3H ; 29. A compound wherein Z=Rl=NH2, R2=R4=H, R3=OS03H ; 30. A compound wherein Z=R1=NH2, R2=R4=H, R3=S03H ; 31. A compound wherein Z=Rl=NH2, R2=R4=H, R3=OS03H ; 32. A compound wherein Z=Rl=NHa, R2=R3=H, R4=S03H ; 33. A compound wherein Z=R1=NH2, R2=R3=H, R4=OS03H ; 34. A compound wherein Z=NH2, R2=NHS03H, R1=R3=R4=H ; 35. A compound wherein Z=NH2, R2 to R4=H, R1=CH2SO3H ; 36. A compound wherein Z=NH2, R2 to R4=H, RI=CH2S03H ; 37. A compound wherein Z=OH, R2 to R4=H, R1=SO3H; 38. A compound wherein Z=OH, R2 to R4=H,. R1=OSO3H; 39. A compound wherein Z=R2=NH2, R3=R4=H, R1=SO3H ; 40. A compound wherein Z=R2=NH2, R3=R4=H, Rl=OS03H ; 41. A compound wherein Z=R2=NH2, R1=R4=H, R3=SO3H ; 42. A compound wherein Z=R2=NH2, Rl=R4=H, R3=OS03H ; 43. A compound wherein Z=R2=NH2, Rl=R3=H, R4=S03H ; 44. A compound wherein Z=R2=NH2, R1=R3=H, R4=OSO3H ; f) a process for the preparation of sulfonic acid/sulfate derivatives of the formula (Ib) and non-toxic salts thereof : 1. A compound wherein Z=OH, Ri=NHS03H, R2=R3=R4=R5=R6=H ; 2. A compound wherein Z=OH, Rl, R3 to R6=H, R2=CH2SO3H ; 3. A compound wherein Z=OH, Ri, R3 to R6=H, R2=CH2OSO3H; 4. A compound wherein Z=OH, Ri, R3 to R6=H, R2=S03H ; 5. A compound wherein Z=OH, Ri, R3 to R6=H, R2=OS03H ;

6. A compound wherein Z=OH, R2 to R6=H, R1=OSO3H ; 7. A compound wherein Z=OH, R2 to R6=H, RI=S03H ; 8. A compound wherein Z=OH, R1=NH2, R3 to R6=H, R2=S03H ; 9. A compound wherein Z=OH, R1=NH2, R3 to R6=H, R2=OS03H ; 10.-A compound wherein Z=OH, R1=NH2, R2=H, R4 to R6=H, R3=S03H ; 11. A compound wherein Z=OH, R1=NH2, R2=H, R4 to R6=H, R3=OS03H; 12. A compound wherein Z=OH, RI=NH2, R2=R3=R5=R6=H, R4=S03H ; 13. A compound wherein Z=OH, R1=NH2, R2=R3=R5=R6=H, R4=OS03H ; 14. A compound wherein Z=OH, R1=NH2, R2=R3=R4=R6=H, R5=SO3H ; 15. A compound wherein Z=OH, R1=NH2, R2=R3=R4=R6=H, R5=OS03H ; 16. A compound wherein Z=OH, R1=NH2, R2 to R5=H, R6=SO3H ; 17. A compound wherein Z=OH, R1=NH2, R2 to R5=H, R6=OS03H ; 18. A compound wherein Z=OH, R2=NHSO3H, Rl, R3 to R6=H ; 19. A compound wherein Z=OH, R2 to R6=H, Ri=CH2S03H ; 20. A compound wherein Z=OH, Ra to R6=H, R1=CH2OS03H ; 21. A compound wherein Z=OH, R2=NH2, R3 to R6 H, RI=SO3H ; 22. A compound wherein Z=OH, R2=NH2, R3 to R6 H, R1=OSO3H ; 23. A compound wherein Z=OH, R2=NH2, Rl, R4 to R6 H, R3=S03H ; 24. A compound wherein Z=OH, R2=NH2, Ri, R4 to R6 H, R3=OS03H ; 25. A compound wherein Z=OH, R2=NH2, Ri=R3=R5=R6=H, R4=S03H ; 26. A compound wherein Z=OH, R2=NH2, Rt=R3=P5=P6=H, R4=OSO3H ; 27. A compound wherein Z=OH, R2=NH2, R1=R3=R4=R6=H, R5=SO3H ; 28. A compound wherein Z=OH, R2=NH2, R1=R3=R4=R6=H, R5=OSO3H ; 29. A compound wherein Z=OH, R2=NH2, R1=R3=R4=R5=H, R6=SO3H ; 30. A compound wherein Z=OH, R2=NH2, R1=R3=R4=R5=H, R6=OSO3H ; 31. A compound wherein Z=NH2, R1=NHSO3H, R2 to R6=H ; 32. A compound wherein Z=R1=NH2, R3 to R6=H, R2=SO3H ; 33. A compound wherein Z=Rl=NH2, R3 to R6=H, R2=OS03H ; 34. A compound wherein Z=R1=NH2, R2=H, R3 to R6=H, R3=S03H ; 35. A compound wherein Z=R1=NH2, R2=H, R3 to R6=H, R3=OSO3H ; 36. A compound wherein Z=R1=NH2, R2=R3=R5=R6=H, R4=SO3H ; 37. A compound wherein Z=Rl=NH2, R2=R3=Rs=R6=H, R4=OS03H ; 38. A compound wherein Z=Ri=NH2, R2=R3=R4=R6=H, Rs=S03H ;

39. A compound wherein Z=Ri=NH2, R2=R3=R4=R6=H, Rs=OS03H ; 40. A compound wherein Z=R1 ? 2 to R5=H, R6=SO3H ; 41. A compound wherein Z=Rl=NH2, R2 to R5=H, R6=OSO3H ; 42. A compound wherein Z=NH2, R1, R3 to R6=H, R2=CH2SO3H ; 43. A compound wherein Z=NH2, Rl, R3 to R6=H, R2=CH2OSO3H ; 44. A compound wherein Z=NH2, Ri, R3 to R6=H, R2=S03H ; 45. A compound wherein Z=NH2, Rl, R3 to R6=H, R2=OS03H ; 46. A compound wherein Z=NH2, R2 to R6=H, R1=OSO3H ; 47. A compound wherein Z=NH2, R2 to R6=H, R1=SO3H ; 48. A compound wherein Z=NH2, R2=NHS03H ; R1=H, R3 to R6=H ; 49. A compound wherein Z=NH2, R2 to R6=H, R1=CH2SO3H ; 50. A compound wherein Z=NH2, R2 to R6=H, R1=CH2OSO3H ; 51. A compound wherein Z=NH2, R2=NH2, R3 to R6=H, RI=S03H ; 52. A compound wherein Z=NH2, R=NH2, R3 to R6=H, R1=OSO3H ; 53. A compound wherein Z=NH2, R2=NH2, Ri, R4 to R6 H, R3=S03H ; 54. A compound wherein Z=R2=NH2, Rl, R4 to R6 H, R3=OS03H ; 55. A compound wherein Z=R2=NH2, R1=R3=R5=R6=H, R4=SO3H ; 56. A compound wherein Z=R2=NH2, R1=R3=R5=R6=H, R4=OSO3H ; 57. A compound wherein Z=R2=NH2, R1=R3=R4=R6=H, R5=SO3H ; 58. A compound wherein Z=R2=NH2, R1=R3=R4=R6=H, R5=OSO3H ; 59. A compound wherein Z=R2=NH2, R1=R3=R4=R5=H, R6=SO3H ; 60. A compound wherein Z=R2=NH2, R1=R3=R4=R5=H, R6=OSO3H ; g) a process for the preparation of sulfonic acid/sulfate derivatives of the formula (Ic) and non-toxic salts thereof : 1. A compound wherein Z=OH, R1=NHSO3H, R2 to R8=H ; 2. A compound wherein Z=OH, RI, R3 to R8=H, R2=CH2SO3H ; 3. A compound wherein Z=OH, Ri, R3 to R8=H, R2=CH2OSO3H ; 4. A compound wherein Z=OH, Rl, R3 to Rs=H, R2=S03H ; 5. A compound wherein Z=OH, Rl, R3 to R8=H, R2=OSO3H ; 6. A compound wherein Z=OH, R1=NH2, R3 to R8=H, R2=S03H ; 7. A compound wherein Z=OH, R1=NH2, R3 to Rs=H, R2=OS03H ; 8. A compound wherein Z=OH, R1=NH2, R2=H, R4 to R8=H, R3=SO3H ; 9. A compound wherein Z=OH, R1=NH2, R2=H, R4 to Rg=H, R3=OS03H ;

