Hoffmann-la Roche Inc.

Roche Vitamins Inc.

Arthur M Felix

Edgar P Heimer

Johannes A Meienhofer

Waleed Danho

Thomas F Mowles

David Robert Bolin

Arnold Trzeciak

Dieter Gillessen

Vincent Stewart Madison

Hideo Ishitsuka

Sidney Spector

Arnold A Liebman

Hugo E Gallo-Torres

David Charles Fry

Alain Fournier

William Lergier

Rolf Studer

Wallace M Dairman

Yumiko Ohta

This invention relates to a novel process for the synthesis of vasoactive intestinal peptide analog Ac(1-31)-NH2 from four protected peptide fragments.

Synthesis of VIP analog

This invention relates to a novel process for the synthesis of vasoactive intestinal peptide analog Ac(1-31)--NH.sub.2 from four protected peptide fragments.

Novel growth hormone releasing factor analogs are presented having a sequence of from about twenty-nine (29) to about forty-four (44) amino acids (SEQ ID NO: 6) wherein Xaa at position 1 is His, 3-MeHis, desNH.sub.2 His, Tyr, or desNH.sub.2 Tyr; Xaa at position 2 is Val, Leu, lie, Ala, D-Ala, N-Methyl-D-Ala, Gly, NIe, or Nval; Xaa at position 8 is Gln, Ser, or Thr; Xaa at position 15 is Ala or Leu; Xaa at position 27 is Met, Nle or Leu; Xaa at position 28 is Ser or Asn; Xaa at position 29 is an amino acid residue sequence (SEQ ID NO: 7) or fragments thereof where the fragment is reduced in number by one to fifteen amino acid residues from the carboxyl-terminus, where the carboxyl terminus can be the free carboxylic acid or the corresponding amide, and the pharmaceutically acceptable acid or base addition salts thereof. The novel growth hormone releasing factor analogs demonstrate enhanced potency for the release of growth hormone, have enhanced enzymatic stability, improved half-life stability in aqueous solution, and can be administered to a subject having a deficiency of growth hormone or for improvement of growth performance in livestock and other warm blooded animals and in fish and other cold blooded marine animals.

Growth hormone releasing factor analogs

Novel growth hormone releasing factor analogs are presented having the formula: ##STR1## wherein R.sub.1 is His, 3-MeHis, desNH.sub.2 His, Tyr, or desNH.sub.2 Tyr; R.sub.2 is Val, Leu, or Ile; R.sub.3 is Ala; R.sub.4 is Met, Leu, Ile, or Nle; R.sub.5 is Ser or Asn; R.sub.6 is an amino acid residue sequence selected from Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu or fragments thereof where the fragment is reduced in number by one to fifteen amino acid residues from the amino acid residue which carries the substituent X; and X is either OH or NH.sub.2, and the pharmaceutically acceptable acid or base addition salts thereof. The novel growth hormone releasing factor analogs demonstrate enhanced potency for the released growth hormone, have enhanced enzymatic stability, and can be administered to a subject having a deficiency of growth hormone or for improvement of growth performance in livestock.

Histidine substituted growth hormone releasing factor analogs

GRF(1-44)-NH.sub.2 is prepared by the trypsin catalyzed enzymatic coupling of Leu-NH.sub.2 to GRF(1-43)-OH. The latter compound may be obtained by recombinant DNA synthesis. Thus the present method provides an economical pathway to the clinically important GRF(1-44)-NH.sub.2 compound.

Process for the enzymatic preparation of GRF(1-44)NH.sub.2

Linear and cyclic Growth Hormone Releasing Factor Analogs and a method for stimulating the release of Growth Hormone in subjects by administering to the subject an effective amount of the compounds of the invention.

Cyclic growth hormone releasing factor analogs and method for the

A method for the solid phase synthesis of multi-sulfated peptides comprising coupling side-chain unprotected hydroxyamino acids to the peptide chain utilizing benzotriazol-1-yl-oxy-tris (dimethyl)-phosphonium hexafluorophosphate (BOP) as a coupling reagent.

Method of peptide synthesis

The invention is directed to analogs of GRF or fragments thereof wherein the fragment is reduced in number by one to fifteen amino acids from the carboxyl end wherein the analogs have the formula: ##STR1## wherein R is desNH.sub.2 -Tyr, Tyr, D-Tyr, Ac-Tyr, His or C.sup..alpha. -Methyl-Tyr; R.sub.1 is Ala, N-Methyl-D-Ala or D-Ala; R.sub.2 is Lys, Ala, Leu, Val or Ile; R.sub.3 is Ala, Leu, Val, Ile, Nle, Nval, .beta.-Ala or .alpha.-Aib; R.sub.4 is Lys, Ala, Leu, Val or Ile; R.sub.5 is Met, Leu, Nle or Ile; R.sub.6 is Asn or Ser; X is hydrogen or --COR.sub.7 ; R.sub.7 is hydrogen, C.sub.1-4 alkyl or halo(C.sub.1-4)alkyl; Y is --OR.sub.8 or --NR.sub.9 R.sub.10 ; R.sub.8 is hydrogen or C.sub.1-5 -alkyl; R.sub.9 and R.sub.10 independently equal hydrogen, C.sub.1-7 alkyl, C.sub.2-4 alkenyl or halo(C.sub.1-4)alkyl; and pharmaceutically acceptable acid or base addition salts thereof. The invention is further directed to pharmaceutical compositions and to methods for treating growth hormone deficiencies.

Polypeptides corresponding to growth hormone releasing factor in which methionine at position 27 has been replaced by a leucine residue retain full growth hormone releasing activity. In the case of the full length (44-amino acid) polypepitide, the leucine analog has full biological activity in the free acid form, unlike the natural growth releasing factor which requires carboxy terminal amidation for full biological activity.

Polypeptides having growth hormone releasing activity

Novel growth hormone releasing factor analogs in which glycine at position 15 is replaced by appropriately selected amino acids demonstrate enhanced potency for the release of growth hormone and the analogs can be administered to a subject having a deficiency of growth hormone.

An improved solution phase synthesis of thymosin .alpha..sub.1 and proceeding through novel intermediates is disclosed.

Synthesis of thymosin .alpha..sub.1

An improved solution phase synthesis of thymosin .alpha..sub.1 and desacetyl thymosin .alpha..sub.1 with t-Boc side chain protection and proceeding through novel intermediates is disclosed.

Synthesis of thymosin .alpha..sub.1 and desacetyl thymosin .alpha..sub.1

Novel hexapeptides corresponding to internal fragments of thymosin .alpha..sub.1 are active as agents which restore and stimulate immune function.

Growing community of inventors

West Caldwell, NJ, United States of America

Arthur M Felix