US4530920A — Nonapeptide and decapeptide analogs of LHRH, usef…

Claim 1

Independent Claim 275 words

A compound of the formula (pyro)Glu-His-A-Ser-B-C-D-Ed-Pro-F (I) and the pharmaceutically acceptable salts thereof wherein: A is tryptophyl, phenylalanyl, 3-(1-naphthyl)-L-alanyl or 3-(2-naphthyl)-L-alanine; B is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl, ; C is an amino acyl residue selected from the group consisting of the radicals represented by the following structural formulas: (a) ##STR17## wherein n is 1 to 5; R 1 is alkyl of 1 to 12 carbon atoms, -NRR 3 wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R 3 is fluoroalkyl, alkyl of 1 to 12 carbon atoms, cycloalkyl, phenyl, benzyl, --(CH 2 ) n -morpholino or --(CH 2 ) n N(R 4 ) 2 wherein n is 1 to 5 and R 4 is lower alkyl; R 2 is hydrogen or R 3 ; or R 1 and R 2 comprise a ring represented by the following structural formulas: ##STR18## wherein n is 1 to 7; A is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl; and X is halo or A or (b) ##STR19## wherein R 5 is alkyl of 1 to 6 carbon atoms, benzyl, phenylethyl, cyclohexyl, cyclopentyl; and R 6 , R 7 and R 8 are hydrogen or alkyl of 1 to 4 carbon atoms; and n is the integer 2-5; or (c) a substituent of the formula ##STR20## wherein R 9 is hydrogen, alkyl of 1 to 12 carbon atoms, phenyl or phenylloweralkyl; E is arginyl or leucyl: and D is leucyl, isoleucyl, nor-leucyl or N-methylleucyl; F is glycinamide or -NH-R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or --NH--CO--NH--R 2 wherein R 2 is hydrogen or lower alkyl.

Claim 2

Dependent Claim 275 words

A compound of the formula (pyro)Glu-His-A-Ser-B-C-D-Ed-Pro-F (I) and the pharmaceutically acceptable salts thereof wherein: A is tryptophyl, phenylalanyl, 3-(1-naphthyl)-L-alanyl or 3-(2-naphthyl)-L-alanine; B is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl, ; C is an amino acyl residue selected from the group consisting of the radicals represented by the following structural formulas: (a) ##STR17## wherein n is 1 to 5; R 1 is alkyl of 1 to 12 carbon atoms, -NRR 3 wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R 3 is fluoroalkyl, alkyl of 1 to 12 carbon atoms, cycloalkyl, phenyl, benzyl, --(CH 2 ) n -morpholino or --(CH 2 ) n N(R 4 ) 2 wherein n is 1 to 5 and R 4 is lower alkyl; R 2 is hydrogen or R 3 ; or R 1 and R 2 comprise a ring represented by the following structural formulas: ##STR18## wherein n is 1 to 7; A is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl; and X is halo or A or (b) ##STR19## wherein R 5 is alkyl of 1 to 6 carbon atoms, benzyl, phenylethyl, cyclohexyl, cyclopentyl; and R 6 , R 7 and R 8 are hydrogen or alkyl of 1 to 4 carbon atoms; and n is the integer 2-5; or (c) a substituent of the formula ##STR20## wherein R 9 is hydrogen, alkyl of 1 to 12 carbon atoms, phenyl or phenylloweralkyl; E is arginyl or leucyl: and D is leucyl, isoleucyl, nor-leucyl or N-methylleucyl; F is glycinamide or -NH-R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or --NH--CO--NH--R 2 wherein R 2 is hydrogen or lower alkyl.

Claim 3

Dependent Claim 92 words

The compound of claim 1 wherein C is an amino acyl residue selected from the group consisting of the radicals represented by the following structrual formulas: (a) ##STR21## wherein n is 4; R 1 is --NRR 3 wherein R is hydrogen, R 3 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl or fluoroalkyl; R 2 is alkyl of 1 to 12 carbon atoms, cycloalkyl or fluoroalkyl; or R 1 and R 2 comprise a ring represented by the following structural formula: ##STR22## wherein n is 1; and A is hydrogen.