10. A compound wherein Z=OH, R1=NH2, R2=R3=H, Rs to Rs=H, R4=S03H; 11. A compound wherein Z=OH, R1=NH2, R2=R3=H, R5 to R8=H, R4=OS03H ; 12. A compound wherein Z=OH, R1=NH2, R2=R3=R4=H, R6 to R8=H, R5=S03H ; 13. A compound wherein Z=OH, R1=NH2, R2=R3=R4=H, R6 to R8=H, R5=OS03H ; 14. A compound wherein Z=OH, RI=NH2, R2=R5=H, R7=R8=H, R6=SO3H ; 15. A compound wherein Z=OH, R1=NH2, R2=R5=H, R7=R8=H, R6=OSO3H ; 16. A compound wherein Z=OH, R1=NH2, R2 to R6=H, R8=H, R7=S03H 17. A compound wherein Z=OH, R1=NH2, R2 to R6=H, R8=H, R7=OS03H ; 18. A compound wherein Z=OH, R1=NH2, R2 to R7 =H, R8=S03H ; 19. A compound wherein Z=OH, R1=NH2, R2 to R7=H, R8=OSO3H ; 20. A compound wherein Z=OH, R2=NHSO3H, R1, R3 to Rg=H ; 21. A compound wherein Z=OH, R2 to R8=H, Rl=CH2S03H ; 22. A compound wherein Z=OH, R2 to R8=H, Rl=CH2OS03H ; 23. A compound wherein Z=OH, R2 to R8=H, R1=SO3H ; 24. A compound wherein Z=OH, R2 to R8=H, R1=OSO3H ; 25. A compound wherein Z=OH, R2=NH2, R3 to R8=H, R1=SO3H ; 26. A compound wherein Z=OH, R2=NH2, R3 to Rg=H, Rt=OS03H ; 27. A compound wherein Z=OH, R2=NH2, R4 to R8=H, R3=S03H ; 28. A compound wherein Z=OH, R2=NH2, Rl, R4 to R8=H, R3=OS03H ; 29. A compound wherein Z=OH, R2=NH2, Rl=R3=H, RS to R8=H, R4=S03H; 30. A compound wherein Z=OH, R2=NH2, R1=R3=H, R5 to Rg=H, R4=OS03H ; 31. A compound wherein Z=OH, R2=NH2, R1=R3=R4=H, R6 to Rg=H, R5=S03H ; 32. A compound wherein Z=OH, R2=NH2, R1=R3=R4=H, R6 to R8=H, R5=OS03H ; 33. A compound wherein Z=OH, R2=NH2, R1=H, R3 to R5=H, R7=R8=H, R6=SO3H ; 34. A compound wherein Z=OH, R2=NH2, R1=H, R3 to R5=H, R7=R8=H, R6=OS03H ; 35. A compound wherein Z=OH, R2=NH2, R1=R8=H, R3 to R6=H, R7=S03H ; 36. A compound wherein Z=OH, R2=NH2, Ri=Rs=H, R3 to R6=H, R7=OS03H ; 37. A compound wherein Z=OH, R2=NH2, R1=H, R3 to R7=H, Rg=S03H ; 38. A compound wherein Z=OH, R2=NH2, R1=H, R3 to R7=H, R8=OSO3H ;

39. A compound wherein Z=NH2, R1=NHSO3H, R2 to Rg=H ; 40. A compound wherein Z=NH2, Rl and R3 to R8=H, R2=CH2SO3H ; 41. A compound wherein Z=NH2, Rl and R3 to R8=H, R2=CH2OSO3H ; 42. A compound wherein Z=NH2, Ri and R3 to R8=H, R2=S03H ; 43. A compound wherein Z=NH2, R1 and R3 to RS=H, R2=OS03H ; 44. A compound wherein Z=R1=NH2, R3 to R8=H, R2=SO3H ; 45. A compound wherein Z=Ri=NH2, Rs to Rs=H, R2=OS03H ; 46. A compound wherein Z=R1=NH2, R2=H, R4 to R8=H, R3=S03H ; 47. A compound wherein Z=R1=NH2, R2=H, R4 to R8=H, R3=OS03H ; 48. A compound wherein Z=Rl=NH2, R2=R3=H, Rs to Rs=H, R4=SO3H ; 49. A compound wherein Z=R1=NH2, R2=R3=H, Rs to R8=H, R4=OSO3H ; 50. A compound wherein Z=R1=NH2, R2=R3=F4=H, R6 to R8=H, R5=S03H ; 51. A compound wherein Z=Rl=NH2, R2=R3=R4=H, R6 to R8=H, R5=OS03H ; 52. A compound wherein Z=R1=NH2, R2=R5=H, R7=R8=H, R6=SO3H ; 53. A compound wherein Z=R) =NH2, R2=R5=H, R7=Rs=H, R6=OS03H ; 54. A compound wherein Z=R1 =NH2, R2 to R6=H, R8=H, R7=SO3H ; 55. A compound wherein Z=R, =NH2, R2. to R6=H, Rg=H, R7=OS03H ; 56. A compound wherein Z=Rl=NH2, R2 to R7=H, R8=SO3H ; 57. A compound wherein Z=R1=NH2, R2 to R7=H, R8=OSO3H ; 58. A compound wherein Z=NH2, R2=NHSO3H, R1 and R3 to R8=H ; 59. A compound wherein Z=NH2, R2 to Rg=H, Rl=CH2S03H ; 60. A compound wherein Z=NH2, R2 to R8=H, R1=CH2OSO3H ; 61. A compound wherein Z=NH2, R2 to R8=H, R1=SO3H ; 62. A compound wherein Z=NH2, R2 to R8=H, R1=OSO3H ; 63. A compound wherein Z=R2=NH2, R3 to R8=H, R1=SO3H ; 64. A compound wherein Z=R2=NH2, R3 to R8=H, R1=OSO3H ; 65. A compound wherein Z=R2=NH2, Rt, R4 to R8=H, R3=SO3H ; 66. A compound wherein Z=R2=NH2, Rl, R4 to R8=H, R3=OS03H ; 67. A compound wherein Z=R2=NH2, R1=R3=H, R5 to R8=H, R4=SO3H ; 68. A compound wherein Z=R2=NH2, R1=R3=H, R5 to Rg=H, R4=OSO3H ; 69. A compound wherein Z=R2=NH2, R1=R3=R4=H, R6 to R8=H, R5=S03H ; 70. A compound wherein Z=R2=NH2, R1=R3=R4=H, R6 ; 71. A compound wherein Z=R2=NH2, Rl=H, R3 to R5=H, R7=R8=H, R6=SO3H ;

