Synthetic vasoactive intestinal peptide analogs

Claim 2

A compound of the formula X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-R.sub.2 -Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4 wherein R represents Asn or Ala; R 1 represents Thr-Arg-Leu-Arg, Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg; R 2 represents Leu, Ile or Nle; R 3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val; R 4 represents Asn-NH 2 or Thr-NH 2 ; and X represents hydrogen or acetylation at the amino terminal, provided that when R 1 is Thr-Arg-Leu-Arg, R may not equal Nle, and the pharmaceutically acceptable acid or base addition salts thereof.

Claim 3

The compound of claim 1 wherein R 2 is norleucine and R, R 1 , R 3 , R 4 and X are as in claim 1.

Claim 4

The compound of claim 1 wherein x represents acetylation and R 2 is Nle and R, R 1 , R 3 and R 4 are as in claim 1.

Claim 5

The compound of claim 2 which is (Ala 9 , Nle 17 )VIP.

Claim 6

The compound of claim 2 which is (Nle 17 , Thr 25 )VIP.

Claim 7

The compound of claim 2 which is (Nle 17 , Thr 28 )VIP.

Claim 8

The compound of claim 2 which is (Nle 17 , Thr 24 )VIP.

Claim 9

The compound of claim 2 which is (Lys 14 , Nle 17 )VIP.

Claim 10

The compound of claim 2 which is (Orn 12 , Nle 17 )VIP.

Claim 11

The compound of claim 2 which is (Nle 17 , Val 26 , Thr 28 )VIP.

Claim 12

The compound of claim 2 which is (Lys 12 , Nle 17 )VIP.

Claim 13

The compound of claim 2 which is (Ser 11 , Phe 13 , Nle 17 )-VIP.

Claim 14

The compound of claim 2 which is (Lys 12 , Nle 17 , Val 26 , Thr 28 )VIP.

Claim 15

The compound of claim 3 which is Ac-(Nle 17 )-VIP.

Claim 16

The compound of claim 3 which is Ac-(Lys 12 , Nle 17 )VIP.

Claim 17

The compound of claim 3 which is Ac-(Ser 11 , Phe 13 , Nle 17 )VIP.

Claim 18

The compound of claim 2 which is (Lys 12 , Lys 14 , Nle 17 , Val 26 , Thr 28 )VIP.

Claim 19

A pharmaceutical composition for the treatment of bronchotracheal constriction disorders in humans comprising a compound of the formula X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-R.sub.2 -Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4 wherein R represents Asn or Ala; R 1 represents Thr-Arg-Leu-Arg, Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg; R 2 represents Leu, Ile or Nle; R 3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val; R 4 represents Asn-NH 2 or Thr-NH 2 ; and X represents hydrogen or acetylation at the amino terminal, provided that when R 1 is Thr-Arg-Leu-Arg, R 2 may not equal Nle, in an amount sufficient to relax bronchotracheal smooth muscle and a pharmaceutically acceptable carrier.

Claim 20

A pharmaceutical composition for the treatment of bronchotracheal constriction disorders in humans comprising a compound of the formula X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-R.sub.2 -Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4 wherein R represents Asn or Ala; R 1 represents Thr-Arg-Leu-Arg, Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg; R 2 represents Leu, Ile or Nle; R 3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val; R 4 represents Asn-NH 2 or Thr-NH 2 ; and X represents hydrogen or acetylation at the amino terminal, provided that when R 1 is Thr-Arg-Leu-Arg, R 2 may not equal Nle, in an amount sufficient to relax bronchotracheal smooth muscle and a pharmaceutically acceptable carrier.

Claim 21

A pharmaceutical composition for the treatment of bronchotracheal constriction disorders in humans comprising a compound of the formula X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-Nle-Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4 wherein R represents Asn or Ala; R 1 represents Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg; R 2 represents Leu, Ile or Nle; R 3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val; R 4 represents Asn-NH 2 or Thr-NH 2 ; and X represents hydrogen or acetylation at the amino terminal, in an amount sufficient to relax bronchotracheal smooth muscle and a pharmaceutically acceptable carrier.

Claim 22

A pharmaceutical composition for the treatment of bronchotracheal constriction disorders in humans comprising a compound of the formula X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-Nle-Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4 wherein R represents Asn or Ala; R 1 represents Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg; R 2 represents Leu, Ile or Nle; R 3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val; R 4 represents Asn-NH 2 or Thr-NH 2 ; and X represents hydrogen or acetylation at the amino terminal, in an amount sufficient to relax bronchotracheal smooth muscle and a pharmaceutically acceptable carrier.

Claim 23

A pharmaceutical composition for the treatment of bronchotracheal constriction disorders in humans according to claim 19 wherein in said compound, X represents acetylation at the amino terminal.

Claim 24

The pharmaceutical composition of claim 18 wherein the pharmaceutically acceptable carrier is suitable for aerosol administration.

Claim 25

The pharmaceutically composition of claim 19 wherein the pharmaceutically acceptable carrier is suitable for aerosol administration.

Claim 26

The pharmaceutical composition of claim 20 wherein the pharmaceutically acceptable carrier is suitable for aerosol administration.

Claim 29

A method of treating bronchotracheal constriction disorders according to claim 25 wherein R 2 is Nle.

Claim 30

A method of treating bronchotracheal constriction disorders according to claim 25 wherein X represents acetylation at the amino terminal.

Claim 31

The method of claim 24, wherein the method of treatment is by aerosol.

Claim 32

The method of claim 25, wherein the method of treatment is by aerosol.

Claim 33

The method of claim 26, wherein the method of treatment is by aerosol.