Claim 4

Dependent Claim 45 words

The compound of claim 2 wherein C is an amino acyl residue wherein R is hydrogen and R 3 is methyl, ethyl, or hexyl; R 2 is the same as R 3 or R 1 and R 2 together form the ring of formula IID.

Claim 5

Dependent Claim 14 words

The compound of claim 3 which is (pyro)Glu-L-Hi s-L-Trp-L-Ser-L-Tyr-D-Eth-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

Claim 6

Dependent Claim 13 words

The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

Claim 7

Dependent Claim 13 words

The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Dhh-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

Claim 8

Dependent Claim 14 words

The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser -L-Tyr-D-Deh-L-MeLeu-L-Arg-L-Pro-NHET and its pharmaceutically acceptable salts.

Claim 9

Dependent Claim 14 words

The compound of claim 3 which is (pyro)Glu-L-His-L-Nal(2) -L-Ser-L-Tyr-D-Deh-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

Claim 10

Dependent Claim 14 words

The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Leu-L-Arg-L-Pro-GlyNH 2 and its pharmaceutically acceptable salts.

Claim 11

Dependent Claim 14 words

The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Den-L-MeLeu-L-Arg-L-Pro-GlyNH 2 and its pharmaceutically acceptable salts.

Claim 12

Dependent Claim 15 words

The compound of claim 3 which is (pyro)Glu-L-His-L-Nal(2) -L-Ser-L-Tyr-D-Deh-L-MeLeu-L-Arg-L-Pro-GlyNH 2 and its pharmaceutically acceptable salts.

Claim 13

Dependent Claim 19 words

The compound of claim 1 wherein A is Trp, B is Tyr, D is Leu and E is Gln.

Claim 14

Dependent Claim 23 words

The compound of claim 12 wherein D is D-Deh and F is GlyNH 2 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Den-L-Leu-L-Gln-L-Pro-GlyNH 2 and its pharmaceutically acceptable salts.

Claim 15

Dependent Claim 21 words

The compound of claim 12 wherein D is D-Deh and F is NHEt which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Leu-L-Gln-L-Pro-NHEt and its pharmaceutically acceptable salts.

Claim 16

Dependent Claim 19 words

The compound of claim 1 wherein A is Trp, B is Tyr, D is Trp and E is Leu.

Claim 17

Dependent Claim 24 words

Tne compound of claim 15 wherein C is Deh and F is GlyNH 2 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Trp-L-Leu-L-Pro-GlyNH 2 and the pharmaceutically acceptable salts thereof.

Claim 18

Dependent Claim 22 words

The compound of claim 15 wherein C is Deh and F is NHEt which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Trp-L-Leu-L-Pro-NHEt and the pharmaceutically acceptable salts thereof.

Claim 19

Dependent Claim 26 words

A method of inhibiting ovulation in a female mammalian subject which method comprises administering to said subject an effective amount of a compound of claim 1.

Claim 20

Dependent Claim 41 words

A method of treating benign prostatic hypertrophy in a male mammalian subject which method comprises administering to said subject an effective amount of a compound of the formula of claim 1 either alone or in admixture with a pnarmaceutically acceptable excipient.

Claim 21

Dependent Claim 36 words

A metnod of treating fibrocystic breast disease in a mammalian subject wnich method comprises administering to said subject an effective amount of a compound of tne formula of claim 1 or a pharmaceutical composition containing same.

Claim 22

Dependent Claim 35 words

A method of lowering, blocking or abolishing gonadal steroid output which method comprises administering to a mammalian subject an effective amount of a compound of the formula of claim 1 or a pharmaceutical composition therof.

Claim 23

Dependent Claim 31 words

A pharmaceutical composition for depression of spermatogenesis and circulating and testicular levels of testosterone comprising a compound of tne formula of claim 1 in admixture witn a pharmaceutically acceptable, non-toxic carrier.

Claim 24

Dependent Claim 33 words

A slow release pharmaceutical composition comprising a compound of claim 1 in the amount of 1% and a glycolide/lactide polymer in the amount of 99% in the form of microspheres or an implant.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1988-07-22	1989-01-21	1989-07-23	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1992-07-22	1993-01-21	1993-07-23	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	1996-07-22	1997-01-21	1997-07-23	$7700.00	Window Closed / Lapsed

Nonapeptide and decapeptide analogs of LHRH, useful as LHRH agonist

Abstract

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