72. A compound wherein Z=R2=NH2, R1=H, R3 to R5=H, R7=R8=H, R6=OS03H ; 73. A compound wherein Z=R2=NH2, R1=R8=H, R3 to R6=H, R7=SO3H ; 74. A compound wherein Z=R2=NH2, RI=Rs=H, R3 to R6=H, R7=OS03H ; 75. A compound wherein Z=R2=NH2, R1=H, R3 to R7=H, R8=S03H ; 76. A compound wherein Z=R2=NH2, Rl=H, R3 to R7=H, R8=OS03H. h) 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: 1. L-Aspartic acid, N-Sulfonic acid 2. L-Aspartic acid, 2 (3-sulfonic acid 3. L-Aspartic acid, 2 (3-sulfate 4. L-aspartic acid, 3a-sulfonic acid 5. L-aspartic acid, 3a-sulfate 6. L-aspartic acid, 3ß-sulfonic acid 7. L-aspartic acid, 3 (3-sulfate 8.2a, 3-dicarboxy, propane-1-sulfonic acid 9.2a, 3-dicarboxy, propane-1-sulfate 10. 1α, 2-carboxy ethane sulfonic acid 11. 1α, 2-carboxy ethane sulfate 12. D-aspartic acid, N-sulfonic acid 13. 2ß, 3-carboxy, propane-1-sulfonic acid 14. 2ß, 3-carboxy, propane-1-sulfate 15. 1ß,2-carboxy ethane-1-sulfonic acid 16. 1 (3, 2-carboxy ethane-1-sulfate 17. D-aspartic acid, 2a-sulfonic acid 18. D-aspartic acid, 2a-sulfonic acid 19. D-Aspartic acid, 3a-sulfonic acid 20. D-Aspartic acid, 3a-sulfate 21. D-Aspartic acid, 3ß-sulfonic acid 22. D-aspartic acid, 3ß-sulfate 23. L-asparagine, N-sulfonic acid 24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid 25. 2a-carboxy, 3-carboxamido, propane-1-sulfate

26. la-carboxy, 2-carboxamido, ethane sulfonic acid 27. la-carboxy, 2-carboxamido, ethane sulfate 28. L-asparagine, 2 (3-sulfonic acid 29. -asparagine, 2p-sulfate 30. L-asparagine, 3a-sulfonic acid 31. L-asparagine, 3a-sulfate 32. L-asparagine, 3p-sulfonic acid 33. L-asparagine, 3p-sulfate 34. D-asparagine, N-sulfonic acid 35. 2ß-carboxy, 3-carboxamido, propane-1-sulfonic acid 36.2ß-carboxy, 3-carboxamido, propane-1-sulfate 37. lß-carboxy, 2-carboxamido, ethane sulfonic acid] 38.. lß-carboxy, 2-carboxamido, ethane sulfate 39. D-asparagine, 2a-sulfonic acid 40. D-asparagine, 2a-sulfate 41. D-asparagine, 3a-sulfonic acid 42. D-asparagine, 3a-sulfate 43. D-asparagine, 3p-sulfonic acid 44. D-asparagine, 3ß-sulfate i) In the compound of the present invention of the formula (Ib) wherein the compound is selected from the group consisting of glutamic acid, glutamin and corresponding de-amino analogs: 1. 1 L-glutamic acid, N-sulfonic acid 2.2a, 4-dicarboxy, butane-1-sulfonic acid 3.2a, 4-dicarboxy, butane-1-sulfate 4. 1α, 3-dicarboxy, propane sulfonic acid 5. 1α, 3-dicarboxy, propane sulfate 6. 1ß,3-dicarboxy, propane sulfate 7. 1ß, 3-dicarboxy, propane sulfonic acid 8. L-glutamic acid, 2p-sulfonic acid 9. L-glutamic acid, 2ß-sulfate 10. L-glutamic acid, 3a-sulfonic acid 11. L-glutamic acid, 3a-sulfate

12. L-glutamic acid, 3ß-sulfonic acid 13. L-glutamic acid, 3 (3-sulfate 14. L-glutamic acid, 4a-sulfonic acid 15. L-glutamic acid, 4a-sulfate 16. L-glutamic acid, 4p-sulfonic acid 17. L-glutamic acid, 4ß-sulfate 18. D-glutamic acid, N-sulfonic acid 19. 2ß, 4-dicarboxy, butane-l-sulfonic acid 20. 2ß, 4-dicarboxy, butane-1-sulfate 21. D-glutamic acid, 2a-sulfonic acid 22. D-glutamic acid, 2a-sulfate 23. D-glutamic acid, 3a-sulfonic acid 24. D-glutamic acid, 3a-sulfate 25. D-glutamic acid, 3p-sulfonic acid 26. D-glutamic acid, 3p-sulfate 27. D-glutamic acid, 4a-sulfonic acid 28. D-glutamic acid, 4a-sulfate 29. D-glutamic acid, 4ß-sulfonic acid 30. D-glutamic acid, 4ß-sulfate 31. L-glutamine, N-sulfonic acid 32. L-glutamine, 2p-sulfonic acid 33. L-glutamine, 2 (3-sulfate 34. L-glutamine, 3a-sulfonic acid 35. L-glutamine, 3a-sulfate 36. L-glutamine, 3p-sulfonic acid 37. L-glutamine, 3 (3-sulfate 38. L-glutamine, 4a-sulfonic acid 39. L-glutamine, 4a-sulfate 40. L-glutamine, 4p-sulfonic acid 41. L-glutamine, 4ß-sulfate 42. 2a-carboxy, 4-carboxamido, butane-1-sulfonic acid 43. 2a-carboxy, 4-carboxamido, butane-1-sulfate 44. la-carboxy, 3-carboxamido, propane-1-sulfonic acid

45. la-carboxy, 3-carboxamido, propane-1-sulfate 46. 1ß-carboxy, 3-carboxamido, propane-1-sulfate 47. 1ß-carboxy, 3-carboxamido, propane-1-sulfonic acid 48. D-glutamine, N-sulfonic acid 49. 2ß-carboxy, 4-carboxamido, butane-1-sulfonic acid 50. 2p-carboxy, 4-carboxamido, butane-1-sulfate 51. D-glutamine, 2a-sulfonic acid 52. D-glutamine, 2a-sulfate 53. D-glutamine, 3a-sulfonic acid 54. D-glutamine, 3a-sulfate 55. D-glutamine, 3p-sulfonic acid 56. D-glutamine, 3p-sulfate 57. D-glutamine, 4a-sulfonic acid 58. D-glutamine, 4a-sulfate 59. D-glutamine, 4p-sulfonic acid 60. D-glutamine, 4 (3-sulfate j) 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: 1. L-homoglutamic acid, N-sulfonic acid 2. Pentane-2a, 5-dicarboxy-1-sulfonic acid 3. Pentane-2a, 5-dicarboxy-1-sulfate 4. Butane-la, 4-dicarboxy-1-sulfonic acid 5. Butane-1α, 4-dicarboxy-1-sulfate 6. L-homoglutamic acid, 2p-sulfonic acid 7. L-homoglutamic acid, 2 (3-sulfate 8. L-homoglutamic acid, 3a-sulfonic acid 9. L-homoglutamic acid, 3a-sulfate 10. L-homoglutamic acid, 3ß-sulfonic acid 11. L-homoglutamic acid, 3ß-sulfate 12. L-homoglutamic acid, 4a-sulfonic acid 13. L-homoglutamic acid, 4a-sulfate 14. L-homoglutamic acid, 4ß-sulfonic acid

