# US 5,708,163 A · Synthesis of the breast tumor-associated antigen defined by monoclonalantibody MBRL and uses thereof

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- Number: US 5,708,163 A
- Document ID: US5708163A
- Status: Granted
- Kind: A
- Application number: 08/430,355
- Filed: 1995-04-28
- Granted: 1998-01-13
- Earliest claimed: 1994-03-15
- Assignees: Sloan-Kettering Institute of Cancer Research
- Inventors: Samuel J. Danishefsky; Mark T. Bilodeau; Shuang Hua Hu; Tae Kyo Park; John T. Randolph; In Jong Kim; Philip O. Livingston
- Web page: https://patentgrep.com/patent/US5708163A

## CPC

- C07H 15/10: containing unsaturated carbon-to-carbon bonds
- A61K 39/0011: {Cancer antigens}
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- C07H 3/06: Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
- C07H 15/18: Acyclic radicals, substituted by carbocyclic rings
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- C07K 1/04: on carriers {(C07K1/003, C07K1/006 take precedence)}
- C07K 9/005: {containing within the molecule the substructure [IMAGE cpc-sch-C07K-1009.gif] with m, n > 0 and m+n > 0, A, B, D, E being heteroatoms; X being a bond or a chain, e.g. muramylpeptides}
- C07K 16/3015: {Breast}
- C07K 16/44: against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2039/812: {Breast}
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention provides a process for synthesizing a compound having the structure: ##STR1## wherein R is H, as well as related oligosaccharides useful as a vaccine for inducing antibodies to human breast cancer cells in an adjuvant therapy therefor.

## Claims

### Claim 1

A process for synthesizing a compound having the structure: ##STR81## wherein R is H which comprises: (a) (i) reacting a compound having the structure: ##STR82## with an epoxidizing agent under suitable conditions to form an epoxide; (ii) cleaving the epoxide formed in step (a) (i) under suitable conditions with R.sub.4 NF wherein each R is independently the same or different and is a linear or branched chain alkyl, aralkyl or aryl group to form a fluoroalcohol; and
(iii) alkylating the fluoroalcohol formed in step (b) (ii) under suitable conditions with a non-nucleophilic base and an organic halide having the formula C.sub.6 H.sub.5 CH.sub.2 X wherein X is Br, Cl, I or F to form a compound having the structure: ##STR83## (b) treating a compound having the structure: ##STR84## with an epoxidizing agent under suitable conditions to form an epoxide; and
(c) coupling the epoxide formed in step (b) with a compound having the structure: ##STR85## under suitable conditions to form a compound having the structure: ##STR86## (d) (i) alkylating the compound formed in step (c) (ii) under suitable conditions with a non-nucleophilic base and an organic halide having the formula C.sub.6 H.sub.5 CH.sub.2 X wherein X is Br, Cl, I or F; and
(ii) de-silylating the compound formed in step (d) (i) under suitable conditions with R.sub.4 NF wherein each R is independently the same or different and is a linear or branched chain alkyl, aralkyl or aryl group;
(iii) treating the compound formed in step (d) (ii) under suitable conditions with a metal alkoxide to form a deprotected disaccharide; and
(iv) alkylating the disaccharide formed in step (d) (iii) under suitable conditions to form a selectively deprotected disaccharide having the structure: ##STR87## (e) (i) coupling the selectively deprotected disaccharide formed in step (d) (iv) with the compound formed in step (a) (iii) under suitable conditions to form a protected trisaccharide; and
(ii) de-protecting the protected trisaccharide formed in step (e) (i) under suitable conditions to form a trisaccharide having the structure: ##STR88## wherein R is H.

### Claim 2

A process for synthesizing a trisaccharide ceramide having the structure: ##STR89## which comprises: (a) synthesizing a trisaccharide having the structure ##STR90## wherein R is PMB; (b) (i) reacting the trisaccharide formed in step (a) with an epoxidizing agent under suitable conditions to form a trisaccharide epoxide; and
(ii) reacting the trisaccharide epoxide formed in step (b) (i) with a compound having the structure: ##STR91## under suitable conditions to form a protected trisaccharide ceramide having the structure: ##STR92## (c) (i) acylating the ceramide formed in step (b) (ii) under suitable conditions; and
(ii) selectively de-protecting the compound formed in step (c) (i) under suitable conditions to form the trisaccharide ceramide.

### Claim 3

A process for synthesizing a mercaptotrisaccharide having the structure: ##STR93## which comprises: (a) coupling a compound having the structure: ##STR94## with a compound having structure: ##STR95## under suitable conditions to form a disaccharide having the structure: ##STR96## (b) coupling the disaccharide formed in step (a) (ii) with a compound having the structure: ##STR97## under suitable conditions to form a trisaccharide having the structure: ##STR98## (c) iodosulfonamidating the trisaccharide formed in step (b) under suitable conditions to form a iodosulfonamide having the structure: ##STR99## and (d) reacting the iodosulfonamide formed in step (c) under suitable conditions with a thiolate to form the mercaptotrisaccharide.