15. L-homoglutamic acid, 4 (3-sulfate 16. L-homoglutamic acid, 5α-sulfonic acid 17. L-homoglutamic acid, 5a-sulfate 18. L-homoglutamic acid, 5ß-sulfonic acid 19. L-homoglutamic acid, 5 (3-sulfate 20. D-homoglutamic acid, N-sulfonic acid 21. Pentane-2ß, 5-dicarboxy-1-sulfonic acid 22. Pentane-2ß, 5-dicarboxy-1-sulfate 23. Butane-1ß, 4-dicarboxy-1-sulfonic acid 24. Butane-lß, 4-dicarboxy-1-sulfate 25. D-homoglutamic acid, 2a-sulfonic acid 26. D-homoglutamic acid, 2a-sulfate 27. D-homoglutamic acid, 3a-sulfonic acid 28. D-homoglutamic acid, 3a-sulfate 29. D-homoglutamic acid, 3ß-sulfonic acid 30. D-homoglutamic acid, 3 (3-sulfate 31. D-homoglutamic acid, 4a-sulfonic acid 32. D-homoglutamic acid, 4a-sulfate 33. D-homoglutamic acid, 4ß-sulfonic acid 34. D-homoglutamic acid, 4p-sulfate 35. D-homoglutamic acid, 5a-sulfonic acid 36. D-homoglutamic acid, 5a-sulfate 37. D-homoglutamic acid, 5ß-sulfonic acid 38. D-homoglutamic acid, 5 (3-sulfate 39. L-homoglutamine, N-sulfonic acid 40. Pentane-2a-carboxy, 5-caxboxamido-1-sulfonic acid 41. Pentane-2a-carboxy, 5-carboxamido-1-sulfate 42. Butane-la-carboxy, 4-carboxamido-1-sulfonic acid 43. Butane-1 a-carboxy, 4-carboxamido-1-sulfate 44. L-homoglutamine, 2ß-sulfonic acid 45. L-homoglutamine, 2ß-sulfate 46. L-homoglutamine, 3a-sulfonic acid 47. L-homoglutamine, 3a-sulfate

48. L-homoglutamine, 3ß-sulfonic acid 49. L-homoglutamine, 3ß-sulfate 50. L-homoglutamine, 4a-sulfonic acid 51. L-homoglutamine, 4a-sulfate 52. L-homoglutamine, 4ß-sulfonic acid 53. L-homoglutamine, 4p-sulfate 54. L-homoglutamine, 5a-sulfonic acid 55. L-homoglutamine, 5a-sulfate 56. L-homoglutamine, 5ß-sulfonic acid 57. L-homoglutamine, 5p-sulfate 58. D-homoglutamine, N-sulfonic acid 59. Pentane-2p-carboxy, 5-carboxamido-l-sulfonic acid 60. Pentane-2p-carboxy, 5-carboxamido-1-sulfate 61. Butane-1-carboxy, 4-carboxamido-l-sulfonic acid 62. Butane-1-carboxy, 4-carboxamido-1-sulfate 63. D-homoglutamine, 2a-sulfonic acid 64. D-homoglutamine, 2a-sulfate 65. D-homoglutamine, 3a-sulfonic acid 66. D-homoglutamine, 3a-sulfate 67. D-homoglutamine, 3p-sulfoiiie acid 68. D-homoglutamine, 3p-sulfate 69. D-homoglutamine, 4a-sulfonic acid 70. D-homoglutamine, 4a-sulfate 71. D-homoglutamine, 4p-sulfonic acid 72. D-homoglutamine, 4i-sulfate 73. D-homoglutamine, 5a-sulfonic acid 74. D-homoglutamine, 5a-sulfate 75. D-homoglutamine, 5ß-sulfonic acid 76. D-homoglutamine, 5ß-sulfate 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.

Table 1

Structure 1 1. L-Aspartic acid, N-Sulfonic acid Z=OH, Rl=NHS03H, R2=R3=R4=H 2. L-Aspartic acid, 2p-sulfonic acid Z=OH, Rt=NH2, R3=R4=H, R2=S03H 3. L-Aspartic acid, 2p-sulfate Z=OH, R1-NH2, R3=R3=H, R2=OSO3H 4. L-aspartic acid, 3a-sulfonic acid Z=OH, Rl=NH2, R2=R4=H, R3=S03H 5. L-aspartic acid, 3a-sulfate Z=OH, R1=NH2, R2=R4=H, R3=OSO3H 6. L-aspartic acid, 3ß-sulfonic acid Z=OH, R1=NH2, R2=R3=H, R4=SO3H 7. L-aspartic acid, 3ß=sulfate Z=OH, R1=NH2, R2=F3=H, R4=OSO3H 8. 2a, 3-dicarboxy, propane-1-sulfonic acid Z=OH, RI=R3=R4=H, R2=CH2CO3H 9.2a, 3-dicarboxy, propane-l-sulfate Z=OH, Rl=R3=R4=H, R2=CH2OS03H 10. la, 2-carboxy ethane sulfonic acid Z=OH, R1=R3=R4=H, R2=SO3H 11. la, 2-carboxy ethane sulfate Z=OH, RI=R3=R4=H, R2=OS03H 12. D-aspartic acid, N-sulfonic acid Z=OH, R2=NHS03H, R1=R3=R4=H, 13. 2ß,3-carboxy,propane-1-sulfonic acid Z=OH, R2=H, Rl=CH2S03H 14. 2ß,3-carboxy,propane-1-sulfate Z=OH, R2=H, R1=CH2OSO3H 15. 1ß,2-carboxy ethane-1-sulfonic acid Z=OH, R2=H, R1=SO3H 16. 1ß, 2-carboxy ethane-1-sulfate Z=OH, R2=H, Rl=OS03H 17. D-aspartic acid, 2α-sulfonic acid Z=OH, R2=NH2, R3=R4=H, R1=SO3H 18. D-aspartic acid, 2a-sulfonic acid Z=OH, R2=NH2, R3=R4=H, R1=SO3H 19. D-Aspartic acid, 3a-sulfonic acid Z=OH, R2=NH2, R1=R4=H, R3=SO3H

20. D-Aspartic acid, 3a-sulfate Z=OH, R2=NH2, Rl=R4=H, R3=OS03H 21. D-Aspartic acid, 3ß-sulfonic acid Z=OH, R2=NH2, R1=R3=H, R4=SO3H 22. D-aspartic acid, 3ß-sulfate Z=OH, R2=NH2, R1=R3=H, R4=OS03H 23. L-asparagine, N-sulfonic acid Z=NH2, R1=NHSO3H, R2=R3=R4=H 24.2a-carboxy, 3-carboxamido, propane-1-sulfonic acid Z=NH2, R1=H, R2=CH2SO3H 25.2a-carboxy, 3-carboxamido, propane-1-sulfate Z=NH2, R1=H, R2=CH2OSO3H 26. la-carboxy, 2-carboxamido, ethane sulfbnic acid Z=NH2, Rl=H, R2=S03H 27. la-carboxy, 2-carboxamido, ethane sulfate Z=NH2, R1=H, R2=OSO3H 28. L-asparagine, 2ß-sulfonic acid Z=R1=NH2, R2=R3=H, R2=SO3H 29. L-asparagine, 2ß-sulfate Z=R1=NH2, R2=R4=H, R3=OSO3H 30.L-asparagine, 3α-sulfonic acid Z=R1=NH2, R2=R4=H, R3=SO3H 31.L-asparagine, 3α-sulfate Z=R1=NH2, R2=R4=H, R3=OSO3H 32. L-asparagine, 3ß-sulfonic acid Z=RI=NH2, R2=R3=H, R4=S03H 33. L-asparagine, 3ß-aulfate Z=R1=NH2, R2=R3=H, R4=OSO3H 34. D-asparagine, N-sulfonic acid Z=NH2, R2=NHS03H, R1=R3=R4=H 35. 2ß-carboxy, 3-carboxamido, propane-1-sulfonic acid Z=NH2, R2 to R4=H, R1=CH2SO3H 36. 2ß-carboxy, 3-carboxamido, propane-1-sulfate Z=NH2, R2 to R4=H, R1=CH2SO3H 37. 1ß-carboxy, 2-carboxamido, ethane sulfonic acid] Z=OH, R2 to R4=H, R1=SO3H 38. 1ß-carboxy, 2-carboxamido, ethane sulfate Z=OH, R2 to R4=H, R1=OSO3H 39. D-asparagine, 2a-sulfonic acid Z=R2=NH2, R3=R4=H, R1=SO3H 40. D-asparagine, 2a-sulfate Z=R2=NH2, R3=R4=H, Rl=OS03H 41. D-asparagine, 3a-sulfonic acid Z=R2=NH2, Rl=R4=H, R3=S03H 42. D-asparagine, 3a-sulfate Z=R2=NH2, Rl=R4=H, R3=OS03H 43. D-asparagine, 3ß-sulfonic acid Z=R2=NH2, Ri =R3=H, Rt=S03H 44. D-asparagine, 3ß-sulfate Z=R2=NH2, R1=R3=H, R4=OSO3H Table 2

Structure 2 1. L-glutamic acid, N-sulfonic acid Z=OH, R1=NHSO3H, R2=R3=R4=R5=R6=H 2.2a, 4-dicarboxy, butane-1-sulfonic acid Z=OH, Ri, R3 to R6=H, R2=CH2S03H 3.2a, 4-dicarboxy, butane-1-sulfate Z=OH, Ri, R3 to R6=H, R2=CH2SO3H 4. la, 3-dicarboxy, propane sulfonic acid Z=OH, Ri, R3 to R6=H, R2=S03H 5. la, 3-dicarboxy, propane sulfate Z=OH, Ri, R3 to R6=H, R2=OSO3H 6. 1ß, 3-dicarboxy, propane sulfate Z=OH, R2 to R6=H, R1=OSO3H 7. 1ß, 3-dicarboxy, propane sulfonic acid Z=OH, R2 to R6=H, R1=SO3H 8. L-glutamic acid, 2ß-sulfonic acid Z=OH, R1=NH2, R3 to R6=H, R2=S03H 9. L-glutamic acid, 2p-sulfate Z=OH, R1=NH2, R3 to R6=H, R2=OS03H 10. L-glutamic acid, 3a-sulfonic acid Z=OH, R1=NH2, R2=H, R4 to R6=H, R3=S03H 11. L-glutamic acid, 3a-sulfate Z=OH, R1=NH2, R2=H, R4 to R6=H, R3=OS03H 12. L-glutamic acid, 3ß-sulfonic acid Z=OH, RI=NH2, R2=R3=R5=R6=H, R4=S03H 13. L-glutamic acid, 3p-sulfate Z=OH, R1=NH2, R2=R3=R5=R6=H, R4=OSO3H 14. L-glutamic acid, 4a-sulfonic acid Z=OH, R1=NH2, R2=R3=R4=R6=H, R5=SO3H 15. L-glutamic acid, 4a-sulfate Z=OH, R1=NH2, R2=R3=R4=R6=H, R5=OSO3H 16. L-glutamic acid, 4ß-sulfonic acid Z=OH, R1=NH2, R2 to R5=H, R6=SO3H 17. L-glutamic acid, 4p-sulfate Z=OH, R1=NH2, R2 to R5=H, R6=OS03H 18. D-glutamic acid, N-sulfonic acid Z=OH, R2=NHS03H, Ri, R3 to R6=H 19. 2p, 4-dicarboxy, butane-1-sulfonic acid Z=OH, R2 to R6=H, Rl=CH2S03H

20. 2p, 4-dicarboxy, butane-1-sulfate Z=OH, R2 to R6=H, R1=CH2OSO3H 21. D-glutamic acid, 2a-sulfonic acid Z=OH, R2=NH2, R3 to R6 H, R1=SO3H 22. D-glutamic acid, 2a-sulfate Z=OH, R2=NH2, R3 to R6 H, R1=OSO3H 23. D-glutamic acid, 3a-sulfonic acid Z=OH, R2=NH2, Ri, R4 to R6 H, R3=S03H 24. D-glutamic acid, 3a-sulfate Z=OH, R2=NH2, Ri, R4 to R6 H, R3=OS03H 25. D-glutamic acid, 3ß-sulfonic acid Z=OH, R2=NH2, R1=R3=R5=R6=H, R4=SO3H 26. D-glutamic acid, 3ß-sulfate Z=OH, R2=NH2, R1=R3=R5=R6=H, R4=OSO3H 27. D-glutamic acid, 4a-sulfonic acid Z=OH, R2=NH2, R1=R3=R4=R6=H, Rs=S03H 28. D-glutamic acid, 4a-sulfate Z=OH, R2=NH2, R1=R3=R4=R6=H, R5=OSO3H 29. D-glutamic acid, 4ß-sulfonic acid Z=OH, R2=NH2, R1=R3=R4=R5=H, R6=SO3H 30. D-glutamic acid, 4 (3-sulfate Z=OH, R2=NH2, R1=R3=R4=R5=H, R6=OSO3H 31. L-glutamine, N-sulfonic acid Z=NH2, R1=NHSO3H, R2 to R6=H 32. L-glutamine, 2ß-sulfonic acid Z=R1=NH2, R3 to R6 =H, R2=S03H 33. L-glutamine, 2ß-sulfate Z=R1=NH2, R3 to R6 =H, R2=OS03H 34. L-glutamine, 3a-sulfonic acid Z=R1=NH2, R2=H, R3 to R6 =H, R3=S03H 35. L-glutamine, 3a-sulfate Z=R1=NH2, R2=H, R3 to R6=H, R3=OSO2H 36. L-glutamine, 3ß-sulfonic acid Z=RI=NH2, R2=R3=R5=R6 =H, R4=SO3H 37. L-glutamine, 3ß-sulfate Z=R1=NH2, R2=R3=R5=R6=H, R4=OSO3H 38. L-glutamine, 4a-sulfonic acid Z=R1=NH2, R2=R3=R4=R6=H, Rs=S03H