### Claim 4

A process of synthesizing a hexasaccharide ceramide having the structure: ##STR100## which comprises: (a) coupling a compound having the structure: ##STR101## with a compound having the structure: ##STR102## under suitable conditions to form a compound having the structure: ##STR103## (b) (i) reacting the compound formed in step (a) with an epoxidizing agent under suitable conditions to form a hexasaccharide epoxide; and
(ii) reacting the hexasaccharide epoxide with a stannyl ether having the structure: ##STR104## under suitable conditions to form a hexasaccharide alcohol; (c) acylating the hexasaccharide alcohol formed in step (b) (ii) under suitable conditions to form a hexasaccharide acetate having the structure: ##STR105## (d) reductively acylating the hexasaccharide acetate formed in step (c) under suitable conditions in the presence of palmitic anhydride to form a hexasaccharide ceramide;
(e) desilylating the hexasaccharide ceramide under suitable conditions to form a partially deprotected hexasaccharide ceramide;
(f) (i) reducing the partially deprotected hexasaccharide ceramide under suitable conditions to form a deprotected hexasaccharide ceramide acetate; and
(ii) acylating the deprotected hexasaccharide ceramide acetate under suitable conditions to form a hexasaccharide ceramide peracetate; and
(g) saponifying the hexasaccharide ceramide peracetate under suitable conditions to form the hexasaccharide ceramide.

### Claim 5

A process of synthesizing a hexasaccharide ceramide having the structure: ##STR106## which comprises: (a) coupling a compound having the structure: ##STR107## with a compound having the structure: ##STR108## under suitable conditions to form a hexasaccharide having the structure: ##STR109## (b) (i) reducing the hexasaccharide formed in step (a) under suitable conditions in the presence of palmitic anhydride to form a palmitoyl amide;
(ii) desilylating the palmitoyl amide with R.sub.4 NF wherein each R is independently the same or different and is a linear or branched chain alkyl, aralkyl or aryl group under suitable conditions to form a partially deprotected hexasaccharide;
(iii) de-protecting the hexasaccharide formed in step (b) (ii) under suitable conditions to form a deprotected hexasaccharide;
(iv) acylating the hexasaccharide formed in step (b) (iii) under suitable conditions to form a hexasaccharide ceramide peracetate; and
(iv) saponifying the hexasaccharide ceramide peracetate under suitable conditions to form the hexasaccharide ceramide.

### Claim 6

A process of synthesizing an allyl hexasaccharide having the structure: ##STR110## which comprises: (a) coupling a compound having the structure: ##STR111## with a compound having the structure: ##STR112## wherein R is H under suitable conditions to form a hexasaccharide having the structure: ##STR113## (b) (i) desilylating the compound formed in step (a) with R.sub.4 NF wherein each R is independently the same or different and is a linear or branched chain alkyl, aralkyl or aryl group under suitable conditions to form a partially deprotected hexasaccharide;
(ii) de-protecting the hexasaccharide formed in step (b) (i) under suitable conditions to form a deprotected hexasaccharide; and
(iii) peracylating the compound formed in step (b) (ii) under suitable conditions to form a hexasaccharide peracetate having the structure: ##STR114## (c) (i) reacting the hexasaccharide peracetate formed in step (b) (iii) with an epoxidizing agent under suitable conditions to form an hexasaccharide epoxide peracetate;
(ii) treating the hexasaccharide epoxide peracetate formed in step (c) (i) with allyl alcohol under suitable conditions to form an allyl hexasaccharide peracetate; and
(iii) saponifying the allyl hexasaccharide peracetate under suitable conditions to form the allyl hexasaccharide.

### Claim 7

A process of synthesizing a hexasaccharide having the structure: ##STR115## which comprises: (a) coupling a compound having the structure: ##STR116## with a compound having the structure: ##STR117## under suitable conditions to form a compound having the structure: ##STR118## (b) (i) acylating the compound formed in step (a) under suitable conditions; and
(ii) reacting the compound formed in step (b) (i) with an epoxidizing agent under suitable conditions to form an epoxide having the structure: ##STR119## (c) (i) treating the epoxide with R.sub.4 NF wherein each R is independently the same or different and is a linear or branched chain alkyl, aralkyl or aryl group under suitable conditions; and
(ii) alkylating the compound formed in step (c) (i) under suitable conditions to form a compound having the structure: ##STR120## wherein R is H or acyl; (d) coupling the compound formed in step (c) (ii) with a compound having the structure: ##STR121## under suitable conditions to form the hexasaccharide.