39. L-glutamine, 4a-sulfate Z=Rl=NH2, R2=R3=R4=R6=H, R5=OS03H 40. L-glutamine, 4ß-sulfonic acid Z=RI=NH2, R2 to Rs=H, R6=SO2H 41. L-glutamine, 4ß-sulfate Z=R1=NH2, R2 to R5=H, R6=OS03H 42.2a-carboxy, 4-carboxamido, butane-l-sulfonic acid Z=NH2, Rl, R3 to R6=H, R2=CH2SO3H 43.2a-carboxy, 4-carboxamido, butane-1-sulfate Z=NH2, Ri, R3 to R6=H, R2=CH2OSO3H 44. la-carboxy, 3-carboxamido, propane-1-sulfonic acid Z= NH2, Rl, R3 to R6=H, R2=S03H 45. la-carboxy, 3-carboxamido, propane-1-sulfate Z= NH2, Rl, R3 to R6=H, R2=OS03H 46. 1ß-carboxy, 3-carboxamido, propane-1-sulfate Z= NH2, R2 to R6=H, RI=OS03H 47. 1ß-carboxy, 3-carboxamido, propane-1-sulfonic acid Z= NH2, R2 to R6=H, R1=SO3H 48. D-glutamine, N-sulfonic acid Z=NH2, R2=NHS03H ; R1=H, R3 to R6=H 49. 2ß-carboxy, 4-carboxamido, butane-1-sulfonic acid Z= NH2, R2 to R6=H, R1=CH2SO3H 50. 2ß-carboxy, 4-carboxamido, butane-1-sulfate Z= NH2, R2 to R6=H, R1=CH2OSO3H 51. D-glutamine, 2a-sulfonic acid Z=NH2, R2=NH2, R3 to R6=H, R1=SO3H 52. D-glutamine, 2a-sulfate Z=NH2, R2=NH2, R3 to R6=H, Rl=OS03H 53. D-glutamine, 3a-sulfonic acid Z=NH2, R2=NH2, Rl, R4 to R6 H, R3=S03H 54. D-glutamine, 3a-sulfate Z=R2=NH2, R1, R4 to R6 H, R3=OS03H 55. D-glutamine, 3ß-sulfonic acid Z=R2=NH2, R1=R3=R5=R6=H, R4=S03H 56. D-glutamine, 3ß-sulfate Z=R2=NH2, R1=R3=R5=R6=H, R4=OSO3H 57. D-glutamine, 4a-sulfonic acid Z=R2=NH2, R1=R3=R4=R6=H, R5=S03H 58. D-glutamine, 4a-sulfate Z=R2=NH2, R1=R3=R4=R6=H, R5=OS03H 59. D-glutamine, 4p-sulfonic acid Z=R2=NH2, R1=R3=R4=R5=H, R6=SO3H 60. D-glutamine, 4ß-sulfate Z=R2=NH2, R1=R3=R4=R5=H, R6=OSO3H Table 3

structure 3 1. L-homoglutamic acid, N-sulfonic acid Z=OH, R1=NHSO3H, R2 to R8=H 2. Pentane-2α, 5-dicarboxy-1-sulfonic acid Z=OH, Ri, R3 to R8=H, R2=CH2SO3H 3. Pentane-2a, 5-dicarboxy-1-sulfate Z=OH, Ri, R3 to R8=H, R2=CH2OSO3H 4. Butane-1α, 4-dicarboxy-1-sulfonic acid Z= OH, Rl, R3 to R8=H, R2=S03H 5. Butane-la, 4-dicarboxy-1-sulfate Z=OH, R1, R3 to R8=H, R2=OSO3H 6. L-homoglutamic acid, 2ß-sulfonic acid Z=OH, R1=NH2, R3 to R8=H, R2=S03H 7. L-homoglutamic acid, 2p-sulfate Z=OH, RI=NH2, R3 to R8=H, R2=OS03H 8. L-homoglutamic acid, 3a-sulfonic acid Z=OH, R1=NH2, R2=H, R4 to R8 H, R3=S03H 9. L-homoglutamic acid, 3a-sulfate Z=OH, R1=NH2, R2=H, R4 to Rs H, R3=OS03H 10. L-homoglutamic acid, 3ß-sulfonic acid Z=OH, R1=NH2, R2=R3=H, R5 to R8=H, R4=SO3H 11. L-homoglutamic acid, 3ß-sulfate Z=OH, R1=NH2, R2=R3=H, R5 to R8=H, R4=OS03H 12. L-homoglutamic acid, 4a-sulfonic acid Z=OH, R1=NH2, R2=R3=R4=H, R6 to R8=H, R5=S03H 13. L-homoglutamic acid, 4a-sulfate Z=OH, R1=NH2, R2=R3=R4=H, R6 to R8=H, R5=OSO3H 14. L-homoglutamic acid, 4p-sulfonic acid Z=OH, R1=NH2, R2=R5=H, R7=R8=H, R6=SO3H 15. L-homoglutamic acid, 4p-sulfate

Z=OH, R1=NH2, R2=R5=H, R7=R8=H, R6=OSO3H 16. L-homoglutamic acid, 5a-sulfonic acid Z=OH, R1=NH2, R2 to R6=H, R8 =H, R7=S03H 17. L-homoglutamic acid, 5a-sulfate Z=OH, R1=NH2, R2 to R6=H, R8 =H, R7=OS03H 18. L-homoglutamic acid, 5ß-sulfonic acid Z=OH, R1=NH2, R2 to R7=H, R8=SO3H 19. L-homoglutamic acid, 5p-sulfate Z=OH, R1=NH2, R2 to R7 =H, R8=OS03H 20. D-homoglutamic acid, N-sulfonic acid Z=OH, R2=NHS03H, Ri, R3 to R8=H 21. Pentane-2ß, 5-dicarboxy-1-sulfonic acid Z=OH, R2 to R8=H, Rl=CH2S03H 22. Pentane-2p, 5-dicarboxy-1-sulfate Z=OH, R2 to R8=H, R1=CH2OSO3H 23. Butane-1ß, 4-dicarboxy-1-sulfonic acid Z=OH, R2 to R8=H, R1=SO3H 24., Butane-1ß, 4-dicarboxy-1-sulfate Z=OH, R2 to R8=H, R1=OSO3H 25. D-homoglutamic acid, 2a-sulfonic acid Z=OH, R2=NH2, R3 to R8=H, R1=SO3H 26. D-homoglutamic acid, 2a-sulfate Z=OH, R2=NH2, R3 to R8=H, R1=OSO3H 27. D-homoglutamic acid, 3a-sulfonic acid Z=OH, R2=NH2, R1, R4 to R8 H, R3=S03H 28. D-homoglutamic acid, 3a-sulfate Z=OH, R2=NH2, Ri, R4 to R8 H, R3=OS03H 29. D-homoglutamic acid, 3ß-sulfonic acid Z=OH, R2=NH2, R1=R3=H, R5 to R8=H, R4=S03H 30. D-homoglutamic acid, 3 (3-sulfate Z=OH, R2=NH2, R1=R3=H, R5 to R8=H, R4=OS03H 31. D-homoglutamic acid, 4a-sulfonic acid Z=OH, R2=NH2, R1=R3=R4=H, R6 to R8=H, R5=S03H 32. D-homoglutamic acid, 4a-sulfate Z=OH, R2=NH2, R1=R3=R4=H, R6 to R8=H, R5=OS03H 33. D-homoglutamic acid, 4ß-sulfonic acid Z=OH, R2=NH2, R1=H, R3 to R5=H, R7=R8=H, R6=SO3H

34. D-homoglutainic acid, 4p-sulfate Z=OH, R2=NH2, R1=H, R3 to R5=H, R7=R8=H, R6=OSO3H 35. D-homoglutamic acid, 5a-sulfonic acid Z=OH, R2=NH2, Ri=R8=H, R3 to R6=H, R7=S03H 36. D-homoglutamic acid, 5a-sulfate Z=OH, R2=NH2, R1=R8=H, R3 to R6=H, R7=OS03H 37. D-homoglutamic acid, 5ß-slufonic acid Z=OH, R2=NH2, Ri=H, R3 to R7=H, R8=S03H 38. D-homoglutamic acid, 5ß-sulfate Z=OH, R2=NH2, R1=H, R3 to R7=H, R8=OSO3H 39. L-homoglutamine, N-sulfonic acid Z=NH2, R1=NHSO3H, R2 to R8=H 40. Pentane-2a-carboxy, 5-carboxamido-1-sulfonic acid Z=NH2, Pi and R3 to R8=H, R2=CH2SO3H 41. Pentane-2a-carboxy, 5-carboxamido-1-sulfate Z=NH2, Pi and R3 to R8=H, R2=CH20SO3H 42. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid Z=NH2, Rl and R3 to R8=H, R2=SO3H 43. Butane-1α-carboxy, 4-carboxamido-1-sulfate Z=NH2, R1 and R3 to R8=H, R2=OS03H 44. L-homoglutamine, 2 (3-sulfonic acid Z=R1=NH2, R3 to R8=H, R2=S03H 45. L-homoglutamine, 2ß-sulfate Z=R1=NH2, R3 to R8=H, R2=OSO3H 46. L-homoglutamine, 3a-sulfonic acid Z=R1=NH2, R2=H, R4 to R8=H, R3=SO3H 47. L-homoglutamine, 3a-sulfate Z=R1=NH2, R2=H, R4 to R8=H, R3=OSO3H 48. L-homoglutamine, 3ß-sulfonic acid Z=Ri=NH2, R2=R3=H, R5 to R8=H, R4=SO3H 49. L-homoglutamine, 3ß-sulfate Z=Rt=MH2, R2=R3=H, Rs to R8=H, R4=OSO3H 50. L-homoglutamine, 4a-sulfonic acid Z=R1=NH2, R2=R3=R4=H, R6 to Rg=H, R5=S03H 51. L-homoglutamine, 4a-sulfate Z=Ri=NH2, R2=R3=R4=H, R6 to R8=H, R5=OSO3H 52. L-homoglutamine, 4ß-sulfonic acid

Z=Ri=NH2, R2=R5=H, R7=Rs=H, R6=S03H 53. L-homoglutamine, 4p-sulfate Z=Rt=NH2, R2=Rs=H, R7=Rs=H, R6=OS03H 54. L-homoglutamine, 5a-sulfonic acid: Z=R1=NH2, R2 to R6=H, R8=H, R7=SO3H 55. L-homoglutamine, 5a-sulfate Z=R1=NH2, R2 to R6=H, R8=H, R7=OS03H 56. L-homoglutamine, 5ß-sulfonic acid Z=R1=NH2, R2 to R7=H, R8=SO3H 57. L-homoglutamine, 5ß-sulfate Z=R1=NH2, R2 to R7=H, R8=OSO3H 58. D-homoglutamine, N-sulfonic acid Z=NH2, R2=NHSO3H, R1 and R3 to R8=H 59. Pentane-2p-carboxy, 5-carboxamido-1-sulfonic acid Z=NH2, R2 to R8=H, Rl=CH2S03H 60. Pentane-2p-carboxy, 5-carboxamido-l-sulfate Z=NH2, R2 to R8=H, R1=CH2OSO3H 61. Butane-l P-carboxy, 4-carboxamido-1-sulfonic acid Z=NH2, R2 to Rg=H, R1=SO3H 62. Butane-1 0-carboy, 4-carboxamido-1-sulfate : Z=NH2, R2 to R8=H, R1=OSO3H 63. D-homoglutamine, 2a-sulfonic acid Z=R2=NH2, R3 to Rs H, R1=SO3H 64. D-homoglutamine, 2a-sulfate Z=R2=NH2, R3 to Rg H, R1=OSO3H 65. D-homoglutamine, 3a-sulfonic acid Z=R2=NH2, R1, R4 to Rg H, R3=SO3H 66. D-homoglutamine, 3a-sulfate Z=R2=NH2, Rl, R4 to Rs H, R3=OSO3H D-homoglutamine, 3ß-sulfonic acid : Z=R2=NH2, R1=R3=H, R5 to Rg=H, R4=S03H D-homoglutamine, 3ß-sulfate : Z=R2=NH2, R1=R3=H, R5 to R8=H, R4==OS03H D-homoglutamine, 4a-sulfonic acid: Z=R2=NH2, R1=R3=R4=H, R6 to R8=H, R5=SO3H 67. D-homoglutamine, 4a-sulfate Z=R2=NH2, R1=R3=R4=H, R6 to R8=H, R5=OSO3H

68. D-homoglutamine, 4ß-sulfonic acid Z=R2=NH2, R1=H, R3 to R5=H, R7=R8=H, R6=SO3H 69. D-homoglutamine, 4p-sulfate Z=R2--NH2, Rl=H, R3 to R5=H, R7=Rs=H, R6=OS03H 70. D-homoglutamine, 5a-sulfonic acid Z=R2=NH2, R1=R8=H, R3 to R6 =H, R7=S03H 71. D-homoglutamine, 5a-sulfate Z=R2=NH2, Ri=R8=H, R3 to R6=H, R7=OS03H 72. D-homoglutamine, 5ß-sulfonic acid Z=R2=NH2, R1=H, R3 to R7=H, R8=SO3H 73. D-homoglutamine, 5ß-sulfate Z=R2=NH2, RI=H, R3 to R7=H, R8=OS03H REFERENCE EXAMPLE 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 AND EXAMPLE 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 S02C12 (2 eq. ) in dry CHUCK at 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 CH2C12 followed 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 S02C12 (2 eq. ) in dry CH2C12 at 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 CH2C12 followed 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 S02C12 (2 eq. ) in dry CH2C12 at 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 CH2C12 followed 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-sulfouic 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 SO2Cl2 (2 eq. ) in dry CH2C12 at 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 CH2C12 followed 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 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 inhibition of osteoclast differentiation (Table A).

Table A: Effect of compound 1 (L-glutamyl-N-sulphonic acid, Ca salt) on osteoclast formation Culture Number of TRAP-positive multinuclear % inhibition conditions cells/well of 96 well plate (Mean SEM) M-CSF 0 M-CSF + 138. 00 ~ 9.37 - RANKL M-CSF+ 109.67 ~ 9. 79 21. 01 RANKL+ compound 1 (0.5 µg/ml) M-CSF + 52. 17 ~ 6. 42 62.19 RANKL + compound 1 (1. 5 µg/ml) M-CSF + 14. 671. 98 89.36 RANKL+ compound 1 (3. 0 µg/ml) M-CSF + 2.83 ~ 1. 05 97.94 RANKL+ compound 1 (5. 0g/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 6.

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 inhibition of osteoclast differentiation (Table B).

Table B: Effect of L-glutamic acid, calcium salt on osteoclast formation Culture Number of TRAP-positive % inhibition conditions multinuclear cells/well of 96 well plate (Mean SEM) M-CSF 0 M-CSF + 158.33 ~ 12.00 RANKL M-CSF + 167.17 ~ 7.95 0 RANKL + compound 2 (0. 5. µg/ml) M-CSF + 152. 83 10.47 3.47 RANKL + compound 2 (1-5 Ag/ml) M-CSF + 130. 50 ~ 13.57 17.37 RANKL + compound 2 (3.0 µg/ml) M-CSF + 119.50 ~ 10. 00 24.52 RANKL+ compound 2 (5. 0 ug/ml) For detail see legend to example 5

Reference example 7 The L-glutamyl-N-sulphonic acid prepared as described in Examples 1 & 2 was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table D).

Table-D: Effect of L-glutamyl-N-sulphonic acid on osteoclast formation Culture Number of TRAP-positive % inhibition conditions multinuclear cells/well of 96 well plate (Mean SEM) M-CSF 0 M-CSF + 146. 83 + 11. 89 RANKL M-CSF + 154.67 8.43 0 RANKL+ compound 3 (0.5 µg/ml) M-CSF + 150.33 ~ 8. 82 0 RANKL+ compound 3 (1. 5 pg/ml) M-CSF + 112. 67 ~ 8. 63 23.23 RANKL + compound 3 (3.0 µg/ml) M-CSF + 110. 00 6. 72 25.08 RANKL + compound 3 (5. 0 µg/ml) For detail see legend to example 5 Reference example 8 The L-glutamic acid was reconstituted in sterilized distilled water and assessed in a dose-dependent manner for inhibition of osteoclast differentiation (Table E).

Table E: Effect of L-glutamic acid on osteoclast formation

Culture Number of TRAP-positive % inhibition conditions multinuclear cells/well of 96 well plate (Mean ~ SEM M-CSF 0 - M-CSF + 156. 00 ~ 12. 26 0 RANKL M-CSF + 173. 33 ~ 6. 50 0 RANKL+ compound 4 (0.5 llg/ml) M-CSF + 155. 00 8. 23 0. 64 RANKL+ compound 4 (1.5 llg/ml) M-CSF + 145. 83~ 14. 71 7. 05 RANKL+ compound 4 (3. 0 llg/ml) M-CSF + 112. 67~ 10. 74 27.77 RANKL + compound 4 (5. 0 tg/ml) For detail see legend to example 5 Reference example 9 The L-Åspartic acid, N-sulphonic acid as prepared in example 3 was mixed with 1 M equivalent of CaCl2 solution and incubated at temperature ranging from 3 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 F). Table F: Effect of L-Aspartic acid, N-sulphonic acid calcium salt on osteoclast formation Culture Number of TRAP-positive % inhibition conditions multinuclear cells/well of 96 well plate (Mean ~SEM) M-CSF 0 M-CSF + 158.33 ~ 11. 26 0 RANKL M-CSF + 127. 30 5. 50 19.70 RANKL+ compound 4 (0. 5 ug/ml) M-CSF + 86. 23 7. 23 45.16 RANKL+ compound 4 (1.5 µg/ml M-CSF + 44.50~ 4. 80 71.90 RANKL+ compound 4 (3.0 g/ml) M-CSF + 26. 67 0. 73 83. 26 RANKL + compound 4 (5. 0 µg/ml)

For detail see legend to example 5 Reference example 10 L-homoglutamic acid, N-sulphonic acid as prepared in example 4 was mixed with 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 inhibition of osteoclast differentiation (Table G).

Table G: Effect of L-homoglutamic acid, N-sulphonic acid, calcium salt on osteoclast formation Culture Number of TRAP-positive % inhibition conditions multinuclear cells/well of 96 well plate (Mean ~ SEM) M-CSF 0 - M-CSF + 146.. 83 12. 00 - RANKL M-CSF + 138.57 7. 95 5.55 RANKL + compound 2 (0.5 llg/ml) M-CSF + 106.23 ~ 10.47 27. 60 RANKL + compound 2 (1. 5 µg/ml M-CSF + 78. 57 13.57 46.40 RANKL + compound 2 (3.0 llg/ml) M-CSF + 46. 2210. 00 68.50 RANK + compound 2 (5. 0 g/ml)

For detail see legend to example 5 Reference example 11 A. In vitro osteoclastogenesis assay For in vitro osteoclastogenesis bone marrow cells were isolated from 5-to 8-wk- old Balb/c mice. Mice were sacrificed by cervical dislocation and femora and tibiae were aseptically removed and dissected free of adherent soft tissues. The bone ends were cut, and the marrow cavity was flushed out with medium MEM from one end of the-bone using a sterile 21-gauge needle. The bone marrow suspension was carefully agitated with a plastic Pasteur pipette to obtain a single- cell suspension. The cells were washed twice and resuspended (106 cells/ml) in a MEM containing 10% FBS. Stromal cell-free, M-CSF-dependent, osteoclast precursor cells were prepared from these cells as previously described (Wani et al.

1999). Briefly, bone marrow cells were incubated for 24 h in a MM containing 10% FBS in the presence of M-CSF (10 ng/ml) at a density of 3 x 105 cells/ml in a 75 cm2 flask. After 24 h, nonadherent cells were harvested and layered on a Ficoll-Hypaque gradient. Cells at the gradient interface were collected, washed and resuspended (5 x 105/ml) in a MEM containing 10% FBS. In this study, we called these stromal cell-free, M-CSF-dependent, nonadherent cells as osteoclast precursors. These osteoclast precursors were added to 96-well plates (100 zl/well) containing plastic coverslips. Each well received further 100 ul of medium containing M-CSF (30 ng/ml), RANKL (30 ng/ml) without or with various

concentrations of purified compound. Cultures were fed every 2-3 days and after incubation for 6 days osteoclast formation was evaluated by tartrate-resistant acid phosphatase (TRAP) staining. The number of TRAP-positive multinucleated cells (MNCs) containing 3 or more nuclei was scored.

B. Characterization of osteoclasts by TRAP staining Osteoclast formation was evaluated by quantification of TRAP-positive MNCs as described previously (Khapli et al. 2003). TRAP is preferentially expressed at high levels in osteoclast and is considered, especially in the mouse, to be an osteoclast marker. Cytochemical staining for TRAP is widely used for identifying the osteoclasts in vivo and in vitro. It is claimed to be specific for osteoclasts in bone. After incubation, cells on cover slips were washed in PBS, fixed in 10% formalin for 10 min and stained for acid phosphatase in the presence of 0. 05 M sodium tartrate. The substrate used was napthol AS-BI phosphate. Only those cells that were strongly TRAP-positive (dark red) counted by light microscopy.

C. IN Vitro Bone resorption assay Osteoclast has the ability to excavate authentic resorption lacunae in vivo and in vitro. Bone resorption is the unique function of the osteoclast and is therefore the most useful means of distinguishing it from other cell types. M-CSF-dependent, non-adherent bone marrow cells were incubated for 10 days on bovine cortical bone slices in the presence of M-CSF, RANKL with or without various concentrations of compounds. Bone slices were examined for resorption pits by reflected light microscopy as previously described (Wani et al. 1999).

BRIEF DESCRIPTION OF THE ACCOMPANYING PLATES Plate 1 : Effect of compound as given in example 3 on RANKL-induced osteoclast differentiation from haemopoietic precursors of monocytes/macrophage lineage.

Mice osteoclast precursors were incubated in the presence of M-CSF and RANKL in the absence and presence of the compound. Photomicrographs showing TRAP- positive osteoclasts in the absence A) and presence of B) of the compound. This compound significantly inhibited osteoclast formation.

Plate 2: Effect of compound as described in example 4 on RANKL-induced osteoclast differentiation from haemopoietic precursors of monocytes/macrophage lineage. Photomicrographs showing TRAP-positive osteoclasts induced by M-CSF and RANKL in the absence A) and presence of B) of compound. This compound showed no inhibitory effect on osteoclast differentiation.